Antimicrobial

Farmaco, 2002 Sep, 57(9), 715 - 22
Synthesis of halogen derivatives of benzo{h}chromene and benzo{a}anthracene with promising antimicrobial activities; Khafagy MM et al.; The synthesis of novel 7-(4-halophenyl)-8,9-dihydro-7H-12-oxa-9,11-diaza-benzo{a}anthracene derivatives has been reported . The key intermediate 3-amino-9-chloro-1-(4-halophenyl)-1H-benzo{h}chromene-2-carbonitrile (3) was obtained by treating 4-halobenzylidenmalononitriles (1a-c) and ethyl 4-halobenzylidenmalonates (1d-f) with 4-chloro-1-naphthol (2) in ethanolic piperidine solution . Antimicrobial activity was shown for most of the synthesized compounds.

Antimicrob Agents Chemother, 2002 Nov, 46(11), 3585 - 90
Cationic hydrophobic peptides with antimicrobial activity; Stark M et al.; The MICs of cationic, hydrophobic peptides of the prototypic sequence KKAAAXAAAAAXAAWAAXAAAKKKK-amide (where X is one of the 20 commonly occurring amino acids) are in a low micromolar range for a panel of gram-negative and gram-positive bacteria, with no or low hemolytic activity against human and rabbit erythrocytes . The peptides are active only when the average segmental hydrophobicity of the 19-residue core is above an experimentally determined threshold value (where X is Phe, Trp, Leu, Ile, Met, Val, Cys, or Ala) . Antimicrobial activity could be increased by using peptides that were truncated from the prototype length to 11 core residues, with X being Phe and with 6 Lys residues grouped at the N terminus . We propose a mechanism for the interaction between these peptides and bacterial membranes similar to the "carpet model," wherein the Lys residues interact with the anionic phospholipid head groups in the bacterial membrane surface and the hydrophobic core portion of the peptide is then able to interact with the lipid bilayer, causing disruption of the bacterial membrane.

J Surg Res, 2002 Sep, 107(1), 7 - 13
Systemic inflammatory response induced by dacron graft and modulation by antimicrobial agents: experimental study; Lozano FS et al.; BACKGROUND: The purpose of this work was to evaluate the effect that different antimicrobial agents and different forms of administering them would have over a systemic inflammatory response (SIR) induced by an intraperitoneally implanted collagen-coated Dacron graft . MATERIALS AND METHODS: Thirty-six male Wistar rats were randomly allocated into six groups of 6 animals each: (I) control, (II) "sham," (III) graft but no antibiotic, (IV) graft plus systemic cefazolin, (V) graft plus locally applied gentamicin, and (VI) graft soaked in rifampicin.After 72 h, mesenteric lymph nodes, liver, kidney, and the implanted graft were sent to the microbiology laboratory and cultured for aerobic and anaerobic organisms in order to evaluate bacterial translocation . Serum cytokines (IL-1beta and TNF-alpha), myeloperoxidase activity in liver and kidney, and superoxide anion and superoxide dismutase activities in liver were also determined to evaluate the level of SIR . RESULTS: Microbiologic and biochemical data indicated that intraperitoneal implantation of a collagen-coated Dacron graft induced a significant (P < 0.05) bacterial translocation and a high inflammatory response, both of which decreased significantly with antibiotic treatment regardless of the means of administration (P < 0.05) . CONCLUSIONS: The present experimental model shows that the antibiotics used, in different means of administration, reduce bacterial translocation and behave as modulators of the SIR induced by an intraperitoneal collagen-coated Dacron graft.

Lancet Infect Dis, 2002 Oct, 2(10), 593 - 604
Bacterial eradication in the treatment of otitis media; Dagan R et al.; Drugs differ in their ability to eradicate various pathogens from the middle-ear cavity during acute otitis media (AOM), and these differences clearly affect clinical outcome . Outcome is derived from differences in the association between concentrations of the drugs at the site of infection and the antimicrobial effect (termed pharmacodynamics) . These differences are even more marked in the present era of antimicrobial resistance . However, since AOM is a self-limiting disease in most cases, difference in clinical outcome is more difficult to ascertain than that of bacteriological outcome, which is measured within 3-5 days . A favourable clinical outcome regardless of the bacteriological effect of the drug can result in false optimism when less-effective antibiotic drugs are used . Inappropriate study design and manipulation of clinical results add to this confusion . In this review we attempt to highlight the evidence regarding bacteriological response to antibiotics in AOM and to draw attention to potential flaws that may mislead clinicians.

J Clin Pharm Ther, 2002 Oct, 27(5), 353 - 5
Quantification of Helicobacter pylori resistance in functional and organic dyspepsia; Rosandic M et al.; OBJECTIVE: To compare the efficacy of Helicobacter pylori eradication in patients with functional and organic dyspepsia . METHODS: The study included a cohort of 160 patients (115 with organic and 45 with functional dyspepsia) with dyspeptic symptoms and gastroscopically confirmed H . pylori infection . Triple therapy with omeprazole 20 mg, amoxicillin 1000 mg and metronidazole 400 mg (OAM) was administered twice a day for a week . Minimal inhibition concentration (MIC) was estimated on cultures from 41 patients with positive H . pylori for determination of antimicrobial sensitivity and primary resistance to amoxicillin and metronidazole . RESULTS: Endoscopic examination at least 6 weeks after therapy showed that 116 (72.5%) patients had H . pylori eradicated, whereas 44 (27.5%) were not . From the latter patients, 10 (23%) had functional dyspepsia and from 116 eradicated patients 35 (30%) had functional dyspepsia . Difference in efficacy of OAM therapy between patients with organic and functional dyspepsia was not significant (P > 0.5) . Percentages of non-eradicated patients with organic and functional dyspepsia were 29.6 and 22.2%, respectively (ratio 1.3 : 1) . MIC from 41 samples showed 18 (44%) in vitro resistant strains . There was no resistance to amoxicillin . CONCLUSIONS: There is no significant difference in H . pylori resistance to the same antibiotic between patients having functional or organic dyspepsia.

Drugs Aging, 2002, 19(9), 647 - 69
HIV disease and advanced age: an increasing therapeutic challenge; Manfredi R; The mean age of patients at both first HIV detection and AIDS diagnosis is progressively rising over time . However, reliable epidemiological estimates, clinical data or controlled therapeutic and outcome figures are lacking for elderly patients, especially with regard to laboratory and clinical response to antiretroviral therapy, treatment tolerability, drug-drug interactions, short- and long-term toxicity, and interactions with underlying illnesses and concurrent pharmacological treatment . In fact, the large majority of randomised, controlled trials evaluating and comparing new antiretroviral drugs or anti-HIV therapeutic strategies, as well as antimicrobial treatment or chemoprophylaxis of HIV-related complications, either excluded patients with advanced age and/or concurrent disorders or did not offer substudies or detailed data analysis focusing on older patients compared with younger ones . The life expectancy of HIV-infected persons receiving highly active antiretroviral therapy (HAART) is now extended (approaching that of the general population), so that the definition of AIDS has lost its epidemiological and clinical significance thanks to the immune reconstitution resulting from potent antiretroviral therapy . However, an ever-increasing number of individuals aged > or =50 years with HIV infection is expected in the coming years, as a result of both increased survival of patients with treated disease and delayed recognition of individuals with occult HIV disease . The limited data available about combined antiretroviral therapy in the elderly seem to show an overlapping virological success rate but a slower and blunted immune recovery compared with younger patients . Thymic output, however, seems somewhat preserved even in adulthood and may contribute to the reconstitution of most of the quantitative and functional T cell abnormalities caused by HIV disease . More attention must be paid to underlying end-organ disorders, as well as expected pharmacological interactions and combined drug toxicity that may interfere with HAART efficacy and patients' compliance with recommended regimens and could lead to increased adverse effects . The available guidelines for antiretroviral treatment and therapy and prophylaxis of AIDS-related illnesses should be regularly updated and should include problems related to HIV disease in an aging population . Specific trials or substudies focusing on older people are warranted to obtain controlled data on all issues of antiretroviral therapy in the elderly, including time and mode of initiation, and modification and salvage HAART regimens . Antiretroviral drug dosage adjustment to take into account underlying pathological conditions or other pharmacological treatments is another emerging issue.

J Am Chem Soc, 2002 Oct 23, 124(42), 12543 - 9
Solid-phase synthesis of fullerene-peptides; Pantarotto D et al.; The solid-phase synthesis of peptides (SPPS) containing {60}fullerene-functionalized amino acids is reported . A new amino acid, fulleropyrrolidino-glutamic acid (Fgu), is used for the SPPS of a series of analogues of different length based on the natural Leu(5)-Enkephalin and on cationic antimicrobial peptides . These fullero-peptides were prepared on different solid supports to analyze the influence of the resin on the synthesis . Optimized protocols for the coupling and deprotection procedures were determined allowing the synthesis of highly pure peptides in sufficient quantities for evaluation of biological activities . In particular, to avoid side reactions of the fullerene moiety with bases and nucleophiles, the removal of the protecting groups was performed under inert conditions (nitrogen or argon in the dark) . We have encountered serious problems with the recovery of the crude compounds, especially when Fgu was inserted in the proximity of the resin core as fullero-peptides tend to remain embedded inside the resin . Eventually, all of the fullero-peptides were easily purified, and the cationic peptides were tested for their antimicrobial activities . They displayed a specific activity against the Gram-positive bacterium S . aureus and also lysed erythrocytes . The availability of a fullero-amino acid easily useable in the SPPS of fullero-peptides may thus open the way to the synthesis of new types of biologically active oligomers.

J Food Prot, 2002 Oct, 65(10), 1632 - 6
Combined effects of mustard flour, acetic acid, and salt against Esherichia coil O157:H7 stored at 5 and 22 degrees C; Rhee MS et al.; The combined effects of acetic acid and mustard flour were investigated to ascertain their impact on Escherichia coli O157:H7 stored at 5 and 22 degrees C . Samples were prepared with various concentrations of acetic acid (0, 0.25, 0.5, 0.75, and 1% {vol/vol}) combined with 10% (wt/vol) Baltimore or Coleman mustard flour and 2% (fixed; wt/vol) sodium chloride . An acid-adapted mixture of three E . coli O157:H7 strains (10(6) to 10(7) CFU/ml) was inoculated into prepared mustard samples that were stored at 5 and 22 degrees C, and samples were assayed periodically for the survival of E . coli O157:H7 . The numbers of E . coli O157:H7 were reduced much more rapidly at 22 degrees C than at 5 degrees C . E . coli O157:H7 was rapidly reduced to below the detection limit (<0.3 log10, CFU/ml) after 1 day at 22 degrees C, whereas it survived for up to 5 days at 5 degrees C . There was no synergistic or additive effect with regard to the killing of E . coli O157:H7 with the addition of small amounts of acetic acid to the mustard flour . When stored at 5 degrees C, mustard in combination with 0.25 (M-0.25), 0.5 (M-0.5), and 0.75% (M-0.75) acetic acid exerted less antimicrobial activity than the control (M-0) . The order of lethality at 5 degrees C was generally M-0.25 = M-0.5 < M-0.75 = M-0 < M-1 . The addition of small amounts of acetic acid (<0.75%) to mustard retards the reduction of E coli O157:H7 . Statistical reduction in populations of E . coli O157:H7 (P < 0.05) was enhanced relative to that of the control (mustard alone) only with the addition of 1% acetic acid . This information may help mustard manufacturers to understand the antimicrobial activity associated with use of mustard flour in combination with acetic acid.

Clin Ther, 2002 Sep, 24(9), 1414 - 25
Open-label, randomized comparison of the efficacy and tolerability of clarithromycin, levofloxacin, and cefuroxime axetil in the treatment of adults with acute bacterial exacerbations of chronic bronchitis; Weiss LR; BACKGROUND: In the absence of a confirmed pathogen, empiric antimicrobial treatment of patients with acute exacerbations of chronic bronchitis and acute bacterial exacerbations of chronic bronchitis (ABECB) is accepted as standard practice and recommended in treatment guidelines . OBJECTIVE: This study compared the efficacy and tolerability of a 10-day course of 3 antimicrobial regimens commonly used to treat adults with ABECB . METHODS: This prospective, open-label, randomized study assessed clarithromycin 500 mg twice daily, levofloxacin 500 mg once daily, and cefuroxime axetil 250 mg twice daily, each administered for 10 days with food, in patients with ABECB . Efficacy was determined on the basis of the clinical response to treatment and need for hospitalization and/or further antimicrobial therapy . RESULTS: A total of 283 patients (150 men, 133 women) with a mean age of 55 years (range, 29 to 86 years) were randomized to receive clarithromycin (n = 97), levofloxacin (n = 94), or cefuroxime axetil (n = 92) . Of 262 clinically assessable patients, clinical cure or improvement occurred in 87.9% (80/91) of those treated with clarithromycin, 87.4% (76/87) of those treated with levofloxacin, and 79.8% (67/84) of those treated with cefuroxime axetil . Eight (8.8%) clarithromycin-treated patients, 6 (6.9%) levofloxacin-treated patients, and 12 (14.3%) cefuroxime axetil-treated patients required a change in antimicrobial therapy to achieve clinical cure/improvement; between-group differences were not significant . No patients treated with clarithromycin required hospitalization for further antimicrobial treatment, compared with 3.4% (3/87) of levofloxacin-treated and 3.6% (3/84) of cefuroxime axetil-treated patients (P = NS) . A total of 6.2% (6/97) of clarithromycin-treated patients were prematurely discontinued from treatment due to adverse events, compared with 7.4% (7/94) and 8.7% (8/92) of levofloxacin- and cefuroxime axetil-treated patients, respectively . CONCLUSION: A high rate of clinical efficacy and tolerability was observed in this population of patients with ABECB treated with clarithromycin 500 mg twice daily, levofloxacin 500 mg once daily, or cefuroxime axetil 250 mg twice daily for 10 days.

Vet Clin North Am Small Anim Pract, 2002 Sep, 32(5), 1101 - 26
Nosocomial infections; Johnson JA; Nosocomial infections and antimicrobial resistance are topics that have been intensely studied in human medicine because of their significant impact on human health . In recent years, concerns have been raised that the use of antibiotics in veterinary medicine, animal husbandry, and agriculture may be contributing to the development of resistance in common bacterial species affecting human beings . Although there is inadequate proof at this time that the resistance is transmitted from animals to people, if antibiotics continue to be used indiscriminately in veterinary medicine, veterinarians may find themselves facing regulations restricting the use of some antibiotics . Nosocomial infections have been reported in veterinary medicine and are likely to increase in prevalence with the increase in intensive care practices in many hospitals . Prolonged hospitalization and the use of invasive devices and procedures increase the risk of nosocomial disease . As in human medicine, organisms isolated in the nosocomial infections reported in veterinary patients have an increasingly broad spectrum of antimicrobial resistance . Despite these findings, the use of empiric and prophylactic antibiotic therapy is still widespread in veterinary medicine . Nosocomial infections and antimicrobial resistance may have a serious impact on the future of {table: see text} veterinary medicine, because the cost and ability to treat our patients may be affected by the loss of access to or effectiveness of antimicrobial drugs . Despite the millions of dollars spent on research to reduce the incidence of nosocomial infections in human patients, the strategies that have consistently proven successful are simple and inexpensive to implement . The most important factor in preventing nosocomial infections is improving the hygiene practices of health care providers . Hand-washing or the use of disposable gloves can dramatically reduce the transmission of bacteria between patients . Aseptic technique should be used in the placement and management of all invasive devices . All staff members should be educated on the risks and symptoms associated with nosocomial infections so that cases can be detected early and treated appropriately . We in the veterinary profession have the opportunity to learn from the experiences of the human medical profession and can take steps to prevent the escalation of nosocomial infections and their impact on our profession.

J Pharm Sci, 2002 Nov, 91(11), 2452 - 64
Activity-bioavailability balance in oral drug development for a selected group of 6-fluoroquinolones; Talens-Visconti R et al.; A nomogram is proposed to select the best candidate in drug development studies with quinolones and is intended to substitute other possible models . The nomogram is referred to as an activity-bioavailability balance (ABB) because it includes the following two criteria: ABB = {(1/gm MIC drug candidate)/ (1/gm MIC ciprofloxacin)}.{(F(calc) drug candidate)/( F(calc) ciproflaxacin)} . The in vitro activity of a group of 4'N-alkyl-ciprofloxacin derivatives was determined together with that of ciprofloxacin, initially against some reference strains and subsequently against 159 clinical isolates of eight selected species . The inverse of the geometric mean of the lowest concentration of drug at which the original inoculum was reduced to no more than two colonies (1/gm MIC), as an antimicrobial activity parameter, and the absolute oral bioavailability index (F(calc)), as predicted from in situ intestinal absorption rate constants, were used for calculation of the ABB values, which ranged from 0.1 to 17 for the species and compounds tested . Ciprofloxacin was the best candidate only against Escherichia coli, whereas 4'N-methyl- and/or 4'N-ethyl-ciprofloxacin showed better or much better ABB values than the model drug, and can be selected as potential drug candidates against the remaining clinical strains . The procedure described could be a useful technique for further drug development studies .

J Pharm Sci, 2002 Nov, 91(11), 2283 - 300
Excipient-drug interactions in parenteral formulations; Akers MJ; Excipients are added to parenteral formulations to enhance or maintain active ingredient solubility (solubilizers) and/or stability (buffers, antioxidants, chelating agents, cryo- and lyoprotectants) . Excipients also are important in parenteral formulations to assure safety (antimicrobial preservatives), minimize pain and irritation upon injection (tonicity agents), and control or prolong drug delivery (polymers) . These are all examples of positive or synergistic interactions between excipients and drugs . However, excipients may also produce negative effects such as loss of drug solubility, activity, and/or stability . This review article will highlight documented interactions, both synergistic and antagonistic, between excipients and drugs in parenteral formulations . The reader will gain better understanding and appreciation of the implications of adding formulation ingredients to parenteral drug products .

Infect Immun, 2002 Nov, 70(11), 6302 - 9
Activation of NKT cells protects mice from tuberculosis; Chackerian A et al.; The T-cell immune response to Mycobacterium tuberculosis is critical in preventing clinical disease . While it is generally accepted that both major histocompatibility complex class I (MHC-I)-restricted CD8(+) and MHC-II-restricted CD4(+) T cells are important for the immune response to M . tuberculosis, the role of non-MHC-restricted T cells is still not clearly delineated . We have previously reported that CD1d(-/-) mice do not differ from CD1d(+/+) mice in their survival following infection with M . tuberculosis . We now show that, although CD1d-restricted NKT cells are not required for optimum immunity to M . tuberculosis, specific activation of NKT cells by the CD1d ligand alpha-galactosylceramide protects susceptible mice from tuberculosis . Treatment with alpha-galactosylceramide reduced the bacterial burden in the lungs, diminished tissue injury, and prolonged survival of mice following inoculation with virulent M . tuberculosis . The capacity of activated NKT cells to stimulate innate immunity and modulate the adaptive immune response to promote a potent antimicrobial immune response suggests that alpha-galactosylceramide administration could have a role in new strategies for the therapy of infectious diseases.

J Biol Chem, 2002 Dec 20, 277(51), 49332 - 40 Epub 2002 Oct 11.
Dermaseptins from Phyllomedusa oreades and Phyllomedusa distincta . Anti-Trypanosoma cruzi activity without cytotoxicity to mammalian cells; Brand GD et al.; Amphibian skin secretions are known as a rich source of biologically active molecules, most of which are alkaloids, biogenic amines, and peptides . Dermaseptins are a class of antimicrobial peptides present in tree frogs of the Phyllomedusa genus . They are cationic molecules of 28-34 residues that permeabilize the membrane of Gram-positive and Gram-negative bacteria, yeasts, and filamentous fungi, showing little or no hemolytic activity . This work reports the isolation, molecular mass analysis, primary structure determination, biological activities, and potential therapeutic applications of an antimicrobial peptide found in the skin secretion of Phyllomedusa oreades, which is a newly described amphibian species endemic of the Brazilian savanna . DS 01 is a 29-residue-long peptide with a molecular mass of 2793.39 Da showing antibacterial properties against Gram-positive and Gram-negative bacteria in the range of 3-25 microm . Anti-protozoan activity was investigated using T . cruzi in its trypomatigote and epimastigote forms cultivated in both cell culture and blood media . Within 2 h after incubation with DS 01 at a final concentration of approximately 6 microm, no protozoan cells were detected . Two synthetic dermaseptins, described previously by our group and named dermadistinctins K and L (DD K and DD L), also had their anti-Trypanosoma cruzi activity investigated and demonstrated similar properties . Toxicity of DS 01 to mouse erythrocytes and white blood cells was evaluated by means of atomic force microscopy and flow cytometry . No morphological alterations were observed at a lytic concentration of DS 01, suggesting its therapeutic value especially as an anti-T . cruzi agent to prevent infections during blood transfusion.

J Immunol Methods, 2002 Dec 1, 270(1), 53 - 62
Detection of dermcidin-derived peptides in sweat by ProteinChip technology; Flad T et al.; Recently, a novel antimicrobial peptide DCD-1, derived from the Dermcidin (DCD) gene and secreted by sweat glands, has been described by Schittek et al . {Nat . Immunol . 2 (2001) 1133.} . Here we describe the application of the surface-enhanced laser desorption/ionisation (SELDI) technology for the detection of DCD-1 and other dermcidin-derived peptides directly from microlitre amounts of human sweat . The advantages of the technique are as follows: (a) it can be carried out with ease and rapidity; (b) multiple samples can be processed simultaneously; (c) prior purification is not required; and (d) only a limited sample volume is necessary for both protein profiling and semiquantitation . Profiling of human sweat from various donors revealed that in addition to DCD-1, other DCD-derived peptide species were also present in significant quantities . Four of five identified peptides were DCD-1 related, while the fifth corresponded to a portion of the DCD protein outside the DCD-1 core . This provides clues as to how the novel protein is processed to its active form, though further work remains to elucidate this fully . Thus, we have demonstrated the applicability of such technology to the detection of DCD-1 and for the protein profiling of sweat in general . Such studies could reveal valuable new biomarkers for diagnosis and treatment of skin and sweat gland disorders.

Biochemistry, 2002 Oct 22, 41(42), 12835 - 42
Design of non-cysteine-containing antimicrobial beta-hairpins: structure-activity relationship studies with linear protegrin-1 analogues; Lai JR et al.; Protegrins are short, cationic peptides that display potent, broad-spectrum antimicrobial activity . PG-1, the first of the five natural analogues discovered, forms a rigid antiparallel two-stranded beta-sheet that is stabilized by two disulfide bonds . The two strands of the sheet are linked by a short two-residue loop segment . Removal of the disulfide bridges (e.g., in Cys --> Ala analogues) is known to cause marked loss of antimicrobial activity . We have used basic principles of beta-hairpin design to develop linear analogues of PG-1 that lack cysteine but nevertheless display PG-1-like activity . Our most potent reengineered molecules contain three essential design features: (i) the four cysteine residues of PG-1 are replaced by residues that have high propensity for beta-strand conformation, (ii) D-proline is placed at the i + 1 position of the reverse turn to promote a type II' beta-turn, and (iii) amino functionality is incorporated at the gamma-carbon of the D-proline residue to mimic the charge distribution of the natural beta-hairpin . Structural studies revealed that the antimicrobial potency of the non-disulfide-bonded peptides can be correlated to the stability of the beta-hairpin conformations they adopt in aqueous solution . The presence of 150 mM NaCl was found to have little effect on the antimicrobial activity of PG-1, but one of our linear analogues loses some potency under these high salt conditions . Despite this discrepancy in salt sensitivity, NMR and CD data indicate that neither PG-1 nor our linear analogue experiences a significant decrease in beta-hairpin conformational stability in the presence of 150 mM NaCl . Thus, salt inactivation is not due to destabilization of the beta-hairpin conformation . Furthermore, our results show that beta-sheet design principles can be used to replace conformation-stabilizing disulfide bridges with noncovalent conformation-stabilizing features.

Biotechnol Bioeng, 2002 Dec 20, 80(6), 599 - 609
Electro-membrane filtration for the selective isolation of bioactive peptides from an alpha(s2)-casein hydrolysate; Bargeman G et al.; For the isolation of the ingredients required for functional foods and nutraceuticals generally membrane filtration has too low a selectivity and chromatography is (too) expensive . Electro-membrane filtration (EMF) seems to be a breakthrough technology for the isolation of charged nutraceutical ingredients from natural sources . EMF combines the separation mechanisms of membrane filtration and electrophoresis . In this study, positively charged peptides with antimicrobial activity were isolated from an alpha(s2)-casein hydrolysate using batch-wise EMF . alpha(s2)-Casein f(183-207), a peptide with strong antimicrobial activity, predominated in the isolated product and was enriched from 7.5% of the total protein components in the feed to 25% in the permeate product . With conventional membrane diafiltration using the same membrane (GR60PP), isolation of this and other charged bioactive peptides could not be achieved . The economics of EMF are mainly governed by the energy costs and the capital investment, which is affected by the flux of the desired peptide . A maximum average transport rate of alpha(s2)-casein f(183-207) during batch-wise EMF of 1.2 g/m2 . h was achieved . Results indicate that an increase in the hydrolysate (feed) concentration, the applied potential difference and the conductivity of the permeate and electrode solutions, and a reduction in the conductivity of the feed result in a higher transport rate of alpha(s2)-casein f(183-207) . This is in line with the expectation that the transport rate is improved when the concentration, the electrical field strength, or the electrophoretic mobility is increased, provided that the electrophoretic transport predominates . The expected energy consumption of the EMF process per gram of peptide transported was reduced by approximately 50% by applying a low overall potential difference and by processing desalinated hydrolysate . Considerable improvements in transport rate, energy efficiency, and process economics seem to be attainable by additional optimization of the process parameters and the EMF module design .

J Leukoc Biol, 2002 Oct, 72(4), 677 - 84
Calcium spikes in activated macrophages during Fcgamma receptor-mediated phagocytosis; Myers JT et al.; Rises in intracellular-free calcium ({Ca(2+)}(i)) have been variously associated with Fcgamma receptor (FcR)-mediated phagocytosis in macrophages . We show here that activation of murine bone marrow-derived macrophages increases calcium spiking after FcR ligation . Ratiometric fluorescence microscopy was used to measure {Ca(2+)}(i) during phagocytosis of immunoglobulin G (IgG)-opsonized erythrocytes . Whereas 13% of nonactivated macrophages increased {Ca(2+)}(i) in the form of one or more spikes, 56% of those activated with lipopolysaccharides (LPS; 18 h at 100 ng/ml) and interferon-gamma (IFN-gamma; 100 U/ml) and 73% of macrophages activated with LPS, IFN-gamma, interleukin (IL)-6 (5 ng/ml), and anti-IL-10 IgG (5 micro g/ml) spiked calcium during phagocytosis . Calcium spikes were inhibited by thapsigargin (Tg), indicating that they originated from endoplasmic reticulum . The fact that activated macrophages showed a more dramatic response suggested that calcium spikes during phagocytosis mediate or regulate biochemical mechanisms for microbicidal activities . However, lowering {Ca(2+)}(i) with ethyleneglycol-bis(beta-aminoethylether)-N,N'-tetraacetic acid or inhibiting calcium spikes with Tg did not inhibit phagosome-lysosome fusion or the generation of reactive oxygen or nitrogen species . Thus, the increased calcium spiking in activated macrophages was not directly associated with the mechanism of phagocytosis or the increased antimicrobial activities of activated macrophages.

Trends Microbiol, 2002, 10(10 Suppl), S8 - 14
Microbial and viral drug resistance mechanisms; McKeegan KS et al.; Microorganisms and viruses have developed numerous resistance mechanisms that enable them to evade the effect of antimicrobials and antivirals . As a result, many have become resistant to almost every available means of treatment . This problem, although not new, is becoming increasingly acute and it is now clear that a fundamental understanding of the mechanisms that microbes and viruses deploy in the development of resistance is essential if we are to gain new insights into ways to combat this problem.

Structure (Camb), 2002 Oct, 10(10), 1363 - 70
Structure of the cathelicidin motif of protegrin-3 precursor: structural insights into the activation mechanism of an antimicrobial protein; Sanchez JF et al.; Cathelicidins are a family of antimicrobial proteins isolated from leucocytes and epithelia cells that contribute to the innate host defense mechanisms in mammalians . Located in the C-terminal part of the holoprotein, the cathelicidin-derived antimicrobial peptide is liberated by a specific protease cleavage . Here, we report the X-ray structure of the cathelicidin motif of protegrin-3 solved by MAD phasing using the selenocysteine-labeled protein . Its overall structure represents a fold homologous to the cystatin family and adopts two native states, a monomer, and a domain-swapped dimer . This crystal structure is the first example of a structural characterization of the highly conserved cathelicidin motif and thus provides insights into the possible mechanism of activation of the antimicrobial protegrin peptide.

Diagn Microbiol Infect Dis, 2002 Sep, 44(1), 69 - 76
Fluoroquinolones for the treatment of outpatient community-acquired pneumonia; Jones RN et al.; The increasing prevalence of beta-lactam and macrolide resistance in bacteria that cause respiratory infections has underscored the need for effective antimicrobial agents . The broad spectrum, excellent oral bioavailability, and once-daily dosing of fluoroquinolones contributed to the introduction of several new agents in the past decade . This class is among the world's most used antimicrobial therapies in community and hospital settings . Fluoroquinolones are generally well tolerated, but safety profiles differ widely among agents . Knowledge of in vitro activity, local microbiologic susceptibility and resistance patterns, adverse effects, and potential drug interactions should influence the selection of the best agent for individual patients . This overview of the fluoroquinolones directs particular attention to use in community-acquired pneumonia and safety.

J Pathol, 2002 Nov, 198(3), 369 - 77
Antimicrobial peptides are expressed and produced in healthy and inflamed human synovial membranes; Paulsen F et al.; The objective of this study was to determine the expression and production of antimicrobial peptides by healthy and inflamed human synovial membranes . Deposition of the antimicrobial peptides lysozyme, lactoferrin, secretory phospholipase A(2) (sPA(2)), matrilysin (MMP7), human neutrophil alpha-defensins 1-3 (HNP 1-3), human beta-defensin 1 (HBD-1), and human beta-defensin 2 (HBD-2) was determined by immunohistochemistry . Expression of mRNA for the antimicrobial peptides bactericidal permeability-increasing protein (BPI), heparin binding protein (CAP37), human cationic antimicrobial protein (LL37), human alpha-defensin 5 (HD5), human alpha-defensin 6 (HD6), HBD-1, HBD-2, and human beta-defensin 3 (HBD-3) was analysed by reverse transcription polymerase chain reaction (RT-PCR) . RT-PCR revealed CAP37 and HBD-1 mRNA in samples of healthy synovial membrane . Additionally, HBD-3 and/or LL37 mRNA was detected in synovial membrane samples from patients with pyogenic arthritis (PA), osteoarthritis (OA) or rheumatoid arthritis (RA) . BPI, HD5, HD6, and HBD-2 mRNAs were absent from all samples investigated . Immunohistochemistry identified lysozyme, lactoferrin, sPA(2), and MMP7 in type A synoviocytes of all samples . HBD-1 was only present in type B synoviocytes of some of the samples . Immunoreactive HBD-2 peptide was only visible in some inflamed samples . HNP1-3 was detected in both healthy and inflamed synovial membranes . The data suggest that human synovial membranes produce a broad spectrum of antimicrobial peptides . Under inflammatory conditions, the expression pattern changes, with induction of HBD-3 in PA (LL37 in RA; HBD-3 and LL37 in OA) as well as down-regulation of HBD-1 . HBD-3 holds therapeutic potential in PA as it has a broad spectrum of antimicrobial activity and accelerates epithelial healing . However, caution is appropriate since defensins also promote fibrin formation and cell proliferation - key elements in joint infection . Clarification of the role of antimicrobial peptides in OA and RA will require further investigation .

J Antibiot (Tokyo), 2002 Aug, 55(8), 696 - 701
New dithiolopyrrolone antibiotics from Saccharothrix sp . SA 233 . I . Taxonomy, fermentation, isolation and biological activities; Lamari L et al.; Three new natural antibacterial and antifungal dithiolopyrrolone antibiotics were isolated along with the known iso-butyropyrrothine and thiolutine from the fermentation broth of an actinomycete strain which was isolated from a saharian palm grove soil collected at Adrar, south Algeria . The strain was identified as Saccharothrix sp . The three new antibiotics exhibited broad antimicrobial activity against gram-positive bacteria, yeasts and fungi in vitro.

Mass Spectrom Rev, 2002 Mar-Apr, 21(2), 87 - 107
Collision-induced fragmentations of the (M-H)- parent anions of underivatized peptides: an aid to structure determination and some unusual negative ion cleavages; Bowie JH et al.; This article describes the fundamental cleavage reactions of (M-H)(-) anions of underivatized peptides that contain up to 25 amino acid residues . The experimental observations of these cleavages have been backed up by molecular modeling, generally at the AM1 level of theory . The basic cleavages are the ubiquitous alpha- and beta-backbone cleavage reactions, which provide information similar to that of the B and Y + 2 cleavages of MH(+) ions of peptides . The residues Asp and Asn also effect cleavages of the backbone (called delta- and gamma-cleavages), by reactions initiated from side chain enolate anions, causing elimination reactions that cleave the backbone between the Asp (Asn) N bond;C backbone bond . Glu and Gln also direct analogous delta- and gamma-cleavages of the backbone, but in this case the processes are initiated by attack of the side chain CO(2) (-) (CONH(-)) to form a lactone (lactam) . Ser and Thr residues undergo characteristic fragmentations of the side chain . These processes, losses of CH(2)O (Ser) and MeCHO (Thr), convert these residues into Gly . In larger peptides, Ser and Thr can effect two backbone cleavage reactions, called gamma- and epsilon -processes . The C-terminal CO(2) (-) (or CONH(-)) forms a hydrogen bond with the side chain OH (of Ser or Thr), placing the C-terminal residue in a position where it may affect S(N) (2) attack at the electrophilic backbone CH of Ser, with concomitant cleavage of the backbone . All of the above negative ion cleavages require the peptide backbone to be conformationally flexible . However, there is a backbone cleavage that requires the peptide to have an alpha-helical conformation in order for the two reacting centers to approach . This cleavage is illustrated for the Glu 23-initiated backbone cleavage at Ile 21 for the (M-H)(-) anion of the antimicrobial peptide caerin 1.1 .

J Biol Chem, 2002 Dec 20, 277(51), 49921 - 6 Epub 2002 Oct 07.
Epithelial innate immunity . A novel antimicrobial peptide with antiparasitic activity in the blood-sucking insect Stomoxys calcitrans; Boulanger N et al.; The gut epithelium is an essential interface in insects that transmit parasites . We investigated the role that local innate immunity might have on vector competence, taking Stomoxys calcitrans as a model . S . calcitrans is sympatric with tsetse flies, feeds on many of the same vertebrate hosts, and is thus regularly exposed to the trypanosomes that cause African sleeping sickness and nagana . Despite this, S . calcitrans is not a cyclical vector of these trypanosomes . Trypanosomes develop exclusively in the lumen of digestive organs, and so epithelial immune mechanisms, and in particular antimicrobial peptides (AMPs), may be the prime determinants of the fate of an infection . To investigate why S . calcitrans is not a cyclical vector of trypanosomes, we have looked in its midgut for AMPs with trypanolytic activity . We have identified a new AMP of 42 amino acids, which we named stomoxyn, constitutively expressed and secreted exclusively in the anterior midgut of S . calcitrans . It displays an amphipathic helical structure and exhibits a broad activity spectrum affecting the growth of microorganisms . Interestingly, this AMP exhibits trypanolytic activity to Trypanosoma brucei rhodesiense . We argue that stomoxyn may help to explain why S . calcitrans is not a vector of trypanosomes causing African sleeping sickness and nagana.

Neuropeptides, 2002 Aug, 36(4), 246 - 51
Langerhans cell expression of neuropeptide Y and peptide YY; Lambert RW et al.; Neuropeptide Y (NPY) and peptide YY (PYY) are structurally related peptides with a variety of known functions . The role of these peptides in the skin is largely unknown, although NPY-like immunoreactivity has been reported in the epidermis . The recent report that these peptides have antimicrobial properties suggests that NPY and PYY may contribute to the skin's defense mechanisms against invading microorganisms . We have demonstrated that Langerhans cells (LC) and a certain BALB/c epidermis-derived dendritic cell line contain mRNA for NPY and PYY using RT-PCR . Furthermore, this dendritic cell line as well as an epidermis-derived dendritic cell line from A/J mice were found to produce NPY and PYY and LC produced PYY, as assessed by radioimmunoassay . These data suggest that the protective function of LC include not only antigen presentation, but also production of antimicrobial peptides .

Bioorg Med Chem Lett, 2002 Nov 4, 12(21), 3171 - 4
The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase; Brown MJ et al.; The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS) . A number of analogues have been synthesised . The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition . The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity . WRS inhibition may contribute to the antibacterial action of chuangxinmycin.

Enferm Infecc Microbiol Clin, 2002 Oct, 20(8), 407 - 11; quiz 412
{Pharmacokinetic and pharmacodynamic concepts for an interpretative reading of the antibiogram}; Soriano F; Both microbiological and epidemiological reading of the antibiogram can be performed without additional pharmacokinetic or pharmacodynamic concepts . However, when the aim is a clinical reading of the antibiogram, knowledge of the pharmacokinetics of antimicrobial agents and of all phenomena occurring between antimicrobial agents and microorganisms is imperative . Pharmacokinetics includes the study of absorption, distribution, metabolism and elimination of drugs . These data provide information on the active concentrations of antimicrobial agents in blood and other fluids as well as in the tissues where infection may develop . Knowledge of metabolism and of elimination pathways complete the main pharmacokinetic parameters of antimicrobial agents . The bactericidal effect of antimicrobial agents can be either concentration- or time-dependent . In the former, high concentrations of antimicrobial agents, much higher than their corresponding MICs, are needed, while in the latter, maintaining the concentration of antimicrobial agents at levels slightly higher than their MICs over time is more important . With these concepts, a microbiological-pharmacological reading of the antibiogram, taking into account dosage, administration pathway and location of the infectious process among other factors, can be achieved . Most working groups, either national or from abroad, have considered both pharmacokinetics and pharmacodynamics in interpretative reading of the antibiogram . In all cases, breakpoints for susceptibility and resistance should be corrected on the basis of data from well designed and performed clinical trials . Clinically oriented breakpoints do not necessarily have to be the same as those based on microbiological or epidemiological concepts, but clinical microbiologists should be able to give an appropriate response to the question and to the application based on that response.

Enferm Infecc Microbiol Clin, 2002 Oct, 20(8), 384 - 7
{Evolution of the use of antibiotics in a hospital long-term care center in Catalonia}; Vaqueiro M et al.; INTRODUCTION: Advanced age, together with immune system changes, malnutrition, chronic disease, and the institutional environment, all contribute to a higher risk of acquiring infection in the elderly . Antibiotics are widely used in geriatric centers, but often their use is not optimal . MATERIAL AND METHODS: Study carried out during the period 1992-1999 in Centro Sociosanitario Albada (Sabadell, Spain) . Data were taken from the Pharmacy Department's unidose registry . We determined the most frequently used antibiotics, the hospital units with highest consumption, the variation in these factors over time, and related costs . RESULTS: A progressive increase in overall antibiotic consumption was observed during the first 5 years of the study with subsequent stabilization . The units showing highest consumption were the Moderate and Highly-Dependent Chronic Unit, the Palliative Care Unit and the Convalescence and Rehabilitation Unit, with significant increases in the Palliative Care Unit in the last two years of the study . Amoxicillin-clavulanate, ciprofloxacin and norfloxacin were the most extensively used antibiotics . Cost increases were seen in the last three years despite the stabilization of antibiotic use . CONCLUSION: We observed a change in the consumption and profile of the antimicrobial agents used in our setting, probably related to changes in the population, increases in parenteral treatment and changes in the criteria for treatment of terminal patients . The establishment of controls for antibiotic use in long-term care centers would lead to improvements in the quality of the care provided.

Infect Dis Clin North Am, 2002 Sep, 16(3), 681 - 95
Bone and joint infections in injection drug users; Kak V et al.; Skeletal infections in injection drug users have an insidious onset, present with indolent symptoms, and often occur in unusual locations . Unless physicians are familiar with the disease entities unique to the injection drug user, the diagnosis is frequently delayed . Systemic signs of infection are often lacking . The organisms causing the infection represent a wide spectrum; hence, empiric therapy is not generally recommended . Plain-film radiographs are of little help for early diagnosis . Imaging studies, especially radionucleotide studies and CT or MR imaging scans, can help localize the site of infection . For etiologic diagnosis of these infections, bone biopsy or needle aspiration of the involved bone or joint is required . The choice of antibiotic agent should be based on culture results and the antimicrobial susceptibility of the causative organism . Treatment may also involve surgical drainage or debridement of affected structures . Failure to manage acute bone and joint infection aggressively inevitably leads to chronic, often incurable, infection . Successful therapy requires a team approach including the internist and consultants from orthopedic surgery, infectious diseases, and substance abuse counselors.

Minerva Chir, 2002 Oct, 57(5), 543 - 60
The current status and future outlook of intestinal transplantation; Abu-Elmagd K et al.; Recently, the clinical reality of intestinal, combined liver-intestinal, and multivisceral transplantation qualified the procedure by the American Health Care Financing Administration (HCFA) as the standard of care for patients with irreversible intestinal failure . The decision was supported by a decade of clinical experience with cumulative improvement in survival . Prior to tacrolimus, the worldwide experience was plagued with uncontrolled rejection, graft versus host disease (GVHD), and fatal infection . These undefeated barriers stemmed from the large gut lymphoid mass and heavy microbial load contained in the intestinal lumen with the absence of an effective immunosuppressive and antimicrobial therapy . With the emerge of small bowel and multivisceral transplantation in 1990, multiple factors, in addition to the clinical introduction of tacrolimus, have sustained and increased these efforts including evolution in surgical techniques and improvements in postoperative care . The most valuable achievement, however, has been the effective control of rejection and treatment of life threatening opportunistic infections . This chapter outlines the common current practice, surgical techniques and postoperative management of the three different types of intestinal transplantation . In addition, new strategies to overcome some of the current immunologic and biologic challenges are defined with the aim of raising the level of such a creative surgery to be a better therapy for TPN dependent patients.

Ann Plast Surg, 2002 Oct, 49(4), 410 - 3
Pyoderma gangrenosum after reduction mammaplasty in an otherwise healthy patient; Lifchez SD et al.; Pyoderma gangrenosum (PG) is a rare postoperative complication of plastic surgery of the breast . Initial signs and symptoms resemble those of infection, and antimicrobial therapy is usually initiated and fails before considering PG as a diagnosis . Therapy consists of immune modulators, and use of corticosteroids is frequent, as is local wound care . Sufficiently small wounds are allowed to heal secondarily, but larger wounds require coverage with either skin grafts or flaps . Long-term (1 year or more) postoperative surveillance is necessary because late failure of the graft or flap can occur.

Sex Transm Dis, 2002 Oct, 29(10), 559 - 67
The etiology and management of genital ulcers in the Dominican Republic and Peru; Sanchez J et al.; BACKGROUND: Clinical diagnosis of genital ulcers is difficult, and diagnostic tests are least available in settings where rates of disease are highest . The World Health Organization (WHO) has developed protocols for the syndromic management of genital ulcers in resource-poor settings . However, because risk factors, patterns and causes of disease, and antimicrobial susceptibilities differ from region to region and over time, they must be adapted to local situations . GOAL: The goal of this study was to determine etiologic factors, evaluate syndromic management, and compare polymerase chain reaction (PCR) testing with other diagnostic alternatives for genital ulcers among patients attending sexually transmitted disease clinics in the Dominican Republic and Peru . STUDY DESIGN: Eighty-one men with genital ulcers in the Dominican Republic and 63 in Peru underwent identical interviews and identical multiplex PCR (M-PCR) tests of genital lesion specimens for etiologic diagnoses . Algorithms for managing genital ulcers were developed . RESULTS: In the Dominican Republic, 5% were M-PCR-positive for, 26% for, and 43% for herpes simplex virus (HSV); in Peru, 10%, 5%, and 43%, respectively, were positive . The WHO algorithm for treating syphilis and chancroid had a sensitivity of 100%, a positive predictive value (PPV) of 24%, and an overtreatment rate of 76% . A modified algorithm for treating only those without vesicular lesions had 88% sensitivity and a 27% PPV, and the overtreatment rate was reduced to 58% . CONCLUSION: HSV caused 43% of genital ulcers in these populations . The modified algorithm had lower sensitivity but a reduced overtreatment rate . M-PCR testing was more sensitive than standard tests and more specific and sensitive than clinical diagnosis.

Mini Rev Med Chem, 2002 Aug, 2(4), 331 - 42
How do channel- and pore-forming helical peptides interact with lipid membranes and how does this account for their antimicrobial activity?
Duclohier H.
Animals and plants defend themselves against pathogenic micro-organisms by the rapid mobilization of polycationic helical amphipathic peptides . Interactions with membranes induce optimal orientation and mutual structural changes, allowing for example to form transbilayer ion channels or pores whose properties are compared in this review . Physicochemical studies of peptide-lipid interactions provide attractive approaches for drug design.

Protein Pept Lett, 2002 Oct, 9(5), 395 - 402
Antibiotic activity of reversed peptides of alpha-helical antimicrobial peptide, P18; Lee SH et al.; P18 (KWKLFKKIPKFLHLAKKF-NH(2)), an a-helical antimicrobial peptide designed from cecropin Amagainin 2 hybrid, was known to have potent antimicrobial activity against bacteria as well as fungi without hemolytic activity . To find the peptides comparable or superior to the antimicrobial activity of P18, the two reversed peptides (Rev-1 and Rev-2) of P18 were designed and synthesized . These peptides were found to have similar antimicrobial activity against bacterial and fungal cells without hemolytic activity as compared with P18 . Furthermore, a reversed peptide, Rev-2 was shown to have a two-fold higher activity in killing some bacterial cells than P18 . Therefore, these results suggested that Rev-2 peptide seems to be an excellent candidate for developing novel peptide antibiotics.

Curr Protein Pept Sci, 2002 Feb, 3(1), 121 - 31
Inhibitory mechanisms of antibiotics targeting elongation factor Tu; Hogg T et al.; Since the pioneering discovery of the inhibitory effects of kirromycin on bacterial elongation factor Tu (EF-Tu) more than 25 years ago {1}, a great wealth of biological data has accumulated concerning protein biosynthesis inhibitors specific for EF-Tu . With the subsequent discovery of over two dozen naturally occurring EF-Tu inhibitors belonging to four different subclasses, EF-Tu has blossomed into an appealing antimicrobial target for rational drug discovery efforts . Very recently, independent crystal structure determinations of EF-Tu in complex with two potent antibiotics, aurodox and GE2270A, have provided structural explanations for the mode of action of these two compounds, and have set the foundation for the design of inhibitors with higher bioavailability, broader spectra, and greater efficacy.

Biochemistry, 2002 Oct 15, 41(41), 12359 - 68
Solution and micelle-bound structures of tachyplesin I and its active aromatic linear derivatives; Laederach A et al.; Tachyplesin I is a 17-residue peptide isolated from the horseshoe crab, Tachypleus tridentatus.It has high antimicrobial activity and adopts a beta-hairpin conformation in solution stabilized by two cross-strand disulfide bonds . We report an NMR structural investigation of wild-type tachyplesin I and three linear derivatives (denoted TPY4, TPF4, and TPA4 in which the bridging cysteine residues are uniformly replaced with tyrosine, phenylalanine, and alanine, respectively) . The three-dimensional aqueous solution structures of the wild type and the active variant TPY4 reveal very similar beta-hairpin conformations . In contrast, the inactive variant TPA4 is unstructured in solution . The arrangement of the tyrosine side chains in the TPY4 structure suggests that the beta-hairpin is stabilized by aromatic ring stacking interactions . This is supported by experiments in which the beta-hairpin structure of TPF4 is disrupted by the addition of phenol, but not by the addition of an equimolar amount of cyclohexanol . We have also determined the structures of wild-type tachyplesin I and TPY4 in the presence of dodecylphosphocholine micelles . Both peptides undergo significant conformational rearrangement upon micelle association . Analysis of the micelle-associated peptide structures shows an increased level of exposure of specific hydrophobic side chains and an increased hydrophobic integy moment . Comparison of the structures in micelle and aqueous solution for both wild-type tachyplesin I and TPY4 reveals two requirements for high antimicrobial activity: a beta-hairpin fold in solution and the ability to rearrange critical side chain residues upon membrane association.

Plant Mol Biol, 2002 Oct, 50(3), 441 - 52
Over-expression of a seed specific hevein-like antimicrobial peptide from Pharbitis nil enhances resistance to a fungal pathogen in transgenic tobacco plants; Koo JC et al.; Two hevein-like peptides from the seed of Pharbitis nil, designated Pharbitis nil antimicrobial peptide 1 (Pn-AMP1) and Pn-AMP2, had been purified previously . Both exhibit potent in vitro antifungal activity against a broad spectrum of phytopathogenic fungi . We now report the isolation of two cDNA clones, designated pnAMP-h1 and pnAMP-h2, and the corresponding genomic clones encoding these proteins from mature seeds of P . nil . Comparison of the deduced amino acid sequence to that of the mature protein suggests that the peptides are produced as a prepropeptide consisting of an N-terminal signal peptide, the mature protein and C-terminal domains . The transcripts of the two genes are accumulated seed--specifically, and the maximum transcripts are observed in the mid-to-late stage of seed development . Constitutive over-expression of the pnAMP-h2 cDNA in transgenic tobacco under the control of the cauliflower mosaic virus 35S promoter conferred enhanced resistance against the oomycete Phytophthora parasitica, the causal agent of black shank disease . Thus the Pn-AMPs may play a role in the protection of seeds and may be useful as a novel gene source to engineer plants resistant to fungal pathogens.

Dent Update, 2002 Sep, 29(7), 325 - 30
Polypharmacy and dentistry: I . Introduction and interactions with local anaesthetics and sedative drugs; Meechan JG; This series of two papers considers the effects of drug interactions in dentistry . In this first paper, the principles of drug interactions will be described . In addition, interactions with drugs used in local anaesthesia and sedation will be discussed . The second paper will concentrate on interactions with analgesics and antimicrobials prescribed in dental practice.

Ther Umsch, 2002 Sep, 59(9), 475 - 9
{Genital infections in prepubertal girls}; Navratil F; Vulvitis and vulvovaginitis are the most common gynecologic complaint in prepubertal girls . The frequently observed therapeutic failures are due mainly to lack of knowledge of the characteristics of this age group, of age and development in appropriate diagnostic procedures and of therapeutic measures similar to those in the adult female patient . Prepubertal girls are anatomically, physiologically and behaviorally at relative risk for vulvovaginitis . Symptoms include pruritus, genital pain, "vulvar dysuria" and discharge . History taking and a general pediatric examination are mandatory, thereafter an age appropriate careful anogenital examination should follow . It requires time, patience and knowledge of the different non traumatizing examination techniques . The findings in girls with vulvovaginitis are variable and erythema, excoriations and discharge can be found . The genital inspection and the use of microscopy and microbiologic studies are helpful in planning an appropriate therapy . The majority of vulvovaginal infections in children are nonspecific but they can also be caused by specific organisms and are mostly bacterial . Yeast infections are not found in otherwise healthy prepubertal girls . The therapeutic approach consists of improved anogenital hygiene, sitz/tub baths and use of non irritating soaps . However if an abnormal population of bacteria is present antimicrobial therapy should be considered . Reassurance and a review of preventive methods are crucial in the management of girls with vulvovaginitis.

Health Econ, 2002 Oct, 11(7), 637 - 47
Superbugs II: how should economic evaluation be conducted for interventions which aim to contain antimicrobial resistance?
Coast J, Smith R, Karcher AM, Wilton P, Millar M.
To date, there has been little examination of the problems associated with conducting economic evaluation for interventions designed to contain antimicrobial resistance . There are two quite different types of intervention aimed at containing antimicrobial resistance: interventions which are designed to avoid the emergence of resistant organisms; and interventions that are designed to avoid the transmission of resistance organisms . Four aspects of economic evaluation where the ease of assessment might be expected to differ across evaluations for these different types of intervention are examined: problems associated with the identification of diffuse impacts, problems associated with comparing current and future impacts, problems associated with uncertainty, and problems associated with difficulties in measurement and valuation . The paper suggests that it may be much easier to conduct rigorous economic evaluations for interventions designed to avoid transmission of resistance, than for those intended to avoid emergence . Unfortunately, the transmission policies, which are likely to be the easiest to evaluate, are not likely to produce an optimal long-term outcome given the apparent irreversibility of much resistance and the potentially severe harms which could be imposed as a result . Given the desirability of avoiding a scenario where, in the evidence-based medicine culture, the most rigorously evaluated policies are followed even though they may be less important, there is the need to consider carefully what, and how, economic evaluation should be conducted in the area of antimicrobial resistance . It is suggested that research should focus on the use of modelling as a means of evaluating optimal policy responses and on trying to resolve some of the difficulties associated with measurement and valuation .

J Pediatr Hematol Oncol, 2002 Oct, 24(7), 558 - 60
Nontuberculous mycobacterial infections in pediatric acute leukemia; Suryanarayan K et al.; We report on 3 children undergoing treatment for acute lymphoblastic leukemia (ALL), who developed systemic nontuberculous mycobacterial (NTM) infections . All 3 patients were treated successfully with 5 months or less of antimicrobial therapy and completed their chemotherapy with no further recurrence of their NTM infection . NTM infections in some children with ALL may be successfully treated with antimicrobial agents without necessarily compromising the ALL treatment . The optimal duration of therapy for NTM remains unclear, but may be shorter than previously reported.

Laryngoscope, 2002 Oct, 112(10), 1758 - 61
Outpatient intravenous antibiotics for chronic rhinosinusitis; Gross ND et al.; OBJECTIVE/HYPOTHESIS: Peripherally inserted central catheter (PICC) lines have greatly facilitated the use of intravenous antibiotics in outpatient medical practice . Otolaryngologic applications for home intravenous therapy through PICC lines have not been well characterized to date . The purpose of the study is to describe indications and complications related to outpatient intravenous antibiotic therapy in patients with chronic rhinosinusitis . STUDY DESIGN: Retrospective cohort study . METHODS: Chart review of patients with chronic rhinosinusitis who were treated at an academic rhinology practice with outpatient intravenous antibiotics over a 3-year period.RESULTS Fourteen patients receiving, in all, 16 courses of intravenous antibiotic therapy through PICC line were identified . The average patient age was 51 years (age range, 36-74 y) . The primary indication for intravenous antibiotic use was the treatment of resistant pathogens (50%) . The most common organisms treated were, and . Other indications included gastrointestinal intolerance of oral antibiotics and extranasal complications of sinusitis . Eighty-eight percent of patients (14 of 16) were able to complete the entire prescribed course of therapy . Three (19%) catheter-related complications occurred, including thrombophlebitis and deep venous thrombosis . All three complications required removal of the PICC line; one of these patients underwent successful reinsertion of a second catheter and completion of treatment . CONCLUSIONS: Peripherally inserted central catheter line delivery of home intravenous antibiotics can be a well-tolerated adjunct to surgery in the outpatient treatment of chronic rhinosinusitis . Resistant infections, intolerance to oral antimicrobials, and extranasal complications of sinusitis are indications for PICC line therapy . Catheter-related complications can be significant and must be considered in patient selection.

Toxicol Lett, 2002 Nov 15, 136(1), 77 - 84
Studies on cytotoxic and genotoxic effects of N-hydroxypyridine-2-thione (Omadine) in L5178Y mouse lymphoma cells; Moller M et al.; The cytotoxicity and genotoxicity of the antifungal and antimicrobial agent Omadine, i.e . N-hydroxypyridine-2-thione (HOPT), has been investigated in L5178Y mouse lymphoma cells in the dark and under UVA irradiation . Omadine inhibits cell growth and induces micronuclei at concentrations >0.5 microM in the absence of light . At a 0.5-microM concentration, an UVA-dose-dependent induction of micronuclei is observed, conditions at which the cytotoxicity and genotoxicity in the dark is negligible . The photogenotoxicity is not accompanied by cytotoxicity . Control experiments with the radical scavengers GSH and GSHOEt implicate the involvement of hydroxyl radicals in the photogenotoxicity of Omadine.

Neuropharmacology, 2002 Sep, 43(4), 778 - 87
Characterization of the interaction between a novel convulsant agent, norbiphen, and GABA(A) and other ligand-gated ion channels; Halliwell RF et al.; A hybrid molecule composed of the antimicrobial, norfloxacin, linked to the non-steroidal anti-inflammatory drug (NSAID), biphenylacetic acid, which we have termed norbiphen, is a lethal convulsant in vivo and an antagonist of rodent GABA(A) receptors in vitro . In the present study, the selectivity, molecular site(s) and mechanism of action of this novel convulsant were investigated using electrophysiological techniques . Sub-maximal GABA-evoked currents recorded from rodent hippocampal neurons were reversibly inhibited by norbiphen (1 microM) to 5+/-2% of control whereas glutamate, NMDA and glycine activated responses were little or unaffected . Sub-maximal GABA-evoked currents recorded from oocytes expressing recombinant human alpha1beta2gamma2s or alpha1beta2 GABA(A) receptors were also reversibly inhibited by norbiphen (1-1000 nM) with an IC(50) (+/-s.e.m.) of 5.7+/-1 and 8.8+/-1 nM, respectively . Similarly, GABA currents recorded from alpha1beta1gamma2s, alpha1beta1 and beta2gamma2s receptors were inhibited with IC(50)s of 16.1+/-1, 18.8+/-1 and 4.2+/-1 nM, respectively . In contrast, norbiphen (100 nM) had little or no effect at rho1 GABA(C) homomers . At alpha1beta2gamma2s receptors, norbiphen had no affect on the GABA reversal potential, and inhibition was not voltage-dependent, suggesting that this compound does not act at the ion channel . The GABA concentration response curve was shifted in a competitive-like fashion by norbiphen (10-300 nM) and a Schild analysis of these data yielded a slope of 0.94+/-0.1 and a pA(2) of 7.77 . Our data reveal a novel, selective and highly potent antagonist of GABA(A) receptors . Norbiphen should be a valuable agent in future studies of this receptor complex.

J Periodontal Res, 2002 Oct, 37(5), 389 - 98
Selection of antimicrobial agents in periodontal therapy; Slots J; BACKGROUND: The recognition over the past 3 decades of microbial specificity in periodontitis has afforded dental practitioners the ability to prevent and treat the disease with a variety of antimicrobial drugs . These include systemic antibiotics, topical antibiotics and topical antiseptics . RESULTS: Systemic antibiotic therapy can be essential in eliminating pathogenic bacteria that invade gingival tissue and in helping control periodontal pathogens residing in various domains of the mouth from where they may translocate to periodontal sites . Frequently used periodontal combination antibiotic therapies are metronidazole-amoxicillin (250-375 mg of each 3 x daily for 8 days) and metronidazole-ciprofloxacin (500 mg of each 2 x daily for 8 days) . Microbiological analysis helps determine the optimal antibiotic therapy and effectiveness of treatment . Topical antibiotics that are commercially available as controlled release devices suffer from several potential problems, including insufficient spectrum of antimicrobial activity in some periodontal polymicrobial infections, risks of producing an antibiotic resistant microbiota, and high acquisition costs . Topical antiseptics of relevance in periodontal treatment include 10% povidone-iodine placed subgingivally by a syringe for 5 min, and 0.1% sodium hypochlorite solution applied subgingivally by patients using an irrigation device . CLINICAL IMPLICATIONS: The present paper recommends periodontal treatment that includes a battery of professionally and patient-administered antimicrobial agents (properly prescribed systemic antibiotics, povidone-iodine and sodium hypochlorite subgingival irrigants, and chlorhexidine mouthrinse) . Available chemotherapeutics can provide effective, safe, practical and affordable means of controlling subgingival colonization of periodontal pathogens and various types of periodontal disease.

J Pept Res, 2002 Oct, 60(4), 198 - 214
Exploring relationships between mimic configuration, peptide conformation and biological activity in indolizidin-2-one amino acid analogs of gramicidin S; Roy S et al.; Indolizidin-2-one amino acids (I2aas, 6S- and 6R-1) possessing 6S- and 6R-ring-fusion stereochemistry were introduced into the antimicrobial peptide gramicidin S (GS) to explore the relationships between configuration, peptide conformation and biological activity . Solution-phase and solid-phase techniques were used to synthesize three analogs with I2aa residues in place of the d-Phe-Pro residues at the turn regions of GS: {(6S)-I2aa4-5,4'-5'}GS (2), {Lys2,2',(6S)-I2aa4-5,4'-5'}GS (3) and {(6R)-I2aa4-5,4'-5'}GS (4) . Although conformational analysis of {I2aa4-5,4'-5'}GS analogs 2-4 indicated that both ring-fusion stereoisomers of I2aa gave peptides with CD and NMR spectral data characteristic of GS, the (6S)-I2aa analogs 2 and 3 exhibited more intense CD curve shapes, as well as greater numbers of nonsequential NOE between opposing Val and Leu residues, relative to the (6R)-I2aa analog 4, suggesting a greater propensity for the (6S)-diastereomer to adopt the beta-turn/antiparallel beta-pleated sheet conformation . In measurements of antibacterial and antifungal activity, the (6S)-I2aa analog 2 exhibited significantly better potency than the (6R)-I2aa diastereomer 4 . Relative to GS, {(6S)-I2aa4-5,4'-5'}GS (2) exhibited usually 1/2 to 1/4 antimicrobial activity as well as 1/4 hemolytic activity . In certain cases, antimicrobial and hemolytic activities of GS were shown to be dissociated through modification at the peptide turn regions with the (6S)-I2aa diastereomer . The synthesis and evaluation of GS analogs 2-4 has furnished new insight into the importance of ring-fusion stereochemistry for turn mimicry by indolizidin-2-one amino acids as well as novel antimicrobial peptides.

Microbiol Immunol, 2002, 46(8), 571 - 3
Menadione-catalyzed luminol chemiluminescent assay for viability of Mycobacterium bovis; Yamashoji S; Stable luminol chemiluminescence was observed 10 min after the addition of menadione to a suspension of Mycobacterium bovis homogenized in Middlebrook 7H9 broth base including OADC enrichment . The chemiluminescence intensity was proportional to the absorbance of the bacterial suspension at 600 nm in a range of 0.005 to 0.15 . Luminol chemiluminescence disappeared after 10 min incubation of M . bovis at over 60% of ethanol or 4 days of cultivation of M . bovis in the presence of 40 microg/ml of streptomycin . The bacterium showing the disappearance of chemiluminescence could not grow after being washed, suggesting that the inhibition concentration of the antimicrobials can be estimated on the basis of the disappearance of chemiluminescence . Menadione-catalyzed luminol chemiluminescent assay was rapid and sensitive in comparison to turbidimetry, tetrazolium (WST-8) reduction assay, and the assay using the Mycobacteria growth indicator tube (MGIT).

Microb Drug Resist, 2002 Fall, 8(3), 187 - 92
Clonal spread of resistant pneumococci despite diminished antimicrobial use; Arason VA et al.; The effects of community-wide interventions to reduce resistance rates are poorly understood . This study evaluated the effect of reduced antimicrobial usage on the spread of penicillin-nonsusceptible pneumococci (PNSP) in four communities in Iceland . The study was performed after interventions to reduce antimicrobial usage and compared to an identical study performed 5 years before . A randomized sample of 953 children was chosen from all 2,900 1- to 6-year-old children living in four well-defined communities . The main outcome measures were nasopharyngeal carriage of PNSP and individual and community use of antimicrobials . Pneumococci were carried by 51.7% of the 743 children enrolled, and 8.1% of the pneumococci were PNSP as opposed to 8.5% in the previous study . The antimicrobial use of participants had been reduced from 1.5 to 1.1 courses/year and the overall use among children <7 years old living in the study areas from 13.6 to 11.1 defined daily dosages/1000 children per day . The prevalence of PNSP increased in the two areas furthest away from the capital area despite reduced consumption . The major risk factors for carriage of PNSP remained the same . Interventions can be effective in reducing antimicrobial use . Pandemic multiresistant clones can also spread fast in small communities with low antimicrobial use, where their appearance may be delayed compared to highly populated urban areas . Clonal spread and herd immunity are important factors to be considered in the evaluation of intervention effects.

Can J Gastroenterol, 2002 Sep, 16(9), 611 - 4
Motion--Helicobacter pylori worsens GERD: arguments for the motion; O'Morain CA et al.; There are several reasons for eradicating Helicobacter pylori in patients with chronic gastroesophageal reflux disease (GERD) . Perhaps the most compelling is the evidence that chronic acid suppression therapy can lead to the development of atrophic gastritis, a premalignant condition, in patients with H pylori infection . Epidemiological data that suggest that H pylori is less prevalent in GERD patients than in control subjects may be susceptible to publication bias, and confounding social and environmental factors may also be involved . Although it has been thought that eradication of the organism might lead to increased esophageal acid exposure, this has not been demonstrated in practice . Studies that appeared to show that GERD could be provoked by antimicrobial therapy of duodenal ulcers also have methodological weaknesses . Underlying GERD symptoms might be unmasked after withdrawal of acid-suppression therapy, for reasons that are unrelated to H pylori . In fact, eradication of the organism has been shown to decrease heartburn in patients with peptic ulcer disease . When H pylori is successfully eradicated in patients with GERD, relapse rates are not increased, and the disease-free interval seems to be prolonged . Eradication of the organism is a wise policy in patients who face long term acid-suppression therapy for GERD.

Eur J Gastroenterol Hepatol, 2002 Oct, 14(10), 1093 - 100
Five minute endoscopic urea breath test with 25 mg of (13)C-urea in the management of Helicobacter pylori infection; Isomoto H et al.; OBJECTIVE: The endoscopic (13)C-urea breath test ((13)C-EUBT), which combines the urea breath test (UBT) with endoscopy, provides high accuracy for the detection of Helicobacter pylori . This study was conducted to determine whether the (13)C-EUBT using low doses of urea and short sampling times could preserve accuracy in the management of H . pylori infection . METHODS: Three hundred and twenty-five patients were randomized to receive the EUBT with 100, 50 or 25 mg of (13)C-urea by endoscopic spraying . The breath samples collected at 5, 10 and 20 min were analysed using an isotope selected non-dispersive infrared spectrometer . H . pylori infection was assessed by the rapid urease test and histology . In each sampling schedule and protocol, cut-off values were calculated by a receiver operating characteristic curve . We applied the EUBT with 25 mg of (13)C-urea at 5 min to the assessment of eradication in 135 patients who had received the antimicrobial treatment or to the detection of the organism in 61 patients with previous partial gastrectomy . RESULTS: Based on histology and the urease test, patients who had discordant results were excluded from the analysis . Using 100 mg of urea, the sensitivity and specificity of the test were both 100% at 10 and 20 min, and the sensitivity and specificity at 5 min were best with 98.6% and 100%, respectively . With 50 mg, they were both 100% at 20 min, and the best combination of sensitivity and specificity at 5 and 10 min was 97.3-96.6% and 97.3-100%, respectively . Even with 25 mg, the sensitivity and specificity were both 100.0% at 20 min, and at the 5 min and 10 min time point, the EUBT yielded a sensitivity of 98.7% and a specificity of 100% . There was a significant positive correlation between the test values of the 5 min (13)C-EUBT with 25 mg of test urea and those of the conventional UBT . The 5 min EUBT with (13)C-urea offered high accuracy in the assessment of H . pylori eradication, with the sensitivity and specificity being 100% and 96.4%, respectively . In patients with previous gastrectomy, the EUBT provided acceptable accuracy (a sensitivity of 96.4% and a specificity of 97.0%) . CONCLUSIONS: Our results indicate that the (13)C-EUBT is an accurate method for detecting H . pylori infection . The EUBT using only 25 mg of (13)C-urea at the early (5 min) time point has satisfactory diagnostic efficacy in pre- and post-eradication treatment settings, providing a less expensive and more rapid way of performing the test . The EUBT may be a reliable method of assessing H . pylori status in the remnant stomach.

Farmaco, 2002 Aug, 57(8), 631 - 9
Synthesis of variously substituted 1,8-naphthyridine derivatives and evaluation of their antimycobacterial activity; Badawneh M et al.; A series of 1,8-naphthyridine derivatives variously substituted in the 2, 3, 4 and 7 positions were synthesized for in vitro evaluation of antimycobacterial activity in accordance with an international program with the tuberculosis antimicrobial acquisition and coordinating facility (TAACF) . Several compounds 4, 8, 12, 14, 19, 29 and 30, when tested at a concentration of 6.25 microg/ml against Mycobacterium tuberculosis H37Rv, showed an interesting activity with % inhibition in the range 38-96% . The most effective substituent in position 2, 4 or 7 of the 1,8-naphthyridine nucleus seem to be the piperidinyl group.

Clin Orthop, 2002 Oct, (403), 80 - 6
Outpatient intravenous antimicrobial therapy for the practicing orthopaedic surgeon; Osmon DR et al.; The medical treatment of many musculoskeletal infections requires prolonged intravenous antimicrobial therapy, much of which is administered outside the hospital under the guidance of an infectious disease specialist . The essential elements of patient selection, antimicrobial administration, and clinical and laboratory monitoring of outpatient intravenous antimicrobial therapy for adult patients with musculoskeletal infection is described in the current study . Orthopaedists who treat patients with musculoskeletal infection should know the essential details of outpatient intravenous antimicrobial therapy to optimize the medical and surgical treatment of patients with these infections.

Clin Orthop, 2002 Oct, (403), 49 - 53
Antimicrobial release kinetics from polymethylmethacrylate in a novel continuous flow chamber; Perry AC et al.; Polymethylmethacrylate is used for local delivery of antimicrobials in the treatment of musculoskeletal infections . A novel continuous flow chamber system was designed to measure in vitro antimicrobial release . Three-millimeter beads containing amikacin, gentamicin, tobramycin, or vancomycin {concentration of 7.5% (weight per weight)} were placed individually in a continuous flow chamber with a total volume of 1 mL Kreb's Ringer buffer flowing at 1 mL/hour . Effluent was sampled hourly for 24 hours and then every 2 hours up to 48 hours; antimicrobial concentrations were measured in triplicate by bioassay . The mean peak concentrations were 40.9, 30.1, 30.0, and 19.1 microg/mL; the mean areas under the concentration time curves (Time 0 to infinity) were 263, 327, 110, and 180 hours x microg/mL of antibiotic; and the mean percentages of initial amount of antimicrobial released were 11.7%, 14.5%, 6.6%, and 10.9% for tobramycin, gentamicin, amikacin, and vancomycin, respectively . The results for each polymethylmethacrylate-antimicrobial agent combination were reproducible . In contrast to other in vitro elution systems, this novel system operates under the premise that there is dynamic flow surrounding polymethylmethacrylate in vivo and permits rapid in vitro comparison of the relative release of antimicrobial agents from polymethylmethacrylate.

Proc Natl Acad Sci U S A, 2002 Oct 15, 99(21), 13705 - 10 Epub 2002 Oct 01.
Overexpression of a pattern-recognition receptor, peptidoglycan-recognition protein-LE, activates imd/relish-mediated antibacterial defense and the prophenoloxidase cascade in Drosophila larvae; Takehana A et al.; In Drosophila, microbial infection activates an antimicrobial defense system involving the activation of proteolytic cascades in the hemolymph and intracellular signaling pathways, the immune deficiency (imd) and Toll pathways, in immune-responsive tissues . The mechanisms for microbial recognition are largely unknown . We report that, in larvae, the imd-mediated antibacterial defense is activated by peptidoglycan-recognition protein (PGRP)-LE, a PGRP-family member in Drosophila . Consistent with this, PGRP-LE binds to the diaminopimelic acid-type peptidoglycan, a cell-wall component of the bacteria capable of activating the imd pathway, but not to the lysine-type peptidoglycan . Moreover, PGRP-LE activates the prophenoloxidase cascade, a proteolytic cascade in the hemolymph . Therefore, PGRP-LE acts as a pattern-recognition receptor to the diaminopimelic acid-type peptidoglycan and activates both the proteolytic cascade and intracellular signaling in Drosophila immunity.

Pediatrics, 2002 Oct, 110(4), 805 - 14
The future of pneumococcal conjugate vaccines for prevention of pneumococcal diseases in infants and children; Pelton SI et al.; Seven-valent pneumococcal conjugate vaccine (PCV7) was licensed in February 2000 . In June 2000, the Advisory Committee on Immunization Practices and the American Academy of Pediatrics recommended the universal administration of pneumococcal conjugate vaccine for all children 23 months of age and younger and for children 24 to 59 months of age who are at high risk for serious pneumococcal disease . Since then, >23 million doses have been administered in the United States . Postlicensure surveillance of invasive pneumococcal disease (IPD) in the United States from the Active Bacterial Core Surveillance program at the Centers for Disease Control and Prevention and the Northern California Kaiser Permanente Vaccine Study Center has reported a decline in IPD and in pneumococcal disease incidence as a result of vaccine serotypes, respectively . During this period, issues critical to the long-term success of PCV7 have become more relevant: Will PCV7 be as effective in groups of children who are at high risk for IPD as in healthy children? Will nonvaccine types replace vaccine serotypes in the nasopharynx and in disease? Why are the results of the clinical trials different for IPD and for acute otitis media? How many doses of PCV7 and what concentrations of antibody are necessary for protection? Will universal administration of PCV7 to children younger than 2 years reduce antimicrobial drug resistance and alter prescribing patterns of physicians for febrile infants? Have there been unanticipated adverse events or benefits observed? The purpose of this report is to review the current data available to address these questions and to identify gaps that will require additional knowledge to determine the ultimate value of pneumococcal conjugate vaccines in reducing the burden of pneumococcal disease in infants and children.

Acad Emerg Med, 2002 Oct, 9(10), 977 - 82
The effects of a high-potency topical steroid on cutaneous healing of burns in pigs; Singer AJ et al.; OBJECTIVE: Burns are dynamic injuries that tend to progress over the course of several days . Steroids inhibit the formation of vasoconstrictive prostanoids that may contribute to this progression of injury . The authors hypothesized that adding topical steroids to a standard antimicrobial agent would reduce the progression of burns and accelerate reepithelialization without increasing infection rates . METHODS: This was a prospective, blinded, controlled, experimental trial . Forty-eight standardized second-degree burns were created by applying an aluminum bar preheated to 80 degrees C to the flanks of isoflurane-anesthetized young pigs for 20 seconds . Three equal sets of 16 burns were randomly treated with silver sulfadiazine cream (SSD), clobetasol propionate 0.05% (CP), or both (SSD+CP) . Daily dressing changes were performed for 14 days . Full-thickness biopsies were taken after injury and at one, two, seven, ten, and 14 days for blinded histopathological evaluation using hematoxylin and eosin (H&E) staining . The primary outcome was the % reepithelialization (REP) calculated by dividing the length of the neoepidermis by the section's total length (interobserver correlation = 0.99) . Depth of injury was measured for each dermal element (collagen; epithelial, mesenchymal, and vascular cells; and vessel thrombosis) . Comparisons across groups were performed using one-way analysis of variance (ANOVA) . A repeated-measures ANOVA was used to compare injury depths over time . This study had 80% power to detect a 33-percentage point difference in REP across groups (two-tailed alpha = 0.05) . RESULTS: Pretreatment burn depths were similar across groups . While burn depth changed over time, there was no difference between the groups in burn injury progression . There was no difference across the groups in REP or infection rates at all times . CONCLUSIONS: Addition of a potent topical steroid to standard antimicrobial topical agents does not reduce burn depth or accelerate reepithelialization after burns.

Lett Appl Microbiol, 2002, 35(4), 285 - 90
Study on the mechanisms of the antibacterial action of some plant alpha,beta-unsaturated aldehydes; Trombetta D et al.; AIMS: In this paper the mechanisms involved in the antibacterial effect of six 2E-alkenals {(E)-2-hexenal, (E)-2-eptenal, (E)-2-octenal, (E)-2-nonenal, (E)-2-decenal and (E,E)-2,4-decadienal} were investigated . METHODS AND RESULTS: We measured the release of carboxyfluorescein (CF) trapped in liposomes of phosphatidylcholine (PC) following exposure to the aldehydes mentioned above, in comparison with that elicited by hexanal and nonanal; the modifications of the thermotropic behaviour of liposomes of dimyristoylphosphatidylcholine (DMPC) induced by (E,E)-2,4-decadienal (the aldehyde endowed with the highest microbicidal activity) were evaluated by means of differential scanning calorimetry . With the exception of hexanal, all aldehydes tested caused rapid CF leakage from PC liposomes . The effectiveness order correlates well with the chain length and the presence of the alpha,beta-double bond . Furthermore (E,E)-2,4-decadienal is able to interact with and cross DMPC bilayers . CONCLUSIONS: The present findings suggest that the 2E-alkenals tested elicit, very likely, a gross perturbation of the lipidic fraction of plasmatic membranes and are able to penetrate into bacterial cells . SIGNIFICANCE AND IMPACT OF THE STUDY: These data represent an interesting background for a rational employment of the plant 2E-alkenals tested as antimicrobial agents.

Am J Clin Dermatol, 2002, 3(8), 529 - 34
Topical treatment of pediatric patients with burns: a practical guide; Palmieri TL et al.; Over 440 000 children receive medical attention for burn injuries each year in the US . Burn wound infections are a major source of morbidity and mortality in these patients . Infected wounds not only heal more slowly, but also may lead to systemic infections . The factors that contribute to wound complications are both the size and depth of the wound . Burn depth is usually categorized into first-degree (superficial, involving only the epidermis), second-degree (partial thickness, involving both epidermis and dermis), and third-degree (full thickness, through the epidermis, dermis, and into fat) . Burns that will not heal within 2 weeks are at least second-degree and should generally be referred to a burn surgeon for possible excision and grafting, due to the increased risk of infection and scarring . The burn wound is dynamic . Proper treatment minimizes the extent of the burn injury, whereas improper treatment (lack of proper wound-care, edema formation, lack of resuscitation) may actually increase the size and/or depth of the wound . Topical antimicrobial agents have been shown to decrease wound-related infections and morbidity in burn wounds when used appropriately . The goal of topical antimicrobial therapy is to control microbial colonization, thus preventing development of invasive infections . A wide variety of agents are available for treatment of burn wounds, including ointments, creams, biological and nonbiological dressings . Topical antimicrobials of choice include bacitracin, neomycin, silver sulfadiazine and mafenide.

J Med Microbiol, 2002 Sep, 51(9), 786 - 90
Prevalence of resistant Helicobacter pylori isolates in Bulgarian children; Boyanova L et al.; The aim of this study was to assess the primary and combined resistances of Helicobacter pylori isolates obtained from paediatric patients in 2000-2001 to seven antimicrobial agents . Resistance rates of pre-treatment isolates from 115 children were investigated by the limited agar dilution method alone and by the E-test . The cut-off concentrations for resistance were: metronidazole >8 mg/L, clarithromycin and azithromycin >1 mg/L, clindamycin >4 mg/L, amoxicillin >0.5 mg/L, tetracycline >4 mg/L and ciprofloxacin >1 mg/L . Primary resistance rates were: metronidazole 15.8%, clarithromycin 12.4%, azithromycin 14.6%, clindamycin 20.0%, amoxicillin 0%, metronidazole + clarithromycin 4.5%, ciprofloxacin 6.0%, metronidazole + clarithromycin + ciprofloxacin 1.2%, tetracycline 3.1% and metronidazole + ciprofloxacin 1.2% . There were no significant age (1-9 years versus 10-18 years) or gender differences . Prevalence of both macrolide-resistant and intermediately susceptible strains was 21.9% for azithromycin and 15.9% for clarithromycin . Of 18 metronidazole-resistant isolates, 77.8% exhibited a metronidazole MIC > or = 32 mg/L . H . pylori resistance rates to metronidazole, clarithromycin and both agents were relatively low in Bulgarian children . However, resistance was found to all drugs tested except for amoxicillin . The consumption of newer macrolides and tetracyclines could be related to the prevalence of resistance to the corresponding agents . There were no significant differences in primary resistance rates of H . pylori to antimicrobial agents between children and adults except for metronidazole . Multi-drug resistance to newer macrolides, metronidazole and ciprofloxacin in association with a slightly elevated amoxicillin MIC (0.38 mg/L) was detected in one strain.

Equine Vet J, 2002 Sep, 34(6), 542 - 8
Chronic pulmonary disease with radiographic interstitial opacity (interstitial pneumonia) in foals; Nout YS et al.; Twelve foals, age 3-9 months, examined at The Ohio State University Veterinary Teaching Hospital between 1995 and 2000 were diagnosed with chronic pulmonary disease associated with marked interstitial opacity on radiographic examination . The most characteristic features were a history of respiratory disease of 1-3 months duration, marked clinical signs of respiratory disease, failure to yield a consistent pathogen from tracheobronchial aspirates and a predominantly interstitial pattern on thoracic radiographs . We attributed these signs to chronic interstitial pneumonia . Foals were treated with broad spectrum antimicrobial and corticosteroid drugs . All 12 foals were discharged alive from hospital and, of the 10 available for follow-up, all were disease-free and performing to expectation 5 months to 5 years after discharge . We conclude that chronic interstitial pneumonia, occuring in foals, is associated with a good prognosis and that corticosteroid therapy may be useful in its treatment.

Planta Med, 2002 Sep, 68(9), 836 - 8
Chemical analysis and antifungal activity of the essential oil of Calea clematidea; Flach A et al.; The chemical composition of the essential oils of Calea clematidea Baker obtained by hydrodistillation of the leaves and flowers was analysed by GC and GC/MS and the oils were assayed for their antifungal activities . The essential oil of the leaves showed a high content of a new natural epoxy terpenoid, named clemateol (ca . 70 %), with minor amounts of o-vanillin (6.5 %), spathulenol (4.2 %), alpha-terpinene (4.0 %), germacrene B (2.9 %), yomogi alcohol (1.8 %), ( E)-caryophylene (1.7 %), m-cymenene (1.6 %), and alpha-gurjunene (1.5 %), while the essential oil of the flowers was characterized by a higher content of thymol methyl ether (ca . 80 %), with minor amounts of clemateol (4.8 %) and o-cymene (4.7 %) . The antimicrobial activity of the oils was also evaluated against dermatophytes for their possible use in pharmaceutical preparations for topical applications . The oil of the leaves (MIC > 3.57 mg/ml), clemateol (MIC > 1.52 mg/ml), and the alcohol 2 (MIC > 2.82 mg/ml) showed a moderate antifungal activity against Trichophyton tonsurans, Trichophyton rubrum, Trichophyton menthagrophytes var . i nterdigitale, Epidermophyton floccosum, Microsporum gypseum, Microsporum canis and Microsporum nanum.

Planta Med, 2002 Sep, 68(9), 808 - 12
Antimicrobial terpenoids from the oleoresin of the Peruvian medicinal plant Copaifera paupera; Tincusi BM et al.; Twelve known diterpenes 1 - 11 and 13, and three known sesquiterpenes 14 - 16, along with a new C(20) - C(15) terpenoid 17, with a structure based on an unprecedented skeleton in which a labdane diterpene is linked to a monocyclic sesquiterpene by an ester bridge, were isolated from the oleoresin of the Peruvian medicinal plant Copaifera paupera (Herzog) Dwyer (Leguminosae) . Their structures were elucidated on the basis of spectral analysis, including homo- and heteronuclear correlation NMR experiments (COSY, ROESY, HMQC and HMBC), and by comparison with data in the literature . The leishmanicidal, antimicrobial, cytotoxic, and aldose reductase inhibitory activities were studied . Compounds 1 and 11 showed significant antimicrobial activity (MIC < 10 microg/ml) against Gram-positive bacteria, comparable with cephotaxime used as control . Compound 2 exhibited moderate cytotoxic activity against four cancer cell lines.

Curr Opin Crit Care, 2002 Oct, 8(5), 465 - 72
New concepts in sepsis; Sessler CN et al.; An estimated 750,000 cases of severe sepsis occur annually in the United States, and the mortality rate is about 30% . As a condition that disproportionately affects the elderly and is related to invasive and immunosuppressive healthcare, increases in the frequency of sepsis are anticipated . The complex pathophysiology of sepsis encompasses the interplay of pro- and anti-inflammatory mediators, activated circulating and resident inflammatory cells, disrupted coagulation, endothelial activation and injury, vasodilatation and vascular hyporesponsiveness to vasoactive mediators, cardiac dysfunction, and cellular dysoxia . Current management of severe sepsis includes eradication of infection through source control and antimicrobial therapy, aggressive and targeted shock resuscitation that includes fluid administration, correction of anemia, vasopressor support, modest inotropic therapy, infusion of human recombinant activated protein C to selected patients, and compulsive supportive care to manage organ dysfunction and to avoid complications.

Curr Opin Crit Care, 2002 Oct, 8(5), 453 - 60
Severe community-acquired pneumonia; Ewig S et al.; Although several pneumonia severity criteria have been firmly established, the exact definition of severe community-acquired pneumonia (CAP) remains elusive . Mortality from CAP remains high, reaching 50% in some series . The particular role of and spp . in severe CAP has been defined more clearly . Microbial diagnosis in the individual patient remains a difficult task . Despite promising new diagnostic tools, concerns about possible mixed origins preclude a change from the currently advocated broad-spectrum approach of antimicrobial treatment . Although there is some evidence that guidelines may optimize outcomes, their role in limiting the spread of resistance has only recently received attention . Finally, although there are promising data on the use of noninvasive positive pressure ventilation to treat pneumonia in patients without chronic obstructive pulmonary disease, its place in the management of acute respiratory failure remains to be defined in randomized studies.

Curr Opin Crit Care, 2002 Oct, 8(5), 435 - 40
Optimizing antimicrobial dosing in the critically ill patient; Goldberg J et al.; "We know everything about antibiotics except how much to give," Maxwell Finland once stated . Finally, with the proliferation of pharmacodynamics as a science, we are addressing the question of how much to give . We have moved from an era of more or less arbitrary antimicrobial dosage selection toward one characterized by evidence-based optimal dosing strategies . Optimizing antimicrobial therapy in critically ill patients is more than just the selection of a suitable dose for a particular patient . Optimizing therapy also involves the selection of an appropriate single or combination antibiotic regimen that is active against the suspected or documented pathogens at the site(s) of infection . The regimen should offer the fewest potential adverse events, and the duration of therapy should be the shortest possible so as not to encourage resistance . Dosing of the chosen regimen should reflect variables that are often ignored, such as the patient's weight and age . The new continuous renal replacement therapies are commonly used in the critical care unit and must be considered . Finally, the cost of the regimen should be considered, but not only the cost to purchase the chosen antimicrobial agent but the cost to administer it (, the cost of minibags or syringes, intravenous tubing, saline flushes {all multiplied by the number of times per day the drug is given}), and, most importantly, if the patient fails to respond to therapy, the cost necessary to re-treat the patient to bring about a cure . In this review, we discuss some of the principles required to optimize antimicrobial dosing and recently obtained data regarding its application to the critically ill patient.

Curr Opin Crit Care, 2002 Oct, 8(5), 421 - 9
Nosocomial pneumonia: emerging concepts in diagnosis, management, and prophylaxis; Craven DE et al.; Nosocomial pneumonia is a dynamic disease with multiple etiologic agents and a changing natural history . The highest attack rates and mortality occur in patients with ventilator-associated pneumonia . Diagnosis of nosocomial pneumonia is often made by clinical criteria that are sensitive but lack specificity . The use of quantitative endotracheal aspirates or bronchoscopy with bronchoalveolar lavage and protected specimen brush clearly improve diagnostic specificity and outcome in patients who are mechanically ventilated . The rapid spread of multidrug-resistant, spp, and has made initial empiric therapy more difficult . Management principles include the use of techniques for more accurate diagnosis and early antimicrobial therapy with appropriate agents along with careful analysis of culture results, clinical response, and potential complications of pneumonia and therapy . Strategies for prophylaxis are of critical importance for risk reduction, improvement in patient outcome, and reduction of hospital costs.

Proc Natl Acad Sci U S A, 2002 Oct 15, 99(21), 13560 - 5 Epub 2002 Sep 30.
Solution structure and dynamics of the outer membrane enzyme PagP by NMR; Hwang PM et al.; The bacterial outer membrane enzyme PagP transfers a palmitate chain from a phospholipid to lipid A . In a number of pathogenic Gram-negative bacteria, PagP confers resistance to certain cationic antimicrobial peptides produced during the host innate immune response . The global fold of Escherichia coli PagP was determined in both dodecylphosphocholine and n-octyl-beta-d-glucoside detergent micelles using solution NMR spectroscopy . PagP consists of an eight-stranded anti-parallel beta-barrel preceded by an amphipathic alpha helix . The beta-barrel is well defined, whereas NMR relaxation measurements reveal considerable mobility in the loops connecting individual beta-strands . Three amino acid residues critical for enzymatic activity localize to extracellular loops near the membrane interface, positioning them optimally to interact with the polar headgroups of lipid A . Hence, the active site of PagP is situated on the outer surface of the outer membrane . Because the phospholipids that donate palmitate in the enzymatic reaction are normally found only in the inner leaflet of the outer membrane, PagP activity may depend on the aberrant migration of phospholipids into the outer leaflet . This finding is consistent with an emerging paradigm for outer membrane enzymes in providing an adaptive response toward disturbances in the outer membrane.

Protein Expr Purif, 2002 Oct, 26(1), 59 - 64
Cloning and expression of functional shikimate dehydrogenase (EC 1.1.1.25) from Mycobacterium tuberculosis H37Rv; Magalhaes ML et al.; Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to be one of the deadliest diseases in the world . TB resurged in the late 1980s and now kills more than 2 million people a year . Possible factors underlying the reemergence of TB are the high susceptibility of human immunodeficiency virus-infected persons to the disease, the proliferation of multi-drug-resistant (MDR) strains, patient noncompliance in completing the standard "short-course" therapy, and decline of health care systems . Thus, there is a need for the development of new antimycobacterial agents to treat MDR strains of M . tuberculosis, to provide for more effective treatment of latent tuberculosis infection, and to shorten the treatment course to improve patient compliance . The shikimate pathway is an attractive target for antimicrobial agents development because it is essential in algae, higher plants, bacteria, and fungi, but absent in mammals . Homologs to enzymes in the shikimate pathway have been identified in the genome sequence of M . tuberculosis . The M . tuberculosis aroE-encoded shikimate dehydrogenase was PCR amplified, cloned, sequenced, and expressed in Escherichia coli BL21(DE3) . Recombinant protein expression was achieved by a low-cost and simple protocol . Although cell lysis resulted in the formation of insoluble aggregates of the recombinant protein, soluble and functional M . tuberculosis shikimate dehydrogenase could be obtained by repeated cycles of freezing and thawing . Enzyme activity measurements demonstrated that there was approximately a 5-fold increase in specific activity for M . tuberculosis shikimate dehydrogenase . Moreover, the enzyme activity was linearly dependent upon the amount of recombinant protein added to the assay mixture, thus, confirming cloning and expression of functional mycobacterial shikimate.

Biopharm Drug Dispos, 2002 Oct, 23(7), 293 - 300
Pharmacokinetics and tissue distribution of intravenous pefloxacin for antibiotic prophylaxis in biliary surgery; Gascon AR et al.; The plasma levels and tissue penetration of pefloxacin were studied after prophylactic administration to patients undergoing elective biliary surgery . Pefloxacin was administered as a single dose of 800 mg given intravenously as an infusion 1 h before surgery . Over a period of two years, cultures of bile and stone were performed after cholecystectomy in order to find the main pathogens present in the geographical area of the hospital of Txagorritxu (Vitoria, Spain), as well as to test the antimicrobial susceptibility of these bacteria to pefloxacin . Thirty seven per cent of the bile and stone cultures were positive, and 75 different species were isolated . E . coli was the predominant microorganism (25%) . Other frequent microorganisms were E . faecium (9.3%), S . epidermidis (6.6%) and Cl . perfringens (6.6%) . Most species isolated were susceptible to pefloxacin, with MIC(90) values of 0.125 microg/ml for E . coli, 0.5 microg/ml for S . epidermidis and 1 microg/ml for Cl . perfringens . E . faecium was resistant, with a MIC(90) value of 8 microg/ml but a MIC(50) of 4 microg/ml (intermediate) . After pefloxacin infusion, adequate drug plasma levels (>MIC(90)) for the most frequent pathogens were found throughout the procedure . Elimination half-life was estimated as 22.03+/-6.91 h; the area under the concentration-time curve from zero to infinite had a value of 275.07+/-130.02 mg h/l and the values for volume of distribution at steady-state and plasma clearance were 96.48+/-28.65 L and 3.60+/-1.83 l/h, respectively . Bile pefloxacin concentrations generally exceeded the minimum inhibitory concentrations for most relevant pathogens . Drug levels in gallbladder and subcutaneous tissues were also above the MIC(90) for extended periods . Patients were observed daily throughout their hospital stay . This included examination of the surgical wound and recording of body temperature . No cases of anaerobic infection were noted in the study patients . Other constants such as hospitalization stay and time of recuperation were normal for this type of surgery . According to these results, pefloxacin presents many features that make it suitable for use as a therapeutic prophylactic agent, such as its broad spectrum of antimicrobial activity and favorable pharmacokinetic properties .

Clin Infect Dis, 2002 Oct 15, 35(8), 982 - 9 Epub 2002 Sep 24.
Has antifungal susceptibility testing come of age?
Rex JH, Pfaller MA.
The in vitro susceptibility of an infecting organism to the antimicrobial agent selected for therapy is one of several factors that influence the likelihood that therapy for an infection will be successful . To appreciate the value of antifungal susceptibility testing, it is helpful to review the overall predictive utility of antibacterial susceptibility testing . After >30 years of study, in vitro susceptibility can be said to predict the response of bacterial infections with an accuracy that is well summarized as the "90-60 rule": infections due to susceptible isolates respond to therapy approximately 90% of the time, whereas infections due to resistant isolates respond approximately 60% of the time . On the basis of a growing body of knowledge, standardized susceptibility testing for selected organism-drug combinations (most notably, Candida species and the azole antifungal agents) has been shown to have similar predictive utility . Antifungal susceptibility testing is now increasingly and appropriately used as a routine adjunct to the treatment of fungal infections.

Eur Biophys J, 2002 Oct, 31(6), 428 - 37 Epub 2002 Jun 28.
Lipid discrimination in phospholipid monolayers by the antimicrobial frog skin peptide PGLa . A synchrotron X-ray grazing incidence and reflectivity study; Konovalov O et al.; We present a first study using synchrotron grazing incidence diffraction and X-ray reflectivity measurements on mixed phospholipid/peptide monolayers at the air/water interface . The thermodynamic properties of the pure and mixed monolayers were characterized using the classical film balance technique . Surface pressure/potential-area isotherms showed that the antimicrobial frog skin peptide PGLa formed a very stable monolayer with two PGLa molecules per kinetic unit and a collapse pressure of ~22 mN/m . X-ray grazing incidence diffraction indicated that the peptide-dimer formation did not lead to self-aggregation with subsequent crystallite formation . However, the scattering length density profiles derived from X-ray reflectivity measurements yield information on the PGLa monolayer that protrudes into the air phase by about 0.8 nm, suggesting that the peptide is aligned parallel to the air/water interface . The monolayers, composed of disaturated phosphatidylcholines or phosphatidylglycerols, were stable up to 60 mN/m and exhibited a first-order transition from a liquid-expanded to a liquid-condensed state around 10 mN/m . Structural details of the phospholipid monolayers in the presence and absence of PGLa were obtained from synchrotron experiments . Thereby, the X-ray data of distearoylphosphatidylcholine/PGLa can be analyzed by being composed of the individual components, while the peptide strongly perturbed the lipid acyl chain order of distearoylphosphatidylglycerol . These results are in agreement that PGLa mixes at a molecular level with negatively charged lipids, but forms separate islands in zwitterionic phosphatidylcholine monolayers and demonstrates that antimicrobial peptides can discriminate between the major phospholipid components of bacterial and mammalian cytoplasmic membranes.

J Clin Microbiol, 2002 Oct, 40(10), 3845 - 7
Reduction of contamination of mycobacterial growth indicator tubes with a modified antimicrobial combination; Chang CL et al.; Culture in the fluorimetric Mycobacteria Growth Indicator Tube (MGIT) treated with a combination of vancomycin, amphotericin B, and nalidixic acid (VAN) showed growth of most strains of 31 mycobacterial species with a less-than-1-day delay . The results were similar to those in the MGIT with polymyxin B, amphotericin B, nalidixic acid, trimethoprim, and azlocillin, but with respiratory specimens, the MGIT with VAN showed a lower contamination rate with no change in the detection rate or time.

J Clin Microbiol, 2002 Oct, 40(10), 3577 - 85
Pilot study of the genetic diversity of the pneumococcal nasopharyngeal flora among children attending day care centers; Sa-Leao R et al.; A pilot study was conducted to determine the genetic diversity of multiple colonies of pneumococci recovered from 37 nasopharyngeal (NP) samples of children . A total of 239 pneumococcal isolates (typically, six to eight colonies per sample) were typed by pulsed-field gel electrophoresis (PFGE) . In most NP samples (89%) the multiple colonies shared common PFGE types and serotypes . However, four samples were heterogeneous (samples A through D): each contained two strains with different PFGE types, antibiotypes, and serotypes . Samples A and B each contained one strain of a vaccine capsular type and another expressing a non-vaccine type (according to the currently licensed seven-valent conjugate vaccine) . In samples B and C the penicillin MIC for one strain was elevated and the other strain was susceptible . In each of the heterogeneous samples, one of the strains was a representative of an internationally disseminated clone . Samples A, C, and D contained strains which carried prophages that were inducible by mitomycin C and that could be visualized by electron microscopy . The comC gene allele (which encodes the competence-stimulating peptide) was the same in both strains found in each of samples A, B, and D . Carriage of multiple pneumococci with distinct properties should favor genetic exchange and provide a dynamic population structure for pneumococci in their ecological reservoir . Quantitative resolution of majority and minority components of the pneumococcal NP flora will be of importance for evaluation of the impact of intervention strategies such as vaccination or introduction of new antimicrobial agents.

Curr Opin Microbiol, 2002 Oct, 5(5), 489 - 95
Therapeutic challenges posed by bacterial bioterrorism threats; Gilligan PH; The events of the autumn of 2001 in the United States made it clear that the spectre of the use of microorganisms to intentionally harm humans is a reality . The current strategy to control disease outbreaks caused by the intentional release of bacteria is to use antimicrobial agents, both therapeutically and prophylactically . However, multidrug-resistant strains of bacterial bioterrorism agents occur naturally or have been bio-engineered, indicating how vulnerable this strategy is.

Curr Opin Microbiol, 2002 Oct, 5(5), 478 - 82
Toward rapid real-time molecular diagnostic to guide smart use of antimicrobials; Boissinot M et al.; Current microbial diagnostic is too slow to provide clinically useful information for the physician to prescribe, only when needed, the appropriate antibiotics . New advances in real-time PCR promise results that will come fast enough to revolutionise the practice of medicine . These novel, fully integrated devices, coupled with appropriate databases, will insure better management of patients, should reduce health costs, and could impact on the spread of antibiotic resistance.

Cutis, 2002 Sep, 70(3), 165 - 8
Fever and rash in a 3-year-old girl: Rocky Mountain spotted fever; Kaufmann JM et al.; Initial symptoms of Rocky Mountain spotted fever (RMSF), a tick-borne illness caused by Rickettsia rickettsii, are nonspecific and include headache, gastrointestinal disturbances, malaise, and myalgias, followed by fever and rash . The classic triad of fever, rash, and history of tick exposure is uncommon at presentation . Clinical manifestations of RMSF range from virtually asymptomatic to severe . Because of the potentially fatal outcome of RMSF, presumptive clinical diagnosis and empiric antimicrobial therapy can be critical . We present the case of a 3-year-old girl from New York State who presented with fever and rash.

Pediatr Infect Dis J, 2002 Sep, 21(9), 839 - 42
Change in epidemiology of health care-associated infections in a neonatal intensive care unit; Nambiar S et al.; BACKGROUND: Gram-negative rods (GNR) and species are important causes of health care-associated infections in neonatal intensive care units (NICUs) . In prior reports, Gram-positive cocci (GPC) have been identified as the most common pathogens causing nosocomial infections in NICUs . OBJECTIVE: To describe the epidemiology of health care-associated infections in a Level III NICU at a free-standing children's hospital . METHODS: All health care-associated infections in neonates from August 1996 to July 2001 were analyzed . Data were collected prospectively by standard surveillance protocols and nosocomial infection site definitions from the National Nosocomial Infection Surveillance system of the Centers for Disease Control and Prevention . RESULTS: During the 5-year study period, 665 pathogens caused 640 infections in the NICU . GNR were the most common pathogens isolated . Of the 665 pathogens 284 (43%) were GNR, followed by 223 (33.5%) GPC, 106 (16%) fungi and 52 (8%) others . spp . were the most common GNR isolated . Ceftazidime resistance was present in 56 of 81 (69%) isolates . Bloodstream and lower respiratory tract infections were the most common sites of infection . More than one-half of the pathogens (388 of 665) were isolated from neonates weighing < or =1000 g . CONCLUSIONS: There is a change in the epidemiology of health care-associated infections in our NICU with a predominance of GNR . This change can impact choice of antimicrobials for the empiric treatment of health care-associated infections in high risk neonates.

J Clin Oncol, 2002 Oct 1, 20(19), 3956 - 63
Prophylaxis of radiation-associated mucositis in conventionally treated patients with head and neck cancer: a double-blind, phase III, randomized, controlled trial evaluating the clinical efficacy of an antimicrobial lozenge using a validated mucositis scoring system; El-Sayed S et al.; PURPOSE: Mucositis occurs in almost all patients treated with radiotherapy for head and neck cancer . The aim of this multicenter, double-blind, prospective, randomized trial was to evaluate the clinical efficacy of an economically viable antimicrobial lozenge (bacitracin, clotrimazole, and gentamicin {BcoG}) in the alleviation of radiation-induced mucositis in patients with head and neck cancer . PATIENTS AND METHODS: One hundred thirty-seven eligible patients were randomized to treatment with either antimicrobial lozenge (69 patients) or placebo lozenge (68 patients) . The primary end point of the study was the time to development of severe mucositis from the start of radiotherapy . Secondary end points included severity and duration of mucositis, pain measurement, radiation therapy interruption, and quality of life . Mucositis was scored using a validated mucositis scoring system . RESULTS: Toxicity profiles were similar between the two arms of the study . The median time to development of severe mucositis from the start of radiotherapy was 3.61 weeks on BCoG and 3.96 weeks on placebo (P =.61) . There were no statistically significant differences between the arms in the extent of severe mucositis as measured by physician, in oral toxicities as recorded by patients, or in radiotherapy delays . CONCLUSION: This study was conducted on the basis of a pilot study that demonstrated the BCoG lozenge to be tolerable and microbiologically efficacious . A validated mucositis scoring system was used . However, in this group of patients treated with conventional radiotherapy, the lozenge did not impact significantly on the severity of mucositis . Whether such a lozenge would be beneficial in treatment situations where rate of severe mucositis is higher (ie, in patients treated with unconventional fractionation or with concomitant chemotherapy) is unknown.

Hum Reprod, 2002 Oct, 17(10), 2529 - 34
Isolation of human cationic antimicrobial protein-18 from seminal plasma and its association with prostasomes; Andersson E et al.; BACKGROUND: Cathelicidins are a group of antibiotic peptides with broad antimicrobial activity . They are considered to be an essential part of the innate immune system . The only known human cathelicidin is the human cationic antimicrobial protein (hCAP-18), from which the antimicrobial peptide LL-37 is released . METHODS AND RESULTS: In the present study, we purified hCAP-18 from seminal plasma and confirmed its identity by N-terminal amino acid sequencing . Gel filtration of seminal plasma showed the presence of hCAP-18 in both a low and a high molecular weight peak . Fractions corresponding to the high molecular form of hCAP-18 also contained dipeptidyl peptidase IV (CD26), a prostasome marker . This finding suggested that hCAP-18 found in fractions corresponding to high molecular weight molecules, is prostasome-associated . Flow cytometry confirmed the association of hCAP-18 with prostasomes and indicated that the molecule is surface bound . Western blot showed the presence of intact hCAP-18 in sperm, prostasomes and ultracentrifuged seminal plasma . CONCLUSIONS: These findings suggest that hCAP-18 may have an important role in antimicrobial defence during human reproduction . The binding of hCAP-18 to prostasomes indicates that protasomes can serve as a reservoir of this precursor of the antibiotic peptide LL-37.

Prev Vet Med, 2002 Sep 30, 55(2), 109 - 20
A survey of group-level antibiotic prescriptions in pig production in France; Chauvin C et al.; There is world-wide concern that antimicrobial use in food-producing animals might contribute to antimicrobial resistance both in animals and in humans . The relationship between antimicrobial use and resistance is likely to be related to frequency of prescription of the compound, dose and duration of treatment . Routine collection of that information is not possible today in France . A postal survey of French pig veterinarians therefore was carried out in October 2000.The questionnaire focused on the last antibiotic group-level prescription made; data were collected on the type of animals, presumptive clinical diagnosis and drug prescription . The list frame was defined using a veterinary yearbook . All practitioners with mention of pig in the treated species or with employment in intensive animal production were sent the questionnaire . Out of the 431 selected practitioners, 303 responded to the self-administered questionnaire (overall return proportion 70%) . 159 prescriptions were received and analysed (response proportion 37%) . Their repartitions according to indications and active compounds were summarised . Mean prescribed daily doses and mean treatment length were calculated for four antibiotics: amoxicillin, colistin, oxytetracycline, tylosin . Prescribed daily dose were in the range of dosages used and recommended in Europe . High variations were encountered in treatment length: from 3 to 21 days.

J Am Board Fam Pract, 2002 Sep-Oct, 15(5), 401 - 6
Human brucellosis; Sauret JM et al.; BACKGROUND: Human brucellosis has a serious medical impact worldwide, and its eradication poses major difficulties . Although human brucellosis is relatively rare in the United States (approximately 100 cases per year), there is concern that this disease is largely underdiagnosed and underreported . Additionally, immigrants from endemic areas are arriving to this country, and Brucella species are considered to be biologic agents for terrorism . Human brucellosis affects all age-groups, and family physicians are not well versed in recognizing and treating this potentially life-threatening condition . METHODS: A literature review from 1975 to 2001 was performed using the key words "human brucellosis," "zoonosis," and "bioterrorism." RESULTS AND CONCLUSIONS: Appropriate antimicrobial therapy and duration of treatment of human brucellosis will reduce morbidity, prevent complications, and diminish relapses . Because of the nonspecific symptoms and rarity of human brucellosis in the United States, family physicians must acquire a detailed dietary and occupational history to diagnose the disease promptly . Family physicians must assume a responsible role in reporting this disease, as well as be aware of persons at high-risk for this disease and the potential sources of infection.

Glob Issues, 1996 Nov, 1(17), 27 - 30
Plan of action . Information; Leduc JW; PIP: This article provides information on WHO inverted question marks strategic plan of action to aid countries around the world in detecting and controlling emerging infectious diseases . Activities are conducted through an organizational structure that ensures cost-sharing among all the 190 member states of WHO . Four major goals incorporating specific tasks are suggested: 1) the strengthening of global surveillance of infectious diseases through WHO collaborating centers; 2) the rebuilding of the international infrastructure to recognize, report, and respond to emerging and resurgent infectious diseases through laboratory and communication improvement 3) the fostering of applied research through greater practical use of the biotechnological revolution, and 4) the enhancement of the international capacity for infectious disease prevention and control through defined and practical public health steps . To implement this program, a workshop has been conducted and the WHONET program for laboratories has been introduced . In addition, clear guidance will be needed on the question of when to make changes in the antimicrobials recommended for specific diseases . The WHO strategy aims to enhance the capacity of local and national public health laboratories, to foster applied research to address practical problems, and to improve infectious disease prevention and control .

Glob Issues, 1996 Nov, 1(17), 20 - 6
The return of infectious disease; Garrett L; PIP: This article presents the history of efforts to control the spread of infectious disease from the post-antibiotic era to 1995 . Since World War II, public health strategy has focused on the eradication of microbes using powerful medical weaponry . The goal was to push humanity through a inverted question markhealth transition, inverted question mark leaving the age of infectious disease permanently behind . But recent developments have shown that this grandiose optimism was premature . As people move across international borders, unwanted microbial hitch-hikers tag along, as happened in the case of Ebola . In large cities, sex industries arise and multiple-partner sex becomes more common, prompting rapid increases in sexually transmitted disease . Moreover, the practice of sharing syringes is a ready vehicle for the transmission of microbes while unhygienic health facilities become centers for the dissemination of disease rather than its control . Black market access to antimicrobials has led to overuse or outright misuse of the drugs and the emergence of resistant bacteria and parasites . Consequently, old organisms, aided by mankind's misuse of disinfectants and drugs, may take on new and more lethal forms . Even when allegations of biological warfare are not flying, it is often difficult to obtain accurate information about outbreaks of disease, particularly in countries dependent on foreign investment or tourism or both . Unfortunately, only 6 laboratories in the world meet security and safety standards that would make them suitable sites for research on the world's deadliest microbes . National security warrants bolder steps involving focusing not only on microbes directly dangerous to humans, but also on those that could pose major threats to crops or livestock . Unfortunately, economic crises have led to budget cuts, particularly in health care, at all levels of government in the US .

Glob Issues, 1996 Nov, 1(17), 10 - 3
New drugs, new vaccines, new diseases . An interview with Dr . Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID); Fuller J; PIP: This document presents an interview with Dr . Anthony Fauci on the development of a new generation of vaccines to prevent and possibly eradicate a legion of deadly diseases ranging from tuberculosis to AIDS . Infections that have caused major devastations in the world today include tuberculosis, malaria, schistosomiasis, filariasis, pneumococcal pneumonia, influenza, AIDS, and Ebola . Agencies should be making sure that the basic research base in microbiology, immunology, antimicrobials, and vaccinology is at the very highest level . The integration of research efforts between countries depends on collaboration between the investigators of home countries with foreign investigators . Among new developments in vaccinology are an acellular pertussis vaccine for pertussis/whooping cough (an extremely contagious disease that causes death), DNA immunization (a new technique applicable to all types of diseases), and transgenic plants for immunization against hepatitis, pertussis, and polio . As of now, AIDS in Western countries has declined, while in Africa and Asia its spread has accelerated . Combination therapy for AIDS has had a profound impact on the level of the virus in the body; however, the treatment is still vague . The good news with regard to AIDS is that education is having an impact; this is exemplified by the situation in Thailand, where the government together with nongovernmental organizations and the military has begun a crash education campaign regarding prostitutes and the use of condoms . Progress is being made in the search for better vaccine candidates . AIDS-like epidemics involving new diseases are bound to emerge at some future point, though, given the long-term historical trend .

AIDS Anal Afr, 1997 Dec, 7(6), 10 - 2
Traditional healers, traditional hospitals and HIV / AIDS: a case study in KwaZulu-Natal; Munk K; PIP: Most people in South Africa with sexually transmitted diseases (STDs) first seek help from traditional healers (THs) . Since people with STDs are at greater risk of contracting and transmitting HIV than are those without STDs, THs comprise a good target group for HIV/AIDS education . A study was funded by the Scandinavian Institute of African Studies in which THs in Amatikulu, Ulundi, Nqutu, Durban, Pietermaritzburg, and other adjacent areas were surveyed about their HIV/AIDS-related knowledge, beliefs, and practices . Most AIDS-educated THs now acknowledge that AIDS exists and are taking protective measures, such as using disposable razor blades to avoid infecting patients with HIV during traditional treatments . However, many THs believe that AIDS has evolved from older, mystical diseases which only THs can cure . Traditional hospitals have proliferated in which HIV/AIDS patients seek treatment from what is more typically perceived by the THs and the general public as morbidity due to witchcraft and other spiritual causes . While each TH has his own blend of medicine against AIDS, the basic ingredients are common among all concoctions . One basic, common ingredient is a plant with documented anti-viral and anti-AIDS properties . The plant, however, is highly toxic and will itself kill the patient after a few days treatment . Another plant has considerable virucidal activity against several RNA and DNA attacking viruses . The traditional medicine was also found to contain plants which have traditionally been used against headaches, respiratory problems, chest and abdominal pains, colds, and dysentery . It also has documented antifungal and antimicrobial effects against common opportunistic infections, as well as being a sedative and painkiller . Traditional treatments against AIDS may help to improve patients' well-being .

Contracept Technol Update, 1997 Dec, 18(12), 152 - 3
Repeating ECPs: what are the recommendations? Ask the experts; AUVDT recommendations for management of gonorrhoea and genital ulcers in Africa; PIP: The African Union Against Venereal Diseases and Treponematoses (AUVDT), inaugurated in 1979, held its 3rd biannual conference in Nairobi in March 1983 with local participants and participants from 15 English and French speaking countries as well as from Europe, USA and Canada . The conference was devoted to high level training and discussion, workshops on genital ulcer diseases (GUD) and scientific sessions during which many papers were read and discussed . Resolutions and recommendations were made concerning STD in Africa and later passed on to relevant health authorities for necessary action . It was agreed that all African governments who have not already done so should set their own STD control committees as soon as possible . The establishment of microbiological laboratories was strongly urged as well as specific training of health workers . It was felt that gonorrhea and genital ulcer disease were the most frequent sexually transmitted diseases and so management recommendations were made . The efficacy of current regimens using penicillin is increasingly dropping and trimethoprim sulfametrole should be substituted . Failure rates of over 10% would indicate the need to review the accepted regimen . The ideal drug should be effective, orally administered as a single dose, whithout harmful side-effects and preferably not masking syphilis . National programs can purchase drugs through WHO's and UNICEF's purchasing channels at very low prices and governments should utilize these channels . Monitoring of antimicrobial sensitivities should be encouraged and assistance should be sought from university departments of microbiology whenever possible . Genital Ulcer Disease (GUD) is an important public health problem in Africa . Chancroid is the most frequently diagnosed and etiologically proven GUD in eastern, central and southern Africa, accounting for 3-60% of GUD cases . Syphilis, herpetic ulceration, lymphogranuloma venereum and donovanosis are other GUDs found in Africa . Consideration of efficacy, availability, and compliance should be given to treatment . Recent studies have shown that single doses or short-term therapy regimens are as efficient for both ulcers and bubos . Syphilis may be treated with benzathine penicillin im or aqueous procaine penicillin G . No current curative therapy is available for herpes . Local management includes keeping lesions clean and dry; symptomatic treatment involves giving analgesics .

Am J Kidney Dis . 2002 Oct;40(4):E17.
Ochrobactrum anthropi bloodstream infection complicating hemodialysis; Daxboeck F et al.; We report two cases of bacteremia with Ochrobactrum anthropi in patients on hemodialysis . Bacteremia became clinically manifest by recurrent febrile episodes during and after dialysis . In one patient, bacteremia persisted after ciprofloxacin therapy and was cleared only by removal of the dialysis catheter and a 3-week course of gentamicin . The second patient remained intermittently bacteremic for more than 3 months, although the dialysis catheter had been replaced . A MEDLINE search revealed only one previous report of O anthropi bloodstream infection in a patient on hemodialysis, but the pathogen is recognized increasingly as a causative agent of human disease, most importantly in debilitated patients . In contrast to most previously described cases, the two patients reported here had no malignancies and were not on immunosuppressive therapy . Treatment of O anthropi infection is challenging because of widespread and unpredictable resistance to antimicrobial agents and discrepancies between in vitro susceptibility and in vivo efficacy .

Am J Kidney Dis, 2002 Oct, 40(4), 832 - 6
Infectious complications of old nonfunctioning arteriovenous grafts in renal transplant recipients: a case series; Nassar GM et al.; Occult infection of old nonfunctioning arteriovenous grafts (AVGs) is frequent among hemodialysis patients . It is a risk factor for bacteremia and serious AVG-related infection . Immunocompromised patients are at increased risk of dissemination of occult AVG infection . We present a series of five renal transplant recipients who developed acute life-threatening infections that originated in their old nonfunctioning AVGs . Their presenting symptoms were noticeably varied . In two patients, infection of the AVG was characterized by local physical signs of infection around the AVG . In three patients, no physical signs of AVG infection were detected by physical examination . Among these, two presented with bacteremia, and one presented with failure to thrive . Detection of AVG infection in the absence of local signs of infection requires a high index of suspicion . Surgical resection and antimicrobial treatment led to a complete cure in four of these patients . One patient developed recurrent bacterial endocarditis and died . Old nonfunctioning AVGs are potential sources of serious infection in renal transplant recipients . Renal transplant recipients with old nonfunctioning AVGs who present with unexplained bacteremia, fever of unknown origin, or failure to thrive should be investigated for occult AVG infection . Screening for occult infection of the old nonfunctioning AVG may be considered before kidney transplantation, especially if the candidate gives a history of previous bacteremia or fever of unknown origin .

Biophys J, 2002 Oct, 83(4), 2074 - 83
Interaction between beta-Purothionin and dimyristoylphosphatidylglycerol: a (31)P-NMR and infrared spectroscopic study; Richard JA et al.; The interaction of beta-purothionin, a small basic and antimicrobial protein from the endosperm of wheat seeds, with multilamellar vesicles of dimyristoylphosphatidylglycerol (DMPG) was investigated by (31)P solid-state NMR and infrared spectroscopy . NMR was used to study the organization and dynamics of DMPG in the absence and presence of beta-purothionin . The results indicate that beta-purothionin does not induce the formation of nonlamellar phases in DMPG . Two-dimensional exchange spectroscopy shows that beta-purothionin decreases the lateral diffusion of DMPG in the fluid phase . Infrared spectroscopy was used to investigate the perturbations, induced by beta-purothionin, of the polar and nonpolar regions of the phospholipid bilayers . At low concentration of beta-purothionin, the temperature of the gel-to-fluid phase transition of DMPG increases from 24 degrees C to ~33 degrees C, in agreement with the formation of electrostatic interactions between the cationic protein and the anionic phospholipid . At higher protein concentration, the lipid transition is slightly shifted toward lower temperature and a second transition is observed below 20 degrees C, suggesting an insertion of the protein in the hydrophobic core of the lipid bilayer . The results also suggest that the presence of beta-purothionin significantly modifies the lipid packing at the surface of the bilayer to increase the accessibility of water molecules in the interfacial region . Finally, orientation measurements indicate that the alpha-helices and the beta-sheet of beta-purothionin have tilt angles of ~60 degrees and 30 degrees, respectively, relative to the normal of the ATR crystal.

Appl Environ Microbiol, 2002 Oct, 68(10), 4996 - 5004
Bcmfs1, a novel major facilitator superfamily transporter from Botrytis cinerea, provides tolerance towards the natural toxic compounds camptothecin and cercosporin and towards fungicides; Hayashi K et al.; Bcmfs1, a novel major facilitator superfamily gene from Botrytis cinerea, was cloned, and replacement and overexpression mutants were constructed to study its function . Replacement mutants showed increased sensitivity to the natural toxic compounds camptothecin and cercosporin, produced by the plant Camptotheca acuminata and the plant pathogenic fungus Cercospora kikuchii, respectively . Overexpression mutants displayed decreased sensitivity to these compounds and to structurally unrelated fungicides, such as sterol demethylation inhibitors (DMIs) . A double-replacement mutant of Bcmfs1 and the ATP-binding cassette (ABC) transporter gene BcatrD was more sensitive to DMI fungicides than a single-replacement mutant of BcatrD, known to encode an important ABC transporter of DMIs . The sensitivity of the wild-type strain and mutants to DMI fungicides correlated with Bcmfs1 expression levels and with the initial accumulation of oxpoconazole by germlings of these isolates . The results indicate that Bcmfs1 is a major facilitator superfamily multidrug transporter involved in protection against natural toxins and fungicides and has a substrate specificity that overlaps with the ABC transporter BcatrD . Bcmfs1 may be involved in protection of B . cinerea against plant defense compounds during the pathogenic phase of growth on host plants and against fungitoxic antimicrobial metabolites during its saprophytic phase of growth.

Appl Environ Microbiol, 2002 Oct, 68(10), 4847 - 52
Prevalence and characterization of non-O157 Shiga toxin-producing Escherichia coli on carcasses in commercial beef cattle processing plants; Arthur TM et al.; Beef carcass sponge samples collected from July to August 1999 at four large processing plants in the United States were surveyed for the presence of non-O157 Shiga toxin-producing Escherichia coli (STEC) . Twenty-eight (93%) of 30 single-source lots surveyed included at least one sample containing non-O157 STEC . Of 334 carcasses sampled prior to evisceration, 180 (54%) were found to harbor non-O157 STEC . Non-O157 STEC isolates were also recovered from 27 (8%) of 326 carcasses sampled after the application of antimicrobial interventions . Altogether, 361 non-O157 STEC isolates, comprising 41 different O serogroups, were recovered . O serogroups that previously have been associated with human disease accounted for 178 (49%) of 361 isolates . Although 40 isolates (11%) carried a combination of virulence factor genes (enterohemorrhagic E . coli hlyA, eae, and at least one stx gene) frequently associated with STEC strains causing severe human disease, only 12 of these isolates also belonged to an O serogroup previously associated with human disease . Combining previously reported data on O157-positive samples (R . O . Elder, J . E . Keen, G . R . Siragusa, G . A . Barkocy-Gallagher, M . Koohmaraie, and W . W . Laegreid, Proc . Natl . Acad . Sci . USA 97:2999-3003, 2000) with these data regarding non-O157-positive samples indicated total STEC prevalences of 72 and 10% in preevisceration and postprocessing beef carcass samples, respectively, showing that the interventions used by the beef-processing industry effected a sevenfold reduction in carcass contamination by STEC.

Appl Environ Microbiol, 2002 Oct, 68(10), 4803 - 8
Replacement of trifluoroacetic acid with HCl in the hydrophobic purification steps of pediocin PA-1: a structural effect; Gaussier H et al.; Trifluoroacetic acid (TFA) is a purification contaminant associated with pediocin PA-1 that interferes with Fourier transform infrared spectroscopy structural analysis . As revealed by circular dichroism, its presence affects the structural folding of pediocin . Consequently, we propose a new pediocin PA-1 purification procedure using HCl instead of TFA in all of the hydrophobic steps . This procedural change does not affect the purification yield or the amount of pediocin PA-1 purified . Furthermore, removing HCl, as opposed to TFA, after purification is an easier procedure to carry out . In fact, the removal of TFA requires more experimentation and results in protein loss . Thus, HCl is a good alternative to TFA in pediocin PA-1 purification and can be extended to the purification of other proteins . We also show that TFA-induced structural modifications do not significantly affect the antimicrobial activity of pediocin PA-1.

Toxicology, 2002 Nov 15, 180(2), 195 - 207
Dietary vitamin E and selenium and toxicity of nitrite and nitrate; Chow CK et al.; Nitrites and nitrates are important antimicrobial and flavoring/coloring agents in meat and fish products . However, nitrites and nitrates may cause methemoglobinemia and other illness, and may react with certain amines to form carcinogenic nitrosamines . The nutritional status of vitamin E and selenium has long been associated with nitrite and nitrate toxicity, although the mechanism involved is not yet clear . Information available recently shows that nitrites and nitrates are both oxidation products and ready sources of nitric oxide (NO*), that NO* reacts rapidly with superoxide to form highly reactive peroxynitrite (ONOO-), and that vitamin E may mediate the generation and availability of superoxide and NO* . Increased formation of ONOO- resulting from nitrite treatment and low intake of vitamin E and selenium may thus be the critical event leading to tissue damage and animal mortality observed previously . The protection against the adverse effects of nitrites/nitrates by vitamin E is attributed to its ability to reduce ONOO- formation, while selenium exerts its protective effects via seleno-enzymes/compounds, which reduce ONOO- formed.

Biomaterials, 2002 Dec, 23(23), 4449 - 58
Poly(epsilon-caprolactone) and poly(epsilon-caprolactone)-polyvinylpyrrolidone-iodine blends as ureteral biomaterials: characterisation of mechanical and surface properties, degradation and resistance to encrustation in vitro; Jones DS et al.; This study describes the physicochemical properties and in vitro resistance to encrustation of solvent cast films composed of either poly(epsilon-caprolactone) (PCL), prepared using different ratios of high (50,000) to low (4000) (molecular weight) m.wt., or blends of PCL and the polymeric antimicrobial complex, poly(vinylpyrrolidone)-iodine (PVP-I) . The incorporation of PVP-I offered antimicrobial activity to the biomaterials . Films were characterised in terms of mechanical (tensile analysis, dynamic mechanical thermal analysis) and surface properties (dynamic contact angle analysis, scanning electron microscopy), whereas degradation (at 37 degrees C in PBS at pH 7.4) was determined gravimetrically . The resistance of the films to encrustation was evaluated using an in vitro encrustation model . Reductions in the ratio of high:low-m.wt . PCL significantly reduced the ultimate tensile strength, % elongation at break and the advancing contact angle of the films . These effects were attributed to alterations in the amorphous content and the more hydrophilic nature of the films . Conversely, there were no alterations in Young's modulus, the viscoelastic properties and glass-transition temperature . Incorporation of PVP-I did not affect the mechanical or rheological properties of the films, indicative of a limited interaction between the two polymers in the solid state . Manipulation of the high:low m.wt . ratio of PCL significantly altered the degradation of the films, most notably following longer immersion periods, and resistance to encrustation . Accordingly, maximum degradation and resistance to encrustation was observed with the biomaterial composed of 40:60 high:low m.wt . ratios of PCL; however, the mechanical properties of this system were considered inappropriate for clinical application . Films composed of either 50:50 or 60:40 ratio of high:low m.wt . PCL offered an appropriate compromise between physicochemical properties and resistance to encrustation . This study has highlighted the important usefulness of degradable polymer systems as ureteral biomaterials.

Perinat Care, 1978 Sep, 2(8), 19 - 25
Drugs in breast milk; Hervada AR et al.; PIP: The amount of drug excreted into breast milk is dependent upon the lipid solubility of the medication, the mechanism of transport, the degree of ionization, and change in plasma pH . The higher the lipid solubility, the greater the concentration in human milk . The majority of drugs are transported into mammary blood capillaries by passive diffusion . The rest are transported by reverse pinocytosis . Once the drug has entered the epithelial cells of breast tissue, the drug molecules are excreted into the human milk by active transport, passive diffusion, or apocrine secretion . The amount of free (active) drug available for transport depends on the degree of protein binding the plasma pH . Another factor affecting excretion of drugs is the time when breast feeding occurs . In the 1st few days of life, when colostrum is present, water-soluble drugs pass through the breast more easily than afterwards when milk is produced . Then lipid-soluble drugs cross in higher concentrations . The effect on nursing infants is dependent on the amount excreted into the milk, the total amount absorbed by the infant, and the toxicity of the drug . The use of the following drugs in breast feeding mothers is reviewed: anticoagulants, antihypertensives and diuretics, antimicrobials, drugs affecting the central nervous system (alcohol, chloral hydrate, meprobamate, lithium, and aspirin), marijuana, other drugs (antihistamines, atropine, ergot alkaloids, laxatives, nicotine, iodides, propylthiouracil, theophylline), hormones (insulin, thyroxine, and oral contraceptives), and radiopharmaceuticals .

Rev Gastroenterol Peru, 1997, 17 Suppl 1, 100 - 106
{TREATMENT AND PREVENTION OF BACTERIAL AND MYCOTICINFECTION IN ACUTE LIVER FAILURE}; Rolando N DRA; Patients with acute liver failure (ALF) have increased susceptibility to nosocomial and opportunistic infections as a result of various immune defects and the need for invasive monitoring procedures . Bacteriologically proven infection was recorded in up to 80% of these patients and, fungal infection in 32% . Clinical signs such as high temperature and high WBC are absent in 30% of the cases . These patients are prone to develop multiple and concomitant infections . The most common infection in ALF patients is pneumonia, accounting for 50% of episodes . These infections occurs early in the course of the disease . Selective parenteral and enteral antisepsis regimens (SPEAR) were evaluated in prospective controlled studies . Although in a initial study there was an overall reduction of infection episodes . A recent study has shown that the administration of oral non-absorbable antibacterials did not confer any additional benefit over prophylactic systemic antibacterials . In conclusion it is clear that antimicrobial prophylaxis does dramatically reduce the risk of infectious complications and contribute to the improvement in mortality from ALF.

Mutat Res, 2002 Sep 26, 520(1-2), 133 - 9
In vivo photochemical micronucleus induction due to certain quinolone antimicrobial agents in the skin of hairless mice; Itoh S et al.; The skin micronucleus test combined with irradiation due to a sunlight simulator having a spectrum almost identical to solar irradiation was used as a novel in vivo testing method for detecting or comparing the photochemical chromosome damage of quinolone antibacterial agents (quinolones) . Eight-week-old male SKH1 hairless mice were orally administered once lomefloxacin (LFLX), a strong in vitro photochemical clastogen, at 25 or 50 mg/kg, followed by light irradiation at 7.9-9.4J/cm2 of ultraviolet A (UVA) . Animals were killed on Days 2, 3, 4, 5 or 8 (the dosing day was designated as Day 1), and the incidence of micronucleus in the epidermis was determined . As results, LFLX at either dose caused significant increases in the micronucleus frequency, which peaked on Day 4 . These changes tended to return to the control level on Day 8 . Then, the micronucleus induction potential of the quinolone derivatives levofloxacin (LVFX) and clinafloxacin (CLFX) at 10, 20 or 40 mg/kg was assessed on Day 4 under the same experimental conditions as for LFLX . Although LVFX was negative even at 40 mg/kg, CFLX dose-dependently induced significant increases in micronucleus frequency at all doses . The correlation of magnitude among the three quinolones in the skin micronucleus test with light irradiation was similar to that in our previous in vitro photochemical clastogenicity study . No significant increase in micronucleus frequency was observed in any of three quinolones employed without light irradiation . In conclusion, the experimental method presented here would be a useful tool for detecting in vivo photochemical chromosome damage and for research on photochemical carcinogenesis of chemicals.

Paediatr Respir Rev, 2002 Jun, 3(2), 115 - 9
Airway mucus in cystic fibrosis; Puchelle E et al.; Defective expression and function of the cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) airway epithelial cells are associated with airway mucus hypersecretion, inflammation and infection that begin early in life and lead, at an advanced stage of the disease, to severe airway obstruction with hyperviscous and adhesive airway mucus . Whether the abnormalities of airway mucus are already present at birth before infection is debatable . In CF, the impaired Cl(-) and HCO(3)(-) secretion associated with increased epithelial Na(+) absorption results in dehydration of airway mucus, decreased antimicrobial functions and impaired mucociliary clearance . Alterations in antibacterial peptide function, as well as the increased mucin expression and secretion (MUC 5AC and MUC 5B), are important biochemical factors responsible for the propensity for infection in CF airways . Alterations in mucin and lipid composition induce an increased viscosity and adhesiveness to the airways that can affect the mucociliary and cough transport . The increased content of pro-inflammation cytokines such as interleukin-8 (IL-8) suggest that, before infection, airway inflammation occurs very early in CF . The development of non-invasive techniques and humanised animal models (xenografts) represents a major opportunity to identify early abnormalities in CF airway mucus.

J Biochem Mol Biol, 2002 May 31, 35(3), 291 - 6
Role of amino acid residues within the disulfide loop of thanatin, a potent antibiotic peptide; Lee MK et al.; Thanatin, a 21-residue peptide, is an inducible insect peptide with a broad range of activity against bacteria and fungi . It has a C-terminal disulfide loop, like the frog skin secretion antimicrobial peptides of the brevinin family . In this study, we tried to find the effect of a number of amino acids between the disulfide bond . Thanatin showed stronger antibacterial activity to Gram negative bacteria than other mutants, except Th1; whereas, the mutant peptides with deletion had higher activity to Gram positive bacteria than thanatin . An increase in the number of amino acid(s) using the alanine residue decreased the antibacterial activity in all of the bacteria . Th1 with deletion of threonine at position 15 (Thr(1)(2)) showed similar antibacterial activity against Gram-negative bacteria, but had higher activity against the Gram positive bacteria . In order to study the structure-function relationship, we measured liposome disruption by the peptides and CD spectra of the peptides . Th1 also showed the highest liposome leaking activity and alpha-helical propensity in the sodium dodecyl sulfate solution, compared with other peptides . Liposome disruption activity was closely correlated with the anti-Gram positive bacterial activity . All of the peptides showed no hemolytic activity . Th1 was considered to be useful as an antimicrobial peptide with broad spectrum without toxicity

J Clin Periodontol, 2002 Jun, 29(6), 540 - 50
Local antimicrobial therapy after initial periodontal treatment; Salvi GE et al.; AIM: The aim of this single-blind, randomized, parallel-designed clinical trial (RCT) was to evaluate the clinical and microbiological effects of three sustained-release biodegradable polymers delivered into periodontal pockets following initial periodontal therapy . METHODS: Forty-seven patients (28 females and 19 males) with a mean age of 51 years (range 29-71) underwent a periodontal examination at baseline (i.e . Week 0) and after 18 weeks . This included the assessment of the Plaque Index (PlI), Bleeding on Probing (BOP), Pocket Probing Depths (PPD) and Probing Attachment Levels (PAL) at six sites per tooth . Two to 4 months prior to baseline, all subjects had received initial periodontal therapy including motivation, instruction in oral hygiene practices and full-mouth scaling and root planing . At the treatment appointment (i.e . Week 2), the patients were randomly assigned to receive either Atridox trade mark, Elyzol Dental Gel or PerioChip at all residual periodontal pockets with a probing depth >/= 5 mm and concomitant BOP . In accordance with the manufacturer's recommendations, Elyzol Dental Gel was applied for a second time 7 days later . In addition to the clinical evaluation, subgingival microbiological samples were collected prior to treatment (i.e . Week 2) and at Weeks 4 and 18 . Analysis of variance/covariance was used to evaluate changes from baseline to Week 18 for the clinical parameters . RESULTS: Between the baseline and 18-week examinations, subjects treated with Atridox showed a significantly greater gain in mean PAL of 0.33 mm +/- 0.09 (SD) than subjects treated with Elyzol Dental Gel {0.03 mm +/- 0.09 (SD)}(p = 0.03) . However, the gain in PAL of 0.16 mm +/- 0.10 (SD) found after PerioChip application did not differ significantly from that obtained following the application of Atridox(p = 0.27) . Of the sites treated with Atridox, 42% gained >/= 1 mm PAL and 9% >/= 2 mm PAL as opposed to the sites treated with Elyzol Dental Gel, in which 34% gained >/= 1 mm PAL and 8% gained >/= 2 mm PAL . Of the sites treated with PerioChip, 36% gained >/= 1 mm and 6% gained >/= 2 mm PAL following a completed initial periodontal therapy . CONCLUSIONS: The application of the three biodegradable sustained release devices tested following initial periodontal therapy resulted in a statistically significant gain in mean PAL for AtridoxTM and a significant reduction in PPD for all three devices during the study period . Furthermore, when sites treated with Atridox were compared with sites treated with Elyzol, a significant difference in mean PAL gain (0.3 mm) was observed.

AIDS Wkly . 2000 Sep 18;:20.
U.S . trials on contraceptive gel begin via the Internet; Training activities at ICDDR et al.; PIP: This article summarizes the training activities conducted at the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) . A course on the management of severely malnourished children was held on March 2-24, 1999, and was attended by participants from Bhutan and Bangladesh . Participants underwent hands-on training, lecture sessions, and were taught on how to prepare low-cost diet for use in the community-based nutritional rehabilitation programs . Another course on child survival interventions was conducted on February 7-18, 1999; 12 paramedics were trained . The center also offered fellowship training for member countries of the South Asian Association for Regional Cooperation in March 1999 . Moreover, ICDDR,B organized one international and two national training courses on the clinical management of diarrheal diseases . In addition, six participants attended a four-week course on emerging and re-emerging pathogens from Japan . Lastly, the ICDDR,B provided training for antimicrobial resistance surveillance in Nepal, which was participated by 13 selected microbiologists and technologists .

Glimpse, 1999 Mar-Jun, 21(1-2), 3 - 4
ICDDR,B's expanding agenda in emerging and re-emerging infectious diseases; International Centre for Diarrhoeal Disease Research et al.; PIP: The International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) is expanding its agenda in emerging and re-emerging infectious diseases (ERIDs) . ERIDs are public health threats that are caused by a number of factors such as environmental changes, rapid population growth, migration of population, and microbes adaptation to modern antibiotics . US Aid for International Development (USAID) has designed a cost-effective strategy against the threat of infectious diseases . Their program focuses on capacity building and strengthening the health systems of developing countries . Moreover, USAID supports the ICDDR,B by providing funds and recognizing it as one of the institutions involved in their global initiative concerning ERIDs . Future ERID funding would be for antimicrobial resistance, reproductive tract infection, tuberculosis and arbour viruses .

Popul Bull, 1997 Jul, 52(2), 1 - 52
Infectious diseases -- new and ancient threats to world health; Olshansky SJ et al.; PIP: Infectious and parasitic diseases remain a leading cause of death and disability in developing countries and are re-emerging as a serious health problem in developed countries . Outbreaks of Ebola, dengue hemorrhagic fever, cholera, and bubonic plague have occurred in low-income countries and multidrug-resistant organisms have surfaced throughout the world . Since 1973, over 28 new disease-causing microbes have been identified . This issue of "Population Bulletin" analyzes the impact of factors such as population growth, urbanization, migration, poverty, travel, agricultural practices, climate changes, natural disasters, and medical technology on the resurgence of infectious and parasitic diseases as well as the influence of diseases such as AIDS on population dynamics and socioeconomic development . Most of these diseases could be prevented, cured, or eradicated with known public health measures . National governments can help reduce poverty, step up immunization programs, and lessen the chances of introducing new diseases . Nongovernmental organizations can disseminate preventive knowledge and monitor disease outbreaks . The medical profession can strengthen infection control precautions and institute surveillance of the use of antibiotics and other antimicrobial agents . Since the geographic isolation that used to contain disease outbreaks has been replaced by permeable international borders, the campaign against infectious and parasitic diseases must be global .

Diagn Afr . 1995 May;:viii-
Research and the development of microbiological services: an example from Nigeria; Obunge O et al.; PIP: A research study funded by the UK Overseas Development Administration provided impetus to the development of laboratory services in Port Harcourt, Rivers State, Nigeria . The Microbiological Laboratory of the University of Port Hartcourt serves a hospital with 500-600 beds and an outpatient department . However, inadequate space, little quality control, lack of interest in medical microbiology by clinicians, and low priority for call on hospital resources limited the efficiency of the laboratory . In 1992 a community-based research study focused on reproductive tract infections (RTIs) and sexually transmitted diseases (STDs) in order to determine baseline data on RTIs and induced abortion among women . A number of activities were undertaken to improve laboratory facilities: the bacteriology section was upgraded, a microbiologist attended a preparatory course on laboratory management of RTIs/STDs at the University of Liverpool, the organization of the laboratory was streamlined and equipment was supplied to deal with microscopic examination of endocervical smears, culture of gonococcal specimens in selective media, and serological tests for syphilis, chlamydia, and HIV . Key factors in developing a central laboratory meant that technical staff maintained routine hospital services; the laboratory developed an ability to deal with routine problems, such as fluctuating power supplies; and regular meetings with clinicians were extended to routine hospital services to ensure that samples were taken correctly . As a consequence of the research studies the Department of Microbiology now acts a coordinating center for the development of peripheral diagnostic services for RTI/STDs . Activities underway include the upgrading of an STD clinic within the hospital; select health centers are to be equipped to provide simple diagnostic services; and a field laboratory is being set up in a rural health center lacking electricity and piped water . The study provided for the first time information on RTIs, antimicrobial resistance, and populations at risk .

Glob AIDSnews, 1993, (4), 9 - 10
Experts call for urgent development of microbicides; Lange J; PIP: The World Health Organization's Global Program on AIDS's (GPA) Chief of clinical research and development reports on the rationale and recommendations of an international meeting in which the GPA called for the urgent development of antimicrobial products capable of preventing HIV infection when inserted in the vagina . The meeting took place in Geneva, November 11-13, 1993 . It was attended by more than 70 people and organizations including scientists, drug company representatives, research funding agencies, drug regulatory authorities, nongovernmental organizations, and women's health advocacy groups which reviewed data on barrier methods against the sexual transmission of HIV and laid out the necessary steps to develop the microbicides . Participants at the meeting recommended studying the safety and efficacy of existing spermicides with antimicrobial activity in preventing HIV transmission; developing new products for intravaginal use capable of preventing the sexual transmission of HIV; researching nonirritating compounds; conducting animal studies; launching phase I-III clinical trials; fostering collaboration in research and other activities; and continuing to promote condom use as central to the prevention of HIV and other STDs .

Perinatol Reprod Hum, 1990 Jan-Mar, 4(1), 32 - 8
{Antimicrobial and immunological properties of human milk}; Castellanos-cruz RC et al.; PIP: Human milk is the ideal food for newborns because of its content of nutrients, immunoprotective factors and their associated antimicrobic properties . Milk is unique because it is made up of cellular components (non-soluble) and soluble components that include 3 types of organic nutrients: 1) proteins which protect the system; 2) lipids which contain antiviral and antiprotozoan properties; and 3) carbohydrates which modify bacterial growth and prevent the adhesion of microorganisms to the epithelial cells along the respiratory and gastrointestinal tracts . These 3 antibacterial, antiviral and antiparasitic components help to reduce incidence of morbidity and mortality due to infectious diseases . author's modified

Network . 1988 Winter;9(2):4.
AIDS: the impact of other sexually transmitted diseases; Piot P; PIP: Due to the fact that an overwhelming majority of patients with Acquired Immune Deficiency Syndrome (AIDS) acquired the infection through sexual contact, it comes as no surprise that the same populations who are at increased risk for various sexually transmitted diseases (STDs) also experience high rates of human immunodeficiency virus (HIV) infection . There is increasing evidence that some STDs may enhance the efficiency of sexual transmissions of HIV . Genital ulcers are among the genital syndromes most convincingly implicated as cofactors for potential sexual transmission of HIV . Several cross-sectional studies among heterosexual men and women in Africa originally revealed that both a history of and the presence of genital ulcers was correlated with HIV infection . These findings are complemented by those of a study of HIV infection in homosexual men in the US . This study reports a strong association between HIV antibodies and a history of syphilis and of oral or anogenital herpes . The association between HIV antibodies and genital ulcers remained after controlling for the level of sexual activity . A prospective study conducted in Nairobi provided evidence that genital ulcers, particularly chancroid, increase the susceptibility to HIV infection among women . Another prospective study in Nairobi of men who acquired an STD from a group of prostitutes known to have a very high rate of HIV infection found that men who acquired genital ulcers had 5 times the rate of HIV infection as men who acquired urethritis . In the same cohort of prostitutes, "chlamydia trachomatis" infection also increased the risk of acquisition of HIV . Effective and inexpensive antimicrobial therapy is available for most bacterial STDs . Programs for the diagnosis and treatment of STDs should be integrated into AIDS control programs . The AIDS epidemic should not become a reason for decreasing support for STD control programs but rather an incentive to initiate or strengthen such programs .

Int J Pharm, 2002 Oct 10, 246(1-2), 17 - 24
Release kinetics and up-take studies of model fluoroquinolones from carbomer hydrogels; Vilches AP et al.; Hydrogels of carbomer (C) loaded with model slightly soluble fluoroquinolone antimicrobials (AMFQ), norfloxacin (I) and ciprofloxacin (II) were prepared to evaluate their physical and delivery properties . Thus, dispersions of 0.25% of C loaded with 0.2-0.5 mol equivalents of AMFQ and 0.2-0.5 mol equivalents of NaOH yielded pseudoplastic hydrogels with a high negative electrokinetic potential and good physical stability . Concentration of AMFQ in the hydrogels was, respectively, 7.2 and 34 times higher than I and II aqueous solubility, indicating a high increase in aqueous compatibility . Release of AMFQ in bicompartimetal Franz type cell occurred by zero order kinetics . Delivery rate constant (k(0)) was five to six times higher as water was replaced by NaCl solution as receptor medium . Release in agar dishes revealed that, even under high dilution, delivery remains modulated . Intestinal absorption flux coefficient in everted rat intestine (k(U)) were measured with reference solutions (RS) of free AMFQ (k(U)(RS) II>k(U)(RS) I) and with hydrogels (H), in which the pattern was reversed since k(U)(H) I>k(U)(H) II . As expected k(U)(H) II was 0.55 times lower than k(U)(RS) II . However, k(U)(H) I was 1.37 times higher than its reference, which cannot be explained from the analysis of k(0) and k(U)(RS) alone . Hydrogels C-AMFQ behave as a reservoir of AMFQ able to deliver it at a constant rate and would be useful to design topical and or systemic dosage forms.

Biochemistry, 2002 Oct 1, 41(39), 11921 - 30
Preassembly of membrane-active peptides is an important factor in their selectivity toward target cells; Sal-Man N et al.; Membrane-active peptides comprise a large group of toxins used in the defense and offense systems of all organisms including plants and humans . They act on diverse targets including microorganisms and mammalian cells, but the factors that determine their target cell selectivity are not yet clear . Here, we tested the role of peptide length and preassembly on the ability of diastereomeric cationic antimicrobial peptides to discriminate among bacteria, erythrocytes, and fungal cells, by using peptides with variable lengths (13, 16, and 19 amino acids long) and their covalently linked pentameric bundles . All the bundles expressed similar potent antifungal activity (minimal inhibitory concentration of 0.2-0.3 microM) and high antimicrobial activity . Hemolytic activity was also observed at concentrations higher than those required for antifungal activity . In contrast, all the monomers showed length-dependent antimicrobial activity, were less active toward bacteria and fungi, and were devoid of hemolytic activity . BIAcore biosensor experiments revealed a approximately 300-fold increase in peptide-membrane binding affinity between the 13- and 19-residue monomers toward zwitterionic (egg phosphatidylcholine (PC)/egg spingomyelin (SM)/cholesterol) vesicles . All the monomeric peptides display a similar high affinity to negatively charged (E . coli phosphatidylethanolamine (PE)/egg phosphatidylglycerol (PG)) vesicles regardless of their length . In contrast, irrespective of the size of the monomeric subunit, all the bundles bind irreversibly and strongly disrupt both PC/SM/cholesterol and PE/PG membranes . Attenuated total reflectance Fourier-transform infrared spectroscopy revealed that peptide assembly also affects structure as observed by an increased alpha-helical and beta-sheet content in membranes and enhances acyl chain disruption of PC/cholesterol . The correlation between the antibacterial activity and ability to depolarize the transmembrane potential of E . coli spheroplasts, as well as the ability to induce calcein release from vesicles, suggests that the bacterial membrane is their target . The data demonstrate that preassembly of cationic diastereomeric antimicrobial peptides is an essential factor in their membrane targeting.

Biochemistry, 2002 Oct 1, 41(39), 11895 - 900
Reaction of lactoperoxidase compound I with halides and thiocyanate; Furtmuller PG et al.; Lactoperoxidase (LPO) is found in mucosal surfaces and exocrine secretions, including milk, tears, and saliva, and has physiological significance in antimicrobial defense which involves (pseudo-) halide oxidation . This study for the first time presents transient kinetic measurements of the reactivity of its competent redox intermediate compound I with halides and thiocyanate, using the sequential stopped-flow technique . Compound I was produced with either H(2)O(2) {(1.1 +/- 0.1) x 10(7) M(-1) s(-1)} or hypochlorous acid {(3.2 +/- 0.1) x 10(7) M(-1) (s-1)} . At pH 7 and 15 degrees C, the two-electron reduction of compound I to native LPO by bromide and iodide has a second-order rate constant of (4.1 +/- 0.1) x 10(4) M(-1) s(-1) and (1.2 +/- 0.04) x 10(8) M(-1) s(-1), respectively . With thiocyanate the reaction is extremely fast (2.0 x 10(8) M(-1) s(-1)), whereas chloride cannot function as electron donor . The results are discussed with respect to known kinetic data of homologous mammalian peroxidases and to the physiological role of LPO in antimicrobial defense.

Contracept Technol Update, 1982 Oct, 3(10), 129 - 34
CDC writes first guidelines for sexually transmitted diseases; How to treat PID; PIP: Once the condition of pelvic inflammatory disease (PID) has been diagnosed clinicans should initiate immediate therapy . If antibiotics are withheld until a specific microbiologic diagnosis is obtained, the possibility of laboratory error and of processing delays hinders appropriate therapy . Evolving knowledge of the definition, etiology, and treatment of PID provides additional rationale for immediate antibiotic administration . PID, which refers to the clinical syndrome attributed to the ascending spread of microorganisms from the vaginal and endocervix to the fallopian tubes and contiguous structures, includes the clinical entities of endometritis, salpingitis, and parametritis, and/or peritonitis . Clinical diagnosis usually involves a history of lower abdominal pain, lower abdominal tenderness, cervical motion tenderness, and adnexal tenderness . Many organisms play a role in the pathogenesis of this syndrome, and clinicians should initiate treatment regimens which are active against the broadest range of pathogens . The treatment of choice is not established . No single agent is active against the entire spectrum of pathogens . Several antimicrobial combinations provide broad spectrum activity against the major pathogens in vitro, but many have not been adequatley evaluated for clinical efficacy in PID . Drugs with optimal anaerobic activity are perferred in patients with a pelvic mass or IUD associated PID . In most other women, drugs with optimal activity against N . gonorrhoea and C . trachomatis may be preferred . Due to the severe longterm complications resulting from PID, including infertility and ectopic pregnancy, clinicians should seriously consider hospitalizing women with PID whenever practical . Criteria for hospitalization are outlined .

Drug Ther (NY), 1973 May, 3(5), 57 - 9, 65
Effects on the infant of drug therapy in nursing mothers; Knowles JA; PIP: The effects of maternal intake while nursing of anticoagulants, antimicrobials, psychopharmacologicals, steroids, thyroid and antithyroid preparations, and miscellaneous drugs, such as cathartics, fluoride, phenylalanine, and radioactive substances, on the infant are enumerated . Mothers taking anticoagulants should not breastfeed because of potential life-threatening hemorrhages in nursing infants . The level of antibiotics in maternal milk is generally so low as to be innocuous . However, the possibility of later allergic reaction in the infant should be considered . Levels of chloramphenicol, erythromycin, naladixic acid, nitrofurantoin, penicillin, streptomycin, and sulfonamides are so low as to be of little significance; however, metronidazole is excreted in breast milk and its effects on newborns are unknown at present; this drug is therefore contraindicated in nursing mothers . No effect on a nursing infant is found with maternal ingestion of alcohol, chlorpromazine, propoxyphene hydrochloride, and diphenylhydantoin; however, codeine, heroin, and morphine, although difficult to find in milk, may cause infant withdrawal symptoms . Phenobarbital and primidone are contraindicated . Oral contraceptives decrease lactation, but transfer effect is unknown . Theouracil is one of the few drugs that is found in higher amounts in mother's milk than in serum . Minute amounts of radioactive products, steroids, anticoagulants, and antineoplastics can cause profound infant effects, and nursing mothers should discontinue nursing if these medications are necessary .

J Immunol, 2002 Oct 1, 169(7), 3883 - 91
The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses; Scott MG et al.; The role of LL-37, a human cationic antimicrobial peptide, in the immune system is not yet clearly understood . It is a widely expressed peptide that can be up-regulated during an immune response . In this report, we demonstrate that LL-37 is a potent antisepsis agent with the ability to inhibit macrophage stimulation by bacterial components such as LPS, lipoteichoic acid, and noncapped lipoarabinomannan . We also demonstrate that LL-37 protects mice against lethal endotoxemia . In addition to preventing macrophage activation by bacterial components, we hypothesized the LL-37 may also have direct effects on macrophage function . We therefore used gene expression profiling to identify macrophage functions that might be modulated by LL-37 . These studies revealed that LL-37 directly up-regulates 29 genes and down-regulated another 20 genes . Among the genes predicted to be up-regulated by LL-37 were those encoding chemokines and chemokine receptors . Consistent with this, LL-37 up-regulated the expression of chemokines in macrophages and the mouse lung (monocyte chemoattractant protein 1), human A549 epithelial cells (IL-8), and whole human blood (monocyte chemoattractant protein 1 and IL-8), without stimulating the proinflammatory cytokine, TNFalpha . LL-37 also up-regulated the chemokine receptors CXCR-4, CCR2, and IL-8RB . These findings indicate that LL-37 may contribute to the immune response by limiting the damage caused by bacterial products and by recruiting immune cells to the site of infection so that they can clear the infection.

Lancet, 2002 Sep 14, 360(9336), 835 - 41
Clinical efficacy of 3 days versus 5 days of oral amoxicillin for treatment of childhood pneumonia: a multicentre double-blind trial; Pakistan Multicentre Amoxycillin Short Course Therapy (MASCOT) pneumonia study group; BACKGROUND: For most infections, especially acute respiratory infections (ARIs), the recommended duration of therapy is not based on strong scientific or clinical criteria . Shorter courses of antibiotics for non-severe pneumonia would result in lower costs, enhance patient compliance, and might help to contain antimicrobial resistance . We aimed to compare the clinical efficacy of 3-day and 5-day courses of amoxicillin in children with non-severe pneumonia . METHODS: We recruited 2000 children, aged 2-59 months, with non-severe pneumonia (WHO criteria) diagnosed in the outpatient departments of seven hospitals . Patients were randomly assigned to 3 days or 5 days of treatment with oral amoxicillin . The primary outcome was treatment failure . Analyses were by intention to treat . FINDINGS: We allocated 1000 children to 3 days of treatment and 1000 to 5 days . Treatment failed in 209 (21%) patients in the 3-day group, and in 202 (20%) in the 5-day group (difference 0.7%; 95% CI -1.8 to 3.2) . In 12 (1%) children in the 3-day group and in 13 (1%) in the 5-day group the disease relapsed (difference 0.1%; -0.6 to 0.8) . Treatment was more likely to fail in children who did not adhere to treatment (p<0.0001), in those younger than 12 months (p<0.0001), in those whose illness lasted for 3 days or longer (p=0.004), in those whose respiratory rate was more than 10 breaths/min above the age-specific cut-off (p=0.004), and in those with vomiting (p=0.009) . Non-adherence was also associated with failure of treatment in the 5-day group (p<0.0001) . INTERPRETATION: Treatment with oral amoxicillin for 3-days was equally as effective as treatment for 5 days in children with non-severe pneumonia . The most important risk factor for treatment failure was non-compliance, which was also associated with longer duration of therapy.

Immunogenetics, 2002 Sep, 54(6), 442 - 5 Epub 2002 Jul 16.
Diversity of the penaeidin antimicrobial peptides in two shrimp species; Cuthbertson BJ et al.; Penaeidins, a unique family of antimicrobial peptides (AMPs) with both proline and cysteine-rich domains, were initially identified in the hemolymph of the Pacific white shrimp, Litopenaeus vannamei . Described here are the results of an investigation of penaeidin diversity in individual shrimp from two species, L . vannamei and L . setiferus (Atlantic white shrimp) . We report the discovery of a novel penaeidin class, designated penaeidin 4 present in both L . vannamei and L . setiferus, and that all penaeidin classes were expressed in a single individual . In addition, nearly all penaeidins, regardless of class, shared an identical leader sequence while differing dramatically in the remainder of the peptide . Several new class 3 isoforms were identified, as well as sequence variants of Lv3a, which differ in the 3' untranslated region . Penaeidin sequence variability (especially of class 3), within and between individuals, is not interpretable as simple allelic polymorphism and may reflect alternate transcriptional mechanisms . Penaeidins are encoded by a small number of genetic loci and are not likely representatives of a large gene family produced by whole gene duplication, but rather may be products of a multi-component locus . Based on phylogenetic analysis, penaeidins fall into three classes where 1 and 2 are combined while classes 3 and 4 remain distinct . Phylogenetic analysis indicates that all classes of penaeidin were likely present in both species prior to speciation.

Clin Ther, 2002 Aug, 24(8), 1292 - 308
A multicenter, open-label, randomized comparison of levofloxacin and azithromycin plus ceftriaxone in hospitalized adults with moderate to severe community-acquired pneumonia; Frank E et al.; BACKGROUND: Changing etiologic patterns and the growing problem of antimicrobial resistance, particularly an increase in macrolide-resistant pneumococcal bacteremia, are causing physicians to adopt new approaches to the treatment of community-acquired pneumonia (CAP) . OBJECTIVE: The relative efficacy and tolerability of levofloxacin monotherapy and azithromycin and ceftriaxone combination therapy were assessed in hospitalized adults with moderate to severe CAP . METHODS: This Phase IV, multicenter, open-label, randomized trial compared 2 treatment regimens: (1) levofloxacin 500 mg PO or IV q24h, and (2) azithromycin 500 mg IV q24h for > or = 2 days plus ceftriaxone 1 g IV q24h for 2 days, followed by an optional transition to azithromycin 500 mg PO q24h at the investigator's discretion . The total duration of therapy was to be a minimum of 10 days in both treatment groups . Ceftriaxone was included in the initial azithromycin regimen to ensure coverage against pneumococcal bacteremia . RESULTS: Of 236 patients in the intent-to-treat population, completion or withdrawal information was available for 110 patients in the levofloxacin group and 114 in the azithromycin group . Baseline demographic and disease characteristics were comparable between groups . At the end of treatment, the clinical success rate (cured + improved) in clinically evaluable patients was 94.1% in the levofloxacin group and 92.3% in the azithromycin group . The respective posttherapy microbiologic eradication rates were 89.5% and 92.3% . Levofloxacin was as well tolerated as azithromycin, with an incidence of drug-related adverse events (AEs) for all body systems of 5.3% and 9.3%, respectively . None of the drug-related AEs were considered serious {corrected} . CONCLUSIONS: In this study in hospitalized patients with moderate to severe CAP, levofloxacin monotherapy was at least as effective as a combination regimen of azithromycin and ceftriaxone in providing coverage against the current causative pathogens in CAP . In addition, levofloxacin was as well tolerated as the combination of azithromycin and ceftriaxone.

Biocell, 2002 Aug, 26(2), 225 - 8
Ciprofloxacin increases hepatic and renal lipid hydroperoxides levels in mice; Weyers AI et al.; Ciprofloxacin (CFX) is an effective and relatively safe antimicrobial used in a variety of human infections . However, adverse drug reactions and positive results in genotoxic tests are reported . In order to understand the possible pathophysiological mechanisms of the toxic effects informed for CFX, lipid hydroperoxides (LOOH) -oxidative mediators of peroxidation- were quantified in liver and kidney of mice, after 15 to 360 minutes of the ciprofloxacin administration at doses of 10 mg/Kg or 100 mg/Kg by i.p . route . The peroxidation in the lipid fraction was evaluated by measuring the amount of hydroperoxides through the oxidation of 1-naphthyldiphenylphospine into its oxide and further quantification by high performance liquid chromatography . The initial content of lipid hydroperoxides (nmol/g tissue) was 253 +/- 3 in kidney and 143 +/- 12 in liver . CFX induced the maximal variation to 728 +/- 101 in kidney (P < 0.05) and 315 +/- 31 in liver (P < 0.01), after 15 min of 100 mg/Kg single dose . The variation in the LOOH levels was significant in kidney with both doses used and in liver after 100 mg/Kg until 60 min after the CFX administration, and then gradually fell to natural levels . The results demonstrated the effect of CFX on lipid oxidation, an indicator of oxidative effect . A natural protective capacity against this oxidation, more efficient in liver than in kidney, was observed.

J Antimicrob Chemother, 2002 Sep, 50 Suppl S1, 1 - 7
The need for antimicrobial resistance surveillance; Felmingham D; Although antimicrobial agents drastically reduced patient morbidity and mortality, bacterial resistance to these agents developed shortly after their introduction . Because the laboratory diagnosis of respiratory tract infection (RTI) is not always possible, and rarely of immediate use, treatment success or failure often depends upon the availability of reliable susceptibility information at the time of therapeutic decision-making . Hence, the need for accurate, up-to-date and timely data is obvious . This information can also be used to help determine the cause of antimicrobial resistance and how it spreads . Desired components of a global RTI surveillance study fall into four categories: programme design, methodology, clinical and dissemination of information . PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is an RTI surveillance study designed to fulfil these requirements . PROTEKT includes all of the features of other successful RTI surveillance studies (e.g . the Alexander Project, SENTRY) and improves on these studies by the addition of other desirable features, such as the determination of resistance mechanisms and the availability of up-to-date local data that can be downloaded to hand-held computers via the worldwide web for use at the bedside.

BMC Infect Dis . 2002 Sep 18;2(1):20.
Expression of human beta-defensins 1 and 2 in kidneys with chronic bacterial infection; Lehmann J et al.; BACKGROUND: Constitutive expression and localization of antimicrobial human beta-defensin-1 (HBD-1) in human kidneys as a potential mechanism of antimicrobial defense has been previously reported . Inducible expression of human beta-defensin-2 (HBD-2) has been described in various epithelial organs but not for the urogenital tract . METHODS: We investigated the gene- and protein expression of HBD-1 and HBD-2 by reverse transcriptase-polymerase chain reaction, and immunohistochemistry in 15 normal human kidney samples and 15 renal tissues with chronic bacterial infection . Additionally, cell culture experiments were performed to study HBD gene expression by real-time RT-PCR in response to inflammatory cytokines TNFalpha and IL-1beta as well as lipopolysaccharide from Gram-negative bacteria . RESULTS: Constitutive HBD-1 gene- and protein expression was detected in normal renal tissue and kidneys with chronic infection . As a novel finding, inducible HBD-2 gene- and protein expression was demonstrated in tubulus epithelia with chronic infection but not in normal renal tissue . In pyelonephritic kidneys HBD-1 and HBD-2 expression showed a similar pattern of localization in distal tubules, loops of Henle and in collecting ducts of the kidney . Furthermore, real-time RT-PCR of kidney derived cell lines stimulated with inflammatory agents TNF-alpha, IL-1beta and LPS revealed a strong increase in relative HBD-2 transcription level and also a slight increase in relative HBD-1 transcription level . CONCLUSIONS: Upregulated HBD-2 expression in renal tubulus epithelium indicates a role of a wider range of human defensins for antimicrobial host defense in the urogenital tract than previously recognized.

J Med Chem, 2002 Sep 26, 45(20), 4494 - 504
Antimicrobial peptides: synthesis and antibacterial activity of linear and cyclic drosocin and apidaecin 1b analogues; Gobbo M et al.; Drosocin and apidaecin Ib are two insect antimicrobial peptides showing a significant sequence homology and a common mechanism of action, which includes stereoselective elements but is devoid of any pore-forming activity . A substantial difference between the two peptides is the presence in the drosocin sequence of an O-glycosylated threonine residue, which is important for its antimicrobial activity . Through the synthesis of a series of differently glycosylated drosocin analogues, we have shown that the antimicrobial activity against several Gram-negative bacteria appears to be modulated by the sugar moiety (Gal vs GalNAc) and the type of glycosidic linkage (alpha-O-, beta-O-, or alpha-C-) . The insertion of a glycosylated threonine residue in the apidaecin Ib sequence improves the sequence homology with drosocin but reduces the antimicrobial activity . To gain information on the possible bioactive conformation of these peptides, we synthesized an unglycosylated cyclic analogue of drosocin, containing an intrachain disulfide bond, and the head-to-tail cyclic analogues of drosocin and apidaecin, as well as their corresponding cyclic dimers . Only the large cyclic dimer of apidaecin partially retained the antimicrobial activity, suggesting that a bending of the peptide chain, in particular in the middle of the molecule, is not a structural element characteristic of the bioactive conformation of drosocin and apidaecin . Experiments aimed at testing the effect of selected drosocin and apidaecin peptides on biological membranes showed that some peptides display a moderate hemolytic activity and that a dissociation between antibacterial activity and cytotoxicity to eukaryotic cells can be achieved in differently glycosylated peptide analogues.

Braz Dent J, 2002, 13(2), 113 - 7
Mechanism of action of sodium hypochlorite; Estrela C et al.; The choice of an irrigating solution for use in infected root canals requires previous knowledge of the microorganisms responsible for the infectious process as well as the properties of different irrigating solutions . Complex internal anatomy, host defenses and microorganism virulence are important factors in the treatment of teeth with asymptomatic apical periodontitis . Irrigating solutions must have expressive antimicrobial action and tissue dissolution capacity . Sodium hypochlorite is the most used irrigating solution in endodontics, because its mechanism of action causes biosynthetic alterations in cellular metabolism and phospholipid destruction, formation of chloramines that interfere in cellular metabolism, oxidative action with irreversible enzymatic inactivation in bacteria, and lipid and fatty acid degradation . The aim of this work is to discuss the mechanism of action of sodium hypochlorite based on its antimicrobial and physico-chemical properties.

J Small Anim Pract, 2002 Sep, 43(9), 388 - 94
Canine and feline pyothorax: a retrospective study of 50 cases in the UK and Ireland; Demetriou JL et al.; Fifty cases (36 dogs and 14 cats) with a confirmed diagnosis of pyothorax were evaluated from five referral institutions in the UK and Ireland . Aetiology, clinical presentation, diagnosis, treatment and outcome of all cases were examined . The underlying cause of pyothorax was determined in 18 per cent of cases . Positive bacteriological cultures of the pleural fluid were obtained in 68.7 per cent of the animals . Treatment modalities included surgery and medical management, involving thoracostomy tube placement, thoracic aspiration, thoracic lavage and antimicrobial therapy . A successful outcome was achieved in 86 per cent of patients.

J Toxicol Sci, 2002 Aug, 27(3), 219 - 28
Comparative articular toxicity of garenoxacin, a novel quinolone antimicrobial agent, in juvenile beagle dogs; Nagai A et al.; The articular toxicity of garenoxacin (formerly T-3811 or BMS-284756) was experimentally examined utilizing juvenile beagle dogs . Garenoxacin and two other reference quinolones were administered at intravenous dosages of 30 and 60 mg/kg . Each group consisted of 3 male dogs (Experiment I) . Oral dosages of 50 mg/kg of 3 compounds were also given daily to male only and female only groups (Experiment II) over a period of 7 days . We evaluated the articular toxicity of garenoxacin compared to ciprofloxacin and norfloxacin . In Experiment I, no articular toxicity was detected in the 30 mg/kg garenoxacin group . One animal from the 60 mg/kg garenoxacin group developed detectable histopathological lesions in the articular cartilages of the shoulder, elbow and knee joints . In the 30 mg/kg ciprofloxacin group and the 30 and 60 mg/kg norfloxacin groups, histopathological articular cartilage lesions of the shoulder, elbow, carpus, hip, knee and tarsus joints were observed in all of the dogs . The area under the plasma concentration-time curve (AUC0-->infinity) values, after the first dose was administered, for the 30 mg/kg groups given garenoxacin, ciprofloxacin and norfloxacin were 164, 68.1 and 65.7 micrograms.hr/mL, respectively . In Experiment II, the degree of histopathological change was most significant in the ciprofloxacin group, followed by the norfloxacin group, and with comparatively the least changes in the garenoxacin group . The AUC0-->infinity values, obtained after the 6th day of antimicrobial administration, were 202 and 173 micrograms.hr/mL for male and female dogs, respectively, from the 50 mg/kg garenoxacin group . The AUC0-->infinity values for the garenoxacin group after the 6th daily administration were 7.8 to 17.0 times greater for male dogs and 3.8 to 13.2 times greater for female dogs than those obtained from the ciprofloxacin and norfloxacin groups . The concentrations of garenoxacin in the synovia, articular cartilage and the synovialis 4 hr following the last garenoxacin administration were 2.0 to 6.5 times higher for male dogs and 1.5 to 3.3 times higher for female dogs than the antimicrobial levels measured in the ciprofloxacin and norfloxacin groups . As discussed above, although the garenoxacin concentrations in plasma and joint tissue were higher than those for ciprofloxacin and norfloxacin, however, the articular toxicity of garenoxacin was much less than that of the other two antimicrobials.

Phytother Res, 2002 Sep, 16(6), 555 - 61
Antimicrobial activity of some species of the family Combretaceae; Elegami AA et al.; Forty eight extracts of four plants of the family Combretaceae were screened for antibacterial activity against standard organisms as well as clinical isolates . The extracts in different solvent systems showed high activity against both standard organisms and clinical isolates . Phytochemical screening revealed that the plants were very rich in tannins to which antibacterial activity may be attributed .

Mol Pharmacol, 2002 Oct, 62(4), 936 - 46
Revisiting an old antimicrobial drug: amphotericin B induces interleukin-1-converting enzyme as the main factor for inducible nitric-oxide synthase expression in activated endothelia; Suschek CV et al.; We have investigated the impact of the widely used antifungal agent Amphotericin B (AmB) on cytokine activated aortic endothelial cells (AEC) and their inflammatory response as monitored by cytokine and inducible nitric-oxide synthase (iNOS) expression as well as high-output nitric oxide synthesis . Because both blood-borne infections and systemically administered drugs will first encounter vessel lining endothelial cells, this cell type represents an important participant in innate immune reactions against xenobiotics . Culturing cytokine-activated AEC in the presence of 1.25 microg/ml AmB, a concentration equivalent to serum levels during patient treatment, we find increases in iNOS promoter activity up to 120%, in iNOS mRNA or protein expressions by factors of up to 3.5 +/- 1.1, and in iNOS activity of up to 180% compared with cells with cytokines only . In parallel, a strong increase in endothelial interleukin (IL)-1beta-converting enzyme (ICE) and IL-1beta expression and activity was observed . Specific inhibition of ICE activity or IL-1beta functionality significantly reduces expression and activity of the iNOS to control values . Because ICE activity is essential for the endogenous synthesis of active IL-1beta, ICE overexpression represents the key signal in the AmB-induced and IL-1beta-mediated effects on iNOS activity . In summary, in endothelial cells, AmB strongly augments cytokine-induced iNOS expression and activity by increasing the expression and activity of the ICE . This adjuvant activity for augmented endogenous cytokine processing adds to the efficacy of the antimycotic activity of AmB . Furthermore, our data underline the relevance of the endothelial iNOS as a potent effector of the innate immune system.

Biochem Biophys Res Commun, 2002 Sep 20, 297(2), 361 - 7
Antimicrobial peptide defenses of the Tarahumara frog, Rana tarahumarae; Rollins-Smith LA et al.; Populations of the Tarahumara frog Rana tarahumarae have decreased markedly in recent years in the northern part of their range . Infection by the chytrid fungus Batrachochytrium dendrobatidis has been implicated in these declines . To determine whether antimicrobial peptides in the skin provide protection against this pathogen, norepinephrine-stimulated skin secretions were tested for their ability to inhibit growth of B . dendrobatidis in vitro . After concentration, crude mixtures of skin peptides inhibited the growth of the chytrid in a concentration-dependent manner . Proteomic analysis led to the identification and characterization of three peptides belonging to the brevinin-1 family of antimicrobial peptides and three belonging to the ranatuerin-2 family . The two most abundant peptides, ranatuerin-2TRa (GIMDSIKGAAKEIAGHLLDNLKCKITGC) and brevinin-1TRa (FLPVIAGIAANVLPKLFCKLTKRC), were active against B . dendrobatidis (MIC of 50 microM for ranatuerin-2TRa and 12.5 microM for brevinin-1TRa against zoospores) . These data clearly show that antimicrobial peptides in the skin secretions of the Tarahumara frog are active against B . dendrobatidis and should provide some protection against infection . Therefore, the observed susceptibility of these frogs to this pathogen in the wild may be due to the effects of additional environmental factors that impair this innate defense mechanism, leading to the observed population declines.

Enferm Infecc Microbiol Clin, 2002 Aug-Sep, 20(7), 335 - 40
{Antimicrobial prophylaxis in surgery}; Cisneros JM et al.; Antimicrobial prophylaxis in surgery refers to a very brief course of an antimicrobial agent initiated just before the start of the procedure . The efficacy of antimicrobials to prevent postoperative infection at the site of surgery (incisional superficial, incisional deep, or organ/space infection) has been demonstrated for many surgical procedures . Nevertheless, the majority of studies centering on the quality of preoperative prophylaxis have found that a high percentage of the antimicrobials used are inappropriate for this purpose . This work discusses the scientific basis for antimicrobial prophylaxis, provides general recommendations for its correct use and specific recommendations for various types of surgery . The guidelines for surgical antimicrobial prophylaxis are based on results from well-designed studies, whenever possible . These guidelines are focussed on reducing the incidence of infection at the surgical site while minimizing the contribution of preoperative administration of antimicrobials to the development of bacterial resistance.

BMC Fam Pract . 2002 Sep 17;3(1):17.
Self-medication and non-doctor prescription practices in Pokhara valley, Western Nepal: a questionnaire-based study; Shankar PR et al.; BACKGROUND: Self-medication and non-doctor prescribing of drugs is common in developing countries . Complementary and alternative medications, especially herbs, are also commonly used . There are few studies on the use of these medications in Pokhara Valley, Western Nepal . METHODS: Previously briefed seventh semester medical students, using a semi-structured questionnaire, carried out the study on 142 respondents . Demographic information and information on drugs used for self-medication or prescribed by a non-allopathic doctor were collected . RESULTS: Seventy-six respondents (54%) were aged between 20 to 39 years . The majority of the respondents (72 %) stayed within 30 minutes walking distance of a health post/medical store . 59% of these respondents had taken some form of self-medication in the 6-month period preceding the study . The common reasons given for self-medication were mild illness, previous experience of treating a similar illness, and non-availability of health personnel . 70% of respondents were prescribed allopathic drugs by a non-allopathic doctor . The compounder and health assistant were common sources of medicines . Paracetamol and antimicrobials were the drugs most commonly prescribed . A significantly higher proportion of young (<40 years) male respondents had used self-medication than other groups . CONCLUSIONS: Self-medication and non-doctor prescribing are common in the Pokhara valley . In addition to allopathic drugs, herbal remedies were also commonly used for self-medication . Drugs, especially antimicrobials, were not taken for the proper duration . Education to help patients decide on the appropriateness of self-medication is required.

Dig Liver Dis, 2002 Jul, 34(7), 489 - 97
Lower concentrations of clarithromycin suppress urease activity, motility, and binding to gastric epithelial cells in Helicobacter pylori isolates; Nobata K et al.; BACKGROUND: Our previous study showed that histological scores of gastric mucosal inflammation and Helicobacter pylori density decreased even in patients who failed to eradicate Helicobacter pylori after antimicrobial therapy including clarithromycin . This may reflect indirect suppressive effects of lower concentrations of clarithromycin on Helicobacter pylori, as suggested in other Gram-negative rod infections . AIMS: To investigate whether clarithromycin suppresses virulence factors of Helicobacter pylori at sub-minimal inhibitory concentration . METHODS: Six clarithromycin-susceptible Helicobacter pylori isolates and 7 clarithromycin-resistant isolates were obtained from patients with peptic ulcer disease . These isolates were analysed for urease activity, motility, and ability to bind to gastric epithelial cells after they were incubated with or without clarithromycin at sub-minimal inhibitory concentrations . RESULTS: Incubation of Helicobacter pylori isolates with clarithromycin at sub-minimal inhibitory concentrations reduced urease activity motility, and binding to gastric epithelial cells in a dose-dependent manner . These findings were observed both in clarithromycin-susceptible and resistant strains . CONCLUSIONS: Suppressive effects of clerithromycin on virulence factors of Helicobacter pylori at sub-minimal inhibitory concentrations may be associated with observed attenuation of gastric inflammation and Helicobacter pylori density in patients who failed in bacterial eradication after triple therapy including clarithromycin.

Pediatr Med Chir, 2002 May-Jun, 24(3), 177 - 85
{Nosocomial infections at a pediatric age}; Zuccotti GV et al.; The overall incidence of nosocomial infections in children ranges from 2.3% to 12.6% . Even if there are great variations among data in literature, most authors agree that nosocomial infections are less frequent in children than in adults . Differences between these two populations concern anatomical sites of infection and microrganisms: in children, most frequent are gastrointestinal infections (10-35%), respiratory infections (5-30%) and bacteremia (10-23%); Gram positive bacteria account for 31-50% of infections, Gram negative for 23-35% and viruses for 22-27% . All these percentages change enormously depending on the type of department and child age . Because of increasing rates of resistance to antimicrobial agents, it is important to identify the main infectious agents and their sensibility, considering carefully when to give antibiotic therapy and what drug should be chosen.

Rev Med Chil, 2002 Jul, 130(7), 798 - 802
{Bone marrow aplasia associated to the use of ticlopidine}; Ruiz C et al.; We report a 58 years old male that developed a bone marrow aplasia associated to the use of ticlopidine, prescribed after coronary artery stenting . The patient developed a pneumonia as a complication . He was admitted to the Intermediate Treatment Unit, receiving wide spectrum antimicrobial therapy and a granulocyte colony stimulating factor (Neupogen(r)) with favourable response . Ticlodipine is an effective antiplatelet agent, but has serious hematological and other side effects . Its prescription requires a close follow up and search for complications.

Kekkaku, 2002 Aug, 77(8), 573 - 84
{Prospects for development of new antituberculous drugs}; Tomioka H; Tuberculosis (TB) is a growing international health concern, since it is the leading infectious cause of death in the world today . Moreover, the resurgence of TB in industrialized countries and the worldwide increase in the prevalence of Mycobacterium avium complex (MAC) infections in immunocompromised hosts have prompted the quest for new antimycobacterial drugs . In particular, the appearance of multidrug-resistant (MDR) strains of M . tuberculosis, which exhibit in vitro resistance to at least two major antituberculous drug (usually INH and RFP) and cause intractable TB, has greatly contributed to the increased incidence of TB . Because of the global health problems of TB, the increasing rate of MDR-TB and the high rate of a co-infection with HIV, the development of potent new antituberculous drugs without cross-resistance with known antimycobacterial agents is urgently needed . In this article, I reviewed the following areas . First, I briefly reviewed some new findings (mainly reported after 2000) on the pharmacological status of rifamycin derivatives (rifabutin, rifapentine, and rifalazil), fluoroquinolones (ciprofloxacin, ofloxacin, sparfloxacin, levofloxacin, gatifloxacin, sitafloxacin, moxifloxacin, and others), and new macrolides (clarithromycin, azithromycin, and roxithromycin) . Second, I described other types of agents which are being developed as antimycobacterial drugs . Some of the agents discussed are already under preliminary clinical investigation, and others appear to be promising candidates for future development . In this review, the status of the development of new antimycobacterial, especially antituberculous agents including oxazolidinone (PNU-100480), 5'-nitroimidazole (CGI 17341), 2-pyridone (ABT-255), new riminophenazines, nitroimidazopyran (PA-824), new ketolides (ABT-773, telithromycin) and defensins (human neutrophil peptide-I), was examined . Third, the development of new antitubercular drugs was discussed according to the potential pharmacological target . New critical information on the whole genome of M . tuberculosis recently elucidated and increasing knowledge on various mycobacterial virulence genes will promote the progression in the identification of genes that code for new drug targets . Using such findings on mycobacterial genomes, drug development using quantitative structure-activity relationship may be possible in the near future . In this review, I described the screening of drugs that have an inhibitory activity against dTDP-rhamnose synthesis of M . tuberculosis, as a new drug target of the organism . In addition, I discussed the usefulness of antisense oligo DNAs specific to mycobacterial genes encoding certain metabolic enzymes or virulence factors that play roles in the bacterial escape from antimicrobial mechanisms of host macrophages . Fourth, I reviewed the drug vehicles which enable efficacious drug delivery to their target in vivo . The usefulness of poly (DL-lactide-co-glycolide) microsphere technology, which enables the encapsulated drugs to deliver the requested doses of them for prolonged time periods by a single shot without causing any toxicity and, moreover, enables the highly targeted delivery of the drugs to host macrophages, was discussed . Fifth, I described adjunctive immunotherapy for the management of patients with mycobacterial infections by giving certain immunomodulators in combination with antimycobacterial drugs . Adjuvant clinical trials using IL-2 or GM-CSF have been found to be efficacious to some extent in improving patients with tuberculosis or disseminated MAC infections . However, it seems that these immunopotentiating cytokines as well as IFN-gamma and IL-12 are not so promising for the therapeutic agents of mycobacterial infections because of the possible induction of immunosuppressive cytokines during adjuvant therapy and, in some cases, severe side-effect . Thus, the development of new classes of immuno-modulators other than cytokines, particularly those with no severe side-effect, is needed . This review dealt with ATP and its analogues which potentiate macrophage antimycobacterial activity via a purinergic P2X7 receptor . Finally, I described the roles of type II alveolar epithelial cells in the establishment of mycobacterial infections in the host lungs and the profiles of drug susceptibilities of M . tuberculosis and MAC organisms replicating within the type II pneumocytes . These findings are useful to precisely assess or predict the in vivo therapeutic activity of a given antimycobacterial drug from its in vitro activity . In this article, I have thoroughly reviewed the status of the development of new antimycobacterial drugs . There are a number of difficulties in the drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability . It should be emphasized that the most urgent goal of chemotherapy of tuberculosis and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable tuberculosis is rapidly increasing in the latter.

Antimicrob Agents Chemother, 2002 Oct, 46(10), 3308 - 10
Antimicrobial properties of milk: dependence on presence of xanthine oxidase and nitrite; Hancock JT et al.; Human and bovine milk inhibited the metabolic activity of Escherichia coli, as shown by luminescence monitoring of constructs expressing the luxCDABE genes . Inhibition was dependent on both xanthine oxidase (XO) activity and on the presence of nitrite, implying that XO-generated nitric oxide functions as an antibacterial agent.

Antimicrob Agents Chemother, 2002 Oct, 46(10), 3164 - 7
Comparison of the in vitro activity of the glycylcycline tigecycline (formerly GAR-936) with those of tetracycline, minocycline, and doxycycline against isolates of nontuberculous mycobacteria; Wallace RJ Jr et al.; We compared the in vitro activity of the glycylcycline tigecycline (formerly GAR-936) with those of tetracycline, doxycycline, and minocycline by broth microdilution against 76 isolates belonging to seven species of rapidly growing mycobacteria (RGM) and 45 isolates belonging to five species of slowly growing nontuberculous mycobacteria (NTM) . By using a resistance breakpoint of >4 micro g/ml for tigecycline and >8 micro g/ml for tetracycline, all RGM were highly susceptible to tigecycline, with inhibition of 50% of isolates at < or =0.12 micro g/ml and inhibition of 90% of isolates at 0.25 micro g/ml for Mycobacterium abscessus and inhibition of both 50 and 90% of isolates at < or =0.12 micro g/ml for M . chelonae and the M . fortuitum group . The MICs of tigecycline were the same for tetracycline-resistant and -susceptible strains, and RGM isolates were 4- to 11-fold more susceptible to tigecycline than to the tetracyclines . In contrast, no slowly growing NTM were susceptible to tigecycline, and isolates of M . marinum and M . kansasii were less susceptible to this agent than to minocycline . This new antimicrobial offers exciting therapeutic potential for the RGM, especially for isolates of the M . chelonae-M . abscessus group, against which the activities of the currently available drugs are limited.

Fitoterapia, 2002 Jul, 73(4), 336 - 9
Antimicrobial and antifungal activity of crude extracts and isolated saponins from Astragalus verrucosus; Pistelli L et al.; The antimicrobial and antifungal properties of several crude extracts and pure saponins, astraverrucins I-VI, from the aerial parts of Astragalus verrucosus were investigated by the disc diffusion method . Antimycotic activity was observed on more polar extracts, but only one saponin showed an appreciable activity.

J Appl Microbiol, 2002, 93(4), 706 - 13
Survival of Escherichia coli O157:H7 in farm water: its role as a vector in the transmission of the organism within herds; McGee P et al.; AIMS: The study aimed to investigate the survival characteristics of Escherichia coli O157:H7 in farm water (FW), and in sterile distilled municipal water (SDW), stored outdoors under field conditions, with or without the addition of faeces (1% w/v), in a farmyard shed and the laboratory at 15 degrees C . METHODS AND RESULTS: Water samples were inoculated with E . coli O157:H7 at 10(3) and 10(6) ml(-1), and sampled over a 31-day period . In FW stored outdoors in a field, E . coli O157:H7 survived for 14 days at temperatures <15 degrees C, at both inoculation levels, while in the laboratory at 15 degrees C, the organism was still detectable at low levels (<1 log10 cfu ml(-1)) after 31 days . The addition of bovine faeces to water outdoors (1% w/v) resulted in survival for 24 days . In SDW inoculated at 10(6) ml(-1) and stored in the laboratory (15 degrees C), only a 2.5 log reduction was observed after 31 days, while the organism could not be detected after 17 days in the field . Preliminary screening of water samples stored outdoors isolated a bacterium which exhibited antimicrobial activity towards E . coli O157:H7 . CONCLUSIONS: The survival of E . coli O157:H7 observed in this study illustrates the potential of farm water to act as a vehicle in the transfer of the organism across a herd . SIGNIFICANCE AND IMPACT OF THE STUDY: The difficulty in extrapolating results from controlled laboratory situations to on-farm conditions is also highlighted in this study.

J Food Prot, 2002 Sep, 65(9), 1394 - 405
Inactivation of acid-adapted and nonadapted Escherichia coli O157:H7 during drying and storage of beef jerky treated with different marinades; Calicioglu M et al.; The inactivation of both acid-adapted and unadapted Escherichia coli O157:H7 during the processing of beef jerky was studied . Following inoculation with the pathogen, beef slices were subjected to different predrying marinade treatments, dried at 60 degrees C for 10 h, and stored at 25 degrees C for 60 d . The predrying treatments evaluated were as follows: (i) no treatment (C), (ii) traditional marinade (TM), (iii) double-strength TM modified with added 1.2% sodium lactate, 9% acetic acid, and 68% soy sauce with 5% ethanol (MM), (iv) dipping into 5% acetic acid for 10 min followed by application of TM (AATM), and (v) dipping into 1% Tween 20 for 15 min and then into 5% acetic acid for 10 min followed by TM (TWTM) . Bacterial survivors were determined during drying and storage using tryptic soy agar with 0.1% pyruvate, modified eosin methylene blue agar, and sorbitol MacConkey agar . Results indicated that bacterial populations decreased during drying in the order of TWTM (4.9 to 6.7 log) > AATM > MM > C > or = TM (2.8 to 4.9 log) predrying treatments . Populations of acid-adapted E . coli O157:H7 decreased faster (P < 0.05) in AATM and TWTM than nonadapted cells during drying, whereas no significant difference was found in inactivation of acid-adapted and nonadapted inocula in C and TM samples . MM was more effective in inactivating the nonadapted than the adapted inoculum . Bacterial populations continued to decline during storage and dropped below the detection limit (-0.4 log10 CFU/cm2) as early as day 0 (after drying) or as late as day 60, depending on acid adaptation, predrying treatment, and agar medium . The results indicated that acid adaptation may not increase resistance to the hurdles involved in jerky processing and that use of additional antimicrobial chemicals or preservatives in jerky marination may improve the effectiveness of drying in inactivating E . coli O157:H7.

Plant Physiol, 1993 Jan, 101(1), 13 - 24
Volatile Products of the Lipoxygenase Pathway Evolved from Phaseolus vulgaris (L.) Leaves Inoculated with Pseudomonas syringae pv phaseolicola; Croft K et al.; Activation of the "lipoxygenase pathway" in plants gives rise to a series of products derived from fatty acids . Analysis by gas chromatography-mass spectroscopy of volatile products produced by Phaseolus vulgaris (L.) cv Red Mexican leaves during a hypersensitive resistance response (HR) to the plant pathogenic bacterium Pseudomonas syringae pv phaseolicola showed evolution of several lipid-derived volatiles, including cis-3-hexenol and trans-2-hexenal, which arise from the 13-hydroperoxide of linolenic acid . These compounds were not produced in detectable amounts by buffer-inoculated leaves, nor did they evolve to such a high degree during comparable stages of the susceptible response . The absence of trans-2,cis-6-nonadienal, a product expected from 9-hydroperoxide of linolenic acid, suggests that lipid peroxidation during the HR proceeded primarily enzymically via bean lipoxygenase, which produces the 13-hydroperoxide, and not via autoxidative processes . The effects of trans-2-hexenal, cis-3-hexenol, and traumatic acid on P.s pv phaseolicola were investigaed . trans-2-Hexenal appeared to be highly bactericidal at low concentrations, whereas cis-3-hexenol was bactericidal only at much higher concentrations . Traumatic acid appeared to have no effect on P.s . pv . phaseolicola at the concentrations tested . These results demonstrate that during plant defense responses against microbial attack, several lipid-derived compounds are produced by the plant, some of which possess antimicrobial activity and conceivably are involved in plant disease resistance . The time of production of these substances, in amounts that would be expected to be antibacterial in vitro, correlated with a slowing down of the growth rate of bacteria in the leaves and was seen at a time before the accumulation of isoflavonoid phytoalexins in the host.

J Inorg Biochem, 2002 Sep 30, 92(1), 65 - 74
Interactions of metal ions with two quinolone antimicrobial agents (cinoxacin and ciprofloxacin) . Spectroscopic and X-ray structural characterization . Antibacterial studies; Lopez-Gresa MP et al.; Several novel metal-quinolone compounds have been synthesized and characterized by analytical, spectroscopic and X-ray diffraction methods . The crystal structure of the four compounds, Na(2){(Cd(Cx)3)(Cd(Cx)3(H2O))}.12H2O, {Co(Cp)2(H2O)2}.9H2O, {Zn(Cp)2(H2O)2}.8H2O and {Cd(HCp)2(Cl)2}.4H2O, is presented and discussed: HCx=1-ethyl-1,4-dihydro-4-oxo(1,3)-dioxolo(4,5-g)cinnoline-3-carboxylic acid and HCp=1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid . In all these compounds the quinolone acts as a bidentate chelate ligand that binds through one carboxylate oxygen atom and the exocyclic carbonyl oxygen atom . Complexes of ciprofloxacin were screened for their activity against several bacteria, showing activity similar to that of the ligand . In addition, the number of bacteria killed after 3 h of incubation with the ligand, {Co(Cp)2(H2O)2}.9H2O, Ni(Cp)2.10H2O and Cu(Cp)2.6H2O, was determined against S . aureus ATCC25923 . There is a direct relationship between the growth rate and the lethal rate . Against growing bacteria, the ligand is the most bactericidal and Cu(Cp)2.6H2O is the less bactericidal . On the contrary, against non-dividing bacteria, the complexes were more bactericidal than the ligand, with Cu(Cp)(2).6H(2)O the most bactericidal compound.

Acta Pol Pharm, 2002 May-Jun, 59(3), 223 - 5
Synthesis and antimicrobial activity of 3-hydroxyimino-5-methyl-2-hexanone(HIMH) and its dioxime derivative; Patil VR et al.; A new oxime, 3-hydroxyimino-5-methyl-2-hexanone (HIMH) has been synthesized by the reaction of 1-pentyl nitrite with 5-methyl-2-hexanone under acidic conditions . The subsequent treatment of HIMH with NH2OH x HCl gives 5-methyl-2,3-hexanedione dioxime (H2MHDDO) . The structures of these compounds have been confirmed by physicochemical and spectral data . A preliminary screening of these compounds for biological activity against several microorganisms has indicated that they are selective growth inhibitors of m-tuberculosis, in particular.

J Clin Oncol, 2002 Sep 15, 20(18), 3891 - 7
Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine; Rai KR et al.; PURPOSE: This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens . PATIENTS AND METHODS: Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States . The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks . Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute-sponsored Working Group criteria . Safety assessments included analysis of lymphocyte subpopulations . Antimicrobial prophylaxis was not mandatory . RESULTS: Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months) . The median duration of response was 15.4 months (range, 4.6 to >or= 38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to >or= 42.0 months), and the median survival time was 35.8 months (range, 8.8 to >or= 47.1 months) . Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week . Ten patients (eight nonresponders and two responders) experienced major infections on-study . Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis . Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up . One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies . CONCLUSION: Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients . However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.

Curr Infect Dis Rep, 2002 Oct, 4(5), 439 - 445
Long Bone Osteomyelitis; Lazzarini L et al.; Osteomyelitis is a complex disease that is often associated with high morbidity and considerable health care costs . Bacteremia, contiguous focuses of infection, penetrating trauma, or surgery are the major predisposing factors for this infection . Bone necrosis and bone destruction occur early in the course of osteomyelitis, leading to a chronic process and eliminating the host's ability to eradicate the pathogens . The presence of poorly vascularized tissues, the adherence to bone structures and implants, and a slow bacterial replication rate are recognized as important factors for the persistence of the infection . Treatment of osteomyelitis is particularly challenging and involves adequate antimicrobial therapy and surgical debridement of all necrotic bone and soft tissues . Antibiotic treatment is usually started on an empiric basis and then modified according to the results of cultures and sensitivity tests . Surgical treatment consists of debridement, obliteration of dead space, adequate soft tissue coverage, restoration of blood supply, and stabilization.

Pharmazie, 2002 Aug, 57(8), 519 - 22
Synthesis of some 3- and 4-substituted 1,5-diphenylpyrrolidine-2,4-diones as potential antimicrobial and antineoplastic agents . Reactions with tetramic acid, Part 5; Saudi MN et al.; The condensation of 1,5-diphenylpyrrolidine-2,4-dione (1) with the carboxyl compounds 2a-f afforded the corresponding 3-arylidene-1,5-diphenylpyrrolidine-2,4-diones 3a-f . Reaction of the parent compound 1 with isatin (4) yielded the condensation product 5 in an acidic medium, whereas compound 6 was obtained in an alkaline medium . The condensation of the primary amines 7a-f with compound 1 afforded the corresponding 4-substituted amino-1,5-diphenyl-delta 3-pyrrolin-2-ones 8a-f . All the compounds synthesized were screened for their antimicrobial activity, and four compounds were selected for screening for their antineoplastic activity . The compounds tested showed both antimicrobial and antineoplastic activities.

Eksp Klin Farmakol, 2002 May-Jun, 65(3), 71 - 4
{Laboratory and clinical study of therapeutic efficacy of medicinal films for surgical procedures}; Golovanenko AL et al.; An analysis of the experimental data showed that anesthetic medicinal films (AMFs) offer an effective medicinal form for the treatment of suppurative inflammatory disorders(SIDs) of soft tissues . The results of preclinical experiments with AMFs showed evidence of anesthetic, antimicrobial, and hemostatic effects . The therapeutic effect was established in the course of clinical investigations and confirmed by the results of cytological, histological, morphological, and bacteriological testing . The experimental data indicate that AMF application offers a promising means of SID treatment . Further development of this medicinal form must lead to an increase in the therapeutic efficacy, decrease the drug dose, and reduce the probability of side effects during the treatment of SIDs in soft tissues of various localization.

Semin Respir Infect, 2002 Sep, 17(3), 246 - 9
The environment as a significant cofactor for multiply resistant nosocomial infections; Cua A et al.; The role of antimicrobial agent control in the war against the development of resistance is not the only issue in this conflict . In this article, the role the environment plays in the spread of pathogens is discussed .

J Mol Med, 2002 Sep, 80(9), 549 - 61 Epub 2002 Jun 19.
Cathelicidins, essential gene-encoded mammalian antibiotics; Zaiou M et al.; Cathelicidins are a class of gene-encoded antibiotics found exclusively in mammals . In vitro and in vivo studies indicate they are effector molecules of mammalian innate immunity that can provide a first line of defense against an array of micro-organisms . Additional functions are described for some members of this class of antimicrobial peptides including chemotactic activity, mitogenesis, and angiogenesis . Therefore these peptides are considered to be multifunctional effector molecules . This review discusses recent progress in cathelicidin research and the functional properties of cathelicidins . Current work in this field suggests that understanding this component of the mammalian innate immune system and related natural antibiotic peptides offer an opportunity for the development of novel therapeutic agents with which to battle the continued problem of antimicrobial resistance.

Insect Biochem Mol Biol, 2002 Oct, 32(10), 1295 - 309
Insect hemocytes and their role in immunity; Lavine MD et al.; The innate immune system of insects is divided into humoral and cellular defense responses . Humoral defenses include antimicrobial peptides, the cascades that regulate coagulation and melanization of hemolymph, and the production of reactive intermediates of oxygen and nitrogen . Cellular defenses refer to hemocyte-mediated responses like phagocytosis and encapsulation . In this review, we discuss the cellular immune responses of insects with emphasis on studies in Lepidoptera and Diptera . Insect hemocytes originate from mesodermally derived stem cells that differentiate into specific lineages identified by morphology, function, and molecular markers . In Lepidoptera, most cellular defense responses involve granular cells and plasmatocytes, whereas in Drosophila they involve primarily plasmatocytes and lamellocytes . Insect hemocytes recognize a variety of foreign targets as well as alterations to self . Both humoral and cell surface receptors are involved in these recognition events . Once a target is recognized as foreign, hemocyte-mediated defense responses are regulated by signaling factors and effector molecules that control cell adhesion and cytotoxicity . Several lines of evidence indicate that humoral and cellular defense responses are well-coordinated with one another . Cross-talk between the immune and nervous system may also play a role in regulating inflammation-like responses in insects during infection.

Insect Biochem Mol Biol, 2002 Oct, 32(10), 1287 - 93
Pattern recognition proteins in Manduca sexta plasma; Yu XQ et al.; Recognition of nonself is the first step in mounting immune responses . In the innate immune systems of both vertebrates and arthropods, such recognition, termed pattern recognition, is mediated by a group of proteins, known as pattern recognition proteins or receptors . Different pattern recognition proteins recognize and bind to molecules (molecular patterns) present on the surface of microorganisms but absent from animals . These molecular patterns include microbial cell wall components such as bacterial lipopolysaccharide, lipoteichoic acid and peptidoglycan, and fungal beta-1,3-glucans . Binding of pattern recognition proteins to these molecular patterns triggers responses such as phagocytosis, nodule formation, encapsulation, activation of proteinase cascades, and synthesis of antimicrobial peptides . In this article, we describe four classes of pattern recognition proteins, hemolin, peptidoglycan recognition protein, beta-1,3-glucan recognition proteins, and immulectins (C-type lectins) involved in immune responses of the tobacco hornworm, Manduca sexta.

Jpn J Ophthalmol, 2002 Jul-Aug, 46(4), 384 - 90
General purpose antimicrobial ophthalmic solutions evaluated using new pharmacokinetic parameter of maximum drug concentration in aqueous; Fukuda M et al.; PURPOSE: In order to determine whether the one-component method for calculating drug concentration in the aqueous (AQC(max)) is useful for selecting an appropriate ophthalmic solution, six general purpose antimicrobial ophthalmic solutions already on the market were investigated . METHODS: The drugs examined were levofloxacin (LVFX), chloramphenicol (CP), erythromycin lactobionate (EM), micronomicin sulfate (MCR), cefmenoxime hydrochloride (CMX), and disodium sulfobenzyl penicillin (SBPC) . Fifty microliters of each solution was instilled into the cul-de-sac of New Zealand White rabbit eyes three times at 15-minute intervals . The drug concentrations in the aqueous humor 10, 30, 60, 120, and 240 minutes after the final instillation were examined by high performance liquid chromatography (HPLC) and/or bioassay . The AQC(max) was calculated using the one-compartment method . RESULTS: The calculated AQC(max) was 2.5 microg/mL (HPLC method) and 2.28 microg/mL (bioassay method) for LVFX, 2.17 microg/mL for CP, and 0.45 microg/mL for EM . The AQC(max) for CMX, MCR, and SBPC could not be calculated by the one-compartment method . CONCLUSIONS: The AQC(max) of LVFX was higher than that of the two other general purpose antimicrobial ophthalmic solutions . The AQC(max) of these drugs might be a useful parameter for selecting an appropriate ophthalmic solution for the treatment of infected eyes.

Expert Opin Investig Drugs, 2002 Sep, 11(9), 1261 - 9
Selenium-based pharmacological agents: an update; May SW; The biochemistry and pharmacology of selenium is a subject of intense current interest, particularly from the viewpoint of public health . Selenium, long recognised as a dietary antioxidant, is now known to be an essential component of the active sites of several enzymes, including glutathione peroxidase and thioredoxin reductase, which catalyse reactions essential to the protection of cellular components against oxidative and free radical damage . A low concentration of selenium in plasma has been identified as a risk factor for several diseases, including cancer, cardiovascular disease, osteoarthritis and AIDS, and several large-scale selenium supplementation human trials are now underway . Evidence is emerging that, at least in the case of cancer, the antitumorigenic effect of selenium supplementation arises at least in part from enhanced production of specific selenium-containing metabolites, not just from maximal expression of selenoenzymes . Therefore a number of novel pharmaceutical agents which are selenium-based or which target specific aspects of selenium metabolism are under development . Among these are orally-active antihypertensive agents, anticancer, antiviral, immunosuppressive and antimicrobial agents, and organoselenium compounds which reduce oxidative tissue damage and edema . It can be anticipated that as our understanding of the basic biology and biochemistry of selenium increases, the coming years will bring further development of new selenium-based pharmaceutical agents with therapeutic potential toward a variety of human diseases.

Am J Health Syst Pharm, 2002 Sep 1, 59(17), 1626 - 31
Pharmacogenomics and infectious diseases: impact on drug response and applications to disease management; Hayney MS; The impact of pharmacogenomics on the prevention, diagnosis, and treatment of infectious diseases is discussed . The application of pharmacogenomics to infectious diseases requires consideration of the genomes of both the pathogen and the host . The pathogen's genome may be used for antigen identification, to identify infecting organisms, and to determine antimicrobial resistance . Diagnostic tool development and vaccine design can be aided by knowing which portions of a pathogen are important antigenic determinants . The unique genetic makeup of a pathogen can facilitate its identification as an augmentation to the traditional culture . Important genes conferring resistance to antibiotics can be detected, and this information can be used to choose appropriate antibiotic therapy . The genome of the host may reveal susceptibility genes and new drug targets that may be used in the treatment of infectious diseases . Thus far, polymorphisms in genes of the host immune system have been associated with susceptibility to infections and response to treatment . Examples of these findings will be described . Pharmacogenomics has the potential to revolutionize the prevention, diagnosis, and treatment of infectious diseases.

Cell Mol Life Sci, 2002 Jul, 59(7), 1138 - 50
The short proline-rich antibacterial peptide family; Otvos L Jr; From the many peptide families that are induced upon bacterial infection and can be isolated from all classes of animals, the short, proline-rich antibacterial peptides enjoy particular interest . These molecules were shown to inactivate an intracellular biopolymer in bacteria without destroying or remaining attached to the bacterial cell membrane, and as such emerged as viable candidates for the treatment of mammalian infections . These peptides were originally isolated from insects, they kill mostly gram-negative bacteria with high efficiency and they show structural similarities with longer insect- and mammal-derived antimicrobial peptides . However, while the distant relatives appear to carry multiple functional domains, apidaecin, drosocin, formaecin and pyrrhocoricin consist of only minimal determinants needed to penetrate across the cell membrane and bind to the target biopolymer . These peptides appear to inhibit metabolic processes, such as protein synthesis or chaperone-assisted protein folding . Pyrrhocoricin derivatives protect mice from experimental infections in vivo, suggesting the utility of modified analogs in the clinical setting . Sequence variations of the target protein at the peptide-binding site may allow the development of new peptide variants that kill currently unresponsive strains or species.

Microbiol Immunol, 2002, 46(7), 483 - 6
Comparative profiles of intramacrophage behavior of Mycobacterium tuberculosis and Mycobacterium avium complex with different levels of virulence; Sano K et al.; Mycobacterium tuberculosis (MTB) and M . avium complex (MAC) strains with different levels of virulence in mice were examined for profiles of interaction with murine peritoneal macrophages (Mphis) . Their growth rates in Mphis were in these orders: H37Ra strain (attenuated) > H37Rv strain (virulent) for MTB, and N-260 strain (moderate virulence) > MAC N-444 strain (low virulence) for MAC . MTB but not MAC caused the necrotic death of host Mphis in terms of increased release of lactate dehydrogenase from infected Mphis . The MTB H37Ra strain induced a greater production of reactive nitrogen intermediates (RNI) by Mphis than the MTB H37Rv strain did . However, this phenomenon was not observed with MAC, implying less important roles of RNI in the expression of Mphi antimicrobial activity against MAC organisms.

Acta Paediatr, 2002, 91(8), 915 - 9
Neutrophil regeneration precedes healing of tissue destruction, as indicated by serum C-reactive protein, in children with cancer recovering from neutropenic fever; Vettenranta K et al.; AIM: To evaluate the relationship between absolute neutrophil count and C-reactive protein (CRP) in the recovery phase of neutropenic fever among paediatric patients with cancer . METHODS: A total of 102 paediatric oncology patients with 177 episodes of fever and neutropenia was studied prospectively in a two-centre setting . Antimicrobial therapy was discontinued 9 d (mean) post-initiation with a mean absolute neutrophil count of 1.8 x 10(9) l(-1) and CRP of 32 mg l(-1) . RESULTS: The mean level of CRP below 20 mg l(-1) was reached on day 12 . The level of CRP peaked on the day following the commencement of antimicrobial therapy . Throughout the episodes of fever and neutropenia higher levels of CRP were associated with a lower absolute neutrophil count . Following defervescence the pace of marrow recovery as evidenced by an increasing absolute neutrophil count to > 0.2 and > 0.5 x 10(9) l(-1) was more rapid than the normalization of serum CRP . There was a 2-3 d lag period between absolute neutrophil count exceeding the level of 200 x 10(6) l(-1) and the return of CRP to a baseline level . All episodes were treated successfully and there were no fatalities . CONCLUSION: Among patients recovering from neutropenia and fever the signs of marrow recovery remain the key criterion in evaluating the safety of discontinuing antimicrobial therapy, with serum CRP remaining more of an indicator of ongoing tissue repair.

Int J Food Microbiol, 2002 Sep 15, 78(1-2), 31 - 41
Emerging foodborne pathogens; Tauxe RV; The broad spectrum of foodborne infections has changed dramatically over time, as well-established pathogens have been controlled or eliminated, and new ones have emerged . The burden of foodborne disease remains substantial: one in four Americans is estimated to have a significant foodborne illness each year . The majority of these illnesses are not accounted for by known pathogens, so more must remain to be discovered . Among the known foodborne pathogens, those more recently identified predominate, suggesting that as more and more is learned about pathogens, they come under control . In addition to the emergence or recognition of new pathogens, other trends include global pandemics of some foodborne pathogens, the emergence of antimicrobial resistance, the identification of pathogens that are highly opportunistic, affecting only the most high-risk subpopulations, and the increasing identification of large and dispersed outbreaks . New pathogens can emerge because of changing ecology or changing technology that connects a potential pathogen with the food chain . They also can emerge de novo by transfer of mobile virulence factors, often through bacteriophage . Though this is rarely observed, it can be reconstructed . Better understanding of the ecology and dynamics of phage transmission among bacteria will help us to understand the appearance of new pathogens in the future . One may look for emerging foodborne pathogens among the silent zoonoses, and among the severe infections affecting the immunocompromised humans . We should expect the unexpected . In the past, separating human sewage and animal manure from human food and water supplies was critical to improving public health . Now, our health depends increasingly on the safety of the feed and water supplies for the animals themselves . The successes of the 20th century and the new challenges we face mean that public health vigilance, careful investigation of new problems, responsible attention to food safety from farm to table, and partnerships to bring about new foodborne disease control measures will be needed for the foreseeable future.

Pharmacotherapy, 2002 Sep, 22(9), 1097 - 104
Differences in antimicrobial drug exposure in patients with various degrees of renal function based on recommendations from dosing references; Bonapace CR et al.; STUDY OBJECTIVE: To calculate and compare 24-hour area under the unbound drug concentration-time curves (AUC(0-24)) of antimicrobials with dosing recommendations from six commonly used dosing references . INTERVENTION: Unbound plasma concentration-time profiles of 13 antimicrobial agents (4 penicillins, 3 cephalosporins, 2 carbapenems, aztreonam, 3 fluoroquinolones) were simulated at steady state using a one-compartment open model for a 70-kg adult based on pharmacokinetic parameters obtained from peer-reviewed literature . Simulations were performed at five levels of creatinine clearance (Cl(cr)) . MEASUREMENTS AND MAIN RESULTS: Differences in AUC(0-24) for each antimicrobial agent were noted among the six references at each level of Cl(cr) as well as within references across the range of Cl(cr) . In addition, up to 16-fold and 3-fold ranges in AUC(0-24) values were observed for beta-lactams and fluoroquinolones, respectively, in one reference based on dosing recommendations at a single level of Cl(cr) (due to more than one dose and/or dosing interval) . CONCLUSION: Clinicians should be aware of differences among common references when selecting dosages of antimicrobial agents, especially for patients with moderate-to-severe renal impairment.

J Indiana Dent Assoc, 2002 Summer, 81(2), 10 - 4
Locally delivered antimicrobials in periodontal treatment; John V et al.; The management of periodontal diseases has included both non-surgical and surgical treatment options . Non-surgical treatment traditionally has referred to the role of mechanical instrumentation of the root surface with either scalers or curettes . However, the introduction of locally delivered anti-microbial medications, which can be placed directly into a periodontal pocket, has provided the practitioner with another treatment option . This article looks at the different locally delivered anti-microbial medications being used in the non-surgical management of periodontal diseases.

Annu Rev Plant Biol, 2002, 53, 275 - 97
The lipoxygenase pathway; Feussner I et al.; Lipid peroxidation is common to all biological systems, both appearing in developmentally and environmentally regulated processes of plants . The hydroperoxy polyunsaturated fatty acids, synthesized by the action of various highly specialized forms of lipoxygenases, are substrates of at least seven different enzyme families . Signaling compounds such as jasmonates, antimicrobial and antifungal compounds such as leaf aldehydes or divinyl ethers, and a plant-specific blend of volatiles including leaf alcohols are among the numerous products . Cloning of many lipoxygenases and other key enzymes within the lipoxygenase pathway, as well as analyses by reverse genetic and metabolic profiling, revealed new reactions and the first hints of enzyme mechanisms, multiple functions, and regulation . These aspects are reviewed with respect to activation of this pathway as an initial step in the interaction of plants with pathogens, insects, or abiotic stress and at distinct stages of development.

Planta Med, 2002 Aug, 68(8), 680 - 4
Structural effects on the bioactivity of dehydroabietic acid derivatives; Gigante B et al.; The synthesis and the evaluation of the antimicrobial activity against a filamentous fungus, yeasts and bacteria of 15 hydrophenanthrene compounds derived from dehydroabietic acid, bearing different functional groups and different stereochemistry of the A/B ring junction are disclosed . The results obtained showed how their activity is dependent of the functionality at C-18, which can be increased by deisopropylation or introduction of other groups into the molecule . While the filamentous fungus tested is sensitive to almost all of the compounds under study, the aldehyde function showed to be of major importance to the inhibition of yeast . Alcohols and aldehyde C-18 derivatives also inhibit the growth of a Gram-positive bacteria, whereas Gram-negative are not sensitive.

Transpl Infect Dis, 2002 Jun, 4(2), 80 - 4
Open lung biopsy in bone marrow transplant recipients has a poor diagnostic yield for a specific diagnosis; Shaikh ZH et al.; The diagnostic yield of open lung biopsy (OLB) in bone marrow transplantation (BMT) recipients having pulmonary infiltrates has not been evaluated recently . Therefore, we reviewed our 2-year experience (1998-99) with such patients at The University of Texas M . D . Anderson Cancer Center . We found 12 BMT recipients who underwent OLB analysis for the evaluation of pulmonary infiltrates . A treatable infectious etiology leading to the initiation or modification of antimicrobial agent administration was found in only two patients having bilateral nodular disease and one having bilateral parenchymal infiltrates . We conclude that OLB in BMT patients having diffuse pulmonary infiltrates has a low diagnostic yield for treatable infectious etiologies.

Rapid Commun Mass Spectrom, 2002, 16(18), 1706 - 13
Mechanistic investigation of the interaction between bisquaternary antimicrobial agents and phospholipids by liquid secondary ion mass spectrometry and differential scanning calorimetry; Pashynskaya VA et al.; Mechanisms of interaction between the antimicrobial drugs decamethoxinum and aethonium, which are based on bisquaternary ammonium compounds, and a phospholipid component of biological membranes, dipalmitoylphosphatidylcholine, were studied by means of liquid secondary ion mass spectrometry (LSIMS) and differential scanning calorimetry (DSC) . Supramolecular complexes of the drugs with this phospholipid were recorded under secondary ion mass spectrometric conditions . The dependence of the structures of these complexes on structural parameters of the dications of the bisquaternary ammonium compounds was demonstrated . Tandem mass spectrometric investigations of the metastable decay of doubly charged ions of decamethoxinum and aethonium complexes with dipalmitoylphosphatidylcholine allowed estimation of structural parameters of these complexes in the gas phase . Interactions of decamethoxinum and aethonium with model membrane assemblies built from hydrated dipalmitoylphosphatidylcholine were studied using DSC . It was shown that while both drugs can interact with model membranes, the mechanisms of such interactions for decamethoxinum and aethonium differ . The correlation between the nature of these interactions and structural and electronic parameters of the dications of the two bisquaternary agents is discussed . Interpretation of combined mass spectrometric and calorimetric experimental data led to proposals that the molecular mechanisms of antimicrobial action of bisquaternary ammonium compounds are related to their effect on the membrane phospholipid components of microbial cells .

Electrophoresis, 2002 Sep, 23(17), 3078 - 83
Determination of residues of enrofloxacin and its metabolite ciprofloxacin in chicken muscle by capillary electrophoresis using laser-induced fluorescence detection; Horstkotter C et al.; A method for the residue analysis of the veterinary antimicrobial agent enrofloxacin and its active desethyl metabolite ciprofloxacin in chicken muscle tissue has been developed and validated . The detection of the analytes was performed by laser-induced fluorescence (LIF) detection using a HeCd laser (lambda(ex) = 325 nm) providing an enhancement in sensitivity and selectivity compared to conventional UV detection . The assay has been validated with satisfying results . The limits of quantification for enrofloxacin and ciprofloxacin were 5 microg/kg and 20 microg/kg, respectively, with a fivefold preconcentration yielded by a sample clean-up with a simple liquid-liquid extraction procedure . Calibration graphs were linear from 5 to 1000 microg/kg for enrofloxacin and from 20 to 1000 microg/kg for ciprofloxacin . The assay allows the detection of contaminated muscle samples at the required maximum residue limit of the European Union, which is 100 microg/kg for the sum of enrofloxacin and ciprofloxacin.

Compend Contin Educ Dent, 1997 Winter, 18 Spec No, 2 - 9
The scientific rationale and development of an optimized stannous fluoride dentifrice, Part 1; Burke MR et al.; Stannous fluoride has been recognized as an effective anticavity therapeutic agent since the early 1950s . There has recently been a resurgence in activity to discover ways to fully exploit its documented antimicrobial activity . Through the use of targeted in vitro methodology to predict in vivo efficacy, a highly optimized stannous fluoride dentifrice has been developed . Careful selection of stabilizing agents formulated into a unique system has resulted in a Colgate Optimized Stannous Fluoride (COSF) dentifrice that has been proven to simultaneously help control supragingival plaque, gingivitis, supragingival calculus, and caries . Furthermore, the COSF dentifrice has been clinically shown not to cause the traditional stannous fluoride staining of dentition.

Hautarzt, 2002 Jul, 53(7), 456 - 65
{Oral antibiotics with antiinflammatory/ immunomodulatory effects in the treatment of various dermatoses}; Brinkmeier T et al.; A range of antibiotics has been shown to modify host functions apart from the antimicrobial potency . They may directly influence phagocyte and lymphocyte function, as well as chemotaxis . Effects on the generation and release of various cytokines involved in the inflammatory process have been studied both in vivo and in vitro . However, the molecular mechanisms have not been elucidated in detail . It is suggested that antibiotics can exert immunopharmacological effects on the basis of structure-activity relationships independent of their antibacterial activity . We present a collection of clinical studies and case reports dealing with the potential benefits of systemic antibiotics in the treatment of selected dermatoses which have primarily been classified as non-infectious . Generally accepted treatments such as dapsone in dermatitis herpetiformis and leukocytoclastic vasculitis or chloroquine in lupus erythematosus have not been considered . Based on existing clinical trials with a higher number of cases the following antibiotics have been shown to be effective: erythromycin in bullous pemphigoid and pityriasis rosea as well as tetracyclines in pemphigus vulgaris, bullous pemphigoid and pustulosis palmaris et plantaris . However, most reports have to be viewed critically due to the uncontrolled study design, particularly in dermatoses with a tendency to spontaneous resolution . Despite this lack of evidence-based data, it is important for the clinician to know about the potential use of antibiotics for various skin disorders as a primary treatment option or steroid-sparing therapeutic adjunct . In clinical practice the use of antibiotics depends on various factors including the severity of the disease, the patient's age, contraindications to conventional therapeutic regiments and economic considerations.

J Infect, 2002 Jul, 45(1), 47 - 53
Bacteraemia due to Stenotrophomonas maltophilia: an analysis of 45 episodes; Friedman ND et al.; OBJECTIVE: Stenotrophomonas maltophilia is an important nosocomial pathogen and a therapeutic challenge . A ten-year review of episodes of bacteraemia due to S . maltophilia was undertaken in light of reports of an increasing frequency of infection . METHODS: A retrospective analysis of bloodstream infections due toS . maltophilia at a tertiary care hospital in Melbourne, Australia . Cases were identified via microbiology laboratory reports, and relevant clinical data were collected from the medical record of each patient . RESULTS: Eighty per cent of these 45 episodes were nosocomial . The most common characteristics in cases of bacteraemia were the presence of an indwelling central venous catheter (CVC) (38/45, 84%) and previous antibiotic therapy (33/45, 73%) . There were 8 deaths (8/44, 18%) within 7 days of bacteraemia . A significant correlation was found between deaths and a failure to remove the CVC (P = 0.01) or treat with appropriate antimicrobials (P = 0.01) . Antibiotic susceptibility testing revealed that isolates were most sensitive to sulphamethoxazole (80%), chloramphenicol (75.5%) and ceftazidime (64.5%) . CONCLUSIONS: S . maltophilia is an important pathogen especially in the highly compromised host . Isolation of this organism from a blood culture should prompt a careful review of the patient with particular emphasis on removal of indwelling CVCs and commencement of appropriate antibiotic therapy .

Br J Nutr, 2002 Sep, 88 Suppl 1, S39 - 49
Probiotics as modulators of the gut flora; Fooks LJ et al.; Probiotic ingestion can be recommended as a preventative approach to maintaining the balance of the intestinal microflora and thereby enhance 'well-being' . Research into the use of probiotic intervention in specific illnesses and disorders has identified certain patient populations that may benefit from the approach . Undoubtedly, probiotics will vary in their efficacy and it may not be the case that the same results occur with all species . Those that prove most efficient will likely be strains that are robust enough to survive the harsh physico-chemical conditions present in the gastrointestinal tract . This includes gastric acid, bile secretions and competition with the resident microflora . A survey of the literature indicates positive results in over fifty human trials, with prevention/treatment of infections the most frequently reported output . In theory, increased levels of probiotics may induce a 'barrier' influence against common pathogens . Mechanisms of effect are likely to include the excretion of acids (lactate, acetate), competition for nutrients and gut receptor sites, immunomodulation and the formation of specific antimicrobial agents . As such, persons susceptible to diarrhoeal infections may benefit greatly from probiotic intake . On a more chronic basis, it has been suggested that some probiotics can help maintain remission in the inflammatory conditions, ulcerative colitis and pouchitis . They have also been suggested to repress enzymes responsible for genotoxin formation . Moreover, studies have suggested that probiotics are as effective as anti-spasmodic drugs in the alleviation of irritable bowel syndrome . The approach of modulating the gut flora for improved health has much relevance for the management of those with acute and chronic gut disorders . Other target groups could include those susceptible to nosocomial infections, as well as the elderly, who have an altered microflora, with a decreased number of beneficial microbial species . For the future, it is imperative that mechanistic interactions involved in probiotic supplementation be identified . Moreover, the survival issues associated with their establishment in the competitive gut ecosystem should be addressed . Here, the use of prebiotics in association with useful probiotics may be a worthwhile approach . A prebiotic is a dietary carbohydrate selectively metabolised by probiotics . Combinations of probiotics and prebiotics are known as synbiotics.

Mol Immunol, 2002 Sep, 39(1-2), 9 - 18
Characterization of an upstream open reading frame in the 5' untranslated region of PR-39, a cathelicidin antimicrobial peptide; Wu H et al.; Cathelicidins are antimicrobial peptides present in humans, and laboratory and domestic animals . These peptides are essential components of innate and acquired immune responses; however, little is known about cathelicidin gene regulation . To investigate the regulatory mechanisms of cathelicidin gene expression, we characterized the promoter of the PR-39 gene, a multifunctional cathelicidin . Deletion analysis identified a negative regulatory element in the 5'-flanking region of the gene located in the sequence from nt (nucleotide(s)) -69 to -63 . Site-directed mutagenesis indicated that ATG and its vicinity nucleotides are critical for the repressive activity of this region . A primer extension assay identified a transcription start site upstream from the negative repressor ATG and 76 nt upstream from the major open reading frame (ORF) . RT-PCR and 3'-RACE further demonstrated that cDNA of PR-39 and the cathelicidin porcine myeloid antimicrobal peptide (PMAP)-23, which share prepro sequence identity, start from nt -79 . Sequencing of this region showed that the 5' untranslated region (UTR) of the gene contains an upstream translation start site and an upstream ORF that functions as a repressor of the PR-39 gene . These findings indicate extensive regulation of the PR-39 gene and suggest a mechanism for the tissue-specific and age-dependent repression of this cathelicidin gene.

Insect Biochem Mol Biol, 2002 Sep, 32(9), 1171 - 9
Characterization of four Toll related genes during development and immune responses in Anopheles gambiae; Luna C et al.; Toll-like receptors (TLRs) are a group of evolutionary conserved proteins with diverse biological functions . In Drosophila melanogaster, Toll protein plays an important role in pattern formation in embryogenesis and in antimicrobial immunity in larvae and adults . In insects, Toll and two other related proteins, Tehao and 18-wheeler have been shown to participate in the activation of the innate immune responses to fungal and bacterial pathogens . In this paper we report the cloning and characterization of four TLR gene from malaria vector mosquito Anopheles gambiae, AgToll, AgToll6, AgTrex, and AgToll9, orthologues of DmToll, DmToll6, DmTollo (Toll8) and DmToll9 (CG5528) in Drosophila melanogaster . The expression profiles of these genes during development, in different adult tissues and after immune challenge were examined . As expected for the orthologue of Drosophila Toll, AgToll was found to be expressed highly in the ovary and may play a role in pattern formation during embryogenesis . AgToll9, surprisingly, was found to be highly expressed in the adult gut . The potential roles of these genes in development and immunity were discussed.

J Vet Pharmacol Ther, 2002 Aug, 25(4), 251 - 8
Efficacy and pharmacokinetics of enrofloxacin and flunixin meglumine for treatment of cows with experimentally induced Escherichia coli mastitis; Rantala M et al.; The efficacy of flunixin alone and together with enrofloxacin in treatment of experimental Escherichia coli mastitis was compared using six cows . The cross-over study design was used . Pharmacokinetics of flunixin and enrofloxacin were also studied in these diseased cows . The response of each cow was similar after the first and second challenge and the individual reaction seemed to explain the severity of clinical signs . The most important predictive factor for outcome of E . coli mastitis was a heavy drop in milk yield . Treatment with enrofloxacin and flunixin enhanced elimination of bacteria, but the difference from those receiving flunixin alone was not significant . Two cows, which had received no antimicrobial treatment (Group 1), were killed on day 4 postchallenge . One cow was killed after the first and the other after the second challenge . Cows receiving combination therapy produced 0.9 L more milk per day during the study period than cows which had only received flunixin (P < 0.05) . Based on our findings, antimicrobial treatment might be beneficial in the treatment of high-yielding cows in early lactation . The absorption of enrofloxacin was delayed after subcutaneous administration, the mean apparent elimination half-life being about 23 h, whereas after i.v . administration elimination t(1/2) was only 1.5 h . The majority of the antimicrobial activity in milk originated from the active metabolite, ciprofloxacin, which could be measured throughout the 120-h follow-up period after the last subcutaneous administration . No differences were present in the pharmacokinetic parameters of flunixin between treatment groups: mean elimination half-life was 5.7-6.2 h, volume of distribution 0.43-0.49 L/kg and clearance 0.13-0.14 L h/kg . No flunixin or merely traces were detected in milk: one of the three cows had a concentration of 0.019 mg/L 8 h after administration.

J Med Chem, 2002 Sep 12, 45(19), 4282 - 99
Novel structures derived from 2-{{(2-pyridyl)methyl}thio}-1H-benzimidazole as anti-Helicobacter pylori agents, Part 1; Kuhler TC et al.; 2-{{(2-Pyridyl)methyl}thio}-1H-benzimidazoles (2, sulfides) exhibit antibacterial properties that are selective for Helicobacter spp., but they also have an inherent susceptibility to metabolic oxidation to furnish 2-{{(2-pyridyl)methyl}sulfinyl}-1H-benzimidazoles (1), which act as proton pump inhibitors (PPIs) . We have discovered five compounds with retained antibacterial potency and selectivity in which the overall framework of the sulfides 2 could be kept intact while structural modifications were made to remove PPI activity . These compounds, 2-{((2-methyl-3-(2-(2-(2-methoxyethoxy)ethoxy)ethylthio)phenyl)methyl)thio}-1H-benzimidazole (79), 2-{((2-methyl-3-(2-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy)ethylthio)phenyl)methyl)thio}-1H-benzimidazole (80), 2-{((2-methyl-3-((2-morpholino)ethylthio)phenyl)methyl)thio}-1H-benzimidazole (86), 2-{{{2-methyl-3-{2-(2-methyl-5-nitroimidazol-1-yl)ethylthio}phenyl}methyl}thio}-1H-benzimidazole (88), and 2-{{{2-methyl-3-{2-(1,2,4-triazol-1-yl)ethylthio}phenyl}methyl}thio}-1H-benzimidazole (89), had minimum bactericidal concentrations (MBCs) of 0.5, 0.5, 1, 2, and 4 microg/mL, respectively . The reported compounds are bactericidal with MBCs within 1 order of magnitude of MBCs of clinically used antimicrobials such as clarithromycin (0.1 microg/mL) or metronidazole (2-4 microg/mL) but differ from these inasmuch that they have an extremely narrow spectrum activity and appear to be species specific.

Eur Respir J, 2002 Aug, 20(2), 432 - 9
Hospital-acquired pneumonia: microbiological data and potential adequacy of antimicrobial regimens; Leroy O et al.; Adequate antimicrobial therapy is a main approach employed to decrease the mortality associated with hospital-acquired pneumonia (HAP) . All methods that optimise empirical treatment without increasing antibiotic selective pressure are relevant . Categorisation of patients according to HAP time of onset, severity and risk factors (American Thoracic Society (ATS) classification) or duration of mechanical ventilation and prior antibiotics (Trouillet's classification) are two such methods . The aim of this study was to catagorise patients with HAP according to these classifications and to determine the frequency of resistant pathogens and the most adequate antimicrobial regimens in each group . A total 124 patients with bacteriologically proven HAP were studied . The ATS classification categorised patients by increasing frequency of resistant pathogens from 0-30.3% . The ATS empirical antibiotic recommendations appeared valid but proposed combinations including vancomycin for 72.5% of patients . Trouillet's classification categorised patients into four groups with a frequency of resistant pathogens from 4.9-35.6% . Vancomycin was proposed for 48.5% of patients . The American Thoracic Society classification appears to be more specific than Trouillet's for predicting the absence of resistant causative pathogens in hospital-acquired pneumonia but could lead to a greater use of vancomycin . Stratification combining the two classifications is an interesting alternative.

Anim Biotechnol, 2002 May, 13(1), 71 - 84
The food safety perspective of antibiotic resistance; McDermott PF et al.; Bacterial antimicrobial resistance in both the medical and agricultural fields has become a serious problem worldwide . Antibiotic resistant strains of bacteria are an increasing threat to animal and human health, with resistance mechanisms having been identified and described for all known antimicrobials currently available for clinical use . There is currently increased public and scientific interest regarding the administration of therapeutic and sub-therapeutic antimicrobials to animals, due primarily to the emergence and dissemination of multiple antibiotic resistant zoonotic bacterial pathogens . This issue has been the subject of heated debates for many years, however, there is still no complete consensus on the significance of antimicrobial use in animals, or resistance in bacterial isolates from animals, on the development and dissemination of antibiotic resistance among human bacterial pathogens . In fact, the debate regarding antimicrobial use in animals and subsequent human health implications has been going on for over 30 years, beginning with the release of the Swann report in the United Kingdom . The latest report released by the National Research Council (1998) confirmed that there were substantial information gaps that contribute to the difficulty of assessing potential detrimental effects of antimicrobials in food animals on human health . Regardless of the controversy, bacterial pathogens of animal and human origin are becoming increasingly resistant to most frontline antimicrobials, including expanded-spectrum cephalosporins, aminoglycosides, and even fluoroquinolones . The lion's share of these antimicrobial resistant phenotypes is gained from extra-chromosomal genes that may impart resistance to an entire antimicrobial class . In recent years, a number of these resistance genes have been associated with large, transferable, extra-chromosomal DNA elements, called plasmids, on which may be other DNA mobile elements, such as transposons and integrons . These DNA mobile elements have been shown to transmit genetic determinants for several different antimicrobial resistance mechanisms and may account for the rapid dissemination of resistance genes among different bacteria . The increasing incidence of antimicrobial resistant bacterial pathogens has severe implications for the future treatment and prevention of infectious diseases in both animals and humans . Although much scientific information is available on this subject, many aspects of the development of antimicrobial resistance still remain uncertain . The emergence and dissemination of bacterial antimicrobial resistance is the result of numerous complex interactions among antimicrobials, microorganisms, and the surrounding environments . Although research has linked the use of antibiotics in agriculture to the emergence of antibiotic-resistant foodborne pathogens, debate still continues whether this role is significant enough to merit further regulation or restriction.

Anim Biotechnol, 2002 May, 13(1), 7 - 27
Why and how antibiotics are used in swine production; Cromwell GL; In summary, published research data clearly show that the use of antibiotics during all phases of growth benefits the rate and efficiency of body weight gain, reduces mortality and morbidity, reduces subclinical disease, and improves health in pigs . Also, antibiotics at breeding and during lactation benefits reproductive and lactational performance in sows . The economic benefits are several-fold greater than the cost of the antibiotic when a cost-effective antibiotic is used for this purpose . Monitoring and surveillance of microbial resistance in animals and humans has continued, with no animal-to-human infection path being clearly delineated . Although the incidence of antibiotic resistance in the human population remains high, there is no clear evidence that the levels or patterns have changed . The high levels of antimicrobial resistance in humans likely result from antibiotics prescribed directly to humans, because well over half of the antibiotics produced in the United States is used in human medicine . Whether antibiotic usage in swine, poultry, and other food-producing animals contributes to antibiotic resistance in the human population will continue to be debated . Even though antibiotics have been fed for nearly 50 years to literally billions of animals, there is still no convincing evidence of unfavorable health effects in humans that can be directly linked to the feeding of subtherapeutic levels of antibiotics to swine or other animals . Hopefully, policy decisions in the future regarding the use of antimicrobials in animals will be based on science and sound risk assessment, and not on emotionalism.

Kansenshogaku Zasshi, 2002 Jul, 76(7), 550 - 7
{Assessing the efficacy of antimicrobial agents based on the Japanese Respiratory Society Guidelines for a community-acquired pneumonia}; Sasaki E et al.; We evaluated the efficacy of antimicrobial agents used for patients with community-acquired pneumonia (CAP) based on the guidelines of Japanese Respiratory Society . A total of ninety-nine hospitalized patients who were suspected to have bacterial pneumonia at the time of admission between January, 1998 and December, 2000 were assessed . Our conclusions were as follows . 1) The rate which was considered as effective by the guidelines were 83.3% (5 of 6 cases), 98.7% (74 of 75 cases), 85.7% (12 of 14 cases), and 100% (4 of 4 cases) for penicillin, cephem, carbapenem and tetracycline, respectively . 2) These guidelines were useful and practical for identifying the etiological organisms, determining the severity of pneumonia and evaluating the efficacy of chemotherapeutic agents in CAP . 3) Gram-positive organisms were isolated more frequently among the "mild" group . The number of isolated gram-negative was increased significantly as the severity of pneumonia progressed from "mild" to "severe" group . 4) Factors such as body temperature and white cells count were not always applicable for evaluating the clinical effect in elderly cases . 5) Risk factors such as underlying diseases, or complications, age (over eighty years old) and specific etiological organisms might influence the ineffectiveness of antimicrobial agents among the cases that had no clinical response . 6) The choice of antibiotic agents for the treatment of CAP should be made with consideration to the local-specific profiles of each medical facility as described in the guidelines.

Kansenshogaku Zasshi, 2002 Jul, 76(7), 542 - 9
{The results of antibiotic susceptibility of gram-negative rods at Tottori University Hospital--the possibility of the sensible use of narrow-spectrum antimicrobial agents}; Kataoka D et al.; The control of hospital-acquired infections is a matter of social concern, especially in the proper use of antimicrobial agents . The fundamentals of treatment for infectious diseases involve the exact identification of the responsible bacteria, and the minimum essential use of narrow-spectrum antimicrobial agents for the identified bacteria . We tested the antimicrobial susceptibility of 13 species which belong to the gram-negative rod type and isolated 50 or more strains at Tottori University Hospital in 2001 . We evaluated the susceptibility pattern for every species, and have proposed a plan for the sensible use of narrow-spectrum antimicrobial agents . The resistant frequency in the present study was equal to or lower than previously reported . We think that it is possible to use narrow-spectrum antimicrobial agents more often, because the susceptible frequency to these agents was fairly high for some species . It is not too much to say that the history of the development of antimicrobial agents has been a road to broad-spectrum . Though the proper use of antimicrobial agents seems to go against this view, we should remain farsighted . Not only is the publicity of proper use indispensable but excellent surveillance is also highly necessary . We hope for the establishment of a good surveillance system gifted with simplicity, universality, high reproduction and continuity.

Hua Xi Yi Ke Da Xue Xue Bao, 1999 Sep, 30(3), 253 - 5
{Detection of HNP1 gene expression by RT-PCR in transfected tracheal epithelial cells}; Wu Q et al.; By using lipofection reagent DOSPER, the plasmid vector carrying the human neutrophil defensin HNP1 gene(pBabe-Neo-HNP1) was transferred into human, rabbit tracheal epithelial cells cultured in serum-free complement medium . Determination of HNP1 mRNA expression in tracheal epithelial cells was performed by reverse transcription-polymerase chain reaction (RT-PCR) . The result showed that HNP1-gene expression was detected both in human and rabbit transfected epithelial cells; while in untransfected epithelial cells, no specific signals were detected by RT-PCR . This result and the result of our previous determination by immunocytochemical staining both demonstrated that the epithelial cells could express the antibiotic peptide when transfected with its gene, suggesting that the mucosal antibiotic peptide gene transfer might develop a new antimicrobial approach to prevention and treatment of respiratory infections.

J Periodontol, 2002 Aug, 73(8), 835 - 42
Effect of locally delivered minocycline microspheres on markers of bone resorption; Oringer RJ et al.; BACKGROUND: Gingival crevicular fluid (GCF) biomarkers associated with bone resorption may be useful to determine periodontal disease status and response to therapy . The pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), a bone-specific degradation product, and interleukin 1-beta (IL-1), a potent bone-resorptive cytokine, have both been associated with periodontal disease activity . Minocycline is a tetracycline derivative possessing antimicrobial effects on periodontal pathogens and inhibitory properties on matrix metalloproteinases (MMPs) associated with tissue destruction . The aim of this study was to evaluate the effect of periodontal treatment in the form of scaling and root planing (SRP) and locally administered minocycline microspheres on the GCF levels of ICTP and IL-1 . METHODS: Forty-eight chronic periodontitis patients were randomly assigned to 2 groups (SRP plus subgingival application of vehicle control {SRP + V}, or SRP plus subgingival application of minocycline microspheres {SRP + M}) and monitored at 8 sites per subject at baseline and 1, 3, and 6 months . Four shallow (PD < or = 3 mm) and 4 deep (PD > or = 5 mm) sites were evaluated for both marker levels and for probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) . Eight periodontally healthy control subjects with no probing depths >3 mm and no loss of attachment were also monitored at the same time intervals . GCF levels of ICTP and IL-1 were determined using radioimmunoassay and enzyme-linked immunosorbent assay techniques, respectively . RESULTS: Significant differences (P<0.001) in GCF levels of ICTP and IL-1 were found between deep and shallow sites at all time points in both treatment groups . In addition, healthy subjects demonstrated significantly reduced levels of both markers compared to both shallow and deep sites in periodontitis patients (P <0.001) . Only the SRP + M treated patients exhibited significant reductions (P <0.05) in both ICTP and IL-1 levels 1 month after treatment . Furthermore, the SRP + M group demonstrated significantly lower IL-1 levels (P <0.02) at 1 month compared to the SRP + V group . CONCLUSIONS: Results of this study indicate that GCF levels of ICTP and IL-1 correlate with clinical measures of periodontal disease and may aid in assessing disease status and response to periodontal therapy . Furthermore, local administration of minocycline microspheres led to a potent short-term reduction in GCF IL-1 levels . Additional studies are needed to address whether repeated administration of scaling and root planing along with minocycline microspheres will achieve long-term reductions in GCF ICTP and IL-1 levels.

Proteins, 2002 Nov 1, 49(2), 191 - 205
Molecular motions and conformational changes of HPPK; Keskin O et al.; 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) belongs to a class of catalytic enzymes involved in phosphoryl transfer and is a new target for the development of novel antimicrobial agents . In the present study, the fundamental consideration is to view the overall structure of HPPK as a network of interacting residues and to extract the most cooperative collective motions that define its global dynamics . A coarse-grained model, harmonically constrained according to HPPK's crystal structure is used . Four crystal structures of HPPK (one apo and three holo forms with different nucleotide and pterin analogs) are studied with the goal of providing insights about the function-dynamic correlation and ligand induced conformational changes . The dynamic differences are examined between HPPK's apo- and holo-forms, because they are involved in the catalytic reaction steps . Our results indicate that the palm-like structure of HPPK is nearly rigid, whereas the two flexible loops: L2 (residues 43-53) and L3 (residues 82-92) exhibit the most concerted motions for ligand recognition and presumably, catalysis . These two flexible loops are involved in the recognition of HPPKs nucleotide and pterin ligands, whereas the rigid palm region is associated with binding of these cognate ligands . Six domains of collective motions are identified, comprised of structurally close but not necessarily sequential residues . Two of these domains correspond to the flexible loops (L2 and L3), whereas the remaining domains correspond to the rigid part of the molecule . Published 2002 Wiley-Liss, Inc.

Arch Pharm (Weinheim), 2002 Jun, 335(6), 283 - 8
Synthesis and antimicrobial activity of some 2-{p-substituted-phenyl}benzoxazol-5-yl-arylcarboxyamides; Temiz-Arpaci O et al.; New 2-{p-substituted-phenyl }benzoxazol-5-yl-arylcarboxyamides derivatives have been synthesized by reacting 5-amino-2-{p-substituted-phenyl }benzoxazoles with substituted-arylcarboxylic acid chlorides . The structures of the synthesized compounds were confirmed by IR and (1)H NMR spectral data . Antimicrobial activities of the compounds were investigated using the two-fold serial dilution technique against different Gram-positive and Gram-negative bacteria and the yeast C . albicans in comparison with standard drugs . Microbiological results indicated that the synthesized compounds possess a broad spectrum of activity, having an MIC value of 25-200 microg/mL at molar concentration values of 3.45 x 10(-5) and 5.74 x 10(-4) against the tested microorganisms.

Arch Pharm (Weinheim), 2002 Jun, 335(6), 267 - 76
New withanolides and other constituents from the fruit of Withania somnifera; Abou-Douh AM; Two new steroidal lactones of the withanolide-type, 5beta, 6alpha, 14alpha, 17beta, 20beta-pentahydroxy-1-oxo-20 S, 22R-witha-2, 24-dienolide (1)and 6alpha, 7alpha-epoxy-5alpha, 14alpha, 17alpha, 23beta-tetrahydroxy-1-oxo-22R-witha-2, 24-dienolide (2), were isolated from the fruit of Withania somnifera (L.) Dunal (Solanaceae) growing in Southern Egypt, together with two known coumarins, scopoletin (3)and aesculetin (4), a known triterpene, viz . Beta-amyrin (5), and two known phytosterols, viz . stigmasterol (6) and sitosterol (7) . The structures of the isolated compounds have been elucidated by spectroscopic methods including UV, IR, (1)H-, (13)C-NMR, DEPT experiments, HRFAB-, FAB-, and EI-mass spectrometry . The in vitro antimicrobial activity of the new withanolide (1) and the alcoholic fruit extract are discussed.

Bone Marrow Transplant, 2002 Sep, 30(5), 311 - 4
The efficacy of prophylactic outpatient antibiotics for the prevention of neutropenic fever associated with high-dose etoposide (VP-16) for stem cell mobilization; Avery RK et al.; High-dose etoposide (2 g/m(2)) plus G-CSF is a very effective regimen for peripheral blood progenitor cell (PBPC) mobilization . Unfortunately, neutropenia is common . The infectious complications associated with high-dose etoposide have not been previously described . After noting a high incidence of hospitalizations for neutropenic fever, we began a vigorous prophylactic antibiotic regimen for patients receiving high-dose etoposide plus G-CSF, attempting to reduce infectious complications . Ninety-eight patients underwent etoposide mobilization between December 1997 and June 2000 . Three chronological patient groups received: (1) no specific antibiotic prophylaxis (n = 44); (2) vancomycin i.v., cefepime i.v., clarithromycin p.o., and ciprofloxacin p.o . (n = 27); and (3) vancomycin i.v., clarithromycin p.o., and ciprofloxacin p.o . (n = 27) . The patients not receiving antibiotic prophylaxis had a 68% incidence of hospitalization for neutropenic fever . In the patients receiving prophylaxis, the incidence was reduced to 26% and 15% respectively, for an overall incidence of 20% (P < 0.001 for comparison between prophylaxed and unprophylaxed groups) . We conclude that etoposide mobilization is associated with a significant incidence of neutropenic fever, which can be substantially reduced by a vigorous antimicrobial prophylactic program.

Annu Rev Entomol, 2003, 48, 163 - 84 Epub 2002 Jun 04.
Male accessory gland secretions: modulators of female reproductive physiology and behavior; Gillott C; Secretions of male accessory glands contain a variety of bioactive molecules . When transferred during mating, these molecules exert wide-ranging effects on female reproductive activity and they improve the male's chances of siring a significant proportion of the female's offspring . The accessory gland secretions may affect virtually all aspects of the female's reproductive activity . The secretions may render her unwilling or unable to remate for some time, facilitating sperm storage and ensuring that any eggs laid will be fertilized by that male's sperm . They may stimulate an increase in the number and rate of development of eggs and modulate ovulation and/or oviposition . Antimicrobial agents in the secretions ensure that the female reproductive tract is a hospitable environment during sperm transfer . In a few species the secretions include noxious chemicals . These are sequestered by developing eggs that are thereby protected from predators and pathogens when laid.

Med Hypotheses, 2002 Oct, 59(4), 429 - 32
Lithium and antidepressants: inhibiting eicosanoids, stimulating immunity, and defeating microorganisms; Lieb J; Infection-emerging, reemerging, antibiotic-resistant, and bioengineered-increasingly threatens mankind . It is widely assumed that immunostimulating agents, were they to exist, would be ideal in battling microorganisms . Various investigators have established lithium and antidepressants as immunostimulants and antimicrobials and they have identified the mechanisms involved . Eicosanoids both depress immunity and activate microorganisms and lithium and antidepressants oppose eicosanoids . Such philosophers of science as Paul Feyerabend have argued that special interests invariably oppose revolutionary paradigms.

Biochem Biophys Res Commun, 2002 Sep 6, 296(5), 1044 - 50
Conformation-dependent antibiotic activity of tritrpticin, a cathelicidin-derived antimicrobial peptide; Yang ST et al.; Tritrpticin, a Trp-rich cationic antimicrobial peptide with a unique amino acid sequence (VRRFPWWWPFLRR), is found in porcine cathelicidin cDNA . Tritrpticin has a broad spectrum of antibacterial and antifungal activities and hemolytic activity comparable to that of indolicidin . To investigate the mechanism of the bacterial killing action of tritrpticin and to identify structural features important for bacterial cell selectivity, we designed several tritrpticin analogs with amino acid substitutions of the Pro and Trp residues . Circular dichroism studies revealed that the substitution of Pro-->Ala (TPA) or Trp-->Phe (TWF) leads to significant conformational changes in SDS micelles, converting the beta-turn to alpha-helix or to poly-L-proline II helix, respectively . Compared to tritrpticin, TPA retained most of its antimicrobial activity, but showed enhanced hemolytic and membrane-disrupting activities . In contrast, TWF showed a 2-4-fold increase in antimicrobial activity against Gram-negative bacteria, but a marked decrease in both hemolytic and membrane-disrupting activities . Taken together, our findings suggest that compared with the beta-turn and alpha-helical structures, the poly-L-proline II helix is crucial for effective bacterial cell selectivity in tritrpticin and its analogs.

Curr Opin Crit Care, 2002 Feb, 8(1), 58 - 69
Prevention and management of ventilator-associated pneumonia; Ewig S et al.; Worldwide, the increasing rates of microbial resistance represent a serious public health problem . Therefore, measures to prevent ventilator-associated pneumonia gain increasing importance . Because antimicrobial treatment in the ICU is a major source of microbial resistance, prevention should be understood not only as the sum of preventive measures but also as part of any management strategy . In this year of review, several important contributions have been made to a better understanding of the relative role of preventive measures . This is particularly true of noninvasive ventilation, continuous aspiration of subglottic secretions, and closed endotracheal suctioning . Management strategies for ventilator-assisted pneumonia remain highly controversial . Despite two decades of vigorous research, there is still no evidence that invasive bronchoscopic techniques should form part of a routine approach to suspected ventilator-assisted pneumonia . Moreover, an impact in terms of important outcome variables could not be consistently demonstrated . In the authors' view, the controversy regarding the relative validity of diagnostic tools should end, and the focus should shift to strategies that define low-risk patients with suspected ventilator-assisted pneumonia who can safely be treated by short-term monotherapy . Finally, several contributions have refined the established treatment regimen . Several new drugs for the treatment of ventilator-assisted pneumonia caused by Gram-positive multiresistant pathogens have been evaluated with promising results.

Clin Diagn Lab Immunol, 2002 Sep, 9(5), 972 - 82
Augmentation of the lipopolysaccharide-neutralizing activities of human cathelicidin CAP18/LL-37-derived antimicrobial peptides by replacement with hydrophobic and cationic amino acid residues; Nagaoka I et al.; Mammalian myeloid and epithelial cells express various peptide antibiotics (such as defensins and cathelicidins) that contribute to the innate host defense against invading microorganisms . Among these peptides, human cathelicidin CAP18/LL-37 (L(1) to S(37)) possesses not only potent antibacterial activity against gram-positive and gram-negative bacteria but also the ability to bind to gram-negative lipopolysaccharide (LPS) and neutralize its biological activities . In this study, to develop peptide derivatives with improved LPS-neutralizing activities, we utilized an 18-mer peptide (K(15) to V(32)) of LL-37 as a template and evaluated the activities of modified peptides by using the CD14(+) murine macrophage cell line RAW 264.7 and the murine endotoxin shock model . By replacement of E(16) and K(25) with two L residues, the hydrophobicity of the peptide (18-mer LL) was increased, and by further replacement of Q(22), D(26), and N(30) with three K residues, the cationicity of the peptide (18-mer LLKKK) was enhanced . Among peptide derivatives, 18-mer LLKKK displayed the most powerful LPS-neutralizing activity: it was most potent at binding to LPS, inhibiting the interaction between LPS and LPS-binding protein, and attaching to the CD14 molecule, thereby suppressing the binding of LPS to CD14(+) cells and attenuating production of tumor necrosis factor alpha (TNF-alpha) by these cells . Furthermore, in the murine endotoxin shock model, 18-mer LLKKK most effectively suppressed LPS-induced TNF-alpha production and protected mice from lethal endotoxin shock . Together, these observations indicate that the LPS-neutralizing activities of the amphipathic human CAP18/LL-37-derived 18-mer peptide can be augmented by modifying its hydrophobicity and cationicity, and that 18-mer LLKKK is the most potent of the peptide derivatives, with therapeutic potential for gram-negative bacterial endotoxin shock.

Clin Infect Dis, 2002 Sep 15, 35(6), 697 - 702 Epub 2002 Aug 26.
Hospital-acquired pneumococcal bacteremia; Canet JJ et al.; To assess the most relevant features of hospital-acquired pneumococcal bacteremia, all cases of pneumococcal bacteremia at a single teaching hospital that occurred during 1988-2000 were prospectively studied . During this period, 374 cases of pneumococcal bacteremia were documented; 39 (10%) of these episodes were hospital acquired . Twenty-nine (74%) cases occurred during the period of December through May . Eleven (28%) of 39 patients had received antimicrobial agents in the month before the onset of bacteremia . All patients had underlying diseases that predisposed them to pneumococcal infection . The most common origin of infection was the respiratory tract, followed by the intra-abdominal region . Fifteen strains were fully susceptible to penicillin, and 20 were intermediately resistant . Only 25 strains were susceptible to erythromycin; all strains that were resistant to erythromycin were penicillin nonsusceptible . Eighteen (46%) of 39 patients died; the mortality rate related to infection was 39%.

J Clin Microbiol, 2002 Sep, 40(9), 3532 - 4
Isolation of Nocardia paucivorans from the cerebrospinal fluid of a patient with relapse of cerebral nocardiosis; Eisenblatter M et al.; Nocardia paucivorans represents a new species of the genus Nocardia that has recently been isolated from bronchial secretions of a patient with chronic lung disease . Here, we report on the course of a disseminated infection caused by this species: i.e., cerebral and subsequent meningeal manifestations, isolation from the cerebrospinal fluid, and in vitro susceptibility to various antimicrobial agents.

Rev Panam Salud Publica, 2002 Jul, 12(1), 11 - 8
The general public's perceptions and use of antimicrobials in Trinidad and Tobago; Parimi N et al.; OBJECTIVE: To determine the general public's perceptions and use of antibiotics in Trinidad and Tobago, a two-island republic in the Caribbean . METHODS: This prospective study surveyed 824 randomly selected households listed in the telephone directory, from November 1998 to January 1999 . Through telephone interviews we determined knowledge about antibiotics and beliefs concerning their safety and efficacy . We studied the influence of age, gender, education, and having private health insurance on knowledge, self-medication, storing medication at home for emergency use ("hoarding"), and asking a private doctor to prescribe antibiotics ("demand prescribing") . RESULTS: For the 824 telephone calls that the interviewers completed, 753 of the households agreed to participate (91.4% response rate) . Of those 753 participants, 699 of them (93%) knew the term "antibiotic," 29% (206/699) said it was a drug for bacterial infections, and 25% (170/690) had asked a doctor for an antibiotic prescription . Penicillin was correctly identified as an antibiotic across age, gender, and education categories, but 36% of respondents incorrectly said Benadryl (diphenhydramine), a common over-the-counter cough and cold formulation, was an antibiotic . Gender was not significantly associated with knowledge of antibiotic safety, with self-medication, or with hoarding antibiotics . On the other hand, completion of tertiary (university) education was significantly associated with correct knowledge of the safety of antibiotics and whether or not they could cure all infections . Of the various antimicrobials, beta-lactams were the ones that survey respondents had used most frequently in the preceding year, and 20% of antibiotics users had used multiple antibiotics in that period . In comparison to persons with private health insurance, more individuals without private health insurance said that antibiotics are safe and do not have side effects, and more of them also incorrectly called aspirin and Benadryl antibiotics . CONCLUSIONS: In Trinidad and Tobago, inappropriate use of antimicrobials results from self-medication, over-the-counter availability at the community pharmacy, prescribing on demand, and lack of regulatory control . In order to contain antibiotic abuse, both the Drug Inspectorate of the Ministry of Health and the Pharmacy Board should exert stricter control on the dispensing of antibiotics at private pharmacies . Further, education of the general public and of health care professionals on antibiotic misuse and appropriate use must be instituted, along with community-based surveillance of antimicrobial resistance trends.

J Hematother Stem Cell Res, 2002 Aug, 11(4), 683 - 94
Mobilization and transduction of CD34(+) peripheral blood stem cells in patients with X-linked chronic granulomatous disease; Ott MG et al.; As a single-gene defect in phagocytes, the X-linked form of chronic granulomatous disease (X-CGD) is a disorder potentially amenable to gene therapy by transfer of a functional copy of the gp91(phox) gene into hematopoietic stem cells (HSC) . Although antimicrobial agents and interferon-gamma (IFN-gamma) have significantly improved its prognosis, CGD is still associated with high morbidity and mortality . The disease can be cured by bone marrow transplantation (BMT); however, BMT in CGD has been associated with unacceptably high rates of morbidity, mortality, and graft failure, except in very selected cases in which an HLA-identical donor is available . Prerequisites for a clinical gene therapy of CGD are an efficient mobilization of peripheral blood stem cells (PBSC) as well as the preservation of their viability and hematopoietic potential following transduction and ex vivo culture . We show that (i) mobilization and collection of CD34(+) cells after a 4-week IFN-gamma-free period by G-CSF results in sufficient numbers of cells for transplantation; (ii) the quality of collected stem cells is not altered in comparison to cells obtained from healthy volunteers as assessed by long-term culture initiating cells (LTC-IC) and progenitor cell expansion; (iii) retroviral transfer of the gp91(phox) gene under defined, serum-free conditions leads to high and stable reconstitution of the respiratory burst activity in X-CGD neutrophils derived from transduced CD34(+) progenitor and LTC-IC . Withdrawal of IFN-gamma in CGD patients may improve mobilization of CD34(+) stem cells by G-CSF . The gene transfer conditions established here are applicable to a clinical approach for gene therapy of X-CGD.

J Small Anim Pract, 2002 Aug, 43(8), 350 - 4
Ulcerative otitis externa responsive to immunosuppressive therapy in two dogs; Hendricks A et al.; Two middle-aged dogs were presented with bilateral severe ulcerative otitis externa without previous history of disease or evidence of other skin disease . Based on the exclusion of microbial infection and other primary causes, histopathological findings and response to immunomodulatory treatment, a diagnosis of presumed immune-mediated ulcerative otitis externa was made in both cases . However, the two cases differed with regard to their histopathological characteristics and the course of the disease . This report indicates that primary ulcerative disease needs to be considered in cases of ulcerative otitis externa which are unresponsive to appropriate antimicrobial therapy.

Appl Environ Microbiol, 2002 Sep, 68(9), 4676 - 8
Escherichia coli O157 and non-O157 isolates are more susceptible to L-lactate than to D-lactate; McWilliam Leitch EC et al.; The antimicrobial effect of L-lactate was much greater than that of D-lactate over a range of concentrations for Escherichia coli O157 and non-O157 strains . Despite this, the intracellular pHs and membrane potentials of L-lactate- and D-lactate-treated cells were similar, suggesting that these factors are not involved in the antimicrobial action of L-lactate.

Clin Microbiol Infect, 2002 Jul, 8(7), 438 - 41
Effect of antioxidants on the immune response of Helicobacter pylori; Akyon Y; Antioxidants are substances capable of inhibiting oxidation . In chronic diseases, inflammatory response cells produce oxygen free radicals . Oxygen free radicals cause DNA damage, and this may lead to gene modifications that might be carcinogenic . Chronic Helicobacter pylori infection causes the production of DNA-damaging free radicals . In recent years, various groups have studied the effects of antioxidants, especially on H . pylori-associated gastric cancer . In most of the studies, it has been shown that H . pylori infection does affect the level of antioxidants measured in the gastric juice, but there are also controversial results . Recent experimental studies, both in vivo and in vitro, have shown that vitamin C and astaxanthin, a carotenoid, are not only free radical scavengers but also show antimicrobial activity against H . pylori . It has been shown that astaxanthin changes the immune response to H . pylori by shifting the Th1 response towards a Th2 T-cell response . Very few experimental studies support the epidemiologic studies, and further studies are needed to describe the effect and the mechanism of antioxidants in the H . pylori immune response.

Clin Microbiol Infect, 2002 Jul, 8(7), 388 - 96
The status of antimicrobial resistance of Helicobacter pylori in eastern Europe; Boyanova L et al.; OBJECTIVE: To evaluate the primary, secondary and combined resistance to five antimicrobial agents of 2340 Helicobacter pylori isolates from 19 centers in 10 countries in eastern Europe . METHODS: Data were available for centers in Bulgaria, Croatia, the Czech Republic, Estonia, Greece, Lithuania, Poland, Russia, Slovenia and Turkey . Susceptibility was tested by agar dilution (seven countries), E test (five countries) and disk diffusion (three countries) methods . Resistance breakpoints (mg/L) were: metronidazole 8, clarithromycin 1, amoxicillin 0.5, tetracycline 4, and ciprofloxacin 1 or 4 in most centers . Primary and post-treatment resistance was assessed in 2003 and 337 isolates respectively . Results for 282 children and 201 adults were compared . RESULTS: Primary resistance rates since 1998 were: metronidazole 37.9%, clarithromycin 9.5%, amoxicillin 0.9%, tetracycline 1.9%, ciprofloxacin 3.9%, and both metronidazole and clarithromycin 6.1% . Isolates from centers in Slovenia and Lithuania exhibited low resistance rates . Since 1998, amoxicillin resistance has been detected in the southeastern region . From 1996, metronidazole resistance increased significantly from 30.5% to 36.4%, while clarithromycin resistance increased slightly from 8.9% to 10.6% . In centers in Greece, Poland, and Bulgaria, the mean metronidazole resistance was slightly higher in adults than in children (39% versus 31.2%, P > 0.05); this trend was not found for clarithromycin or amoxicillin (P > 0.20) . Post-treatment resistance rates exhibited wide variations . CONCLUSIONS: In eastern Europe, primary H . pylori resistance to metronidazole is considerable, and that to clarithromycin is similar to or slightly higher than that in western Europe . Resistance to amoxicillin, ciprofloxacin and tetracycline was detected in several centers . Primary and post-treatment resistance rates vary greatly between centers.

Eur J Biochem, 2002 Sep, 269(17), 4367 - 74
Effects of a tryptophanyl substitution on the structure and antimicrobial activity of C-terminally truncated gaegurin 4; Won HS et al.; Gaegurin 4 (GGN4), a 37-residue antimicrobial peptide, consists of two amphipathic alpha helices (residues 2-10 and 16-32) connected by a flexible loop region (residues 11-15) . As part of an effort to develop new peptide antibiotics with low molecular mass, the activities of C-terminally truncated GGN4 analogues were tested . Delta24-37 GGN4, a peptide analogue with 14 residues truncated from the C-terminus of GGN4, showed a complete loss of antimicrobial activity . However, the single substitution of aspartic acid 16 by tryptophan (D16W) in the Delta24-37 GGN4 completely restored the antimicrobial activity, without any significant hemolytic activity . In contrast, neither the D16F nor K15W substitution of the Delta24-37 GGN4 allowed such a dramatic recovery of activity . In addition, the D16W substitution of the native GGN4 significantly enhanced the hemolytic activity as well as the antimicrobial activity . The structural effect of the D16W substitution in the Delta24-37 GGN4 was investigated by CD, NMR, and fluorescence spectroscopy . The results showed that the single tryptophanyl substitution at position 16 of the Delta24-37 GGN4 induced an alpha helical conformation in the previously flexible loop region in intact GGN4, thereby forming an entirely amphipathic alpha helix . In addition, the substituted tryptophan itself plays an important role in the membrane-interaction of the peptide.

Jpn J Antibiot, 2002 Jun, 55(3), 291 - 301
{In vitro resistance acquisition in Mycoplasma gallisepticum against ofloxacin, tylosin and spectinomycin}; Takahashi I et al.; To clarify a mechanism of acquired resistance of two Mycoplasma gallisepticum (MG) strains against ofloxacin (OFLX) along with tylosin (TS) and spectinomycin (SPCM) as the controls, in vitro resistance acquisition test was carried out for 10 subcultures of each strain with increasing the amount of antimicrobials, and maximum growth allowance concentrations (MAC) in 10th and primary subcultures were compared . Acquisition of resistance in the strains against OFLX was moderate and MAC of the 10th subculture increased twice for one strain and 16 times for another one as compared to that of their primary subcultures . Acquisition of resistance in the strains against TS was also moderate and MAC of the 10th subculture increased 8 times for both strains as compared to that of the primary subcultures . Acquisition of resistance against SPCM was quite different between the strains . Namely the MAC of one strain increased 512 times, while another one did not acquire any resistance.

Jpn J Antibiot, 2002 Jun, 55(3), 259 - 69
{Phototoxicity studies of pazufloxacin mesilate, a novel parenteral quinolone antimicrobial agent--in vitro and in vivo studies}; Nagasawa M et al.; Phototoxicity of pazufloxacin mesilate (PZFX mesilate), a novel parenteral quinolone antimicrobial agent, were evaluated in vitro and in vivo studies . In vitro, phototoxicity for cultured cells of PZFX, which is active principle of PZFX mesilate, was studied, and stability for long-wavelength ultraviolet (UVA) was examined . In vivo, phototoxicity tests in guinea pigs and rats, and photoallergenicity tests in guinea pigs were conducted . In the phototoxicity test on cultured cells, CHL/IU cells were irradiated UVA of 300-3000 mJ/cm2 in the presence of PZFX, ofloxacin (OFLX), lomefloxacin (LFLX) or sparfloxacin (SPFX) at 10 micrograms/mL . Phototoxic potencies for cultured cells of the quinolones tested were SPFX > LFLX > OFLX > PZFX . In addition, changes in ultraviolet absorption spectrum and residual rate of PZFX, OFLX, LFLX and SPFX were examined after UVA irradiation of 300-3000 mJ/cm2 to each solution . PZFX was stable for UVA compared with OFLX and LFLX . In the phototoxicity test of guinea pigs, each quinolone was administered intraperitoneally daily for 7 days, and UVA of about 11 J/cm2 was irradiated at 30 minutes after the last administration . Dose levels of each quinolone were 65 and 130 mg/kg of PZFX mesilate (dose levels converted to PZFX: 50 and 100 mg/kg), 50 and 100 mg/kg of nalidixic acid (NA), 100 mg/kg of OFLX, enoxacin (ENX), ciprofloxacin (CPFX), LFLX and SPFX . Grade of skin reaction (erythema) at 24 hours after UVA irradiation decreased in the order: SPFX > CPFX > NA > ENX = OFLX > LFLX > PZFX mesilate . Thus, PZFX mesilate was found to have the weakest phototoxicity . In the maximum plasma concentration of quinolones from 0.5 to 2.5 hours after administration, corresponding to the time of UVA irradiation, the concentration of the group administered PZFX mesilate was about 4.1 times higher than that of CPFX group, and about 1.3 times higher than that of SPFX group . The area under the blood concentration-time curve (AUC0.5-2.5) of the group administered PZFX mesilate was the same as that of SPFX group, and about 3.2 times larger than that of CPFX group . These data showed that phototoxicity of PZFX mesilate was also weaker than that of CPFX or SPFX in consideration of AUC0.5-2.5 . In the phototoxicity test of rats injected intravenously, no phototoxicity was observed at 130 mg/kg of PZFX mesilate . In the photoallergenicity test of guinea pigs, no photoallergenicity was observed by PZFX mesilate . As mentioned above, from in vitro studies PZFX was found to be stable for UVA irradiation compared with OFLX and LFLX, and phototoxicity for cultured cells of PZFX was weaker than that of SPFX, LFLX or OFLX . In addition, from in vivo studies phototoxicity of PZFX mesilate was found to be weaker than that of NA, OFLX, ENX, CPFX, LFLX or SPFX, and no photoallergenicity was observed . Therefore, photosensitive potency of PZFX mesilate might be less than that of other quinolones.

Gastroenterology, 2002 Sep, 123(3), 835 - 44
Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats; Frazer DM et al.; BACKGROUND & AIMS: Hepcidin is an antimicrobial peptide thought to be involved in the regulation of intestinal iron absorption . To further investigate its role in this process, we examined hepatic and duodenal gene expression in rats after the switch from a control diet to an iron-deficient diet . METHODS: Adult rats on an iron-replete diet were switched to an iron-deficient diet and the expression of iron homeostasis molecules in duodenal and liver tissue was studied over 14 days . Intestinal iron absorption was determined at these same time-points by measuring the retention of an oral dose of (59)Fe . RESULTS: Iron absorption increased 2.7-fold within 6 days of switching to an iron-deficient diet and was accompanied by an increase in the duodenal expression of Dcytb, divalent metal transporter 1, and Ireg1 . These changes precisely correlated with decreases in hepatic hepcidin expression and transferrin saturation . No change in iron stores or hematologic parameters was detected . CONCLUSIONS: This study showed a close relationship between the expression of hepcidin, duodenal iron transporters, and iron absorption . Both hepcidin expression and iron absorption can be regulated before iron stores and erythropoiesis are affected, and transferrin saturation may signal such changes.

Boll Chim Farm, 2002 May-Jun, 141(3), 238 - 42
Antimicrobial activity of Verbascum macrurum Ten . (Scrophulariaceae); Guarino C; The Author presents the results regarding the antibacterial action of extracts of Verbascum macrurum Ten. . The leaves of this species, gathered on the slopes of Mt . Matese, were ground and four extracts were made as follows: with dicholoromethane, ethonol and water (70:30 v/v), water and methanol . The antibacterial activity of each of the samples was tested and it is demonstrated that the extract with the ethanol/water was the most activity one.

Boll Chim Farm, 2002 May-Jun, 141(3), 181 - 7
New 3-pyridinecarbonitrile derivatives and their antimicrobial properties; Barsoum FF et al.; 2-Alkoxy-4,6-diaryl-3-pyridinecarbonitriles 2a-f were prepared through the reaction of 1,3-diaryl-2-propen-1-ones 1a-c with malononitrile in the appropriate alcohol in the presence of sodium . The reaction was assumed to take place through Michael addition followed by cyclization due to the alkoxide nucleophilic attack at one of the nitrile groups . This assumption was substantiated by isolation of the open-chain Michael adduct 4, followed by independent cyclization to the corresponding 2-alkoxy-3-pyridinecarbonitriles 2 upon treatment with the appropriate alcohol in the presence of sodium . Bromination of 4a,b with bromine in glacial acetic acid, afforded directly the corresponding 2-bromo-3-pyridinecarbonitriles 6a,b . The latters readily underwent nucleophilic substitution with different amines . The antimicrobial properties of the prepared compounds against Gram positive, Gram-negative, acid-fast bacteria and yeast were screened . Many of the prepared compounds show remarkable antimicrobial activity.

J Am Acad Dermatol, 2002 Sep, 47(3), 347 - 50
The antimicrobial peptide LL-37 is expressed by keratinocytes in condyloma acuminatum and verruca vulgaris; Conner K et al.; BACKGROUND: LL-37 is a peptide belonging to the cathelicidin family of antimicrobial peptides . Recent investigations have suggested that the expression of antimicrobial peptides is an important mechanism for resistance to microbial infection . OBJECTIVE: The aim of this study was to determine whether LL-37 is expressed in papillomavirus-infected epidermis from patients with condyloma acuminatum or verruca vulgaris . METHODS: Biopsy specimens from 3 patients with condyloma and 2 patients with verruca vulgaris and 6 normal skin samples were studied by immunostaining with an antibody specific to LL-37 and control rabbit serum . Western blots were performed on skin extracts from normal skin and verrucae . RESULTS: A large increase in the expression of LL-37 was seen within keratinocytes of all involved samples and in the extracts of verrucae analyzed by Western blot . CONCLUSION: This study shows the antimicrobial peptide LL-37 is induced within the epidermis during the development of verruca vulgaris . This expression represents a previously unknown immunologic response to papillomavirus infection and may represent an important step in the pathogenesis of this disorder.

Genetics, 2002 Aug, 161(4), 1599 - 607
Historical intensity of natural selection for resistance to tuberculosis; Lipsitch M et al.; Infections have long been thought to exert natural selection on humans . Infectious disease resistance is frequently invoked as a mechanism shaping human genetic diversity, but such hypotheses have rarely been quantitatively evaluated with direct measures of disease-related mortality . Enhancement of genetically determined resistance to tuberculosis by natural selection has been proposed as a factor explaining the decline of tuberculosis in Europe and North America in the period 1830-1950 (before the advent of antimicrobial chemotherapy) and the apparently reduced susceptibility of Europeans and their descendants to tuberculosis infection and/or disease . We used Swedish vital statistics from 1891 to 1900 to estimate that individuals who escaped mortality from pulmonary tuberculosis (PTB) during the European tuberculosis epidemic would have enjoyed a fitness advantage of 7-15% per generation compared to individuals who were susceptible to PTB mortality; individuals with 50% protection would have had a selection coefficient of 4-7%/generation . Selection during the peak of the European TB epidemic could have substantially reduced the frequency of already rare alleles conferring increased susceptibility to PTB mortality, but only if the phenotypic effects of these alleles were very large . However, if resistant alleles were rare at the beginning of this period, 300 years would not have been long enough for such selection to increase their frequency to epidemiologically significant levels . Reductions in the frequency of rare susceptibility alleles could have played at most a small part in the decline of the epidemic in the century preceding 1950 . Natural selection by PTB deaths during the European TB epidemic alone cannot account for the presently low level of TB disease observed among Europeans and their descendants just prior to the appearance of antibiotic treatment.

J Antibiot (Tokyo), 2002 Jun, 55(6), 557 - 64
Atroviridins A-C and neoatroviridins A-D, novel peptaibol antibiotics produced by Trichoderma atroviride F80317 . I . Taxonomy, fermentation, isolation and biological activities; Oh SU et al.; Seven new peptaibols, atroviridins A-C composed of 20 residue amino acids and neoatroviridins A-D with 18 residues, were isolated from the culture broth of fungal strain F80317 . The strain F80317 was identified as Trichoderma atroviride from its morphological and cultural characteristics . These compounds showed antimicrobial activity against Gram-positive bacteria and phytopathogenic fungi, and exhibited significant cytotoxicity to human cancer cell lines in vitro . Atroviridins showed significant membrane-perturbing activity responsible to their antibiotic action.

Scand J Infect Dis, 2002, 34(7), 520 - 8
Survival of patients with bacteraemia in relation to initial empirical antimicrobial treatment; Hanon FX et al.; Our objective was to determine the impact on mortality of the coverage and spectrum of initial empirical antimicrobial treatment among bacteraemic patients in the county of Northern Jutland, Denmark . Patients aged > 15 y from the bacteraemia register who had their first episode of bacteraemia between 1996 and 1998 were retrospectively included . Outcome was defined as survival from the day that the first positive blood culture was taken . Follow-up was 180 d . Survival probability was estimated using a Cox proportional hazard model . Conservative treatment was defined as penicillin G, ampicillin or similar, methicillin or similar, metronidazole, sulfamethoxazole, trimethoprim or a combination of these . We studied 2058 primary episodes of bacteraemia . The distribution of empirical antimicrobial treatments was: conservative/covered, 25.8%; non-conservative/covered, 36.9%; conservative/did not cover, 16.0%; non-conservative/did not cover, 4.8%; and no antimicrobial, 16.5% . After adjusting for risk factors, patients receiving a treatment that covered the microorganism(s) had an increased survival (relative risk {RR} = 0.50 {0.32-0.77}; p = 0.002) . Among covered episodes, receiving a conservative treatment significantly increased survival (RR = 0.69 {0.54-0.88}; p = 0.002) . This study confirms that appropriate empirical antimicrobial treatment increases the survival of bacteraemic patients . Furthermore, conservative treatment was associated with a longer survival among patients covered by empirical therapy.

Int J Med Microbiol, 2002 Jul, 292(2), 75 - 9
Molecular analysis of antibiotic tolerance in pneumococci; Mitchell LS et al.; Widespread pneumococcal resistance and the emergence of tolerance underscores the need to develop new antimicrobials . Uncovering the mechanisms of autolysin activation could yield not only new antibacterial targets but also ways to eradicate a pool of bacteria facilitating the spread of resistance . Although several genes contributing to antibiotic tolerance among pneumococci have been identified, those important in the clinical arena thus far are in a single gene cluster, vex/pep27/vncS/vncR . Mutations within this signal transduction system represent at least one mechanism, which explains tolerance to both penicillin and vancomycin . Since mutations in this locus do not result in tolerance to penicillin alone, there must be other, yet unknown, mutations which account for tolerance to a single antibiotic . In the case of pneumococci, there exist two more autolysins other than LytA suggesting our understanding of how bacteria die is currently only at the beginning.

Int J STD AIDS, 2002 Aug, 13(8), 522 - 39
Facts and myths on recurrent vulvovaginal candidosis--a review on epidemiology, clinical manifestations, diagnosis, pathogenesis and therapy; Mardh PA et al.; Approximately three-quarters of all women will experience an episode of vulvovaginal candidosis at least once in their life and 5-10% of them will have more than one attack . Women suffering from three to four attacks within 12 months will be diagnosed with recurrent vulvovaginal candidosis (RVVC) . This review covers the large number of proposed aetiological factors for RVVC . The diagnosis of the condition made by conventional means by health providers is often false and is also often misdiagnosed by the affected woman herself . The review covers various methods of diagnosing RVVC and the current knowledge on potential pathogenetic mechanisms proposed for genital candida infections . Treatment of RVVC, including local and systemic antimicrobial therapy and behaviour modification to decrease the risk of recurrences, are discussed . Recent knowledge on drug resistance in candida is also included.

J Immunol, 2002 Sep 1, 169(5), 2516 - 23
Identification of multiple novel epididymis-specific beta-defensin isoforms in humans and mice; Yamaguchi Y et al.; Defensins comprise a family of cationic antimicrobial peptides that are characterized by the presence of six conserved cysteine residues . We identified two novel human beta-defensin (hBD) isoforms by mining the public human genomic sequences . The predicted peptides conserve the six-cysteine motif identical with hBD-4, termed hBD-5 and hBD-6 . We also evaluated the characteristics of the mouse homologs of hBD-5, hBD-6, and HE2beta1, termed mouse beta-defensin (mBD)-12, mBD-11, and mouse EP2e (mEP2e) . The mBD-12 synthetic peptide showed salt-dependent antimicrobial activity . We demonstrate the epididymis-specific expression pattern of hBD-5, hBD-6, mBD-11, mBD-12, and mEP2e . In situ hybridization revealed mBD-11, mBD-12, and mEP2e expression in the columnar epithelium of the caput epididymis, contrasting with the predominant expression of mBD-3 in the capsule or septum of the whole epididymis . In addition, the regional specificity of mBD-11, mBD-12, and mEP2e was somewhat overlapping, but not identical, in the caput epididymis, suggesting that specific regulation may work for each member of the beta-defensin family . Our findings indicated that multiple beta-defensin isoforms specifically and cooperatively contribute to the innate immunity of the urogenital system.

Biol Reprod, 2002 Sep, 67(3), 804 - 13
Novel antimicrobial peptide of human epididymal duct origin; von Horsten HH et al.; HE2, a gene expressed specifically in human epididymis, gives rise to multiple mRNAs that encode a group of small cationic secretory peptides . Localization of HE2 within the defensin gene cluster and prediction that beta-defensin-like modules exist suggest that these peptides have antimicrobial activity and represent components of the innate epithelial defense system of the epididymal duct . Reverse transcription-polymerase chain reaction analysis confirmed the occurrence of eight human HE2-derived transcripts, including minor mRNA variants, that had previously been shown only in animal species . Employing isoform-specific antibodies against the predicted HE2 products, multiple 4- to 8-kDa peptides were detected in human epididymal epithelium, epididymal fluid, and ejaculate . N-terminal microsequencing has suggested a proteolytic processing of these peptides by a furin-like proprotein convertase, which cleaves a propiece from the longer precursor peptides . HE2alpha and HE2beta1, representing major peptide isoforms in the human epididymis, were recombinantly expressed, and their susceptibility to furin cleavage was demonstrated in vitro and in vivo . Processed recombinant peptides and chemosynthetic fragments were included in antimicrobial tests . In addition to the beta-defensin-like HE2beta1 with its expected antibacterial function, HE2alpha C-terminal fragments showed antibacterial activity against Escherichia coli, although it showed no significant similarity to beta-defensins nor to any other known protein family.

Int Endod J, 2001 Apr, 34(3), 237 - 43
Antimicrobial effectiveness of electro-chemically activated water as an endodontic irrigation solution; Marais JT et al.; AIM: The aim of this in vitro study was to evaluate the antimicrobial effectiveness of electro-chemically activated water (ECA) as an endodontic irrigation solution . METHODOLOGY: The root canals of 60 caries-free, single-rooted, adult, maxillary, anterior human teeth were instrumented and irrigated in a similar method to that used for in vivo root canal treatment . The external root surface of each tooth was sealed, maintaining the access cavities patent and the root canals were inoculated with a suspension containing four bacteria . The teeth were randomly divided into four groups (n = 15) . Each group was irrigated ultrasonically with one of the following solutions: distilled water (control), NaOCl (3.5%), and ECA, the latter at pHs 7.0 and 9.0 . Antimicrobial effectiveness was established directly after irrigation and again 7 days later, by counting colony-forming units on blood agar plates and by spectrophotometric analysis . RESULTS: Large numbers of bacteria were present in the canals of teeth irrigated with distilled water . No bacteria were observed following irrigation with NaOCl . Neither of the ECA solutions were found to be effective against all the bacteria . Although some reduction in the number of bacteria was evident in the ECA groups, this was not statistically significant (P > 0.05) when compared to sodium hypochlorite . CONCLUSION: Within the confines of this study ECA did not demonstrate antimicrobial effectiveness.

J Nat Prod, 2002 Aug, 65(8), 1107 - 10
New furanoid diterpenes from Caesalpinia pulcherrima; Ragasa CY et al.; Four new cassane-type furanoditerpenoids (1-4) were isolated from the air-dried leaves of Caesalpinia pulcherrima . Their structures were elucidated by spectral data interpretation . The exocyclic methylene compound 1 readily isomerized and oxidized to the benzofuran 4 . Benzyl 2,6-dimethoxybenzoate (5) was also identified in this study . Antimicrobial tests on 1-5 indicated that they were active against several bacteria (S . aureus, E . coli, P . aeruginosa, and B . subtilis) and fungi (C . albicans and T . mentagrophytes).

Sheng Wu Gong Cheng Xue Bao, 2002 May, 18(3), 352 - 5
{Cloning and expression of the cecropin B-thanatin hybrid antimicrobial peptide in Escherichia coli}; Weng HB et al.; A 44-residue hybrid peptide (CB (1-24)-Arg-Ser-Tyr-Tan (4-21)) incorporating 1-24 residues of cecropin B (CB) and 4-21 residues of thanatin (Tan) was designed and constructed . The CB-Tan gene was cloned into expression plasmid pGEX-3X and expressed in E . coli BL21 . The fusion protein was purified by affinity chromatography . After digested with enterokinase the gene product released with antibacterial activity and gave one band in Tricine-SDS-PAGE.

Nature, 2002 Aug 22, 418(6900), 889 - 92
A saponin-detoxifying enzyme mediates suppression of plant defences; Bouarab K et al.; Plant disease resistance can be conferred by constitutive features such as structural barriers or preformed antimicrobial secondary metabolites . Additional defence mechanisms are activated in response to pathogen attack and include localized cell death (the hypersensitive response) . Pathogens use different strategies to counter constitutive and induced plant defences, including degradation of preformed antimicrobial compounds and the production of molecules that suppress induced plant defences . Here we present evidence for a two-component process in which a fungal pathogen subverts the preformed antimicrobial compounds of its host and uses them to interfere with induced defence responses . Antimicrobial saponins are first hydrolysed by a fungal saponin-detoxifying enzyme . The degradation product of this hydrolysis then suppresses induced defence responses by interfering with fundamental signal transduction processes leading to disease resistance.

Pediatr Infect Dis J, 2002 Aug, 21(8), 753 - 8
Claims of equivalence in randomized controlled trials of the treatment of bacterial meningitis in children; Krysan DJ et al.; OBJECTIVE: To evaluate claims of therapeutic equivalence in studies of the treatment of bacterial meningitis in children . METHODS: We performed a systematic review of randomized controlled trials of antimicrobial therapy for bacterial meningitis in children indexed in MEDLINE and published after 1980 and that claimed equivalency . The sample size of each trial was compared with the minimum sample size needed to rigorously claim equivalence . The primary endpoint was case fatality . RESULTS: Twenty-five studies were identified that met the inclusion criteria . Two of these were specifically designed to test equivalence, and the remaining based claims of equivalence on failed tests of superiority . The majority of these trials (24 of 25) that claimed equivalence had sufficient sample size to exclude a 20% difference in mortality between the tested therapies . Only 3 of the 25 trials could exclude a 10% difference in mortality . CONCLUSION: Few of the trials in this study had sufficient sample size to claim equivalence within 10% of the expected mortality . Proving equivalency is challenging because large sample sizes are often needed to ensure adequate statistical power to rule out clinically important differences between the standard of care and new therapies.

Pharmacol Ther, 2002 Feb-Mar, 93(2-3), 293 - 305
Virulence- and antibiotic resistance-associated two-component signal transduction systems of Gram-positive pathogenic bacteria as targets for antimicrobial therapy; Stephenson K et al.; Two-component signal transduction systems are central elements of the virulence and antibiotic resistance responses of opportunistic bacterial pathogens . These systems allow the bacterium to sense and respond to signals emanating from the host environment and to modulate the repertoire of genes expressed to allow invasion and growth in the host . The integral role of two-component systems in virulence and antibiotic sensitivity, and the existence of essential two-component systems in several pathogenic bacteria, suggests that these systems may be novel targets for antimicrobial intervention . This review discusses the potential use of two-component systems as targets for antimicrobial therapy against Gram-positive pathogens and the current status in the development of inhibitors specific for these systems.

J Med Assoc Ga, 2002 Summer, 91(2), 20 - 3
The Georgia Emerging Infections Program: monitoring trends in invasive pneumococcal disease; Farley MM et al.; The active, population-based surveillance system of the Georgia EIP has provided valuable insights into the characteristics of invasive pneumococcal disease in Georgia and continues to provide an important mechanism to assess the impact of the newly introduced PCV7 vaccine . The problem of antimicrobial resistance has been carefully documented among isolates from invasive pneumococcal disease in all age groups, particularly young children . Fluoroquinolone resistance is now present in our area and will require close monitoring in the coming months and years . Over 80% of invasive pneumococcal disease and over 85% of penicillin and cefotaxime resistant invasive disease occurring in young children in our surveillance area involve serotypes included in the new conjugate vaccine approved for use in children . Preliminary data suggest an early decline in invasive pneumococcal disease in young children has occurred since the introduction of the conjugate vaccine and the effect upon the prevalence of antimicrobial resistance remains to be determined . The high rates of invasive pneumococcal disease, the significant associated morbidity and mortality and antimicrobial resistance highlight the need for enhanced prevention measures in both adults and children . Ongoing surveillance in the Georgia EIP will allow accurate measurement of the impact of prevention efforts, provide essential information on trends in antimicrobial resistance and document any changes in the pneumococcal serotypes responsible for invasive disease in the conjugate vaccine era.

Arzneimittelforschung, 2002, 52(7), 572 - 7
Synthesis and antifungal and antioxidant properties of some new 5-substituted-4-amino(or aryl)-3-mercapto-4(H)-1,2,4-triazoles; Marakos P et al.; The synthesis and antifungal and antimicrobial evaluation of some new 5-substituted-4-amino(or aryl)-3-mercapto-4(H)-1,2,4-triazoles is reported . The involvement of the new compounds in free radical processes is also investigated and their lipophilicity is calculated and related to the determined antioxidant activity . Compounds 7a, 7b and 7c exhibited interesting antioxidant properties at concentration 0.01 mmol/l, expressed by their capacity to inhibit Fe2+/ascorbate induced hepatic microsomal lipid peroxidation, to scavenge OH.and to interact with nitrogen centered radicals such as 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH) . Moreover, compound 6a showed activity against Aspergillus versicolor, possessing a MIC of 82 micrograms/ml.

EMBO Rep, 2002 Sep, 3(9), 852 - 6 Epub 2002 Aug 16.
Reverse genetics in the mosquito Anopheles gambiae: targeted disruption of the Defensin gene; Blandin S et al.; Anopheles gambiae, the major vector of human malaria parasite, is an important insect model to study vector-parasite interactions . Here, we developed a simple in vivo double-stranded RNA (dsRNA) knockout approach to determine the function of the mosquito antimicrobial peptide gene Defensin . We injected dsRNA into adults and observed efficient and reproducible silencing of Defensin . Analysis of the knockdown phenotype revealed that this peptide is required for the mosquito antimicrobial defense against Gram-positive bacteria . In contrast, in mosquitoes infected by Plasmodium berghei, no loss of mosquito viability and no significant effect on the development and morphology of the parasite midgut stages were observed in the absence of Defensin . We conclude that this peptide is not a major antiparasitic factor in A . gambiae in vivo . Our results open new perspectives for the study of mosquito gene function in vivo and provide a basis for genome-scale systematic functional screens by targeted gene silencing.

J Eukaryot Microbiol, 2002 Jul-Aug, 49(4), 319 - 23
In vitro leishmanicidal activity of a monoclonal antibody mimicking a yeast killer toxin; Savoia D et al.; The microbicidal effect of a monoclonal antiidiotypic antibody, mimicking the activity of a yeast killer toxin, characterized by a wide antimicrobial spectrum, has been evaluated in vitro against two relevant species of protozoan parasites, Leishmania major and Leishmania infantum . The antiidiotypic antibody exerted a significant and dose-dependent antileishmanial activity against parasite promastigotes in comparison to an irrelevant isotype-matched monoclonal antibody . This is the first demonstration that an antibody, which had been already shown to be fungicidal and bactericidal, may also exert a direct microbicidal activity against protozoa.

Rinsho Byori, 2002 Jul, 50(7), 706 - 11
{Quality control for antimicrobial susceptibility test using correlation between MIC results}; Ueno T et al.; The method of National Committee for Clinical Laboratory Standards (NCCLS) is widely used for the daily quality control of the antimicrobial susceptibility test . This method, however, cannot detect the accidental error, although it is useful to detect the systematic error in the examination . We developed a computer program using the correlation between the various antimicrobial susceptibility test results to detect an accidental error . The combinations of the MIC results determined for two antimicrobial agents which showed a high correlation coefficient (> or = 0.7), were selected from 98 bacterial species (2122 strains) isolated from January 2000 to December 2000 at Oita Medical University Hospital . Subsequently, a total of 127 combinations of antimicrobial agents for 13 species were selected on the basis of acceptable correlation ranges . Then, the method were verified with 666 strains (5753 combinations) isolated during the period of January to June, 2001 . Twenty-six strains (47 combinations) were identified as an unexpected result, and the occurrence of error were confirmed in 3 strains (12 combinations) . These results suggest that this method which evaluated the correlation between MICs against different antimicrobial agents is applicable for the quality control of antimicrobial susceptibility testings.

Rinsho Byori, 2002 Jul, 50(7), 698 - 701
{Future outlook for LAS, LIS}; Murai T; In Japan, the application of LAS/LIS was started in some hospitals in the 1970's . Thereafter, these systems rapidly developed, becoming established in new national medical university hospitals in the late 1970's, referring to the system introduced in the central laboratory of each hospital . Currently, the LAS/LIS application system is employed in the central laboratory . In addition, this system provides diagnostic information based on laboratory data, responds to various questions regarding clinical examinations, develops strategies for controlling hospital infection using the infection control system, and provides information on the appropriate use of antimicrobial agents . In the future, this system may become even more useful . In this study, we reviewed the current status and issues of the mutual utilization of medical information among medical institutions to achieve further advances.

J Mol Evol, 2002 Sep, 55(3), 347 - 55
When comparative information leads us astray: the receptor-binding region of colicin E9; Dorit RL et al.; In an effort to develop derivatives of the Escherichia coli antimicrobial protein colicin E9 that exhibit novel interactions with a target cell, we mutagenized a 10-amino acid region located at the C terminus of the colicin receptor-binding domain . We subsequently selected for those colicin molecules that retain the antimicrobial phenotype and found that, despite a mutagenic strategy that alters every amino acid in the targeted domain, more than 70% of the engineered colicins retained antimicrobial activity . This result is all the more surprising given the extensive phylogenetic conservation of this receptor-binding domain, which originally suggested the operation of strong selective constraints on the amino acid sequence of this region . This apparent contradiction between our experimental results and the comparative data is resolved by exploring the fitness consequences of the experimentally induced amino acid substitutions . In 17 of 52 cases we examined, the fitness of cells harboring the functional engineered colicins was lower than that of our control line (containing wild-type colicin E9), and in 33 of 52 cases, equal to it . Paradoxically, two of the engineered colicins appear to confer a higher fitness to the producer cell lines . While the mechanism linking changes in the amino acid sequence of the colicin receptor-binding domain and the growth rate of the cells remains unclear, these results illustrate the surprising versatility of the colicin/receptor interaction and underscore the importance of distinguishing molecular function from organismal fitness.

J Biochem Mol Biol Biophys, 2002 Apr, 6(2), 85 - 91
S-methyldithiocarbazate and its Schiff bases: evaluation of bondings and biological properties; Tarafder MT et al.; Eight selective nitrogen-sulfur donor ligands have been synthesized from the condensation of S-methyldithiocarbazate (SMDTC) with aldehydes and ketones with a view to evaluating their antimicrobial and cytotoxic activities, and also to correlate the biological properties with the structure of the ligands . The compounds were all characterized by elemental analyses and other physicochemical techniques . SMDTC and the Schiff bases were screened for antimicrobial and cytotoxic activities . SMDTC showed very large inhibition zones (24-44 mm) against bacteria and fungi with a minimum inhibitory concentration (MIC) of 390-25,000 and 1562-6250 microg ml(-1), against different bacteria and fungi, respectively . Streptomycin and nystatin were used as the internal standards against bacteria and fungi, respectively . SMDTC along with its Schiff bases with pyridine-2-carboxaldehyde, acetylacetone and 2,3-butanedione were strongly antifungal and the MIC values were comparable to nystatin . Most of the Schiff bases were strongly cytotoxic . In particular, those with pyridine-2-carboxaldehyde and 2,3-butanedione have CD(50) values of 5.5, 1.9-2.0 microg ml(-1), respectively, against leukemic cells, while against colon cancer cells, the values were 3.7 and 2.0 microg ml(-1), respectively . The glyoxal Schiff base was strongly active only against leukemic cell with CD(50) value of 4.0 microg ml(-1) . The present findings have been compared with standard drugs.

Expert Opin Pharmacother, 2002 Sep, 3(9), 1301 - 11
Alternative and rescue treatment regimens for Helicobacter pylori eradication; Xia HH et al.; Eradication therapy has been incorporated into clinical practice . The regimens currently recommended for first-line treatment include a 2-week bismuth-based triple therapy (mainly in developing countries), a 1 - 2 week proton pump inhibitor (PPI)-based triple therapy and a 1-week ranitidine bismuth citrate (RBC)-based triple therapy . However, these regimens fail to eradicate Helicobacter pylori in up to 20% of patients due to poor compliance, inadequate treatment duration, smoking, old age and bacterial resistance to nitroimidazoles and/or macrolides in particular . Therefore, alternative regimens that avoid nitroimidazoles and/or macrolides or overcome bacterial resistance to these drugs, improve compliance, minimise side effects and/or reduce costs have been evaluated . One-week quadruple therapy, which adds a PPI or histamine receptor 2-blocker to bismuth-based triple therapy, usually achieves an eradication rate of 90% when used as an alternative first-line therapy but the efficacy decreases when used as a rescue therapy . Several new triple therapies that may be used as alternative and/or rescue therapies have been evaluated . Among these are furazolidone-based (furazolidone plus an antibiotic and a bismuth salt, a PPI or RBC), fluoroquinolone-based (levofloxacin or moxifloxacin plus an antibiotic and a PPI) and ecabet sodium-based (ecabet plus two antibiotics) triple therapies . Recently, rifabutin has been used in combination with a PPI and amoxycillin as a rescue therapy, with satisfactory eradication rates . In addition, a number of new antimicrobial agents are currently under investigation in in vitro studies but the clinical values of these agents needs to be confirmed.

Biochemistry, 2002 Aug 27, 41(34), 10723 - 31
Position-dependent hydrophobicity of the antimicrobial magainin peptide affects the mode of peptide-lipid interactions and selective toxicity; Tachi T et al.; Cationic antimicrobial peptides are promising candidates as novel antibiotics of clinical usefulness . Magainin 2, a representative antimicrobial peptide isolated from the skin of the African clawed frog Xenopus leavis, electrostatically recognizes anionic lipids that are abundant in bacterial membranes, forming a peptide-lipid supramolecular complex pore, whereas the peptide does not effectively bind to zwitterionic phospholipids constituting the outer leaflets of mammalian cell membranes because of the low hydrophobicity of the peptide {Matsuzaki, K . (1999) Biochim . Biophys . Acta 1462, 1-10} . In this study, two magainin analogues with enhanced hydrophobicity, MG-H1 (GIKKFLHIIWKFIKAFVGEIMNS) and MG-H2 (IIKKFLHSIWKFGKAFVGEIMNI), with identical amino acid compositions were designed and interactions with lipid bilayers and biological activities were examined in comparison with those of MG (GIGKWLHSAKKFGKAFVGEIMNS = F5W-magainin 2) . The apparent hydrophobicities and hydrophobic moments of MG-H1 and MG-H2, conventionally calculated assuming that all residues are involved in helix formation, were almost the same . MG-H2 behaved like MG except for greatly enhanced activity against zwitterionic membranes and erythrocytes . In contrast, despite a very similar calculated hydrophobicity, the observed hydrophobicity of MG-H1 was larger than that of MG-H2 because of a tendency toward helix fraying near the termini . Therefore, the physicochemical parameters of only the helical portion should be considered in characterizing peptide-lipid interactions, although this point was overlooked in most studies . Moreover, MG-H1 induced aggregation and/or fusion of negatively charged membranes . Furthermore, the peptide hydrophobicity was found to affect pore formation rate, pore size, and pore stability . These observations demonstrate that the hydrophobicity of the peptide also controls the mode of action and is dependent on the position of the hydrophobic amino acids in the peptide sequence.

Ann Hematol, 2002 Jul, 81(7), 374 - 7 Epub 2002 Jun 19.
Infectious complications after autologous hematopoietic stem cell transplantation: comparison of patients with acute myeloid leukemia, malignant lymphoma, and multiple myeloma; Auner HW et al.; It is yet undetermined whether patients with different hematological malignancies have different propensities to infectious complications after high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (HSCT) . We retrospectively analyzed 136 cycles of HDC and autologous HSCT in 114 patients with acute myeloid leukemia (AML, 24 cycles), non-Hodgkin's lymphoma/Hodgkin's disease (NHL/HD, 55 cycles), and multiple myeloma (MM, 57 cycles) with respect to early infectious complications . Median duration of neutropenia was longer in patients with AML and NHL/HD than in patients with MM (11 days vs 8 days) and after conditioning including total body irradiation (TBI) compared with chemotherapy only preparative regimens (11 days vs 7 days) . Fever requiring antimicrobial therapy was observed in 88 percent of cycles, with fever of unknown origin (FUO) accounting for 60 percent of febrile episodes . There was no proven fungal infection, but one case of probable invasive pulmonary aspergillosis . Microbiologically documented infections were seen in 29 percent and clinically documented infections in 11 percent . Response to first-line empirical antibiotic therapy was better for FUO than for documented infections (70 percent vs 40 percent) . Patients with TBI as part of their conditioning regimen had more overall infections than patients without TBI (96 percent vs 82 percent) . There were no differences with respect to the type or incidence of infections between patients with AML, NHL/HD, and MM . Patients with different hematological malignancies have similar rates of early infectious complications after HDC and autologous HSCT . TBI may be associated with an increased risk for infections in the early post-transplant period.

Intensive Care Med, 2002 Aug, 28(8), 1030 - 5 Epub 2002 Apr 25.
Associations between empirical antimicrobial therapy at the hospital and mortality in patients with severe community-acquired pneumonia; Rello J et al.; INTRODUCTION: The aim of the study was to examine different antibiotic choices and their relation to outcomes . METHODS: We reviewed patients with severe community-acquired pneumonia (SCAP) from two multicenter studies . Empirical antimicrobial regimens were classified as: macrolides alone (group M); macrolides plus betalactams (group MB); macrolides plus betalactam/betalactamase inhibitor (group MBI); every regimen including aminoglycosides (group A); non-pseudomonal third-generation cephalosporins alone (group C); another betalactam alone (first- and second-generation cephalosporins, or betalactam/betalactamase inhibitor) (group B); fluoroquinolones (group F); and other regimens (group Misc) . RESULTS: Initial distribution of regimens was: group MB: 261 patients; group A: 65 patients; group C: 31 patients; group B: 23 patients; group M: 18 patients; group MBI: 13 patients; group F: 11 patients; group Misc: 38 patients . The lowest overall mortality was associated with initial treatment with a macrolide plus other agent (or alone) . No deaths were documented among the 13 patients receiving amoxicillin/clavulanate plus a macrolide . The excess mortality for initial treatment with group A was significantly higher (14.2%; CI 95% 27.3-1.1) than the overall mortality rate between patients receiving a macrolide plus other agents . No significant differences were documented when mortality was adjusted for intubated patients . CONCLUSION: Clinicians select the empirical antibiotic regimen after classifying patients according to likely pathogens and prognosis . The inclusion of a macrolide as part of the initial therapeutic regimen for SCAP appears to be as safe and effective as alternative options . Addition of a macrolide agent to a betalactam/betalactamase inhibitor or using a macrolide alone was a marker for less severe disease.

Br J Ophthalmol, 2002 Sep, 86(9), 969 - 74
Iris nodules associated with infectious uveitis; Myers TD et al.; BACKGROUND/AIM: Iris nodules are an uncommon clinical sign in uveitis . The diseases most commonly associated with iris nodules and uveitis include sarcoidosis, Vogt-Koyanagi-Harada syndrome, multiple sclerosis, Fuchs' heterochromic iridocyclitis, and metastatic infection . While many of these diseases may be appropriately treated with immunosuppressive medication, the management of infectious uveitis is antimicrobial therapy . Inappropriate immunosuppressive therapy may result in a poor outcome for the patient with an infection . Consequently, cases of uveitis with iris nodules were reviewed to identify clinical features that may help differentiate infection from non-infectious inflammation . METHODS: The clinical database of 1353 consecutive patients evaluated at a tertiary care referral based North American uveitis clinic were retrospectively reviewed to identify cases of infectious uveitis with iris nodules . A Medline search was performed to identify additional cases . From these cases information regarding clinical presentation, diagnosis, treatment, and outcome were collected . RESULTS: Three cases (three eyes) were identified from the authors' own records of infectious uveitis with iris nodules . An additional 25 cases of infectious uveitis with iris nodules were identified in 22 published reports . Analysis of the authors' cases and these reports showed that infectious uveitis with iris nodules was specifically characterised by some or all of the following: (1) creamy, soft appearance to the nodule(s), (2) unilateral disease, (3) persistence or growth of the nodule(s) despite corticosteroid therapy, (4) marked inflammatory response in the anterior chamber and/or vitreous humour, and/or (5) history suggesting a potential source of septic emboli . CONCLUSION: Certain features of the clinical history and examination are useful in the diagnosis of metastatic infection in patients presenting with uveitis and iris nodules.

Cleve Clin J Med, 2002 Aug, 69(8), 621 - 6, 629-31
Inflammatory bowel disease: sorting out the treatment options; Wolf JM et al.; An increasing array of treatments such as immunosuppressive drugs and tumor necrosis factor inhibitors can offer patients with ulcerative colitis and Crohn disease improved relief from symptoms with fewer adverse effects . Several additional drugs have shown promise, including nicotine, antimicrobials, and heparin.

J Chem Ecol, 2002 Jun, 28(6), 1103 - 15
Does the odor from sponges of the genus Ircinia protect them from fish predators?
Pawlik JR, McFall G, Zea S.
Caribbean sponges of the genus Ircinia contain high concentrations of linear furanosesterterpene tetronic acids (FTAs) and produce and exude low-molecular-weight volatile compounds (e.g., dimethyl sulfide, methyl isocyanide, methyl isothiocyanate) that give these sponges their characteristic unpleasant garlic odor . It has recently been suggested that FTAs are unlikely to function as antipredatory chemical defenses, and this function may instead be attributed to bioactive volatiles . We tested crude organic extracts and purified fractions isolated from Ircinia campana, I . felix, and I . strobilina at naturally occurring concentrations in laboratory and field feeding assays to determine their palatability to generalist fish predators . We also used a qualitative technique to test the crude volatile fraction from I . felix and I . strobilina and dimethylsulfide in laboratory feeding assays . Crude organic extracts of all three species deterred feeding of fishes in both aquarium and field experiments . Bioassay-directed fractionation resulted in the isolation of the FTA fraction as the sole active fraction of the nonvolatile crude extract for each species, and further assays of subfractions suggested that feeding deterrent activity is shared by the FTAs . FTAs deterred fish feeding in aquarium assays at concentrations as low as 0.5 mg/ml (fraction B, variabilin), while the natural concentrations of combined FTA fractions were > 5.0 mg/ml for all three species . In contrast, natural mixtures of volatiles transferred from sponge tissue to food pellets and pure dimethylsulfide incorporated into food pellets were readily eaten by fish in aquarium assays . Although FTAs may play other ecological roles in Ircinia spp., these compounds are effective as defenses against potential predatory fishes . Volatile compounds may serve other defensive functions (e.g., antimicrobial, antifouling) but do not appear to provide a defense against fish predators.

Oncol Nurs Forum, 2002 Aug, 29(7), 1063 - 80
A research review of the current treatments for radiation-induced oral mucositis in patients with head and neck cancer; Shih A et al.; PURPOSE/OBJECTIVES: To review the research studies on the current treatments for radiation therapy-(RT-) induced mucositis in patients with head and neck cancer . DATA SOURCES: MEDLINE search of the literature from 1966-2001 . DATA SYNTHESIS: Four types of agents (i.e., antimicrobial, coating, anti-inflammatory, and cytokine-like agents) have been evaluated for the management of RT-induced oral mucositis in patients with head and neck cancer . Most of the published studies had relatively small sample sizes and used inconsistent measures to evaluate the extent and severity of oral mucositis . Therefore, definitive conclusions regarding the effectiveness of any of the agents tested in the prevention and treatment of RT-induced oral mucositis cannot be drawn . CONCLUSIONS: Oral mucositis remains the most common complication among patients with head and neck cancer . Although a number of strategies and products are being investigated and new directions are promising, the therapies tested to date have not produced consistent results . IMPLICATIONS FOR NURSING: The most effective measure to treat RT-induced mucositis in patients with head and neck cancer is frequent oral rinsing with a bland mouthwash, such as saline or a sodium bicarbonate rinse, to reduce the amount of oral microbial flora . Dental care, consistent oral assessments, and the initiation of a standardized oral hygiene protocol before the initiation of cancer treatment are the most effective approaches for oral mucositis.

Infect Immun, 2002 Sep, 70(9), 4961 - 7
Control of mycobacterial replication in human macrophages: roles of extracellular signal-regulated kinases 1 and 2 and p38 mitogen-activated protein kinase pathways; Blumenthal A et al.; Intracellular persistence of mycobacteria may result from an intricate balance between bacterial replication and signaling events leading to antimicrobial macrophage activities . Using human monocyte-derived macrophages, we investigated the relevance of mitogen-activated protein kinase activation for the growth control of Mycobacterium avium isolates differing in their abilities to multiply intracellularly . The highly replicative smooth transparent morphotype of M . avium strain 2151 induced significantly less p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation than the smooth opaque morphotype of the same strain, which was gradually eliminated from macrophage cultures . Inhibition of the p38 pathway by highly specific inhibitors did not significantly affect mycobacterial replication within macrophages, regardless of the in vitro virulence of the M . avium strain . However, repression of the ERK1/2 pathway further enhanced intracellular growth of highly replicative M . avium strains, although it did not increase survival of the poorly replicating M . avium isolate . Inhibition of the ERK1/2 pathway resulted in decreased tumor necrosis alpha (TNF-alpha) secretion irrespective of the virulence of the M . avium isolate used for infection, revealing that TNF-alpha could have been only partially responsible for the control of intracellular M . avium growth . In conclusion, ERK1/2- and TNF-alpha-independent pathways are sufficient to limit intramacrophage growth of less-virulent M . avium strains, but early ERK1/2 activation in infected macrophages is critically involved in controlling the growth of highly replicative M . avium strains.

J Biol Chem, 2002 Oct 25, 277(43), 41163 - 70 Epub 2002 Aug 14.
C/EBPalpha regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism . Cross-talk between C/EBP pathway and iron metabolism; Courselaud B et al.; Originally identified as a gene up-regulated by iron overload in mouse liver, the HEPC gene encodes hepcidin, the first mammalian liver-specific antimicrobial peptide and potential key regulator of iron metabolism . Here we demonstrate that during rat liver development, amounts of HEPC transcripts were very low in fetal liver, strongly and transiently increased shortly after birth, and reappeared in adult liver . To gain insight into mechanisms that regulate hepatic expression of hepcidin, 5'-flanking regions of human and mouse HEPC genes were isolated and analyzed by functional and DNA binding assays . Human and mouse HEPC promoter-luciferase reporter vectors exhibited strong basal activity in hepatoma HuH-7 and mouse hepatocytes, respectively, but not in non-hepatic U-2OS cells . We found that CCAAT/enhancer-binding protein alpha (C/EBPalpha) and C/EBPbeta were respectively very potent and weak activators of both human and mouse promoters . In contrast, co-expression of hepatocyte nuclear factor 4alpha (HNF4alpha) failed to induce HEPC promoter activity . By electrophoretic mobility shift assay we demonstrated that one putative C/EBP element found in the human HEPC promoter (-250/-230) predominantly bound C/EBPalpha from rat liver nuclear extracts . Hepatic deletion of the C/EBPalpha gene resulted in reduced expression of HEPC transcripts in mouse liver . In contrast, amounts of HEPC transcripts increased in liver-specific HNF4alpha-null mice . Decrease of hepcidin mRNA in mice lacking hepatic C/EBPalpha was accompanied by iron accumulation in periportal hepatocytes . Finally, iron overload led to a significant increase of C/EBPalpha protein and HEPC transcripts in mouse liver . Taken together, these data demonstrate that C/EBPalpha is likely to be a key regulator of HEPC gene transcription and provide a novel mechanism for cross-talk between the C/EBP pathway and iron metabolism.

Curr Opin Immunol, 2002 Oct, 14(5), 666 - 72
Recent advances in mucosal vaccines and adjuvants; Eriksson K et al.; Mucosal vaccines may be used both to prevent mucosal infections through the activation of antimicrobial immunity and to treat systemic inflammatory diseases through the induction of antigen-specific mucosal tolerance . New, efficient mucosal adjuvants for human use have been designed based on, amongst others, bacterial toxins and their derivatives, CpG-containing DNA, and different cytokines and chemokines, with the aim of improving the induction of mucosal Th1 and Th2 responses . Mucosal delivery systems, in particular virus-like particles, have been shown to enhance the binding, uptake and half-life of the antigens, as well as target the vaccine to mucosal surfaces . DNA vaccines are currently being developed for administration at mucosal surfaces . However, there have also been failures, such as the withdrawal of an oral vaccine against rotavirus diarrhea and a nasal vaccine against influenza, because of their potential side effects.

J Nat Toxins, 2002 Aug, 11(3), 245 - 50
Biological activities of skin secretions of the salamander Tylototriton verrucosus; Lai R et al.; Water-soluble skin secretions of salamander Tylototriton verrucosus, first described by Anderson in 1871, were studied for their biological and enzymatic activities . They were found to be toxic to mice with an intraperitoneal LD50 of 11.5 mg/kg . Using Sephadex G-75 gel filtration, it was proven that the toxic components of the secretions are proteins with molecular weights ranging from 30,000 to 50,000 Da . The secretions of T . verrucosus display a wide spectrum of antimicrobial activities and also contain both proteolytic activity and trypsin inhibitory activity . In contrast, neither hemolytic nor hemorrhagic activities were found . The secretions were determined to have phospholipase A2 activity; however, no acetylcholine esterase activity was detectable under the assay conditions.

Neurosurgery, 2002 Jul, 51(1), 79 - 85; discussion 86-7
Spinal epidural abscesses: clinical manifestations, prognostic factors, and outcomes; Soehle M et al.; OBJECTIVE: This study was performed to evaluate the clinical manifestations and prognostic factors for outcomes among patients with nontuberculous spinal epidural abscesses . METHODS: The records and magnetic resonance imaging/computed tomographic results for patients treated between 1994 and 2000 were retrospectively evaluated . Outcomes were assessed after 11 months, using scores ranging from 0 (dead) to 4 (no neurological deficits) . RESULTS: All 25 patients (mean age, 62 yr) underwent surgery and subsequently received antibiotics . Back/neck pain (72% of patients), leukocytosis (64%), fever (60%), and motor deficits (56%) were the most common symptoms at admission . Outcomes were assessed as poor for 40% of the patients and as good (no deficit or independently ambulatory) for 60% . Low leg muscle strength grades (r = 0.68, P < 0.001) and high white blood cell (WBC) counts (r = -0.56, P = 0.006) at admission were significantly correlated with low outcome scores . From the time of admission until 14 days after surgery, the poor-outcome group exhibited significantly (P < 0.005) higher WBC counts, compared with the good-outcome group . The same was true for C-reactive protein levels, with the exception that no differences between groups were observed until 8 days after surgery . Factors such as cervicothoracic abscess locations (P = 0.041), lower limb motor deficits (P = 0.005), complete paralysis (P = 0.005), and WBC counts of more than 14,000 cells/microl (P = 0.049) at admission were observed to be prognostic for poor outcomes . CONCLUSION: Surgical decompression combined with antimicrobial therapy remains the recommended treatment . In addition to abscess locations and motor deficits, inflammatory markers such as WBC counts and C-reactive protein levels are prognostic for outcomes.

Pediatr Infect Dis J, 2002 Jun, 21(6), 605 - 12; discussion 613-4
Rapid diagnosis in pediatric infectious diseases: the past, the present and the future; Nissen MD et al.; The focus of rapid diagnosis of infectious diseases of children in the last decade has shifted from variations of the conventional laboratory techniques of antigen detection, microscopy and culture to that of molecular diagnosis of infectious agents . Pediatricians will need to be able to interpret the use, limitations and results of molecular diagnostic techniques as they are increasingly integrated into routine clinical microbiology laboratory protocols . PCR is the best known and most successfully implemented diagnostic molecular technology to date . It can detect specific infectious agents and determine their virulence and antimicrobial genotypes with greater speed, sensitivity and specificity than conventional microbiology methods . Inherent technical limitations of PCR are present, although they are reduced in laboratories that follow suitable validation and quality control procedures . Variations of PCR together with advances in nucleic acid amplification technology have broadened its diagnostic capabilities in clinical infectious disease to now rival and even surpass traditional methods in some situations . Automation of all components of PCR is now possible . The completion of the genome sequencing projects for significant microbial pathogens, in combination with PCR and DNA chip technology, will revolutionize the diagnosis and management of infectious diseases.

Eur J Biochem, 2002 Aug, 269(16), 3869 - 80
Structures and mode of membrane interaction of a short alpha helical lytic peptide and its diastereomer determined by NMR, FTIR, and fluorescence spectroscopy; Oren Z et al.; The interaction of many lytic cationic antimicrobial peptides with their target cells involves electrostatic interactions, hydrophobic effects, and the formation of amphipathic secondary structures, such as alpha helices or beta sheets . We have shown in previous studies that incorporating approximately 30%d-amino acids into a short alpha helical lytic peptide composed of leucine and lysine preserved the antimicrobial activity of the parent peptide, while the hemolytic activity was abolished . However, the mechanisms underlying the unique structural features induced by incorporating d-amino acids that enable short diastereomeric antimicrobial peptides to preserve membrane binding and lytic capabilities remain unknown . In this study, we analyze in detail the structures of a model amphipathic alpha helical cytolytic peptide KLLLKWLL KLLK-NH2 and its diastereomeric analog and their interactions with zwitterionic and negatively charged membranes . Calculations based on high-resolution NMR experiments in dodecylphosphocholine (DPCho) and sodium dodecyl sulfate (SDS) micelles yield three-dimensional structures of both peptides . Structural analysis reveals that the peptides have an amphipathic organization within both membranes . Specifically, the alpha helical structure of the L-type peptide causes orientation of the hydrophobic and polar amino acids onto separate surfaces, allowing interactions with both the hydrophobic core of the membrane and the polar head group region . Significantly, despite the absence of helical structures, the diastereomer peptide analog exhibits similar segregation between the polar and hydrophobic surfaces . Further insight into the membrane-binding properties of the peptides and their depth of penetration into the lipid bilayer has been obtained through tryptophan quenching experiments using brominated phospholipids and the recently developed lipid/polydiacetylene (PDA) colorimetric assay . The combined NMR, FTIR, fluorescence, and colorimetric studies shed light on the importance of segregation between the positive charges and the hydrophobic moieties on opposite surfaces within the peptides for facilitating membrane binding and disruption, compared to the formation of alpha helical or beta sheet structures.

Lett Appl Microbiol, 2002, 35(3), 176 - 80
Susceptibility of Escherichia coli O157 and non-O157 isolates to lactate; McWilliam Leitch EC et al.; AIMS: To examine the effect of temperature on the antimicrobial efficacy of lactate and propionate against O157 and non-O157 Escherichia coli isolates . METHODS AND RESULTS: Lactate and, to a lesser extent, propionate effectively reduced viability at 37 degrees C . Ethanol enhanced this effect . Reducing the temperature to 20 or 5 degrees C caused an increase in survival in the presence of these organic acids with or without ethanol . At 20 degrees C the deltapH, membrane potential and intracellular lactate anion concentration were less than at 37 degrees C . CONCLUSIONS: The efficacy of lactate and propionate against E . coli O157 and non-O157 isolates is reduced at lower temperatures, perhaps due to the reduction in the deltapH, membrane potential and intracellular lactate anion concentration . SIGNIFICANCE AND IMPACT OF THE STUDY: These findings suggest that the usefulness of organic acids as decontaminants for E . coli O157 is temperature dependent.

Crit Rev Food Sci Nutr, 2002 Jul, 42(4), 353 - 75
Whey components: millennia of evolution create functionalities for mammalian nutrition: what we know and what we may be overlooking; Walzem RL et al.; Nutrition is undergoing a revolution owing to the recognition that some foods contain trophic, health-promoting factors distinct from essential nutrients . In this revolution, whey is increasingly being viewed as more than a source of proteins with a particularly nutritious composition of essential amino acids . Milk evolved under continuous Darwinian selection pressure to nourish mammalian neonates . Evolutionary pressure appears to have led to the elaboration of a complex food that contains proteins, peptides, complex lipids, and oligosaccharides that act as growth factors, toxin-binding factors, antimicrobial peptides, prebiotics, and immune regulatory factors within the mammalian intestine . Importantly, these trophic macromolecules are not essential, although the health benefits that their biological activities within the intestine provide likely contributed to neonatal survival . Human and bovine milks contain many homologous components, and bovine whey may prove to be a source for molecules capable of providing biological activities to humans when consumed as food ingredients . To approach this potential, food and nutrition research must move beyond the description of food ingredients as delivering only essential nutrients and develop a mechanistic understanding of the interactions between dietary components and the metabolic and physiological properties of the intestine.

Rev Argent Microbiol, 2002 Apr-Jun, 34(2), 66 - 71
{Isolation and characterization of Shiga-toxin-producing Escherichia coli from frozen hamburgers and soft cheeses}; Gomez D et al.; Shiga toxin producing-Escherichia coli (STEC), an important emerging foodborne pathogen, has been associated with bloody and non-bloody diarrhea, hemorrhagic colitis, hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura . The cattle have been shown to be a major reservoir of STEC and raw foods such as ground beef and milk are the most common vehicles of infection . In the present study, the prevalence of STEC in 95 samples of frozen hamburgers and in 114 samples of soft cheese was established in 8.4% and 0.9%, respectively . The genotypic and phenotypic characteristics of the strains were determined . The virulence genes stx1, stx2, eaeA and EHEC-hlyA were identified by PCR and by colony blot hybridization assays . Serotyping, antimicrobial susceptibility and production of Stx using specific cytotoxicity assays on Vero cells were also determined . All STEC strains were characterized as eaeA-/EHEC-hlyA+ . The stx2 genotype was prevalent (77.8%), and four different O:H serotypes were found, comprising: O8:H19 (5 strains), O113:H21 (1), O8:H16 (1), and O39:H49 (1) . One STEC strain was nontypable . Although soft cheese complimented the microbiological quality controls for the coliform counts, the detection of STEC in one sample raises doubts concerning the effectiveness of the current quality controls . These data contribute to the implementation of strategies for the prevention and control of HUS.

Curr Opin Biotechnol, 2002 Jun, 13(3), 267 - 74
Ecology and physiology of infectious bacteria--implications for biotechnology; Wilson BA et al.; Escalating incidents of life-threatening infections by antibiotic-resistant bacteria in recent years have provided strong impetus to discover new antibiotics and alternative treatment modalities . The need to couple information about bacterial physiology and ecology with innovative technologies will become ever more critical in the search for new antibiotics and for other therapies, including probiotics, improved vaccines, alternative antimicrobials and antitoxins.

Izv Akad Nauk Ser Biol, 2002 Jul-Aug, (4), 437 - 41
{The mechanism of bactericidal activity in phagosomes of neutrophils}; Murav'ev RA et al.; Myeloperoxidase plays the key role in antimicrobial of phagocytes . This enzyme uses hydrogen peroxide and chloride to catalyze hypochlorous acid formation . HOCl is the most probable agent in the oxygen-dependent bactericidal activity in the phagocyte phagosome . Chlorination markers indicate HOCl generation in the quantities lethal for bacteria . Enzymatic assay for myeloperoxidase indicates proceeding of other reactions involved in bactericidal activity . Superoxide integrates many activities of this kind and is important for physiological function of myeloperoxidase . Elucidation of phagosomes biochemistry can help us to understand why certain pathogens survive in such unfavorable environment.

Int J Pharm, 2002 Aug 21, 242(1-2), 55 - 62
Application of microencapsulation in textiles; Nelson G; The textile roots of yeast microencapsulation technology was introduced as were the wide range of applications in food and other business sectors . In microencapsulation in general the number of commercial applications in the textile industry continues to grow particularly in the textile industries of Western Europe, Japan and North America . The move by the more developed countries into textiles with new properties and added value, into medical textile and technical textiles for example has encouraged the industry to use microencapsulation processes as a means of imparting finishes and properties on textiles which were not possible or cost-effective using other technology . Textile manufacturers are demonstrating increasing interest in the application of durable fragrances to textile as well as skin softeners . Other potential applications include, insect repellents, dyes, vitamins, antimicrobials, phase change materials and in specific medical applications, antibiotics, hormones and other drugs . Examples of each technology are described . A short summary of a new microencapsulation technology with roots in the textile industry, yeast based microencapsulation, is also described.

Anticancer Res, 2002 Jul-Aug, 22(4), 2103 - 7
High concentration of beta-defensin-2 in oral squamous cell carcinoma; Sawaki K et al.; We have previously reported the presence of human beta-defensin-2 (HBD-2), a peptide with antimicrobial and cytotoxic properties, in oral squamous cell carcinomas . The aim of the present study was to measure the concentration of HBD-2 in abnormal tissues such as oral squamous cell carcinomas . HBD-2 was extracted from tissue samples in the presence of retinoic acid and subjected to reversed-phase HPLC . The fraction representing peak 17 (P17) was obtained by elution using a linear gradient of acetonitrile . Amino acid sequencing and homology studies were subsequently performed, and the molecular weight of P17 was calculated to be 432702 daltons . This molecular weight was consistent with HBD-2 . The concentration of HBD-2 in the oral squamous cell carcinoma samples was 3.85+/-1.87 microg/mg which was much higher than in normal oral epithelium (0.04+/-0.02 microg/mg).

Genetika, 2002 Jul, 38(7), 922 - 8
{Development of fluoroquinolone (ciprofloxacin) resistance in Mycoplasma hominis in the presence of Hela cells}; Momynaliev KT et al.; The effect of cocultivation of eukaryotic HeLa cells and Mycoplasma hominis mycoplasma on the resistance of the latter to fluoroquinolones (ciprofloxacin) was examined . It was shown that cocultivation of the M . homonis and HeLa cells during 24 h with subsequent addition of ciprofloxacin resulted in an increase of the mircoplasma resistance to this antimicrobial agent . In the M . hominis cells cultivated in the presence of HeLa cells and the increasing concentration of ciprofloxacin mutations in the parC gene were observed only at low concentrations of the antimicrobial agent, while mutations in the gyrA gene were never detected . A gradual elevation of ciprofloxacin concentration up to 10 micrograms/ml resulted in the reversion of the parC mutations in mycoplasmas . Mycoplasma cells resistant to high flouroquinolone concentrations and isolated after cocultivation with the HeLa cells were characterized by the wild-type genotype in respect of the gyrA and parC genes . It was shown for the first time that infection of HeLa cells resulted in the appearance of genome rearrangements in M . hominis cells.

Cell Microbiol, 2002 Aug, 4(8), 471 - 82
Using small molecules to study big questions in cellular microbiology; Ward GE et al.; High-throughput screening of small molecules is used extensively in pharmaceutical settings for the purpose of drug discovery . In the case of antimicrobials, this involves the identification of small molecules that are significantly more toxic to the microbe than to the host . Only a small percentage of the small molecules identified in these screens have been studied in sufficient detail to explain the molecular basis of their antimicrobial effect . Rarer still are small molecule screens undertaken with the explicit goal of learning more about the biology of a particular microbe or the mechanism of its interaction with its host . Recent technological advances in small molecule synthesis and high-throughput screening have made such mechanism-directed small molecule approaches a powerful and accessible experimental option . In this article, we provide an overview of the methods and technical requirements and we discuss the potential of small molecule approaches to address important and often otherwise experimentally intractable problems in cellular microbiology.

Eur J Clin Microbiol Infect Dis, 2002 Jul, 21(7), 549 - 52 Epub 2002 Jun 28.
Comparison of the E test and agar dilution method for antimicrobial suceptibility testing of Helicobacter pylori; Glupczynski Y et al.; A multicentre study was carried out in order to validate the E test in comparison with the reference agar dilution method for testing the susceptibility of Helicobacter pylori to amoxicillin, clarithromycin, and metronidazole . Ten clinical isolates and one control collection isolate ( Helicobacter pylori ATCC 43504) were tested blindly at four centres according to a uniform methodology . The E test showed excellent intra- and inter-laboratory correlations with the agar dilution method for amoxicillin and clarithromycin (>98% agreement within 2 log(2) dilution steps) . For metronidazole, however, the E test revealed significantly higher minimum inhibitory concentration values (>2 log(2)) against 5 of the 10 Helicobacter pylori strains tested . Overall, neither method was found reliable for testing the susceptibility of Helicobacter pylori to metronidazole, since both tended to lack reproducibility.

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