Clin Microbiol Infect, 2004 Apr, 10(4), 269 - 71 Does molecular typing make any contribution to the care of patients with infection? Humphreys H. Molecular typing has been used extensively to study the epidemiology of infection, but there are few studies on the role of typing in the clinical management of infected patients . Examples of this include distinguishing relapse of infection from new infection, determining the significance of colonisation with potential pathogens, assessing the capacity of isolates to spread and cause serious illness, and linking changes in antimicrobial resistance with treatment . Further studies in selected patient groups and greater collaboration between molecular microbiologists, clinical microbiologists and infectious disease physicians are required to determine the impact of molecular typing in these and other scenarios. Drugs, 2004, 64(8), 837 - 59 Advances in sepsis therapy; Gluck T et al.; During the past 3 years new insights have been gained into the fundamental elements that underlie the pathogenesis of sepsis, and after years of frustrating failures, progress in the basic understanding of sepsis has translated into successful new therapies . These new treatment strategies have significantly improved the outcome of patients experiencing the puzzling syndrome of severe sepsis . More effective supportive therapies with early, goal-oriented therapy including volume resuscitation, catecholamine therapy and transfusion improve the chances for survival in septic shock . Novel endocrine management with hydrocortisone replacement therapy for relative adrenal insufficiency in septic shock patients and strict blood glucose control provide a survival advantage in critically ill patients . Administering appropriate antimicrobial therapy, nutritional support and ventilation protocols with low tidal volumes have now been shown to benefit septic patients . Finally, human recombinant activated protein C (drotrecogin alfa), which ameliorates sepsis-induced disseminated intravascular coagulation and exerts several other favourable effects on endothelial cells, has been shown to reduce mortality in patients with severe sepsis . On the basis of newly discovered pathophysiological mechanisms of sepsis, several other adjuvant therapies for sepsis are in various stages of preclinical and clinical development . Individualised and optimal supportive care with efforts to reverse the precipitating cause of sepsis remains the mainstay of therapy for severe sepsis . How these new and often expensive regimens will fit into the standard treatment approach to sepsis remains to be defined by future clinical investigations. Biotechnol Prog, 2004 Mar-Apr, 20(2), 426 - 42 A dynamic mathematical model to clarify signaling circuitry underlying programmed cell death control in Arabidopsis disease resistance; Agrawal V et al.; Plant cells undergo programmed cell death in response to invading pathogens . This cell death limits the spread of the infection and triggers whole plant antimicrobial and immune responses . The signaling network connecting molecular recognition of pathogens to these responses is a prime target for manipulation in genetic engineering strategies designed to improve crop plant disease resistance . Moreover, as alterations to metabolism can be misinterpreted as pathogen infection, successful plant metabolic engineering will ultimately depend on controlling these signaling pathways to avoid inadvertent activation of cell death . Programmed cell death resulting from infection of Arabidopsis thaliana with Pseudomonas syringae bacterial pathogens was chosen as a model system . Signaling circuitry hypotheses in this model system were tested by construction of a differential-equations-based mathematical model . Model-based simulations of time evolution of signaling components matched experimental measurements of programmed cell death and associated signaling components obtained in a companion study . Simulation of systems-level consequences of mutations used in laboratory studies led to two major improvements in understanding of signaling circuitry: (1) Simulations supported experimental evidence that a negative feedback loop in salicylic acid biosynthesis postulated by others does not exist . (2) Simulations showed that a second negative regulatory circuit for which there was strong experimental support did not affect one of two pathways leading to programmed cell death . Simulations also generated testable predictions to guide future experiments . Additional testable hypotheses were generated by results of individually varying each model parameter over 2 orders of magnitude that predicted biologically important changes to system dynamics . These predictions will be tested in future laboratory studies designed to further elucidate the signaling network control structure. Folia Microbiol (Praha), 2003, 48(6), 731 - 5 Susceptibility of Escherichia coli to C2-C18 fatty acids; Marounek M et al.; The antimicrobial activity of C2-C18 fatty acids was determined in vitro in cultures of two strains of Escherichia coli grown on glucose . Antimicrobial activity was expressed as IC50 (a concentration at which only 50% of the initial glucose in the cultures was utilized) . Utilization of glucose was inhibited by caprylic acid (IC50 0.30-0.85 g/L) and capric acid (IC50 1.25-2.03 g/L) . Neither short-chain fatty acids (C2-C6) nor fatty acids with longer chain (C12-C18) influenced substrate utilization . Caproic acid, however, decreased cell yield in cultures of E . coli in a dose-dependent manner . No inhibition of glucose utilization was produced with unsaturated fatty acids, oleic and linoleic . Calcium ions added in excess reversed the antimicrobial effect of capric acid, but not that of caprylic acid . Antimicrobial activity of caprylic and capric acid decreased when the bacteria were grown in the presence of straw particles, or repeatedly subcultured in a medium containing these compounds at low concentrations . Counts of viable bacteria determined by plating decreased after incubation with caprylic and capric acid (30 min; 1 g/L) at pH 5.2 from > 10(9) to approximately 10(2)/mL . A reduction of a mere 0.94-1.96 log10 CFU was observed at pH 6.5-6.6 . It can be concluded that caprylic acid, and to a lesser extent also capric acid, has a significant antimicrobial activity toward E . coli . Effects of other fatty acids were not significant or absent. Folia Microbiol (Praha), 2003, 48(6), 709 - 24 Nonmammalian vertebrate antibiotic peptides; Sima P et al.; With the exception of cyclostomes, all vertebrates share the common immune strategy of adaptive, highly specific immunity, based on the products of recombination-activating genes and recombined noninherited receptors for antigens . In addition, they have retained ancient vectors of innate immunity, such as antimicrobial peptides, which are widespread in all eukaryotic organisms and show a high degree of structural homology across most animal taxa . Recently, these substances have become the objects of intensive study for their outstanding bioactive properties with the aim to be applied as very efficient antibiotics, antimicrobials, and even cancerostatics in clinical practice. Przegl Lek, 2003, 60(11), 710 - 5 {The effect of antiinflammatory therapy with dexamethasone and dexamethasone with pentoxifylline on the course of bacterial meningitis}; Bociaga-Jasik M et al.; Despite of antimicrobial therapy mortality rate in the bacterial meningitis (BM) is high . The aim of the study was to assess the influence of anti-inflammatory treatment with dexamethasone and dexamethasone with pentoxifylline on the course of this disease and concentration of proinflammatory cytokines TNF-alpha, IL-1 beta, II-8 in the cerebrospinal fluid (CSF) . 42 patients with the BM were analysed . They were divided into three groups on the basis of applied therapy: A--treated only with antibiotics, A+D--treated with antibiotics and dexamethasone, A+D+P--treated with antibiotics, dexamethasone and pentoxifylline . Anti-inflammatory therapy did not have impact on the resolution of inflammation (pleocytosis, protein and glucose level) in the CSF . However, it was established that adjuvant treatment with dexa-methasone and pentoxifylline has beneficial effect on the course of the BM . In this group 61.5% of patients recovered, in comparison with 28.6% in the group A+D and 26.7% in the group A . Mortality rate was: in the group A--33%, A+D--21.4%, A+D+P--7.7% (p = 0.01) . Correlation between the outcome of the BM in the investigated groups and cytokines concentration in CSF was observed . In the group A+D+P all patients responded to the therapy with decrease of cytokine concentration, and coefficients of variation were low (TNF-alpha--1%, IL-1 beta--23.6%, IL-8--18.9%) . Also in the group A+D decrease of cytokines concentration in the CSF was observed, however was not such significant in all cases . In the group of patients treated only with antibiotics concentration of cytokines in the CSF varied, even increased in some of them . Our investigation indicates that inhibition of cytokines production in central nervous system (CNS) with dexamethasone and pentoxifylline improves the outcome of BM and is associated with the reduction of neurological sequels and deaths. Acta Neurochir (Wien), 2004 Apr, 146(4), 411 - 4; discussion 414 Epub 2004 Feb 16. Nocardia brain abscess mimicking brain tumour in immunocompetent patients: report of two cases and review of the literature; Menku A et al.; Nocardia brain abscess is a rare intracranial lesion and has been reported in immunocompromised patients . An optimal treatment approach has not been established . However, early diagnosis and appropriate antimicrobial therapy are very important factors for a good outcome . We report two unusual cases of Nocardia brain abscess simulating brain tumour in immunocompetent patients . One of the cases was presumed to be a primary brain tumour and the other a metastatic brain tumour . They underwent surgical gross total resection . After Nocardia asteroides was seen on Gram's stain and subsequently identified by culture, appropriate antibiotic therapy was initiated. Intensive Care Med, 2004 May, 30(5), 976 - 9 Epub 2004 Apr 01. Steady-state plasma and intrapulmonary concentrations of piperacillin/tazobactam 4 g/0.5 g administered to critically ill patients with severe nosocomial pneumonia; Boselli E et al.; OBJECTIVE: To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of piperacillin/tazobactam (P/T) administered to critically ill patients with severe bacterial pneumonia . DESIGN: Prospective, open-label study . SETTING: An intensive care unit and research ward in a university hospital . PATIENTS: Ten adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation . INTERVENTIONS: All subjects received a 30-min intravenous infusion of P/T 4 g/0.5 g every 8 h . The steady-state plasma and ELF concentrations of P/T were determined by high-performance liquid chromatography . MEASUREMENTS AND MAIN RESULTS: The mean+/-SD steady-state plasma trough, peak, and intermediate concentrations were 8.5+/-4.6 microg/ml, 55.9+/-21.6 microg/ml, and 24.0+/-13.8 microg/ml for piperacillin, and 2.1+/-1.0 microg/ml, 4.8+/-2.1 microg/ml, and 2.4+/-1.2 microg/ml for tazobactam, respectively . The mean+/-SD steady-state intermediate ELF concentrations were 13.6+/-9.4 microg/ml for piperacillin and 2.1+/-1.1 microg/ml for tazobactam, respectively, showing a mean percentage penetration of piperacillin and tazobactam into ELF of 56.8% and 91.3 %, respectively, with a P/T ratio of 6.5:1 . CONCLUSION: Our results show that during the treatment of severe nosocomial pneumonia, a regimen of P/T 4 g/0.5 g every 8 h might provide insufficient concentrations into lung tissue to exceed the MIC of many causative pathogens . This suggests that higher doses of P/T should be administered in order to maximize the antibiotic concentration at the site of infection, or that a second antimicrobial agent should be used in association. Eur J Clin Pharmacol, 2004 May, 60(3), 149 - 53 Epub 2004 Apr 01. Public drug procurement: the lessons from a drug tender in a teaching hospital of a transition country; Milovanovic DR et al.; INTRODUCTION: There are scarce descriptions of hospital drug procurement in the primary literature . The aim of this study was to analyse the drug tender led by a clinical pharmacologist in a 1200-bed university hospital in Serbia, a developing country in socio-economic transition, and to give recommendations for future steps in hospital drug policy . PROCEDURE AND OUTCOMES: Drug tendering was conducted according to the public procurement law from January to April 2003 . Analysis included the method of defined daily doses and anatomical therapeutic chemical classification, as well as minimal tender prices, free market prices, essential drugs and domestic and foreign manufacturers . The drug tender list consisted of 548 products, 1,315,501 pharmaceutical units and 312 drug entities, among which 164 were essential . For purchasing purposes, 479 drug formulations were selected, costing approximately 1.4 million Euros (approximately 10% of hospital budget) . Three-quarters of the expenditure consisted of antimicrobials (29.1%), cytotoxics (28.8%) and intravenous infusions (17.7%) . The top 20 drugs consumed 62.2% of the total drug expenditure . Competition for the most expensive and/or most used drugs was the key for financial success of applicants, even when they offered a limited number of drugs . The tender achieved 4.6% and 17.2% cost savings in comparison with minimal tender price and free-market price, respectively . The tender did not provide a fair balance between domestic and foreign manufacturers . CONCLUSION: The drug tender is resource-consuming, laborious, and risky job . Aggregation of individual tenders, on a national level and/or regional ones, is probably the best choice for hospitals in transition countries at this time. Mem Inst Oswaldo Cruz, 2004 Feb, 99(1), 107 - 10 Epub 2004 Mar 31. Antimicrobial susceptibility determined by the E test, Löwenstein-Jensen proportion, and DNA sequencing methods among Mycobacterium tuberculosis isolates discrepancies, preliminary results; Freixo MI et al.; Mycobacterium tuberculosis strains resistant to streptomycin (SM), isoniazid (INH), and/or rifampin (RIF) as determined by the conventional Lowenstein-Jensen proportion method (LJPM) were compared with the E test, a minimum inhibitory concentration susceptibility method . Discrepant isolates were further evaluated by BACTEC and by DNA sequence analyses for mutations in genes most often associated with resistance to these drugs (rpsL, katG, inhA, and rpoB) . Preliminary discordant E test results were seen in 75% of isolates resistant to SM and in 11% to INH . Discordance improved for these two drugs (63%) for SM and none for INH when isolates were re-tested but worsened for RIF (30%) . Despite good agreement between phenotypic results and sequencing analyses, wild type profiles were detected on resistant strains mainly for SM and INH . It should be aware that susceptible isolates according to molecular methods might contain other mechanisms of resistance . Although reproducibility of the LJPM susceptibility method has been established, variable E test results for some M . tuberculosis isolates poses questions regarding its reproducibility particularly the impact of E test performance which may vary among laboratories despite adherence to recommended protocols . Further studies must be done to enlarge the evaluated samples and looked possible mutations outside of the hot spot sequenced gene among discrepant strains. Clin Orthop, 2004 Mar, (420), 63 - 71 Treatment of the infected hip replacement; Hanssen AD et al.; Selection of the suitable treatment method for an infected hip arthroplasty requires careful assessment of patient-related variables and expected treatment goals . The basic treatment options include antibiotic suppression, open debridement, resection arthroplasty, arthrodesis, reimplantation of another prosthesis, and amputation . Successful treatment of infection requires complete debridement of all infected and foreign material and appropriate antimicrobial therapy . When possible, the preferred treatment approach is insertion of another prosthesis with a delayed reconstructive treatment technique . Patients now are presenting with an increasing incidence of resistant organisms and severe bone loss, which increases the difficulty of treatment. Biosci Biotechnol Biochem, 2004 Mar, 68(3), 571 - 7 Purification, characterization, and sequencing of novel antimicrobial peptides, Tu-AMP 1 and Tu-AMP 2, from bulbs of tulip (Tulipa gesneriana L.); Fujimura M et al.; Novel antimicrobial peptides (AMP), designated Tu-AMP 1 and Tu-AMP 2, were purified from the bulbs of tulip (Tulipa gesneriana L.) by chitin affinity chromatography and reverse-phase high-performance liquid chromatography (HPLC) . They bind to chitin in a reversible way . They were basic peptides having isoelectric points of over 12 . Tu-AMP 1 and Tu-AMP 2 had molecular masses of 4,988 Da and 5,006 Da on MALDI-TOF MS analysis, and their extinction coefficients of 1% aqueous solutions at 280 nm were 3.3 and 3.4, respectively . Half of all amino acid residues of Tu-AMP 1 and Tu-AMP 2 were occupied by cysteine, arginine, lysine, and proline . The concentrations of peptides required for 50% inhibition (IC(50)) of the growth of plant pathogenic bacteria and fungi were 2 to 20 microg/ml . The structural characteristics of Tu-AMP 1 and Tu-AMP 2 indicated that they were novel thionin-like antimicrobial peptides, though Tu-AMP 2 was a heterodimer composes of two short peptides joined with disulfide bonds. J Antimicrob Chemother, 2004 May, 53(5), 848 - 52 Epub 2004 Mar 31. Concentrations of fosfomycin in the cerebrospinal fluid of neurointensive care patients with ventriculostomy-associated ventriculitis; Pfausler B et al.; OBJECTIVE: The present study was performed to test the ability of fosfomycin to penetrate into the CSF of neurointensive care patients with ventriculostomy-associated ventriculitis . PATIENTS AND METHODS: Six patients requiring neurointensive care monitoring, including extraventricular drainage due to secondary obstructive hydrocephalus, were enrolled into the study . All patients received 8 g of fosfomycin intravenously three times a day over a period of at least 5 days . Concentrations of fosfomycin in the CSF and plasma were measured after single-dose administration and at steady state . RESULTS: Mean values of the fosfomycin area under the time-concentration curves for the dosing interval of 8 h (AUC(8)) were 929 +/- 280 and 225 +/- 131 mg.h/L for plasma and CSF after single-dose administration, respectively (P < 0.03) . The ratios of the AUC(8) for CSF to the AUC(8) for plasma were 0.23 +/- 0.07 after a single dose and 0.27 +/- 0.08 following multiple doses (P > 0.05, not significant) . Additional in vitro experiments have shown that fosfomycin exerts non-concentration-dependent microbial growth inhibition . At steady state, the time above MIC (t > MIC) values were 98%, 92% and 61% for pathogens with MIC values of 8, 16 and 32 mg/L, respectively . CONCLUSION: The present pharmacokinetic study indicates that 8 g of fosfomycin three times per day should provide sufficient antimicrobial concentrations in the CSF for the overall treatment period . Thus, the co-administration of fosfomycin could be useful for the treatment of ventriculitis caused by susceptible pathogens. Immunology, 2004 Apr, 111(4), 391 - 9 Allicin inhibits SDF-1alpha-induced T cell interactions with fibronectin and endothelial cells by down-regulating cytoskeleton rearrangement, Pyk-2 phosphorylation and VLA-4 expression; Sela U et al.; Allicin, a major ingredient of fresh garlic extract that is produced during the crushing of garlic cloves, exerts various beneficial biological effects, including a broad spectrum of antimicrobial activity, antihyperlipidaemic and antihypertensive effects . However, how allicin affects the immune system is less well known, and its effect on human T cells has never been studied . Here, we examined the in-vitro effects of allicin on the functioning of T cells related to their entry to inflamed extravascular sites . We found that allicin (20-100 microm) inhibits the SDF-1alpha (CXCL12)-induced T cell migration through fibronectin (FN), and that this inhibition is mediated by the down-regulation of (i) the reorganization of cortical actin and the subsequent T cell polarization, and (ii) T cell adhesion to FN . Moreover, allicin also inhibited T cell adhesion to endothelial cells and transendothelial migration . The mechanisms underlying these inhibitory effects of allicin are associated with its ability to down-regulate the phosphorylation of Pyk2, an intracellular member of the focal adhesion kinases, and to reduce the expression of the VCAM-1- and FN-specific alpha4beta1-integrin (VLA-4) . The ability of allicin to down-regulate these chemokine-induced and VLA-4-mediated T cell functions explains its beneficial biological effects in processes where T cells play an important role and suggests that allicin may be used therapeutically with chronic inflammatory diseases. Biotechnol Lett, 2004 Feb, 26(4), 287 - 91 Antinematodal activity and the mechanism of the antimicrobial peptide, HP (2-20), against Caenorhabditis elegans; Jang SH et al.; The peptide HP (2-20), derived from the N-terminal sequence of Helicobacter pylori ribosomal protein L1 (RPL1), has a nematicidal activity against eggs and worms of Caenorhabditis elegans . Eggs treated with HP (2-20) (69%) has a higher fluorescence intensity with propidium iodide staining, which was similar to that of melittin (82%) but higher than untreated cells (5.7%) . Confocal microscopy showed that the peptides were located in the shell of the eggs and the inner and outer surfaces of the worms . HP (2-20) therefore may exert its antinematodal activity by disrupting the structure of the egg's shell and the cell membrane via pore formation or by direct interaction with the lipid bilayers in a detergent-like manner. Gen Dent, 2003 Mar-Apr, 51(2), 176 - 81; quiz 182-3 The role of the general dentist in periodontal care; Trovato JP; Epidemiologic studies find the rate of periodontal disease in the U.S . to be of sufficient significance that periodontal therapy should not be placed uniquely in the domain of the specialist . It is advisable that periodontal record-keeping and treatment, particularly with nonsurgical techniques including scaling and root planing and subantimicrobial and antimicrobial therapy, become part of the daily routine in the general practitioner's office. Gen Dent, 2003 Sep-Oct, 51(5), 424 - 8 Microbiology and management of periodontal infections; Brook I; The term periodontal disease refers to all diseases that involve the supportive structures of the periodontium . Peridontal diseases commonly begin as a gingivitis and progress to periodontitis . Necrotizing ulcerative gingivitis (NUG) is the most fulminate form of gingivitis . The two main forms of periodontitis are chronic periodontitis (also known as adult periodontitis) and aggressive periodontitis (also known as early onset periodontitis, destructive periodontitis, and juvenile periodontitis) . Gingivitis treatment involves removing dental plaques and maintaining good oral hygiene . Periodontitis therapy should include root debriding, draining the infected root, and surgically resecting inflamed periodontal tissues . Systemic antimicrobials often are indicated in NUG, chronic periodontitis, and aggressive periodontitis . When possible, antimicrobial selection should be based upon culture and susceptibility testing of the subgingival flora. Unfallchirurg, 2004 Apr, 107(4), 325 - 7 {Varicella associated necrotizing fasciitis in a child}; Groger A et al.; We present a rare case of necrotizing fasciitis in an 5-year-old infant with preexisting varicella infection . Initially, the patient showed acute pain and swelling of the left thorax with high inflammatory parameters and varicella-specific skin affections . MRT presented diffuse soft tissue swelling of the left chest consistent with necrotizing fasciitis . After aggressive surgical debridement of necrotic tissue and extirpation of axillary lymph nodes, the clinical course improved under appropriate parenteral antimicrobial therapy using penicillin and clindamycin . In conclusion, necrotizing fasciitis should be suspected in any child with a history of varicella infection and increasing complaints of pain and swelling in an extremity or other body area associated with increasing fever, erythema, lethargy, and irritability . Shock, multiorgan failure, and death will ensue if the diagnosis is not promptly recognized. Parasite Immunol, 2003 Nov-Dec, 25(11-12), 597 - 608 Consumption of L-arginine mediated by Entamoeba histolytica L-arginase (EhArg) inhibits amoebicidal activity and nitric oxide production by activated macrophages; Elnekave K et al.; In this study we discuss the cloning and expression of Entamoeba histolytica arginase (EhArg), an enzyme that catalyses the hydrolysis of L-arginine to L-ornithine and urea . L-norvaline, a competitive inhibitor of E . histolytica L-arginase, inhibits the growth of the parasite, which suggests that the catabolism of L-arginine mediated by EhArg is essential . Nitric oxide (NO) is an antimicrobial agent that inhibits some key enzymes in the metabolism of Entamoeba histolytica . NO is synthesized by activated macrophages from L-arginine, the substrate of NO synthase (NOS-II) . We show that E . histolytica inhibits NO mediated amoebicidal activity of activated macrophages by consuming L-arginine present in the medium. Nahrung, 2004 Feb, 48(1), 69 - 72 Enhanced bactericidal action and masking of allergen structure of soy protein by attachment of chitosan through maillard-type protein-polysaccharide conjugation; Usui M et al.; The soy protein-chitosan conjugate was formed by the Maillard reaction in dry state (relative humidity 65%) at 60 degrees C for 2 weeks to improve the functional properties . The antimicrobial activity of the Maillard-type soy protein-chitosan conjugates enhanced 2-3 times that of soy protein-chitosan mixture . The soy protein-chitosan conjugate showed excellent emulsifying property with the progress of Maillard-type conjugation . The allergenicity of soy protein was greatly decreased by the attachment of chitosan through Maillard reaction . The immonoblotting analysis with patient's sera revealed that soy protein-chitosan conjugate was more effective to mask the allergen structure of soy protein causing from 34 kDa-protein (Gly m Bd 30K) than soy protein-galactomannan conjugate . The Western blotting showed that allergen (34 kDa-protein) was completely masked by soy protein-chitosan conjugation, while it was not completely masked by soy protein-galactomannan conjugation. Life Sci, 2004 Apr 30, 74(24), 3043 - 52 Propyl paraben inhibits voltage-dependent sodium channels and protects cardiomyocytes from ischemia-reperfusion injury; Ji X et al.; The effects of propyl paraben, an antimicrobial preservative, on voltage-dependent sodium current and myocardial ischemia-reperfusion injury were investigated in isolated adult rat cardiomyocytes . Whole cell voltage-clamp recording showed that propyl paraben reversibly blocked the voltage-gated sodium channel both in concentration- and voltage-dependent manners . Propyl paraben (500 microM but not 100 microM) significantly shifted the steady-state inactivation of the sodium channel toward the hyperpolarizing direction at the V(1/2) point . Consistent with the above result, the propidium iodide (PI) uptake test revealed that pretreatment with 500 microM but not 100 microM of propyl paraben significantly reduced cell death induced by 45 min of sustained ischemia followed by 15 h of reperfusion (42.37 +/- 7.01% of cell viability in control and 71.05 +/- 7.06% in the propyl paraben group), suggesting that propyl paraben can protect myocytes from ischemia-reperfusion injury . These results indicate a possible correlation between the inhibition of sodium current and cardioprotection against ischemia-reperfusion injury. Eur J Med Chem, 2004 Mar, 39(3), 267 - 72 Synthesis of some 2-{(benzazole-2-yl)thioacetylamino}thiazole derivatives and their antimicrobial activity and toxicity; Turan-Zitouni G et al.; Some 2-{(benzazole-2-yl)thioacetylamino}thiazole derivatives (III) were synthesized by reacting 4-methyl-2-(chloroacetylamino)thiazole derivatives (I) with benzazol-2-thiole (II) in acetone in the presence of K(2)CO(3) . The chemical structures of the compounds were elucidated by (1)H NMR and FAB(+)-MS spectral data . The prepared compounds were tested for antimicrobial activity and toxicity. Eur J Med Chem, 2004 Mar, 39(3), 249 - 55 Tetrazolo{1,5-a}quinoline as a potential promising new scaffold for the synthesis of novel anti-inflammatory and antibacterial agents; Bekhit AA et al.; Three series of tetrazolo{1,5-a}quinoline derivatives have been synthesized . The first series was synthesized starting by the condensation of tetrazolo{1,5-a}quinoline-4-carboxaldehyde 2 with substituted thiosemicarbazides, followed by cyclization of the resulting thiosemicarbazones 3 with malonic acid in the presence of acetyl chloride to give pyrimidyl derivatives 4a-c . The second series was prepared by the condensation of the latter compounds 4a-c with the selected aromatic aldehydes to afford the arylidene derivatives 5a-f . The third series 7a-c was synthesized by condensation of tetrazolo{1,5-a}quinoline-4-carboxaldehyde 2 with the appropriate acetophenone, followed by cyclocondensation of the formed alpha,beta-unsaturated ketones with thiourea . The newly synthesized compounds were evaluated for their anti-inflammatory and antimicrobial activities . Four compounds were proved to be as active as indomethacin in animal models of inflammation. Bioorg Med Chem, 2004 Apr 15, 12(8), 1955 - 62 Analogues of antifungal tjipanazoles from rebeccamycin; Voldoire A et al.; Analogues of antifungal tjipanazoles were obtained by semi-synthesis from rebeccamycin, an antitumor antibiotic isolated from cultures of Saccharothrix aerocolonigenes . The antiproliferative activities of the new compounds were evaluated in vitro against nine tumor cell lines . The effect on the cell cycle of murine leukemia L1210 cells was examined and the antimicrobial activities against two Gram positive bacteria, a Gram negative bacterium and a yeast were determined . The inhibitory properties toward four kinases and toward topoisomerase I were evaluated . The most cytotoxic compound in the series was a dinitro derivative characterized as a potent topoisomerase I inhibitor. Bioorg Med Chem, 2004 Apr 15, 12(8), 1845 - 52 Synthesis, antimicrobial activity and conformational analysis of novel substituted pyridines: BF(3)-promoted reaction of hydrazine with 2-alkoxy pyridines; Goda FE et al.; Some new 2-alkoxy-3-cyano-4,6-diarylpyridines 3,4 were synthesized by condensation of different alpha,beta-unsaturated ketones 1 with malononitrile 2, followed by cyclization in sodium alkoxide/alcohol system . Lewis acid-catalyzed reaction of 4 with hydrazine afforded the corresponding 1H-pyrazolo{3,4-b}pyridines 5 . The potency of the results as antimicrobial agents has been evaluated . The structure of the newly prepared compounds was assessed by microanalysis, IR and NMR spectra . Molecular mechanics (MM2) and semiemperical (AM1) molecular orbital calculations have been performed for the most biologically active compounds 5b and c to get insight into their molecular structures and to learn more about their stable molecular conformations. Comp Biochem Physiol B Biochem Mol Biol, 2004 Mar, 137(3), 413 - 20 Phospholipase A2 in porifera; Nevalainen TJ et al.; Phospholipase A2 (PLA2) catalytic activity was measured in aqueous extracts of 83 freeze-dried specimens representing 55 marine sponge species collected from the east coast of Australia including the Great Barrier Reef . High levels (>500 u/l) of PLA2 activity (defined as the amount of activity that releases 1 micromol of fatty acid per min) were found in four out of 55 species (7%), moderate activities (100-499 u/l) in 6/55 (11%), low activities (1-99 u/l) in 11/55 (20%) and no PLA2 activity in 34/55 (62%) . Species with high PLA2 activity levels included Cymbastela coralliophila (2118 u/l, specific activity 10,590 u/g of protein), Acanthella cavernosa (1318 u/l, specific activity 2470 u/g), Spirastrella vagabunda (1036 u/l, specific activity 1727 u/g and Theonella swinhoei (567 u/l, specific activity 354 u/g) . It was postulated that poriferan PLA2 may be involved in eicosanoid metabolism and antimicrobial and toxic defence of the animal. Acta Pharm, 2004 Mar, 54(1), 13 - 26 Synthesis and antimicrobial evaluation of naphtho{2,1-b}pyrano{2,3-d}pyrimidine and pyrano{3,2-e}{1,2,4}triazolo{1,5-c}pyrimidine derivatives; Eid FA et al.; Several novel naphtho{2,1-b}pyrano{2,3-d}pyrimidines, pyrano{3,2-e}{1,2,4}triazolo{1,5-c}pyrimidines and their coumarin-3-yl derivatives were synthesized . Some of these derivatives exhibited pronounced antimicrobial activities. J Org Chem, 2004 Apr 2, 69(7), 2251 - 6 Antineoplastic agents 491 . Synthetic conversion of aaptamine to isoaaptamine, 9-demethylaaptamine, and 4-methylaaptamine; Pettit GR et al.; Aaptamine (1) was used as starting material for synthetic transformation to isoaaptamine (2), 9-demethylaaptamine (5), and 4-methylaaptamine (6) . A general method for the selective O-demethylation of such 1H-benzo{de}{1,6}-naphthyridine (1) marine sponge constituents at position C-9 has been developed . Selective O-demethylation of aaptamine (1) and 1-methylaaptamine (11) with 48% hydrobromic acid led to 9-demethylaaptamine (5) and isoaaptamine (2), respectively . A selection of other aaptamine derivatives were synthesized, and their structures were unambiguously determined by X-ray methods . In addition, their cancer cell growth inhibitory properties were evaluated against the murine P388 lymphocytic cell line and a minipanel of human cancer cell lines . Evaluation as inhibitors of the PKC signal transduction pathway and against a selection of microorganisms was also undertaken . Aaptamine derivatives 3 and 5 had broad-spectrum antimicrobial activities. Med Clin North Am, 2004 Mar, 88(2), 483 - 94 Acute and chronic prostatitis; Hua VN et al.; In summary, prostatitis is a complex syndrome that spans a spectrum from acute prostatitis with a straightforward presentation to CP-CPPS with a complex array of symptoms . The identification of prostatic or pelvic pain becomes a requirement for the diagnosis of CP-CPPS . The NIH system of prostatitis categorization is a refinement of the traditional classification of prostatitis by Drach et al, which was based on the localization test of Meares and Stamey . The NIH categorization system allows for a framework to define the disease process, and the NIH-CPSI was created to quantify the symptoms of chronic prostatitis . Integral to the classification of prostatitis is the presence or absence of inflammation, determined by looking for leukocytes in the EPS, seminal fluid, and VB3 specimens . In addition, the role of bacteria as a cause in category III prostatitis continues to be debated . Future research into using inflammatory markers (eg, tumor necrosis factor-alpha, interleukin-2) and using PCR to identify the presence of bacteria may further refine the pathophysiology of prostatitis . The mainstream treatment of chronic prostatitis involves antimicrobials, non-steroidal anti-inflammatory medications, and alpha-blockers . The potential role of asymptomatic category IV chronic prostatitis in the etiology of prostate cancer may be delineated further with future research. Biotechnol Lett, 2004 Feb, 26(3), 185 - 91 Cloning, expression, and biological function of a dTDP-deoxyglucose epimerase (gerF) gene from Streptomyces sp . GERI-155; Sohng JK et al.; GERI-155 is a macrolide antibiotic containing two deoxyhexose molecules which has antimicrobial activities against gram-positive bacteria . The deoxyhexose biosynthetic gene cluster of GERI-155 from Streptomyces sp . GERI-155 genome has now been isolated . Four orf were identified and a putative orf, supposed to code for the dTDP-deoxyglucose epimerase gene, was designated as gerF . gerF was expressed in E . coli using recombinant expression vector pHJ3 . The recombinant protein expressed in a soluble form . The enzyme was purified by Ni-affinity column using imidazole buffer as eluents . The molecular mass of the expressed protein correlated with the predicted mass (36,000 Da) deduced from the cloned gene sequence data . The purified enzyme produced maltol from dTDP-4-keto-6-deoxyglucose and it was confirmed that the expressed protein was dTDP-deoxyglucose epimerase catalyzing epimerization of C-3 and C-5 or C-3 of dTDP-4-keto-6-deoxyglucose. Nat Immunol, 2004 May, 5(5), 488 - 94 Epub 2004 Mar 28. TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM; Couillault C et al.; Both plants and animals respond to infection by synthesizing compounds that directly inhibit or kill invading pathogens . We report here the identification of infection-inducible antimicrobial peptides in Caenorhabditis elegans . Expression of two of these peptides, NLP-29 and NLP-31, was differentially regulated by fungal and bacterial infection and was controlled in part by tir-1, which encodes an ortholog of SARM, a Toll-interleukin 1 receptor (TIR) domain protein . Inactivation of tir-1 by RNA interference caused increased susceptibility to infection . We identify protein partners for TIR-1 and show that the small GTPase Rab1 and the f subunit of ATP synthase participate specifically in the control of antimicrobial peptide gene expression . As the activity of tir-1 was independent of the single nematode Toll-like receptor, TIR-1 may represent a component of a previously uncharacterized, but conserved, innate immune signaling pathway. Thorax, 2004 Apr, 59(4), 318 - 23 Linkage of neutrophil serine proteases and decreased surfactant protein-A (SP-A) levels in inflammatory lung disease; Rubio F et al.; BACKGROUND: In patients with cystic fibrosis (CF) neutrophils are recruited in excess to the airways yet pathogens are not cleared and the patients suffer from chronic infections . Recent studies have shown a deficiency in airway fluids from patients with CF and other inflammatory pulmonary conditions of surfactant protein A (SP-A), a pattern recognition molecule that facilitates uptake of microbes by macrophages and neutrophils . METHODS: In vitro simulations were used to test the hypothesis that decreased SP-A levels in CF might be the result of degradation by neutrophil serine proteases . RESULTS: Very low levels of the neutrophil granule serine proteases cathepsin G, elastase, and proteinase-3 rapidly degraded pure SP-A when tested in buffered saline . The order of potency was cathepsin G>elastase>proteinase-3 . The addition of cathepsin G or elastase to normal bronchoalveolar lavage (BAL) fluid caused a dose dependent degradation of endogenous native SP-A . Cathepsin G and elastase were present in the BAL fluid from many patients with CF . Simple incubation of protease positive BAL fluid from patients with CF caused a time dependent degradation of added SP-A or, where present, endogenous SP-A . The degradation of SP-A by protease(s) in BAL fluid of patients with CF was abrogated by diisopropylfluorophosphate and monocyte/neutrophil elastase inhibitor . CONCLUSIONS: The findings strongly suggest that the neutrophil serine proteases cathepsin G and/or elastase and/or proteinase-3 contribute to degradation of SP-A and thereby diminish innate pulmonary antimicrobial defence. Antimicrob Agents Chemother, 2004 Apr, 48(4), 1307 - 12 Antimicrobial and DNA gyrase-inhibitory activities of novel clorobiocin derivatives produced by mutasynthesis; Galm U et al.; Twenty-eight novel clorobiocin derivatives obtained from mutasynthesis experiments were investigated for their inhibitory activity towards Escherichia coli DNA gyrase and for their antibacterial activities towards clinically relevant gram-positive and gram-negative bacteria in comparison to novobiocin and clorobiocin . Clorobiocin was the most active compound both against E . coli DNA gyrase in vitro and against bacterial growth . All tested modifications of the 3-dimethylallyl-4-hydroxybenzoyl moiety reduced biological activity . The highest activities were shown by compounds containing a hydrophobic alkyl substituent at position 3 of the 4-hydroxybenzoyl moiety . Polar groups in this side chain, especially amide functions, strongly reduced antibacterial activity . Replacement of the alkyl side chain with a halogen atom or a methoxy group at the same position markedly reduced activity . Transfer of the pyrrole carboxylic acid moiety from O-3" to O-2" of L-noviose moderately reduced activity, whereas the complete absence of the pyrrole carboxylic acid moiety led to a loss of activity . Desclorobiocin derivatives lacking the chlorine atom at C-8 of the 3-amino-4,7-dihydroxycoumarin moiety also showed low activity . Lack of a methyl group at O-4" of L-noviose resulted in an inactive compound . From these findings it appears that clorobiocin represents a "highly evolved" structure optimized for bacterial transport and DNA gyrase inhibition. Antimicrob Agents Chemother, 2004 Apr, 48(4), 1112 - 7 In vivo detection and quantification of tetracycline by use of a whole-cell biosensor in the rat intestine; Bahl MI et al.; An Escherichia coli biosensor strain, harboring the plasmid pTGFP2, was introduced into the gastrointestinal tract of gnotobiotic rats that continuously received drinking water containing tetracycline . Plasmid pTGFP2 contains a transcriptional fusion between a green fluorescent protein (GFP) gene and a tetracycline-regulated promoter and was shown to produce a proportional GFP signal in response to exposure to various tetracycline concentrations when harbored by an E . coli strain . The plasmid was highly unstable in the host bacteria colonizing the intestinal system of the animals, and rapid plasmid loss was observed . Reintroduction of the E . coli MC4100/pTGFP2 strain into animals already colonized by the plasmid-free E . coli strain the day before euthanasia made it possible to extract and analyze the biosensors from intestinal samples . The induction of GFP in the biosensor cells extracted from the animals was estimated on a single-cell basis by use of flow cytometry, and the mean induction of GFP in the samples was compared to a standard curve prepared from known tetracycline concentrations . The results showed that the bioavailable tetracycline concentration within the bacterial growth habitat of the intestine was proportional to the concentration of tetracycline in drinking water but represented only approximately 0.4% of the intake concentration . This is a significant finding which will help to clarify antimicrobial therapy in the intestinal environment. J Mol Biol, 2004 Apr 9, 337(5), 1073 - 7 The tylosin-resistance methyltransferase RlmA(II) (TlrB) modifies the N-1 position of 23S rRNA nucleotide G748; Douthwaite S et al.; The methyltransferase RlmA(II) (TlrB) confers resistance to the macrolide antibiotic tylosin in the drug-producing strain Streptomyces fradiae . The resistance conferred by RlmA(II) is highly specific for tylosin, and no resistance is conferred to other macrolide drugs, or to lincosamide and streptogramin B (MLS(B)) drugs that bind to the same region on the bacterial ribosome . In this study, the methylation site of RlmA(II) is identified unambiguously by liquid chromatography/electrospray ionization mass spectrometry as the N-1 position of 23S rRNA nucleotide G748 . This position is contacted by the mycinose sugar moiety of tylosin, which is absent from the other drugs . The selective resistance to tylosin conferred by m(1)G748 illustrates how differences in drug structure facilitate the drug fit at the MLS(B)-binding site . This observation is of relevance for the rational design of novel antimicrobials targeting the MLS(B) site, especially if the antimicrobials are to be used against pathogens possessing m(1)G748. Res Vet Sci, 2004 Jun, 76(3), 195 - 8 In vitro susceptibility of field isolates of Francisella tularensis subsp . holarctica recovered in Spain to several antimicrobial agents; Garcia del Blanco N et al.; Forty-two recent (1997-1999) Spanish isolates of Francisella tularensis subsp.holarctica were tested in a broth microdilution method for their susceptibilities to 29 antimicrobial agents, including penicillins, cephalosporins, cephamicins, monobactams, penems, aminoglycosides, tetracyclines, macrolides, quinolones, chloramphenicol and fosfomycin . The isolates were resistant to beta-lactam antibiotics and susceptible to chloramphenicol, ciprofloxacin, levofloxacin and norfloxacin. Berl Munch Tierarztl Wochenschr, 2004 Mar-Apr, 117(3-4), 81 - 7 {Antimicrobial susceptibility testing of bacteria isolated from animals: considerations concerning the predefinition of breakpoints from the clinical pharmacological viewpoint}; Kietzmann M et al.; In vitro susceptibility tests are performed to receive information for selecting the most suitable antibacterial agent . As result of in vitro susceptibility tests, the minimum inhibitory concentration (MIC) indicates bacteria as resistant or sensitive . To determine MIC, therapeutically relevant breakpoints have to be defined . Microbiological criteria, chemical and physical characteristics as well as pharmacokinetic and toxicological (tolerance) properties of the antimicrobial compounds have to be considered in the selection of the therapeutic agent in addition to clinical experiences . Using some concentration and time dependent antibiotics as examples, it is demonstrated that the above mentioned criteria are not sufficiently considered in currently defined breakpoints. Intensive Care Med, 2004 Jun, 30(6), 1089 - 96 Epub 2004 Mar 26. Surveillance of antimicrobial use and antimicrobial resistance in intensive care units (SARI): 1 . Antimicrobial use in German intensive care units; Meyer E et al.; OBJECTIVE: To study antimicrobial use for benchmarking and ensuring quality of antimicrobial treatment and to identify risk factors associated with the high use of antimicrobials in German intensive care units (ICUs) through implementation of the SARI (Surveillance of Antimicrobial Use and Antimicrobial Resistance in ICUs) system . DESIGN: Prospective, unit-based surveillance on antimicrobial use from February, 2000, until June, 2002 . The data are standardised by use of the defined daily dose (DDD) for each antimicrobial defined by the WHO and by calculating use per 1000 patient days . SETTING: The data were obtained from 35 German ICUs and stratified by type of ICU (medical, surgical, interdisciplinary) . RESULTS: To date, the project covers a total of 266,013 patient days in 744 reported ICU months and 354,356 DDDs . Mean antimicrobial use density (AD) was 1,332 DDD/1000 patient days and was correlated with length of stay . Penicillins with beta-lactamase inhibitor (AD 338.3) and quinolones (155.5) were the antimicrobial group with the highest ADs . Comparison with US ICARE (Intensive Care Antimicrobial Resistance Epidemiology)/AUR (Antimicrobial Use and Resistance) data revealed a higher AD for glycopeptides and 3rd generation cephalosporins in ICARE/AUR ICUs, but a higher AD for carbapenems in German SARI ICUs regardless of the type of ICU . In the multivariate analysis, length of stay was an independent risk factor for an AD above the 75% percentile of the total amount of antimicrobials used (OR 1.96 per day); likewise, for the AD above the 75% percentile of carbapenems (OR 1.90 per day) and penicillins with extended spectrum (OR 2.01 per day) . High use of glycopeptides and quinolones (AD >75% percentile) correlated with central venous catheter (CVC) rate (OR 1.14 per CVC day per 100 patient days and 1.16, respectively) . CONCLUSION: The SARI data on antimicrobials serve ICUs as a benchmark by which to improve the quality of antimicrobial drug administration and for international comparison. Can Respir J, 2004 Mar, 11(2), 131 - 7 Inpatient care of community-acquired pneumonia: the effect of antimicrobial guidelines on clinical outcomes and drug costs in Canadian teaching hospitals; Marras TK et al.; BACKGROUND: Evidence supporting antibiotic treatment guidelines and respiratory quinolones (RQs) in community-acquired pneumonia (CAP) is limited . OBJECTIVE: To study associations among guideline adherence, specific antibiotics, clinical outcomes and antibiotic costs . METHODS: A retrospective cohort study in three tertiary care university teaching hospitals in Toronto, Ontario, studying CAP inpatients between November 1997 and June 2000 . The period encompassed 12 months when an early version of empirical antibiotic guidelines was used (early cohort) and 18 months when recent guidelines (including RQs) were used (recent cohort) . RESULTS: Six hundred ninety-eight cases of CAP were reviewed, and 91% were guideline adherent . In multivariable analyses, no association was observed between guideline adherence and mortality or duration of hospitalization . Guideline-adherent cases received fewer antibiotics in both cohorts and 0.9 days less of intravenous antibiotics (P=0.04) in the recent cohort . There was no significant difference in antibiotic cost according to guideline adherence, but recent cohort guideline-adherent cases had lower drug costs than early cohort guideline-adherent cases . Antibiotic selection was associated with illness severity and was mirrored by clinical outcomes, despite controlling for the pneumonia severity index (PSI) . Treatment with anaerobic agents (odds ratio 2.7, P=0.001) or cephalosporin plus macrolide (odds ratio 2.7, P=0.02) was associated with higher mortality . Treatment with RQ monotherapy was associated with a 2.3 day shorter duration of intravenous therapy (P<0.0001) and a 19.19 dollars lower total antibiotic cost (P<0.0001) . CONCLUSION: Findings support empirical treatment guidelines for CAP and their recommendations regarding RQs . The association between mortality and anaerobic coverage or combination therapy may reflect prognostic information available at presentation but not captured by the PSI. J Dent Res, 2004 Apr, 83(4), 333 - 7 Expression of adrenomedullin and its receptors in human salivary tissue; Kapas S et al.; Adrenomedullin is a multifunctional peptide produced by a wide range of different cells and tissues . This study was designed to investigate whether adrenomedullin is present in human saliva and in salivary glands . It was expected that saliva may contain high concentrations of adrenomedullin, which has antimicrobial activity in vitro, which may have functional implications in the oral cavity . Saliva from the submandibular and parotid glands contained higher concentrations of adrenomedullin than did the circulation, but lower concentrations than in whole saliva . This suggests that oral epithelium may contribute the majority of the adrenomedullin peptide found in saliva . Specific adrenomedullin receptors were found in cell lines from the submandibular (HSG) and parotid (HSY) salivary glands . These findings suggest a paracrine/autocrine role for adrenomedullin in these tissues; however, the concentration of adrenomedullin in saliva was insufficient to suggest a significant antimicrobial action in the healthy oral cavity. J Antimicrob Chemother, 2004 May, 53(5), 832 - 6 Epub 2004 Mar 24. Efficacy of allicin, the reactive molecule of garlic, in inhibiting Aspergillus spp . in vitro, and in a murine model of disseminated aspergillosis; Shadkchan Y et al.; OBJECTIVES: The evaluation of allicin, the biologically active compound responsible for the antimicrobial activities of freshly crushed garlic cloves, in inhibiting Aspergillus spp . in vitro and in a murine model of disseminated aspergillosis . METHODS: Pure allicin was prepared by reacting synthetic alliin with a stabilized preparation of the garlic enzyme alliinase . We tested the in vitro efficacy of pure allicin against 31 clinical isolates of Aspergillus spp . using a microdilution broth method and following the NCCLS guidelines (document M-38P) . Subsequently, the in vivo efficacy of allicin was tested in immunocompetent mice infected intravenously (iv) with Aspergillus fumigatus conidia . Allicin (5 mg/kg body weight) was administered iv once daily for 5 days post-infection or orally (po) (9 mg/kg body weight) for 5 days pre-infection and 10 days post-infection . No ill effects were observed in allicin-treated uninfected mice . RESULTS: The in vitro MICs and MFCs of allicin were between 8 and 32 mg/L, indicating that allicin in its pure form may be an effective fungicide in vitro . Time-kill studies indicate that allicin exerts its fungicidal activity within 2-12 h of administration in vitro . Allicin treatment significantly prolonged survival of infected mice (P < 0.01) from mean survival time (MST) = 7.7 days in untreated mice to MST = 21.3 and 13.9 days for allicin iv and po treated mice, respectively . Allicin iv treatment led to a significant (P < 0.001) 10-fold reduction in fungal burden in A . fumigatus infected mice as evaluated by quantitative fungal cultures of kidney tissue samples . CONCLUSIONS: These favourable results, despite the short half-life of this compound in vivo, support further studies of controlled sustained release or more prolonged administration of allicin as a treatment for aspergillosis. Am J Respir Crit Care Med, 2004 Jul 15, 170(2), 133 - 40 Epub 2004 Mar 24. Effects of interferon-gamma 1b on biomarker expression in patients with idiopathic pulmonary fibrosis; Strieter RM et al.; In a recent study of IFN-gamma 1b in 330 patients with idiopathic pulmonary fibrosis (IPF), progression-free survival was unchanged; however, a trend toward lower mortality was seen in IFN-gamma 1b-treated patients compared with placebo-treated patients (9.9 vs . 16.7%; p = 0.08) . The purpose of this randomized, double-blind, placebo-controlled trial was to characterize molecular effects of subcutaneous IFN-gamma 1b (200 microg) thrice weekly for 6 months versus placebo in 32 patients with IPF . Messenger RNA in transbronchial lung biopsies and bronchoalveolar lavage cell pellet and protein levels in bronchoalveolar lavage fluid (BALF) and plasma were evaluated . After IFN-gamma 1b treatment, IFN-inducible T cell-alpha chemoattractant/CXCL11 (a chemokine with immunomodulatory, antiangiogenic, and defensin-like antimicrobial properties) increased in BALF (p = 0.016) and plasma (p < 0.001); BALF levels of epithelial neutrophil-activating protein-78/CXCL5 (p = 0.054), platelet-derived growth factor A (p = 0.033), and Type I procollagen (p = 0.096) were lower; and IFN-gamma levels were higher (p = 0.093) versus placebo . For messenger RNA in transbronchial biopsies, trends (p > 0.05 and <or= 0.10) associated with IFN-gamma 1b treatment included an increase in IFN-inducible T cell-alpha chemoattractant/CXCL11, a decrease in elastin, and smaller increases for Type III procollagen and platelet-derived growth factor B . Changes in biomarkers of fibrosis, angiogenesis, proliferation, immunomodulation, and antimicrobial activity suggest that IFN-gamma 1b may affect IPF through multiple pathways. Dev Comp Immunol, 2004 Jun, 28(7-8), 747 - 54 Organization and expression analysis of the zebrafish hepcidin gene, an antimicrobial peptide gene conserved among vertebrates; Shike H et al.; Hepcidin is an antimicrobial peptide and iron-regulatory molecule that is conserved among vertebrates . Mutations or over-expression of the human hepcidin gene have been found in patients with hemochromatosis and refractory anemia . To further understand the function and regulation of hepcidin, animal models are needed . We sequenced cDNA, genes and upstream regions of zebrafish hepcidin and analyzed gene expression by kinetic PCR . Zebrafish hepcidin genes consist of two introns and three exons that encode a prepropeptide (91 amino acids) . The amino acid sequences and gene organization were remarkably conserved between zebrafish and other species . Elevated gene expression was observed in abdominal organs, skin, and heart in fish that developed signs of infection following bacterial injection . Zebrafish may be a suitable model organism for further study of hepcidin gene regulation. Dev Comp Immunol, 2004 Jun, 28(7-8), 701 - 11 Effect of experimental microbial challenge on the expression of defense molecules in Eisenia foetida earthworm; Kohlerova P et al.; Earthworms are able to protect themselves against invading pathogens due to efficient innate defense mechanisms . Currently, two types of antimicrobial factors including lysozyme-like molecule and factors with hemolytic activity, as well as a pattern recognition protein named coelomic cytolytic factor (CCF) have been identified in Eisenia foetida earthworms . However, the modulations of these defense molecules during in vivo immune response have not been addressed . In this study, we investigated the effect of experimental challenge with live Gram-negative and Gram-positive bacteria and with beta-1,3-glucan on the expression of CCF and the hemolytic factor fetidin . In parallel, we followed levels of hemolytic activity and lysozyme-like activity in the coelomic fluid of challenged earthworms . We show that the biosynthesis of CCF, but not fetidin, is up-regulated upon microbial stimulation . Parenteral administration of bacteria or microbial polysaccharides in earthworms results, in the coelomic fluid, in augmented level of CCF, increased lysozyme-like activity and decreased hemolytic activity . The decreased hemolytic activity of the coelomic fluid reflects the increase of the whole protein content in the absence of synthesis of hemolytic proteins. J Nat Prod, 2004 Mar, 67(3), 506 - 9 Antineoplastic agents . 380 . Isolation and X-ray crystal structure determination of isoaaptamine from the Republic of Singapore Hymeniacidon sp . and conversion to the phosphate prodrug hystatin 1; Pettit GR et al.; By use of bioassay (murine P388 lymphocytic leukemia cell line) guided isolation procedures, extracts of the Republic of Singapore marine sponge Hymeniacidon sp . were found to contain demethyloxyaaptamine (1) and aaptamine (3) as prominent cancer cell growth inhibitory constituents accompanied by the trace, albeit more active, component isoaaptamine (4) . The isolation, X-ray structure elucidation, and antineoplastic and antimicrobial activities of isoaaptamine (4) have been summarized . Because of instability, isoaaptamine (4) was converted to a stable sodium phosphate prodrug designated hystatin 1 (7). Nucleosides Nucleotides Nucleic Acids, 2004, 23(1-2), 317 - 37 Synthesis of azole nucleoside 5'-monophosphate mimics (P1Ms) and their inhibitory properties of IMP dehydrogenases; Wang G et al.; IMPDH inhibitors have potential antimicrobial, anticancer and immunomodulatory effects . Nucleoside inhibitors of IMPDH exert their inhibitory effects via nucleoside 5'-MPs . Conversion of nucleoside analogs to NMPs by cellular nucleoside kinases is not assured, and usually is inefficient . In order to bypass cellular phosphorylation, a series of azole nucleoside 5'-MP mimics (P1Ms) based on ribavirin, EICAR and bredinin were synthesized and screened against human and C . albicans IMP dehydrogenises . P1Ms 8, 16, 25, 28 and 29 demonstrated substantial IMPDH inhibition with Ki values in low micromolar range. Presse Med, 2004 Mar 13, 33(5), 327 - 9 {Treatment with oral antibiotics of febrile neutropenia in onco-haematology . The experience of the EORTC antimicrobial group}; Cometta A et al.; THE CONTEXT: Up until the nineties, the intravenous administration of a broad spectrum antibiotic was the classical treatment of any patient presenting with febrile neutropenia . Since then, in patients considered at low risk and with expected of neutropenia less than 7-10 days, oral antibiotherapy has become an attractive option . TWO LARGE STUDIES: A study by the antimicrobial group of the EORTC (European organisation for research and treatment of cancer) and a North American study have compared the efficacy of an oral combination of ciprofloxacine and amoxicillin/clavulanic acid with that of an intravenous antibiotherapy in low-risk patients presenting febrile neutropenia . In both studies, the success rate was the same in the group of patients treated with oral antibiotics and those treated with intravenous antibiotics . RESERVATIONS: These two studies were conducted in hospitalised patients . No conclusions can be drawn with regard to out-patient treatment . Out-patient management would only be possible after appropriate selection of patients at low risk. J Inorg Biochem, 2004 Apr, 98(4), 601 - 15 Syntheses, crystal structures and antimicrobial activities of monomeric 8-coordinate, and dimeric and monomeric 7-coordinate bismuth(III) complexes with tridentate and pentadentate thiosemicarbazones and pentadentate semicarbazone ligands; Nomiya K et al.; Novel bismuth(III) complexes 1-4 with the tridentate thiosemicarbazone ligand of 2N1S donor atoms {Hmtsc (L1); 2-acetylpyridine (4N-morpholyl thiosemicarbazone)}, the pentadentate double-armed thiosemicarbazone ligand of 3N2S donor atoms {H2dmtsc (L3); 2,6-diacetylpyridine bis(4N-morpholyl thiosemicarbazone)} and the pentadentate double-armed semicarbazone ligand of 3N2O donor atoms {H2dasc (L4b); 2,6-diacetylpyridine bis(semicarbazone)}, were prepared by reactions of bismuth(III) nitrate or bismuth(III) chloride and characterized by elemental analysis, thermogravimetric and differential thermal analysis (TG/DTA), FTIR and NMR (1H and 13C) spectroscopy . The crystal and molecular structures of complexes 1, 2a, 2b and 4b, and the "free" ligand L1 were determined by single-crystal X-ray structure analysis . The dimeric 7-coordinate bismuth(III) complex {Bi(dmtsc)(NO3)}2, 1, and the monomeric 7-coordinate complexes {Bi(Hdasc)(H2O)}(NO3)2.H2O (major product), 2a, and {Bi(dasc)(H2O)}NO3.H2O (minor product), 2b, all with pentagonal bipyramidal bismuth(III) centers, are depicted with one electron pair (6s2) of the bismuth(III) atom, deprotonated forms of multidentate thiosemicarbazone or semicarbazone ligands, and monodentate NO3 or H2O ligands, respectively . These complexes are related to the positional isomers of one electron pair of the bismuth(III) atom; 1 has an electron pair positioned in the pentagonal plane (basal position), while 2a and 2b have an electron pair in the apical position . The monomeric 8-coordinate complex {Bi(mtsc)2(NO3)}, 4b, which was obtained by slow evaporation in MeOH of the 1.5 hydrates 4a, was depicted with one electron pair of the bismuth(III) atom, two deprotonated mtsc- ligand and one nitrate ion . On the other hand, crystals of the complex "{Bi(mtsc)Cl2}", 3, prepared by a reaction of BiCl3 with L1 showed several polymorphs (3a, 3b, 3c and 3d) due to coordination and/or solvation of dimethyl sulfoxide (DMSO) used in the crystallization . Bismuth(III) complexes 1 and 4a showed selective and effective antibacterial activities against Gram-positive bacteria . The structure-activity relationship was discussed. Clin Ther, 2004 Feb, 26(2), 271 - 81 Effects of blood loss and fluid volume replacement on serum and tissue gentamicin concentrations during colorectal surgery; Markantonis SL et al.; BACKGROUND: The prophylactic administration of antimicrobial agents to surgical patients has become standard practice to minimize the risk for postsurgical infection . During surgery, factors such as renal clearance, fluid administration, and blood loss contribute to drug concentrations achieved in the blood and tissues . The aminoglycoside gentamicin was chosen to investigate these factors because it is used for standard antimicrobial prophylaxis in colorectal surgery . OBJECTIVE: The aim of this study was to investigate the effects of surgical blood loss and fluid volume replacement on gentamicin concentrations in serum and in 3 tissue types (subcutaneous fat, epiploic fat, and colonic wall) in patients undergoing colorectal surgery . METHODS: This uncontrolled, open-label study was conducted at the Aretaieion Hospital (Athens, Greece) between November 2002 and March 2003 . Patients selected for this study were scheduled to undergo elective colorectal surgery of ? 2-hour duration with general and epidural anesthesia and to receive gentamicin as major antimicrobial prophylaxis . Blood and tissue samples were obtained concurrently at specific times throughout each procedure . The effect of intraoperative blood loss on gentamicin concentrations and its pharmacokinetic properties was determined . RESULTS: Sixteen patients completed the study (11 men, 5 women; white race, 16 patients {100%}; mean {SD} age, 61 {3} years {range, 39-80 years}) . Mean (SEM) serum gentamicin concentration was found to be insufficient; the maximum plasma drug concentration/minimum inhibitory concentration (MIC) ratio was <8:1 for pathogens commonly isolated in the surgical unit of the hospital (MIC: 1-4 microg/mL) . The mean (SEM) concentration at first surgical incision was 7.83 (0.82) microg/mL and decreased to 2.60 (0.28) microg/mL at skin closure, resulting in borderline effectiveness even for susceptible gram-positive microorganisms (MIC approximately 1.0) . Initially, mean (SEM) tissue gentamicin concentrations in subcutaneous fat, epiploic fat, and colonic wall were low (2.02 {0.34} microg/mL, 2.41 {0.42} microg/mL, and 1.93 {0.38} microg/mL, respectively) and decreased approximately 1.0 microg/mL ( approximately 50%) by skin closure . Statistically significant positive correlations were found between gentamicin concentrations in serum and tissues (P </= 0.03) . A strong negative correlation was found between the intravenously administered fluids and gentamicin concentrations in serum and tissues (P </= 0.04) . CONCLUSIONS: In this study, the administration of a 2-mg/kg dose of gentamicin as antimicrobial prophylaxis during colorectal surgery associated with significant intraoperative blood loss and therefore requiring significant fluid replacement did not achieve concentrations of the drug above MICs for gram-negative microorganisms throughout the procedures in either serum or tissue samples. Arzneimittelforschung, 2004, 54(2), 119 - 24 Synthesis and preliminary antimicrobial evaluation of new 7-(N-pyrrolyl) derivatives of cephalosporins; Bijev A et al.; A series of seven new cephalosporins was prepared for preliminary microbiological evaluation by N-acylation of 7-aminocephalosporanic acid with substituted N-pyrrolylcarboxylic acids via mixed anhydrides . The chemical structure of the compounds were confirmed by IR, 1H-NMR and mass spectral data . The 7-(N-pyrrolyl) cephalosporin derivatives were tested in vitro by the disc diffusion method upon 3 strains and subsequent determination of the minimal inhibitory concentration (MIC) of the most active ones upon 29 strains . The products of the series exhibited antibacterial activity . They showed selective potency against gram-positive and were practically inactive against gram-negative microorganisms . The compound 3-{(acetyloxy)methyl}-7-({2-{3-(ethoxycarbonyl)-2-methyl-5-phenyl-1H-1-pyrrolyl}acetyl}amino)-6-oxo-7,7a-dihydro-2H,6H-aceto{2,1-b}{1,3}thiazine-4-carboxylic acid (4a) was outlined as more active than the reference cefazolin (CAS 23325-78-2) in regard to S . pyogenes and some strains of S . aureus, the MIC of 4a against S . pyogenes were at least 4-fold lower . The toxicological evaluations of the starting N-pyrrolylcarboxylic acids showed no acute toxicity. Nippon Rinsho, 2004 Mar, 62(3), 489 - 94 {Second-line eradication therapy for H . pylori infection}; Murakami K et al.; The widespread use of eradication therapy for Helicobacter pylori has lead to an increase in antibiotic-resistant strains and the problem of retreatment in cases of eradication failure . Retreatment in cases of eradication failure has achieved relatively good results with regimens containing bismuth compounds and tetracyclines in the world, but consensus has not been reached in Japan and each institution has its own policy . An triple therapy consisted of proton pump inhibitor, amoxicillin and metronidazole has been reported to show a good cure rate as a second line therapy in Japan, but metronidazole has not been approved by the Japanese regulatory authority for use against bacterial infections, including H . pylori, despite its worldwide use as an antimicrobial agent in H . pylori eradication regimens. Arch Pharm (Weinheim), 2004 Mar, 337(3), 140 - 7 Synthesis and antimicrobial evaluation of some novel cholestane heterocyclic derivatives; Elmegeed GA et al.; This study was performed to investigate the reactivity of 5alpha-cholestan-3-one (1) towards various chemical reagents to produce new steroidal heterocyclic derivatives . The aminothieno{2, 3:2, 3}cholestane derivative 2 was synthesized according to Gewald's conditions . The diazonium salt of compound 2 coupled with malononitrile to afford dicyanomethylenhydrazinothieno{2', 3':2, 3}cholestane derivative 5 . The behavior of compound 5 towards nitrogen nucleophiles and several active methylene reagents was investigated . Additionally, a variety of steroidal heterocyclic derivatives like compounds 15a, b-22a, b were synthesized starting with 5alpha-cholestan-3-one (1) . The structures of the compounds were established based on the analytical and spectral data . The in vitro antimicrobial activity of some newly synthesized compounds against bacteria and fungi was studied. AJNR Am J Neuroradiol, 2004 Mar, 25(3), 395 - 401 Neurobrucellosis: clinical and neuroimaging correlation; Al-Sous MW et al.; BACKGROUND AND PURPOSE: Manifestation of nervous system involvement by neurobrucellosis, a treatable infection, is not well documented . We investigated patterns of nervous system involvement and determined if neuroimaging abnormalities correlated with clinical manifestations of neurobrucellosis . METHODS: We reviewed 23 MR imaging studies (17 of brain, six of spine) and seven CT scans of brain in 23 patients (14 male and nine female patients; age range 17-71 years) with positive Brucella titers in their serum and CSF . RESULTS: Twelve patients had central nervous system (CNS) involvement, four had peripheral nervous system (PNS) involvement, two had combined PNS and CNS involvement, and five had isolated hearing loss . Imaging findings were variable: five of seven brain CT studies were normal, and 10 of 23 MR studies were normal (eight brain, one thoracic, one lumbar) . One brain CT study showed subthalamic hemorrhage, mild perivascular enhancement, left caudate lacunae, and diffuse white matter changes . One other brain CT study showed enhancement of the tentorium in addition to white matter changes . Abnormal MR findings were basal meningeal enhancement (n = 3), lumbar nerve root enhancement (n = 3), granuloma of the suprasellar region (n = 1), diffuse white matter changes (n = 7), and spinal cord atrophy (n = 1) . All patients improved after treatment with three antimicrobial drugs for 3-12 months . Seven patients had follow-up imaging; the enhancement disappeared but the white matter and ischemic changes persisted despite almost complete clinical recovery . CONCLUSION: Clinical-radiologic correlation in neurobrucellosis varies from a normal imaging study despite positive clinical findings, to a variety of imaging abnormalities that reflect either an inflammatory process, an immune-mediated process, or a vascular insult. Int J Antimicrob Agents, 2004 Mar, 23 Suppl 1, S75 - 8 Prevention of catheter-related infections: the potential of a new nano-silver impregnated catheter; Samuel U et al.; Contaminated or infected catheters are a major source of nosocomial infections responsible for >40% of all episodes of nosocomial sepsis in acute-care hospitals . Antibiotics as well as surface modifications with, for example, hydrogels proved to be of little value in preventing the contamination of indwelling catheters . The even distribution of 10(12-13) activated silver nanoparticles per gram in various polymers, e.g . polyurethane and silicone, results in an excellent antimicrobial activity against a broad spectrum of organisms in vitro . Substantial reduction of incrustation of these catheters was also observed . These preliminary experimental data warrant clinical studies. Int J Antimicrob Agents, 2004 Mar, 23 Suppl 1, S17 - 23 Controversies in antibiotic prophylaxis in urology; Grabe M; Antibiotic prophylaxis in urologic surgery remains controversial . However, progress has been made and some of the controversies have been answered . Firstly, it is important to underline that urologic diagnostic and therapeutic procedures can induce surgical site infections (SSIs), bacteriuria, pyelonephritis and septicaemia in a substantial number of patients, too great to be neglected . Secondly, as patients are different and have various risk factors, a careful assessment of the patient and its individual risk is crucial . Thirdly, the same procedure may be totally different from one individual to another and they can rarely be grouped as standard procedures . A floating level of invasiveness is followed by a variation of the risk of infection . Fourthly, the pathogens and their susceptibility pattern vary extensively in Europe so that no clear-cut recommendations as for the choice of antibiotics can be given . Basic principles of antibiotic prophylaxis in terms of timing, mode of administration and length of regiment apply for urologic interventions . Thus, clean operations will usually not require antimicrobial prophylaxis except for those including the implant of a prosthetic device, while clean-contaminated will benefit from preventive antimicrobials . It is the task of the urologists to carefully assess each individual patient and procedure to opt for an optimal prophylaxis. Chem Phys Lipids, 2004 Mar, 128(1-2), 135 - 48 The isoprostanoid pathway in plants; Thoma I et al.; Higher plants are generally unable to synthesize arachidonic acid, and thus, do neither form prostaglandins nor C20-isoprostanes . Instead, plants utilize linolenic acid for the synthesis of prostaglandin-like compounds of the jasmonate type via the lipoxygenase/allene oxide synthase pathway and C18-isoprostanoids, termed phytoprostanes, via a nonenzymatic, free radical catalyzed pathway analogous to the isoprostane pathway in animals . Both pathways are constitutively present in many if not all plants . Formation of jasmonates can be triggered by specific stimuli interacting with membrane receptors while phytoprostane synthesis can be induced by ROS and heavy metals . Jasmonates are established plant signal compounds that induce defense responses including accumulation of antimicrobial secondary metabolites (phytoalexins) . Preliminary data indicates that phytoprostanes also induce phytoalexins in a variety of plant species suggesting a possible function of phytoprostanes as mediators of defense reactions in response to oxidative stress in plants. Trends Biotechnol, 2004 Mar, 22(3), 142 - 6 Potential applications of microbial surfactants in biomedical sciences; Singh P et al.; The main commercial use of biosurfactants is in pollution remediation because of their ability to stabilize emulsions . This enhances the solubility and availability of hydrophobic pollutants, thus increasing their potential for biodegradation . One useful property of many biosurfactants that has not been reviewed extensively is their antimicrobial activity . Several biosurfactants have strong antibacterial, antifungal and antiviral activity . Other medically relevant uses of biosurfactants include their role as anti-adhesive agents to pathogens, making them useful for treating many diseases and as therapeutic and probiotic agents . Here, we discuss some of the new and exciting applications and related developments of various microbial surfactants in the field of biomedical sciences. Biochemistry, 2004 Mar 30, 43(12), 3590 - 9 Energetics of pore formation induced by membrane active peptides; Lee MT et al.; Antimicrobial peptides are known to form pores in cell membranes . We study this process in model bilayers of various lipid compositions . We use two of the best-studied peptides, alamethicin and melittin, to represent peptides making two types of pores, that is, barrel-stave pores and toroidal pores . In both cases, the key control variable is the concentration of the bound peptides in the lipid bilayers (expressed in the peptide-lipid molar ratio, P/L) . The method of oriented circular dichroism (OCD) was used to monitor the peptide orientation in bilayers as a function of P/L . The same samples were scanned by X-ray diffraction to measure the bilayer thickness . In all cases, the bilayer thickness decreases linearly with P/L and then levels off after P/L exceeds a lipid-dependent critical value, (P/L)* . OCD spectra showed that the helical peptides are oriented parallel to the bilayers as long as P/L < (P/L)*, but as P/L increases over (P/L)*, an increasing fraction of peptides changed orientation to become perpendicular to the bilayer . We analyzed the data by assuming an internal membrane tension associated with the membrane thinning . The free energy containing this tension term leads to a relation explaining the P/L-dependence observed in the OCD and X-ray diffraction measurements . We extracted the experimental parameters from this thermodynamic relation . We believe that they are the quantities that characterize the peptide-lipid interactions related to the mechanism of pore formation . We discuss the meaning of these parameters and compare their values for different lipids and for the two different types of pores . These experimental parameters are useful for further molecular analysis and are excellent targets for molecular dynamic simulation studies. Clin Infect Dis, 2004 Apr 1, 38(7), 934 - 8 Epub 2004 Mar 15. Role of infectious diseases consultants in management of antimicrobial use in hospitals; Sunenshine RH et al.; The Infectious Diseases Society of America Emerging Infections Network (EIN) surveyed its members to characterize antimicrobial restriction policies in their hospitals and the involvement of infectious diseases consultants in this process . Of the 502 respondents (73%), 250 (50%) indicated that their hospital pharmacies would not dispense certain antimicrobials without approval of infectious diseases consultants . Moreover, 89% agreed that infectious diseases consultants need to be directly involved in the approval process . At hospitals with control policies, commonly restricted agents included lipid formulations of amphotericin B, carbapenems, fluoroquinolones, piperacillin-tazobactam, and vancomycin . Only 46 EIN members (18%) reported remuneration of infectious diseases consultants for participation in the approval process . Pediatric infectious diseases consultants were more likely to practice in hospitals with restriction policies than were adult infectious diseases consultants (64% vs . 45%; P<.001) . Similarly, teaching hospitals were more likely to have antimicrobial-control policies than were nonteaching facilities (60% vs . 17%; P<.001). Med Oncol, 2004, 21(1), 21 - 30 Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo; Vigushin DM et al.; Gliotoxin is a natural mycotoxin with immunosuppressive and antimicrobial activity . Inhibition of farnesyltransferase (IC50 80 microM) and geranylgeranyltransferase I (IC50 17 microM) stimulated interest in the potential antitumor activity of this epidithiodioxopiperazine . Gliotoxin inhibited proliferation of six breast cancer cell lines in culture with mean +/- SD IC50 289 +/- 328 microM (range 38-985 microM); intracellular farnesylation of Lamin B and geranylgeranylation of Rap1A were inhibited in a dose-dependent manner . In randomized controlled studies using the N-methyl-N-nitrosourea rat mammary carcinoma model, gliotoxin had pronounced antitumor activity in vitro and little systemic toxicity when administered to 10 animals at 10 mg/kg by subcutaneous injection weekly for 4 wk compared with 10 controls . Single doses up to 25 mg/kg were well tolerated . The present studies confirm that gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with pronounced antitumor activity and favorable toxicity profile against breast cancer in vitro and in vivo. Endocrinology, 2004 Jul, 145(7), 3165 - 73 Epub 2004 Mar 19. The androgen-regulated epididymal sperm-binding protein, human beta-defensin 118 (DEFB118) (formerly ESC42), is an antimicrobial beta-defensin; Yenugu S et al.; Spermatozoa bind a variety of proteins as they pass through the proximal regions of the epididymis, where they acquire forward motility and fertilizing ability . Recent evidence indicates that certain epididymis-specific secretory proteins that bind sperm have antibacterial activity and may function as part of the innate immune system . We reported earlier that ESC42, now designated human beta-defensin 118 (DEFB118), is a sperm-binding protein . In this study, we demonstrate that DEFB118 has potent antibacterial activity that is dose, time, and structure dependent . Incubation of Escherichia coli for 60 min with 10 microg/ml DEFB118 reduced bacterial survival to 20% of the control, and 25 microg/ml reduced survival to 5% of the control . DEFB118 concentrations of 50 and 100 microg/ml further reduced survival to less than 2 and 1%, respectively . A biphasic effect of salt concentration on the antibacterial activity of DEFB118 was observed . Reduction of disulfide bonds and alkylation of cysteines resulted in the complete loss of antibacterial activity . DEFB118 caused rapid permeabilization of both outer and inner membranes of E . coli and striking morphological alterations in the bacterial surfaces visible by scanning electron microscopy consistent with a membrane-disruptive mechanism of bacterial killing . In contrast, eukaryotic cell membranes were not permeabilized by DEFB118, as indicated by the rat erythrocyte hemolytic assay . Studies on DEFB118 inhibition of macromolecular synthesis and membrane permeability in E . coli were consistent with a primary effect at the cell membrane level . DEFB118 may contribute to epididymal innate immunity and protect the sperm against attack by microorganisms in the male and female reproductive tracts. Contraception, 2004 Apr, 69(4), 333 - 8 Contraceptive efficacy of antimicrobial peptide Nisin: in vitro and in vivo studies; Aranha C et al.; Sexually transmitted infections and unplanned pregnancies present a great risk to the reproductive health of women . Therefore, female-controlled vaginal products directed toward disease prevention and contraception are needed urgently . In the present study, efforts were made to evaluate the contraceptive potential of Nisin . The effect of Nisin on sperm motility was assessed under in vitro and in vivo conditions . The results showed that sperm motility was completely inhibited with Nisin . The minimum effective concentration of Nisin required to immobilize sperm (80-100 x 10(6)) in vitro within 20 s was found to be 50 microg in rat, 200 microg in rabbit and 300-400 microg in monkey and human . The effect on sperm motility was observed to be dose- and time-dependent . Intravaginal administration of Nisin (200 microg) before mating during proestrus-estrous transition phase caused complete arrest of sperm motility and blockage of conception . Subacute toxicity studies in rats indicated that, repetitive intravaginal application of Nisin at the dose of 200 microg for 14 consecutive days induced no abnormalities either in the length of estrous cycle or in the morphology of vaginal epithelial cells . No histopathological abnormalities in vaginal tissue or any change in blood and serum biochemical profiles were observed . Furthermore, no adverse effects were observed on subsequent reproductive performance, neonate survival and development of pups . It is suggested that Nisin, with its antibacterial and spermicidal activities, could be developed as a potent vaginal contraceptive for future use in humans. Enferm Infecc Microbiol Clin, 2003 May, 21 Suppl 2, 64 - 71 {The future of antimicrobial susceptibility testing}; Martinez-Martinez L; Antimicrobial susceptibility testing is one of the more clinically relevant activities on the management of infected patients . There is not definitive demonstration that, from a clinical point of view, obtaining MIC is better than determining clinical categories, but several evidences indicate that MIC values are actually useful . Several studies have shown that it is more relevant to demonstrate resistance than to demonstrate susceptibility . Different committees have established breakpoints for defining clinical categories that may differ in some cases . It would be necessary to reach an agreement in defining these breakpoints, as well as in standardizing methods for antibiogram . The introduction of the Etest has been one of the main methodological developments in the last years, but its cost may limit its use . Several automatic methods have been developed with improved level of automation and being able of providing susceptibility testing results on the same day of the inoculation of panels . Some methods based on digital lecture are able to automatically read disk diffusion plates . Although major advances in molecular methods have been obtained, we are still far of its routine use in clinical laboratories; it is possible that microchips may contribute in this direction . Computers have been successfully applied to the development of expert systems for interpretative reading of the antibiogram and for developing surveillance programs for resistant microorganisms . Obtaining rapid susceptibility testing results that are made available to the clinician as soon as possible has great clinical impact in terms of therapeutic success, better antimicrobial use and reduced costs. Enferm Infecc Microbiol Clin, 2003 May, 21 Suppl 2, 37 - 43 {Blood cultures and cerebrospinal fluid}; Pascual A; Despite the important advances in the molecular diagnosis of infectious diseases, blood cultures keeps being a key tool for the diagnosis of sepsis . Currently, the conventional methods are being adapted to shorten the time of emission of final results, particularly those related to identification and susceptibility to antimicrobial agents . The direct information from microbiologists to clinicians improves the choice of antimicrobial therapy and decreases the costs of hospitalization . In infectious meningitis, although the use of conventional methods, Gram stain and culture, is needed, the application of new molecular methods will be particularly useful since the number on pathogens and their resistance or virulence genes to be detected, are more limited. Enferm Infecc Microbiol Clin, 2003 May, 21 Suppl 2, 32 - 6 {The role of the microbiologist in the control of nosocomial infection and antibiotic therapy}; Bouza E; The microbiologist is a key figure in the control of hospital infection and in antimicrobial policy . Some of the contributions to the area of documentation and information can be summarized as follows: information on the development of isolation of sentinel microorganisms and their distribution in services and areas, the development of resistance of the various microorganisms to the most commonly used antimicrobial agents, molecular characterization of the isolated microorganisms causing epidemic outbreaks and the control of environmental microorganisms posing a threat to hospitals.Concerning interventions, microbiologists make a substantial contribution to teaching activity and to the continuing education required to maintain optimal knowledge on infections and microbiology in hospitals . They also recommend therapeutic approaches to the presence of isolated microorganisms and specific situations, collaborate in the design of antimicrobial prophylaxis and illustrate the policy of patient isolation . Microbiologists play a key role in decisions to introduce new drugs in hospitals and in programs to limit their inappropriate use.Finally, microbiologists and microbiology services constitute a central element where all the activities required for the diagnosis, treatment and control of infection performed by the various hospital services converge. Biochem J, 2004 Jun 15, 380(Pt 3), 859 - 65 Effects of the antimicrobial peptide temporin L on cell morphology, membrane permeability and viability of Escherichia coli; Mangoni ML et al.; Antimicrobial peptides are produced by all organisms in response to microbial invasion and are considered as promising candidates for future antibiotics . There is a wealth of evidence that many of them interact and increase the permeability of bacterial membranes as part of their killing mechanism . However, it is not clear whether this is the lethal step . To address this issue, we studied the interaction of the antimicrobial peptide temporin L with Escherichia coli by using fluorescence, confocal and electron microscopy . The peptide previously isolated from skin secretions of the frog Rana temporaria has the sequence FVQWFSKFLGRIL-NH2 . With regard to fluorescence microscopy, we applied, for the first time, a triple-staining method based on the fluorochromes 5-cyano-2,3-ditolyl tetrazolium chloride, 4',6-diamidino-2-phenylindole and FITC . This technique enabled us to identify, in the same sample, both living and total cells, as well as bacteria with altered membrane permeability . These results reveal that temporin L increases the permeability of the bacterial inner membrane in a dose-dependent manner without destroying the cell's integrity . At low peptide concentrations, the inner membrane becomes permeable to small molecules but does not allow the killing of bacteria . However, at high peptide concentrations, larger molecules, but not DNA, leak out, which results in cell death . Very interestingly, in contrast with many antimicrobial peptides, temporin L does not lyse E . coli cells but rather forms ghost-like bacteria, as observed by scanning and transmission electron microscopy . Besides shedding light on the mode of action of temporin L and possibly that of other antimicrobial peptides, the present study demonstrates the advantage of using the triple-fluorescence approach combined with microscopical techniques to explore the mechanism of membrane-active peptides in general. Curr Med Chem, 2004 Mar, 11(6), 765 - 73 Developing inhibitors to selectively target two-component and phosphorelay signal transduction systems of pathogenic microorganisms; Stephenson K et al.; Two-component signal transduction systems and their expanded variants known as phosphorelays are integral elements of the virulence and antimicrobial resistance responses of a wide range of pathogenic bacteria and fungi and also regulate essential functions . As a consequence, two-component systems and phosphorelays are recognized targets for the development of novel antimicrobial agents and a number of chemically synthesized inhibitors from different chemical classes have been identified by compound library screens . However, in the majority of cases these compounds do not appear to be selective for signal transduction pathways and exert their effect by multiple mechanisms of action . The key to designing molecules to selectively disrupt signal transduction may lie with the conserved features of response regulators and the structural analysis of complexes of signaling proteins. Annu Rev Immunol, 2004, 22, 817 - 90 CD1: antigen presentation and T cell function; Brigl M et al.; This review summarizes the major features of CD1 genes and proteins, the patterns of intracellular trafficking of CD1 molecules, and how they sample different intracellular compartments for self- and foreign lipids . We describe how lipid antigens bind to CD1 molecules with their alkyl chains buried in hydrophobic pockets and expose their polar lipid headgroup whose fine structure is recognized by the TCR of CD1-restricted T cells . CD1-restricted T cells carry out effector, helper, and adjuvant-like functions and interact with other cell types including macrophages, dendritic cells, NK cells, T cells, and B cells, thereby contributing to both innate and adaptive immune responses . Insights gained from mice and humans now delineate the extensive range of diseases in which CD1-restricted T cells play important roles and reveal differences in the role of CD1a, CD1b, and CD1c in contrast to CD1d . Invariant TCR alpha chains, self-lipid reactivity, and rapid effector responses empower a subset of CD1d-restricted T cells (NKT cells) to have unique effector functions without counterpart among MHC-restricted T cells . This review describes the function of CD1-restricted T cells in antimicrobial responses, antitumor immunity, and in regulating the balance between tolerance and autoimmunity. Annu Rev Immunol, 2004, 22, 361 - 403 Autoimmune and inflammatory mechanisms in atherosclerosis; Wick G et al.; The present review focuses on the concept that cellular and humoral immunity to the phylogenetically highly conserved antigen heat shock protein 60 (HSP60) is the initiating mechanism in the earliest stages of atherosclerosis . Subjecting arterial endothelial cells to classical atherosclerosis risk factors leads to the expression of HSP60 that then may serve as a target for pre-existent cross-reactive antimicrobial HSP60 immunity or bona fide autoimmune reactions induced by biochemically altered autologous HSP60 . Endothelial cells can also bind microbial or autologous HSP60 via Toll-like receptors, providing another possibility for targetting adaptive or innate immunological effector mechanisms. Annu Rev Immunol, 2004, 22, 181 - 215 Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense; Yang D et al.; Mammals generate a diverse array of antimicrobial proteins, largely represented by defensins or cathelicidins . The direct in vitro microbicidal activity of antimicrobial proteins has long been considered an important innate immune defense, although the in vivo relevance has only very recently been established for certain defensins and cathelicidins . Mammalian defensins and cathelicidins have also been shown to have multiple receptor-mediated effects on immune cells . Beta-defensins interact with CCR6; murine beta-defensin-2 in addition activates TLR4 . Cathelicidins act on FPRL1-expressing cells . Furthermore, several defensins have considerable immunoenhancing activity . Thus, it appears that mammalian antimicrobial proteins contribute to both innate and adaptive antimicrobial immunity. J Manag Care Pharm, 2004 Mar-Apr, 10(2), 152 - 8 Improving antimicrobial use: longitudinal assessment of an antimicrobial team including a clinical pharmacist; Arnold FW et al.; BACKGROUND: Inappropriate antimicrobial utilization in hospitalized patients has been associated with adverse effects, emergence of resistant bacteria, and increased health care cost . Participation of clinical pharmacists, working as an integral part of a hospital antimicrobial management team (AMT), has been shown to improve antimicrobial use; however, the long-term impact of such a team on antimicrobial use is unclear . OBJECTIVE: Our primary objective was to evaluate whether the number of recommendations to improve antimicrobial use made by a hospital AMT decreased over time . Our secondary objective was to identify and evaluate the acceptance of AMT recommendations with respect to the clinical service, site of infection, and category of suboptimal use . METHODS: We retrospectively reviewed antimicrobial utilization data collected by the team for the 3-year period from July 1996 to June 1999 at the Veterans Affairs Medical Center in Louisville, Kentucky . The total number of antimicrobial treatment episodes and the number of recommendations were grouped into periods of 6 months each during the 3 years . The type of recommendation, type of infection, and clinical service (medicine versus surgery) were reviewed for the entire 3-year period . RESULTS: The number of antimicrobial treatment episodes for each of the 6-month consecutive periods was 404, 526, 406, 549, 507, and 612 . The proportion of episodes requiring team recommendations was constant over the 5 consecutive periods: 39%, 37%, 36%, 36%, 35%, and 37% . (P = 0.8) . Acceptance rates of AMT recommendations by the internal medicine and general surgery services remained stable over the length of the study, 84% and 69%, respectively . The distribution of patients treated by the site of infection also remained stable over the study period . CONCLUSION: Our results demonstrate that despite the long-term presence of an AMT, the proportion of antimicrobial episodes requiring intervention and the percentage of accepted recommendations remained constant over a 3-year period . Having new resident physicians in teaching hospitals or staff turnover in managed care organizations may necessitate the continued presence of an active AMT. J Chem Inf Comput Sci, 2004 Mar-Apr, 44(2), 515 - 21 Designing antibacterial compounds through a topological substructural approach; Molina E et al.; A novel application of TOPological Substructural MOlecular DEsign (TOPS-MODE) was carried out in antibacterial drugs using computer-aided molecular design . Two series of compounds, one containing antibacterial and the other containing non-antibacterial compounds, were processed by a k-means cluster analysis in order to design training and predicting series . All clusters had a p-level < 0.005 . Afterward, a linear classification function has been derived toward discrimination between antibacterial and non-antibacterial compounds . The model correctly classifies 94% of active and 86% of inactive compounds in the training series . More specifically, the model showed a global good classification of 91%, i.e., 263 cases out of 289 . In predicting series, the model has shown overall predictabilities of 91 and 83% for active and inactive compounds, respectively . Thereby, the model has a global percentage of good classification of 89% . The TOPS-MODE approach, also, similarly compares with respect to one of the most useful models for antimicrobials selection reported to date. J Antibiot (Tokyo), 2004 Jan, 57(1), 52 - 8 Tripropeptins, novel antimicrobial agents produced by Lysobacter sp; Hashizume H et al.; Planar structures of tripropeptins (TPPs) were elucidated by spectroscopic studies including various NMR measurements . Stereochemistry of constituent amino acids of tripropeptin C (TPPC) (3) was identified by marfey's method except hydroxyproline which was determined by studies of NMR and CD spectra . The absolute structure of 3 was determined by analyses of the fragments obtained by Birch reduction and LiBH4 reduction of 3 . The configuration of the fatty acid, isolated from acid hydrolysate of 3, was determined to be (3R)-hydroxy-13-methyltetradecanoic acid from MS, NMR spectra and negative sign of the optical rotation. J Anim Sci, 2004 Mar, 82(3), 845 - 50 Effects of dietary energy and starch concentrations for newly received feedlot calves: II . Acute-phase protein response; Berry BA et al.; Two hundred forty five market-stressed bull and steer calves (205 +/- 14 kg) were received in January and September 2001 to determine the response of acute-phase proteins to dietary energy and starch concentrations and to determine whether acute-phase proteins could be used as a diagnostic or prognostic tool for calves affected by bovine respiratory disease . On arrival, calves were randomly assigned to one of two dietary energy levels (0.85 or 1.07 Mcal of NEg/kg of DM) and one of two dietary starch levels (34 or 48% of dietary ME from starch; n = 5 pens/treatment) . All calves were weighed, and plasma and serum samples were collected from a subset of animals (n = 6 calves/pen; 30 calves/treatment) on d 0, 7, 14, 28, and 42 of the receiving period . This subset of calves (n = 120) was used for all subsequent analyses . Concentrations of fibrinogen (Fb), haptoglobin (Hp), and serum amyloid-A (SaA) were determined . In addition, samples were collected from the subset of calves when they received medical treatment and 7 d following treatment to measure serum concentrations of Hp and SaA . Serum concentrations of Fb, Hp, and SaA did not differ among dietary treatments, but decreased (P < 0.03) as day of the receiving period increased . Fibrinogen (P < 0.001) and the ratio of Fb:total blood protein were greater (P < 0.003) in calves treated multiple times than in calves never treated or treated once for bovine respiratory disease . In addition, on d 0 and 7, Hp concentration increased (antimicrobial treatment x day interaction, P < 0.03) as the number of antimicrobial treatments increased, and was greater on d 14 and 28 in calves treated multiple times than in calves never treated or treated once . Haptoglobin concentration was greater (P < 0.05) in calves on medical treatment days compared with recovery days (7 d after medical treatment) . Although diet seemed to have little effect on acute-phase protein response, these results suggest that haptoglobin may be useful as a diagnostic tool to make management decisions regarding treatment protocols for calves with bovine respiratory disease. J Chromatogr A, 2004 Mar 12, 1029(1-2), 57 - 65 Optimization by experimental design and artificial neural networks of the ion-interaction reversed-phase liquid chromatographic separation of twenty cosmetic preservatives; Marengo E et al.; Particular attention are recently receiving antimicrobial agents added as preservatives in hygiene and cosmetics commercial products, since some of them are suspected to be harmful to the human health . The preservatives used belong to different classes of chemical species and are generally used in their mixtures . Multi-component methods able to simultaneously determinate species with different chemical structure are therefore highly required in quality control analysis . This paper presents an ion interaction RP-HPLC method for the simultaneous separation of the 20 typical antimicrobial agents most used in cosmetics and hygiene products, that are: benzoic acid, salicylic acid, 4-hydroxybenzoic acid, methyl-, ethyl-, propyl-, butyl-, benzyl-benzoate, methyl-, ethyl-, propyl-, butyl-, benzyl-paraben, o-phenyl-phenol, 4-chloro-m-cresol, triclocarban, dehydroacetic acid, bronopol, sodium pyrithione and chlorhexidine . For the development of the method and the optimization of the chromatographic conditions, an experimental design was planned and models were built by the use of artificial neural network to correlate the retention time of each analyte to the variables and their interactions . The neuronal models developed showed good predictive ability and were used, by a grid search algorithm, to optimize the chromatographic conditions for the separation of the mixture. Kekkaku, 2004 Feb, 79(2), 39 - 46 {Relations between clinical subtypes of Mycobacterium avium pulmonary disease and polyclonal infections detected by IS1245 based restriction fragment length polymorphism analysis}; Kuwabara K et al.; INTRODUCTION: The epidemiology of Mycobacterium avium-intracellulare (MAC) infections has not been completely defined . Recently some reports presented polyclonal MAC infections . The purpose of this study was to reveal the clonal diversity of Mycobacterium avium isolates and the relation between clinical subtype of lung disease and polyclonal infection . METHODS: We categorized pulmonary Mycobacterium avium infection to three clinical subtypes, tuberculosis like type, bronchiectasis with preexisting tuberculosis type and nodular bronchiectasis type . Mycobacterium avium isolates of 11 patients were studied for their heterogeneity using IS1245 based RFLP analysis . The insertion sequence IS1245 is repetitive element identified only in Mycobacterium avium . Standard method of IS1245 based RFLP analysis has been proposed as a suitable technique for typing of Mycobacterium avium isolates for epidemiological and taxonomic studies . At least three distinct colonies were subcultured to single clone . The subclones of the isolates were analyzed by IS1245 based RFLP technique and some subclones were also examined by antimicrobial susceptibility test . RESULTS: Two of three patients of tuberculosis like type were considered to be monoclonal infection because only a single genotype was identified . And only one of four patients of bronchiectasis with preexisting tuberculosis type was considered to be polyclonal infection despite of long-term observation . Although isolates were collected in two or more occasions in clinical course over one year period, only a single genotype was observed in two patients . In contrast, three of four patients of nodular bronchiectasis type had multiple genotypes . Isolates recovered from patients with monoclonal infection pattern following long-term treatment with clarithromycin monotherapy became resistant to clarithromycin . In contrast, three strains derived from one nodular bronchiectasis patient were susceptible to clarithromycin despite of long-term chemotherapy including clarithromycin . The susceptibility patterns of the other drugs were also apparently different . Strain conversion due to repeated polyclonal infection was considered . These results of the antimicrobial susceptibility test supported clonal diversity of the Mycobacterium avium infection . DISCUSSION: IS1245 based RFLP analysis possesses a discriminatory power between the isolates on clonal level . This study demonstrates that polyclonal infections are common in nodular bronchiectasis type and monoclonal infections are common in tuberculosis like type and bronchiectasis with preexisting tuberculosis type . And not only simultaneous polyclonal infection but also repeated polyclonal infection were observed in a nodular bronchiectasis type patient . Drug susceptibility test showed long-term chemotherapy including clarithromycin could change the susceptibility of clarithromycin to resistant in patients with monoclonal infection . In contrast patients with repeated polyclonal infection pattern would avoid drug resistance because of strain conversion . This multiple susceptibility patterns identified in this study would not have been detected by the standard susceptibility test without subculture . And we also need the treatment strategy considering the polyclonal infection . CONCLUSIONS: Polyclonal infections are considered to be common in pulmonary Mycobacterium avium infection, especially nodular bronchiectasis type . Clonal diversity of Mycobacterium avium infection is an important factor to perform chemotherapy and drug susceptibility test. Fitoterapia, 2004 Mar, 75(2), 201 - 3 Antimicrobial activity of four Artemisia species of Iran; Ramezani M et al.; The antimicrobial activities of methanol extracts of four species of Artemisia species of Iran are reported. Ann Fr Anesth Reanim, 2004 Mar, 23(2), 116 - 23 {Antimicrobial prophylaxis in surgical procedures: assessment of the guidelines application and validation of antibiotic prophylaxis kits}; Gindre S et al.; INTRODUCTION: Surgical wounds infections represent a major cause of morbidity and are at the origin of an increase in the postoperative mortality rate . Those infections represent in France one-fourth of the nosocomial infections . Combine with the elementary hygiene rules and the surgical "good practices", antimicrobial prophylaxis with antibiotics is an essential tool for the reduction of the surgical wound infections rate . In the French hospitals, antimicrobial prophylaxis represents one-third of the antibiotic prescriptions . The rules for the application of surgical prophylaxis are based on current guidelines for antibiotic prophylaxis, however, guidelines are not totally respected . MATERIALS AND METHODS: Study 1: assessment of the guidelines application (practical audit) of the antibiotic antimicrobial prophylaxis in surgery, and of their impact on the established prescriptions: three audits were realized with four years interval (1994, 1998 and 2002), in order to estimate the evolution in the application of the current guidelines, which indirectly estimate the evolution of the guidelines impact . Study 2: assessment of the use of an antibiotic kit through a prospective comparative study of two groups: exposed patients vs non-exposed patients . Nominatives kits contained the recommended antibiotics with recommended posology and the instructions for each surgical procedure . RESULTS: Study 1: this study showed a significant increase in the antibiotics prescription volume since 1994 (+23%) . After a temporary increase from 1994 to 1998, the conformity of the effective prescriptions with the current guidelines for the indication to realize or not to realize an antibiotic surgical prophylaxis decreases of 7% between 1998 and 2002 . Nevertheless, we noticed an overall improvement in the guidelines application for the modalities of the antimicrobial prophylaxis when it was prescribed in a valid indication . Persistent weak points were in 2002 the antibiotic molecule choice (error rate of 25%), the duration of prescription (rate of abnormal prolonged antibiotic prophylaxis of 19%), and the timing of administration (error rate of 31%) . Study 2: antibiotic kits have permitted to increase the accordance of the antimicrobial prophylaxis prescriptions with the guidelines . Antibiotic prophylaxis was in total agreement with guidelines for 82% of exposed patients vs 41 for non-exposed patients . Choice of the antibiotic molecule, timing of administration and duration of prescription were the parameters particularly well rectified by this new antibiotic prophylaxis technical . CONCLUSION: In this study, guidelines diffusion seems to be an essential but also an insufficient point for the improvemen