Bactericidal

Clin Infect Dis, 2005 Jan 15, 40(2), 239 - 45 Epub 2004 Dec 20.
A European organization for research and treatment of cancer-international antimicrobial therapy group study of secondary infections in febrile, neutropenic patients with cancer; Akova M et al.; BACKGROUND: Neutropenic patients with cancer may develop several episodes of fever and infection during chemotherapy-induced myeloaplasia . METHODS: To identify risk factors for secondary infectious episodes among patients who responded to initial antibiotic therapy, we retrospectively analyzed 2 consecutive, prospective, randomized clinical trials performed by the International Antimicrobial Therapy Group of the European Organization for Research and Treatment of Cancer during 1991-1994 . RESULTS: Of 1720 patients with their first episode of febrile neutropenia, 836 responded to the initial antibiotic regimen and were therefore suitable for our analysis . A secondary infection was observed in 129 (15%) of 836 patients that occurred at a median of 10 days (range, 1-28 days) after the onset of the primary febrile episode . Factors at both baseline and day 4 were analyzed . Age of >16 years (odds ratio {OR}, 3.46; P<.001), acute leukemia in first induction (OR, 3.17; P<.001), presence of intravenous line (OR, 1.88; P=.04), severe neutropenia (defined as an absolute granulocyte count of <100 cells/mm(3)) on day 4 (OR, 2.72; P<.001), and type of documentation of the primary episode (i.e., microbiologically documented cause or unexplained fever; OR, 2.56; P=.001) were found to be risk factors for secondary infection . The risk of death was higher among patients who developed a secondary infectious episode than among those who did not (5.4% vs . 1.4%; P<.01) . CONCLUSIONS: The clinical parameters described above may help to identify neutropenic patients at risk of developing secondary infection.

Am J Gastroenterol, 2005 Jan, 100(1), 201 - 6
The emerging role of the liver in iron metabolism; Sharma N et al.; Iron is essential in health and well-being and its dysregulation is a common theme in disease . Recent advances in our understanding of the molecular biology underlying hemochromatosis and anemia has provided insight into the complex mechanisms implicated in iron metabolism . The proximal small bowel is the major site of iron absorption and, it is becoming increasingly clear that the regulation of this process involves the liver and, in particular, the hepatic antimicrobial peptide hepcidin . A number of studies have shown hepcidin to have an inhibitory function at the level of small bowel iron absorption, although its exact site of action remains to be elucidated . Clearly, identifying the target of hepcidin is of importance and is likely to lead to the development of therapeutic agents in the treatment of iron disorders.

Bull World Health Organ, 2004 Dec, 82(12), 928 - 934 Epub 2005 Jan 05.
The antimicrobial resistance containment and surveillance approach - a public health tool; Simonsen GS et al.; Antimicrobial drug resistance (AMR) is widely recognized as a global public health threat because it endangers the effectiveness of treatment of infectious diseases . In 2001 WHO issued the Global Strategy for Containment of Antimicrobial Resistance, but it has proved difficult to translate the recommendations of the Global Strategy into effective public health actions . The purpose of the Antimicrobial Resistance Containment and Surveillance (ARCS) approach is to facilitate the formulation of public health programmes and the mobilization of human and financial resources for the containment of AMR . The ARCS approach highlights the fundamental link between rational drug use and containment of AMR . Clinical management of human and animal infections should be improved through better disease control and prevention, high quality diagnostic testing, appropriate treatment regimens and consumer health education . At the same time, systems for supplying antimicrobial drugs should include appropriate regulations, lists of essential drugs, and functional mechanisms for the approval and delivery of drugs . Containment of AMR is defined in the ARCS approach as the continuous application of this package of core interventions . Surveillance of the extent and trends of antimicrobial resistance as well as the supply, selection and use of antimicrobial drugs should be established to monitor the process and outcome of containment of AMR . The ARCS approach is represented in the ARCS diagram (<A HREF="/img/revistas/bwho/v82n12/fig_2_9100.gif">Fig . 2</A>) which provides a simplified, but comprehensive illustration of the complex problem of containment and monitoring of AMR.

Curr Opin Immunol, 2005 Feb, 17(1), 88 - 94
CD1 assembly and the formation of CD1-antigen complexes; Hava DL et al.; The CD1 antigen presentation system presents lipid antigens to effector T cells, which have diverse roles in antimicrobial responses, antitumor immunity and in regulating the balance between tolerance and autoimmunity . The trafficking of CD1 molecules and lipid antigens facilitates their intersection and binding in specific intracellular compartments . Recent studies have now identified unexpected accessory molecules that are critical to CD1 assembly and lipid loading . The atomic structures of CD1-antigen complexes have defined both the orientation of polar headgroups between the alpha1 and alpha2 helices of CD1 and the manner in which distinct CD1 isoforms bind a range of lipids that have different lengths and numbers of hydrocarbon chains.

Curr Opin Immunol, 2005 Feb, 17(1), 11 - 7
Sensing and signaling during infection in Drosophila; Royet J et al.; Most of the progress in dissecting the Drosophila antimicrobial response over the past decade has centered around intracellular signaling pathways in immune response tissues and expression of genes encoding antimicrobial peptide genes . The past few years, however, have witnessed significant advances in our understanding of the recognition of microbial invaders and subsequent activation of signaling cascades . In particular, the roles of peptidoglycan recognition proteins, which have known homologues in mammals, have been recognized and examined at the structural and functional levels.

J Control Release, 2005 Jan 20, 102(1), 223 - 33
Incorporation of low molecular weight biocides into polystyrene-divinyl benzene beads with controlled release characteristics; Iconomopoulou SM et al.; Triclosan and phosphonium salt biocides have been separately incorporated into polystyrene-divinylbenzene (PS-DVB) beads by suspension polymerization . Ultraviolet (UV) absorption measurements have been used to monitor the release of these low molecular weight biocides out of the PS-DVB beads immersed in water-ethanol mixtures and in physiological saline . The release of the biocide agents is strongly dependent on either the DVB or/and the antimicrobial composition ratio in the beads . An increase of biocide incorporation in the PS/DVB beads was accompanied by a corresponding enhancement of its concentration in liquid mixtures . On the contrary, higher cross-linking densities hindered the biocide migration out of the beads by diminishing its release rate into either the aqueous ethanol solutions or the natural serum . Moreover, Fourier transform Raman (FT-Raman) spectra and Attenuated Total Reflectance Infrared (ATR-FTIR) measurements of the PS-DVB-Triclosan and PS-DVB-phosphonium salt beads, before and after their immersion in water-ethanol solutions, gave a similar qualitative evidence of the biocide release.

FEMS Microbiol Rev, 2005 Jan, 29(1), 99 - 117
Some lessons from Rickettsia genomics; Renesto P et al.; Sequencing of the Rickettsia conorii genome and its comparison with its closest sequenced pathogenic relative, i.e., Rickettsia prowazekii, provided powerful insights into the evolution of these microbial pathogens . However, advances in our knowledge of rickettsial diseases are still hindered by the difficulty of working with strict intracellular bacteria and their hosts . Information gained from comparing the genomes of closely related organisms will shed new light on proteins susceptible to be targeted in specific diagnostic assays, by new antimicrobial drugs, and that could be employed in the generation of future rickettsial vaccines . In this review we present a detailed comparison of the metabolic pathways of these bacteria as well as the polymorphisms of their membrane proteins, transporters and putative virulence factors . Environmental adaptation of Rickettsia is also discussed.

Peptides, 2005 Mar, 26(3), 369 - 75
Deletion of two C-terminal Gln residues of 12-26-residue fragment of melittin improves its antimicrobial activity; Sun X et al.; In our previous paper it was shown that the two C-terminal Gln residues of a C-terminal 15-residue fragment, Mel(12-26) (GLPALISWIKRKRQQ-NH(2)), of melittin and a series of individual substituted analogues might not involved in the interaction with bacterial membranes . In this paper, peptides with one and two Gln residues deletion, respectively, Mel(12-25) and Mel(12-24), were synthesized and characterized . Both of the deletion peptides showed higher antimicrobial activities than the parent peptide, Mel(12-26) . If both of the Gln residues of Mel(12-26) were respectively replaced by a hydrophilic amino acid Gly, the antimicrobial activity increased slightly . If the Gln residue of Mel(12-25) was replaced by a hydrophobic amino acid Leu, the antimicrobial activity changed little, although the substituted peptide possessed much higher hydrophobicity and higher alpha-helical conformation percentage in 1,1,1,3,3,3-hexafluoro-2-propanol/water determined by circular dichroism spectroscopy (CD) than the parent peptide . These results indicated that the two C-terminal residues might be indeed not involved in the binding to bacterial membranes . The antimicrobial activity increasing with the residue deletion may be caused by the decrease of the translational and rotational entropic cost of the binding of the peptides to bacterial membranes because of the lower molecular weights of the deletion peptides.

Biochim Biophys Acta, 2005 Jan 18, 1721(1-3), 73 - 80 Epub 2004 Nov 06.
cDNA microarray analysis of lactoferrin expression in non-neoplastic human hepatocyte PH5CH8 cells; Tamura T et al.; Lactoferrin (LF), a milk protein belonging to the iron transporter transferrin family, is known as a primary defense protein against pathogenic microorganisms . Previously, we found that bovine and human LFs prevented hepatitis C virus infection in cultured human hepatocytes by a direct interaction with the virus . Since LF is proposed to have transcriptional regulatory activity in addition to its antimicrobial function, we sought to identify the target genes that these two types of LF have in common . To this end, we were the first to perform microarray analysis (9970 genes) using human hepatocytes that expressed bovine or human LF by retrovirus-mediated gene transfer . In the results, LF could give a variety of expression profiles in the human hepatocytes, and showed that 9 and 19 genes were commonly up-regulated (more than 2.0-fold) and down-regulated (less than 0.50-fold), respectively, in both bovine and human LF-expressing cells compared with control cells . Among these genes, we found that gamma-aminobutyric acid (GABA)-B receptor 2 was transcriptionally down-regulated by bovine and human LFs, but not by human transferrin . Furthermore, we obtained the suggestive result that LF may modulate the level of intracellular cAMP . This modulation is one of the cellular responses that the GABA-B receptor modifies . This is the first report of microarray analysis applied to search inclusively for the target genes of LF.

Nippon Geka Gakkai Zasshi, 2004 Dec, 105(12), 734 - 6
{Pulmonary infection in immunocompromised hosts}; Suzuki T et al.; While typical pulmonary infections can be cured with antimicrobial agents, three types require surgical lung resection: those in immunocompromised patients; those with acquired resistance to medication; and those caused by microorganisms against which there are no effective drugs . We discuss these three types from the viewpoint of physicians . With the development of chemotherapy for malignant disease, patients with leukemia can be cured with bone marrow transplantation . During the leukopenia accompanying chemotherapy, Aspergillus sp . can infect the lungs . Aspergillus infections are resistant to antimicrobial agents, and thus surgical resection is necessary . Aspergillus infections may occur in previous sites of pulmonary tuberculosis lesions after the tuberculosis is cured producing massive hemoptysis . In this case, surgical resection is also needed . When patients who are immunocompromised due to various underlying diseases become infected with multidrug-resistant tuberculosis, they require surgical resection . Finally, when lesions of nontubercular mycobacterial infection are found, these patients also require surgical lung resection.

J Investig Med, 2004 Nov, 52(7), 470 - 4
Clinical experience with drotrecogin alfa in treating gram-positive and -negative pathogens in patients with severe sepsis; Cone LA et al.; BACKGROUND: Newer concepts in the management of severe sepsis and, in particular, in the understanding of the relationship between proinflammatory and procoagulant activities during severe infection have led to the introduction of activated protein C (drotrecogin) into the therapeutic program . The combination of effective antimicrobial therapy, aggressive supportive care, and efforts to antagonize procoagulants and inhibitors of fibrinolysis was used in this study . METHODS: We treated 12 patients with severe sepsis using this combination of antimicrobial agents and drotrecogin . All patients presented with hypotension and organ failure and some with multiple organ failure . Infected patients were separated into those with gram-positive and those with gram-negative infections . RESULTS: In contrast to an expected mortality rate of nearly 40% in this group of patients, only 2 (9%) expired . Both deaths were due to infection by gram-negative organisms in patients with complicated abdominal infections and concurrent cancer . All patients with gram-positive organisms survived . CONCLUSION: Those patients with infections caused by gram-positive organisms seemed to have a better prognosis than those with gram-negative infections, perhaps because their illnesses are less complicated by local disease . Although our study is small, it suggests that activated protein C will have a significant beneficial effect on the future treatment of severe sepsis and can reduce the mortality rate significantly . Further improvement in survival rates will require more effective treatment of local disease and associated noninfectious ailments.

J Clin Invest . 2005 Jan 13; {Epub ahead of print}
Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance; Marriott HM et al.; Macrophages are critical effectors of bacterial clearance and must retain viability, despite exposure to toxic bacterial products, until key antimicrobial functions are performed . Subsequently, host-mediated macrophage apoptosis aids resolution of infection . The ability of macrophages to make this transition from resistance to susceptibility to apoptosis is important for effective host innate immune responses . We investigated the role of Mcl-1, an essential regulator of macrophage lifespan, in this switch from viability to apoptosis, using the model of pneumococcal-associated macrophage apoptosis . Upon exposure to pneumococci, macrophages initially upregulate Mcl-1 protein and maintain viability for up to 14 hours . Subsequently, macrophages reduce expression of full-length Mcl-1 and upregulate a 34-kDa isoform of Mcl-1 corresponding to a novel BH3-only splice variant, Mcl-1(Exon-1) . Change in expression of Mcl-1 protein is associated with mitochondrial membrane permeabilization, which is characterized by loss of mitochondrial inner transmembrane potential and translocation of cytochrome c and apoptosis-inducing factor . Following pneumococcal infection, macrophages expressing full-length human Mcl-1 as a transgene exhibit a delay in apoptosis and in bacterial killing . Mcl-1 transgenic mice clear pneumococci from the lung less efficiently than nontransgenic mice . Dynamic changes in Mcl-1 expression determine macrophage viability as well as antibacterial host defense.

Toxicol In Vitro, 2005 Mar, 19(2), 199 - 206
Influences of ozone exposure upon macrophage responsivity to N-formyl-methionyl-leucyl-phenylalanine: mobility and metabolic changes; Klestadt D et al.; Alveolar macrophages represent one of the first lines of cell defence in the lungs . They employ several mechanisms, including phagocytosis and secretion of reactive oxygen and nitrogen species . fMLP, a formylated peptide of bacterial origin, is a potent inducer of phagocyte chemotaxis and is also involved in generating antimicrobial agents such as nitric oxide (NO) and hydrogen peroxide (H(2)O(2)) . In this study we analysed the in vitro effects of fMLP on the mobility of the THP-1 cell line, which served as a model for alveolar macrophages . Cell mobility and cytotoxicity were also analysed after pre-exposures to an atmosphere polluted with ozone (0.03-0.5ppm) followed by a fMLP treatment . Finally, the secreted molecules (H(2)O(2) and NO) were measured after ozone exposures ranging from 5 to 30min and fMLP action . Activation by fMLP alone induced cell movement, whereas pre-exposure to the ozone concentrations decreased it . Addition of fMLP had different effects on cytotoxicity, mobility and metabolite secretion by the cells: (1) cytotoxicity increased depending on ozone concentrations and exposure times; (2) during the first 5min and for all ozone concentrations, an average decrease of 50% of activated cell mobility was observed; (3) H(2)O(2) was increased, even in combination with ozone; (4) NO was detected at 731nM, a result that was not affected by ozone pre-exposure.

Biochem Biophys Res Commun, 2005 Feb 18, 327(3), 945 - 51
Maximins S, a novel group of antimicrobial peptides from toad Bombina maxima; Wang T et al.; Amphibian skin secretions are rich in antimicrobial peptides acting as important components of innate defense system against invading microorganisms . A novel type of peptide, designated as maximin S, was deduced by random sequencing of 793 clones from a constructed Bombina maxima skin cDNA library . The putative primary structures of maximin S peptides can be grouped into five species, in which maximin S1 has 14 amino acid residues and the rest of maximin S peptides (S2-S5) all have 18 amino acid residues . Unlike most of the amphibian antimicrobial peptides so far identified, the newly characterized four maximin S precursors are composed of maximin S1 and different combinations of tandem repeated maximin S2-S5 linked by internal peptides . Except maximin S1, the predicted secondary structures of maximin S2-S5 show a similar amphipathic alpha-helical structure . MALDI-TOF mass spectrometry analysis of partially isolated skin secretions of the toad indicates that most of the deduced maximin S peptides are expressed . Two deduced maximin S peptides (S1, S4) were synthesized and their antimicrobial activities were tested . Maximin S4 only had an antibiotic activity against mycoplasma and had no antibacterial or antifungal activity toward tested strains . Maximin S1 had no activity under the same conditions.

Anal Biochem, 2005 Feb 1, 337(1), 149 - 53
Studies on the membrane interactions of the cyclotides kalata B1 and kalata B6 on model membrane systems by surface plasmon resonance; Kamimori H et al.; In this study we have demonstrated the interactions of kalata B1 and its naturally occurring analogue kalata B6 with five model lipid membranes and have analyzed the binding kinetics using surface plasmon resonance . Two kalata peptides showed a higher affinity for the phosphatidylethanolamine-containing membranes, indicating that the peptides would bind selectively to bacterial membranes . Also we have optimized the procedure for the immobilization of five liposome mixtures and have shown that the procedure provides reproducible levels of immobilized liposomes and could be used to screen the selective binding of putative antimicrobial peptides to model mammalian or microbial phospholipid membranes.

J Fluoresc, 2004 Nov, 14(6), 705 - 10
The interaction between levofloxacine hydrochloride and DNA mediated by Cu2+; Song G et al.; Levofloxacin (LEV) is a fluoroquinolone antimicrobial agent . LEV also inhibits DNA synthesis and is bactericidal . The mechanisms of the interaction among LEV, DNA and Cu2+ are studied by fluorescence method . In the paper, the results show that LEV and Cu2+ can form binary complex, and also LEV and DNA can form complex mediated by Cu2+ . The composition of the complex is determined . The affects to the reaction are also found.

Protein J, 2004 Nov, 23(8), 501 - 8
Ocellatins: new antimicrobial peptides from the skin secretion of the South American frog Leptodactylus ocellatus (Anura: Leptodactylidae); Nascimento AC et al.; The emergence, in recent years, of microbial resistance to commonly used antibiotics has aroused a search for new naturally occurring bactericidal and fungicidal agents that may have clinical utility . In the present study, three new antimicrobial peptides were purified from the electrical-stimulated skin secretion of the South American frog Leptodactylus ocellatus by reversed-phase chromatographic procedures . Ocellatin 1 (1GVVDILKGAGKDLLAHLVGKISEKV25-CONH2), ocellatin 2 (1GVLDIFKDAAKQILAHAAEKQI25-CONH2) and ocellatin 3 (1GVLDILKNAAKNILAHAAEQI21-CONH2) are structurally related peptides . These peptides present hemolytic activity against human erythrocytes and are also active against Escherichia coli . Ocellatins exhibit significant sequence similarity to other amphibian antimicrobial peptides, mainly to brevinin 2ED from Rana esculenta.

J Crit Care, 2004 Dec, 19(4), 271 - 8
Computerized physician order entry in the critical care and general inpatient setting: A narrative review; Rothschild J; Computerized physician order entry (CPOE) is an increasingly used technologic tool for entering clinician orders, especially for medications and laboratory and diagnostic tests . Studies in hospitalized patients, including critically ill patients, have demonstrated that CPOE, especially with decision support, improves several outcomes . These improved outcomes include clinical measures such as reductions in serious medication errors and enhanced antimicrobial management of critically ill patients resulting in reduced length of stay . Additionally, several process outcomes have improved with CPOE such as increased compliance with evidence-based practices, reductions in unnecessary laboratory tests and cost savings in pharmacotherapeutics . Future studies are needed to demonstrate the benefits of more patient specific decision support interventions and the seamless integration of CPOE into a wireless, computerized medication administration system.

Appl Microbiol Biotechnol . 2005 Jan 13; {Epub ahead of print}
A novel actinomycete strain de-replication approach based on the diversity of polyketide synthase and nonribosomal peptide synthetase biosynthetic pathways; Ayuso A et al.; The actinomycetes traditionally represent one of the most important sources for the discovery of new metabolites with biological activity; and many of these are described as being produced by polyketide synthases (PKS) and nonribosomal peptide synthetases (NRPS) . We present a strain characterization system based on the metabolic potential of microbial strains by targeting these biosynthetic genes . After an initial evaluation of the existing bias derived from the PCR detection in a well defined biosynthetic systems, we developed a new fingerprinting approach based on the restriction analysis of these PKS and NRPS amplified sequences . This method was applied to study the distribution of PKS and NRPS biosynthetic systems in a collection of wild-type actinomycetes isolated from tropical soil samples that were evaluated for the production of antimicrobial activities . We discuss the application of this tool as an alternative characterization approach for actinomycetes and we comment on the relationship observed between the presence of PKS-I, PKS-II and NRPS sequences and the antimicrobial activities observed in some of the microbial groups tested.

J Biol Chem . 2005 Jan 12; {Epub ahead of print}
Transcriptional responses of Escherichia coli to S-nitrosoglutathione under defined chemostat conditions reveal major changes in methionine biosynthesis; Flatley J et al.; Nitric oxide and nitrosating agents exert powerful antimicrobial effects and are central to host defence and signal transduction . Nitric oxide and S-nitrosothiols can be metabolised by bacteria but only a few enzymes have been shown to be important in responses to such stresses . Glycerol-limited chemostat cultures in defined medium of Escherichia coli MG1655 were used to provide bacteria in defined physiological states before applying nitrosative stress by addition of S-nitrosoglutathione (GSNO) . Exposure to 200 mM GSNO for 5 min was sufficient to elicit an adaptive response as judged by the development of NO-insensitive respiration . Transcriptome profiling experiments were used to investigate the transcriptional basis of the observed adaptation to the presence of GSNO . In aerobic cultures, only seventeen genes were significantly up-regulated, including genes known to be involved in NO tolerance, particularly hmp (encoding the NO-consuming flavohemoglobin Hmp) and norV (encoding flavorubredoxin) . Significantly, none of the up-regulated genes were members of the Fur regulon . Six genes involved in methionine biosynthesis or regulation were significantly up-regulated; metN, metI and metR were shown to be important for GSNO tolerance since mutants in these genes exhibited GSNO growth sensitivity . Furthermore, exogenous methionine abrogated the toxicity of GSNO supporting the hypothesis that GSNO nitrosates homocysteine, thereby withdrawing this intermediate from the methionine biosynthetic pathway . Anaerobically, ten genes showed significant up-regulation, of which norV, hcp, metR and metB were also up-regulated aerobically . The data presented here reveal new genes important for nitrosative stress tolerance and demonstrate that methionine biosynthesis is a casualty of nitrosative stress.

Compend Contin Educ Dent, 2004 Jul, 25(7 Suppl 1), 46 - 53
Effectiveness of a triclosan/copolymer dentifrice on microbiological and inflammatory parameters; Xu T et al.; According to the US Surgeon General's report, "Oral Health in America," published in 2000, most adults in the United States show some degree of periodontal pathology, with severe periodontal diseases affecting about 14% of middle-aged adults . Periodontal diseases are polymicrobial-induced inflammatory diseases, and they vary from mild gingival inflammation to severe deterioration of the periodontium, ie, loss of periodontal supportive tissues and, ultimately, tooth loss . New evidence shows that periodontal diseases may impact systemic health . For this reason, the maintenance of a healthy mouth is becoming increasingly important for the overall health of the body . This article summarizes laboratory research conducted during the development of a novel, multibenefit, oral-care technology based on triclosan--a broad-spectrum antibacterial agent--and a polyvinylmethylether/maleic acid copolymer . This unique combination of agents is found in Colgate Total, a clinically proven efficacious dentifrice for control of dental plaque and gingivitis . Data are presented that demonstrate the unique antibacterial properties of this dentifrice: (1) a broad-spectrum antimicrobial profile; (2) the long-lasting retention of triclosan on hydroxyapatite and epithelial cells; and (3) molecular evidence of antibacterial activity against specific pathogens in clinical dental plaque . In addition, data are presented that demonstrate the anti-inflammatory effects of triclosan on specific cytokines, the interruption of inflammatory pathways, and the inhibition of bone resorption . Overall, these data support the multibenefit clinical effects of Colgate Total and suggest a plurality of mechanisms of action.

Br J Pharmacol, 2005 Jan, 144(1), 80 - 7
Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug; Jia L et al.; SQ109 is a novel {1,2}-diamine-based ethambutol (EMB) analog developed from high-throughput combinatorial screening . The present study aimed at characterizing its pharmacodynamics and pharmacokinetics.The antimicrobial activity of SQ109 was confirmed in vitro (Mycobacterium tuberculosis-infected murine macrophages) and in vivo (M . tuberculosis-infected C57BL/6 mice) and compared to isoniazid (INH) and EMB . SQ109 showed potency and efficacy in inhibiting intracellular M . tuberculosis that was similar to INH, but superior to EMB . In vivo oral administration of SQ109 (0.1-25 mg kg(-1) day(-1)) to the mice for 28 days resulted in dose-dependent reductions of mycobacterial load in both spleen and lung comparable to that of EMB administered at 100 mg kg(-1) day(-1), but was less potent than INH at 25 mg kg(-1) day(-1) . Monitoring of SQ109 levels in mouse tissues on days 1, 14 and 28 following 28-day oral administration (10 mg kg(-1) day(-1)) revealed that lungs and spleen contained the highest concentration of SQ109, at least 10 times above its MIC.Pharmacokinetic profiles of SQ109 in mice following a single administration showed its C(max) as 1038 (intravenous (i.v.)) and 135 ng ml(-1) (p.o.), with an oral T(max) of 0.31 h . The elimination t(1/2) of SQ109 was 3.5 (i.v.) and 5.2 h (p.o.) . The oral bioavailability was 4% . However, SQ109 displayed a large volume of distribution into various tissues . The highest concentration of SQ109 was present in lung (>MIC), which was at least 120-fold (p.o.) and 180-fold (i.v.) higher than that in plasma . The next ranked tissues were spleen and kidney . SQ109 levels in most tissues after a single administration were significantly higher than that in blood . High tissue concentrations of SQ109 persisted for the observation period (10 h).This study demonstrated that SQ109 displays promising in vitro and in vivo antitubercular activity with favorable targeted tissue distribution properties.British Journal of Pharmacology (2005) 144, 80-87 . doi:10.1038/sj.bjp.0705984.

Water Res, 2005 Jan-Feb, 39(2-3), 331 - 9 Epub 2004 Nov 24.
Modeling antimicrobial contaminant removal in slow sand filtration; Rooklidge SJ et al.; Slow sand filters are used in rural regions where source water may be subjected to antimicrobial contaminant loads from waste discharges and diffuse pollution . A numerical model (LETA) was derived to calculate aqueous antimicrobial concentrations through time and depth of a slow sand filter and estimate accumulating contaminant mass in the schmutzdecke . Input parameters include water quality variables easily quantified by water system personnel and published adsorption, partitioning, and degradation coefficients . Simulation results for the tetracycline, quinolone, and macrolide classes of antimicrobials suggested greater than 3-log removal from 1mug/L influent concentrations within the top 40cm of the sand column, with schmutzdecke antimicrobial concentrations comparable to other land-applied waste biosolids . A 60-day challenge experiment injecting 1mug/L tylosin to a pilot slow sand filter showed an average 0.1mg/kg of the antimicrobial remaining in the schmutzdecke layer normally removed during filter maintenance, and this value was the same order of magnitude as the sorbed concentration predicted by the LETA model.

Lett Appl Microbiol, 2005, 40(2), 138 - 45
Characterization of minimal bacteriocin operon from Prevotella nigrescens ATCC 25261; Kaewsrichan J et al.; Abstract j . kaewsrichan, c.w.i . douglas and r . teanpaisan . 2004.Aims: To characterize a minimal bacteriocin operon of Prevotella nigrescens ATCC 25261 . Methods and Results: A genomic DNA library of Pr . nigrescens ATCC 25261 was constructed and screened for bacteriocin production by an agar overlay assay . Sequence analysis of the bacteriocin-producing recombinant plasmid, pGP2, has shown that the insert DNA consists of 4868 base pairs, termed nig locus . There is a cluster of four genes within the nig locus, respectively designated nigA, B, C and D . Deleting 160 nucleotides at the 3'-end of nigAB resulted in loss of bacteriocin production, indicating that nigAB may belong to a bacteriocin operon . nigA is thought to be the bacteriocin gene, while nigB may encode an immunity protein . Escherichia coli containing pGP2 expressed the bacteriocin, which is similar in size, antimicrobial activity, and biochemical properties to that purified from Pr . nigrescens ATCC 25261 . Conclusion: nig Locus is a chromosomal fragment of Pr . nigrescens ATCC 25261, consisting of 4868 base pairs, and has been proved to be important for bacteriocin production . Significance and Impact of the Study: This is the first report of the successful cloning and expression of the bacteriocin from Pr . nigrescens ATCC 25261 into E . coli . This will facilitate the construction of bacteriocin analogues and permit investigation of their structure/function relationships.

Lett Appl Microbiol, 2005, 40(2), 106 - 10
Development of a bioactive packaging cellophane using Nisaplin as biopreservative agent; Guerra NP et al.; Abstract n.p . guerra, c.l . macias, a.t . agrasar and l.p . castro . 2004.Aims: Production of a nisin-containing cellophane-based coating to be used in the packaging of chopped meat . Methods and Results: The adsorption of nisin to cellophane 'P' type surface was studied at 8, 25, 40 and 60 degrees C using different concentrations of nisin . Then, the antimicrobial activity of adsorbed nisin to cellophane surface was determined in fresh veal meat for effectiveness in reducing the total aerobic bacteria . The adsorption of nisin to cellophane was higher at 8 degrees C . The developed bioactive cellophane reduced significantly the growth of the total aerobic bacteria (by ca 1.5 log units) through 12 days of storage at 4 degrees C . Conclusions: Bioactive cellophane packaging could be used for controlling the microbial growth in chopped meat . Significance and Impact of the Study: Nisin-adsorbed bioactive cellophane would result in an extension of the shelf life of chopped meat under refrigeration temperatures.

Planta Med, 2004 Dec, 70(12), 1144 - 1149

Alencar NM, Figueiredo IS, Vale MR, Bitencurt FS, Oliveira JS, Ribeiro RA, Ramos MV.
Latex from Calotropis procera is widely used in folk medicine as a rich source of biologically active compounds capable of promoting diverse benefits such as control of dermal fungal infections, antimicrobial activities and pain relief among other useful properties . The aim of this work was to characterize the anti-inflammatory effect of a non-dialysable protein fraction recovered from the rubber-free latex using three different experimental models when administrated intravenously . In vivo neutrophil migration induced by carrageenin (500 mug) was severely inhibited by doses of latex proteins reaching maximum inhibition (80 %) at 100 mg/kg . Paw edema exacerbated by the effect of carrageenin was almost completely suppressed after 4 hours and was controlled within the first hour following latex protein administration . However, the same latex fraction was completely unable to control the paw edema invoked with dextran stimulation (400 mug), suggesting that the inhibitory effect of the latex is likely to be cell-mediated . Iphosphamide-induced vesical edema in mice was also largely prevented by the latex protein fraction . These results indicate that an effect similar to that of mesna, the classical drug used for this purpose, is operative . Our findings suggest that the sample tested seems to act over a wide spectrum as a novel anti-inflammatory agent . The results also suggest that the active molecules are of a proteinaceous nature despite the presence of numerous secondary metabolites naturally occurring in the C . procera latex.

Protein Expr Purif, 2005 Feb, 39(2), 160 - 8
Expression of SMAP-29 cathelicidin-like peptide in bacterial cells by intein-mediated system; Morassutti C et al.; In this work, the intein fusion approach was used for expression and purification of cathelicidin-like peptide SMAP-29 from Escherichia coli cultures . To overcome the high toxicity of the antimicrobial peptide against host cells, both C- and N-terminal fusions with Sce VMA intein were evaluated . The fusion of SMAP-29 with the N-terminus of intein had a dramatic lethal effect . In contrast, chimeric constructs harboring SMAP-29 linked to the C-terminus of intein displayed no significant inhibition of bacterial growth . Expression of intein-SMAP fusion protein was then induced in ER2566 E . coli strain by IPTG addition and different experimental conditions were tested in order to optimize the recovery of the soluble protein complex . Peptide purification was carried out by affinity chromatography: the chitin binding domain linked to intein was used to immobilize the chimeric protein on a chitin column and intein-mediated splicing of target peptide was obtained by thiol addition . Microbroth dilution assay showed that recombinant SMAP-29 displayed a high, dose-dependent bactericidal activity . These data demonstrate that the fusion of SMAP-29 with C-intein was able to inactivate the antimicrobial properties of the cathelicidin peptide allowing the expression of fusion protein in the host cell . The intein-mediated purification supplied an effective way to recover the fusion partner in its proper biologically active form.

Eur J Med Chem, 2005 Jan, 40(1), 113 - 23
Biological and physicochemical properties of gemini quaternary ammonium compounds in which the positions of a cross-linking sulfur in the spacer differ; Shirai A et al.; We synthesized two novel gemini quaternary ammonium compounds (gemini QACs), 4,4'-{1,6-(2,5-dithiahexane)}bis(1-alkylpyridinium bromide) and 4,4'-{1,6-(3,4-dithiahexane)}bis(1-alkylpyridinium bromide), which are essentially two dimerized pyridinium salts . Three gemini QACs in which the positions of a cross-linking sulfur in the spacer differ, in addition to the previously described 4,4'-{1,6-(1,6-dithiahexane)}bis(1-alkylpyridinium bromide) to both gemini compounds, were determined for their antimicrobial, hemolytic and surface activities and molecular hydrophobicity . Comparative biological and physicochemical studies concluded that the position of sulfur in the spacer chain for three gemini QAC series influences the surface activity, the hydrophobicity and the electron density of the ammonium nitrogen, and that their biological properties are ascribable to the variation of these parameters caused by the position of the sulfur.

Structure (Camb), 2005 Jan, 13(1), 29 - 41
Siderocalin (Lcn 2) Also Binds Carboxymycobactins, Potentially Defending against Mycobacterial Infections through Iron Sequestration; Holmes MA et al.; Siderocalin, a member of the lipocalin family of binding proteins, is found in neutrophil granules, uterine secretions, and at markedly elevated levels in serum and synovium during bacterial infection; it is also secreted from epithelial cells in response to inflammation or tumorigenesis . Identification of high-affinity ligands, bacterial catecholate-type siderophores (such as enterochelin), suggested a possible function for siderocalin: an antibacterial agent, complementing the general antimicrobial innate immune system iron-depletion strategy, sequestering iron as ferric siderophore complexes . Supporting this hypothesis, siderocalin is a potent bacteriostatic agent in vitro under iron-limiting conditions and, when knocked out, renders mice remarkably susceptible to bacterial infection . Here we show that siderocalin also binds soluble siderophores of mycobacteria, including M . tubercu losis: carboxymycobactins . Siderocalin employs a degenerate recognition mechanism to cross react with these dissimilar types of siderophores, broadening the potential utility of this innate immune defense.

Bone Marrow Transplant . 2005 Jan 10; {Epub ahead of print}
Steroids prevent engraftment syndrome after autologous hematopoietic stem cell transplantation without increasing the risk of infection; Mossad S et al.; Summary:Engraftment syndrome (ES) following autologous hematopoietic stem cell transplantation (AHSCT) is characterized by fever and rash . In January 2002, we instituted steroid prophylaxis for ES from day +4 to +14 . This study was conducted to assess whether this practice increased the risk of infection . In total, 194 consecutive patients were reviewed, 111 did not receive steroid prophylaxis (group A), and 83 did (group B) . Initial antimicrobial prophylaxis was the same in both groups . There were no significant differences between groups in age, gender, race, prior radiation therapy, number of prior chemotherapy regimens, disease status at transplant, mobilization regimen, days of leukopheresis, CD34(+) cell dose, and days to platelet and neutrophil engraftment . Group B had significantly fewer patients with non-Hodgkin's lymphoma and multiple myeloma, shorter median duration from diagnosis to transplant, lower risk of ES, and shorter mean length of hospital stay . The incidence of early and late microbiologically confirmed infections was not significantly different between groups . Types of infections and types of organisms identified were similar in both groups . Hospital readmission rates were similar in both groups . Steroid prophylaxis significantly decreases the risk of ES following AHSCT, and is associated with shortened hospitalization, without increasing risk of infection.Bone Marrow Transplantation advance online publication, 10 January 2005; doi:10.1038/sj.bmt.1704769.

Curr Opin Infect Dis, 2004 Dec, 17(6), 533 - 40
Clinical utility of antifungal pharmacokinetics and pharmacodynamics; Andes D; PURPOSE OF REVIEW: Historically the anti-infective dose and dosing interval chosen in clinical trials have been based on an arbitrary goal of maintaining drug levels in serum above the minimum inhibitory concentration of infecting pathogens for most if not all of the dosing interval . Subsequent United States Food and Drug Administration approval of a dosing regimen is then based on clinical success in treatment trials . Over the past decade, the emergence of drug resistance has limited the clinical utility of an increasing number of antimicrobial agents . However, early in drug development clinical trials do not often define the impact of infection with these less susceptible pathogens . The field of pharmacodynamics provides analysis tools that can help predict the likelihood of treatment success with various antimicrobial treatment regimens against susceptible and resistant pathogens . RECENT FINDINGS: In-vitro and animal model studies have begun to define the pharmacodynamic characteristics of a variety of antifungal compounds . In-vivo studies have demonstrated that the pharmacodynamic target associated with efficacy is similar among antifungal drugs within the same class and have shown the importance of considering protein . Analysis of clinical trial data suggests that the pharmacodynamic target identified in animal model studies is predictive of outcomes in humans . SUMMARY: Antifungal pharmacodynamics can be used to understand the relationship between drug dosing, in-vitro susceptibility and treatment efficacy . Consideration of these relationships can be used to optimize dosing regimens with current antifungal agents, to develop susceptibility breakpoint guidelines, and in the design of dosing regimens for drugs in early development.

Appl Biochem Biotechnol, 2005 Jan, 120(1), 1 - 14
Expression of Human beta-Defensin-2 With Multiple Joined Genes in Escherichia coli; Xu Z et al.; Human beta-defensin (HBD)-2 is a small cationic peptide with a broad range of antimicrobial activity . In this study, multiple copies of the hBD2 gene were linked in tandem, and a number of different Escherichia coli expression vectors were evaluated, including pQE-30, pBV220, pET-28a(+), and pGEX-4T-2 . No expression of multiple joined genes was detectable in the pQE-30 expression system, whereas in pBV220 with one or two joined hBD2 genes and in pET-28a(+) with one, two, or four copies, target proteins were expressed at a low level . Only when pGEX-4T-2 was applied as expression plasmid with one or two joined hBD2 genes were target proteins expressed in high level, and the expressed fusion proteins account for 26 and 16% of the total insoluble proteins, respectively . In the pGEX-4T-2 and pET-28a(+) expression systems, the effects of multiple joined genes on the growth of host strains and plasmid stability were examined . Host cells containing plasmid carrying fewer copies of hBD2 genes were faster in cell growth . Plasmid stability decreased with an increase in multiple joined genes, which was especially noticeable in the pET-28a(+) system . Furthermore, the presence of glucose in culture medium brought about a positive effect on plasmid stability when using pET28-nhBD2 as expression vectors.

Appl Environ Microbiol, 2005 Jan, 71(1), 261 - 9
A clp Gene Homologue Belonging to the Crp Gene Family Globally Regulates Lytic Enzyme Production, Antimicrobial Activity, and Biological Control Activity Expressed by Lysobacter enzymogenes Strain C3; Kobayashi DY et al.; Lysobacter enzymogenes strain C3, a biological control agent for plant diseases, produces multiple extracellular hydrolytic enzymes and displays antimicrobial activity against various fungal and oomycetous species . However, little is known about the regulation of these enzymes or their roles in antimicrobial activity and biocontrol . A study was undertaken to identify mutants of strain C3 affected in extracellular enzyme production and to evaluate their biocontrol efficacy . A single mini-Tn5-lacZ(1)-cat transposon mutant of L . enzymogenes strain C3 that was globally affected in a variety of phenotypes was isolated . In this mutant, 5E4, the activities of several extracellular lytic enzymes, gliding motility, and in vitro antimicrobial activity were reduced . Characterization of 5E4 indicated that the transposon inserted in a clp gene homologue belonging to the Crp gene family of regulators . Immediately downstream was a second open reading frame similar to that encoding acetyltransferases belonging to the Gcn5-related N-acetyltransferase superfamily, which reverse transcription-PCR confirmed was cotranscribed with clp . Chromosomal deletion mutants with mutations in clp and between clp and the acetyltransferase gene verified the 5E4 mutant phenotype . The clp gene was chromosomally inserted in mutant 5E4, resulting in complemented strain P1 . All mutant phenotypes were restored in P1, although the gliding motility was observed to be excessive compared with that of the wild-type strain . clp mutant strains were significantly affected in biological control of pythium damping-off of sugar beet and bipolaris leaf spot of tall fescue, which was partially or fully restored in the complemented strain P1 . These results indicate that clp is a global regulatory gene that controls biocontrol traits expressed by L . enzymogenes C3.

Yi Chuan, 2003 Mar, 25(2), 198 - 200
{Use of PCR related methods in detection of gene mutation.}; Yan ZQ et al.; Many inherited diseases and drug resistance have been attributed to mutations in corresponding genes.In this paper,several techniques based on PCR used in diagnosis were concluded.The development and research progress of Mismatch PCR were discussed in details.Some information about an assay that we developed for detection of antimicrobial resistance to quinolones was also described.

Yi Chuan, 2003 Mar, 25(2), 146 - 50
{Recombination and Fusion Expression of Porcine Defensin Gene PBD-I in E.coli.}; Luo G et al.; The porcine defensin gene PBD-I was amplified by RT-PCR,then the gene was inserted into expression vector PinPoint(TM) Xa-3.Recombinant plasmid named as ppd-1 was transformed into E.Coli JM109,which could effectively produce fusion protein induced with IPTG.The positive clone of PBD-I gene expressed 17kDa fusion protein by SDS-PAGE electrophoresis.Expression of PBD-I gene didn't increase distinctly along with time.The expression of PBD-I gene lays a foundation in research on antimicrobial activities and its mechanism of the defensin.

Trends Parasitol, 2005 Jan, 21(1), 35 - 41
Sabotage and exploitation in macrophages parasitized by intracellular protozoans; Denkers EY et al.; Macrophages are crucial in immunity to infection . They possess potent antimicrobial function, and efficiently process and present peptide antigens for T-cell activation . Despite this, the intracellular protozoan parasites Toxoplasma gondii, Trypanosoma cruzi and Leishmania spp . target macrophages for infection . Each has adopted unique strategies to subvert macrophage antimicrobial functions . The parasites sabotage killing activities through sophisticated manipulation of intracellular macrophage signaling pathways . These subversive activities are probably dictated by the need to evade microbicidal effector function, as well as to avoid proinflammatory pathology that can destabilize the host-parasite interaction . The molecular details of how intracellular protozoans manipulate macrophage signal transduction pathways for their own ends are beginning to emerge.

Clin Ther, 2004 Nov, 26(11), 1728 - 57
Daptomycin: a cyclic lipopeptide antimicrobial agent; Jeu L et al.; OBJECTIVES: The aims of this article were: to summarize the pharmacology, pharmacokinetics, and efficacy of daptomycin; to explore its safety profile; and to discuss its current and potential roles as an antimicrobial therapy . METHODS: A literature search was conducted using the MEDLINE (1966-August 2004) and International Pharmaceutical Abstracts (1970-August 2004) databases with the search terms daptomycin, LY146032, and lipopeptide antibiotics . Abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy and documents submitted to the US Food and Drug Administration were also reviewed . RESULTS: Phase III study results suggest no difference in efficacy or tolerability between daptomycin 4 mg/kg IV QD and vancomycin or semisynthetic penicillins for complicated skin and skin-structure infections . Animal studies suggest daptomycin may be useful for the treatment of endocarditis . Daptomycin is not indicated for pneumonia, with poorer outcomes than conventional treatment It is available as an IV medication and exhibits 92% plasma protein binding in vitro . In healthy adult humans, daptomycin has a volume of distribution of 0.1 L/kg and a plasma elimination half-life of approximately 9 hours, and is eliminated primarily by renal excretion (approximately 54%) . In patients with reduced renal function, including those receiving hemodialysis and peritoneal dialysis, the dose interval should be 48 hours . No dosage adjustment appears to be necessary for mild to moderate hepatic impairment . The use of daptomycin in patients with severe hepatic impairment has not been assessed . The most commonly reported adverse events include constipation, nausea, injection-site reactions, headache, and diarrhea . Patients should also be monitored regularly for skeletal muscle toxicity . CONCLUSIONS: Daptomycin may be useful for complicated skin and skin-structure infections and gram-positive pathogens resistant to conventional antimicrobials . However, limited data are currently available for duration of treatment beyond 14 days and at doses >4 mg/kg QD.

APMIS, 2004 Dec, 112(11-12), 838 - 55
Application of molecular genetic methods in macrolide, lincosamide and streptogramin resistance diagnostics and in detection of drug-resistant Mycobacterium tuberculosis; Jalava J et al.; Jalava J, Marttila H . Application of molecular genetic methods in macrolide, lincosamide and streptogramin resistance diagnostics and in detection of drug-resistant Mycobacterium tuberculosis . APMIS 2004;112:838-55.Antimicrobial susceptibility testing has traditionally been based on measurements of minimal inhibitory concentrations of antimicrobials . Molecular genetic studies on antimicrobial resistance have produced a great deal of genetic information which can be used for diagnosis of antimicrobial resistance determinants . Bacteria can acquire resistance to macrolides, lincosamides and streptogramin antibiotics by modification of the target site of the drugs, by active efflux of the drugs, and by inactivation of the drugs . The genetic backgrounds of these resistance mechanisms are well known and several molecular methods for detection of resistance determinants have been developed . Outbreaks of multidrug-resistant tuberculosis have focused international attention on the emergence of Mycobacterium tuberculosis strains that are resistant to antimycobacterial agents . Knowledge of the antimycobacterial resistance genetics and progress in molecular methods has made it possible to develop rapid molecular methods for susceptibility testing . This review presents the genetic background of drug resistance and introduces some methods for genotypic susceptibility testing.

Protein Pept Lett, 2005 Jan, 12(1), 49 - 67
Immunocontinuum: perspectives in antimicrobial peptide mechanisms of action and resistance; Yount NY et al.; Antimicrobial peptides are present in organisms spanning virtually every kingdom, and employ sophisticated mechanisms to exert rapid microbicidal action consistent with their key roles in host defense . Offsetting these mechanisms, some microbial pathogens have evolved complex countermeasures to neutralize exposure to and subvert mechanisms of antimicrobial peptides . The following discussion highlights recent advances that offer greater understanding of the mechanisms of action and resistance of antimicrobial peptides.

Protein Pept Lett, 2005 Jan, 12(1), 41 - 7
Antimicrobial peptide microbicides targeting HIV; Cole AM; Cationic antimicrobial peptides and proteins are among the earliest molecular effectors of the innate arm of immunity in humans and other vertebrates . This review, inspired by recent emphasis on the development of topical preventatives for sexually transmitted infections, describes antimicrobial peptides and proteins in the context of microbicide design and development . Particular emphasis is placed on the defensin family of peptides.

Protein Pept Lett, 2005 Jan, 12(1), 31 - 9
Amphiphilic alpha-helical antimicrobial peptides and their structure/function relationships; Dennison SR et al.; To facilitate microbial membrane invasion, amphiphilic alpha-helical antimicrobial peptides (alpha-AMPs) show a spatial segregation of hydrophobic and hydrophilic residues about the alpha-helical long axis . Here we discuss potential mechanisms by which these peptides are able to disrupt membrane structure and the structural characteristics, which are required for function.

Protein Pept Lett, 2005 Jan, 12(1), 27 - 9
Are oblique orientated alpha-helices used by antimicrobial peptides for membrane invasion?
Dennison SR, Harris F, Phoenix DA.
Oblique orientated alpha-helices are highly specialised protein structural elements that penetrate membranes at a shallow angle and are used to promote membrane destabilisation by a number of protein classes . Here, the use of extended hydrophobic moment methodology shows that the amphibian extrudates, aurein 1.2 and citropin 1.1, may use oblique orientated alpha-helices in their antimicrobial action and that such use may be shared by other antimicrobial peptides . This appears to be the first systematic analysis of these peptides for the possession of oblique orientated alpha-helical structure.

Protein Pept Lett, 2005 Jan, 12(1), 19 - 25
Antimicrobial peptides: cooperative approaches to protection; Patrzykat A et al.; Reports of cationic antimicrobial peptides (CAPs) have become standard fare in research literature . But with several hundred peptides described to date, the investigator who tries to navigate the proposed models of their activity is only treated to a generous serving of incongruencies . Rather than acting in isolation as antimicrobial molecules, CAPs also may synergize with other molecules of innate immunity and modulate both innate and adaptive immune systems, thus providing a link between the various mechanisms that result in host protection.

Protein Pept Lett, 2005 Jan, 12(1), 13 - 8
Plant defense and antimicrobial peptides; Castro MS et al.; Plants are constantly exposed to a large array of pathogenic organisms and the survival in these conditions demands quick defense responses which include the synthesis of defense peptides and proteins with antimicrobial properties . The main groups of antimicrobial peptides found in plants are thionins, defensins and lipid transfer proteins . They constitute interesting candidates to engineer disease resistance in plants.

Protein Pept Lett, 2005 Jan, 12(1), 3 - 11
Insect antimicrobial peptides: structures, properties and gene regulation; Bulet P et al.; Antimicrobial peptides (AMPs) are part of the armament that insects have developed to fight off pathogens . Insect AMPs are typically cationic and often made of less than 100 amino acid residues . Although their structures are diverse, most of the AMPs can be assigned to a limited number of families . The most common structures are represented by peptides assuming a alpha-helical conformation in organic solutions or disulfide-stabilized beta-sheets with or without alpha-helical domains present . The diverse activity spectrum of these peptides may indicate different modes of action . Genetic analysis in the Drosophila model evidenced that multiple signal transduction pathways are activating the genes coding AMPs.

Curr Protein Pept Sci, 2005 Jan, 6(1), 85 - 101
Defensins - components of the innate immune system in plants; Lay FT et al.; Plant defensins are small (c.a . 5 kDa), basic, cysteine-rich proteins with antimicrobial activities . They are ubiquitous in plants and form part of the innate immunity arsenal . Plant defensins are encoded by small multigene families and are expressed in various plant tissues, but are best characterized in seeds . They are typically produced as preproteins, however, a small subset are produced as larger precursors with C-terminal prodomains . To date, the three-dimensional solution structures of seven seed- and two floral-derived defensins have been elucidated by (1)H-NMR spectroscopy . Despite limited amino acid sequence identities, these defensins have comparable global folds with features that are characteristic of the cysteine-stabilized alphabeta (CSalphabeta) motif . Interestingly, their structures are remarkably similar to those of insect defensins and scorpion toxins . Functionally, these proteins exhibit a diverse array of biological activities, although they all serve a common function as defenders of their hosts . This review describes the distribution, biosynthesis, structure, function and mode of action of plant defensins and reflects on their potential in agribiotechnological applications.

Curr Protein Pept Sci, 2005 Jan, 6(1), 61 - 75
Bacterial lantibiotics: strategies to improve therapeutic potential; Cotter PD et al.; Lantibiotics are ribosomally-synthesised antimicrobial peptides produced by Gram-positive bacteria that are characterised by the presence of lanthionine and/or methyllanthionine residues . Other unusual post-translationally modified amino acids, most frequently dehydroalanine and dehydrobutyrine, can also be present . While it has been frequently suggested that these peptides have the potential to be utilised in a wide range of medical applications, to date no actual therapeutic applications have been convincingly described . More recently, however, they have been the focus of much attention as a consequence of improved biotechnological capabilities, an improved understanding of lantibiotic biosynthesis and mode of action, and their high specific activity against multi-drug resistant bacteria . This review concerns the fundamental analyses that have revealed the importance of individual amino acids in these peptides and has permitted the implementation of rational mutagenesis strategies ('intelligenetics') to alter individual residues with a view to ultimately widening the active pH range, improve stability, and enhance binding to cell wall targets with the ultimate aim of optimising their antimicrobial activity . It is hoped that as a consequence of this improved knowledge the most suitable application of individual lantibiotics will become apparent . It should also prove possible, in the near future, to generate tailor-made lantibiotics and utilise biosynthetic enzymes to incorporate modified amino acids into non-lantibiotic peptides . In the shorter term, the extensive characterisation of lantibiotics will be instrumental in reassuring drug industry regulators of their safety and facilitate the widespread application of these novel antimicrobial agents in medicine.

Curr Protein Pept Sci, 2005 Jan, 6(1), 53 - 60
Defensins - Non-antibiotic Use for Vaccine Development; Biragyn A; Vaccines should elicit protective and long lasting immune memory, which depends on well choreographed responses between innate and acquired immunity . Defensins are small host defense peptides of innate immunity hitherto reported to have antimicrobial activity, which also orchestrate chemotaxis and activation of effector immune cells, including immature dendritic cells . This review analyzes the biological meaning of the immunomodulatory and immunoenhancing features of defensins and their use for the development of novel vaccines to combat cancer and clinically relevant diseases.

Curr Protein Pept Sci, 2005 Jan, 6(1), 35 - 51
A Re-evaluation of the Role of Host Defence Peptides in Mammalian Immunity; Bowdish DM et al.; Host defence peptides are found in all classes of life and are a fundamental component of the innate immune response . Initially it was believed that their sole role in innate immunity was to kill invading microorganisms, thus providing direct defence against infection . Evidence now suggests that these peptides play diverse and complex roles in the immune response and that, in higher animals, their functions are not restricted to the innate immune response . In in vitro experiments certain host defence peptides have been demonstrated to be potent antimicrobial agents at modest concentrations, although their antimicrobial activity is often strongly reduced or ablated in the presence of physiological concentrations of ions such as Na(+) and Mg(2+) . In contrast, in experiments done in standard tissue culture media, the composition of which more accurately represents physiological levels of ions, mammalian host defence peptides have been demonstrated to have a number of immunomodulatory functions including altering host gene expression, acting as chemokines and/or inducing chemokine production, inhibiting lipopolysaccharide induced pro-inflammatory cytokine production, promoting wound healing, and modulating the responses of dendritic cells and cells of the adaptive immune response . Animal models indicate that host defence peptides are crucial for both prevention and clearance of infection . As interest in the in vivo functions of host defence peptides is increasing, it is important to consider whether in mammals the direct antimicrobial and immunomodulatory properties observed in vitro are physiologically relevant, especially since many of these activities are concentration dependent . In this review we summarize the concentrations of host defence peptides and ions reported throughout the body and compare that information with the concentrations of peptides that are known have antimicrobial or immunomodulatory functions in vitro.

Curr Protein Pept Sci, 2005 Jan, 6(1), 23 - 34
The cathelicidins - structure, function and evolution; Tomasinsig L et al.; The cathelicidin family of host defense peptides includes a group of cationic and usually amphipathic peptides that display a variety of activities related to host defense functions, among which the most acknowledged is a direct antimicrobial activity against various microbial pathogens . All members of this family are synthesized as precursors characterized by an N-terminal cathelin-like domain which is relatively well conserved also in evolutionary distant vertebrates . By contrast, the C-terminal region, which carries the active peptide, appears to be a focus for genetic mechanisms that have selectively generated a considerable sequence diversity . This process is particularly striking in Cetartiodactyls, where repeated gene duplication events and subsequent divergence have produced an array of distinct family members . The corresponding mature cathelicidin peptides are considerably diverse in length, amino acid sequence and structure, variously adopting alpha-helical, elongated or beta-hairpin conformations . The diverse nature of these peptides may account for distinct functions and for a diverse spectrum of activity and/or antimicrobial potency.

Curr Protein Pept Sci, 2005 Jan, 6(1), 7 - 21
Primate beta-defensins - Structure, Function and Evolution; Crovella S et al.; Host defense peptides (HDPs) are endogenous antibiotics that play a multifunctional role in the innate immunity of mammals . Among these, beta-defensins contribute to mucosal and epithelial defense, also acting as signal molecules for cellular components of innate and adaptive immunity . Numerous members of this family have been identified in mammalian and avian species, and genomic studies in human and mouse indicate a considerable complexity in their gene organization . Recent reports on the evolution of primate and rodent members of this family indicate quite a complex pattern of variation . In this review we briefly discuss the evolution of mammalian beta-defensins in relation to other types of defensins, and then concentrate on the evolution of beta-defensins 1 to 4 in primates . In particular, the surprisingly varied patterns of evolution, which range from neutral or weakly purifying, to positive selection to a high level of conservation are analyzed in terms of possible genetics, structural or functional implications, as well as to observed variations on the antimicrobial activity in vitro . The role of polymorphisms in the genes encoding for these host defense peptides in determining susceptibility to human diseases are also briefly considered.

Curr Pharm Des, 2005, 11(1), 37 - 53
Probiotic research in Australia, New Zealand and the Asia-Pacific region; Crittenden R et al.; Although the epicentres of probiotic research in the past decade have been Japan and Europe, researchers in the Asia-Pacific region have actively contributed to the growing understanding of the intestinal microbial ecosystem, and interactions between gut bacteria, diet and health of the human host . A number of new probiotic strains have been developed in the region that have been demonstrated to have beneficial impacts on health in animal and human trials, including improved protection against intestinal pathogens and modulation of the immune system . Probiotics targeted to animals, including aquaculture, feature heavily in many Asian countries . Developments in probiotic technologies have included microencapsulation techniques, antimicrobial production in fermented meats, and synbiotic combinations . In particular, the impact of resistant starch on the intestinal environment and fermentation by intestinal bacteria has been intensively studied and new probiotic strains selected specifically for synbiotic combinations with resistant starch . This paper provides an overview of probiotic research within Australia, New Zealand and a number of Asian countries, and lists scientists in the Asia-Pacific region involved in various aspects of probiotic research and development.

Biomacromolecules, 2005 Jan-Feb, 6(1), 220 - 8
Functionalized Micellar Assemblies Prepared via Block Copolymers Synthesized by Living Free Radical Polymerization upon Peptide-Loaded Resins; Becker ML et al.; Hybrid peptidic-synthetic amphiphilic block copolymers, synthesized by living free radical polymerization (LFRP) on solid support, have been utilized as precursors for nanoscale materials possessing bio-available peptides . LFRP initiators, coupled to the peptide terminus upon the resin, facilitated the growth of homo- and block copolymers via nitroxide mediated radical polymerization (NMRP) or atom transfer radical polymerization (ATRP) . Herein, the versatile solid-support synthesis of the antimicrobial peptide tritrpticin, coupling of living free radical polymerization initiators to the peptide-loaded resin, and the controlled radical polymerization of various monomers to yield amphiphilic diblock copolymers are described . Assembly of the peptidic-synthetic block copolymers into micelles and a preliminary assessment of their in vitro biological properties are detailed.

Wien Med Wochenschr, 2004 Nov, 154(21-22), 539 - 47
{On the biological properties of fragrance compounds and essential oils}; Buchbauer G; In the present review the physiological and/or pharmacological properties of essential oils and of single fragrance compounds are discussed . Essential oils are known and have been used since ancient times as natural medicines . As natural products essential oils are dependent on climate and their composition varies according to conditions of soil, to solar irradiation, to harvest time, to production methods, to storage conditions and similar facts which are discussed in chapter 2 of this review . The next chapters deal with the therapeutic use of essential oils in treating diseases, disorders or ailments of the nervous system, against cancer and as penetration enhancers . For space-saving reasons, however, the manifold antimicrobial and antifungal properties of these natural products have been left out . In the last chapter, the pros and cons in the use of essential oils in therapy are also discussed.

Circ Res, 2005 Jan 7, 96(1), 15 - 26
Innate immunity and angiogenesis; Frantz S et al.; Activation of an innate immune response is among the first lines of defense after tissue injury . Restoring blood flow to the site of injured tissue is often a necessary prerequisite for mounting an initial immune response to pathogens and for subsequent initiation of a successful repair of wounded tissue . The multiple links among pathogen recognition and suppression, increased angiogenesis, and tissue repair are the topics of this review, which examines of the roles of antimicrobial peptides, mammalian toll-like receptors (TLRs), inflammatory cytokines, and putative "danger" signals, among other signaling pathways, in triggering, sustaining, and then terminating an angiogenic response.

Neurosurg Focus . 2004 Dec 15;17(6):E1.
General principles in the medical and surgical management of spinal infections: a multidisciplinary approach; Quinones-Hinojosa A et al.; OBJECT: Infections along the spinal axis are characterized by an insidious onset, and the resulting delays in diagnosis are associated with serious neurological consequences and even death . Infections of the spine can affect the vertebral bodies, intervertebral discs, spinal canal, and surrounding soft tissues . Neurological dysfunction occurs when the spinal cord becomes compressed, edematous, or ischemic due to compression by abscess or vascular compromise . The aim of this paper was to detail general diagnostic and management principles for this disease . METHODS: Recent progress in medical technologies, including the development of potent antimicrobial drugs, advanced imaging, and improved surgical methods, have dramatically reduced morbidity and mortality rates for spinal infections; however, debate still exists on the proper management of this disease . In this paper, the authors review the current management protocols for spinal infections at their institution, focusing on medical and surgical treatments for vertebral osteomyelitis, intervertebral disc space infections, and spinal canal and soft-tissue abscesses . CONCLUSIONS: Technological advances in imaging modalities, pharmaceutics, and surgery have resulted in excellent outcomes and have greatly reduced the morbidity and mortality rates associated with spinal infections . Currently, treatment of spinal infections requires a multidisciplinary team that includes infectious diseases experts, neuroradiologists, and spine surgeons . The key to successful management of spinal infections is early detection.

Phytomedicine, 2004 Nov, 11(7-8), 701 - 3
Antimicrobial activity of Securidaca longipedunculata; Ajali U et al.; The folk herbal uses of Securidaca longipedunculata in the treatment of diarrhea, boils, gonorrhea, and cough prompted phytochemical analyses and antimicrobial activity screening of extracts of the root . Some flavonoids isolated showed activity against many micro-organisms . These flavonoids were isolated using chromatographic methods.

Int J Oral Maxillofac Implants, 2004, 19 Suppl, 128 - 39
Antimicrobial treatment of peri-implant diseases; Heitz-Mayfield LJ et al.; PURPOSE: To review the literature on the treatment of peri-implant diseases . Specific emphasis was placed on the use of antimicrobial therapy, defined as local or systemic administration of antiseptic and/or antibiotic agents . MATERIALS AND METHODS: A search of MEDLINE, the Cochrane Controlled Trials Register, and The Cochrane Health Group Specialized Register was conducted, and articles published in English until July 31, 2003, were included . The results of experimental animal studies and human research are presented . RESULTS: A variety of antimicrobial treatment regimens in combination with nonsurgical or surgical debridement with and without regenerative therapy were reported . Use of antimicrobials varied between studies with respect to type of drug, dosage, delivery system, duration, and commencement of antibiotic administration . Patient compliance and adverse effects related to the antimicrobials were mostly not mentioned . DISCUSSION: While the majority of the case reports and studies presented showed positive outcomes following antimicrobial treatment, there were no non-medicated controls included, so the relative effect of the antimicrobial agent(s) cannot be evaluated . CONCLUSIONS: Although antimicrobials are widely used for the treatment of peri-implant diseases, evidence of their benefit is limited, and randomized, controlled human trials should be initiated where ethically possible . In addition, prospective cohort studies designed to monitor consecutive cases treated using specific treatment protocols are required.

Biol Pharm Bull, 2005 Jan, 28(1), 148 - 50
Lipid Membrane-Binding Properties of Tryptophan Analogues of Linear Amphipathic beta-Sheet Cationic Antimicrobial Peptides Using Surface Plasmon Resonance; Kamimori H et al.; Using a surface plasmon resonance (SPR) system, we investigated the lipid membrane-binding properties of four analogues of the 18-residue linear amphipathic beta-sheet cationic antimicrobial peptide (KIGAKI)(3)-NH(2), each of which contains a single isoleucine-to-tryptophan substitution . The results of the SPR study revealed significant differences in the binding characteristics of the peptides depending upon the position of tryptophan residues . These peptides showed higher binding affinity to membranes containing acidic phospholipids than zwitterionic phospholipids . The addition of dimethylsulfoxide to the running buffer was effective in maintaining the solubility of these peptide solutions and obtaining concentration-dependent sensorgrams for the kinetic analysis in this study . The kinetic binding data of SPR correlated closely with both the ability of the peptides to lyse liposomes with the same phospholipid composition and bactericidal activity . The results demonstrate that SPR may be a valuable tool to predict the membrane lytic properties of antimicrobial peptides.

J Clin Microbiol, 2005 Jan, 43(1), 140 - 3
Synergy tests by E test and checkerboard methods of antimicrobial combinations against Brucella melitensis; Orhan G et al.; Two different synergy testing methods, the checkerboard and the E test methods, were used to compare the in vitro efficacies of various antimicrobial combinations against 16 Brucella melitensis strains isolated from blood cultures . The rate of agreement of the E test and checkerboard methods was found to be 55% . The most concordant results were found for the streptomycin-doxycycline combination in 12 (75%) tests, in which four strains showed synergistic activity by E test and antagonistic activity by the checkerboard method and in which one strain showed antagonistic activity by both methods . Even though each of these methods uses different conditions and endpoints, the results of both methods frequently agreed.

Zhonghua Nei Ke Za Zhi, 2004 Nov, 43(11), 815 - 9
{The adverse reactions of parenteral norvancomycin in 1031 patients.}; Liu Y et al.; OBJECTIVE: To investigate the safety of norvancomycin, and provide basis for its rational use in clinical practice . METHODS: We documented all adverse events occurred in inpatients who receive intravenous infusion of norvancomycin, then we evaluated the relationship between adverse events and norvancomycin and calculated the rates of adverse reaction . RESULTS: 1031 patients were enrolled in this study from March 2002 to June 2003 and 965 of them could be evaluated . 80 adverse reactions occurred in 965 patients who received norvancomycin, giving a total adverse reaction rate of 8.29% . The systemic adverse reactions included renal impairment (4.04%), hepatic impairment (2.38%) and allergic reaction (1.76%) . 15 patients discontinued the treatment because of the adverse reaction . The rates were higher in patients who use other antimicrobial agents concomitantly or whose age >/= 60 years . The rates of renal impairment were higher in those with age >/= 60 years, and the rates of hepatic impairment were higher in whose received this agent longer than 14 days . These factors were independent risk factors (P < 0.05) . CONCLUSIONS: The overall adverse reaction rate of norvancomycin was low . A few patients experienced drug-related reaction, most of these adverse reactions were mild and tolerable . The adverse reactions tended to occur in older patients, those who use other antibiotic concomitantly or those who receive this agent longer than 14 days.

Yi Chuan Xue Bao, 2004 Dec, 31(12), 1344 - 50
{Molecular cloning and expression of Attacin from housefly (Musca domestica)}; Geng H et al.; The antimicrobial peptides of insect are the main components of their non-specific immune system, and play a major role in the defense against the foreign disease-related microbes . In this report, a full length cDNA of Attacin, an insect antimicrobial peptide was cloned from housefly (Musca domestica) by homology cloning approach in combine with 3' and 5' RACE . Sequence analysis and phylogenetical study showed that this cDNA contained 778 nucleotides, with a 627 bp open reading frame (ORF) flanked with a 44 bp 5'UTR and a 107 bp 3'UTR . The encoded 208 amino acids housefly Attacin shared a high similarity of 50%-70% with that of the other dipterous insects . In addition, the phylogenetical analysis also indicated that the Attacin from housefly was in the same branch with those of other species, suggesting that they come from the same ancestor . The expression of Attacin transcript was measured by semi-quantitive RT-PCR . The results demonstrated that the expression of housefly Attacin is inducible, and that the level varies with the time of induction and the kinds of pathogens.

Dent Assist, 2004 Nov-Dec, 73(6), 20, 22 - 4, 63
Local chemotherapeutics as an adjunct to scaling and root planing; Breault LG et al.; Gingival diseases are the most widely held diseases in America . In some patients, periodontal disease appears in a generalized form, but more often it appears in localized areas . Furthermore, after treatment with scaling and root planing (SRP) in generalized cases, the disease is often reduced to a few local areas in the patient's mouth . Since periodontitis is a bacterial infection with known pathogenic microorganisms, the local delivery of antimicrobials has been considered to be a possible solution for treating and controlling localized forms of periodontal disease . Three current local chemotherapeutic agents are reviewed in this paper: doxycycline gel, chlorhexidine chip and minocycline microspheres . With the advancement of local drug delivery systems, clinicians and their patients have new alternatives for treatment of periodontal disease.

J Periodontol, 2004 Nov, 75(11), 1516 - 23
Effects of combined systemic administration of low-dose doxycycline and alendronate on endotoxin-induced periodontitis in rats; Buduneli E et al.; BACKGROUND: Doxycycline has been widely used in periodontal treatment for its antimicrobial and anti-enzymatic effects . Recently, bisphosphonates have been shown to inhibit alveolar bone resorption . The aim of the present study was to evaluate the effects of doxycycline and the bisphosphonate alendronate on the gingival tissue levels of prostaglandin E2 (PGE2), prostaglandin F2alpha (PGF2alpha), leukotriene B4 (LTB4), and platelet-activating factor (PAF) in endotoxin-induced periodontal breakdown in rats . METHODS: Experimental periodontitis was induced by repeated injection of Escherichia coli endotoxin (LPS) and 44 adult male Sprague-Dawley rats were divided into five study groups as follows: LPS, doxycycline + LPS, alendronate + LPS, doxycycline + alendronate + LPS, and saline control . Doxycycline and alendronate were given either as a single agent or as a combination therapy during the 7-day study period . At the end of the 1-week protocol, the rats were sacrificed, the gingival tissues were dissected and extracted, and the extracts were analyzed for PGE2, PGF2alpha, LTB4, and PAF levels . The defleshed jaws were analyzed morphometrically for alveolar bone loss . Data were evaluated statistically by using parametric tests . RESULTS: Alveolar bone loss measurements revealed significantly higher values in LPS, doxycycline + LPS, alendronate + LPS, and doxycycline + alendronate + LPS groups in comparison to the saline control group (P <0.05) . Combined administration of doxycycline and alendronate exhibited the most prominent inhibition on gingival tissue levels of PGE2 and PGF2alpha (P<0.05) . Doxycycline + alendronate + LPS group also significantly reduced LTB4 and PAF levels, although doxycycline provided the most reduction in the levels of these mediators (P <0.05) . CONCLUSIONS: Alendronate and/or doxycycline may provide significant inhibition of the major inflammatory mediators of periodontal tissue destruction, and combined administration of these agents may provide beneficial effects in periodontal treatment . However, this hypothesis must be further verified by clinical human trials before introducing its use in dental practice.

J Biol Chem . 2005 Jan 4; {Epub ahead of print}
A molecular mechanism for LPS protection of gram-negative bacteria from antimicrobial peptides; Papo N et al.; Cationic antimicrobial peptides serve as the first chemical barrier between all organisms and microbes . One of their main targets is the cytoplasmic membrane of the microorganisms . However, it is not yet clear why some peptides are active against one particular bacterial strain but not against others . Recent studies suggested that the lipopolysaccharide outer membrane (LPS) is the first protective layer that actually controls peptide binding and insertion into Gram-negative bacteria . In order to shed light onto these interactions, we synthesized and investigated a 12-mer amphipathic -helical antimicrobial peptide (K5L7) and its diastereomer (4D-K5L7) (containing four D amino acids) . Interestingly, although both peptides strongly bind LPS bilayers and depolarize bacterial cytoplasmic membranes, only the diastereomer kills Gram-negative bacteria . ATR-FTIR, CD, and surface plasmon resonance (SPR) spectroscopies revealed that only the diastereomer penetrates the LPS layer . In contrast, K5L7 binds cooperatively to the polysaccharide chain and the outer phosphate groups . As a result, the self-associated K5L7 is unable to traverse through the tightly packed LPS molecules, revealed by epifluorescence studies with LPS giant unilamellar vesicles (GUVs) . The difference in the peptides' modes of binding is further demonstrated by the ability of the diastereomer to induce LPS miscellization, as shown by transmission electron microscopy . In addition to increasing our understanding of the molecular basis of the protection of bacteria by LPS, this study presents a potential strategy to overcome resistance by LPS, and it should help in the design of antimicrobial peptides for future therapeutic purposes.

Drugs Aging, 2004, 21(15), 993 - 1012
Perioperative pharmacotherapy in patients with left ventricular assist devices; Dang NC et al.; Heart failure remains the leading cause of death in Western countries, affecting 4.9 million individuals and causing >300 000 deaths annually in the US alone . The disease is highly prevalent in the elderly population and often follows a course of progressive disability and deterioration . An estimated 15 000 patients with end-stage heart failure could benefit from heart transplant each year . Yet, as a result of a significant shortage of donor organs, only 2500 hearts are donated annually, and approximately one-third of patients awaiting heart transplant die each year . Mechanical circulatory support, primarily in the form of left ventricular assist devices (LVADs), has come to the forefront of treatment for severe congestive heart failure by providing a feasible alternative to patients who might otherwise die awaiting heart transplant . The arrival of LVADs has resulted in a dramatic shift in the management of heart failure, one that will undoubtedly affect and include a vast proportion of elderly patients . While LVADs represent a surgical approach to a disease that has traditionally been managed medically, the pharmacological application throughout the perioperative period remains of critical importance.Five primary classes of drugs bear specific application to the LVAD population: (i) drugs that provide haemodynamic support; (ii) antimicrobials; (iii) anticoagulants and antiplatelets; (iv) agents that promote myocardial recovery; and (v) miscellaneous other medications . Drugs that provide haemodynamic support are subdivided into inotropes, vasopressors and pulmonary vasodilators . Some combination of these medications is usually administered within the perioperative period in order to maintain stable patient haemodynamics and assure proper LVAD function . Antimicrobials are of paramount importance in the pre-, intra- and postoperative periods to minimise the risk of infection, an unfortunately common complication of LVAD therapy that can have potentially morbid consequences . Anticoagulants and antiplatelet medications are necessary for certain types of LVADs and serve to curb the incidence of device thrombus formation and associated embolic phenomena . Pharmacotherapeutic agents that facilitate myocardial recovery are being investigated as adjuncts to LVAD support so that bridge to recovery can become a realistic outcome for a growing number of LVAD patients . The miscellaneous class of medications used with LVADs includes those that minimise the risk of bleeding in select patients and those that enhance proper vitamin and nutrient status in the postoperative period, the attainment of which may serve vital to a successful recovery.

Rev Med Chil, 2004 Oct, 132(10), 1211 - 6
{Antimicrobial susceptibility of shiga toxin producing E coli (STEC) strains isolated from human infections and food}; Reyes MS et al.; BACKGROUND: Shiga toxin-producing E coli (STEC) are zoonotic pathogens associated to sporadic episodes of bloody diarrhea, foodborne outbreaks, and Hemolytic Uremic Syndrome (HUS), with worldwide public health impact . Antibiotic use in STEC infections is controversial because of the potential to increase production and secretion of Shiga toxins . AIM: To study the in vitro antimicrobial susceptibility profile of STEC . MATERIAL AND METHODS: The in vitro susceptibility profile against 10 antimicrobials of STEC strains isolated from 29 meat products, 20 patients with diarrhea and 9 HUS patients was studied . Minimal Inhibitory Concentrations (microg/ml) by agar dilution method for ampicillin, cloramphenicol, ciprofloxacin, amikacin, gentamycin, cotrimoxazol, ceftriaxone, tetracycline, fonsfomycin and azihromycin were measured according to NCCLS recommendations . RESULTS: Strains from patients with diarrhea or HUS were all susceptible to the 10 antimicrobials and only 13.7% had intermediate resistance to cloramphenicol . Strains from meat products had a similar susceptibility profile, with only 3.5% resistance to tetracycline, 3.5% intermediate resistance to cloramphenicol and 7% to fosfomycin . All 58 strains were considered resistant to azithromycin (MIC >32 microg/ml) . CONCLUSIONS: Similarity of susceptibility profiles between STEC strains from human and food origin suggests a role of food chain in transmission to humans.

Am J Vet Res, 2004 Dec, 65(12), 1730 - 3
Comparison of the use of regulatory assays and high-performance liquid chromatography for detection of residues of ceftiofur sodium metabolites in tissue specimens of culled dairy cattle; Payne MA et al.; OBJECTIVE: To compare the results of regulatory screening and confirmation assays with those of high-performance liquid chromatography (HPLC) in the detection of ceftiofur metabolites in the tissues of culled dairy cattle . ANIMALS: 17 lactating Holstein dairy cows . PROCEDURE: Daily IM injections of ceftiofur sodium were administered at a dose of 2.2 mg of ceftiofur equivalents/kg (n = 6) or 1.0 mg of ceftiofur equivalents/kg (10) for 5 days . Following withdrawal times of 12 hours (high-dose ceftiofur) and either 5 or 10 days (low-dose ceftiofur), cows were slaughtered and liver, kidney, and diaphragmatic muscle specimens were harvested and analyzed by HPLC and standard regulatory methods that included the following assays: the swab test on premises, the fast antimicrobial screen test, the calf antibiotic and sulfa test, and the 7-plate bioassay confirmation test . RESULTS: In all tissue specimens, residues of ceftiofur and desfuroylceftiofur-related metabolites, as measured by HPLC, were less than regulatory tolerance, as defined by the FDA . False-positive screening assay results were more likely for tissue specimens that had been frozen for shipment to a federal laboratory, compared with fresh tissue specimens that were assayed at the slaughter establishment (23% vs 3% false-positive results, respectively) . CONCLUSIONS AND CLINICAL RELEVANCE: The observation that fresh tissues had negative results on screening assays, whereas subsets of the same tissue specimens had false-positive results on screening assays following freezing, suggests that freezing and thawing interferes with microbial inhibition-based regulatory screening assays.

Biofactors, 2004, 22(1-4), 319 - 21
Biological activity in traditional Alaska pollack sikhae during low temperature fermentation; Cha YJ et al.; Biological activity was examined on Alaska pollack sikhae produced with 4 treatments (by irradiating at 5 or 10 kGy, or by adding either 0.1 or 0.3% of chitooligosaccharide), compared with control (2-step fermentation only) during fermentation at -2 degrees C . The extracts (500 ppm level) of sikhae had antimicrobial activities against 4 different strains of food poisoning bacteria such as Staphy . aureus, B . subtilis, B . cereus, and L . monocytogenes . Antioxidative activity (EDA(50), 11.55 mg/mL) in control group increased with time up to 60 days of fermentation but decreased thereafter, while those levels in other products were kept within 10.60-18.30 mg/mL ranges during fermentation . Inhibitory activity of angiotensin-I converting enzyme (ACE) (IC(50), 1.51-2.89 mg/mL) in all products was observed during fermentation except at 0 day . Inhibitory activity of xanthine oxidase (XO) (IC(50), 0.65-0.87 mg/mL) in all products also increased with time up to 30 days of fermentation . Without irradiating or adding of chitooligosaccharide, Alaska pollack sikhae showing biological activities was enough by 2-step fermentation and storage at -2 degrees C only.

Biofactors, 2004, 21(1-4), 119 - 21
Protective effects of green tea catechins on alveolar macrophages against bacterial infections; Yamamoto Y et al.; Bacterial pneumonia in immunocompromised patients as well as elderly persons often becomes a life threatening disease, even when effective antibiotics are used extensively . In addition, the appearance of antibiotic-resistant bacteria in medical facilities as well as in patients requires another approach to treat such patients besides treatment with antibiotics . In this regard, green tea catechins, such as epigallocatechin gallate (EGCg), may be one of the potential agents for such purpose due to its possible potential immunomodulatory as well as antimicrobial activity . The studies by us showed that EGCg enhanced the in vitro resistance of alveolar macrophages to Legionella pneumophila infection by selective immunomodulatory effects on cytokine formation . Furthermore, the tobacco smoking-induced impairment of alveolar macrophages regarding antibacterial as well as immune activity was also recovered by EGCg treatment . These results indicate that EGCg may be a possible potential immunotherapeutic agent against respiratory infections in immunocompromised patients, such as heavy smokers.

Biofactors, 2004, 21(1-4), 55 - 61
Multifunctional peptides encrypted in milk proteins; Meisel H; Many bioactivities of milk are latent in that they are inactive within the protein sequence, requiring enzymatic proteolysis for release of bioactive peptides from milk proteins precursors . Bioactivities of peptides encrypted in major milk proteins are latent until released and activated, e.g . during gastrointestinal digestion or food processing . Bioactive peptides can be produced in vivo following intake of milk proteins, and the proteolytic system of bacterial species used in the production of fermented milk products and cheese can contribute to the liberation of bioactive peptides or precursors thereof . Activated peptides are potential modulators of various regulatory processes in the living system: immunomodulatory peptides stimulate the activities of cells of the immune system and several cytomodulatory peptides inhibit cancer cell growth, antimicrobial peptides kill sensitive microorganisms, angiotensin-I-converting enzyme (ACE)-inhibitory peptides exert an hypotensive effect, opioid peptides are opioid receptor ligands which can modulate absorption processes in the intestinal tract, mineral binding peptides may function as carriers for different minerals, especially calcium . Many milk-derived peptides reveal multifunctional properties, i.e . specific peptide sequences having two or more different biological activities have been reported . Milk protein-derived bioactive peptides are claimed to be health enhancing components that can be used to reduce the risk of disease or to enhance a certain physiological function.

Ann Intern Med, 2005 Jan 4, 142(1), 47 - 55
Narrative review: diseases that masquerade as infectious cellulitis; Falagas ME et al.; For cellulitis that does not respond to conventional antimicrobial treatment, clinicians should consider, among other explanations, several noninfectious disorders that might masquerade as infectious cellulitis . Diseases that commonly masquerade as this condition include thrombophlebitis, contact dermatitis, insect stings, drug reactions, eosinophilic cellulitis (the Wells syndrome), gouty arthritis, carcinoma erysipelatoides, familial Mediterranean fever, and foreign-body reactions . Diseases that uncommonly masquerade as infectious cellulitis include urticaria, lymphedema, lupus erythematosus, sarcoidosis, lymphoma, leukemia, Paget disease, and panniculitis . Clinicians should do an initial diagnostic work-up directed by the findings from a detailed history and complete physical examination . In many cases, skin biopsy is the only tool that helps identify the correct diagnosis . Special tests may also be needed.

J Leukoc Biol . 2005 Jan 3; {Epub ahead of print}
Psoriatic scales: a promising source for the isolation of human skin-derived antimicrobial proteins; Harder J et al.; Patients with psoriasis, a chronic, hyperproliferative and noninfectious skin disease, suffer surprisingly fewer cutaneous infections than would be expected . This observation led us to the hypothesis that a local "chemical shield" in the form of antimicrobial proteins provides psoriatic skin with resistance against infection . We subsequently began a systematic analysis of in vitro antimicrobially active proteins in psoriatic-scale extracts . A biochemical approach with rigorous purification and characterization combined with antimicrobial testing identified a number of mostly new human antibiotic peptides and proteins . In this review, we will focus on the most prominent antimicrobial proteins in psoriatic-scale extracts, which we identified as the S100-protein psoriasin, human beta-defensin 2 (hBD-2), RNase 7, lysozyme, and human neutrophil defensin 1-3 . Apart from these cutaneous, antimicrobial proteins, only a few others, including hBD-3, have been characterized . A great number of minor antimicrobial proteins await further structural characterization.

Theriogenology, 2005 Feb, 63(3), 716 - 21
Oregano improves reproductive performance of sows; Allan P et al.; Natural herbs are being explored as alternatives to antimicrobials . The objective of the present study was to determine the effect of strategic addition of oregano to prefarrowing and lactation diets of sows under field conditions . Alternate farrowing groups were given diets containing 1000ppm oregano (dried leaf and flower of Origanum vulgare, enriched with 500g/kg of cold-pressed essential oils of O . vulgare) in prefarrowing and lactation diets . Overall, 801 oregano-treated sows, including 601 primiparous and 1200 multiparous (parity 2.99 +/- 0.43, mean +/- S.E.) and 1809 untreated control sows (705 primiparous and 1104 multiparous; parity 3.04 +/- 0.38), were used . Sows fed oregano had lower annual sow mortality rate (4.02 +/- 0.4% versus 6.92 +/- 1.11%, mean +/- S.E.; P = 0.003), lower sow culling rate during lactation (8.01 +/- 1.11% versus 14.02 +/- 1.33%, P = 0.02), increased farrowing rate (77.02 +/- 2.31% versus 69.91 +/- 2.32%, P = 0.01), increased number of liveborn piglets per litter (10.49 +/- 1.5 versus 9.95 +/- 1.22, P < 0.05), and decreased stillbirth rate (0.909 +/- 0.01 versus 0.807 +/- 0.01, P = 0.05) . In addition, multiparous sows fed oregano had higher (P = 0.04) daily voluntary feed intake compared to non-treated sows (7.7 +/- 0.32kg versus 7.0 +/- 0.42kg, P = 0.04) . Additional studies are needed to elucidate the effects of oregano on the gastrointestinal, immune and urogenital system in swine and to determine if it has any adverse effects.

Peptides, 2005 Feb, 26(2), 307 - 16
Effects of pexiganan alone and combined with betalactams in experimental endotoxic shock; Giacometti A et al.; To investigate the efficacy of pexiganan, a 22-residue magainin analog, alone and combined with betalactmas antibiotics in three experimental rat models of Gram-negative septic shock . Adult male Wistar rats were given (i) an intraperitoneal injection of 1mg Escherichia coli 0111:B4 LPS; (ii) 2x10(10)CFU of E . coli ATCC 25922; and (iii) intra-abdominal sepsis induced via cecal ligation and puncture . For each model, all animals were randomized to receive intraperitoneally isotonic sodium chloride solution, 1mg/kg pexiganan, 1mg/kg polymyxin B, 20mg/kg imipenem, 60mg/kg piperacillin alone and combined with 1mg/kg pexiganan . Each group included 15 animals . Lethality, bacterial growth in blood or intra-abdominal fluid, endotoxin and TNF-alpha concentrations in plasma . All compounds reduced the lethality when compared to controls . Piperacillin and imipenem significantly reduced the lethality and the number of E . coli in abdominal fluid compared with saline treatment . Pexiganan showed a slightly lower antimicrobial activity than betalactams even though it achieved a substantial higher decrease in endotoxin and TNF-alpha plasma concentrations than imipenem and piperacillin . No statistically significant differences were noted for antimicrobial and antiendotoxin activities between pexiganan and polymyxin B . Combination between pexiganan and betalactams showed to be the most effective treatment in reducing all variables measured . The use of a novel antimicrobial compound able to bind to LPS associated to potent antibiotics such as betalactams may become an important future consideration for sepsis treatment.

Peptides, 2005 Feb, 26(2), 297 - 306
Protegrin structure-activity relationships: using homology models of synthetic sequences to determine structural characteristics important for activity; Ostberg N et al.; The protegrin family of antimicrobial peptides is among the shortest in sequence length while remaining very active against a variety of microorganisms . The major goal of this study is to characterize easily calculated molecular properties, which quantitatively show high correlation with antibacterial activity . The peptides studied have high sequence similarity but vary in activity over more than an order of magnitude . Hence, sequence analysis alone cannot be used to predict activity for these peptides . We calculate structural properties of 62 protegrin and protegrin-analogue peptides and correlate them to experimental activities against six microbe species, as well as hemolytic and cytotoxic activities . Natural protegrins structures were compared with synthetic derivatives using homology modeling, and property descriptors were calculated to determine the characteristics that confer their antimicrobial activity . A structure-activity relationship study of all these peptides provides information about the structural properties that affect activity against different microbial species.

Arch Biochem Biophys, 2005 Feb 1, 434(1), 51 - 9
Reaction of ferrous lactoperoxidase with hydrogen peroxide and dioxygen: an anaerobic stopped-flow study; Jantschko W 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 . LPO compound III (a ferrous-dioxygen complex) is known to be formed rapidly by an excess of hydrogen peroxide and could participate in the observed catalase-like activity of LPO . The present anaerobic stopped-flow kinetic analysis was performed in order to elucidate the catalytic mechanism of LPO and the kinetics of compound III formation by probing the reactivity of ferrous LPO with hydrogen peroxide and molecular oxygen . It is shown that ferrous LPO heterolytically cleaves hydrogen peroxide forming water and oxyferryl LPO (compound II) . The two-electron oxidation reaction follows second-order kinetics with the apparent bimolecular rate constant being (7.2+/-0.3)x10(4)M(-1)s(-1) at pH 7.0 and 25 degrees C . The H(2)O(2)-mediated conversion of compound II to compound III follows also second-order kinetics (220M(-1)s(-1) at pH 7.0 and 25 degrees C) . Alternatively, compound III is also formed by dioxygen binding to ferrous LPO at an apparent bimolecular rate constant of (1.8+/-0.2)x10(5)M(-1)s(-1) . Dioxygen binding is reversible and at pH 7.0 the dissociation constant (K(D)) of the oxyferrous form is 6muM . The rate constant of dioxygen dissociation from compound III is higher than conversion of compound III to ferric LPO, which is not affected by the oxygen concentration and follows a biphasic kinetics . A reaction cycle including the redox intermediates compound II, compound III, and ferrous LPO is proposed, which explains the observed (pseudo-)catalase activity of LPO in the absence of one-electron donors . The relevance of these findings in LPO catalysis is discussed.

Int J Pediatr Otorhinolaryngol, 2005 Jan, 69(1), 117 - 22
A case of the otogenic variant of Lemierre's syndrome with atypical sequelae and a review of pediatric literature; Masterson T et al.; We report a case of an 8-year-old girl who presented with the clinical picture of Lemierre's syndrome (LS) secondary to bilateral mastoiditis . She developed unilateral sensorineural hearing loss (SNHL) along with internal jugular vein (IJV) thrombosis, septic arthritis of her ankle and cervical fasciitis . Combined antimicrobial, anticoagulant and surgical treatment helped reverse all the effects of the sequelae, including nearly all the hearing loss . This is a unique case of this uncommon variant of the syndrome and with an uncommonly reported complication . The literature indicates that pediatric cases are a minority and enforces that successful management rests on awareness of the condition, vigil and promptness of communication of a multidisciplinary pediatric team.

Pediatr Infect Dis J, 2004 Dec, 23(12), 1077 - 80
Children's views of microbes: current beliefs about bacteria in Italian grade school children; Milandri M; INTRODUCTION: The misuse of antibacterials and the consequent emergence of resistance indicate that enhanced awareness is required among clinicians, patients and the general population of the collaborative roles of the bacterial ecosystem in health preservation . The objective of this work is to assess school students' knowledge and perception of microbes . METHODS: In preparation for a meeting of health professionals concerning antimicrobial policies, a questionnaire for administration to children from fourth to eighth school grades was developed, exploring their understanding of bacteria, use of antibiotics and hygiene . SETTING: Twenty-eight classrooms in north-central Italy, 7 from fourth to fifth grade and 21 from sixth to eighth grade . RESULTS: Four hundred ninety-nine students with a mean age of 12 years participated in the study . For 60% of the children, the notion of bacteria centered on their harmfulness; only 25% of the interviewees acknowledged a positive role . Antibiotics were perceived as the absolute weapon against both viruses and bacteria by 56% of respondents and most cases of domestic health impairment by 46% of respondents . The proportions of children being treated at the time once or more than once with an antibiotic were 23 and 24%, respectively . Little difference emerged between the notion of cleansing as opposed to disinfecting . CONCLUSION: Children's confused understanding of bacteria and the lack of a specific contribution from schools suggest that health professionals should engage further in educational activities in the community to overcome this problem . Relevant policies may benefit from being targeted at children directly because they are more open to new ideas and can spread in their milieu the idea of a "reconciliation" with the microbial world.

Inflamm Bowel Dis, 2004 Nov, 10(6), 763 - 70
Autoantibodies against the bactericidal/permeability-increasing protein from inflammatory bowel disease patients can impair the antibiotic activity of bactericidal/permeability-increasing protein; Schinke S et al.; Bactericidal/permeability-increasing protein (BPI) is an antineutrophil cytoplasmic autoantibody (ANCA) target antigen in inflammatory bowel disease (IBD) . The aim of this study was to characterize binding regions of BPI-autoantibodies and to analyze their ability to block the antibiotic effect of BPI . Sera of 24 ulcerative colitis and Crohn's disease patients were examined in indirect immuno-fluorescence, ANCA enzyme-linked immunosorbent assay (ELISA), and by epitope mapping with 13mer peptides and Western blot for presence of BPI-autoantibodies . IgG preparations were used to determine inhibition of BPI's antimicrobial function by BPI-autoantibodies in a bacterial growth inhibition assay . BPI-autoantibodies were detected by ELISA in 18/24 patients . Epitope mapping and western blotting revealed an additional 3 patients with BPI-autoantibodies . IgG preparations of all patients with Crohn's disease and 9 of 12 ulcerative colitis patients could inhibit the antibiotic function of BPI in vitro as compared with healthy control subjects . Inhibiting BPI-autoantibodies correlated with extraintestinal manifestations, peripheral blood leukocyte counts, and anemia . BPI-autoantibodies recognizing the N-terminal portion were associated with greater mucosal damage and intestinal extent of disease . BPI is a frequent target antigen of autoantibodies in ulcerative colitis and Crohn's disease . Inhibition of the antibiotic function mediated by the N-terminal region of BPI by these autoantibodies may contribute to a proinflammatory environment in IBD patients.

Orv Hetil, 2004 Oct 31, 145(44), 2227 - 30
{Role of moxifloxacin in the treatment of community-acquired pneumonia}; Mathe A et al.; INTRODUCTION: Community-acquired pneumonia is a common cause of morbidity and mortality throughout the world . Moxifloxacin, a new generation fluoroquinolone have become an attractive therapeutic alternative in the treatment of community-acquired pneumonia because of its excellent pharmacokinetic parameters and wide antimicrobial spectrum . AIMS: The authors reviewed the role of moxifloxacin in the treatment of community-acquired pneumonia based on their experience and the data of the literature . METHODS: The authors studied the clinical outcome of the patients treated with moxifloxacin due to community-acquired pneumonia in their hospital ward between May 1, 2002 and May 1, 2003 . RESULTS: Four patients with pneumonia were treated ineffectively by moxifloxacin during a year . Serious clinical and radiological progression occurred to each patient despite moxifloxacin therapy, and two patients had to be admitted to intensive care unit . Three patients were successfully treated by 2nd or 3rd generation cephalosporin and clarithromycin, but one patient died . CONCLUSIONS: The authors call attention with these cases to the fact that in clinical trials oral moxifloxacin therapy was not more efficient either clinically or microbiologically than standard therapy in the treatment of community-acquired pneumonia . Moxifloxacin therapy is recommended to be reserved to patients allergic or not responsive to other antibiotics, and in the case of infections due to penicillin-resistant pneumococci.

Ned Tijdschr Tandheelkd, 2004 Nov, 111(11), 425 - 9
{Impact of antibiotics on the indication for periodontal surgery}; Abbas F et al.; The present paper describes the use of oral antibiotics in the treatment of severe periodontitis based on the composition of the subgingival flora . Antimicrobial therapy is applied within the concept of the three basic steps in periodontal treatment . It is demonstrated in the literature that the use of antibiotics based on clinical and microbiological parameters, can reduce the need of periodontal access surgery . Proper infection control is also related to favourable outcome of regenerative periodontal procedures and periodontal plastic surgery . Therefore, the proper use of antibiotics may result in a shift in indication for different modalities of periodontal surgery.

Clin Lab Sci, 2001 Spring, 14(2), 118 - 24
Complications and risks in hematopoietic stem cell transplant patients; Smith LA et al.; Hematopoietic stem cell transplantation is a recognized treatment for hematological diseases such as leukemia and lymphoma, certain solid organ tumors, and a limited number of immunologic disorders . The major risks associated with this procedure are infections and development of graft-vs-host disease . Bacterial or viral agents are the most common cause of infections, but fungal and protozoan organisms may also be isolated . Bacterial infections occur most frequently in the first 30 days after transplant, whereas the onset of viral infections usually occurs later during the first three months posttransplant . Studies have demonstrated that there are a variety of predisposing factors that influence the type of infection a patient develops . These include underlying disease, type of chemotherapy regimen, type of antimicrobial and antiviral regimen, presence of graft-vs-host disease, and period of severe neutropenia posttransplant . Of these, the period of neutropenia appears to be the most significant . Graft-vs-host disease is seen in those patients who have received allogeneic hematopoietic stem cell transplants . New antimicrobial and antiviral agents and manipulation of the hematopoietic stem cell transplant to select specific cell types for infusion have provided some methods to prevent or decrease the number and severity of infections or to prevent/control graft-vs-host disease.

Biopolymers . 2004 Dec 29; {Epub ahead of print}
Engineering disulfide bonds of the novel human beta-defensins hBD-27 and hBD-28: Differences in disulfide formation and biological activity among human beta-defensins; Schulz A et al.; Human beta-defensins comprise a large number of peptides that play a functional role in the innate and adaptive immune system . Recently, clusters of new beta-defensin genes with predominant expression in testicular tissue have been discovered on different chromosomes by bioinformatics . beta-Defensins share a common pattern of three disulfides that are essential for their biological effects . Here we report for the first time the chemical synthesis of the new fully disulfide-bonded beta-defensins hBD-27 and hBD-28, and compare the results with synthetic procedures to obtain the known hBD-2 and hBD-3 . While hBD-27 was readily converted into a product with the desired disulfide pattern by oxidative folding, hBD-28 required a selective protective group strategy to introduce the three disulfide bonds . The established synthetic processes were applied to the synthesis of hBD-2, which, like hBD-27, was accessible by oxidative folding, whereas hBD-3 required a selective strategy comparable to hBD-28 . Experimental work demonstrated that trityl, acetamidomethyl, and t-butyl are superior to other protection strategies . However, the suitable pairwise arrangement of the protective groups can be different, as shown here for hBD-3 and hBD-28 . Determination of the minimum inhibitory concentration against different bacteria revealed that hBD-27, in contrast to other beta-defensins tested, has virtually no antimicrobial activity . Compared to the other peptides tested, hBD-27 showed almost no cytotoxic activity, measured by hemoglobin release of erythrocytes . This might be due to the low positive net charge, which is significantly higher for hBD-2, hBD-3, and hBD-28 . (c) 2004 Wiley Periodicals, Inc . Biopolymers (Pept Sci), 2005.

Acta Paediatr Taiwan, 2004 Jul-Aug, 45(4), 242 - 5
Influenza B virus associated pneumonia: report of one case; Lu KC et al.; Influenza A virus is a more common cause of pneumonia than influenza B virus . Influenza virus pneumonia complicated with acute respiratory distress syndrome (ARDS) is rare and has a high mortality rate . In addition to pneumonia, influenza occasionally causes neurologic, cardiac, renal, or muscular complications . Hepatic involvement in influenza virus infection has been rarely reported . We reported the case of a 7-year-old girl who was initially treated for upper respiratory tract infection, but she was transferred to the pediatric intensive care unit for intubation and ventilation after her condition deteriorated to lobar pneumonia with ARDS and liver function impairment within 7 days . Influenza B virus infection was confirmed by virus culture and serological study . Respiratory viruses, such as respiratory syncytial virus, adenovirus, influenza virus, and parainfluenza virus, are common causes of pneumonia in children; moreover, they should be considered especially in the presence of persistent leukopenia, low CRP value, lack of growth of bacterial cultures, and poor response to antimicrobial therapy . We should describe its course, diagnosis, and treatments in detail; furthermore, we reported this case to emphasize that influenza B virus may cause transient liver dysfunction and it is an etiology of pneumonia as well as ARDS.

Vet Rec, 2004 Dec 4, 155(23), 733 - 8
Survey of the knowledge, attitudes and practice of Italian beef and dairy cattle veterinarians concerning the use of antibiotics; Busani L et al.; Between June and September 2002 a telephone survey of Italian beef and dairy cattle veterinarians was made to obtain information about their use of antibiotics and their perception of the problem of antimicrobial resistance . A total of 106 veterinarians, selected at random from the membership lists of two professional societies, were interviewed by telephone, using a structured questionnaire concerning their background, training and continuing education activities, and current type of practice; their diagnostic, treatment, and prophylactic practices for mastitis, calf scours and respiratory disease; and their perception of the threat posed by antimicrobial resistance . The median age of the interviewees was 42.5 (range 28 to 75) years; 62 per cent treated only dairy cattle, 10 per cent treated only beef cattle and 28 per cent treated both . Laboratory support was requested 'frequently' or 'always' by 67 per cent of the veterinarians when treating mastitis, by 37 per cent when treating calf scours and by 17 per cent when treating respiratory diseases . Twenty per cent reported using prophylactic antibiotics 'often' or 'sometimes' for calf scours, 28 per cent for respiratory diseases, and 62 per cent reported their use 'always' or 'often' for mastitis . Fluoroquinolones, phenicols or third/fourth-generation cephalosporins were prescribed as first-choice drugs by 54 per cent for calf scours, by 12 per cent for bacterial respiratory diseases and by 6 per cent for mastitis . Therapeutic failure was reported 'often' (21 per cent) or 'sometimes' (64 per cent) and was the main predictor in a multivariate model of the use of newer antibiotics . The level of awareness of the problem of antibiotic resistance was high, although more than half of the interviewees were confident that new antimicrobial drugs were already available to replace those of lower effectiveness.

Ocul Immunol Inflamm, 2004, 12(4), 317 - 322
Indocyanine green angiography in ocular tuberculosis; Tayanc E et al.; Purpose: To assess indocyanine green (ICG) angiography as a method for evaluating the extent of choroidal involvement and to compare ICG angiography with fundus fluorescein angiography (FFA) in ocular tuberculosis . Methods: FFA and ICG angiography were performed on two patients who had ocular tuberculosis findings during fundus examination . The patients were given topical dexamethasone phosphate, topical cyclopentolate, and oral prednisolone acetate in addition to systemic antimicrobial therapy . Both examinations were repeated after treatment . Results: In one patient, two hypofluorescent lesions that corresponded to the choroidal tuberculomas were noted with ICG angiography . Only one lesion was found during ophthalmoscopic examination and FFA . After treatment, these lesions persisted, but became less hypofluorescent . In the other patient, ICG angiography showed a hypofluorescent choroidal lesion corresponding to the choroidal tuberculoma that was larger than its appearance on FFA . This lesion remained hypofluorescent in all phases of ICG angiography and became less hypofluorescent after treatment . Conclusions: ICG angiography is a useful method to determine the extent of the choroidal lesion and the stage of disease and to evaluate treatment results in tuberculosis patients.

Dev Cell, 2005 Jan, 8(1), 125 - 32
An Antioxidant System Required for Host Protection against Gut Infection in Drosophila; Ha EM et al.; A fundamental question that applies to all organisms is how barrier epithelia efficiently manage continuous contact with microorganisms . Here, we show that in Drosophila an extracellular immune-regulated catalase (IRC) mediates a key host defense system that is needed during host-microbe interaction in the gastrointestinal tract . Strikingly, adult flies with severely reduced IRC expression show high mortality rates even after simple ingestion of microbe-contaminated foods . However, despite the central role that the NF-kappaB pathway plays in eliciting antimicrobial responses, NF-kappaB pathway mutant flies are totally resistant to such infections . These results imply that homeostasis of redox balance by IRC is one of the most critical factors affecting host survival during continuous host-microbe interaction in the gastrointestinal tract.

J Inorg Biochem, 2005 Feb, 99(2), 538 - 45
Synthetic, spectral, thermal and antimicrobial studies on some mixed 1,3-dithia-2-stannacyclopentane derivatives with dialkyldithiocarbamates; Chauhan HP et al.; 1,3-Dithia-2-stannacyclopentane derivatives with dialkyldithiocarbamates of the types (I) and (II) (where R=CH(3), C(2)H(5) and -CH(2)-CH(2)-) have been synthesized by the reaction of 2,2-dichloro-1,3-dithia-2-stannacyclopentane and sodium/ammonium salts of dialkyldithiocarbamates in 1:1 and 1:2 molar ratios, respectively, in anhydrous benzene . These newly synthesized derivatives have been characterized by elemental analyses (C, H, N, S and Sn), thermal {thermogravimetry (TG) and differential thermal analyses (DTA)} as well as spectral {UV, IR and multinuclear NMR ((1)H, (13)C and (119)Sn)} studies . The monodentate behaviour of the dialkyldithiocarbamate ligands was confirmed by IR and (119)Sn NMR spectral data and distorted tetrahedral structures have been suggested for both type (I) and (II) compounds . The free ligands and their tin complexes have also been screened for their antibacterial and antifungal activities . These results made it desirable to delineate a comparison between free ligands and their tin complexes . These exhibit higher antibacterial effect than some of the previously investigated antibiotics.

J Inorg Biochem, 2005 Feb, 99(2), 397 - 408
Antimicrobial and mutagenic properties of organotin(IV) complexes with isatin and N-alkylisatin bisthiocarbonohydrazones; Bacchi A et al.; A new series of ligands is synthesised starting from thiocarbonohydrazide and isatin (H(2)itc) or N-alkylisatin (methyl, H(2)mtc; butyl, H(2)btc; pentyl, H(2)ptc); the X-ray structure of H(2)mtc is discussed . The bis imine ligands are reacted with diorganotin(IV) compounds, obtaining monometallic complexes . In order to establish unequivocally their coordination geometry, the X-ray structures of (C(2)H(5))(2)Sn(Hmtc)Cl.THF (THF, tetrahydrofuran) and (C(6)H(5))Sn(Hptc)Cl(2) are determined . In (C(2)H(5))(2)Sn(Hmtc)Cl.THF, the ligand results monodeprotonated and, essentially, monodentate through the sulphur atom, while in (C(6)H(5))Sn(Hptc)Cl(2) the ligand is still monodeprotonated but SNO tridentate . The organotin(IV) complexes of isatin and N-methylisatin exhibit good antibacterial activity, better than that of the corresponding N-butyl and N-pentylisatin derivatives . Gram positive bacteria are the most sensitive microorganisms . No growth inhibition of fungi is detected up to the concentration of 100 mug/ml . H(2)mtc shows mutagenic activity with and without metabolic activation, whereas no mutagenicity is found for its organotin complexes and for the other compounds.

Transplant Proc, 2004 Nov, 36(9), 2699 - 2702
Effects of azithromycin on cyclosporine-induced gingival hyperplasia in renal transplant patients; Tokgoz B et al.; BACKGROUND: Gingival hyperplasia is a well-known complication of cyclosporine therapy, affecting 21% to 35% of renal transplant patients . Metronidazole, clarithromycin, and azithromycin, all azalid antimicrobial agents derived from the macrolide antibiotic erythromycin, have been used for treatment . Marked improvements in gingival hyperplasia have been recorded in particular with azithromycin . The aim of the present study was to investigate histopathological features of cyclosporine-induced gingival hyperplasia and to evaluate the quantitative efficacy of short-term azithromycin therapy . METHODS: Eighteen renal transplant patients with cyclosporine-induced gingival hyperplasia were included in the study . All patients received azithromycin with a dose of 500 mg/d for 3 consecutive days . Changes in gingival hyperplasia were evaluated by measuring the gingival sulcus depth to the cementum-enamel junction of every tooth in each of the four quadrants on days 0, 7, 30, 90, 180 . Gum biopsies were obtained on days 0 and 30; the degree of inflammation was classified as "mild," "intermediate," and "severe" . RESULTS: Gingival hyperplasia was reduced in all treated patients throughout the study . The degree of improvement was more significant between 0 to 7 and 7 to 30 days than at other times (respectively, P < .0001 and P < .002) . Histopathologically, eight patients had severe and one patient moderate chronic inflammation at the beginning of therapy . Three other biopsies were reported as papilloma, mucosal hyperplasia, and normal gingival tissue biopsy . CONCLUSIONS: Azithromycin appears to be useful to treat cyclosporine-induced gingival hyperplasia in renal transplant patients . Treatment is inexpensive and free from known adverse effects.

Int J Pharm, 2005 Jan 20, 288(2), 263 - 71 Epub 2004 Dec 10.
Partition of antimicrobial additives in an intravenous emulsion and their effect on emulsion physical stability; Han J et al.; A number of antimicrobial agents are potentially applicable to the preservation of small-volume parenteral emulsions . However, the physical stability of these emulsions is of paramount importance in ensuring their safety, and it is possible that antimicrobial additives could reduce the emulsion stability by a number of mechanisms . We have studied the effects of several antimicrobial agents on the physical stability of Diprivan((R)), an intravenous anaesthetic emulsion . A particular problem is that many antimicrobial additives require an acidic pH in order to be effective (e.g . sodium benzoate, sodium metabisulphite) and the emulsion surface potential is insufficient to stabilize the emulsion to coalescence under these conditions . In addition several antimicrobial agents (e.g . methyl paraben and benzoic acid) partition into the oil phase of the emulsion, requiring the use of increased concentrations to remain effective . We describe an assay technique to quantify the oil partition, liposomal partition, and droplet surface adsorption of the additives . This illustrates that significantly more additive is partitioned out of the water phase than might be predicted from simple oil/water partition experiments.

Int J Antimicrob Agents, 2005 Jan, 25(1), 1 - 10
A multidisciplinary approach to antimicrobial stewardship: evolution into the 21st century; Paskovaty A et al.; In the 21st century, we face the problems of escalating antibiotic resistance, difficult-to-treat infections and slowed new drug development . Healthcare practitioners are increasingly recognising the importance of good antimicrobial stewardship . Various strategies such as formulary management, prior approval, clinical pathways, post-prescribing evaluation and intravenous to oral conversion have been used singly or in combination to improve prescribing and reduce costs . Combining a multifaceted approach with a full-time dedicated multidisciplinary team appears to be capable of yielding satisfactory clinical and economic outcomes and most importantly, sustaining efforts of antimicrobial stewardship . The multidisciplinary approach to antibiotic management should be tailored to fit the individual needs of an institution . More data are needed to document effects on curbing resistance.

J Hosp Infect, 2005 Feb, 59(2), 156 - 8
Prescription auditing and antimicrobial resistance at a tertiary care hospital in New Delhi, India; Wattal C et al.; This paper reports the antibiotic consumption data of Sir Ganga Ram Hospital, New Delhi and bacterial resistance over a seven-year period . Cephalosporins, penicillins and fluoroquinolones were the most widely prescribed antibiotics . A correlation was seen between Escherichia coli resistance to third-generation cephalosporins and increased cephalosporin use, as well as resistance to co-amoxyclav and its use.

J Hosp Infect, 2005 Feb, 59(2), 108 - 12
Prophylaxis of sternal wound infections with gentamicin-collagen implant: randomized controlled study in cardiac surgery; Eklund AM et al.; Postoperative infections may lead to prolonged hospital stay and increased morbidity, mortality and hospital costs, especially in heart surgery . Finding new means to prevent infections would benefit both the patient and society . The aim of this study was to assess if locally administered gentamicin prevents sternal wound infections in coronary artery bypass (CABG) surgery . We randomized 542 consecutive CABG patients to two groups: those who received gentamicin-collagen implant under their sternum before closure (N=272) and controls (N=270) . The subjects received routine intravenous antimicrobial prophylaxis (85% cefuroxime, 14% cefuroxime and vancomycin), and were followed-up for three months . The sternal wound infection rate was 4.0% (11/272) in the gentamicin group and 5.9% (16/270) in the control group . The mediastinitis rates were 1.1 and 1.9%, respectively . This treatment was safe and easy to administer, and no side-effects occurred . No statistically significant difference was demonstrated between infection rates in the two groups . This is the first study on the use of gentamicin-collagen sponge as prophylaxis in cardiac surgery . Our data show that infection was reduced slightly in the gentamicin-collagen group compared with the control group, but the study population was too small to draw conclusions . Further evaluation is needed, and the results may warrant another larger, better-powered study.

J Nat Prod, 2004 Dec 28, 67(12), 2117 - 2120
Structural Activity Relationship Studies of Zebra Mussel Antifouling and Antimicrobial Agents from Verongid Sponges; Diers JA et al.; Several dibromotyramine derivatives including moloka'iamine were selected as potential zebra mussel (Dreissena polymorpha) antifoulants due to the noteworthy absence of fouling observed on sponges of the order Verongida . Sponges of the order Verongida consistently produce these types of bromotyrosine-derived secondary metabolites . Previously reported antifouling data for the barnacle Balanus amphitrite(EC(50) = 12.2 muM) support the results reported here that the compound moloka'iamine may be a potential zebra mussel antifoulant compound (EC(50) = 10.4 muM) . The absence of phytotoxic activity of the compound moloka'iamine toward Lemna pausicostata and, most importantly, the compound's significant selectivity against macrofouling organisms such as zebra mussels suggest the potential utility of this compound as a naturally derived antifoulant lead.

J Nat Prod, 2004 Dec 28, 67(12), 2111 - 2112
Karnatakafurans A and B: Two Dibenzofurans Isolated from the Fungus Aspergillus karnatakaensis; Manniche S et al.; Karnatakafurans A (1) and B (2), two novel dibenzofurans, have been isolated from the Specie Novum Aspergillus karnatakaensis Frisvad . The compounds were the major secondary metabolites and were isolated through UV-guided fractionation of the organic extract . The structures were elucidated by spectroscopic methods including MS and NMR . The compounds were tested for antimicrobial and antimalarial activity and proved to be moderately active against Plasmodium falciparum.

Med Mal Infect, 2004 Nov, 34(11), 514 - 21
Human health impact from antimicrobial use in food animals; Tollefson L et al.; There is accumulating evidence that the use of antimicrobials in food-producing animals has adverse human health consequences . The use of antibiotics in food animals selects for resistant pathogens and resistance genes that may be transferred to humans through the consumption or handling of foods of animal origin . Recent studies have demonstrated that antimicrobial-resistance among foodborne bacteria may cause excess cases of illness, prolonged duration of illness, and increased rates of bacteremia, hospitalization, and death . The continued availability of safe and effective antimicrobials for humans and animals depends upon the responsible use of these products.

J Ethnopharmacol, 2005 Jan 15, 96(3), 515 - 9 Epub 2004 Nov 30.
Antimicrobial activity, toxicity and the isolation of a bioactive compound from plants used to treat sexually transmitted diseases; Tshikalange TE et al.; Extracts of six ethnobotanically selected medicinal plants (Anredera cordifolia, Elaeodendron transvaalense, Elephantorrhiza burkei, Senna petersiana, Terminalia sericea and Rauvolfia caffra) used traditionally to treat sexually transmitted diseases (STD's) were investigated for antibacterial activity using the agar dilution method . Of the six collected, Terminalia sericea, Senna petersiana and Anredera cordifolia were also investigated for cytotoxicity . The phytochemical studies on Senna petersiana resulted in the isolation of luteolin, which also showed antimicrobial activity . Only the Senna petersiana extract and luteolin isolated from it were tested for antiviral activity and showed some activity at the highest non-toxic concentration of 24 and 500mug/ml, respectively . The results of the antimicrobial screening support the ethnomedicinal uses of these plants to some extent.

Drug Metab Pharmacokinet, 2003, 18(5), 319 - 26
Distribution characteristics of grepafloxacin, a fluoroquinolone antibiotic, in lung epithelial lining fluid and alveolar macrophage; Deguchi Y et al.; The purpose of this study was to investigate the distribution of Grepafloxacin (GPFX), a new quinolone antimicrobial agent, in the lung epithelial lining fluid (ELF) and the alveolar macrophage (AM) in rats, which are potential infection sites in respiratory tract infections . We also aimed to clarify the mechanism governing the transferability of GPFX into the alveolus compartment from a kinetic point of view . The AUC ratios of ELF/plasma and AM/plasma after the oral administration of GPFX were 5.69 +/- 1.00 and 352 +/- 57, respectively, which were several-fold greater than those of ciprofloxacin (CPFX) . Pharmacokinetic analyses of time profiles of GPFX concentrations in ELF and AM revealed that the influx clearance from plasma to ELF across the alveolar barrier is 5-fold greater than the efflux clearance from ELF . In addition, the permeability of GPFX across the cultured AM cell membrane was 7-fold and 11-fold greater than that of levofloxacin (LVFX) and CPFX, respectively . The extent of intracellular binding to AM cells (expressed as a constant (alpha)) was the greatest for GPFX, followed by CPFX and LVFX . There was a significant correlation between the alpha value and the partitioning to the immobilized artificial membrane (IAM) column, which consists of phospholipid residues covalently bound to silica . These results suggest that GPFX is highly distributed in ELF and AM, and that the high transferability of GPFX into ELF may be attributable to the existence of asymmetrical transport across the alveolar barrier . In addition, it was suggested that both rapid permeability across the AM cell membrane and avid binding to the membrane phospholipids may be responsible for the high accumulation of GPFX in AM.

Drug Metab Pharmacokinet, 2002, 17(3), 237 - 44
Muscle distribution of antimicrobial agents after a single intravenous administration to rats; Araki H et al.; The purpose of this study was to evaluate the distribution of three fluoroquinolones (pazufloxacin, ciprofloxacin and ofloxacin) and a beta-lactam, ceftazidime in the tissue interstitial and intracellular spaces after a single intravenous administration to rats based on muscle microdialysis . The unbound concentration in the tissue interstitial fluid (C(isf,u)) after administration was estimated from the concentration in the dialysate by muscle microdialysis, the in vitro permeability rate constant, and the previously reported effective dialysis coefficient . The C(isf,u)s of pazufloxacin, ciprofloxacin, ofloxacin and ceftazidime in the muscle were close to their unbound concentrations in the venous plasma . These results were consistent with ones previously obtained at steady state . Based on these results, the total concentration in the tissue interstitial fluid (C(isf)) was calculated from the ratio of plasma protein binding, the plasma concentration, and previously reported interstitial-to-plasma albumin ratio in muscle of rats . The calculated C(isf) was compared with the muscle concentration (C(m)) obtained using the homogenized tissue . The C(isf) of ceftazidime was higher than the C(m) . The C(isf) of pazufloxacin was found to be almost equal to its C(m) . The C(isf)s of ciprofloxacin and ofloxacin were lower than their C(m)s with the exception of the values at 5 min after administration . These results indicate that ceftazidime is mainly distributed in the interstitial space of the muscle, that pazufloxacin is distributed equally in both the interstitial space and the tissue cells, and that ciprofloxacin and ofloxacin are mainly distributed in the tissue cells rather than the interstitial space.

J Leukoc Biol . 2004 Dec 23; {Epub ahead of print}
Defensin deficiency, intestinal microbes, and the clinical phenotypes of Crohn's disease; Wehkamp J et al.; Crohn's disease is a chronic, inflammatory disease of the intestinal mucosa . Although intestinal bacteria are implicated in disease pathogenesis, the etiology is still unclear . The main location of disease is the small intestine (ileum) and the colon . Ileal disease has been linked to a mutation in the NOD2 gene . Defensins are antimicrobial peptides and in the ileum, are mainly expressed in Paneth cells, epithelial cells that also express NOD2 . In the colon, defensins are expressed by enterocytes or metaplastic Paneth cells . Crohn's disease patients with ileal involvement, compared with controls or Crohn's patients without ileal involvement, have diminished expression of ileal Paneth cell defensins . This decrease is even more pronounced in Crohn's patients displaying a NOD2 mutation . In contrast, Crohn's disease of the colon is characterized by an impaired induction of beta-defensins in enterocytes . The colonic expression of the constitutive beta-defensin 1 is also decreased in the inflamed colonic mucosa, but this decrease is less specific to Crohn's disease, as it can also be found in ulcerative colitis patients . In conclusion, the regional localizations of Crohn's disease, ileal or colonic disease, can be linked to different defensin profiles . Crohn's disease of the ileum is associated with diminished defensin expression in Paneth cells . Crohn's disease of the colon is associated with diminished beta-defensin expression in enterocytes . Thus, it can be speculated that decreased defensin levels lead to a weakened intestinal barrier function to intestinal microbes and might be crucial in the pathophysiology of Crohn's disease.

Infect Immun, 2005 Jan, 73(1), 583 - 91
Interaction and cellular localization of the human host defense peptide LL-37 with lung epithelial cells; Lau YE et al.; LL-37 is a human cationic host defense peptide that is an essential component of innate immunity . In addition to its modest antimicrobial activity, LL-37 affects the gene expression and behavior of effector cells involved in the innate immune response, although its mode of interaction with eukaryotic cells remains unclear . The interaction of LL-37 with epithelial cells was characterized in tissue culture by using biotinylated LL-37 and confocal microscopy . It was demonstrated that LL-37 was actively taken up into A549 epithelial cells and eventually localized to the perinuclear region . Specific inhibitors were used to demonstrate that the uptake process was not mediated by actin but required elements normally involved in endocytosis and that trafficking to the perinuclear region was dependent on microtubules . By using nonlinear regression analysis, it was revealed that A549 epithelial cells have two receptors for LL-37B, with high and low affinity for LL-37, respectively . These results indicate the mode of interaction of LL-37 with epithelial cells and further our understanding of its role in modulating the innate immune response.

Infect Immun, 2005 Jan, 73(1), 546 - 51
Replication dynamics of Mycobacterium tuberculosis in chronically infected mice; Munoz-Elias EJ et al.; The dynamics of host-pathogen interactions have important implications for the design of new antimicrobial agents to treat chronic infections such as tuberculosis (TB), which is notoriously refractory to conventional drug therapy . In the mouse model of TB, an acute phase of exponential bacterial growth in the lungs is followed by a chronic phase characterized by relatively stable numbers of bacteria . This equilibrium could be static, with little ongoing replication, or dynamic, with continuous bacterial multiplication balanced by bacterial killing . A static model predicts a close correspondence between "viable counts" (live bacteria) and "total counts" (live plus dead bacteria) in the lungs over time . A dynamic model predicts the divergence of total counts and viable counts over time due to the accumulation of dead bacteria . Here, viable counts are defined as bacterial CFU enumerated by plating lung homogenates; total counts are defined as bacterial chromosome equivalents (CEQ) enumerated by using quantitative real-time PCR . We show that the viable and total bacterial counts in the lungs of chronically infected mice do not diverge over time . Rapid degradation of dead bacteria is unlikely to account for the stability of bacterial CEQ numbers in the lungs over time, because treatment of mice with isoniazid for 8 weeks led to a marked reduction in the number of CFU without reducing the number of CEQ . These observations support the hypothesis that the stable number of bacterial CFU in the lungs during chronic infection represents a static equilibrium between host and pathogen.

Cell Microbiol, 2005 Jan, 7(1), 39 - 51
Age-associated mortality in immune challenged mosquitoes (Aedes aegypti) correlates with a decrease in haemocyte numbers; Hillyer JF et al.; Summary Mosquitoes vector pathogens . One aspect that has been overlooked in mosquito-pathogen relationships is the effect of host age on immune competence . Here, we show that there is age-associated mortality following immune challenge with Escherichia coli . This mortality correlates with a decrease in haemocyte numbers (blood cells) and a decreased ability to kill E . coli . Although the number of haemocytes decreases, the available haemocytes retain their phagocytic ability regardless of age, and we estimate that individual granulocytes can phagocytose approximately 1500 E . coli . Moreover, transcription profiles for cecropin, defensin and gambicin in E . coli challenged mosquitoes do not change with age, indicating that the increased susceptibility is not attributed to fewer humoral antimicrobial peptides . These results suggest that a contributing factor for the age-associated mortality is the decrease in circulating haemocytes, which reduces the overall phagocytic capacity of mosquitoes . To our knowledge, this is the first report detailing an age-associated decline in the immunological capabilities of mosquitoes following challenge with an infectious agent . These data also call for caution in the analysis and interpretation of experimental results when mosquito age has not been closely monitored . Lastly, a model for haemocyte function is presented.

Drug News Perspect, 1998 Nov, 11(9), 582 - 95
Advances in antifungal chemotherapy; Fromtling RA; The American Society for Microbiology sponsored the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), a premier annual scientific conference, in San Diego, California, September 24-27, 1998 . At the ICAAC several sessions were held which focused on the pathogenesis of fungal disease, the in vitro susceptibility testing of new azole (voriconazole, Syn-2869, SCH-56592, carbendazim), echinocandin-like (FK-463, LY-303366, MK-0991), polyene (patricins) and established antifungal agents (fluconazole, itraconazole, amphotericin B, nystatin, terbinafine), the experimental in vivo activity of these new antifungal drugs in various animal models of fungal disease, and the clinical activity of fluconazole, itraconazole and liposomal amphotericin B formulations . (c) 1998 Prous Science . All rights reserved.

Antimicrob Agents Chemother, 2005 Jan, 49(1), 388 - 97
Hemolysis of erythrocytes by granulysin-derived peptides but not by granulysin; Li Q et al.; Granulysin, a 9-kDa protein localized in human cytolytic T lymphoctyes and natural killer cell granules, is cytolytic against tumors and microbes but not against red blood cells . Synthetic peptides corresponding to the central region of granulysin recapitulate the lytic activity of the intact molecule, and some peptides cause hemolysis of red blood cells . Peptides in which cysteine residues were replaced by serine maintain their activity against microbes but lose activity against human cells, suggesting their potential as antibiotics . Studies were undertaken to determine the mechanism of resistance of red blood cells to granulysin and sensitivity to a subset of granulysin-derived peptides . Granulysin lyses immature reticulocytes, which have mitochondria, but not red blood cells . Granulysin lyses U937 cells but not U937 cells lacking mitochondrial DNA and a functional respiratory chain (U937rho(o) degrees cells), further demonstrating the requirement of intact mitochondria for granulysin-mediated death . Peptide G8, which corresponds to helix 2/loop 2/helix 3, lyses red blood cells, while peptide G9, which is identical except that the cysteine residues were replaced by serine, does not lyse red blood cells . Granulysin peptide-induced hemolysis is markedly inhibited by an anion transporter inhibitor and by Na(+), K(+), and Ca(2+) channel blockers but not by Na(+)/K(+) pump, cotransport, or Cl(-) channel blockers . Although recombinant granulysin and G9 peptide do not induce hemolysis, they both competitively inhibit G8-induced hemolysis . The finding that some derivatives of granulysin are hemolytic may have important implications for the design of granulysin-based antimicrobial therapeutics.

J Dent Res, 2005 Jan, 84(1), 9 - 20
The junctional epithelium: from health to disease; Bosshardt DD et al.; The junctional epithelium is located at a strategically important interface between the gingival sulcus, populated with bacteria, and the periodontal soft and mineralized connective tissues that need protection from becoming exposed to bacteria and their products . Its unique structural and functional adaptation enables the junctional epithelium to control the constant microbiological challenge . The antimicrobial defense mechanisms of the junctional epithelium, however, do not preclude the development of gingival and periodontal lesions . The conversion of the junctional to pocket epithelium, which is regarded as a hallmark in disease initiation, has been the focus of intense research in recent years . Research has shown that the junctional epithelial cells may play a much more active role in the innate defense mechanisms than previously assumed . They synthesize a variety of molecules directly involved in the combat against bacteria and their products . In addition, they express molecules that mediate the migration of polymorphonuclear leukocytes toward the bottom of the gingival sulcus . Periodontopathogens-such as Actinobacillus actinomycetemcomitans or, in particular, Porphyromonas gingivalis-have developed sophisticated methods to perturb the structural and functional integrity of the junctional epithelium . Research has focused on the direct effects of gingipains, cysteine proteinases produced by Porphyromonas gingivalis, on junctional epithelial cells . These virulence factors may specifically degrade components of the cell-to-cell contacts . This review will focus on the unique structural organization of the junctional epithelium, on the nature and functions of the various molecules expressed by its cells, and on how gingipains may attenuate the junctional epithelium's structural and functional integrity.

Cryobiology, 2004 Dec, 49(3), 230 - 40
Suppression of cold ischemic injury in stored kidneys by the antimicrobial peptide bactenecin; McAnulty JF et al.; BACKGROUND: Cold ischemic injury plays an important role in short- and long-term function of kidneys after transplant . Antimicrobial peptides have not previously been studied for their impact on cold ischemia in transplanted kidneys . METHODS: Bactenecin (l- and d-forms) was added to University of Wisconsin (UW) preservation solution for 3-day cold storage of dog kidneys . Effects on membrane permeability were studied in synthetic liposomes and in kidney cortex tissue slices . The role of bactenecin as a tissue mitogen and direct cytoskeletal stabilizer were studied with cultured cells and in vitro . RESULTS: Bactenecin (both l- and d- forms) resulted in significant decreases in postoperative serum creatinine and time required for return of creatinine to the normal range showing the effect was independent of chirality . Bactenecin permeabilized synthetic liposomes and altered kidney cortex tissue slice membrane permeability characteristics, irrespective of chirality . Neither did bactenecin act as a mitogen for either primary renal tubule or Madin-Darby canine kidney (MDCK) cells stored in UW solution, nor did it appear to directly affect cytoskeletal dynamics . CONCLUSIONS: These results show that the antimicrobial peptide bactenecin can improve the quality of static cold storage of kidneys . The mechanism of its action is independent of receptor binding and does not appear to involve either an effect on the cytoskeleton or via activity as a mitogen . Current evidence best supports the hypothesis that bactenecin protects against cold ischemic injury by a controlled permeabilization of the membranes of the kidney during cold storage.

Izv Akad Nauk Ser Biol, 2004 Nov-Dec, (6), 678 - 81
{Intracellular transformation of phagosomes}; The rationale for pathogen-inactivation treatment of blood components; National Blood Service, Colindale, London, UK . john.barbara@nbs.nhs.uk

Blood transfusion provides an ideal portal of entry for microorganisms . Although current residual risks of microbial infection by transfusion are extremely low in the developed world, the requirements for even safer blood are paradoxically increasing . Such requirements are partly a legacy of the tragic transmissions of human immunodeficiency virus (HIV) by blood early in the acquired immunodeficiency syndrome pandemic and are legally expressed in consumer protection laws imposing strict product liability . Enhanced safety is called for, not only for recognized agents (especially bacteria, which cause most current transfusion-transmissible infections {TTIs}and have only recently been addressed) but also for potential future "emerging" TTIs . These possibilities are not merely theoretical . TTIs of HIV-1, HIV-2, hepatitis B virus vaccine escape mutants, human herpesvirus 8, West Nile fever virus, and variant Creutzfeld-Jakob disease amply demonstrate the continual emergence of such threats . For recognized agents, the possibilities of test errors, misreporting, process-control failures, and false-negative results (although rare with modern automation) remain . In principle, an all-embracing, pan-effective microbe-inactivation procedure offers a potential solution to blood safety concerns . Such procedures may also allow the removal of several existing antimicrobial interventions . However, blood services remain to be convinced that the various prerequisites for safe and effective pathogen inactivation have been met . Not the least of these prerequisites is that all blood components can be inactivated to provide a single streamlined alternative blood safety strategy . Furthermore, the huge potential value of effective pathogen-inactivation systems for developing countries should not be forgotten once such systems are perfected.

J Pharm Sci, 2005 Feb, 94(2), 382 - 96
Effects of benzyl alcohol on aggregation of recombinant human interleukin-1-receptor antagonist in reconstituted lyophilized formulations; Roy S et al.; A major limitation in the successful development of multidose protein formulations is protein aggregation induced by antimicrobial preservatives such as benzyl alcohol, which are included to maintain product sterility . Studies were conducted to evaluate the strategy of developing lyophilized formulations of a therapeutic protein, recombinant human interlukin-1 receptor antagonist (rhIL-1ra), to be reconstituted with a bacteriostatic amount (0.9% w/v) of benzyl alcohol in water . The strategy was based on the following hypotheses . The first was that benzyl alcohol would foster aggregation during reconstitution of the lyophilized sample . The second hypothesis was that the extent of benzyl alcohol-induced protein aggregation would correlate directly with the degree of structural perturbation of rhIL-1ra in the dried solid after lyophilization . Differential structural retention of rhIL-1ra in the dried solid was obtained by using a combination of formulation variables important for lyophilization and included: protein concentration, type of stabilizer, and presence or absence of NaCl . Infrared spectroscopic analysis of the lyophilized samples indicated that high initial solution protein concentration and the stabilizer sucrose minimized structural perturbation of rhIL-1ra during lyophilization . In contrast, NaCl was destabilizing . Reconstitution of the dried solid with 0.9% (w/v) benzyl alcohol caused a greater degree of protein aggregation than reconstitution with water, confirming our first hypothesis . In support of our second hypothesis, the extent of aggregation induced by benzyl alcohol during reconstitution was strongly modulated by the degree of retention of native rhIL-1ra secondary structure during lyophilization . During storage of the reconstituted lyophilized samples at room temperature, benzyl alcohol did not accelerate aggregation of rhIL-1ra . This study demonstrated that for development a multidose lyophilized protein formulation involving reconstitution with a solution of benzyl alcohol, protein structural perturbations during freeze-drying should be minimized with a stabilizing excipient and appropriate choice of protein concentration and tonicity modifier . Furthermore, postreconstitution storage at reduced temperature (e.g., room temperature or 4 degrees C) could minimize the risk of preservative-induced protein aggregation . (c) 2004 Wiley-Liss, Inc . and the American Pharmacists Association J Pharm Sci 94:382-396, 2005.

Clin Infect Dis, 2005 Jan 1, 40(1), 127 - 35 Epub 2004 Dec 01.
Nonantimicrobial effects of antibacterial agents; Pasquale TR et al.; One of the major advances in modern medicine was the development of antimicrobial chemotherapy . However, many antibacterial agents have unexpected or undesirable nonantimicrobial effects on humans . Microbes and man share many essentials of life, including DNA, adenosine triphosphate, and other biochemical pathways . Hence, some of these nonantimicrobial effects may also turn out to be pharmacologically useful . Oral hypoglycemic agents (i.e., sulfonylureas) and a certain diuretic agent (acetazolamide) are derivatives of sulfonamides . Erythromycin has been used clinically for its stimulatory effect on gastrointestinal motility . Macrolides, lincosamides, and tetracyclines have been known for their immunomodulatory effects . A tetracycline has been used to treat the syndrome of inappropriate antidiuretic hormone . Aminoglycosides may influence mucus production in patients with cystic fibrosis . Other antimicrobials may have side effects that are not therapeutically useful, such as osmotic diuresis with high-dose beta -lactam administration, neuromuscular blockade of aminoglycosides, dysglycemia of fluoroquinolones, and serotonin syndrome with oxazolidinones.

Shock, 2005 Jan, 23(1), 54 - 58
ENDOGENOUS INTERLEUKIN-12 IMPROVES THE EARLY ANTIMICROBIAL HOST RESPONSE TO MURINE ESCHERICHIA COLI PERITONITIS; Weijer S et al.; Interleukin (IL)-12 is a heterodimeric proinflammatory cytokine formed by a p35 and a p40 subunit . To determine the role of IL-12 in abdominal sepsis, p35 gene-deficient (IL-12 knockout, KO) mice and normal wild-type (WT) mice were injected intraperitoneally with Escherichia coli . Peritonitis was associated with a bacterial dose-dependent increase in IL-12 p40 and IL-12 p75 concentrations in peritoneal fluid and plasma . Whereas at 6 h postinfection, IL-12 KO and WT mice displayed similar bacterial counts, at 20 hours IL-12 KO mice had significantly more bacteria in liver homogenates and were more susceptible to progressing to systemic infection . In addition, IL-12 KO mice demonstrated higher levels of proinflammatory cytokines in peritoneal fluid and increased lung and liver injury . IL-12 deficiency did not influence the recruitment of cells to the site of the infection . These data suggest that endogenous IL-12 is involved in the early antibacterial host response during abdominal sepsis.

Clin Neuropharmacol, 2004 Nov-Dec, 27(6), 293 - 8
The potential of minocycline for neuroprotection in human neurologic disease; Zemke D et al.; Minocycline is a member of the tetracycline class of molecules with broad-spectrum antibiotic activity . The unique properties of minocycline result in increased tissue distribution when compared with the other tetracyclines . Of particular interest is the ability of minocycline to diffuse into the central nervous system at clinically effective levels . Aside from its antimicrobial properties, minocycline has been found to have beneficial effects on inflammation, microglial activation, matrix metalloproteinases, nitric oxide production, and apoptotic cell death . Concordantly, minocycline has been found to have neuroprotective effects in animal models of a number of diseases including stroke, multiple sclerosis, and Parkinson disease . The proven safety of minocycline over decades of use as an antibiotic suggests that it may have potential for development into an effective treatment of multiple neurologic conditions in humans.

J Am Chem Soc, 2004 Dec 29, 126(51), 17025 - 31
Synthesis and derivatization of daptomycin: a chemoenzymatic route to acidic lipopeptide antibiotics; Grunewald J et al.; Daptomycin is a branched cyclic nonribosomally assembled acidic lipopeptide, which is the first clinically approved antibiotic of this class . Here we show that the recombinant cyclization domain of the Streptomyces coelicolor calcium-dependent antibiotic (CDA) nonribosomal peptide synthetase (NRPS) is a versatile tool for the chemoenzymatic generation of daptomycin derivatives . Linear CDA undecapeptide thioesters with single exchanges at six daptomycin-specific residues were successfully cyclized by CDA cyclase . Simultaneous incorporation of all six of these residues into the peptide backbone and elongation of the N-terminus of CDA by two residues yielded a daptomycin derivative that lacked only the beta-methyl group of l-3-methylglutamate . Bioactivity studies with several substrate analogues revealed a significant role of nonproteinogenic constituents for antibacterial potency . In accordance with acidic lipopeptides, the bioactivity of the chemoenzymatic assembled daptomycin analogue is dependent on the concentration of calcium ions . Single deletions of the four acidic residues in the peptide backbone suggest that only two aspartic acid residues are essential for antimicrobial potency . These two residues are strictly conserved among other nonribosomal acidic lipopeptides and the EF-motif of ribosomally assembled calmodulin . Based on these findings CDA cyclase is a versatile catalyst that can be used to generate novel daptomycin derivatives that are otherwise difficult to obtain by chemical modification of the parental tridecapeptide to improve further its therapeutic activity.

J Biol Chem . 2004 Dec 17; {Epub ahead of print}
The C-terminal domain of pediocin-like antimicrobial peptides (class IIa bacteriocins) is Involved in specific recognition of the C-terminal part of cognate immunity proteins and in determining the antimicrobial spectrum; Johnsen L et al.; The pediocin-like bacteriocins contain two domains: a cationic N-terminal beta-sheet domain that mediates binding of the bacteriocin to the target cell surface and a more hydrophobic C-terminal hairpin-like domain that penetrates into the hydrophobic part of the target cell membrane . The two domains are joined by a hinge, which enables movement of the domains relative to each other . In this study, 12 different hybrid bacteriocins were constructed by exchanging domains between five different bacteriocins . The hybrid bacteriocins were by-and-large highly potent when constructed such that the recombination point was in the hinge region, indicating that the two domains function independently . Use of optimal recombination points was, however, crucial . Shifting the recombination point just one residue from the hinge could reduce the activity of the hybrid by 3 to 4 orders of magnitude . The active hybrids displayed similar target cell specificities as the parental bacteriocin from which their membrane-penetrating C-terminal hairpin domain was derived . The results also indicate that the negatively charged aspartate reside in the hinge of most pediocin-like bacteriocins interacts with the C-terminal hairpin domain - perhaps by interacting with the positively charged residue that is present at one of the last three positions in the C-terminal end of most pediocin-like bacteriocins . Bacteria that produce pediocin-like bacteriocins also produce a cognate immunity protein that protects the producer from being killed by its own bacteriocin . Four different active hybrid immunity proteins constructed by exchanging regions between three different immunity proteins were tested for their ability to confer immunity to the hybrid bacteriocins . The results showed that the C-terminal half of the immunity proteins contains a region that directly or indirectly specifically recognizes the membrane-penetrating C-terminal hairpin domain of pediocin-like bacteriocins . The implications these results have on how pediocin-like bacteriocins and their immunity proteins interact with cellular specificity determinants are discussed.

Int J Cancer . 2004 Dec 17; {Epub ahead of print}
Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells; Heilborn JD et al.; Human cathelicidin antimicrobial protein hCAP18/LL-37 is an effector molecule of the nonspecific innate immune system . hCAP18/LL-37 is present in leukocytes and is expressed in skin and other epithelia, where it is upregulated in association with inflammation and injury . In addition, antimicrobial proteins including cathelicidins have been proposed to play a role in the nonspecific defense against tumors . To assess its potential role in tumor host defense, we investigated the expression of hCAP18/LL-37 in a series of breast carcinomas . Unexpectedly, we found that hCAP18/LL-37 was strongly expressed in the tumor cells and not in the adjacent stroma . To test the hypothesis that hCAP18/LL-37 may provide a growth advantage for the tumor cells, we treated human epithelial cell lines with synthetic biologically active LL-37 peptide and found a significant increase in cell proliferation . In addition, transgenic expression of hCAP18 in 2 different human epithelial cell lines resulted in increased proliferation of both cell types . These findings do not support the hypothesis that LL-37 has an antitumor effect, but rather suggest that hCAP18/LL-37 may promote tumor cell growth in breast cancer . (c) 2004 Wiley-Liss, Inc.

Semin Arthritis Rheum, 2004 Dec, 34(3), 617 - 22
Mycobacterium chelonae tenosynovitis of the hand; Mateo L et al.; Objective Tenosynovitis of the hand due to atypical mycobacteria is an uncommon condition . We present a case of tenosynovitis of the hand due to Mycobacterium chelonae in a patient without a recognized penetrating injury, who was treated successfully with clarithromycin and antituberculous medications and without debridement . We reviewed the available literature to summarize the experience with this infectious entity . Methods Case report and review of the literature (MEDLINE 1976-2003) . Only cases that were sufficiently detailed were included . Results Twelve cases of upper extremity infection due to M . chelonae have been reported: hand tenosynovitis in most and arthritis in a few . These infections resulted from percutaneous inoculation or hematogenous seeding . The clinical course was indolent initially but insidiously destructive . Previously, treatment always included surgical excision of the infected tissues and antibiotic therapy . This is the first case of M . chelonae musculoskeletal infection that resolved with only antimicrobial therapy . Conclusions Musculoskeletal infections by nontuberculous mycobacteria are clinically indistinguishable from those of tuberculosis and diagnosis is usually delayed . Prompt diagnosis of atypical mycobacteria with appropriate antimicrobial treatment may avoid the need for surgical debridement . Relevance We recommend a trial of antibiotics for M . chelonae before surgical debridement.

Mol Immunol, 2005 Mar, 42(5), 575 - 9
Detection of individual human neutrophil alpha-defensins (human neutrophil peptides 1, 2 and 3) in unfractionated gingival crevicular fluid-A MALDI-MS approach; Lundy FT et al.; The role of antimicrobial peptides is particularly important in the oral cavity where there is constant challenge by microorganisms . The alpha-defensins are a group of cationic peptides that comprise 30-50% of the total protein in azurophilic granules of human neutrophils . They include the human neutrophil peptides (HNP) 1, 2 and 3 which have almost identical amino acid sequences but differ in their biological activities . The amino acid sequence similarities of the defensins have made it difficult to unequivocally determine the presence of individual defensins using antibody-based techniques . However, by virtue of their cationic nature we postulated that the defensins would fly particularly well in mass spectrometry and that this characteristic would allow facile identification of individual HNPs in unfractionated gingival crevicular fluid (GCF) from periodontitis patients and healthy controls . Although there was variability in levels of defensins detected in periodontal health and disease, HNP-1 was always identified as the major peak in the triad and HNP-3 as the minor peak, lending support to the hypothesis that HNP-2 may arise by post-translational proteoyltic cleavage of HNP-3 rather than HNP-1 . The finding that the defensins were more abundant in a higher proportion of the healthy sites studied could be linked to a more intact defensin barrier in periodontal health.

FEMS Immunol Med Microbiol, 2005 Jan 1, 43(1), 91 - 8
Protein-bound polysaccharide isolated from basidiomycetes inhibits endotoxin-induced activation by blocking lipopolysaccharide-binding protein and CD14 functions; Asai Y et al.; The protein-bound polysaccharide isolated from basidiomycetes (PSK) is a biological response modifier capable of exhibiting various biological activities, such as antitumor and antimicrobial effects . In the present study, we found that PSK suppressed interleukin (IL)-6 production in murine peritoneal macrophages stimulated with endotoxic lipopolysaccharide (LPS) and its synthetic lipid A (compound 506) . Nitric oxide production and p38 mitogen-associated protein kinase phosphorylation induced in a murine macrophage cell line, J774-A1, by LPS and compound 506 were also inhibited by PSK . Further, PSK distinctly suppressed nuclear factor-kappaB activation in Ba/F3 cells expressing mouse Toll-like receptor 4 and MD-2, following stimulation with LPS and compound 506, however, not with Taxol . These PSK-induced inhibitory activities were caused by inhibition of the physical associations of LPS with LPS-binding protein (LBP) and CD14 . PSK also protected mice from LPS-induced lethality, presumably by down-regulating IL-6 and tumor necrosis factor-alpha concentrations in serum . These findings indicate that PSK, which also has an ability to regulate LBP/CD14 functions, may be useful for clinical control of endotoxic sepsis.

Vet Microbiol, 2005 Jan 5, 105(1), 57 - 64 Epub 2004 Nov 30.
Determination of Mycoplasma bovis susceptibilities against six antimicrobial agents using the E test method; Francoz D et al.; The objective of this study was to determine the susceptibility of Mycoplasma bovis against six antibiotics using the E test methodology . Fifty-eight isolates of M . bovis originating from 55 affected cattle were evaluated . Specimen originated from: lung tissue, synovial fluid, tracheo-bronchial wash, milk, and external or inner ear discharge . Antimicrobial agents tested were azythromycin, clindamycin, erythromycin, enrofloxacin, spectinomycin and tetracycline . The E test strips were placed on the surface of Hayflick plates on which organism suspension was spread . Plates were incubated at 35 degrees C in a candle jar for 72h . MICs were then read by determining where the growth inhibition zone intersected with the MIC scale on the strip . M . bovis Donetta isolate was used as a control . All MICs were >256mug/ml for erythromycin . MIC(50) and MIC(90) obtained for azythromycin were 3 and >256mug/ml, respectively . MIC(50) and MIC(90) obtained for tetracycline were 4 and 8mug/ml, respectively . MIC(50) and MIC(90) obtained for spectinomycin were 2 and >1021mug/ml, respectively . MIC(50) and MIC(90) obtained for clindamycin were 0.19 and >256mug/ml, respectively . MIC(50) and MIC(90) obtained for enrofloxacin were 0.19 and 0.25mug/ml, respectively . Resistance was not associated with the specimen source except for azythromycin . M . bovis susceptibilities were easily determined by the E test which demonstrated the efficacy of enrofloxacin and the acquired resistance to tetracycline, spectinomycin, azythromycin and clindamycin.

Immunology, 2005 Jan, 114(1), 121 - 32
Conditional expression of liver-enriched transcriptional activator protein augments Acholeplasma laidlawii-induced granulysin gene expression in a human monocytic cell line, THP-1; Kida Y et al.; The antimicrobial protein granulysin is considered to play an important role in the defence mechanism against bacterial infection . We previously reported that Acholeplasma laidlawii-induced transactivation of the granulysin promoter in a human monocytic cell line, THP-1, is regulated by activator protein-1 and CCAAT/enhancer binding protein-beta (C/EBPbeta), but not by nuclear factor-kappaB . Moreover, liver-enriched transcriptional inhibitory protein (LIP), a C/EBPbeta isoform, was strongly induced in A . laidlawii-stimulated THP-1 cells . However, the level of liver-enriched transcriptional activator protein (LAP), another C/EBPbeta isoform, was essentially constant . Accordingly, we speculated that LIP would down-regulate A . laidlawii-induced granulysin gene expression in THP-1 cells . In the present study, we examined whether LAP augments A . laidlawii-induced granulysin gene expression using conditional LAP-expressing THP-1 cells in a tetracycline-controlled expression system . Our results indicated that conditional expression of LAP augmented A . laidlawii-induced expression of granulysin mRNA . In addition, the granulysin protein was observed in A . laidlawii-stimulated, LAP-expressing THP-1 cells . Our results suggest that the expression of LAP plays a critical role in the expression of the granulysin gene in macrophages.

Eur J Biochem, 2004 Dec, 271(23-24), 4621 - 8
Weapons of STAT destruction; Horvath CM; The signal transducer and activator of transcription (STAT) family of proteins function to activate gene transcription downstream of myriad cytokine and growth factor signals . The prototype STAT proteins, STAT1 and STAT2, are required for innate and adaptive antimicrobial immune responses that result from interferon signal transduction . While many viruses have evolved the ability to avoid these antiviral cytokines, the Paramyxoviruses are distinct in their abilities to interfere directly with STAT proteins . Individual paramyxovirus species differ greatly in their precise mechanism of STAT signaling evasion, but a virus-encoded protein called V plays a central role in this process . The theme of V-dependent interferon evasion and its variations provide significant insights into virus-host interactions and viral immune evasion that can help define targets for antiviral drug design . Exposure of the viral weapons of STAT destruction may also be instructive for application to STAT-directed therapeutics for diseases characterized by STAT hyperactivity.

Radiat Res, 2005 Jan, 163(1), 115 - 23
Priority list of research areas for radiological nuclear threat countermeasures; Pellmar TC et al.; Pellmar, T . C., Rockwell, S . and the Radiological/Nuclear Threat Countermeasures Working Group . Priority List of Research Areas for Radiological Nuclear Threat Countermeasures . Radiat . Res . 163, 115-123 (2005).To help the nation prepare for the possibility of a terrorist attack using radiological and nuclear devices, the Office of Science and Technology Policy and the Homeland Security Council established an interagency working group . The working group deliberated on the research needs for radiological/ nuclear threat countermeasures and identified and prioritized 18 areas for further attention . The highest priorities were given to research on (1) radioprotectors for use prior to exposure; (2) therapeutic agents for postexposure treatment; (3) antimicrobial therapy for infections associated with radiation exposure; (4) cytokines and growth factors; (5) mechanisms of radiation injury at the molecular, cellular, tissue and organism levels; and (6) automation of biodosimetric assays . High priority was given to (1) developing biomarkers for biodosimetry; (2) enhancing training in the radiation sciences; (3) exploring the consequences of combined injury; (4) establishing a repository of information regarding investigational countermeasures; and (5) following the health of an exposed population to better prepare for subsequent events . The research areas that the committee felt required the attention of the radiation research community are described in this report in an effort to inform this community about the needs of the nation and to encourage researchers to address these critical issues.

Chem Res Toxicol, 2004 Dec, 17(12), 1659 - 66
Lactoperoxidase-catalyzed activation of carcinogenic aromatic and heterocyclic amines; Gorlewska-Roberts KM et al.; Lactoperoxidase, an enzyme secreted from the human mammary gland, plays a host defensive role through antimicrobial activity . It has been implicated in mutagenic and carcinogenic activation in the human mammary gland . The potential role of heterocyclic and aromatic amines in the etiology of breast cancer led us to examination of the lactoperoxidase-catalyzed activation of the most commonly studied arylamine carcinogens: 2-amino-1-methyl-6-phenylimidazo{4,5-b}-pyridine (PhIP), benzidine, 4-aminobiphenyl (ABP), 2-amino-3-methylimidazo{4,5-f}quinoline (IQ), and 2-amino-3,8-dimethylimidazo{4,5-f}quinoxaline (MeIQx) . In vitro activation was performed with lactoperoxidase (partially purified from bovine milk or human milk) in the presence of hydrogen peroxide and calf thymus DNA . Products formed during enzymatic activation were monitored by HPLC with ultraviolet and radiometric detection . Two of these products were characterized as hydrazo and azo derivatives by means of mass spectrometry . The DNA binding level of (3)H- and (14)C-radiolabeled amines after peroxidase-catalyzed activation was dependent on the hydrogen peroxide concentration, and the highest levels of carcinogen binding to DNA were observed at 100 muM H(2)O(2) . Carcinogen activation and the level of binding to DNA were in the order of benzidine > ABP > IQ > MeIQx > PhIP . One of the ABP adducts was identified, and the level at which it is formed was estimated to be six adducts/10(5) nucleotides . The susceptibility of aromatic and heterocyclic amines for lactoperoxidase-catalyzed activation and the binding levels of activated products to DNA suggest a potential role of lactoperoxidase-catalyzed activation of carcinogens in the etiology of breast cancer.

Eur J Clin Microbiol Infect Dis, 2004 Oct, 23(10), 772 - 5
Efficacy and safety of sequential moxifloxacin for treatment of community-acquired pneumonia associated with atypical pathogens; Hoeffken G et al.; In two prospective, randomized studies intravenous (IV)/oral (PO) moxifloxacin (400 mg q.i.d.) was compared to IV/PO antimicrobial comparator agents for the treatment of hospitalized patients with community-acquired pneumonia . Reported here are the pooled data for the sub-population with atypical pathogens . Of 101 intent-to-treat patients with atypical pathogens, a total of 39 moxifloxacin-treated and 47 comparator-treated subjects were microbiologically valid and included in the analysis . Clinical and bacteriological success rates were 95% for the moxifloxacin-treated and 94% for the comparator-treated subjects at the test-of-cure visit . The results indicate IV/PO moxifloxacin (400 mg q.i.d.) is an effective monotherapy for patients with CAP due to atypical pathogens.

Curr Opin Drug Discov Devel, 2004 Mar, 7(2), 211 - 22
Bacterial targets to antimicrobial leads and development candidates; Rogers BL; The unabated spread of drug-resistant bacterial pathogens continues to pose a significant threat to patient health . However, there are now several new and improved derivatives from established classes of antibiotics that have recently been approved or are in late-stage development . In drug discovery, screening of new targets derived from genomic-based discovery stratagems has resulted in a number of potent antibacterial leads . Further optimization and development of these promising compounds offer the opportunity to develop new classes of antimicrobials that act through modes of action that are unlikely to be affected by resistance mechanisms defined to date . In addition, new discoveries in biochemical mechanisms of antibiotic action continue to help identify new approaches to design novel antibiotic analogs.

Allergy Asthma Proc, 2004 Sep-Oct, 25(5), 297 - 304
Identification and quantification of innate immune system mediators in human breast milk; Armogida SA et al.; Breast-feeding decreases the risk of breast cancer in mothers and infection, allergy, and autoimmunity in infants . The presence of mediators of the innate immune system in human milk, including soluble defensins, cathelicidins, and toll-like receptors (TLRs), has not been researched thoroughly . The whey fractions of colostrum and transitional and mature milk (n = 40) from normal mothers (n = 18) and from mothers with autoimmune or allergic diseases (n = 22) were analyzed for defensins by competitive enzyme-linked immunosorbent assay, and expression of messenger RNA (mRNA) for defensins, TLRs, and cathelicidin-derived antimicrobial peptide (LL-37) by cells in breast milk was determined by semiquantitative reverse-transcription-polymerase chain reaction . In whey, human neutrophil-derived a-defensin 1 (HNP-1) and human beta-defensin 2 (HBD-2) were present in the highest concentrations (median, 33.0 and 31.3 microg/mL, respectively), human alpha-defensin 6 (HD-6) was present in moderate amounts (3.1 microg/mL), and HD-5 and HBD-1 were present in the lowest concentrations (2.4 and 1.7 microg/mL, respectively) . There was great variability of defensin levels between subjects, but there was no relation to autoimmune or allergic diagnosis . HNP-1, HD-5, and HD-6 were present in significantly higher levels in colostrum than in mature milk . Regarding defensin mRNA expression in the breast milk cells, 95% of the samples (n = 41) were positive for HBD-1, 68% were positive for HD-5, 22% were positive for HBD-3, 15% were positive for HBD-2, 5% were positive for HBD-4, and 2% were positive for HD-6; 88% (14/16) were positive for HNP-1 . Breast milk cells also expressed mRNA for TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR9, CD14, and LL-37 . Human breast milk contains high concentrations of multiple defensin proteins and cells in breast milk express mRNA for these defensins, multiple TLRs, and LL-37 . The innate immune system in breast milk is complex and likely provides protection for maternal breast tissue and the developing digestive tract of newborns.

Pediatr Infect Dis J, 2004 Oct, 23(10), 963 - 5
Antibiotic lock with vancomycin and urokinase can successfully treat colonized central venous catheters in pediatric cancer patients; De Sio L et al.; We used an antibiotic lock technique with vancomycin in combination with urokinase in 10 consecutive eligible children with Gram-positive catheter-related bacteremia persisting after appropriate intravenous antibiotics . Treatment was successful in sterilizing all colonized central venous catheters, avoiding device removal and delay of further chemotherapy . The antibiotic lock technique may represent a safe and effective therapeutic option in patients with selected, uncomplicated catheter-related bacteremias resistant to systemic antimicrobial therapy, particularly when maintaining a venous access is mandatory.

J Vet Pharmacol Ther, 2004 Dec, 27(6), 503 - 14
Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine; McKellar QA et al.; The rise in incidence of antimicrobial resistance, consumer demands and improved understanding of antimicrobial action has encouraged international agencies to review the use of antimicrobial drugs . More detailed understanding of relationships between the pharmacokinetics (PK) of antimicrobial drugs in target animal species and their action on target pathogens {pharmacodynamics (PD)} has led to greater sophistication in design of dosage schedules which improve the activity and reduce the selection pressure for resistance in antimicrobial therapy . This, in turn, may be informative in the pharmaceutical development of antimicrobial drugs and in their selection and clinical utility . PK/PD relationships between area under the concentration time curve from zero to 24 h (AUC(0-24)) and minimum inhibitory concentration (MIC), maximum plasma concentration (C(max)) and MIC and time during which plasma concentrations exceed the MIC have been particularly useful in optimizing efficacy and minimizing resistance . Antimicrobial drugs have been classified as concentration-dependent where increasing concentrations at the locus of infection improve bacterial kill, or time-dependent where exceeding the MIC for a prolonged percentage of the inter-dosing interval correlates with improved efficacy . For the latter group increasing the absolute concentration obtained above a threshold does not improve efficacy . The PK/PD relationship for each group of antimicrobial drugs is 'bug and drug' specific, although ratios of 125 for AUC(0-24):MIC and 10 for C(max):MIC have been recommended to achieve high efficacy for concentration-dependent antimicrobial drugs, and exceeding MIC by 1-5 multiples for between 40 and 100% of the inter-dosing interval is appropriate for most time-dependent agents . Fluoroquinolones, aminoglycosides and metronidazole are concentration-dependent and beta-lactams, macrolides, lincosamides and glycopeptides are time-dependent . For drugs of other classes there is limited and conflicting information on their classification . Resistance selection may be reduced for concentration-dependent antimicrobials by achieving an AUC(0-24):MIC ratio of greater than 100 or a C(max):MIC ratio of greater than 8 . The relationships between time greater than MIC and resistance selection for time-dependent antimicrobials have not been well characterized.

J Vet Pharmacol Ther, 2004 Dec, 27(6), 397 - 414
Principles of pharmacodynamics and their applications in veterinary pharmacology; Lees P et al.; Pharmacodynamics (PDs) is the science of drug action on the body or on microorganisms and other parasites within or on the body . It may be studied at many organizational levels--sub-molecular, molecular, cellular, tissue/organ and whole body--using in vivo, ex vivo and in vitro methods and utilizing a wide range of techniques . A few drugs owe their PD properties to some physico-chemical property or action and, in such cases, detailed molecular drug structure plays little or no role in the response elicited . For the great majority of drugs, however, action on the body is crucially dependent on chemical structure, so that a very small change, e.g . substitution of a proton by a methyl group, can markedly alter the potency of the drug, even to the point of loss of activity . In the late 19th century and first half of the 20th century recognition of these facts by Langley, Ehrlich, Dale, Clarke and others provided the foundation for the receptor site hypothesis of drug action . According to these early ideas the drug, in order to elicit its effect, had to first combine with a specific 'target molecule' on either the cell surface or an intracellular organelle . It was soon realized that the 'right' chemical structure was required for drug-target site interaction (and the subsequent pharmacological response) . In addition, from this requirement, for specificity of chemical structure requirement, developed not only the modern science of pharmacology but also that of toxicology . In relation to drug actions on microbes and parasites, for example, the early work of Ehrlich led to the introduction of molecules selectively toxic for them and relatively safe for the animal host . In the whole animal drugs may act on many target molecules in many tissues . These actions may lead to primary responses which, in turn, may induce secondary responses, that may either enhance or diminish the primary response . Therefore, it is common to investigate drug pharmacodynamics (PDs) in the first instance at molecular, cellular and tissue levels in vitro, so that the primary effects can be better understood without interference from the complexities involved in whole animal studies . When a drug, hormone or neurotransmitter combines with a target molecule, it is described as a ligand . Ligands are classified into two groups, agonists (which initiate a chain of reactions leading, usually via the release or formation of secondary messengers, to the response) and antagonists (which fail to initiate the transduction pathways but nevertheless compete with agonists for occupancy of receptor sites and thereby inhibit their actions) . The parameters which characterize drug receptor interaction are affinity, efficacy, potency and sensitivity, each of which can be elucidated quantitatively for a particular drug acting on a particular receptor in a particular tissue . The most fundamental objective of PDs is to use the derived numerical values for these parameters to classify and sub-classify receptors and to compare and classify drugs on the basis of their affinity, efficacy, potency and sensitivity . This review introduces and summarizes the principles of PDs and illustrates them with examples drawn from both basic and veterinary pharmacology . Drugs acting on adrenoceptors and cardiovascular, non-steroidal anti-inflammatory and antimicrobial drugs are considered briefly to provide a foundation for subsequent reviews in this issue which deal with pharmacokinetic (PK)-PD modelling and integration of these drug classes . Drug action on receptors has many features in common with enzyme kinetics and gas adsorption onto surfaces, as defined by Michaelis-Menten and Langmuir absorption equations, respectively . These and other derived equations are outlined in this review . There is, however, no single theory which adequately explains all aspects of drug-receptor interaction . The early 'occupation' and 'rate' theories each explain some, but not all, experimental observations . From these basic theories the operational model and the two-state theory have been developed . For a discussion of more advanced theories see Kenakin (1997).

J Microbiol Immunol Infect, 2004 Dec, 37(6), 359 - 65
Stenotrophomonas maltophilia bacteremia in adults: four years' experience in a medical center in northern Taiwan; Wang WS et al.; Stenotrophomonas maltophilia has become an important nosocomial pathogen in immunocompromised patients in Taiwan . Patients with underlying diseases such as diabetes, uremia, and solid malignancy are extremely vulnerable to this organism . S . maltophilia bacteremia has a mortality rate of up to 62% if appropriate antibiotics are not instituted early . Knowledge of the risk factors for infection as well as local susceptibility patterns is helpful in determining which patients should receive empirical antibiotics active against S . maltophilia . This study assessed the characteristics of 50 episodes of S . maltophilia bacteremia in 48 patients admitted between March 3, 1999 and May 21, 2003 . The new fluoroquinolone levofloxacin showed promising in vitro activity against S . maltophilia in view of the increasing resistance of isolates to trimethoprim-sulfamethoxazole . For patients at risk for S . maltophilia infection, such as those receiving mechanical ventilation in the ICU or those with multiple vascular access devices, the need for antimicrobial agents to which S . maltophilia is normally sensitive should be considered in selecting empiric therapy.

Ann Pharmacother, 2005 Jan, 39(1), 32 - 8 Epub 2004 Dec 14.
Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia; Ariano RE et al.; BACKGROUND: Pharmacodynamic investigations with antimicrobials define the relationship between the infecting organism and achievable drug concentrations with clinical outcome . OBJECTIVE: To examine this relationship for meropenem in a population of patients who are at high risk of infection-related morbidity and mortality . METHODS: The study was a retrospective analysis of a multicenter, randomized, blinded clinical trial . A population-based predictive model was created using data from adults with febrile neutropenia and the nonparametric modeling program, NPEM . Patient age, body weight, and serum creatinine level were covariates in the model used to predict unbound concentrations for each patient . Pathogen susceptibility was estimated using product literature minimum inhibitory concentrations for effectiveness against 50% of microorganisms (MIC(50)) for specific organisms . The pharmacodynamic index of percent time above MIC (% T>MIC) was analyzed for its association with clinical outcome . RESULTS: A 2-compartment pharmacokinetic model using patient covariates of body weight and renal function best described the pharmacokinetics of meropenem in febrile neutropenic patients . Sixty patients with confirmed gram-positive or -negative bacteremia were studied . An average of 83% T>MIC was identified for the 42 clinical responders compared with 59% T>MIC for the 18 nonresponders (p = 0.04) . An 80% clinical response rate was evident when the % T>MIC for meropenem exceeded 75% of the dosing interval (p = 0.01) . CONCLUSIONS: To our knowledge, this is the first published report of a relationship between a pharmacodynamic index and clinical outcome in a febrile neutropenic population . Based on this relationship, dosing with intravenous meropenem 500 mg every 6 hours is predicted to be comparable to the currently recommended 1 g every 8 hours for serious infections . Our model provides further justification for a prospective clinical trial to evaluate a pharmacodynamically targeted meropenem dosing schedule as to its ability to improve clinical outcome in these patients.

Ann Pharmacother . 2004 Dec 14; {Epub ahead of print}
Rifaximin: A New Treatment for Travelers' Diarrhea (CE) (February); Pakyz AL; OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions and precautions, and dosing recommendations of rifaximin, a new nonabsorbed antimicrobial agent for travelers' diarrhea . DATA SOURCES: A MEDLINE search (1966-July 2004) was conducted to extract human and animal research data in the English language on rifaximin . STUDY SELECTION AND DATA EXTRACTION: Randomized, double-blind, placebo-controlled trials were reviewed and included to evaluate the efficacy of rifaximin in the treatment of travelers' diarrhea . DATA SYNTHESIS: Rifaximin is approved for the treatment of travelers' diarrhea in patients >/=12 years of age with diarrhea caused by noninvasive strains of Escherichia coli . Rifaximin was superior to placebo and trimethoprim/sulfamethoxazole and equivalent to ciprofloxacin in the primary clinical endpoint of the time to the last unformed stool passed . CONCLUSIONS: Rifaximin is a viable alternative to ciprofloxacin for the treatment of travelers' diarrhea . As rifaximin is not systemically absorbed, it offers the advantage of leading to the development of less resistance compared with systemically absorbed antibiotics, in addition to fewer systemic adverse effects and drug interactions . However, the potential for cross-resistance between rifaximin and rifampin, as well as with other classes of antibiotics, is of concern and needs to be elucidated . ((CE)) This article is approved for continuing education credit ACPE UNIVERSAL PROGRAM NUMBER: 407-000-05-xxx-H01.

J Public Health (Oxf), 2004 Dec, 26(4), 359 - 64
What has happened to antimicrobial usage in primary care in the United Kingdom since the SMAC report? - Description of trends in antimicrobial usage using the General Practice Research Database; Smith GE et al.; BACKGROUND: The aim of the study was to assess antibiotic prescribing within the United Kingdom for three of the Standing Medical Advisory Committee recommendations 'four things which could be done' . METHODS: We conducted a retrospective survey of morbidity and antibiotic prescribing data between 1993 and 2001 using the national General Practice Research Database . Antibiotic prescribing was linked to diagnoses of cough/cold and sore throat; length of antibiotic course for uncomplicated cystitis . RESULTS: The rate of antibiotic prescribing for cough/cold declined between 1993 (43.7 per 1000 patient years at risk) and 1999 (23.5 per 1000 patient years at risk) and has since increased slightly (to 30.5 per 1000 patient years at risk in 2001) . Antibiotic prescribing for sore throat declined between 1995 (80.6 per 1000 patient years at risk) and 1999 and has since remained static (42.1 per 1000 patient years at risk in 2001) . Trimethoprim was the most commonly used antibiotic for episodes of uncomplicated cystitis and the prescription of 3 day (or less) courses has increased from 16.4 per cent in 1998 to 41.5 per cent in 2001 . CONCLUSIONS: For the SMAC recommendation to limit prescribing for uncomplicated cystitis to 3 days in otherwise fit women there has been demonstrable impact since the publication of the SMAC report . For two recommendations (no prescribing of antibiotics for simple coughs and colds; no prescribing of antibiotics for viral sore throats) the impact has been less clear against the background of a general reduction in antimicrobial prescribing.

Farmaco, 2004 Dec, 59(12), 929 - 37
Novel adamantylated pyrimidines and their preliminary biological evaluations; Orzeszko B et al.; The synthesis of adamantylated pyrimidines was based on the reaction of 3-(adamantan-1-yl)-3-oxopropionic acid ethyl ester with urea, thiourea, guanidine as well as acetamidine, respectively . Then the compounds obtained were converted into respective bromo-, thio- and S-alkyl derivatives . The molecular structures for some compounds were studied by X-ray methods . The significant anticancer and antimicrobial properties of {2-(6-adamantan-1-yl-2-methylpyrimidin-4-ylthio)ethyl}dimethylamine were found.

Mol Plant Microbe Interact, 2004 Dec, 17(12), 1306 - 17
Apoplastic extracts from a transgenic wheat line exhibiting lesion-mimic phenotype have multiple pathogenesis-related proteins that are antifungal; Anand A et al.; A transgenic wheat line constitutively expressing genes encoding a class IV acidic chitinase and an acidic beta-1,3-glucanase, showed significant delay in spread of Fusarium head blight (scab) disease under greenhouse conditions . In an earlier work, we observed a lesion-mimic phenotype in this transgenic line when homozygous for transgene loci . Apoplastic fluid (AF) extracted from the lesion-mimic plants had pathogenesis-related (PR) proteins belonging to families of beta-1,3-glucanases, chitinases, and thaumatin-like proteins (TLPs) . AF had growth inhibitory activity against certain fungal pathogens, including Fusarium graminearum and Gaeumannomyces graminis var . tritici . Through a two-step ion-exchange chromatography protocol, we recovered many PR proteins and a few uncharacterized proteins . Three individual protein bands corresponding to a TLP (molecular mass, 16 kDa) and two beta-1,3-glucanases (molecular mass, 32 kDa each) were purified and identified by tandem mass spectrometry . We measured the in vitro antifungal activity of the three purified enzymes and a barley class II chitinase (purified earlier in our laboratory) in microtiter plate assays with macroconidia or conidiophores of F . graminearum and Pyrenophora tritici-repentis . Mixtures of proteins revealed synergistic or additive inhibitory activity against F . graminearum and P . tritici-repentis hyphae . The concentrations of PR proteins at which these effects were observed are likely to be those reached in AF of cells exhibiting a hypersensitive response . Our results suggest that apoplastic PR proteins are antifungal and their antimicrobial potency is dependent on concentrations and combinations that are effectively reached in plants following microbial attack.

Phytother Res, 2004 Nov, 18(11), 947 - 9
Effect of essential oil concentration on the pH of nutrient and Iso-sensitest broth; Hood JR et al.; The role of pH on the antimicrobial activity of essential oils has not been well studied . The effect of four essential oils: Backhousia citriodora, Melaleuca alternifolia, Lavandula angustifolia and Santalum spicatum (0.1% to 10%) on the pH of two commonly used media, nutrient broth and Iso-sensitest broth, was therefore undertaken . Small (less than 0.5 pH units) but statistically significant differences between the pH of the two media followed the addition of M . alternifolia, L . angustifolia and S . spicatum essential oil . In general the effect on pH was greatest at higher concentrations and the fall in pH was greatest in the nutrient broth . The addition of B . citriodora essential oil to nutrient broth resulted in a fall in pH from 7.29 +/- 0.02 (no oil) to 5.2 +/- 0.03 (10% oil) . This effect was not observed in the Iso-sensitest broth .

Anaesthesist, 2004 Dec, 53(12), 1189 - 94
{Spondylodiscitis after perioperative peridural catheter.}; Muller M et al.; Peridural anaesthesia is used to avoid operative, postoperative and chronic pain, especially in surgery, gynecology and urology . Complications have rarely been described but can entail serious local and systemic sequelae . Three cases with spondylitis and spondylodiscitis after peridural anaesthesia are presented . The failure to recognize the peridural catheter as the cause of vertebral pain led to therapeutic delay in two cases . The result of antimicrobial therapy and in two cases radical surgical treatment was complete recovery . The occurrence of spondylodiscitis after the use of peridural catheters is often a late manifestation of disseminated pathogens . The insidious progression of infection and non-specificity of clinical symptoms may lead to diagnostic delay . Awareness of the possibility of even delayed complications after the use of peridural anaesthesia is important.

J Biol Chem . 2004 Dec 13; {Epub ahead of print}
Site-directed mutagenesis of the active site region in the quinate/shikimate 5-dehydrogenase YdiB of Escherichia coli; Lindner HA et al.; YdiB and its paralog AroE are members of the quinate/shikimate 5-dehdrogenase family . Enzymes from this family function in the shikimate pathway that is essential for survival of microorganisms and plants, and represent potential drug targets . Recent YdiB and AroE crystal structures revealed the presence of a NAD(P)-binding and a catalytic domain . We carried out site-directed mutagenesis of eight putative active site residues in YdiB from E . coli and analyzed structural and kinetic properties of the mutant enzymes . Our data indicate critical roles for an invariant lysine and aspartate residue in substrate binding, and allowed us to differentiate between two previously proposed models for the binding of the substrate in the active site . Comparison of several YdiB and AroE structures led us to conclude that, upon cofactor-binding and domain closure, the two identified binding residues are repositioned to bind to the substrate . While the lysine residue contributes to some extent to the stabilization of the transition state, we did not identify any residue as catalytically essential . This indicates that catalysis does not operate through a general acid-base mechanism, as thought originally . Our improved understanding of the medically and agriculturally important quinate/shikimate 5-dehydrogenase family at the molecular level may prove useful in the development of novel herbicides and antimicrobial agents.

Biochemistry, 2004 Dec 21, 43(50), 15759 - 66
Solution structure of cryptdin-4, a mouse paneth cell alpha-defensin; Jing W et al.; Mammalian defensins are abundant antimicrobial peptides that contribute to host defense . They are characterized by several conserved amino acids, including six invariant cysteine residues which form three intramolecular disulfide bonds and stabilize the tertiary structure . Cryptdin-4 (Crp4), a mouse alpha-defensin with potent in vitro bactericidal activity, has a primary structure distinct from all known alpha-defensins in that its polypeptide backbone uniquely lacks three residues between Cys(IV) and Cys(V) . NMR diffusion experiments showed that Crp4 is monomeric in solution, and its three-dimensional solution structure, determined by two-dimensional proton NMR, consists of a triple-stranded antiparallel beta-sheet with the beta-strands joined to each other by a series of tight turns and a beta-hairpin . However, the overall beta-sheet content in Crp4 is lower than that of other alpha-defensin structures, while the shape and orientation of the Crp4 beta-hairpin also differ from those of other alpha-defensin structures . These structural characteristics combined with the high overall cationicity of Crp4 may contribute to its broad bactericidal spectrum and membrane disruptive activity.

Zhonghua Nan Ke Xue, 2004 Nov, 10(11), 830 - 1, 835
{Transperineal puncture drug injection in the treatment of chronic prostatitis}; Zhang J et al.; OBJECTIVE: To investigate the effect of transperineal puncture drug injection in the treatment of chronic prostatitis . METHODS: Forty cases of chronic prostatitis underwent transperineal puncture drug injection . Bacterial culture and antimicrobial agent sensitivity tests were conducted on the prostatic fluid of the patients . A sensitive antimicrobial agent was selected, mixed with lidocaine and dexamethasone, and injected transperineally into the prostate at intervals of 7 days and 4 times as one course . After one month, the effect was evaluated and the patients were followed up for 6 months . RESULTS: Among the 40 cases, the cure rate was 52.5% (21/ 40), the alleviation rate 40% (16/40), the nullity rate 7.5% (3/40) and the total effectivity rate 92.5% . No relapse was found in the 28 followed-up cases . CONCLUSION: Transperineal puncture drug injection is a safe and effective way in the treatment of chronic prostatitis.

AIDS Rev, 2004 Jul-Sep, 6(3), 161 - 8
Defensins: natural anti-HIV peptides; Chang TL et al.; Mammalian defensins are small cationic antimicrobial peptides predominantly found in leukocytes and epithelial cells engaged in host defense . These peptides act as effector molecules in innate immunity as well as regulators in adaptive immunity . Increasing evidence indicates that defensins are effective inhibitors of HIV-1 . While the level of defensins in HIV-1 infected individuals has not been determined, neutropenia and neutrophil dysfunction associated with HIV disease progression may result in altered alpha-defensin production . This review provides an overview of the structure and function of defensins, and focuses on the anti-HIV-1 activity of defensins and the mechanism of this activity . Although many questions remain, studying the complex function of defensins in innate immunity against HIV has implications for our further understanding of disease progression and for the development of novel approaches to prevention and therapy.

Arch Pharm Res, 2004 Nov, 27(11), 1093 - 8
Synthesis and antimicrobial activity of certain novel quinoxalines; Refaat HM et al.; In this study, certain 3-methyl-2-{4-(substituted amino carbonyl)anilino} quinoxalines, (2a-d) and (3a-d), were synthesized from the new key compound 2-{4-(ethoxycarbonyl)anilino}-3-methyl quinoxaline (1) . In addition, a series of 2-{4-(arylidene hydrazinocarbonyl)anilino}-3-methyl quinoxalines (5a-e), as well as their cyclized oxadiazolinyl derivatives (6a-e), and a series of 2-{4-N2-acylhydrazinocarbonyl) anilino}-3-methyl quinoxalines (7a-d), as well as their cyclized oxadiazoiyl derivatives (8a-d) were also prepared . Some of these derivatives were evaluated for antimicrobial activity in vitro . It was found that all the selected compounds exhibit antimicrobial activity and that compound 5b had a broad spectrum of activity.

J Infect Dis, 2005 Jan 1, 191(1), 65 - 74 Epub 2004 Nov 29.
Macrophages play a dual role during pulmonary tuberculosis in mice; Leemans JC et al.; Pulmonary macrophages provide the preferred hiding and replication site of Mycobacterium tuberculosis but display antimicrobial functions . This raises questions regarding the role of macrophages during tuberculosis . We depleted lungs of activated macrophages (activated macrophage(-) mice) and compared this with nonselective macrophage depletion (macrophage(-) mice) . Although nonselective depletion of macrophages after infection improved clinical outcome, depletion of activated macrophages led to impaired resistance, reflected by enhanced mycobacterial outgrowth . The production of tumor necrosis factor- alpha and numbers of granuloma decreased after depletion of activated macrophages . Both macrophage(-) and activated macrophage(-) mice showed polarized production of interferon- gamma by splenocytes and lymph-node cells and were able to attract and activate T cells in the lung . These data demonstrate that the dual role of macrophages is associated with the activation state of macrophages and that extensive apoptosis found in patients with tuberculosis could be part of a host defense strategy, as long as these cells are not activated.

Am J Obstet Gynecol, 2004 Dec, 191(6), 2090 - 6
Host defense proteins in vernix caseosa and amniotic fluid; Akinbi HT et al.; OBJECTIVE: This study was undertaken to define the spectrum, activity, and spatial distribution of antimicrobial peptides in vernix caseosa and amniotic fluid in the absence of clinical chorioamnionitis . STUDY DESIGN: Characterization of innate immune proteins in vernix and amniotic fluid obtained from pregnancies with gestational ages greater than 37 weeks by Western analysis, immunohistochemistry, and antimicrobial growth inhibition assay . RESULTS: Lysozyme, lactoferrin, human neutrophil peptides 1-3, and secretory leukocyte protease inhibitor were identified by Western analysis in vernix suspensions (n = 25) and amniotic fluid samples (n = 10) . Three other important antimicrobial proteins, human beta defensin-2, lactoperoxidase, and LL-37 were not detected . Amniotic fluid and soluble extracts of vernix exhibited muramidase (lysozyme) activity, and there was selective efficacy in inhibiting growth of common perinatal pathogens . Antimicrobial peptides were concentrated in discrete, organized, acellular "granules" embedded in the vernix lipid matrix . CONCLUSION: In the absence of chorioamnionitis, vernix and amniotic fluid contain an organized pool of antimicrobial peptides with a defined spectrum of bioactivity against common bacterial and fungal pathogens.

Indian J Med Res, 2004 Nov, 120(5), 463 - 7
Evaluation of three methods to determine the antimicrobial susceptibility of Mycobacterium tuberculosis; Muralidhar S et al.; BACKGROUND & OBJECTIVES: Tuberculosis continues to be a major public health problem in India, especially with the emergence of drug resistance . A study was carried out to establish a rapid and accurate method of susceptibility testing for Mycobacterium tuberculosis using three methods viz., proportion method by agar dilution on Middlebrook 7H11 agar, proportion method using the conventional Lowenstein-Jensen (L-J) medium and E test strip method . METHODS: A total of seventy five clinical isolates from pulmonary and extrapulmonary sites were characterised and speciated by biochemical tests, growth and other standard parameters, and eight random isolates, also by polymerase chain reaction (PCR) . Antimicrobial susceptibility of M.tuberculosis was performed by proportion method on L-J medium and Middlebrook 7H11 agar medium for isoniazide (INH), rifampicin (RIF), ethambutol (EMB), streptomycin (STM) and ciprofloxacin (CIP) using recommended critical concentrations . The two methods were compared with the E test method . RESULTS: The 75 M.tuberculosis strains were isolated from sputum (47), pus (23), aspirate fluid (2), skin tissue (2) and gastric aspirate (1) . Of these 49 (65.3%) isolates were sensitive and one (1.3%) was resistant to all the five drugs tested and by all the three methods . Eleven (14.7%) isolates were resistant to INH alone by the three methods . The E test method detected one isolate resistant to INH and 2 to RIF which were missed by the other two methods . The results obtained by all the three methods compared well . INTERPRETATION & CONCLUSION: The three methods viz., proportion methods with L-J, Middlebrook 7H11 agar and the E test concurred fully in 57 isolates (76%) . Association between L-J and Middlebrook 7H11 agar methods was 59 per cent . E test and the L-J methods did not differ significantly for all the drugs . The finding show that the E test method is superior to the other two methods in terms of simplicity of performance and the rapidity of results . Another advantage is that the MIC values can also be obtained simultaneously by this method.

J Dairy Sci, 2005 Jan, 88(1), 317 - 23
Escherichia coli Strain Nissle 1917: Significant Reduction of Neonatal Calf Diarrhea; von Buenau R et al.; Inappropriate daily use of antimicrobial drugs for the treatment of intestinal diseases is associated with an increased risk of antibiotic resistance . Thus, the establishment of new forms of therapy is still needed . Our objective was to examine the effect of the nonpathogenic Escherichia coli strain Nissle 1917 on the prophylaxis and treatment of neonatal calf diarrhea in a hypothesis-generating study (study I) and a subsequent confirmatory clinical study (study II) under field conditions . Both trials were designed as consecutive, placebo-controlled, single-blind comparisons of 2 groups of animals . Immediately after birth, healthy calves were assigned to either the E . coli Nissle 1917 or the placebo group . The study medication was administered orally 1/d before the first feeding . The treatment was continued for the first 10 to 12 d of life . For each animal, the studies ended on d 20 to 22 of life . In both trials, the number of calves developing diarrhea was defined as the primary target criterion . A total of 335 newborn calves were included in the studies (study I: n = 172; study II: n = 163) . Study I showed that the incidence of diarrhea was 65.2% under placebo and 26.5% under E . coli Nissle 1917 . In study II, the corresponding figures were 63.0% under placebo and 12.2% under E . coli Nissle 1917 . It can be concluded that the administration of viable E . coli bacteria, strain Nissle 1917, has a clear beneficial effect on the prophylaxis and treatment of neonatal calf diarrhea.

J Dairy Sci, 2005 Jan, 88(1), 1 - 6
Influence of thermal processing conditions on flavor stability in fluid milk: benzaldehyde; Potineni RV et al.; Flavor loss in dairy products has been associated with enzymatic degradation by xanthine oxidase . This study was conducted to investigate the influence of milk thermal processing conditions (or xanthine oxidase inactivation) on benzaldehyde stability . Benzaldehyde was added to whole milk which had been thermally processed at 4 levels: (1) none or raw, (2) high temperature, short time (HTST) pasteurization, (3) HTST pasteurization, additionally heated to 100 degrees C (PAH), and (4) UHT sterilized . Additionally, PAH and UHT milk samples containing benzaldehyde (with and without ferrous sulfate) were spiked with xanthine oxidase . Azide was added as an antimicrobial agent (one additional pasteurized sample without) and the microbial load (total plate count) was determined on d 0, 2, and 6 . The concentration of benzaldehyde and benzoic acid in all milk samples were determined at d 0, 1, 2, 4, and 6 (stored at 5 degrees C) by gas chromatography/mass spectrometry in selective ion monitory mode . Over the 6-d storage period, more than 80% of the benzaldehyde content was converted (oxidized) to benzoic acid in raw and pasteurized milk, whereas no change in the benzaldehyde concentration was found in PAH or UHT milk samples . Furthermore, the addition of xanthine oxidase or xanthine oxidase plus ferrous sulfate to PAH or UHT milk samples did not result in benzaldehyde degradation over the storage period.

J Leukoc Biol . 2004 Dec 9; {Epub ahead of print}
Interactions between neutrophil-derived antimicrobial peptides and airway epithelial cells; van Wetering S et al.; Most antimicrobial peptides have been discovered based on activity-guided purification procedures, which used assays to determine their antimicrobial activity . Nevertheless, recent studies have shown that antimicrobial peptides also exert a range of other functions . Based on these observations, antimicrobial peptides are now not only implicated in host defense against infection but also in other immune reactions, inflammation, and wound-repair processes . The activities of neutrophil defensins and the cathelicidin hCAP-18/LL-37, antimicrobial peptides that are abundantly expressed in the human neutrophil, are the subject of an increasing number of studies . Exposure to neutrophil defensins and hCAP-18/LL-37 results in increases in mediator expression and release, chemotaxis, and proliferation of inflammatory and epithelial cells and fibroblasts, and the mechanisms underlying these effects have been partly elucidated . This review is focused on the effects of neutrophil defensins and hCAP-18/LL-37 on airway epithelial cells.

Microbiol Mol Biol Rev, 2004 Dec, 68(4), 669 - 85
Metagenomics: application of genomics to uncultured microorganisms; Handelsman J; Metagenomics (also referred to as environmental and community genomics) is the genomic analysis of microorganisms by direct extraction and cloning of DNA from an assemblage of microorganisms . The development of metagenomics stemmed from the ineluctable evidence that as-yet-uncultured microorganisms represent the vast majority of organisms in most environments on earth . This evidence was derived from analyses of 16S rRNA gene sequences amplified directly from the environment, an approach that avoided the bias imposed by culturing and led to the discovery of vast new lineages of microbial life . Although the portrait of the microbial world was revolutionized by analysis of 16S rRNA genes, such studies yielded only a phylogenetic description of community membership, providing little insight into the genetics, physiology, and biochemistry of the members . Metagenomics provides a second tier of technical innovation that facilitates study of the physiology and ecology of environmental microorganisms . Novel genes and gene products discovered through metagenomics include the first bacteriorhodopsin of bacterial origin; novel small molecules with antimicrobial activity; and new members of families of known proteins, such as an Na(+)(Li(+))/H(+) antiporter, RecA, DNA polymerase, and antibiotic resistance determinants . Reassembly of multiple genomes has provided insight into energy and nutrient cycling within the community, genome structure, gene function, population genetics and microheterogeneity, and lateral gene transfer among members of an uncultured community . The application of metagenomic sequence information will facilitate the design of better culturing strategies to link genomic analysis with pure culture studies.

J Antimicrob Chemother, 2005 Jan, 55(1), 95 - 101 Epub 2004 Dec 8.
Effect of formulary policy decisions on antimicrobial drug utilization in British Columbia; Marra F et al.; Background: Formularies are used routinely for management of drug expenditures yet evaluations of their impact remain rare . The objective of this study was to analyse the impact of addition or deletion of antimicrobials from the provincial formulary on drug utilization . METHODS: We obtained data from the British Columbia PharmaNet database on all outpatient oral antimicrobial prescriptions from 1996 to 2000 and converted them to their defined daily dose (DDD) equivalents according to the ATC system . Trends in utilization associated with a changing formulary status of new antimicrobial agents were analysed . Maximum likelihood estimation was used to determine the rate of increase in utilization resulting from addition to the formulary . Models were adjusted for seasonal and temporal trends as well as serial correlation . RESULTS: During this time period, clarithromycin was on formulary, later delisted, and then relisted again . Valaciclovir and famciclovir were also added to the formulary . During the time clarithromycin was off the formulary, the rate of change in its monthly consumption was 0.0061 DDD/1000 population/day; following its relisting, the rate of change increased by 818% to 0.0560 DDD/1000 population/day (P=0.002) . After the listing of valaciclovir on the formulary, the rate of change in its monthly consumption increased 57% from a baseline of 0.0014 to 0.0022 DDD/1000 population/day (P=0.07) . A similar effect was seen with the addition of famciclovir to the formulary whereby the rate of change in monthly consumption increased from 0.0008 (before addition to the formulary) to 0.0018 (after addition to the formulary) (P </= 0.001) . CONCLUSIONS: Listing of antimicrobials on provincial or countrywide formularies is followed temporally with increased utilization . However, before governmental agencies can institute reference-based pricing or co-payment programmes, the effect of such a programme on the emergence of antimicrobial resistance and on patient outcomes needs further study.

J Ethnopharmacol, 2005 Jan 4, 96(1-2), 151 - 8
Chemical composition and antimicrobial activity of the essential oils of Chrysanthemum indicum; Shunying Z et al.; Three essential oils from three samples: fresh, air-dried and processed flowers of Chrysanthemum indicum, obtained by hydrodistillation, were analyzed by GC-MS . The results show that major constituents of the three oils were 1,8-cineole, camphor, borneol and bornyl acetate, but the percentage of these compounds varied greatly because of the processing of flowers . The antimicrobial activity of essential oils from air-dried and processed flowers was evaluated against 15 microorganisms including three yeasts and seven clinical isolated strains using disc paper and broth microdilution methods . Our results show that both essential oils possessed significant antimicrobial effect, however, some difference in antimicrobial activity between two oils was observed for several microorganisms, which was attributed to the variation in percentage of the components . With higher percentage of camphor, the oil of the processed flowers exhibited, in many cases, greater bacteriostatic activity than that of the air-dried ones.

Lipids, 2004 Jul, 39(7), 675 - 80
2-methoxylated fatty acids in marine sponges: defense mechanism against mycobacteria?
Carballeira NM, Cruz H, Kwong CD, Wan B, Franzblau S.
A series of saturated 2-methoxylated FA having even-numbered chains with 8-14 carbons were synthesized, and their spectroscopic data are presented for the first time . The 2-methoxylated C10-C14 acids were prepared from the corresponding 2-hydroxylated FA, whereas the 2-methoxyoctanoic acid was synthesized starting with heptaldehyde . All of the methoxylated FA displayed some degree of inhibition (between 2 and 99%) of Mycobacterium tuberculosis H(37)Rv at 6.25 microg/mL . The most inhibitory FA was 2-methoxydecanoic acid, with a minimum inhibitory concentration of 200-239 microM against M . tuberculosis H(37)Rv as determined by both the microplate Alamar Blue assay and the green fluorescent protein microplate assay . These results are discussed in terms of the possible role of the 2-methoxylated FA as antimicrobial lipids produced either by marine sponges, or the associated marine symbiotic bacteria, as a defense mechanism in a highly competitive environment.

Phytochemistry, 2004 Aug, 65(15), 2239 - 45
3-hydroxypropionic acid as a nematicidal principle in endophytic fungi; Schwarz M et al.; 3- Hydroxypropionic acid was isolated by bioactivity-guided fractionation of extracts obtained from submerged cultures of several endophytic fungi isolated from above-ground plant organs . This compound showed selective nematicidal activity against the plant-parasitic nematode Meloidogyne incognita with LD50 values of 12.5-15 microg/ml . Activity against the saprophytic Caenorhabditis elegans was fivefold lower . No antimicrobial, cytotoxic or phytotoxic effects were observed . Propionic acid and D- and L-lactic acids were not active against either nematode species . Based on morphological features and ITS, 18S and 28S rDNA analyses, the producing strains were identified as Phomopsis phaseoli isolated from the leaf of a tropical tree, and four strains of Melanconium betulinum isolated from twigs of Betula pendula and B . pubescens in Germany . This is the first report of 3-hydroxypropionic acid in fungi, and of the nematicidal activity of this metabolite.

Indian J Exp Biol, 2004 Nov, 42(11), 1112 - 6
Occurrence of chromium resistant thermotolerant coliforms in tannery effluent; Verma T et al.; Twenty six thermotolerant strains resistant to high levels of chromium (50-250 microg/ml) were isolated from treated tannery effluent . They were also found resistant to multiple heavy metals and antibiotics . Majority of them were resistant to copper and bacitracin . Nine strains representing different resistance patterns were selected for plasmid profile and conjugation studies . Agarose gel electrophoresis results revealed that 6 strains harboured a single plasmid, whereas 3 strains exhibited 2 plasmid bands . Among antimicrobials, co-trimazole and bacitracin and among metals, Cu2+, Cd2+, Zn2+ and Ni2+ resistance were transferred most frequently at variable rates . However, chromium resistance was transferred in 6 strains with a frequency ranging 19-49x10(-2) . Resistance to Co2+ and Hg2+ did not transfer under environmental conditions . Among the nine strains, three were found predominantly uropathogenic Escherichia coli (UPEC) serotype 04, whereas two strains were untypable . In addition, 4 transconjugants also showed a positive result after serotyping.

Acta Orthop Belg, 2004 Oct, 70(5), 417 - 22
Limb-sparing surgery for primary malignant tumours of the pelvis; Aydinli U et al.; Treatment of malignant tumours of the pelvis represents one of the most difficult problems in musculoskeletal oncology . The aim of this paper is to present our results in 16 cases of primary malignant pelvic tumours following resection only or following reconstruction with autogenous or allogenous bone grafts without using megaprostheses, and to assess the possibility to restore acceptable function with autogenous or allogenous bone grafts while avoiding the high risks of massive endoprostheses . Wound complication was the most common complication in our series, with 10 patients requiring additional treatment in the form of local surgical debridement, appropriate multi-drug antimicrobial therapy and wound care . Secondary pelvic reconstruction was performed in two patients with chondrosarcoma, due to local recurrence . External hemipelvectomy was not required in any patient . Morbidity also included the sacrifice of nerve roots in 4 patients . The mean follow-up was 42.4 months (range, 24 to 60) . One patient is alive with disease, five patients have died of metastatic disease (2 of them had evidence of local recurrence), and the remaining ten patients are alive with no evidence of disease . Major blood loss and long operation time, aggressive radical surgery due to the frequent delay in diagnosis, and wound complications after surgery are important points that should be considered in the treatment of primary malignant pelvic tumours . Therefore, the management requires meticulous preoperative investigation, a multidisciplinary approach and experienced surgeons.

South Med J, 2004 Nov, 97(11), 1104 - 6
Right arm pyomyositis and necrotizing fasciitis complicated with subcutaneous emphysema and pneumomediastinum in a patient with diabetes mellitus and iatrogenic Cushing syndrome; Lee CH et al.; We report a case of subcutaneous emphysema and pneumomediastinum secondary to pyomyositis and necrotizing fasciitis over the right arm of a woman with underlying diabetes mellitus and iatrogenic Cushing syndrome . Gas produced by the culprit pathogen extensively dissected the subcutaneous fat and fascia of the patient's right arm and distantly spread to her face, neck, back, and thoracic wall and penetrated the soft tissue cephalically bordering her sternum, resulting in pneumomediastinum . The patient improved-with antimicrobial therapy and localized debridement and fasciotomy over her right arm.

Am J Med, 2004 Nov 8, 117 Suppl 9A, 26S - 29S
Immunomodulatory effects of macrolides: implications for practicing clinicians; Siddiqui J; Macrolides are regarded as the drugs of choice for the treatment of diffuse panbronchiolitis (DPB) due to their favorable effects on patient outcomes . These drugs decrease sputum production, thereby improving pulmonary function . Moreover, these effects are independent of dosing with respect to clarithromycin, erythromycin, and roxithromycin . The marked success of macrolides in this disease is a direct effect of impeding the inflammatory cascade . With their abilities to reduce the secretion of proinflammatory cytokines, ameliorate the infiltration of inflammatory cells into the airways, and reduce mucus secretion, macrolides are able to improve pulmonary function and quality of life in patients with chronic inflammatory diseases of the airways . Although prolonged use of macrolides raises concerns of increased adverse effects, data do not support such occurrences . With respect to concerns of resistance, it should be noted that in Japan, where macrolides are part of the treatment for DPB, these agents continue to be used effectively as antimicrobial agents . Therefore, the potential benefits of the immunomodulatory effects of macrolides in other conditions such as cystic fibrosis, chronic sinusitis, asthma, and chronic bronchitis are under investigation.

Onkologie, 2004 Oct, 27(5), 487 - 91
The innate immune response in the central nervous system and its role in glioma immune surveillance; Friese MA et al.; The innate immune system encompasses natural killer (NK) cells, macrophages and granulocytes, the complement system and antimicrobial peptides . Recognition pathways of the innate immune system include microbial non-self recognition, missing-self recognition and induced- self recognition . The central nervous system (CNS) participates in responses of the innate immune system . However, immune inhibitory and anti-inflammatory mechanisms physiologically outbalance and counteract immune activity and thereby limit immune-mediated tissue damage in the brain . Human gliomas appear to take advantage of this immunosuppressive milieu . Moreover, glioma cells themselves interfere with anti-tumor immune responses by expressing immune inhibitory cell surface molecules, such as HLA-G, or by releasing soluble immunosuppressants such as transforming growth factor (TGF)-beta . Yet, although glioma cells exhibit all cellular features of malignancy, these tumors very rarely metastasize outside the brain, raising the possibility of immune-mediated control of these cells outside, but not inside, the brain . Accordingly, activating the innate immune system by forcing glioma cells to express danger signals such as NKG2D ligands is a promising strategy of immunotherapy for these tumors .

Pharmacotherapy, 2004 Dec, 24(12 Pt 2), 232S - 8S
Economics of antibiotic use policies; Paladino JA; Today more than ever, hospitals must effectively manage the use of antibiotics to control costs and preserve their usefulness . To achieve this goal, antibiotic management must evolve from overly simplistic antibiotic cost containment to more complex, multidisciplinary, appropriate use programs that are founded on clinical outcomes-based pharmacoeconomic analyses . This article addresses common cost-containment activities as they relate to antibiotics and examines their consequences . Examples of successful antimicrobial stewardship and the role of pharmacoeconomic analyses also are provided . Cost-effectiveness studies of cefepime are presented to illustrate the utility of these analyses and provide information that can form the basis for decisions regarding placement of cefepime on hospital formularies.

Pharmacotherapy, 2004 Dec, 24(12), 1807 - 12
Fatal hypoglycemia associated with levofloxacin; Friedrich LV et al.; Fluoroquinolones are generally regarded as safe antimicrobial agents with relatively few adverse effects or drug interactions . Thus, they enjoy widespread use for treatment of community- and hospital-acquired infections . Although uncommon, hypoglycemia has been reported with all the fluoroquinolones and appears to occur most frequently in elderly patients with type 2 diabetes mellitus who are receiving therapy with oral hypoglycemics . The exact mechanism of this effect is unknown but is postulated to be a result of blockage of adenosine 5'-triphosphate-sensitive potassium channels in pancreatic beta-cell membranes . We report a case of fatal hypoglycemia related to levofloxacin administration in an elderly patient with diabetes . As with other fluoroquinolones, levofloxacin can cause profound and prolonged hypoglycemia . Clinicians should be cognizant of this potential adverse effect in patients with diabetes who are receiving levofloxacin therapy.

Khirurgiia (Sofiia), 2003, 59(3), 29 - 33
{Clinical and microbiological characteristic of nosocomial infections according to the materials of IIIrd surgery, UMBAL "St . George" - Plovdiv, for a period of 10 years}
{Antimicrobial photodynamic therapy for prevention of alveolar ostitis and post-extraction pain}
Neugebauer J, Jozsa M, Kubler A.

Klinik und Poliklinik fur Zahnarztliche Chirurgie und Mund-, Kiefer- und Plastische Gesichtschirurgie, Universitat zu Koln . Joerg.neugebauer@medizin.uni-koeln.de

AIM: Alveolar ostitis occurs with an incidence of 3-25% after tooth extraction . Antimicrobial photodynamic therapy (aPDT) with HELBO Blue and TheraLite laser enables local decontamination of the extraction socket . The aim of the study was to evaluate the possibility of aPDT with HELBO Blue and diode soft laser to reduce the prevalence of alveolar ostitis . MATERIAL AND METHODS: In an intraindividual study with 100 patients in 130 jaws, one or multiple contralateral teeth were removed at 1-week intervals . Randomly each side was treated with or without aPDT with a standardized protocol . At recall the evaluation of the extraction socket was performed by the investigator and the postoperative pain sensation was judged by the patient on an analog pain scale (0-100) . RESULTS: In the group with aPDT alveolar ostitis occurred at one extraction site and in the control group without aPDT in 13 cases . The subjective pain assessment on the day after tooth removal was scored with 11.2+/-9.8 in the aPDT-group and with 19.0+/-12.2 in the control group . One week after extraction the pain sensation in the aPDT group was scored with 2.4+/-9.2 and in the control group with 13.1+/-25.2 . The difference was significantly lower with p=0.000 for the 1st and 8th post-surgical days in the aPDTgroup . CONCLUSIONS: The significantly lower incidence of alveolar ostitis after antimicrobial photodynamic therapy seems to be a new and promising possibility for the prevention of alveolar ostitis.

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz, 2004 Dec, 47(12), 1129 - 35
{Complications of infectious diseases and benefits of immunization}; Heininger U; Significant progress regarding hygiene, nutrition, and antimicrobial treatment as well as immunizations have lead to a significant decline of morbidity and mortality of infectious diseases in the recent past . Furthermore, immunizations are one of the most cost-effective tools for prevention . However, lack of perception of the substantial risks of complications associated with infectious diseases cause doubts about the necessity of immunizations today . This development is highly worrisome and needs to be adequately addressed by informing physicians and the public about the risks of vaccine-preventable diseases, efficiency, safety and benefits of available vaccines, as well as providing convincing arguments justifying current immunization recommendations . These activities are indispensable for successful implementation and continuation of current immunization programs.

Acta Crystallogr D Biol Crystallogr, 2004 Dec, 60(Pt 12 Pt 2), 2310 - 9 Epub 2004 Dec.
Structure of shikimate kinase from Mycobacterium tuberculosis reveals the binding of shikimic acid; Pereira JH et al.; Tuberculosis made a resurgence in the mid-1980s and now kills approximately 3 million people a year . The re-emergence of tuberculosis as a public health threat, the high susceptibility of HIV-infected persons and the proliferation of multi-drug-resistant strains have created a need to develop new drugs . Shikimate kinase and other enzymes in the shikimate pathway are attractive targets for development of non-toxic antimicrobial agents, herbicides and anti-parasitic drugs, because the pathway is essential in these species whereas it is absent from mammals . The crystal structure of shikimate kinase from Mycobacterium tuberculosis (MtSK) complexed with MgADP and shikimic acid (shikimate) has been determined at 2.3 A resolution, clearly revealing the amino-acid residues involved in shikimate binding . This is the first three-dimensional structure of shikimate kinase complexed with shikimate . In MtSK, the Glu61 residue that is strictly conserved in shikimate kinases forms a hydrogen bond and salt bridge with Arg58 and assists in positioning the guanidinium group of Arg58 for shikimate binding . The carboxyl group of shikimate interacts with Arg58, Gly81 and Arg136 and the hydroxyl groups interact with Asp34 and Gly80 . The crystal structure of MtSK-MgADP-shikimate will provide crucial information for the elucidation of the mechanism of the shikimate kinase-catalyzed reaction and for the development of a new generation of drugs against tuberculosis.

J Clin Microbiol, 2004 Dec, 42(12), 5588 - 95
Phenotypic profiles of enterotoxigenic Escherichia coli associated with early childhood diarrhea in rural Egypt; Shaheen HI et al.; Enterotoxigenic Escherichia coli (ETEC) causes substantial diarrheal morbidity and mortality in young children in countries with limited resources . We determined the phenotypic profiles of 915 ETEC diarrheal isolates derived from Egyptian children under 3 years of age who participated in a 3-year population-based study . For each strain, we ascertained enterotoxin and colonization factor (CF) expression, the O:H serotype, and antimicrobial susceptibility . Sixty-one percent of the strains expressed heat-stable enterotoxin (ST) only, 26% expressed heat-labile enterotoxin (LT) alone, and 12% expressed both toxins . The most common CF phenotypes were colonization factor antigen I (CFA/I) (10%), coli surface antigen 6 (CS6) (9%), CS14 (6%), and CS1 plus CS3 (4%) . Fifty-nine percent of the strains did not express any of the 12 CFs included in our test panel . Resistance of ETEC strains to ampicillin (63%), trimethoprim-sulfamethoxazole (52%), and tetracycline (43%) was common, while resistance to quinolone antibiotics was rarely detected . As for the distribution of observed serotypes, there was an unusually wide diversity of O antigens and H types represented among the 915 ETEC strains . The most commonly recognized composite ETEC phenotypes were ST CS14 O78:H18 (4%), ST (or LTST) CFA/I O128:H12 (3%), ST CS1+CS3 O6:H16 (2%), and ST CFA/I O153:H45 (1.5%) . Temporal plots of diarrheal episodes associated with ETEC strains bearing common composite phenotypes were consistent with discrete community outbreaks either within a single or over successive warm seasons . These data suggest that a proportion of the disease that is endemic to young children in rural Egypt represents the confluence of small epidemics by clonally related ETEC strains that are transiently introduced or that persist in a community reservoir.

J Clin Microbiol, 2004 Dec, 42(12), 5493 - 501
Amoebal coculture of "Mycobacterium massiliense" sp . nov . from the sputum of a patient with hemoptoic pneumonia; Adekambi T et al.; A nonphotochromogenic, rapidly growing Mycobacterium strain was isolated in pure culture from the sputum and the bronchoalveolar fluid of a patient with hemoptoic pneumonia by using axenic media and an amoebal coculture system . Both isolates grew in less than 7 days at 24 to 37 degrees C with an optimal growth temperature of 30 degrees C . The isolates exhibited biochemical and antimicrobial susceptibility profiles overlapping those of Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium immunogenum, indicating that they belonged to M . chelonae-M . abscessus group . They differed from M . abscessus in beta-galactosidase, beta-N-acetyl-beta-glucosaminidase, and beta-glucuronidase activities and by the lack of nitrate reductase and indole production activities, as well as in their in vitro susceptibilities to minocycline and doxycycline . These isolates and M . abscessus differed from M . chelonae and M . immunogenum by exhibiting gelatinase and tryptophane desaminase activities . Their 16S rRNA genes had complete sequence identity with that of M . abscessus and >99.6% similarity with those of M . chelonae and M . immunogenum . Further molecular investigations showed that partial hsp65 and sodA gene sequences differed from that of M . abscessus by five and three positions over 441 bp, respectively . Partial rpoB and recA gene sequence analyses showed 96 and 98% similarities with M . abscessus, respectively . Similarly, 16S-23S rRNA internal transcribed spacer sequence of the isolates differed from that of M . abscessus by a A-->G substitution at position 60 and a C insertion at position 102 . Phenotypic and genotypic features of these two isolates indicated that they were representative of a new mycobacterial species within the M . chelonae-M . abscessus group . Phylogenetic analysis suggested that these isolates were perhaps recently derived from M . abscessus . We propose the name of "Mycobacterium massiliense" for this new species . The type strain has been deposited in the Collection Institut Pasteur as CIP 108297(T) and in Culture Collection of the University of Goteborg, Goteborg, Sweden, as CCUG 48898(T).

J Clin Microbiol, 2004 Dec, 42(12), 5444 - 52
Heterogeneity among virulence and antimicrobial resistance gene profiles of extraintestinal Escherichia coli isolates of animal and human origin; Maynard C et al.; Extraintestinal pathogenic Escherichia coli (ExPEC) isolates collected from different infected animals and from human patients with extraintestinal infections in 2001 were characterized for their phenotypic and genotypic antimicrobial resistance profiles, genotypes, and key virulence factors . Among the 10 antimicrobial agents tested, resistance to ampicillin, tetracycline, and sulfonamides was most frequent . Multiresistant strains were found in both the animal and the human groups of isolates . Resistance gene distribution was assessed by colony hybridization . Similar antibiotic resistance patterns could be observed in the animal and the human isolates . Although some resistance genes, such as bla(TEM), sulI, and sulII, were equally represented in the animal and human ExPEC isolates, differences in the distributions of tetracycline {tet(D)}, chloramphenicol (catI, catIII, and floR), and trimethoprim (dhfrI, dhfrV, dhfrVII, and dhfrXIII) resistance genes were observed between the animal and the human isolates . Approximately one-third of the ExPEC isolates possessed a class 1 integron . The four major different variable regions of the class 1 integron contained aminoglycoside (aadA1, aadA2, aadA5, and aadA6) and/or trimethoprim (dhfrIb, dhfrXII, and dhfrXVII) resistance genes . The ExPEC strains belonged to different phylogenetic groups, depending on their host origin . Strains isolated from animal tissues belonged to either a commensal group (group A or B1) or a virulent group (group B2 or D), while the majority of the human isolates belonged to a virulent group (group B2 or D) . Although the limited number of isolates evaluated in the present study prevents firm epidemiological conclusions from being made, on a more global scale, these data demonstrate that extraintestinal isolates of E . coli can possess relatively distinct intra- and intergroup resistance gene profiles, with animal isolates presenting a more heterogeneous group than human isolates.

Microbiology, 2004 Dec, 150(Pt 12), 4023 - 31
New endophytic isolates of Muscodor albus, a volatile-antibiotic-producing fungus; Ezra D et al.; Muscodor albus, an endophytic fungus originally isolated from Cinnamomum zeylanicum, produces a mixture of volatile organic compounds (VOCs) in culture and its spectrum of antimicrobial activity is broad . Using the original isolate of M . albus as a selection tool, it has been possible to find other culturally and biochemically unique wild-type isolates of this organism existing as endophytes in a variety of other plant species, including Grevillea pterifolia (fern-leafed grevillea), Kennedia nigriscans (snake vine) and Terminalia prostrata (nanka bakarra) growing in the northern reaches of the Northern Territory of Australia . Interestingly, none of the new isolates had a culture morphology that was identical to the original isolate, nevertheless each possessed hyphal characteristics that resembled that isolate . Furthermore, their ITS-5.8S rDNA sequences were 96-99 % identical to that of M . albus and the isolates were considered M . albus on the basis of the DNA sequence data . However, the VOCs produced by these new isolates greatly differed in quality from the original strain by virtue of the production of naphthalene, naphthalene, 1,1'-oxybis-, and one or more other compounds . In bioassays with a range of test micro-organisms, including fungi and bacteria, each isolate possessed biological activity but the range of activity was great . Artificial mixtures of some of the VOCs mimicked the effects of the VOCs of the fungus . The value of these observations to the biology and practical uses of M . albus in agriculture and other applications is discussed.

J Leukoc Biol . 2004 Dec 6; {Epub ahead of print}
Neutrophils and keratinocytes in innate immunity--cooperative actions to provide antimicrobial defense at the right time and place; Borregaard N et al.; The human neutrophil is a professional phagocyte of fundamental importance for defense against microorganisms, as witnessed by the life-threatening infections occurring in patients with neutropenia or with defects that result in decreased microbicidal activity of the neutrophil {1, 2} . Likewise, the skin and mucosal surfaces provide important barriers against infections . Traditionally, these major defense systems, the epithelial cells and the neutrophils, have been viewed as limited in their armory: The epithelial cells provide defense by constituting a physical barrier, and the neutrophils provide instant delivery of preformed antimicrobial substances or on-the-spot assembly of the multicomponent reduced nicotinamide adenine dinucleotide phosphate oxidase from stored components for the generation of reactive oxygen metabolites . Recent research has shown that epithelial cells are highly dynamic and able to generate antimicrobial peptides in response not only to microbial infection itself {3-6} but more importantly, to the growth factors that are called into play when the physical barrier is broken, and the risk of microbial infection is imminent {7} . Likewise, the neutrophil changes its profile of actively transcribed genes when it diapedeses into wounded skin {8} . This results in generation of signaling molecules, some of which support the growth and antimicrobial potential of keratinocytes and epithelial cells . This paper will highlight some recent advances in this field.

Br J Pharmacol . 2004 Dec 6; {Epub ahead of print}
Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug; Jia L et al.; SQ109 is a novel {1,2}-diamine-based ethambutol (EMB) analog developed from high-throughput combinatorial screening . The present study aimed at characterizing its pharmacodynamics and pharmacokinetics . The antimicrobial activity of SQ109 was confirmed in vitro (Mycobacterium tuberculosis-infected murine macrophages) and in vivo (M . tuberculosis-infected C57BL/6 mice) and compared to isoniazid (INH) and EMB . SQ109 showed potency and efficacy in inhibiting intracellular M . tuberculosis that was similar to INH, but superior to EMB . In vivo oral administration of SQ109 (0.1-25 mg kg(-1) day(-1)) to the mice for 28 days resulted in dose-dependent reductions of mycobacterial load in both spleen and lung comparable to that of EMB administered at 100 mg kg(-1) day(-1), but was less potent than INH at 25 mg kg(-1) day(-1) . Monitoring of SQ109 levels in mouse tissues on days 1, 14 and 28 following 28-day oral administration (10 mg kg(-1) day(-1)) revealed that lungs and spleen contained the highest concentration of SQ109, at least 10 times above its MIC . Pharmacokinetic profiles of SQ109 in mice following a single administration showed its Cmax as 1038 (intravenous (i.v.)) and 135 ng ml(-1) (p.o.), with an oral Tmax of 0.31 h . The elimination t1/2 of SQ109 was 3.5 (i.v.) and 5.2 h (p.o.) . The oral bioavailability was 4% . However, SQ109 displayed a large volume of distribution into various tissues . The highest concentration of SQ109 was present in lung (>MIC), which was at least 120-fold (p.o.) and 180-fold (i.v.) higher than that in plasma . The next ranked tissues were spleen and kidney . SQ109 levels in most tissues after a single administration were significantly higher than that in blood . High tissue concentrations of SQ109 persisted for the observation period (10 h) . This study demonstrated that SQ109 displays promising in vitro and in vivo antitubercular activity with favorable targeted tissue distribution properties.

Diagn Microbiol Infect Dis, 2004 Dec, 50(4), 283 - 5
Epidural abscess and osteomyelitis due to Actinobacillus actinomycetemcomitans; Patel SM et al.; Actinobacillus actinomycetemcomitans is a microaerophilic, fastidious Gram-negative rod that most commonly causes periodontitis and odontogenic infections . We report the first case of an epidural abscess and osteomyelitis due to this organism resulting from self-extraction of carious teeth . The patient responded to surgical debridement and prolonged antimicrobial therapy with intravenous ceftriaxone.

J Mol Biol, 2005 Jan 21, 345(3), 521 - 33
Crystal structures of complexes between the R61 DD-peptidase and peptidoglycan-mimetic beta-lactams: a non-covalent complex with a "perfect penicillin"; Silvaggi NR et al.; The bacterial D-alanyl-D-alanine transpeptidases (DD-peptidases) are the killing targets of beta-lactams, the most important clinical defense against bacterial infections . However, due to the constant development of antibiotic-resistance mechanisms by bacteria, there is an ever-present need for new, more effective antimicrobial drugs . While enormous numbers of beta-lactam compounds have been tested for antibiotic activity in over 50 years of research, the success of a beta-lactam structure in terms of antibiotic activity remains unpredictable . Tipper and Strominger suggested long ago that beta-lactams inhibit DD-peptidases because they mimic the D-alanyl-D-alanine motif of the peptidoglycan substrate of these enzymes . They also predicted that beta-lactams having a peptidoglycan-mimetic side-chain might be better antibiotics than their non-specific counterparts, but decades of research have not provided any evidence for this . We have recently described two such novel beta-lactams . The first is a penicillin having the glycyl-L-alpha-amino-epsilon-pimelyl side-chain of Streptomyces strain R61 peptidoglycan, making it the "perfect penicillin" for this organism . The other is a cephalosporin with the same side-chain . Here, we describe the X-ray crystal structures of the perfect penicillin in non-covalent and covalent complexes with the Streptomyces R61 DD-peptidase . The structure of the non-covalent enzyme-inhibitor complex is the first such complex to be trapped crystallographically with a DD-peptidase . In addition, the covalent complex of the peptidyl-cephalosporin with the R61 DD-peptidase is described . Finally, two covalent complexes with the traditional beta-lactams benzylpenicillin and cephalosporin C were determined for comparison with the peptidyl beta-lactams . These structures, together with relevant kinetics data, support Tipper and Strominger's assertion that peptidoglycan-mimetic side-chains should improve beta-lactams as inhibitors of DD-peptidases.

Biochemistry, 2004 Dec 14, 43(49), 15610 - 6
Membrane translocation mechanism of the antimicrobial peptide buforin 2; Kobayashi S et al.; The antimicrobial peptide magainin 2 isolated from the skin of the African clawed frog Xenopus laevis crosses lipid bilayers by transiently forming a peptide-lipid supramolecular complex pore inducing membrane permeabilization and flip-flop of membrane lipids {Matsuzaki, K., Murase, O., Fujii, N., and Miyajima, K . (1996) Biochemistry 35, 11361-11368} . In contrast, the antimicrobial peptide buforin 2 discovered in the stomach tissue of the Asian toad Bufo bufo gargarizans efficiently crosses lipid bilayers without inducing severe membrane permeabilization or lipid flip-flop, and the Pro(11) residue plays a key role in this unique property {Kobayashi, S, Takeshima, K., Park, C . B., Kim, S . C., and Matsuzaki, K . (2000) Biochemistry 39, 8648-8654} . To elucidate the translocation mechanism, the secondary structure and the orientation of the peptide in lipid bilayers as well as the effects of the peptide concentration, the lipid composition, and the cis-trans isomerization of the Pro peptide bond on translocation efficiency were investigated . The translocation efficiencies of F10W-buforin 2 (BF2), P11A-BF2, and F5W-magainin 2 (MG2) across egg yolk L-alpha-phosphatidyl-DL-glycerol (EYPG)/egg yolk L-alpha-phosphatidylcholine (1/1) bilayers were dependent supralinearly on the peptide concentration, suggesting that the translocation mechanisms of these peptides are similar . The incorporation of the negative curvature-inducing lipid egg yolk L-alpha -phosphatidylethanolamine completely suppressed the translocation of BF2, indicating the induction of the positive curvature by BF2 on the membrane is related to the translocation process, similarly to MG2 . In pure EYPG, where the repulsion between polycationic BF2 molecules is reduced, membrane permeabilization and coupling lipid flip-flop were clearly observed . Structural studies by use of Fourier transform infrared-polarized attenuated total reflection spectroscopy indicated that BF2 assumed distorted helical structures in EYPG/EYPC bilayers . A BF2 analogue with an alpha-methylproline, which fixed the peptide bond to the trans configuration, translocated similarly to the parent peptide, suggesting the cis-trans isomerization of the Pro peptide bond is not involved in the translocation process . These results indicate that BF2 crosses lipid bilayers via a mechanism similar to that of MG2 . The presence of Pro(11) distorts the helix, concentrating basic amino acid residues in a limited amphipathic region, thus destabilizing the pore by enhanced electrostatic repulsion, enabling efficient translocation.

Am J Health Syst Pharm, 2004 Nov 15, 61(22), 2430 - 5
ASHP therapeutic position statement on strategies for identifying and preventing pneumococcal resistance; Billeter M; The incidence of drug-resistant S . pneumoniae continues to increase, causing significant morbidity and mortality . Health care providers should seize the opportunity to promote the judicious use of antimicrobials and aggressive vaccination with the pneumococcal vaccines as a means to lessen this significant health problem.

Internist (Berl) . 2004 Dec 4; {Epub ahead of print}
{Infectiological emergencies in oncology.}; Schiel X et al.; Infections in immunosuppressed patients have always to be regarded as emergencies, as they have a high rate of complications and mortality . The most important risk factor is severity and duration of granulocytopenia . Risk scores help to identify patients who, despite their immune deficiency have a low risk of complications . Diagnostic measures to identify the causative microorganism and the source of infection is necessary . However, diagnostic investigation must not delay the immediate onset of antimicrobial treatment . Patients often have to be treated empirically as the identification of the causative microorganism or the source of infection are often unknown at the beginning of clinical symptoms . Empirical treatment has to be broad to cover possible microorganisms . Especially meningitis, abdominal infections, sepsis and pneumonia can be regarded as infectiological emergencies . Patients with these infections have to be treated with intensive antimicrobial treatemt, taking into account the possible causative agents.

Med Oral Patol Oral Cir Bucal, 2004, 9 Suppl, 25 - 31; 19-24
Treatment options in odontogenic infection; Maestre-Vera JR; Most infections of the oral cavity are primary, odontogenic infections, with dental caries, gingivitis, and periodontitis the most common . Treating these infections will encompass odontologic, antimicrobial, surgical or combined treatment . Antimicrobial treatment includes the use of betalactams, macrolydes, tetracyclins, metronidazole, clindamycin, or combined treatment . The most commonly used ones are administered orally . PK/ PD parameters predict THE clinical and microbiological efficacy of the antibiotic . The three indices that are generally used to measure clinical efficacy are: T >MIC (time during which the concentration is above the minimum inhibitory concentration), Cmax/ MIC (ratio between peak concentration and the minimum inhibitory concentration) and AUC/ MIC (ratio between the area under the curve and the minimum inhibitory concentration) . Amoxicillin/ clavulanic acid is one of the antibiotics recommended for the treatment of odontogenic infections due to its wide spectrum, low incidence of resistance, pharmacokinetic profile, tolerance and dosage.

Med Oral Patol Oral Cir Bucal, 2004, 9 Suppl, 6 - 10; 1-5
Oral flora in the age of molecular biology; Perea EJ; The present work describes the fundamental aspects of the molecular methods that are applied to oral microbiology: probes, PCR, multiple real time PCR, 16S rDNA, and proteomics . Likewise, it presents the results obtained by applying these methods to the study of the bacterial flora encountered inside the mouth . By identifying 16S rDNA, up to 132 known species and 215 new, unknown phylotypes have been detected inside patients s periodontal pockets . We are currently using a commercial system based on multiple PCR (genomic amplification), followed by reverse hybridization to detect the five species known to cause periodontal disease . We also summarize the findings derived from the application of proteomic techniques to the study of odontologic infections pathogenesis and from the use of molecular methods in the study of resistance to antimicrobial agents . Finally, it puts forth the problems that remain unsolved with respect to oral flora and the treatment of odontogenic infections . Traditional culture methods continue to be indispensable, as they make it possible to later work with the cultured microorganisms.

Med Oral Patol Oral Cir Bucal, 2004 Nov-Dec, 9(5), 369 - 76; 363-9
Consensus statement on antimicrobial treatment of odontogenic bacterial infections; Bascones Martinez A et al.; The infection of the oral cavity is a common public health problem and constant cause for antibiotic prescription, with 10% of antibiotics used to treat this problem . However, few studies have so far aimed to determine its incidence . Added to this, its relationship with certain sytemic diseases (cardiac, endocrine, etc) confers this pathology vital importance . In spite of the frequency and importance of odontogenic infection, the current dispersion in criteria regarding key aspects in classification, terminology and therapeutic recommendations is noticeable . The main objective of this document, compiled as a consensus statement by specialists in microbiology and odontology, is to establish useful recommendations for all of those involved in the clinical management of this pathology . Special attention has been placed on the rise in bacterial resistance observed over the last years, specifically the proliferation of betalactamase producing strains . Another important factor causing the resistance to appear is lack of therapeutic compliance, specially what regards dosage and treatment duration . Therefore, this pathology constitutes a complex problem which requires the instauration of broad spectrum antimicrobials, well tolerated and a convenient posology so that patients receive the adequate dose over the necessary period . High doses of amoxicillin/clavulanate (2000 mg/125 mg) have showed good results and power to overcome resistance . Other agents such as metronidazole and clindamycin, followed by de claritromycin and azithromycin have also proved to be active against most of microorganisms responsible for odontogenic infection.

Stem Cells, 2004, 22(7), 1263 - 78
Comparison of gene expression of umbilical cord vein and bone marrow-derived mesenchymal stem cells; Panepucci RA et al.; Mesenchymal stem cells (MSCs) give origin to the marrow stromal environment that supports hematopoiesis . These cells present a wide range of differentiation potentials and a complex relationship with hematopoietic stem cells (HSCs) and endothelial cells . In addition to bone marrow (BM), MSCs can be obtained from other sites in the adult or the fetus . We isolate MSCs from the umbilical cord (UC) veins that are morphologically and immunophenotpically similar to MSCs obtained from the BM . In culture, these cells are capable of differentiating in vitro into adipocytes, osteoblasts, and condrocytes . The gene expression profiles of BM-MSCs and of UC-MSCs were compared by serial analysis of gene expression, then validated by reverse transcription polymerase chain reaction of selected genes . The two lineages shared almost all of the first thousand most expressed transcripts, including vimentin, galectin 1, osteonectin, collagens, transgelins, annexin A2, and MMP2 . Nevertheless, a set of genes related to antimicrobial activity and to osteogenesis was more expressed in BM-MSCs, whereas higher expression in UC-MSCs was observed for genes that participate in pathways related to matrix remodeling via metalloproteinases and angiogenesis . Finally, cultured endothelial cells, CD34+ HSCs, MSCs, blood leukocytes, and bulk BM clustered together, separated from seven other normal nonhematopoietic tissues, on the basis of shared expressed genes . MSCs isolated from UC veins are functionally similar to BM-MSCs, but differentially expressed genes may reflect differences related to their sites of origin: BM-MSCs would be more committed to osteogenesis, whereas UC-MSCs would be more committed to angiogenesis.

Prev Vet Med, 2004 Dec 15, 66(1-4), 163 - 74
The effect of antimicrobial growth promoter withdrawal on the health of weaned pigs in Finland; Laine T et al.; The use of the antimicrobial growth promoters (AGPs) carbadox and olaquindox has been banned in the European Union (EU) since September 1999 . We studied the effects of the withdrawal on the health of weaned piglets on two types of piglet-producing farms (farrowing herds and farrow-to-finish herds) from the different regions of Finland . Farms with no major problems with post-weaning diarrhoea were selected for the study to better evaluate the effect of AGPs alone . Data on production, medication and incidence of diarrhoea were collected from 73 farms during 1 year after the withdrawal . On 29 of these farms, the data collection began 4 months before the withdrawal . The health management of the pigs is considered good in Finland, and special attention has been paid to improve the husbandry practices and management of the farms . Eighty-two percent of the farms in the study were free of both Mycoplasma hyopneumoniae and Sarcoptes scabiei infection . Brachyspira hyodysenteriae infection was not detected in any of the farms . The median number of sows in the herds was 56.0 (IQR=43.0; 72.5) in 2000 . The level of antimicrobial use in each herd was classified as low, moderate and high when the percentage of weaned pigs treated for diarrhoea during a 4-month period was 0-5%, 6-19% and > or =20%, respectively . Only on four herds (14%), there was an increase in the level of antibiotic use after the AGP withdrawal, when seasonally corresponding 4-month periods were compared . Fourty-one percent of these 29 farms were categorized as low users of antimicrobials, 38% as moderate users and 21% as high users . The level of antimicrobial use for treatment of diarrhoea after weaning (and the incidence of diarrhoea in weaned piglets) did not increase significantly after the withdrawal of AGPs from weaner feeds according to farmers' evaluations . In this study, the Escherichia coli infection was the most-common cause of diarrhoea in weaned pigs . The age at weaning did not change after the withdrawal of AGPs.

Steroids, 2004 Oct, 69(11-12), 743 - 756
Secosteroids of marine origin; Sica D et al.; This review describes the isolation from marine organisms of all secosteroids reported in the literature from 1972 to 2004 . Secosteroids are highly oxidized metabolites with bond cleavage in the rings of the steroid tetracyclic nucleus . All secosteroids are grouped in accordance with their ring joined to side chain as 5,6-, 9,11-, 9,10- 8,9-, 8,14- and 13,17-secosteroids and the structures and the synthetic works, where available, are reported . Furthermore, this review gives details on the biological activities of the isolated secosteroids (e.g . antiproliferative, antifouling, antiinflammatory, antimicrobial, ichthyotoxic and antiviral).

Cell Mol Biol (Noisy-le-grand) . 2004 Dec 31;Suppl.50:OL649-OL655 {Epub ahead of print}
FUNCTIONAL AGE-DEPENDENT CHANGES IN BRONCHOALVEOLAR LAVAGE RAT CELLS; Goldman A et al.; Alveolar macrophages (AM) are located at the first line of non-specific defense against inhaled antigens in the lower respiratory tract and therefore represent the major effector cell in antimicrobial defense . Since children under 2 years are known to manifest increased susceptibility to lung infections we used a rat model to study functional capacities of the AM during different stages of development . We analyzed several steps of the phagocytic process (adherence, chemotaxis and ingestion) as well as two different mechanisms of cytotoxicity {antibody dependent cellular cytotoxicity (ADCC) and cytotoxicity triggered by immune complex (ICC)} and tumor necrosis factor (TNF-alpha) secretion . We used young (4-6 weeks old), intermediate (16-25 weeks old) and adult (36-45 weeks old) rats . Adherence and phagocytic capacities of AM were lower in young rats compared to intermediate and adult animals . Chemotaxis towards the C5a complement component was low in the first two months of life, then it increased in the intermediate group and fell again in adults . Bronchoalveolar lavage (BAL) cells from young rats did not produce detectable TNF-alpha levels even when stimulated with phorbol 12-myristate 13-acetate (PMA) . When we studied two different cytotoxic mechanisms we found that ICC markedly declines from youth to adulthood while ADCC showed a steady increase from youth to adulthood . In conclusion, our data show differences that may help to explain in part the enhanced susceptibility to pulmonary infections found in young children.

Arch Pathol Lab Med, 2004 Dec, 128(12), 1351 - 9
Combinatorial genetic technology for the development of new anti-infectives; Laios E et al.; CONTEXT: We previously developed a novel technology known as instant evolution for high-throughput analysis of mutations in Escherichia coli ribosomal RNA . OBJECTIVE: To develop a genetic platform for the isolation of new classes of anti-infectives that are not susceptible to drug resistance based on the instant evolution system . DESIGN: Mutation libraries were constructed in the 16S rRNA gene of E coli and analyzed . In addition, the rRNA genes from a number of pathogenic bacteria were cloned and expressed in E coli . The 16S rRNA genes were incorporated into the instant-evolution system in E coli . SETTING: The Department of Biological Sciences, Wayne State University, Detroit, Mich . MAIN OUTCOME MEASURES: Ribosome function was assayed by measuring the amount of green fluorescent protein produced by ribosomes containing mutant or foreign RNA in vivo . RESULTS: We have developed a new combinatorial genetic technology (CGT) platform that allows high-throughput in vivo isolation and analysis of rRNA mutations that might lead to drug resistance . This information is being used to develop anti-infectives that recognize the wild type and all viable mutants of the drug target . CGT also provides a novel mechanism for identifying new drug targets . CONCLUSIONS: Antimicrobials produced using CGT will provide new therapies for the treatment of infections caused by human pathogens that are resistant to current antibiotics . The new therapeutics will be less susceptible to de novo resistance because CGT identifies all mutations of the target that might lead to resistance during the earliest stages of the drug discovery process.

J Mass Spectrom, 2004 Dec, 39(12), 1541 - 53
Fragmentation studies on the antibiotic avilamycin A using ion trap mass spectrometry; Eichhorn P et al.; A comprehensive study on the fragmentation pattern of the antimicrobial growth promoter avilamycin A was conducted in a quadrupole ion trap mass spectrometer equipped with an electrospray ionization (ESI) source . Performing multiple-stage experiments on the deprotonated molecule (m/z 1401) and its principal product ions showed that a sequential shortening of the oligosaccharide backbone took place, which can be attributed to the localization of the negative charge in the terminal dichloroisoeverninic acid . Under (+)-ESI conditions, avilamycin A readily formed an intense sodium-cationized molecule, {M + Na}(+) (m/z 1425) . Structural elucidation of the second-, third- and fourth-generation fragment ions revealed that all of the structures shared a common molecular portion comprising a central monosaccharide . This observation allowed us to assign confidently the complexation site of the alkali metal cation . In addition to the monosodiated molecule, the full-scan mass spectral acquisition also yielded a less abundant disodiated molecule, {M - H + 2Na}(+) (m/z 1447) . Multiple-stage experiments on this ion indicated that the second sodium ion compensates for the negative charge located at either of two positions within the molecule . While deprotonation of the phenolic hydroxyl group in the dichloroisoeverninic acid moiety was suggested to be driven by charge stabilization in the aromatic ring (in analogy with the deprotonated molecule in the (-)-ESI mode), the deprotonation at an alpha-carbon of an ester side-chain substituent in the oligosaccharide part was believed to provide a stable chelation-like coordination site for the cation.

Clin Infect Dis, 2004 Dec 15, 39(12), 1829 - 33 Epub 2004 Dec 15.
Are antimicrobial-impregnated catheters effective? Replace the water and grab your washcloth, because we have a baby to wash; McConnell SA et al.; Significant controversy surrounds the usefulness of central venous catheters (CVCs) impregnated with antimicrobial agents (A-CVCs) for the prevention of catheter-related bloodstream infections (CRBSIs) . In a recent issue of Clinical Infectious Diseases, we reviewed 11 published trials of A-CVCs versus uncoated CVCs, and we concluded that there is a lack of solid evidence to support a benefit of A-CVCs in reducing the rate of CRBSIs . A response to our review was recently published in Clinical Infectious Diseases . In this response, our colleagues assert that there is a large body of evidence that demonstrates a powerful decrease in the risk of infection, and they conclude that we should not waste precious resources while we perform additional research to confirm what we have already found to be true . Although these authors agree with us on the significant shortcomings of the studies used to support the use of A-CVCs, they dismiss the need for additional trials to demonstrate that the use of A-CVCs does reduce infections . This dismissal, however, cannot be justified, because of the existence of an ongoing, federally supported, multicenter, prospective, placebo-controlled trial, led by our colleagues, that compares the rate of CRBSIs among patients randomized to receive either an A-CVC or a "placebo" uncoated CVC . That our colleagues are leading a trial that assesses the efficacy of A-CVCs versus placebo uncoated CVCs supports our viewpoint that the truth regarding the protective role of A-CVCs has yet to be determined . Because of the significant cost, potential toxicity, and risk of increased antimicrobial resistance associated with the use of A-CVCs, and until the results of the important trial conducted by our colleagues convincingly demonstrate that A-CVCs reduce the rate of clinically significant events (not just catheter colonization), we recommend that the use of A-CVCs be limited to investigational settings.

Clin Infect Dis, 2004 Dec 1, 39(11), 1660 - 6 Epub 2004 Dec 1.
Superinfection following smallpox vaccination (Vaccinia), United States: surveillance January 2003 through January 2004; Vellozzi C et al.; BACKGROUND: Superinfection is an adverse event following smallpox vaccination . The clinical presentation is similar to that of a large normal vaccine reaction or "robust take," and the frequency is unknown . METHODS: We retrospectively reviewed all reported severe local reactions consistent with superinfection among United States civilian smallpox vaccinees from January 2003 through January 2004 . We applied a standard case definition and estimated the frequency of superinfection following smallpox vaccination . RESULTS: We identified 48 reported cases for further review among 36,043 smallpox vaccinees . Two (4%) of the 48 reported cases met the case definition for superinfection; neither of the patients had a pathogenic organism isolated from their infection site . Both were treated with antibiotics and resolved their infection . Of the 46 cases determined not to be superinfection, 41 (89%) were temporally consistent with a large normal vaccine reaction . Thirty (75%) of 40 reported case patients for whom data were available received antibiotic therapy . CONCLUSIONS: Superinfection following smallpox vaccination is rare . Most of the reported superinfection cases were probably large normal smallpox vaccine reactions . Educating providers about the normal response to smallpox vaccine may decrease the overdiagnosis of superinfection and the unnecessary use of antimicrobials.

Intensive Care Med, 2005 Jan, 31(1), 64 - 70 Epub 2004 Dec 2.
Risk factors for late-onset ventilator-associated pneumonia in trauma patients receiving selective digestive decontamination; Leone M et al.; OBJECTIVE: To determine the independent risk factors for late-onset ventilator-associated pneumonia (VAP) in trauma patients receiving selective digestive decontamination (SDD).DESIGN: A 4-year, prospective cohort study of trauma patients meeting the following criteria: injury severity score >15, and duration of mechanical ventilation >5 days . Predictors of late-onset VAP occurrence were assessed by logistic regression analysis.POPULATION: All patients received SDD consisting of polymixin E, gentamicin, and amphotericin B applied in nostrils, mouth, and gut with a 3-day course of parenteral cefazolin . VAP was suspected on clinical and radiological signs, and confirmed by the presence of at least one microorganism at a concentration of at least 10(4) CFU/ml on the broncho-alveolar lavage.MEASUREMENT: Independent risk factors for late-onset VAP.RESULTS: A late-onset VAP was diagnosed in 90 (56%) out of 159 patients . Predicting factors for late-onset VAP were: use of non-depolarizing muscle relaxant agents for intubation {3.4 (CI 1.08-10.73)}, duration of intubation {1.06 (CI 1.01-1.17)}, length of intensive care unit (ICU) stay {1.05 (CI 1.02-1.09)}, and prior tracheal colonization {1.03 (CI 1.02-1.21)} . Exposure to prior antimicrobial treatment, except SDD, conferred protection {0.3 (0.12-0.74)}.CONCLUSION: This study confirms the role of duration of intubation, length of ICU stay, and prior tracheal colonization in the development of late-onset VAP . The results also highlight the importance of the initial management on the development of late-onset VAP . The type of neuromuscular blocking agents to intubate trauma patients should be evaluated in future studies.

Nat Med, 2004 Dec, 10(12 Suppl), S122 - 9
Antibacterial resistance worldwide: causes, challenges and responses; Levy SB et al.; The optimism of the early period of antimicrobial discovery has been tempered by the emergence of bacterial strains with resistance to these therapeutics . Today, clinically important bacteria are characterized not only by single drug resistance but also by multiple antibiotic resistance-the legacy of past decades of antimicrobial use and misuse . Drug resistance presents an ever-increasing global public health threat that involves all major microbial pathogens and antimicrobial drugs.

Arch Immunol Ther Exp (Warsz), 2004 Nov-Dec, 52(6), 441 - 6
The search for a genetic defect in Polish patients with chronic granulomatous disease; Jurkowska M et al.; Introduction: Chronic granulomatous disease (CGD)is a rare inherited disorder in which phagocytic cells are unable to generate superoxide anions.Patients with CGD are predisposed to recurrent bacterial and fungal infections because the superoxide-generating NADPH oxidase activity is needed for efficient killing of microbes.Among the at least 5 subunits cre-ating a functional NADPH oxidase, a molecular defect located in any of the gp91 phox, p22 phox, p47 phox , or p67 phox subunits may cause CGD . Material/Methods: In this study,8 patients were diagnosed with CGD on the basis of clinical findings and absence of nitroblue tetrazolium reduction in phagocytes . Southern blot analysis, GeneScan, and direct sequencing were performed to define particular DNA mutations . Results: Among 6 X-linked CGD (X-CGD)patients,4 different mutations were identified in the X-linked CYBB gene (encoding gp91 phox)by direct sequencing . A novel missense mutation, located in the NADPH-binding region of gp91 phox ,was found in 2 brothers . One frameshift 1578delA, one splicing 252G->A mutation, and one partial gene deletion were also identified . The molecular defect in the NCF1 gene (encoding p47 phox )was established in 2 patients . One was DeltaGT/DeltaGT homozygote, the other carried, besides this GT deletion on one allele, a unique Phe118stop mutation on the other . Conclusions: In general, the X-CGD patients within the group followed a more severe clinical course than the patients with an NCF1 defect . However, the lack of a straightforward genotype phenotype correlation indicates that the clinical severity of CGD depends also on other antimicrobial host-defense systems.

Biomaterials, 2005 May, 26(14), 2081 - 8
Silver ion release from antimicrobial polyamide/silver composites; Kumar R et al.; Silver ion (Ag(+)) the versatile antimicrobial species was released in a steady and prolonged manner from a silver-filled polyamide composite system . Metallic silver powder having varying specific surface area (SSA) has been used as a resource of biocide in polyamide . Strong evidences are found showing the release of the antimicrobial species from the resulting composite upon soaking it in water due to the interaction of the diffused water molecules with the dispersed silver powder within the matrix . The Ag(+) release was observed as increasing with time and concentration of the silver powder and is found to be influenced by the SSA of the silver powder, changes in the physical state of the composite specimen as a result of the water diffusion and the composite morphology . It is observed that the Ag(+) release increases initially which is followed by a marginal increase between day 4 and 6 . Composites containing higher amounts of silver (4 and 8wt%) exhibit a further rise in Ag(+) release from the sixth day of storage in water . Composite containing silver particles with the lowest specific surface area (0.78m(2)/g) showed highest Ag(+) release . SEM shows a finer dispersion of the silver powder (4wt%) having lowest SSA . However particles with higher (1.16 and 2.5m(2)/g) SSA possess an agglomerated morphology leading to lower Ag(+) release . The composites are found to release Ag(+) at a concentration level capable of rendering an antimicrobial efficacy.

Biomaterials, 2005 May, 26(14), 2013 - 20
The resistance of polyvinylpyrrolidone-Iodine-poly(-caprolactone) blends to adherence of Escherichia coli; Jones DS et al.; In this study, the resistance of biodegradable biomaterials, composed of blends of poly(-caprolactone) (PCL) and the polymeric antimicrobial complex, polyvinylpyrrolidone-iodine (PVP-I) to the adherence of a clinical isolate of Escherichia coli is described . Blends of PCL composed of a range of high (50,000gmol(-1)) to low (5000gmol(-1)) molecular weight ratios of polymer and either devoid of or containing PVP-I (1% w/w) were prepared by solvent evaporation . Following incubation (4h), there was no relationship between m . wt . ratio of PCL in films devoid of PVP-I and adherence of E . coli . Conversely, microbial adherence to PCL containing PVP-I decreased as the ratio of high:low m . wt . polymer was decreased and was approximately 1000 fold lower than that to comparator films devoid of PVP-I . Following periods of immersion of PVP-I containing PCL films under sink conditions in phosphate buffered saline, subsequent adherence of E . coli was substantially reduced for 2 days (40:60m . wt . ratio) and 6 days (100:0m . wt . ratio) . Concurrent exposure of PCL and E . coli to sub-minimum inhibitory concentrations (sub-MIC) of PVP-I significantly reduced microbial adherence to the biomaterial; however, the molecular weight ratio of PCL did not affect this outcome . Pretreatment of PCL with similar sub-MIC of PVP-I prior to inclusion within the microbial adherence assay significantly decreased the subsequent adherence of E . coli . Greatest reduction in adherence was observed following treatment of PCL (40:60m . wt . ratio) with 0.0156% w/w PVP-I . In conclusion, this study has illustrated the utility of PVP-I as a suitable therapeutic agent for incorporation within PCL as a novel biomaterial . Due to the combined antimicrobial and biodegradable properties, these biomaterials offer a promising strategy for the reduction in medical device related infection.

Acta Pol Pharm, 2004 Jul-Aug, 61(4), 259 - 62
Anti-tuberculosis activity of some N-pentopyranosylamines; Moczulska A; With the advent of multidrug-resistant Mycobacterium tuberculosis, new effective drugs are rapidly needed . Thirty-two derivatives of some N-pentopyranosylamines were prepared and tested under the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) program . This communication is presenting their antituberculosis activity in the primary screen.

Ter Arkh, 2004, 76(10), 91 - 4
{Significance of antibacterial therapy of Chlamydophila pneumoniae infection in patients with bronchial asthma}; The state of the science of health care epidemiology et al.; Being aware and implementing the latest and best scientific evidence in infection control and health care epidemiology is critical to enhancing patient outcomes . In this review, the latest published scientific data in health care epidemiology and patient safety were reviewed for the period May 2003-May 2004 . Medline reviews and reviews of infection control and infectious diseases journals were used for this period . The latest guidelines and publications on antimicrobial resistance, nursing or infection control professional staffing, West Nile virus, and Severe Acute Respiratory Syndrome (SARS) are included . Awareness of these and other important infection control publications is essential if the latest measures are to be implemented to prevent and control health care-associated infections.

J Biol Chem . 2004 Nov 30; {Epub ahead of print}
Correlation of three-dimensional structures with the antibacterial activity of a group of peptides designed based on a non-toxic bacterial membrane anchor; Wang G et al.; To understand the functional differences between a non-toxic membrane anchor corresponding to the N-terminal sequence of the Escherichia coli enzyme IIAGlc and a toxic antimicrobial peptide aurein 1.2 of similar sequence, a series of peptides was designed to bridge the gap between them . An alteration of a single residue of the membrane anchor converted it into an antibacterial peptide . Circular dichroism spectra indicate that all peptides are disordered in water but helical in micelles . Structures of the peptides were determined in membrane-mimetic micelles by solution NMR spectroscopy . The quality of the distance-based structures was improved by including backbone angle restraints derived from a set of chemical shifts (1Ha, 15N, 13Ca, and 13Cb) from natural abundance two-dimensional heteronuclear correlated spectroscopy . Different from the membrane anchor, antibacterial peptides possess a broader and longer hydrophobic surface, allowing a deeper penetration into the membrane, as supported by intermolecular nuclear Overhauser effect (NOE) cross peaks between the peptide and short-chain dioctanoyl phosphatidylglycerol . An attempt was made to correlate the NMR structures of these peptides with their antibacterial activity . The activity of this group of peptides does not correlate exactly with helicity, amphipathicity, charge, the number of charges, the size of the hydrophobic surface, nor hydrophobic transfer free energy . However, a correlation is established between the peptide activity and membrane-perturbation potential, which is defined by interfacial hydrophobic patches and basic residues in the case of cationic peptides . Indeed, 31P solid-state NMR spectroscopy of lipid bilayers showed that the extent of lipid vesicle disruption by these peptides is proportional to their membrane perturbation potential.

J Am Geriatr Soc, 2004 Dec, 52(12), 2010 - 5
Indicators of recurrent hospitalization for pneumonia in the elderly; El Solh AA et al.; OBJECTIVES: To identify modifiable risk factors of late unplanned readmissions for elderly with community-acquired pneumonia . DESIGN: A case-control study . SETTING: Three university-affiliated tertiary-care hospitals . PARTICIPANTS: Two hundred four case-control pairs . Case patients referred to all patients readmitted with pneumonia 30 days to 1 year after discharge . Control subjects were matched for age, admission date, and residence before admission . MEASUREMENTS: Baseline sociodemographic information, clinical data, activity of daily living (ADLs) information, and Charlson Comorbidity Index score were obtained . The Pneumonia Severity Index was calculated with swallowing dysfunction and pattern and extent of radiographic abnormalities, antimicrobial coverage, and total duration recorded . RESULTS: Median time to readmission was 123 days (interquartile range=65-238 days) . Readmission was not associated with increased severity or length of hospital stay . In a Cox proportional hazards regression model, swallowing dysfunction (hazard ratio (HR)=2.15, 95% confidence interval (CI)=1.46-2.97), current smoking (HR=2.04, 95% CI=1.48-2.82), use of tranquilizers (HR=1.5, 95% CI=1.02-2.22), and lower ADL scores (HR=1.06, 95% CI=1.02-1.10) were independently associated with readmission for pneumonia . The receipt of angiotensin-converting enzyme inhibitors (HR=0.46, 95% CI=0.27-0.78) and prior pneumococcal vaccination (HR=0.59, 95% CI=0.42-0.82) had a protective effect . CONCLUSION: Although there are limited effective measures to improve functional status, preventive strategies that include smoking cessation and pneumococcal vaccination should be actively pursued . Routine evaluation of swallowing dysfunction and use of pharmacological agents to improve the cough reflex deserve further evaluation in multicenter controlled trials.

Dermatol Ther, 2004, 17(6), 491 - 8
Therapy of nontuberculous mycobacterial infections; Jogi R et al.; Mycobacterial infections are increasing in incidence worldwide, partly as a result of the increase in immunocompromised individuals . They cause a large number of cutaneous infections with a broad array of manifestations . Because of their diverse manifestations and sometimes fastidious nature, infections with mycobacteria are often misdiagnosed, leading to delay in and sometimes failure of therapy . In addition, many mycobacteria display both in vitro and in vivo drug resistance to antimicrobial agents . Early recognition of affected patients, initiation of appropriate antimicrobial therapy based on current guidelines, and tailoring of therapy after susceptibility testing is available are therefore essential to the successful treatment of mycobacterial infections.

Expert Opin Emerg Drugs, 2004 Nov, 9(2), 223 - 36
Use of cytokines in infection; Aoki N et al.; Infectious disease remains an ever-growing health concern worldwide due to increasing antibiotic-resistant microbial strains, immune-compromised populations, international traffic and globalisation, and bioterrorism . There exists an urgent need to develop novel prophylactic and therapeutic strategies . In addition to classic antibiotic therapeutics, immune-modulatory molecules such as cytokines or their inhibitors represent a promising form of antimicrobial therapeutics or immune adjuvant used for the purpose of vaccination . These molecules, in the form of either recombinant protein or transgene, exert their antimicrobial effect by enhancing infectious agent-specific immune activation or memory development, or by dampening undesired inflammatory and immune responses resulting from infection and host defence mechanisms . In the last two decades, a number of cytokine therapy-based experimental and clinical trials have been conducted, and some of these efforts have led to the routine clinical use of cytokines . For instance, although IFNs have been used to treat hepatitis C with great success, many other cytokines are yet to be fully evaluated for their antimicrobial potential . This review discusses the biology and therapeutic potential of selected immune modulatory cytokines and their inhibitors, including granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, IFN-gamma, IL-12 and TNF.

J Pharm Sci, 2005 Feb, 94(2), 240 - 5
Tea tree oil concentration in follicular casts after topical delivery: Determination by high-performance thin layer chromatography using a perfused bovine udder model; Biju SS et al.; Tea tree oil, a popular antimicrobial agent is recommended for the treatment of acne vulgaris, a disease of the pilosebaceous unit . Tea tree oil formulations (colloidal bed, microemulsion, multiple emulsion, and liposomal dispersion containing 5% w/w tea tree oil) were applied to bovine udder skin . The follicular uptake of tea tree oil upon application was determined by a cyanoacrylate method . Tea tree oil was determined by quantifying terpinen-4-ol content using high-performance thin layer chromatography . The accumulation of tea tree oil in the follicular casts was 0.43 +/- 0.01, 0.41 +/- 0.009, 0.21 +/- 0.006, and 0.16 +/- 0.005 percentage by weight (milligram oil/gram of sebum plug) for microemulsion, liposomal dispersion, multiple emulsion, and colloidal bed, respectively . This is the first study of its kind to quantify tea tree oil concentration in the follicles . (c) 2004 Wiley-Liss, Inc . and the American Pharmacists Association J Pharm Sci 94:240-245, 2005.

Vet Clin Pathol, 2004, 33(4), 223 - 7
Molecular cloning and expression of canine hepcidin; Fry MM et al.; BACKGROUND: Hepcidin is a recently identified acute phase protein with antimicrobial and iron regulatory functions . It has been suggested that hepcidin may be the key mediator of anemia of chronic disease . Our research group is interested in developing a diagnostic assay to measure hepcidin in dogs . OBJECTIVES: The objectives of this study were to clone and sequence the canine hepcidin gene and to gather preliminary data about tissue expression of hepcidin in dogs . METHODS: RNA was extracted from fresh canine liver tissue and cDNA was generated and amplified . Standard reverse transcription polymerase chain reaction techniques were used with degenerate primers based on sequence homology between several other species . The amino acid (AA) sequence was compared with known sequences in other species . Tissue expression of canine hepcidin was determined by Western blot . RESULTS: The canine hepcidin cDNA sequence encoded a highly conserved protein of 85 AAs with 8 cysteine residues at the C-terminal end . This protein was likely the precursor form (pro-hepcidin) of a smaller secreted peptide . Phylogenetic analysis showed that human hepcidin was more homologous with canine than with rodent hepcidin . In dogs, as in people, hepcidin was expressed most strongly in the liver . Western blotting showed a clear band of approximately 9 kDa, consistent with pro-hepcidin . Weak expression was also detected in canine kidney and lung tissues . CONCLUSION: The results of this study establish the basis for future investigation involving canine hepcidin and suggest that the dog may be a suitable model for studying the role of hepcidin in human health and disease.

Front Biosci, 2005 Jan 1, 10, 608 - 19 Print 2005 Jan 1.
Tetracycline protects myocardium against ischemic injury; Kagawa N et al.; Stress pretreatments protect myocardium from ischemic injury . We hypothesized that tetracycline, an antibiotic, may induce a stress response via the inhibition of mitochondrial translation as it induces the cold stress response by translational inhibition in E . coli . If so, tetracycline may protect myocardium from ischemic injury as stress pretreatments do . Thus, we investigated the effects of tetracycline on myocardial ischemia and its association with stress response . In a dog model of acute ischemia, 4mg/kg tetracycline injected 30 min prior to the occlusion improved the functional recovery from stunning of myocardium caused by ischemia . The same dosage of tetracycline dramatically reduced the size of infarct area in murine hearts analyzed by tetrazolium staining . In HeLa cells, tetracycline induced molecules that were increased by cold stress, which suggests that tetracycline may induce a cold stress-like response in mammalian cells . These molecules were also induced by ischemic stress in murine hearts, suggesting that the stress response caused by translational inhibition in mitochondria may be associated with the cardioprotection by tetracycline . Our results suggest that a subclinical dosage of tetracycline may protect heart from ischemic injury . Therefore, tetracycline may be of great use in suppressing the development of infarction caused by myocardial ischemia . This study is also important for providing new insights into the non-antimicrobial effects of tetracycline and its derivatives.

J Coll Physicians Surg Pak, 2003 Dec, 13(12), 728 - 34
An update on the diagnosis of tuberculosis; Butt T et al.; Tuberculosis (TB) continues to be the bane of mankind . Early diagnosis is the cornerstone of tuberculosis control strategies . Recent years have seen major advances in the fields of biotechnology and molecular biology with introduction of several new diagnostic techniques for tuberculosis and improvement in the existing ones . The new automated culture techniques have appreciably reduced the time required for detection and antimicrobial susceptibility testing . The molecular amplification techniques like the Polymerase Chain Reaction (PCR) have made the same-day diagnosis a reality . Improvements in serology and introduction of novel new techniques like the bacteriophage assays have also shown a lot of promise . However, most of these new techniques are too expensive and sophisticated to be of any practical benefit to the vast majority of TB patients living in underdeveloped countries like Pakistan for whom an early and inexpensive diagnosis remains as elusive as ever . In this article various existing modalities as well as the new advances in TB diagnostics are reviewed.

Langmuir, 2004 Dec 7, 20(25), 11084 - 91
Microscopic visualization of alamethicin incorporation into model membrane monolayers; Volinsky R et al.; Lipid interactions and cooperative assembly properties are fundamental determinants for the action of antimicrobial membrane-active peptides . Here we analyze the interactions and aggregation properties of alamethicin, an antimicrobial pore-forming peptide, with films formed at the air/water interface . Surface-area/pressure isotherms, Brewster angle microscopy, and fluorescence-confocal microscopy provided detailed information on the morphologies and structural properties of the peptide and its effect on the film components . The pressure-area analysis and microscopy experiments facilitated unprecedented visualization of the structural consequences of alamethicin association at the air/water interface, with pure phospholipid films, and within mixed phospholipid/polydiacetylene (PDA) films . The analysis exposed the kinetic features and the interplay between the peptide aggregates and film constituents . In particular, the results demonstrate the use of phospholipid/PDA film assemblies for studying membrane-peptide association and interactions within two-dimensional films.

Biochemistry, 2004 Dec 7, 43(48), 15169 - 78
Targeting DNA with novel diphenylcarbazoles; Dias N et al.; Double-stranded DNA is a therapeutic target for a variety of anticancer and antimicrobial drugs . Noncovalent interactions of small molecules with DNA usually occur via intercalation of planar compounds between adjacent base pairs or minor-groove recognition by extended crescent-shaped ligands . However, the dynamic and flexibility of the DNA platform provide a variety of conformations that can be targeted by structurally diverse compounds . Here, we propose a novel DNA-binding template for construction of new therapeutic candidates . Four bisphenylcarbazole derivatives, derived from the combined molecular architectures of known antitumor bisphenylbenzimidazoles and anti-infectious dicationic carbazoles, have been designed, and their interaction with DNA has been studied by a combination of biochemical and biophysical methods . The substitutions of the bisphenylcarbazole core with two terminal dimethylaminoalkoxy side chains strongly promote the interaction with DNA, to prevent the heat denaturation of the double helix . The deletion or the replacement of the dimethylamino-terminal groups with hydroxyl groups strongly decreased DNA interaction, and the addition of a third cationic side chain on the carbazole nitrogen reinforced the affinity of the compound for DNA . Although the bi- and tridentate molecules both derive from well-characterized DNA minor-groove binders, the analysis of their binding mode by means of circular and linear dichroism methods suggests that these compounds form intercalation complexes with DNA . Negative-reduced dichroism signals were recorded in the presence of natural DNA and synthetic AT and GC polynucleotides . The intercalation hypothesis was validated by unwinding experiments using topoisomerase I . Prominent gel shifts were observed with the di- and trisubstituted bisphenylcarbazoles but not with the uncharged analogues . These observations, together with the documented stacking properties of such molecules (components for liquid crystals), prompted us to investigate their binding to the human telomeric DNA sequence by means of biosensor surface plasmon resonance . Under conditions favorable to G4 formation, the title compounds showed only a modest interaction with the telomeric quadruplex sequence, comparable to that measured with a double-stranded oligonucleotide . Their sequence preference was explored by DNase I footprinting experiments from which we identified a composite set of binding sequences comprising short AT stretches and a few other mixed AT/GC blocks with no special AT character . The variety of the binding sequences possibly reflects the coexistence of distinct positioning of the chromophore in the intercalation sites . The bisphenylcarbazole unit represents an original pharmacophore for DNA recognition . Its branched structure, with two or three arms suitable to introduce a structural diversity, provides an interesting scaffold to built molecules susceptible to discriminate between the different conformations of nucleic acids.

Nat Immunol, 2005 Jan, 6(1), 57 - 64 Epub 2004 Nov 28.
Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection; Glaser R et al.; Human healthy skin is continuously exposed to bacteria, but is particularly resistant to the common gut bacterium Escherichia coli . We show here that keratinocytes secrete, as the main E . coli-killing compound, the S100 protein psoriasin in vitro and in vivo in a site-dependent way . In vivo treatment of human skin with antibodies to psoriasin inhibited its E . coli-killing properties . Psoriasin was induced in keratinocytes in vitro and in vivo by E . coli, indicating that its focal expression in skin may derive from local microbial induction . Zn(2+)-saturated psoriasin showed diminished antimicrobial activity, suggesting that Zn(2+) sequestration could be a possible antimicrobial mechanism . Thus, psoriasin may be key to the resistance of skin against E . coli.

Science, 2004 Nov 26, 306(5701), 1515 - 6
Keeping the leaves green above us; Gfeller A et al.; The plant immune system relies to a great extent on the highly regulated expression of hundreds of defense genes encoding antimicrobial proteins, such as defensins, and antiherbivore proteins, such as lectins . The expression of many of these genes is controlled by a family of mediators known as jasmonates; these cyclic oxygenated fatty acid derivatives are reminiscent of prostaglandins . The roles of jasmonates also extend to the control of reproductive development . How are these complex events regulated? Nearly 20 members of the jasmonate family have been characterized . Some, like jasmonic acid, exist in unmodified forms, whereas others are conjugated to other lipids or to hydrophobic amino acids . Why do so many chemically different forms of these mediators exist, and do individual jasmonates have unique signaling properties or are they made to facilitate transport within and between cells? Key features of the jasmonate signal pathway have been identified and include the specific activation of E3-type ubiquitin ligases thought to target as-yet-undescribed transcriptional repressors for modification or destruction . Several classes of transcription factor are known to function in the jasmonate pathway, and, in some cases, these proteins provide nodes that integrate this network with other important defensive and developmental pathways . Progress in jasmonate research is now rapid, but large gaps in our knowledge exist . Aimed to keep pace with progress, the ensemble of jasmonate Connections Maps at the Signal Transduction Knowledge Environment describe (i) the canonical signaling pathway, (ii) the Arabidopsis signaling pathway, and (iii) the biogenesis and structures of the jasmonates themselves.

Fitoterapia, 2004 Dec, 75(7-8), 750 - 3
Antimicrobial activity of alkaloidal fraction from barks of Himatanthus lancifolius; Souza WM et al.; The alkaloidal fraction from Himatanthus lancifolius barks demonstrated a broad-spectrum in vitro antimicrobial activity for most of the Gram (+) and Gram (-) tested microorganisms.

Crit Care, 2004 Dec, 8(6), 425 - 6 Epub 2004 Dec.
Qualitative cultures in ventilator-associated pneumonia - can they be used with confidence?
Luna CM, Chirino A.
The sensitivity and specificity of the radiographic and clinical evidence used to diagnose ventilator-associated pneumonia vary depending on the number of clinical criteria present . Bacteriological confirmation that rules out other diseases can be achieved by quantitative or qualitative cultures of tracheal aspirate . The rate of tracheal colonization in ventilated patients reduces the usefulness of qualitative cultures, but the absence of multiresistant micro-organisms in cultures from patients on prior antibiotics or a sterile culture in patients without prior antimicrobials may provide sufficient justification to stop or de-escalate antibiotics . However, more accurate guidance regarding whether antibiotics are unnecessary and should be stopped is provided by quantitative culture.

Crit Care, 2004 Dec, 8(6), R422 - 30 Epub 2004 Dec.
Ventilator associated pneumonia: comparison between quantitative and qualitative cultures of tracheal aspirates; Camargo LF et al.; INTRODUCTION: Deferred or inappropriate antibiotic treatment in ventilator-associated pneumonia (VAP) is associated with increased mortality, and clinical and radiological criteria are frequently employed to establish an early diagnosis . Culture results are used to confirm the clinical diagnosis and to adjust or sometimes withdraw antibiotic treatment . Tracheal aspirates have been shown to be useful for these purposes . Nonetheless, little is known about the usefulness of quantitative findings in tracheal secretions for diagnosing VAP . METHODS: To determine the value of quantification of bacterial colonies in tracheal aspirates for diagnosing VAP, we conducted a prospective follow-up study of 106 intensive care unit patients who were under ventilatory support . In total, the findings from 219 sequential weekly evaluations for VAP were examined . Clinical and radiological parameters were recorded and evaluated by three independent experts; a diagnosis of VAP required the agreement of at least two of the three experts . At the same time, cultures of tracheal aspirates were analyzed qualitatively and quantitatively (10(5) colony-forming units {cfu}/ml and 10(6) cfu/ml) RESULTS: Quantitative cultures of tracheal aspirates (10(5) cfu/ml and 10(6) cfu/ml) exhibited increased specificity (48% and 78%, respectively) over qualitative cultures (23%), but decreased sensitivity (26% and 65%, respectively) as compared with the qualitative findings (81%) . Quantification did not improve the ability to predict a diagnosis of VAP . CONCLUSION: Quantitative cultures of tracheal aspirates in selected critically ill patients have decreased sensitivity when compared with qualitative results, and they should not replace the latter to confirm a clinical diagnosis of VAP or to adjust antimicrobial therapy.

Expert Rev Anti Infect Ther, 2004 Dec, 2(6), 845 - 52
Dalbavancin: an investigational glycopeptide; Guay DR; Glycopeptide antimicrobials have been a component of our therapeutic armamentarium for nearly 50 years . Although vancomycin, and more recently teicoplanin, have performed yeoman service over the years, the specter of bacterial resistance among Gram-positive aerobes has created doubts concerning how long they will continue to be useful antimicrobial agents . In an attempt to prolong the utility of the glycopeptides, efforts are underway to create new derivatives with improved pharmacologic and pharmacokinetic properties . One example of an improved glycopeptide from the pharmacokinetic perspective is dalbavancin (BI397)--a teicoplanin analog currently undergoing human testing . Elimination of this compound from the body occurs extremely slowly, with terminal disposition half-lifes of up to 200 h in healthy volunteers, thus allowing once-weekly dosing . Although not generally considered to be a potential alternative for the treatment of infections due to glycopeptide-resistant Gram-positive pathogens, dalbavancin may still be considered an advance on existing agents based on its patient-convenient once-weekly dosing regimen.

Am J Vet Res, 2004 Nov, 65(11), 1525 - 32
Microbiologic findings in feedlot cattle with acute interstitial pneumonia; Woolums AR et al.; OBJECTIVE: To test the hypothesis that feedlot cattle with acute interstitial pneumonia (AIP) have bacterial infection of the lung or liver and concurrent bovine respiratory syncytial virus (BRSV) infection significantly more often than pen mates without AIP ANIMALS: 39 feedlot cattle with signs consistent with AIP and no history of treatment with antimicrobials and 32 healthy control cattle from the same pens . PROCEDURES: Lung and liver specimens were obtained postmortem for bacterial or mycoplasmal culture and histologic examination; lung tissue was assessed for BRSV infection immunohistochemically . RESULTS: Among affected cattle, 26 had AIP confirmed histologically . Lung tissue from 11 cattle with AIP yielded microbial respiratory tract pathogens on culture; tissues from control animals yielded no microbial growth . In 4 cattle with AIP and 2 control animals, liver abscesses were detected; bacteria were isolated from abscessed tissue in 3 and 1 of those animals, respectively . Immunohistochemically, 9 cattle with AIP and no control animals were BRSV-positive . Histologically, 9 AIP-affected cattle had only acute alveolar damage with exudation, and the other 17 had acute exudation with type II pneumocyte hyperplasia . No lesions of AIP were detected in control animals . Only 4 AIP-affected cattle had bacterial infection of the lung with concurrent BRSV infection . CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that microbial respiratory tract pathogens are more common in cattle with AIP than in healthy pen mates . Control of bacterial pneumonia late in the feeding period may reduce the incidence of AIP at feedlots where AIP is a problem.

Infect Control Hosp Epidemiol, 2004 Nov, 25(11), 967 - 73
Surveillance for transmission and antibiotic adverse events among neonates and adults exposed to a healthcare worker with pertussis; Friedman DS et al.; BACKGROUND: During a hospital obstetric rotation, a medical student demonstrated classic symptoms of pertussis . The diagnosis was confirmed by isolation of Bordetella pertussis . Because this exposure occurred in a high-risk hospital setting, control measures were undertaken to prevent transmission and illness . OBJECTIVES: To identify secondary cases of pertussis, to determine compliance with chemoprophylaxis recommendations, and to monitor for adverse events associated with chemoprophylaxis following a hospital exposure to pertussis . PATIENTS: More than 500 individuals were potentially exposed, including 168 neonates; antimicrobial chemoprophylaxis was administered to 281 individuals . Fifty-eight neonates and 194 adults began azithromycin chemoprophylaxis; 18 neonates and 2 adults began erythromycin chemoprophylaxis . METHODS: Active surveillance was instituted for (1) secondary cases of pertussis among healthcare coworkers, obstetric patients, their neonates, and labor companions and (2) antibiotic compliance and tolerance . RESULTS: No secondary cases of pertussis were confirmed by laboratory tests; however, 26 suspected cases and 5 clinically compatible cases were identified . Antibiotic courses were completed by 95% of the individuals who initiated therapy . Neonates taking azithromycin had statistically significantly less gastrointestinal distress compared with neonates taking erythromycin (12% vs 50%; P = .002); there were no cases of infantile hypertrophic pyloric stenosis . CONCLUSIONS: Although it was not possible to assess the effectiveness of the antibiotic regimens, the lack of laboratory-confirmed secondary cases suggests control measures were successful . Data from the 58 neonates who received azithromycin suggest it may be well tolerated in this age group.

J Chemother, 2004 Oct, 16(5), 497 - 501
Capnocytophaga spp . brain abscess in an immunocompetent host: problems in antimicrobial chemotherapy and literature review; Sabbatani S et al.; The fourth case report of a brain abscess due to the fastidious Gram-negative organism Capnocytophaga spp . is described and discussed on the grounds of clinical, microbiological, and therapeutic evidence . A probable origin from a cat bite and/or an underlying severe mandibulary granuloma is suspected . Due to lack of clinical and neuroradiological response to neurosurgery and a combination of imipenem-amikacin-clindamycin-fluconazole, second-line empiric llnezolid treatment proved rapidly successful, in the absence of further microbial isolations . In vitro antimicrobial susceptibility testing is often unpredictable for Capnocytophaga spp., and agents usually active on Gram-positive organisms may also be effective, both in vitro and in vivo . Due to its favorable brain penetration and its dual mode of administration, linezolid may be an alternative option for patients with multiple risk factors, brain abscess of suspected polymicrobial origin, and lack of response to empiric or culture-driven therapeutic attempts.

Nippon Geka Gakkai Zasshi, 2004 Nov, 105(11), 716 - 9
{Preventative strategies of nosocomial pneumonia}; Soma K et al.; This article reviews the epidemiology, risk factors, pathogenesis, diagnosis, treatment, and prophylaxis of ventilator-associated pneumonia (VAP), which is one of the most important infectious complications during the perioperative period . The definition of VAP is a nosocomial pneumonia occurring more than 48 h after endotracheal intubation and initiation of mechanical ventilation . Early liberation from the ventilator and the use of non-invasive positive-pressure ventilation are useful in preventing VAP . The early institution of appropriate antimicrobial therapy contributes to a good outcome . The initial therapy to ensure adequate coverage of potentially infective organisms should be accompanied by deescalation, or discontinuation, when the microbiological data became available . Useful preventative strategies include subglottic suctioning of pooled secretions just above the endotracheal tube cuff and oral care because of the pathogenesis of VAP.

Nippon Geka Gakkai Zasshi, 2004 Nov, 105(11), 709 - 15
{Appropriate antibiotic prophylaxis and treatment in surgery--comprasion between concept of North America and that of Japan}; Takesue Y et al.; Three principles must be followed to maximize the benefits of antimicrobial prophylaxis (AMP): 1) use an AMP agent that is bactericidal with a spectrum that covers the most probable intraoperative contaminants; 2) the initial dose of AMP agents should be given no more than 30 min before the skin is incised: and 3) maintain effective levels of antibiotics throughout the surgery and until at most a few hours after the incision is closed in the operating room . These recommendations have become standardized in North America and Europe . A few controversies, however, persist in Japan, especially concerning the duration of AMP . Most practitioners recommend that prophylaxis be continued until postoperative day 3 to 4 . However, some authors reported that the administration of AMP agents for 3 to 4 days causes the development of resistant strains . It is thus necessary to formulate national guidelines for appropriate AMP which are validated by the results of randomized, controlled trials conducted in Japan . In the treatment of postoperative infections, Gram-stain-based antibiotic selection is necessary and full knowledge of the interrelationships between pharmacokinetics and pharmacodynamics is important for determining effective regimens . The time that serum levels exceed the minimum inhibitory concentration is the most significant parameter determining the efficacy of beta-lactams, whereas the log area under the curve and peak serum level are the major parameters for aminoglycosides and new quinolones, respectively . Careful application of these concepts should allow surgeons to use more optimal dosing regimens in Japan.

Semin Perinatol, 2004 Aug, 28(4), 304 - 11
First line of defense in early human life; Yoshio H et al.; Innate antimicrobial peptides are considered to play an important role in host defense against microbial invasion . They are expressed in a wide variety of organisms . In the case of human beings, defensins and the cathelicidin LL-37 appear to be the major microbicidal peptides . With respect to human neonates, only few investigations have been performed in this context, revealing the presence of alpha-defensins and LL-37 in neutrophils and vernix caseosa . In addition, beta-defensins are present in tracheal aspirates and breast milk, whereas LL-37 has been detected in the skin of the newborn baby . During recent years, immunomodulatory activities such as chemotaxis have emerged as important functions of antimicrobial peptides . Thus, these innate effectors may work synergistically to provide a first line of defense against infection, as well as to promote interactions between the innate and adaptive immunity in newborn infants.

J Pharm Pharmacol, 2004 Dec, 56(12), 1519 - 25
Novel thiocyanato complexes with potent cytotoxic and antimicrobial properties; Hossain MS et al.; The aim of the present study was to assess the cytotoxic and antimicrobial properties of seven new thiocyanato complexes: Ni(C(9)H(11)N(2)O)(SCN), Cu(C(9)H(11)N(2)O)(SCN), Pd(C(9)H(11)N(2)O)(SCN), Pt(C(9)H(11)N(2) O) (SCN), K{Ti(C(9)H(11)N(2)O)(SCN)(3)}, Au(C(9)H(11)N(2)O)(SCN), and K{V(O)(C(9)H(11)N(2)O)(SCN)} (T(1)-T(7), respectively) . All the complexes showed toxicity against brine shrimp nauplii (Artemia salina L.) . The titanium-based complex, T(5), exhibited potent toxicity, with a lethal concentration 50% (the concentration of test compound that kills 50% of A . salina) value of 1.59 microg mL(-1) . These new complexes also exhibited promising antibacterial and antifungal properties . A macrodilution technique was used to estimate the minimum inhibitory concentrations of the seven bioactive complexes . Minimum inhibitory concentrations were found to be 8-64 microg mL(-1) against the tested bacterial species.

Risk Anal, 2004 Oct, 24(5), 1153 - 64
Bayesian Monte Carlo uncertainty analysis of human health risks from animal antimicrobial use in a dynamic model of emerging resistance; Cox LA Jr et al.; Recent qualitative analyses warn of potential future human health risks from emergence of antibiotic resistance in food-borne pathogens due to the use of similar antimicrobial drugs in both food animals and human medicine . While historical data suggest that human health risks from some animal antimicrobials, such as virginiamycin (VM), have remained low (McDonald et al., 2001), there is a widespread concern that "resistance epidemics" or endemics could arise in the future . How reassuring is the past about the future? This article applies quantitative risk assessment methods to help find out, using human health risks from VM and the nearly identical human antimicrobial quinupristin-dalfopristin (QD) as a case study . A dynamic simulation model is used to predict the risks of emerging resistance to human antimicrobials in human populations from given input assumptions . Bayesian Monte Carlo uncertainty analysis allows past data to constrain and inform selection of input parameter values, and thus to predict the possible future resistance patterns that are consistent with historical data . The results show that health risks from VM use in food animals are highly sensitive to the human prescription rate of QD . For realistic prescription rates, quantitative risks are less than 1 x 10(-6) even for members of the most-threatened (ICU patient) population, while societal risks are <1 excess statistical death per year for the whole U.S . population . Such quantitative estimates complement more qualitative assessments that discuss the possibility of future "resistance epidemics" (or endemics) without quantifying their probabilities.

J Agric Food Chem, 2004 Dec 1, 52(24), 7272 - 8
Phenolic compounds from the leaf extract of artichoke (Cynara scolymus L.) and their antimicrobial activities; Zhu X et al.; A preliminary antimicrobial disk assay of chloroform, ethyl acetate, and n-butanol extracts of artichoke (Cynara scolymus L.) leaf extracts showed that the n-butanol fraction exhibited the most significant antimicrobial activities against seven bacteria species, four yeasts, and four molds . Eight phenolic compounds were isolated from the n-butanol soluble fraction of artichoke leaf extracts . On the basis of high-performance liquid chromatography/electrospray ionization mass spectrometry, tandem mass spectrometry, and nuclear magnetic resonance techniques, the structures of the isolated compounds were determined as the four caffeoylquinic acid derivatives, chlorogenic acid (1), cynarin (2), 3,5-di-O-caffeoylquinic acid (3), and 4,5-di-O-caffeoylquinic acid (4), and the four flavonoids, luteolin-7-rutinoside (5), cynaroside (6), apigenin-7-rutinoside (7), and apigenin-7-O-beta-D-glucopyranoside (8), respectively . The isolated compounds were examined for their antimicrobial activities on the above microorganisms, indicating that all eight phenolic compounds showed activity against most of the tested organisms . Among them, chlorogenic acid, cynarin, luteolin-7-rutinoside, and cynaroside exhibited a relatively higher activity than other compounds; in addition, they were more effective against fungi than bacteria . The minimum inhibitory concentrations of these compounds were between 50 and 200 microg/mL.

J Periodontol, 2004 Oct, 75(10), 1387 - 96
Effectiveness of adjunctive low-dose doxycycline therapy on clinical parameters and gingival crevicular fluid laminin-5 gamma2 chain levels in chronic periodontitis; Emingil G et al.; BACKGROUND: Laminin-5 (Ln-5) is involved in the apical migration of epithelial cells during the development of periodontal pockets . Low-dose doxycycline (LDD) can therapeutically modulate the host response with its non-antimicrobial properties . In the present randomized, double-blind, placebo-controlled, parallel arm study, the effectiveness of LDD in combination with non-surgical periodontal therapy on gingival crevicular fluid (GCF) Ln-5 gamma2 chain fragment levels and clinical parameters in patients with chronic periodontitis was examined over a 12-month period . METHODS: GCF samples were collected and clinical parameters including probing depth (PD), clinical attachment level, gingival index (GI), and plaque index were recorded . Thirty chronic periodontitis patients were randomized either to low-dose doxcycline or placebo groups . LDD group received doxycycline (20 mg, b.i.d.) for 3 months plus scaling and root planing (SRP), while placebo group was given placebo capsules b.i.d . for 3 months plus SRP . The patients were evaluated every 3 months during the 12-month study period . All clinical parameters and GCF sampling were repeated at each visit . GCF Ln-5 gamma2 chain fragment levels were determined by Western immunoblotting using specific antibody and quantitated by computerized image analysis . Friedman test was used for intragroup comparisons followed by Wilcoxon signed rank test to analyze significance of changes over time . The Mann-Whitney test was used to determine differences between both LDD and placebo groups . RESULTS: Both groups revealed significant improvements in all clinical parameters over the 12-month period (P < 0.0125) . LDD group showed a significantly greater reduction in the mean PD scores at 9 and 12 months and in the mean GI scores at all time points than the placebo group (P < 0.05) . In the LDD group, GCF Ln-5 gamma2 chain fragment levels were significantly reduced at 3 months (P < 0.0125) and then slightly increased during the rest of the study period . In the placebo group, GCF 45 and 70 kDa Ln-5 gamma2 chain fragments tended to decrease at 3 months compared to baseline, but did not reach significance; these levels continued to increase throughout the remainder of the study period . GCF Ln-5 gamma2 chain fragment levels in LDD group were significantly lower than those of the placebo group during the study period (P < 0.05) . CONCLUSIONS: The present data indicate that LDD therapy in combination with SRP therapy can reduce GCF Ln-5 gamma2 chain fragment levels and improve clinical periodontal parameters in patients with chronic periodontitis . Since matrix metalloproteinases (MMP)-mediated fragmentation of laminin-5 can contribute to pocket formation by stimulating epithelial cell migration, the reduction of Ln-5 gamma2 chain fragment levels could provide a new mechanism by which LDD, adjunctive to SRP, inhibits periodontal disease more effectively than SRP alone . Thus, these results provide extended and additional information about the effectiveness of the LDD therapy as an adjunct to non-surgical periodontal therapy in the long-term management of periodontal disease.

East Mediterr Health J, 2003 Jan-Mar, 9(1-2), 159 - 66
First report of Escherichia coli O157 among Iraqi children; Shebib ZA et al.; We determined the prevalence of enterohaemorrhagic Escherichia coli, especially E . coli O157, and other enteropathogens among 200 children with bloody diarrhoea and 100 age-matched controls at two Baghdad hospitals . Bacterial and parasitic agents were found in 39.5% and 28.5% of cases, respectively; no pathogen was detected in 32% . E . coli O157 was identified in 11.5% and more than one pathogen was found in 15.5% of cases . The most common pathogens were enteropathogenic E . coli (EPEC) (5%); E . coli other than E . coli O157 or EPEC (15%); Entamoeba histolytica (25%) and Giardia lamblia (3.5%) . All isolates of E . coli O157:H7 were sensitive to cephalexin, ciprofloxacin, gentamicin and nalidixic acid and resistant to erythromycin, polymyxin B and vancomycin . Resistance to 6 or more antimicrobial agents was common (50% of isolates).

Antimicrob Agents Chemother, 2004 Dec, 48(12), 4903 - 6
Antimicrobial susceptibility of Bordetella bronchiseptica isolates from porcine respiratory tract infections; Kadlec K et al.; MICs for 349 Bordetella bronchiseptica isolates from respiratory tract infections of swine were determined by broth microdilution . The lowest MIC at which 90% of isolates tested are inhibited (MIC90) was that of tetracycline and enrofloxacin (0.5 microg/ml), whereas the highest MIC90s were those of tilmicosin and cephalothin (32 microg/ml) as well as streptomycin (256 microg/ml).

Antimicrob Agents Chemother, 2004 Dec, 48(12), 4562 - 5
Comparative in vitro activities of linezolid, telithromycin, clarithromycin, levofloxacin, moxifloxacin, and four conventional antimycobacterial drugs against Mycobacterium kansasii; Alcaide F et al.; Mycobacterium kansasii is one of the most pathogenic and frequent nontuberculous mycobacteria isolated from humans . Patients with adverse drug reactions, resistant isolates, or suboptimal response require alternative treatment regimens . One hundred forty-eight consecutive clinical isolates of M . kansasii were tested for antimicrobial susceptibilities by the BACTEC 460 system (NCCLS) with two different inoculation protocols, one conventional and one alternative . In the alternative protocol, the inoculum 12B vial was incubated until the growth index was between 250 and 500 . Four conventional antimycobacterial drugs (isoniazid, rifampin, streptomycin, and ethambutol) were studied with standard critical concentrations . The in vitro activities of linezolid, telithromycin, clarithromycin, levofloxacin, and moxifloxacin were determined by measuring radiometric MICs . All isolates tested were identified as M . kansasii genotype I and were resistant to isoniazid at a concentration of 0.4 mug/ml . One hundred twenty isolates (81.1%) were inhibited by 1 microg of isoniazid per ml . A high level of resistance to isoniazid (>10 microg/ml) was observed in six isolates (4.1%) . Only five strains (3.4%) were resistant to rifampin (>1 microg/ml) . All isolates studied were susceptible to streptomycin and ethambutol . The MICs at which 90% of the isolates were inhibited (in micrograms per milliliter) were as follows: linezolid, 1 (range, < or =0.25 to 2); telithromycin, >16 (range, 4 to >16); clarithromycin, 0.5 (range, < or =0.03 to 1); levofloxacin, 0.12 (range, 0.12 to 0.25); and moxifloxacin, 0.06 (range, < or =0.06 to 0.12) . The susceptibility testing results with both inoculation protocols showed perfect correlation . In conclusion, all M . kansasii isolates showed decreased susceptibility to isoniazid, but resistance to rifampin was infrequent . Quinolones, especially moxifloxacin, were the most active antimicrobial agents tested, followed by clarithromycin . Linezolid also showed good activity against these microorganisms, but telithromycin's in vitro activity was poor.

Antimicrob Agents Chemother, 2004 Dec, 48(12), 4513 - 9
Intranasal interleukin-12 treatment promotes antimicrobial clearance and survival in pulmonary Francisella tularensis subsp . novicida infection; Pammit MA et al.; Francisella tularensis is a highly virulent facultative intracellular bacterium and is considered a potential biological warfare agent . Inhalation tularemia can lead to the development of bronchopneumonia, which is frequently fatal without medical intervention . Treatment strategies that directly target the respiratory mucosa may extend the efficacy of therapy, particularly for the medical management of acute aerosol exposure . To this end, we describe an intranasal (i.n.) strategy for the treatment of pulmonary Francisella infection in mice that uses a combinatorial approach with the conventional antibiotic gentamicin and interleukin 12 (IL-12) . The i.n . administration of IL-12 alone promoted bacterial clearance and extended the time to death but did not prevent mortality against lethal pulmonary challenge with Francisella tularensis subsp . novicida . However, i.n . treatment with gentamicin and IL-12 therapeutically at 8 and 24 h after challenge markedly enhanced the rate of survival (70 to 100%) against pulmonary infection compared to the rates of survival for animals treated with antibiotic alone (17%) or IL-12 alone (0%) . A delay in combinatorial therapy over a span of 4 days progressively decreased the efficacy of this treatment regimen . This combinatorial treatment was shown to be highly dependent upon the induction of endogenous gamma interferon and may also involve the activation of natural killer cells . Together, these findings suggest that IL-12 may be a potent adjunct for chemotherapy to enhance drug effectiveness against pulmonary Francisella infection.

Curr Opin Biotechnol, 2004 Dec, 15(6), 599 - 606
Exploiting natural peptide diversity: novel research tools and drug leads; Adermann K et al.; During the course of evolution, nature has developed a vast number of peptides in all living and past species that display an exceeding diversity of structure and biological effects, such as hormonal and enzyme-controlling activity, communication between cells, and participation in host defence . Sensitive mass spectrometric technologies have been introduced and facilitate access to new natural peptides, even in trace amounts, and allow the quantitative determination of the peptide status of cells, organs and whole organisms (peptidomics) . Among the large number of new biologically active peptides identified from an increasing variety of natural sources, regulators of ion channels, chemoattractants, protease inhibitors, metabolism-related hormones, cytotoxins, and antimicrobials have been found . These novel peptides serve as research tools and have potential as diagnostic biomarkers and for the development of peptide and peptidometic drugs.

Urologiia, 2004 Sep-Oct, (5), 37 - 9
{Ejaculate microflora sensitivity to lactoferrin in chronic prostatitis}
{In Process Citation}
{No authors listed}

There are three directions in pathogenetic treatment of chronic prostatitis (CP) which is conducted in parallel to etiotropic one (antimicrobial): general immunological; improving arterial inflow and venous outflow; creation of prostatic secretion outflow and that of seminal vesicles by means of contractions of the pelvic and perineal muscles, muscular fibers of the prostatic gland . The latter two directions can be managed with physiotherapy . It is proposed to use combination of drugs with physiotherapy conducted by means of the devices {see text}.

Adv Gerontol, 2004, 14, 79 - 91
{Immunomodulators and cytokines in the treatment of internal diseases, associated with immunologic status disturbance in elderly patients}; C-reactive protein (CRP) and autoimmune disease: facts and conjectures; Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294-0006, USAC-reactive protein (CRP) is a blood component comprised of five identical subunits with a combined molecular mass of 110 kDa; in the presence of Ca++ it binds phosphocholine (PC) with high affinity . Ligand-bound CRP activates complement and the protein reportedly binds various Fc receptors . Coincident with a now decade-long resurgence in clinical interest in associations of CRP with disease, our laboratory has been investigating the biology of CRP in vivo using human CRP transgenic mice (CRPtg) . At that time we confirmed that CRP affects a host defense function mediated at least in part through the elimination of pathogens . Less appreciated and not as well understood as CRP's ability to bind antigen and aid in the elimination of microbes, is its known ability to bind autoantigens and presumed capacity to promote clearance of apoptotic cells . These latter properties of CRP have long been suspected to contribute to homeostasis and to autoimmune disease . In this article we review and update the evidence generated in CRPtg by our group and in vitro by others' that indicates CRP is more than just an antimicrobial molecule and convenient marker of inflammation-rather, it protects against autoimmunity . A mechanistic hypothesis is presented to account for this cause-and-effect relationship.

Rev Argent Microbiol, 2004 Jul-Sep, 36(3), 125 - 9
{Susceptibility to colistin: evaluation of breakpoints available in disk diffusion test}; Rodriguez CH et al.; Infections produced by multidrug resistant organisms are one of the greatest problems in health centers . Often, only polymyxines show good activity "in vitro" against the carbapenem resistant gram-negative strains; but the National Committee for Clinical Laboratory Standards (NCCLS) documents do not currently provide interpretative criteria for testing the polymyxines . The antimicrobial activity of colistin, and the correlation between the agar dilution test and disk diffusion test were evaluated against 186 gram-negative strains isolated at the Hospital de Clinicas "Jose de San Martin" of Buenos Aires city . All susceptibility tests were performed according to the NCCLS recommendations . Were evaluated two breakpoints, NCCLS 1981 (< or = 8 mm and > or = 11 mm), and R . Jones 2001 (< or = 11 mm and > or = 14 mm) . Discrepancies on interpretative category were found (0.5% minor; 2.2% major and 4.4% very major) with NCCLS 1981, and (18.9% minor; 3.8% major and 0.5% very major) with R . Jones 2001 criteria . Conclusions . In spite of the fact that the breakpoint used by R . Jones 2001 decreases the very major error but increases the minor error, according to our results we recommend the use of MIC methods to assist the therapeutic application of colistin; however resistance to colistin was not detected with zone diameters > or = 16 mm.

Infect Immun, 2004 Dec, 72(12), 7311 - 4
Expression of a beta-defensin mRNA, lingual antimicrobial peptide, in bovine mammary epithelial tissue is induced by mastitis; Swanson K et al.; The expression of a beta-defensin, the lingual antimicrobial peptide (LAP), in response to mastitis was investigated by real-time PCR of RNA from mastitic and control udder quarters . There was a positive relationship between somatic cell count in milk and LAP expression . In situ hybridization showed that LAP mRNA was expressed in epithelial cells of mastitic tissue . These results suggest that LAP plays a role in the innate immune response to mastitis.

Infect Immun, 2004 Dec, 72(12), 7140 - 6
Characterization of a defensin from the sand fly Phlebotomus duboscqi induced by challenge with bacteria or the protozoan parasite Leishmania major; Boulanger N et al.; Antimicrobial peptides are major components of the innate immune response of epithelial cells . In insect vectors, these peptides may play a role in the control of gut pathogens . We have analyzed antimicrobial peptides produced by the sand fly Phlebotomus duboscqi, after challenge by injected bacteria or feeding with bacteria or the protozoan parasite Leishmania major . A new hemolymph peptide with antimicrobial activity was identified and shown to be a member of the insect defensin family . Interestingly, this defensin exhibits an antiparasitic activity against the promastigote forms of L . major, which reside normally within the sand fly midgut . P . duboscqi defensin could be induced by both hemolymph or gut infections . Defensin mRNA was induced following infection by wild-type L . major, and this induction was much less following infections with L . major knockout mutants that survive poorly in sand flies, due to specific deficiencies in abundant cell surface glycoconjugates containing phosphoglycans (including lipophosphoglycan) . The ability of gut pathogens to induce gut as well as fat body expression of defensin raises the possibility that this antimicrobial peptide might play a key role in the development of parasitic infections.

Infect Immun, 2004 Dec, 72(12), 7124 - 30
Interactions of pulmonary collectins with Bordetella bronchiseptica and Bordetella pertussis lipopolysaccharide elucidate the structural basis of their antimicrobial activities; Schaeffer LM et al.; Surfactant proteins A (SP-A) and D (SP-D) play an important role in the innate immune defenses of the respiratory tract . SP-A binds to the lipid A region of lipopolysaccharide (LPS), and SP-D binds to the core oligosaccharide region . Both proteins induce aggregation, act as opsonins for neutrophils and macrophages, and have direct antimicrobial activity . Bordetella pertussis LPS has a branched core structure and a nonrepeating terminal trisaccharide . Bordetella bronchiseptica LPS has the same structure, but lipid A is palmitoylated and there is a repeating O-antigen polysaccharide . The ability of SP-A and SP-D to agglutinate and permeabilize wild-type and LPS mutants of B . pertussis and B . bronchiseptica was examined . Previously, wild-type B . pertussis was shown to resist the effects of SP-A; however, LPS mutants lacking the terminal trisaccharide were susceptible to SP-A . In this study, SP-A was found to aggregate and permeabilize a B . bronchiseptica mutant lacking the terminal trisaccharide, while wild-type B . bronchiseptica and mutants lacking only the palmitoyl transferase or O antigen were resistant to SP-A . Wild-type B . pertussis and B . bronchiseptica were both resistant to SP-D; however, LPS mutants of either strain lacking the terminal trisaccharide were aggregated and permeabilized by SP-D . We conclude that the terminal trisaccharide protects Bordetella species from the bactericidal functions of SP-A and SP-D . The O antigen and palmitoylated lipid A of B . bronchiseptica play no role in this resistance.

Am J Physiol Lung Cell Mol Physiol . 2004 Nov 19; {Epub ahead of print}
Differential effects of alpha- and beta-defensin on cytokine production by cultured human bronchial epithelial cells; Sakamoto N et al.; Defensins are cysteine-rich cationic antimicrobial peptides that play an important role in innate immunity and are known to contribute to the regulation of host adaptive immunity . In addition to direct antimicrobial activities, it has been recently reported that alpha-defensins, mainly present in neutrophils in the lung, have a cytotoxic effect and induce IL-8 production from airway epithelial cells . Though beta-defensins are expressed in epithelial cells in various tissues, including lung, there are no reports of their effects on cytokine synthesis in airway epithelial cells . The aim of the present study was to determine the effects of both alpha- and beta-defensins on the cytokine production, transcription factor binding activity and cytotoxicity in primary cultured human bronchial epithelial cells (HBECs) . We used human neutrophil peptide-1 (HNP-1; alphadefensin) and human beta-defensin-2 (HBD-2) to stimulate HBECs . The results showed that treatment of HBECs with HNP-1, but not HBD-2, increased IL-8 and IL-1beta mRNA expression in a dose-dependent manner and also enhanced IL-8 protein secretion and NF-kappaB DNA binding activity . The 24 h treatment with >20 microg/ml of HNP-1 or >50 microg/ml of HBD-2 were cytotoxic to HBECs . These results suggest that alpha- and beta-defensins have different effects on cytokine synthesis by airway epithelial cells and we speculate that they play different roles in inflammatory lung diseases.

Vet Pathol, 2004 Nov, 41(6), 673 - 81
Early pathophysiologic feature of arthropathy in juvenile dogs induced by ofloxacin, a quinolone antimicrobial agent; Yabe K et al.; Arthropathy in dogs induced by ofloxacin, a quinolone antimicrobial agent, was pathophysiologically investigated . In the in vivo studies, ofloxacin was administered orally once or twice at 20 mg/kg/day to male juvenile (3-month-old, n=3) or adult (36-month-old, n=2) dogs, and the humeral and femoral heads were examined pathologically . Unlike adult dogs, fluid-filled vesicles were macroscopically observed on the articular surfaces of one juvenile dog 24 hours after a single treatment with ofloxacin . These lesions were seen in all juvenile dogs by twice dosing . Microscopically, fissures or cavity formations in the middle zone of the articular cartilage were noted only in juvenile dogs . Furthermore, the cartilage matrix from the abnormal area to the articular surface showed a decreased safranin-O staining intensity, suggesting proteoglycan depletion . Ultrastructurally, chondrocytes in the middle zone of juvenile dogs displayed dilatation of the cisternae in the rough endoplasmic reticulum as an initial hallmark . In the in vitro studies, chondrocytes isolated from the articular cartilage of naive juvenile dogs were exposed to ofloxacin at 6.3-100 microg/ml for 24 hours . Although no changes were noted in the deoxyribonucleic acid synthesis, protein synthesis, or proteoglycan release at concentrations of up to 100 microg/ml, the proteoglycan synthesis was evidently decreased in a dose-dependent manner from 12.5 microg/ml . The results obtained suggest that the inhibitory action of ofloxacin on proteoglycan syntheses in the chondrocytes may largely contribute to the early morphologic features in the articular cartilage of the juvenile dog.

Biochimie, 2004 Sep-Oct, 86(9-10), 607 - 16
Peptidomic and proteomic analyses of the systemic immune response of Drosophila; Levy F et al.; Insects have developed an efficient host defense against microorganisms, which involves humoral and cellular mechanisms . Numerous data highlight similarities between defense responses of insects and innate immunity of mammals . The fruit fly, Drosophila melanogaster, is a favorable model system for the analysis of the first line defense against microorganisms . Taking advantages of improvements in mass spectrometry (MS), two-dimensional (2D) gel electrophoresis and bioinformatics, differential analyses of blood content (hemolymph) from immune-challenged versus control Drosophila were performed . Two strategies were developed: (i) peptidomic analyses through matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS and high performance liquid chromatography for molecules below 15 kDa, and (ii) proteomic studies based on 2D gel electrophoresis, MALDI-TOF fingerprinting and database searches, for compounds of greater molecular masses . The peptidomic strategy led to the detection of a large number of peptides induced in the hemolymph of challenged flies as compared to controls . Of these, 28 were characterized, amongst which were antimicrobial peptides . The 2D gel electrophoresis strategy led to the detection of 70 spots differentially regulated by at least fivefold after microbial infection . This approach yielded the identity of a series of proteins that were related to the Drosophila immune response, such as proteases, protease inhibitors, prophenoloxydase-activating enzymes, serpins and a Gram-negative binding protein-like protein . This strategy also brought to light new candidates with a potential function in the immune response (odorant-binding protein, peptidylglycine alpha-hydroxylating monooxygenase and transferrin) . Interestingly, several molecules resulting from the cleavage of proteins were detected after a fungal infection . Together, peptidomic and proteomic analyses represent new tools to characterize molecules involved in the innate immune reactions of Drosophila.

Comp Biochem Physiol C Toxicol Pharmacol, 2004 Oct, 139(1-3), 31 - 8
Purification and characterization of antimicrobial peptides from the skin secretions of the mink frog (Rana septentrionalis); Bevier CR et al.; Skin secretions were obtained from male, female, and juvenile specimens of the mink frog (Rana septentrionalis) by electric stimulation and shown to contain 10 peptides that differentially inhibited the growth of microorganisms . The elution profiles of secretions from the three groups following reverse-phase HPLC were almost identical indicating that there were no major sexual or developmental differences in chemical composition . Four peptides of the brevinin-1 family, with potent antimicrobial activity and strong hemolytic activity, two members of ranatuerin-2 family and three members of the temporin family, were purified and characterized structurally . A 21-amino-acid C-terminally alpha-amidated peptide (GIWDTIKSMGKVFAGKILQNL.NH(2)) with broad-spectrum antimicrobial activity was also isolated from the skin secretions . This peptide shows limited structural similarity with the N-terminal region of brevinin-2 peptides previously isolated from R . temporaria skin but lacks the C-terminal cyclic heptapeptide domain associated with this family . Molecular and morphological data support the placement of R . septentrionalis in the R . catesbeiana species group, but analysis based upon the distribution of the molecular forms of the antimicrobial peptides is indicative of a closer phylogenetic relationship between R . septentrionalis and the frogs of the R . pipiens and R . boylii groups.

Int J Antimicrob Agents, 2004 Dec, 24(6), 572 - 7
Comparison of E-test and disk diffusion assay to evaluate resistance of Helicobacter pylori isolates to amoxicillin, clarithromycin, metronidazole and tetracycline in Costa Rica; Lang L et al.; MIC distribution and susceptibility to four antimicrobial agents were determined by E-test for 94 Helicobacter pylori isolates from Costa Rica . Disk diffusion was evaluated as an alternative method to determine susceptibility and compared with the E-test results by linear regression analysis and an error-rate bounded method . Thirty-eight (40.4%) of the isolates were resistant to metronidazole, 5.3% to clarithromycin and 5.3% to amoxicillin . No isolate was resistant to tetracycline . Multiple resistance was found in 4.3% of the isolates . H . pylori isolates were categorised as resistant to amoxicillin, clarithromycin and tetracycline when inhibition diameters were less than 25, 21 and 25 mm, respectively, in the disk diffusion assay . A breakpoint diameter for metronidazole with disk diffusion could not be firmly established.

Int J Antimicrob Agents, 2004 Dec, 24(6), 536 - 47
Antimicrobial peptides: premises and promises; Reddy KV et al.; Antimicrobial peptides (AMPs) are an important component of the natural defences of most living organisms against invading pathogens . These are relatively small (< 10kDa), cationic and amphipathic peptides of variable length, sequence and structure . During the past two decades several AMPs have been isolated from a wide variety of animals, both vertebrates and invertebrates, and plants as well as from bacteria and fungi . Most of these peptides are obtained from different sources like macrophages, neutrophils, epithelial cells, haemocytes, fat body, reproductive tract, etc . These peptides exhibit broad-spectrum activity against a wide range of microorganisms including Gram-positive and Gram-negative bacteria, protozoa, yeast, fungi and viruses . A few peptides have also been found to be cytotoxic to sperm and tumour cells . AMPs are classified based on the three dimensional structural studies carried out with the help of NMR . The peptides are broadly classified into five major groups namely (a) peptides that form alpha-helical structures, (b) peptides rich in cysteine residues, (c) peptides that form beta-sheet, (d) peptides rich in regular amino acids namely histatin, arginine and proline and (e) peptides composed of rare and modified amino acids . Most of these peptides are believed to act by disrupting the plasma membrane leading to the lysis of the cell . AMPs have been found to be excellent candidates for developing novel antimicrobial agents and a few of these peptides show antimicrobial activity against pathogens causing sexually transmitted infection (STI), including HIV/HSV . Peptides, namely magainin and nisin have been shown to demonstrate contraceptive properties in vitro and in vivo . A few peptides have already entered clinical trials for the treatment of impetigo, diabetic foot ulcers and gastric helicobacter infections . In this review, we discuss the source, structures and mode of action with special reference to therapeutic considerations of various AMPs.

Infect Dis Clin North Am, 2004 Dec, 18(4), 993 - 1016, xi
Antimicrobial therapy of community-acquired pneumonia; File TM Jr et al.; Community-acquired pneumonia (CAP) is a common disorder that is potentially life-threatening, especially in older adults and patients with comorbid disease . Despite substantial progress in therapeutic options, CAP remains a primary cause of death from infectious disease in the United States . The mainstay of treatment for most patients is appropriate antimicrobial therapy This article reviews the principles for initial antimicrobial therapy, highlights some of the differences in approaches to antimicrobial drug selection in selected guidelines, and includes new recommendations for empiric and pathogen-directed therapy of CAP.

Infect Dis Clin North Am, 2004 Dec, 18(4), 883 - 97
Nonresponses and treatment failures with conventional empiric regimens in patients with community-acquired pneumonia; Tan JS; Although most patients with suspected CAP respond to empiric therapy,a small number of patients do not respond in the expected fashion . Age and underlying comorbid conditions have a strong influence on the course of illness . Less common causes of treatment failures include overwhelming infection, antimicrobial resistance, and misdiagnosis . It is a common practice for empiric antimicrobial treatment of CAP to be initiated without microbiologic studies . Clinicians carefully should observe these patients for unusual or slow responses and should be ready to pursue a more extensive search for the cause of treatment failure.

Infect Dis Clin North Am, 2004 Dec, 18(4), 829 - 41
Empiric treatment of ambulatory community-acquired pneumonia: always include treatment for atypical agents; Marrie TJ; There are no data from proper studies to answer whether it is necessary to include antibiotics that are active against atypical pneumonia agents as part of the empiric therapy of CAP . Until such data are available, clinical judgment and severity of the pneumonic illness are the best guides to empiric antimicrobial therapy.

Am J Geriatr Pharmacother, 2004 Mar, 2(1), 24 - 35
Comparison of anti-infective drug use in elderly persons in Manitoba, Nova Scotia, and Saskatchewan, Canada: relationship to drug insurance reimbursement policies; Sketris IS et al.; BACKGROUND: Antimicrobial drug resistance continues to be a concern . Inappropriate use of antimicrobial agents is a well-documented contributory factor in the development of resistance . Canadian publicly funded drug insurance (pharmacare) programs have various approaches to reimbursement for antimicrobial drugs and promoting the appropriate prescribing of these agents . OBJECTIVE: The objective of this study was to examine changes in antimicrobial use over a 3-year period in relation to the reimbursement policies of the public drug insurance programs for elderly persons in Manitoba, Nova Scotia, and Saskatchewan . METHODS: The pharmacare databases of the 3 provincial drug insurance programs were accessed for fiscal years 1995/96, 1996/97, and 1997/98 . Antimicrobial drug use was reported as mean age- and sex-standardized defined daily doses (DDDs) dispensed per 1000 beneficiaries per year . Provincial antimicrobial drug use was compared and related to provincial reimbursement policies . RESULTS: The rates and types of antimicrobial drugs dispensed to elderly beneficiaries of the Manitoba, Nova Scotia, and Saskatchewan pharmacare programs varied . Between fiscal years 1995/96 and 1997/98, DDDs of antimicrobials per 1000 beneficiaries per year decreased by 11.5% in Saskatchewan and increased by 1.2% in Manitoba and 6.2% in Nova Scotia . Rates of use of broadspectrum agents such as amoxicillin/clavulanate, azithromycin, clarithromycin, and fluoroquinolones were lower in the provinces that had reimbursement guidelines . Even when reimbursement policies were similar, as for fluoroquinolones in Manitoba and Saskatchewan, rates of use varied markedly, possibly as a result of the method of implementing the reimbursement guidelines . Use of fluoroquinolones, macrolides, penicillins, beta-lactamase-resistant penicillins, and tetracyclines was lower and use of sulfonamides and trimethoprim was greater in Saskatchewan than in Nova Scotia and Manitoba . CONCLUSIONS: The reimbursement guidelines of provincial drug insurance programs are among the factors affecting the use of antimicrobial agents . Both the type of reimbursement policy and the policy implementation mechanism affected the rate of utilization . Further research is needed to link drug-use information with data such as antimicrobial resistance patterns, diagnoses, physician visits, and hospitalizations.

Zhonghua Xue Ye Xue Za Zhi, 2004 Aug, 25(8), 470 - 2
{Pulmonary disease caused by nontuberculous mycobacteria after allogeneic hematopoietic stem cell transplantation--a case report and literature review}; Chen B et al.; OBJECTIVE: To report a case with pulmonary disease caused by nontuberculous mycobacteria (NTM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a literature review . METHODS: Case report and literature review . RESULTS: A patient with acute non-lymphocytic leukemia was treated by allo-HSCT . Her NTM lung disease developed after HSCT was successfully treated with a 3 antimicrobials combination of clarithromycin, levofloxacin and capreomycin for 10 months . CONCLUSION: NTM infections are infrequent in allo-HSCT recipients and have a good clinical prognosis if correctly treated.

Mol Microbiol, 2004 Dec, 54(5), 1287 - 94
Inhibition of peptide bond formation by pleuromutilins: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin; Schlunzen F et al.; Tiamulin, a prominent member of the pleuromutilin class of antibiotics, is a potent inhibitor of protein synthesis in bacteria . Up to now the effect of pleuromutilins on the ribosome has not been determined on a molecular level . The 3.5 A structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin provides for the first time a detailed picture of its interactions with the 23S rRNA, thus explaining the molecular mechanism of the antimicrobial activity of the pleuromutilin class of antibiotics . Our results show that tiamulin is located within the peptidyl transferase center (PTC) of the 50S ribosomal subunit with its tricyclic mutilin core positioned in a tight pocket at the A-tRNA binding site . Also, the extension, which protrudes from its mutilin core, partially overlaps with the P-tRNA binding site . Thereby, tiamulin directly inhibits peptide bond formation . Comparison of the tiamulin binding site with other PTC targeting drugs, like chloramphenicol, clindamycin and streptogramins, may facilitate the design of modified or hybridized drugs that extend the applicability of this class of antibiotics.

Am J Clin Dermatol, 2004, 5(5), 369 - 71
Spotlight on adapalene in acne vulgaris; Waugh J et al.; Adapalene (Differin) is a retinoid agent indicated for the topical treatment of acne vulgaris . In clinical trials, 0.1% adapalene gel has proved to be effective in this indication and was as effective as 0.025% tretinoin gel, 0.1% tretinoin microsphere gel, 0.05% tretinoin cream and 0.1% tazarotene gel once every two days; however, the drug was less effective than once-daily 0.1% tazarotene gel . It can be used alone in mild acne or in combination with antimicrobials in inflammatory acne and has proved efficacious as maintenance treatment . Adapalene has a rapid onset of action and a particularly favorable tolerability profile compared with other retinoids . These attributes can potentially promote patient compliance, an important factor in treatment success . Adapalene is, therefore, assured of a role in the first-line treatment of acne vulgaris.

Ann Ig, 2004 Jan-Apr, 16(1-2), 173 - 8
{Surgical chemoprophylaxis in the Emilia Romagna region}; Moro ML et al.; The aim of this study is to assess the compliance with evidence based medicine of the practices of administration of perioperative surgical chemoprophylaxis in the Emilia Romagna region . Prospective study of 1 month duration including 31 of the 36 public hospital existing in the region . For all the patients admitted to one of the 121 participating units and undergoing a surgical operation, data were collected on the surgical prophylaxis administered, including type of antibiotic, time of administration and duration . Surgical prophylaxis was given in 4,946 surgical operations of the 6,167 included in the study . The median frequency of surgical prophylaxis administration was 81% ranging from 67% to 97% in different Local Health Authorities . Chemoprophylaxis was given also for surgical operations where, according to systematic literature reviews, the cost-benefit ratio is absolutely unfavourable to the use of antibiotics . In 2,120 cases (42.9%) the time of administration was not perioperative and, thus, differed from the recommended practice: in 264 cases (5%), antibiotics were administered after the operation . In 42.6% of the cases the duration of administration was not a short-term prophylaxis, being longer than 24 hours: in these 2,108 cases, the median duration was 4 days ranging form 1 to 90 days . In 48% of the cases cefazolin was administered; in 1,347 cases (23.4%), instead, a third or fourth generation cephalosporin was used . The survey pointed out an overuse of antibiotics, both for indications and duration, even when clear evidences of efficacy are lacking; moreover, the criteria for selection of specific antibiotics frequently did not take into account the risk of selecting antimicrobial resistance strains.

J Food Prot, 2004 Nov, 67(11), 2603 - 7
Colicin concentrations inhibit growth of Escherichia coli O157:H7 in vitro; Callaway TR et al.; Escherichia coli O157:H7 is a virulent foodborne pathogen that causes severe human illness and inhabits the intestinal tract of food animals . Colicins are antimicrobial proteins produced by E . coli strains that inhibit or kill other E . coli . In the present Study, the efficacy of three pore-forming colicins (El, N, and A) were quantified in vitro against E . coli O157:H7 strains 86-24 and 933 . Colicins E1 and N reduced the growth of E . coli O157:H7 strains, but the efficacy of each colicin varied among strains . Colicin E1 was more effective against both strains of E . coli O157:H7 than colicins A and N and reduced (P < 0.05) populations of E . coli O157:H7 at concentrations <0.1 microg/ml . These potent antimicrobial proteins may potentially provide an effective and environmentally sound preharvest strategy to reduce E . coli O157:H7 in food animals.

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