Epidemiol Infect, 2001 Oct, 127(2), 221 - 7 An outbreak of diarrhoea due to multiple antimicrobial-resistant Shiga toxin-producing Escherichia coli O26:H11 in a nursery; Hiruta N et al.; An outbreak due to Shiga toxin-producing Escherichia coli O26:H11 (STEC) occurred at a nursery in southeastern Japan in 1997 . Thirty-two children had watery or bloody diarrhoea but none of them suffered from haemolytic-uremic syndrome . All of the STEC O26 were isolated during the period from 23 July to 22 August from 24 children, 3 nurses, and 2 food samples . These organisms had stx1 and eae genes but none of the other genes for which we tested (stx2, bfp, and EAF plasmid) . They also possessed multiple antimicrobial resistances, which were encoded by a transmissible plasmid, and showed mostly identical genomic pulsed-field gel electrophoretic patterns . The results of this investigation suggested that contaminated food was the main contributing factor to this multiple antimicrobial-resistant STEC O26 infection, and person-to-person transmission also contributed to the spread of this outbreak. Drugs, 2001, 61(12), 1801 - 33 Lansoprazole: an update of its place in the management of acid-related disorders; Matheson AJ et al.; Lansoprazole is an inhibitor of gastric acid secretion and also exhibits antibacterial activity against Helicobacter pylori in vitro . Current therapy for peptic ulcer disease focuses on the eradication of H . pylori infection with maintenance therapy indicated in those patients who are not cured of H . pylori and those with ulcers resistant to healing . Lansoprazole 30 mg combined with amoxicillin 1g, clarithromycin 250 or 500mg, or metronidazole 400 mg twice daily was associated with eradication rates ranging from 71 to 94%, and ulcer healing rates were generally >80% in well designed studies . In addition, it was as effective as omeprazole- or rabeprazole-based regimens which included these antimicrobial agents . Maintenance therapy with lansoprazole 30 mg/day was significantly more effective than either placebo or ranitidine in preventing ulcer relapse . Importantly, preliminary data suggest that lansoprazole-based eradication therapy is effective in children and the elderly . In the short-term treatment of patients with gastro-oesophageal reflux disease (GORD), lansoprazole 15, 30 or 60 mg/day was significantly more effective than placebo, ranitidine 300 mg/day or cisapride 40 mg/day and similar in efficacy to pantoprazole 40 mg/day in terms of healing of oesophagitis . Lansoprazole 30 mg/day, omeprazole 20 mg/day and pantoprazole 40 mg/day all provided similar symptom relief in these patients . In patients with healed oesophagitis . 12-month maintenance therapy with lansoprazole 15 or 30 mg/day prevented recurrence and was similar to or more effective than omeprazole 10 or 20 mg/day . Available data in patients with NSAID-related disorders or acid-related dyspepsia suggest that lansoprazole is effective in these patients in terms of the prevention of NSAID-related gastrointestinal complications, ulcer healing and symptom relief . Meta-analytic data and postmarketing surveillance in >30,000 patients indicate that lansoprazole is well tolerated both as monotherapy and in combination with antimicrobial agents . After lansoprazole monotherapy commonly reported adverse events included dose-dependent diarrhoea, nausea/vomiting, headache and abdominal pain . After short-term treatment in patients with peptic ulcer, GORD, dyspepsia and gastritis the incidence of adverse events associated with lansoprazole was generally < or = 5% . Similar adverse events were seen in long-term trials, although the incidence was generally higher (< or = 10%) . When lansoprazole was administered in combination with amoxicillin, clarithromycin or metronidazole adverse events included diarrhoea, headache and taste disturbance . In conclusion, lansoprazole-based triple therapy is an effective treatment option for the eradication of H . pylori infection in patients with peptic ulcer disease . Preliminary data suggest it may have an important role in the management of this infection in children and the elderly . In the short-term management of GORD, lansoprazole monotherapy offers a more effective alternative to histamine H2-receptor antagonists and initial data indicate that it is an effective short-term treatment option in children and adolescents . In adults lansoprazole maintenance therapy is also an established treatment option for the long-term management of this chronic disease . Lansoprazole has a role in the treatment and prevention of NSAID-related ulcers and the treatment of acid-related dyspepsia; however, further studies are needed to confirm its place in these indications . Lansoprazole has emerged as a useful and well tolerated treatment option in the management of acid-related disorders. ASDC J Dent Child, 2001 May-Jun, 68(3), 183 - 8, 152 Antimicrobial and buffer capacity of crude extracts of chewing sticks (Miswaki) from Kenya; Kemoli AM et al.; The use of Chewing sticks (Miswaki) in the third world for control of dental plaque is very popular . Some of the studies that have been conducted on this subject have reported marked decrease in the incidences of dental caries and periodontal diseases in the users of Miswaki, when compared to the users of the conventional toothbrush living under similar conditions . Various mechanisms by which the Miswaki contributes to this phenomenon have been suggested . The purpose of the present study was to investigate in vitro, the anti-microbial action, the potential acid buffer capacity and fluoride content of crude aqueous extracts of eight commonly used chewing sticks from three regions in Kenya . The results obtained in the study, showed that one of the Miswaki had remarkable antibiotic activity against three stains of oral bacteria . Three of the Miswaki had significant acid buffer capacity . None of the eight Miswaki showed any significant fluoride release. Vet Clin North Am Food Anim Pract, 2001 Nov, 17(3), 517 - 34 Immunology of inflammatory diseases of the bowel; Waters WR; During the past century, research on animal diseases has focused on the characterization of specific etiologies and disease control strategies . Many diseases affecting domestic animals have been successfully controlled using various methods, including vaccination, management, vector control, or antimicrobial agents . A number of microorganisms have proven resistant to these efforts . Control of these organisms requires the development of new strategies . As practitioners and researchers, we need to consider approaches that encompass the entire realm of disease expression from molecular to immune responses and interactions with other functional systems (e.g., endocrine, neurologic, and vascular systems) . We need a basic understanding of effective immune responses enabling the tailoring of vaccines to produce the desired response . This tailoring of host responses is augmented by the use of vaccines that use host growth factors, cytokines, or costimulatory molecules to bias the ensuing response . Intestinal microbial flora of food-producing animals can be managed to optimize health and minimize colonization by pathogenic organisms, especially zoonotic agents . New systems for the delivery of cytokines and other factors that favor optimal intestinal health and homeostasis need to be researched and evaluated . With time, it is likely that our clients and the consumers will be less tolerant of antibiotic usage . They will be more aware of the zoonotic potential of many microbes that colonize food animals . Food safety issues will be a continuing concern, as will the protection of our water supply from contamination from feedlots and pasture runoff . We are in the dawn of a new century, and, it is hoped, a new era of discovery of enteric disease pathogenesis and control. Clin Infect Dis, 2001 Dec 1, 33(11), 1938 - 43 Epub 2001 Oct 24. Disseminated Mycobacterium avium complex disease among patients infected with human immunodeficiency virus, 1985-2000; Horsburgh CR Jr et al.; Disseminated Mycobacterium avium complex disease remains a substantial cause of morbidity and mortality among patients with acquired immunodeficiency syndrome . From 1985 through 2000, we studied 1458 consecutive patients at Grady Memorial Hospital, Atlanta, with disseminated M . avium complex disease . There was a peak of 198 patients in the 1995, which decreased to 66 patients in 2000 . In 1997, significantly more patients than in 1991 or 1994 were female (P<.001) or black (P<.001) and significantly fewer had acquired human immunodeficiency virus through homosexual contact (P<.001) . In 1997, 50 (51%) of 99 of patients acquired M . avium complex disease despite receiving antimicrobial prophylaxis, but 32 (89%) of 36 patients did not adhere to the prophylaxis regimen . The median duration of survival of patients in 1991 was 110 days, whereas in 1994 it was 185 days, and in 1997 it was 339 days (P<.001) . Prolonged survival was associated with receiving therapy that included clarithromycin and receiving combination antiretroviral therapy that included a protease inhibitor. Eur J Gastroenterol Hepatol, 2001 Nov, 13(11), 1281 - 4 Should anti-Helicobacter therapy be different in patients with dyspepsia compared with patients with peptic ulcer diathesis? de Boer WA, Tytgat GN. Physicians should try to reach an optimal cure rate with initial anti-Helicobacter therapy . Helicobacter pylori infection in patients with peptic ulcer disease (PUD) is more likely to be cured then in patients with 'functional' dyspepsia (FD) . Differences in cure rates of 5-15% are usually reported, which is considered to be clinically relevant . Different strains (virulent v . non-virulent) in PUD and FD may induce different alterations in the gastric mucosa, and thereby either facilitate or impair antimicrobial efficacy . A study in this journal showed that triple therapy with ranitidine bismuth citrate (RBC) was superior to triple therapy with a proton pump inhibitor (PPI), but only in the more-difficult-to-cure FD patients . Clinicians should be aware that most published treatment studies have included only PUD patients . This means that in clinical practice the cure rates obtained in patients with FD or even uninvestigated dyspepsia will usually be lower then those reported in the literature . One way to deal with this is to consider prolonging the duration of an initial anti-Helicobacter therapy from 7 to 10 or 14 days in patients without ulcers. Cancer Res, 2001 Nov 1, 61(21), 7709 - 12 A proapoptotic peptide for the treatment of solid tumors; Mai JC et al.; We have designed a novel peptide, DP1, which is able to mediate significant induction of apoptosis in solid tumors by local injection . This peptide, comprised of a protein transduction domain (PTD), PTD-5, fused to an antimicrobial peptide, (KLAKLAK)2, was able to trigger rapid apoptosis in a variety of cell lines in vitro, including MCA205 murine fibrosarcomas and human head and neck tumors . Furthermore, direct injection of DP1 into day 7 established MCA205 tumors in C57BL/6 mice resulted in the induction of tumor apoptosis and subsequent reduction in tumor volume . These results suggest that DP1 may be used clinically to treat accessible solid tumors or as an adjuvant therapy in conjunction with radiotherapy, standard chemotherapy, immunotherapy, or surgical debulking. Int J Antimicrob Agents, 2001 Oct, 18(4), 329 - 33 Optimising antibiotic prescribing in primary care; McNulty CA; Prudent antimicrobial prescribing in the community may help to prevent the relentless increase in resistance, highlighted worldwide by numerous parliamentary documents . Antibiotic guidance, developed by primary care professionals and disseminated locally with outreach workshops, helps to reduce the use of broad-spectrum antimicrobials . Computerised guidance, audit of antibiotic use and restricted laboratory sensitivity reporting moves the prescriber towards the selection of recommended drugs . Educational campaigns and patient leaflets given at the consultation help to modify patients' expectations . Primary care physicians need to consider how much pharmaceutical representatives and free samples influence their prescribing . This multi-faceted approach needs to be backed up with a research programme developing the evidence base for management guidance of antimicrobial use in primary care. Clin Microbiol Infect, 2001, 7 Suppl 4, 83 - 90 Role of antibiotic prophylaxis for the prevention of intravascular catheter-related infection; Carratala J; Intravascular catheters have become essential tools for the management of patients in modern medical practice, but there are complications . In particular, catheter-related infection remains a major cause of nosocomial infection and primary septicemia . The development of preventive strategies to reduce the incidence of catheter-related infection is an important goal for all health providers . Over recent years, significant advances in prophylactic measures for the prevention of catheter-related infection have been made . This paper reviews strategies based on antibiotic prophylaxis such as systemic administration of antibiotics, application of antibiotic ointments to the skin insertion site as well as catheter flushing with antibiotics, the antibiotic-lock technique and the use of antimicrobial impregnated catheters. Clin Diagn Lab Immunol, 2001 Nov, 8(6), 1204 - 12 Modulation of Mycobacterium bovis-specific responses of bovine peripheral blood mononuclear cells by 1,25-dihydroxyvitamin D(3); Waters WR et al.; Historically, administration of vitamin D has been considered beneficial in the treatment of tuberculosis . The interaction of this vitamin {i.e., 1,25-dihdroxyvitamin D(3) {1,25(OH)(2)D(3)}} with the antitubercular immune response, however, is not clear . In the present study, in vitro recall responses of peripheral blood mononuclear cells (PBMC) from cattle infected with Mycobacterium bovis were used to study the immune-modulatory effects of 1,25(OH)(2)D(3) on M . bovis-specific responses in vitro . Addition of 1 or 10 nM 1,25(OH)(2)D(3) inhibited M . bovis-specific proliferative responses of PBMC from M . bovis-infected cattle, affecting predominantly the CD4(+) cell subset . In addition, 1,25(OH)(2)D(3) inhibited M . bovis-specific gamma interferon (IFN-gamma) production yet enhanced M . bovis-specific nitric oxide (NO) production . Lymphocyte apoptosis, measured by flow cytometry using annexin-V staining, was diminished by addition of 1,25(OH)(2)D(3) to PBMC cultures . These findings support the current hypothesis that 1,25(OH)(2)D(3) enhances mycobacterial killing by increasing NO production, a potent antimicrobial mechanism of activated macrophages, and suggest that 1,25(OH)(2)D(3) limits host damage by decreasing M . bovis-induced IFN-gamma production. Diagn Microbiol Infect Dis, 2001 Sep-Oct, 41(1-2), 71 - 8 In vitro susceptibility of Stenotrophomonas maltophilia to various antimicrobial combinations; Krueger TS et al.; Stenotrophomonas maltophilia has emerged as a significant pathogen in compromised patients, causing infections which are difficult to treat . Clinical isolates from patients in the Tucson area were tested against single and combination antibiotics using three testing methods . Ticarcillin/clavulanate, trimethoprim/sulfamethoxazole and trovafloxacin provided comparable inhibitory activity, in vitro . Ciprofloxacin, imipenem and ticarcillin were active less often . Agreements between disk diffusion and broth microdilution results were poor for ciprofloxacin and trimethoprim/sulfamethoxazole; however, agreement was > or = 90% for the other drugs tested . Major or very major errors were observed with ticarcillin, ticarcillin/clavulanate, and trovafloxacin . The addition of aztreonam to ticarcillin/clavulanate enhanced the activity compared to ticarcillin/clavulanate alone using the double-disk diffusion, broth microdilution (checkerboard), and time-kill testing methods . Trovafloxacin exhibited good activity by all three methods, with bactericidal activity at > or = 2x MIC . These results indicate that the newer fluoroquinolones or the triple combination of ticarcillin/clavulanate plus aztreonam may be potential options for treatment of infection caused by S . maltophilia in patients who are intolerant to or fail trimethoprim/sulfamethoxazole therapy. Cochrane Database Syst Rev . 2001;(3):CD001439. Antibiotics versus placebo for prevention of postoperative infection after appendectomy; Andersen BR et al.; BACKGROUND: Appendicitis is the most common cause of acute abdominal pain requiring surgical intervention . The cause of appendicitis is unclear and the mechanism of pathogenesis continues to be debated . Despite improved asepsis and surgical techniques, postoperative complications, such as wound infection and intraabdominal abscess, still account for a significant morbidity . Several studies implicate that postoperative infections are reduced by administration of antimicrobial regimes . OBJECTIVES: The objective of this review is to compare the use of antibiotics with placebo or no treatment in patients undergoing appendectomy . Will these patients benefit from antimicrobial prophylaxis? The outcomes are described according to the nature of the appendix, as either simple appendicitis (including the non-infectious stage) and complicated appendicitis . This review do not attempt to compare the effect of different regimens, a clinical question that is addressed in another review undertaken by this Group (CCCG) . SEARCH STRATEGY: We searched The Cochrane Controlled Trials Register (Cochrane Library 2000 issue 4), Medline (January 1966 to September 2000), Embase and the Cochrane Colorectal Cancer Group specialised register (September 2000) . In addition we manually searched the reference lists of the primary identified trials . SELECTION CRITERIA: Randomised Controlled Trials (RCT) and Controlled Clinical Trials (CCT) in which any antibiotic regime were compared to placebo in patients suspected of having appendicitis undergoing appendectomy were evaluated . Both studies on children and adults were reviewed . The outcome measures of the studies were either wound infection, intraabdominal abscess, length of stay in hospital or mortality . DATA COLLECTION AND ANALYSIS: Eligibility and trial quality were assessed, recorded and cross-checked by to reviewers . MAIN RESULTS: Forty-four studies including 9298 patients were included in this review . The overall result is that use of antibiotics is superior to placebo for the outcome wound infection and intraabdominal abscess, with no apparant difference in the nature of the removed appendix . Studies exclusively on children and studies examining topical application reported results in favour to the above although the results were not significant . REVIEWER'S CONCLUSIONS: Antibiotic prophylaxis is effective in the prevention of postoperative complications in appendectomised patients, whether the administration are given pre-, per- and post-operatively and could be considered for routine in emergency appendectomies. Environ Sci Technol, 2001 Oct 15, 35(20), 4103 - 10 Microbial inhibitors for U.S . EPA drinking water methods for the determination of organic compounds; Winslow SD et al.; Preservation of chemical analytes in drinking water samples is necessary to obtain accurate information concerning contaminant occurrence . Sample preservation to prevent biodegradation is important for most samples and analytes . With the unique demands of environmental methods, it is not always possible to kill all microorganisms without having undesirable effects . To find a suitable preservative, the sample, analysis, and preservation needs should be considered . During method development of U.S . Environmental Protection Agency (EPA) Methods 526 (for unstable semivolatile compounds) and 532 (for phenylurea pesticides), a number of studies were conducted to identify compatible microbial inhibitors . Copper sulfate was successfully used in Method 532 and is an excellent first-choice antimicrobial agent for many applications . Copper sulfate can catalyze hydrolysis reactions for some pesticides such as those analyzed in Method 526 . Under these conditions, a nonmetal compound of antimicrobial activity must be considered . During the development of Method 526, a survey of alternate organic based antimicrobial compounds found that diazolidinyl urea worked well in the method . Several other candidate microbial inhibitors were identified that could have application to other environmental methods . A general approach to selecting antimicrobial compounds in future environmental methods in water matrixes is discussed. Aliment Pharmacol Ther, 2001 Jun, 15(6), 831 - 41 Anti-inflammatory and tissue-protectant drug effects: results from a randomized placebo-controlled trial of gastritis patients at high risk for gastric cancer; Fischbach LA et al.; BACKGROUND: The inflammatory process involving Helicobacter pylori-associated gastritis is thought to lead to epithelial damage and contribute to the development of gastric cancer . Evidence exists from animal and in vitro studies suggesting that tetracyclines have both anti-inflammatory and tissue-protectant effects unrelated to their antimicrobial activity . We attempted to modulate components of H . pylori's inflammatory process by: (i) eliminating the infection; (ii) using tetracycline to alter the host's reaction to the infection without reducing the bacterial load; and (iii) using calcium to counteract the effect of excessive dietary salt . METHODS: We conducted a 16-week placebo-controlled clinical trial with 374 H . pylori-associated gastritis patients randomly assigned to one of five groups: (1) triple therapy consisting of metronidazole, amoxicillin and bismuth subsalicylate for 2 weeks, followed by bismuth alone for 14 weeks; (2) calcium carbonate; (3) triple therapy and calcium carbonate; (4) tetracycline; or (5) placebo . RESULTS: Subjects in the tetracycline and triple therapy groups, but not the calcium carbonate only group, showed a reduction in inflammation and epithelial damage vs . those in the placebo group, independent of a change in H . pylori density and other factors . Our results also indicate that epithelial damage may be affected by mechanisms independent of H . pylori density or inflammation . CONCLUSION: The results are consistent with the hypothesis that tetracycline can decrease inflammation independent of a reduction in the bacterial load . More research is needed to investigate mechanisms leading to epithelial damage which are independent of H . pylori density and inflammation. Aliment Pharmacol Ther, 2001 Jun, 15(6), 773 - 82 Guidelines for adults on self-medication for the treatment of acute diarrhoea; Wingate D et al.; Acute uncomplicated diarrhoea is commonly treated by self-medication . Guidelines for treatment exist, but are inconsistent, sometimes contradictory, and often owe more to dogma than evidence . An ad hoc multidisciplinary group has reviewed the literature to determine best practice . In general it is recognized that treatment of acute episodes relieves discomfort and social dysfunction . There is no evidence that it prolongs the illness . Self-medication in otherwise healthy adults is safe . Oral loperamide is the treatment of choice . Older anti-diarrhoeal drugs are also effective in the relief of symptoms but carry the risk of unwanted adverse effects . Oral rehydration solutions do not relieve diarrhoea, and confer no added benefit for adults who can maintain their fluid intake . Probiotic agents are, at present, limited in efficacy and availability . Antimicrobial drugs, available without prescription in some countries, are not generally appropriate for self-medication, except for travellers on the basis of medical advice prior to departure . Medical intervention is recommended for the management of acute diarrhoea in the frail, the elderly (> 75 years), persons with concurrent chronic disease, and children . Medical intervention is also required when there is no abatement of the symptoms after 48 h, or when there is evidence of deterioration such as dehydration, abdominal distension, or the onset of dysentery (pyrexia > 38.5 degrees C and/or bloody stools). Mol Cell, 2001 Oct, 8(4), 921 - 30 A plant defense response effector induces microbial apoptosis; Narasimhan ML et al.; Osmotin is a tobacco PR-5 protein that has antifungal activity and is implicated in host-plant defense . We show here that osmotin induces apoptosis in Saccharomyces cerevisiae . Induction of apoptosis was correlated with intracellular accumulation of reactive oxygen species and was mediated by RAS2, but not RAS1 . Osmotin treatment resulted in suppression of transcription of stress-responsive genes via the RAS2/cAMP pathway . It was therefore concluded that osmotin induced proapoptotic signaling in yeast . The results indicate that the ability of antimicrobial proteins to induce microbial apoptosis could be an important factor in determining a pathogen's virulence and could therefore be targeted for the design of new antifungal drugs. Eur J Biochem, 2001 Nov, 268(21), 5589 - 600 Amphipathic alpha helical antimicrobial peptides; Giangaspero A et al.; Antimicrobial peptides (AMPs) that assume an amphipathic alpha helical structure are widespread in nature . Their activity depends on several parameters including the sequence, size, degree of structure formation, cationicity, hydrophobicity and amphipathicity . The analysis of numerous natural AMPs provided representative values for these parameters and led to a sequence template with which to generate potent artificial lead AMPs . Sequences were then varied in a rational manner, using both natural and nonproteinogenic amino acids, to probe the individual roles of each parameter in modulating biological activity . A high cationicity combined with a stabilized amphipathic alpha helical structure conferred enhanced cidal activity towards all the cell types considered, and was a requirement for Gram-positive bacteria and fungi . An elevated helicity also correlated with increased hemolytic activity . The structural requirements for activity against several Gram-negative bacteria were instead considerably less stringent, so that it persisted in peptides in which formation of a helical structure and/or amphipathicity were impeded . Either a reduced charge or a reduced hydrophobicity resulted in generally inactive peptides . These observations, combined with the kinetics of bacterial membrane permeabilization and time-killing are discussed in terms of currently accepted models of action for this type of peptide . The simple guidelines obtained in this study allowed the design of highly active shortened AMPs and may be generally useful in the development of this type of peptides as anti-infective agents. Biochemistry, 2001 Nov 6, 40(44), 13281 - 7 Interactions of bismuth with human lactoferrin and recognition of the Bi(III)-lactoferrin complex by intestinal cells; Zhang L et al.; Several bismuth compounds are currently used as antiulcer drugs, but the mechanism of action still remains unclear . The antimicrobial activity of Bi(III) complexes toward Gram-negative bacteria is reported to be dependent on the iron uptake system {Domenico, P., et al . (1996) J . Antimicrob . Chemother . 38, 1031-1040} . Electronic absorption and 13C NMR spectroscopic data show that Bi(III) binds to human lactoferrin at the specific Fe(III) sites along with either carbonate or oxalate as the synergistic anion . The uptake of Bi(III) by apo-hLF was rapid {minutes in 10 mM Hepes buffer and 5 mM bicarbonate (pH 7.4)}, and almost equal in both lobes . The presence of ATP facilitates the release of Bi(III) from the Bi2-hLF complex when the pH is lowered . The Bi2-hLF complex blocked the uptake of the radiolabeled 59Fe-hLF complex into rat IEC-6 cells . Surprisingly, apo-hLF (but not apotransferrin) was almost as effective in blocking 59Fe uptake as bismuth-loaded lactoferrin . These results suggest that Bi(III)-loaded hLF might be recognized by the lactoferrin receptor and be taken up into cells. Pharm Res, 2001 Sep, 18(9), 1315 - 9 Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: screening in an infectious disease model; Suarez S et al.; PURPOSE: Targeted delivery of rifampicin loaded microspheres to the alveolar macrophage, the host cell for Mycobacterium tuberculosis (MTB), may be an effective targeted approach to pulmonary tuberculosis therapy . A guinea pig infection model has been adopted as a post-treatment screening method for antimicrobial effect . Insufflation and nebulization methods of drug delivery were evaluated . METHODS: Rifampicin alone (RIF, 1.03-1.72 mg/kg), within poly(lactide-co-glycolide) microspheres (R-PLGA, equivalent to 1.03-1.72 mg/kg) or polymer microparticles alone (PLGA) were administered by insufflation or nebulization, 24 h before bacterial aerosol exposure . Animals were infected with an aerosol containing a small number (2 x 10(5) cfu/mL) of virulent H37Rv strain of MTB . Lung and spleen tissue samples were collected 28 days after infection for quantitative bacteriology and histopathological analysis . RESULTS: There was a dose-effect relationship between insufflated R-PLGA and burden of bacteria in the lungs . In addition, guinea pigs treated with R-PLGA had a significantly smaller number of viable bacteria (P < 0.05), reduced inflammation and lung damage than lactose or saline control, PLGA or RIF treated animals . CONCLUSIONS: These studies indicate the potential of R-PLGA, delivered by insufflation or nebulization directly to the lungs, to affect the early development of pulmonary TB. Euro Surveill, 2001 Jan, 6(1), 5 - 14 National policies for preventing antimicrobial resistance - the situation in 17 European countries in late 2000; Therre H; A survey carried out within Member States of the European Union and Norway shows that in all but two countries national surveillance of microorganisms resistant to antibiotics existed in December 2000 . In Italy, Ireland and Scotland, the systems were set up very recently (respectively in 1998, 1999 and 1999) . Moreover, excepting of Ireland and Scotland, all countries have a national system for data collection on the consumption of antibiotics, namely since 2000 in Austria, Italy and Luxembourg . Several of these systems were set up after 1998 when the recommendations of the European conference 'The Microbial Threat' held in Copenhague were published . In addition, a certain number of other measures have been undertaken since then: education campaigns to the population in England and Wales, in Ireland or in France, creation of committees specifically in charge of consumption surveillance in Italy or of the prevention of resistance in Belgium or in Ireland, publications of recommendations on the good use of antibiotics in Austria and in Finland, etc. J Biol Chem, 2002 Jan 4, 277(1), 67 - 74 Epub 2001 Oct 26. Optimization of microbial specificity in cyclic peptides by modulation of hydrophobicity within a defined structural framework; Kondejewski LH et al.; In the present study we have utilized the structural framework of the analog GS14K4 (cyclo(VKLd-KVd-YPL KVKLd-YP, where d denotes a d-amino acid)), to examine the role of hydrophobicity in microbial activity and specificity . The hydrophobicity of GS14K4 was systematically altered by residue replacements in the hydrophobic sites of the molecule to produce a series of analogs that were either less or more hydrophobic than the parent compound . Circular dichroism spectroscopy and reversed-phase high performance liquid chromatography analysis showed that the molecules were structurally similar and only differed in overall hydrophobicity . The hydrophobicity of GS14K4 was found to be the midpoint for hemolytic activity, with more hydrophobic analogs exhibiting increased hemolytic activity and less hydrophobic analogs showing decreased hemolytic activity . For antimicrobial activity there were differences between the hydrophobicity requirements against Gram-positive and Gram-negative microorganisms . The hydrophobicity of GS14K4 was sufficient for maximum activity against Gram-negative microorganisms and yeast, with no further increases in activity occurring with increasing hydrophobicity . With Gram-positive microorganisms significant increases in activity with increasing hydrophobicity were seen in three of the six microorganisms tested . A therapeutic index (calculated as a measure of specificity of the peptides for the microorganisms over human erythrocytes) served to define the boundaries of a therapeutic window within which lay the optimum peptide hydrophobicity for each microorganism . The therapeutic window was found to be at a lower hydrophobicity level for Gram-negative microorganisms than for Gram-positive microorganisms, although the limits were more variable for the latter . Our results show that the balance between activity and specificity in the present cyclic peptides can be optimized for each microorganism by systematic modulation of hydrophobicity. FEBS Lett, 2001 Oct 19, 507(1), 95 - 100 Structural study of novel antimicrobial peptides, nigrocins, isolated from Rana nigromaculata; Park S et al.; Novel cationic antimicrobial peptides, named nigrocin 1 and 2, were isolated from the skin of Rana nigromaculata and their amino acid sequences were determined . These peptides manifested a broad spectrum of antimicrobial activity against various microorganisms with different specificity . By primary structural analysis, it was revealed that nigrocin 1 has high sequence homology with brevinin 2 but nigrocin 2 has low sequence homology with any other known antimicrobial peptides . To investigate the structure-activity relationship of nigrocin 2, which has a unique primary structure, circular dichroism (CD) and homonuclear nuclear magnetic resonance spectroscopy (NMR) studies were performed . CD investigation revealed that nigrocin 2 adopts mainly an alpha-helical structure in trifluoroethanol (TFE)/H(2)O solution, sodium dodecyl sulfate (SDS) micelles, and dodecylphosphocholine micelles . The solution structures of nigrocin 2 in TFE/H(2)O (1:1, v/v) solution and in SDS micelles were determined by homonuclear NMR . Nigrocin 2 consists of a typical amphipathic alpha-helix spanning residues 3-18 in both 50% TFE solution and SDS micelles . From the structural comparison of nigrocin 2 with other known antimicrobial peptides, nigrocin 2 could be classified into the family of antimicrobial peptides containing a single linear amphipathic alpha-helix that potentially disrupts membrane integrity, which would result in cell death. Farmaco, 2001 Sep, 56(9), 689 - 93 Synthesis and microbiological activity of some 4-butyl-2H-benzo{1,4}thiazin-3-one derivatives; Guarda VL et al.; The synthesis and physicochemical properties of 4-butyl-2H-benzo{1,4}thiazin-3-one derivatives are described . These new compounds were synthesised by alkylation in 4-N position and acylation and/or alkylation of 6-NH2 by phase transfer catalysis . Acid hydrolysis of 6-alkylacylamino group yielded 6-alkylamino-4-butyl-2H-benzo{1,4}thiazin-3-ones . The antimicrobial in vitro activity was determined on five compounds. Farmaco, 2001 Sep, 56(9), 641 - 6 Synthesis and biological evaluation of some new 3 ,4-dihydropyrimidin-4-ones; Modha J et al.; Condensation of 5-cyano-2-hydrazino-3-N-methyl-6-phenyl/p-chlorophenyl-3,4-dihydropyrimidin-4-one (3a and 3b) with 2,4-bisalkyl/arylamino-6-chloro-s-triazine (4) gave the corresponding 2,4-bisalkyl/arylamino-6-{5'-cyano-3'-N-methyl}-6'-phenyl/pchlorophenyl-3',4'-dihydropyrimidin-4'-one-2'-yl-hydrazino-s-triazines (5a-n and 6a-n) . The compounds 4 have been prepared by the condensation of cyanuric chloride and different alkyl/aryl amines . The reaction between 5-cyano-3-N-methyl-2-methylthio-6-phenyl/p-chlorophenyl-3,4-dihydropyrimidin-4-one (2a and 2b) with hydrazine hydrate furnished 3a and 3b, respectively . The condensation of 6-phenyl/p-chlorophenyl/5-cyano-2-mercapto-3,4-dihydropyrimidin-4-one (1a and 1b) with methyl iodide yielded 2a and 2b, respectively . All the products have been evaluated in vitro for their antimicrobial activity against several microbes and antitubercular activity against Mycobacterium tuberculosis H37 Rv. Lakartidningen, 2001 Sep 26, 98(39), 4202 - 5 {Clinical guidelines developed by the STRAMA group in the county of Stockholm: skin and soft tissue infections}; Lundbergh P; In 1999 the County Medical Officer in Stockholm County established the third regional STRAMA-group (Swedish Strategic Programme for The Rational Use of Antimicrobial Agents and Surveillance of Resistance) to deal with skin and soft tissue infections . The group decided to publish guidelines for physicians in the county, and this third book was distributed among the 7,000 physicians in Stockholm County. Med Clin North Am, 2001 Nov, 85(6), 1583 - 94 Therapy of nosocomial pneumonia; Cross JT Jr et al.; HAP remains a major cause of morbidity and mortality among hospitalized patients . Although early appropriate therapy results in improved outcomes, the cause of HAP frequently is not known at the time antimicrobial therapy is initiated . Most cases of HAP result from microaspiration of oropharyngeal secretions previously colonized with pathogenic bacteria, and the spectrum of potential pathogens is broad . Taking several factors into account can narrow this spectrum, including severity of illness, length of stay before the onset of pneumonia, and presence of risk factors for specific pathogens . When therapy has been initiated, follow-up of microbial studies and careful monitoring of the patient's course is important . The clinical improvement, even when therapy is appropriate, frequently takes days; therapy should not be changed for the first 2 to 3 days unless frank deterioration is noted . Patients who fail to respond or experience clinical deterioration should be re-examined carefully, and thought should be given to the possibility of other noninfectious processes. Med Clin North Am, 2001 Nov, 85(6), 1381 - 96 What diagnostic tests are needed for community-acquired pneumonia? Smith PR. Diagnostic tests play an important part in the evaluation and management of patients with CAP . Tests have key roles in diagnosing the presence of CAP and in assessing severity . An ideal test for microbiologic diagnosis in CAP is not yet available, and initial antimicrobial therapy usually is empiric . Nonetheless, when appropriately applied and correctly performed, tests for the identification of pathogens in CAP are useful and cost-effective. Spine, 2001 Nov 1, 26(21), 2397 - 9 Pneumococcal vertebral osteomyelitis: a unique case with atypical clinical course; Poyanli A et al.; STUDY DESIGN: A case report . OBJECTIVES: To report and discuss a case of pneumococcal vertebral osteomyelitis with meningitis in a previously healthy 51-year-old immunocompetent woman who presented with acute onset lower back pain . SUMMARY OF BACKGROUND DATA: To the authors' knowledge, pneumococcal vertebral osteomyelitis with meningitis in an immunocompetent person with no other predisposing factor has not been reported previously . METHODS: The patient was diagnosed to have pneumococcal meningitis 10 days after the onset of acute and severe lower back pain . Significant improvement of clinical symptoms from meningitis was achieved with appropriate antimicrobial treatment . Lumbar CT and MRI scans were performed on persistence of fever and lower back pain . Loss of height and peridiscal inflammation at L3-L4 and epidural and bilateral psoas abscesses were detected . RESULTS: Diagnosis of pneumococcal vertebral osteomyelitis was established after evaluation of the material obtained from CT-guided aspiration of the psoas abscess and biopsy of the L3 body . With appropriate antimicrobial treatment, the patient's complaints resolved completely . CONCLUSION: To the authors' knowledge, this is the first reported case of pneumococcal vertebral osteomyelitis with meningitis. Med Wieku Rozwoj, 2001 Apr-Jun, 5(2), 149 - 55 {Is therapeutic drug monitoring (TDM) in paediatric patients necessary?}; Prokopczyk J et al.; There is increasing discussion about the clinical usefulness of routine TDM of selected drugs in paediatrics . Routine TDM is performed as a way to individualize dosing requirements so as to achieve "therapeutic" concentrations in all patients, independently of age and individual drug response . The therapeutic ranges established for most drugs are based upon studies performed in adults . Extrapolation of these ranges to paediatric patients, especially to neonates, is questionable because drugs disposition and pharmacodynamics differ in this population compared to adults . The scepticism of the value of routine TDM in paediatric patients concerns antiepileptic drugs and digoxin . Recently also the value of vancomycin TDM in neonates has been the subject of discussion, resulting in new recommendation for dosing schedule in this age group . Therapeutic monitoring of methotrexate, especially administered in high doses in anticancer therapy is not questioned . Aminoglycosides have an extremely important role in paediatric antimicrobial therapy . They are still frequently used in the neonatal period . The rationale for monitoring of aminoglycosides is a narrow therapeutic range resulting in risk of oto- and nephrotoxicity, and large inter- and intra-subject variation in pharmacokinetics . Routine TDM is not recommended for paediatric patients (other than neonates) with normal renal function and without chronic illnesses associated with changes in pharmacokinetics of aminoglycosides . In these patients the peak and trough concentrations are within the therapeutic range using standard dosing regimes . Therapeutic monitoring of aminoglycosides is still obligatory in neonates, especially in premature and low birthweight neonates because of particularly wide inter-patient and intra-patient pharmacokinetic variability and risk of oto- and nephrotoxicity. J Antimicrob Chemother, 2001 Nov, 48(5), 667 - 75 BMS-284756 (T-3811ME) a new fluoroquinolone: in vitro activity against Legionella, efficacy in a guinea pig model of L . pneumophila pneumonia and pharmacokinetics in guinea pigs; Edelstein PH et al.; The activity of BMS-284756 was studied against extracellular Legionella spp . and intracellular Legionella pneumophila, and for the treatment of guinea pigs with L . pneumophila pneumonia . The BMS-284756 MIC(50) of 22 different Legionella spp . strains was 0.008 mg/L, compared with 0.016 and 0.125 mg/L for levofloxacin and azithromycin, respectively . BMS-284756 (1 mg/L) reduced the intracellular concentrations of two L . pneumophila strains grown in guinea pig alveolar macrophages by c . 1.5 log(10 )cfu/mL, and was more active than erythromycin, but less active than azithromycin or levofloxacin at the same drug concentrations . Efficacy studies of BMS-284756, levofloxacin and azithromycin were performed in guinea pigs with L . pneumophila pneumonia . In infected guinea pigs given BMS-284756 10 mg/kg ip, mean peak plasma levels were 1.8 mg/L at 0.5 h and 0.7 mg/L at 1 h post-dose . The elimination half-life in plasma was 0.5 h, and the AUC(0-24 )was 1.7 mg*h/L, about 2% of the AUC(0-24 )for a single 400 mg oral dose in man . Sixteen of 18 L . pneumophila-infected guinea pigs treated with BMS-284756 10 mg/kg ip once daily for 5 days survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin 15 mg/kg ip once daily for 2 days . All 12 animals that were treated with levofloxacin 10 mg/kg ip once daily for 5 days survived . None of 12 control animals treated with saline survived . Animals treated with BMS-284756 had significantly higher residual lung counts of L . pneumophila at the end of therapy than did animals treated with levofloxacin or azithromycin, which may be attributable to the very low drug concentrations that were obtained . BMS-284756 was more active than erythromycin against L . pneumophila in infected macrophages, and effectively treated animals with experimental L . pneumophila pneumonia . These data support further studies of BMS-284756 for the treatment of Legionnaires' disease. Hum Reprod, 2001 Nov, 16(11), 2338 - 42 Effects of treatment with carnitines in infertile patients with prostato-vesiculo-epididymitis; Vicari E et al.; BACKGROUND: We have recently shown that patients with prostato-vesiculo-epididymitis (PVE) have a greater reactive oxygen species (ROS) overproduction than patients with prostatitis or prostato-vesiculitis . Since this biochemical stress persists even after treatment with antimicrobials, it may relate to an imbalance between pro- and anti-oxidant factors at the epididymal level . METHODS: To evaluate the effects of antioxidant treatment of patients with PVE, whether in the presence or absence of pro-oxidant factors, abacterial PVE infertile patients with normal (<1x10(6)/ml, group A, n = 34) or abnormal (>1x10(6)/ml, group B, n = 20) seminal white blood cell (WBC) concentrations received carnitines (L-carnitine 1 g and acetyl-carnitine 0.5 g twice/day) for 3 months followed by a wash-out period of 3 months . Semen parameters, ROS production and pregnancy outcome were evaluated before, during and following carnitine treatment . RESULTS: Carnitines increased sperm forward motility and viability in group A patients . This was associated with a significant reduction in ROS production which persisted during wash-out . Carnitines increased only the percentage of viable spermatozoa in group B patients . Within 3 months after the discontinuation of carnitines, the rate of spontaneous pregnancy in group A patients was significantly higher than that of group B patients, being 11.7% (4/34) compared with 0% . CONCLUSION: These results indicate that carnitines are only an effective treatment in patients with abacterial PVE and elevated ROS production when seminal WBC concentration is normal. Am J Med Sci, 2001 Oct, 322(4), 209 - 12 Long-term suppressive antimicrobial therapy for intravascular device-related infections; Baddour LM; Infectious Diseases Society of America's Emerging Infections Network; BACKGROUND: Long-term suppressive antimicrobial therapy is an alternative treatment choice in patients with medical device-related infection who are not eligible for surgical device removal for attempted cure . There is a paucity of data published that examines this treatment option . METHODS: Members of the Infectious Diseases Society of America's Emerging Infections Network were polled to identify patients with intravascular device-related infections who were not candidates for surgery and were given long-term antimicrobial therapy to suppress clinical manifestations of infection . RESULTS: Clinical and microbiologic data were collected retrospectively for 51 patients . Sixty-nine percent of patients were men; vascular grafts were the most common type of medical device infected {30 (58.8%) patients} . Sixty-three percent (32 of 51) of cases involved gram-positive cocci . A variety of antimicrobials were administered as chronic suppressive therapy, with beta-lactams used most frequently (39.2%) . Therapy ranged from 3 months to 10 years . Three (7.32%) of 41 patients in whom follow-up data were available developed relapsing infection while on long-term suppressive therapy . Three other patients suffered drug adverse events . CONCLUSIONS: Overall, long-term suppressive therapy was well-tolerated and efficacious in preventing signs of infection relapse. West Indian Med J, 2001 Jun, 50(2), 105 - 8 Non-antimicrobial properties of tetracyclines--dental and medical implications; Rawal SY et al.; The tetracyclines are a group of broad-spectrum antimicrobial agents . The first of these compounds, chlortetracycline was isolated from Streptomyces aureofaciens by Benjamin Duggar and introduced into the market in 1948 . In 1952, tetracycline was derived semisynthetically from chlortetracycline by removal of its chlorine atom by catalytic hydrogenation . Methacycline, doxycycline and minocycline are all semi-synthetic derivatives . The tetracyclines are closely congeneric derivatives of the polycyclic napthacenecarboxamide . The tetracyclines possess a wide range of antimicrobial activity against gram-positive and gram-negative bacteria . In vitro, these drugs are primarily bacteriostatic . Tetracyclines have been used extensively as antimicrobial agents for the treatment of various types of periodontal diseases until light was shed on their equally important non-antimicrobial properties by Golub . The tetracyclines and their non-antimicrobial, chemically modified analogues have properties that appear to modulate host response by inhibiting the activity of the matrix metalloproteinases that cause collagen destruction . They also inhibit osteoclast function, stimulate osteoblastic bone formation, and regulate angiogenesis. Fitoterapia, 2001 Nov, 72(7), 825 - 8 Antimicrobial activity of Symplocos cochinensis; Khan MR et al.; The methanol extracts of leaves, root and stem barks of Symplocos cochinchinensis and their fractions obtained by partition (petrol, dichloromethane, ethyl acetate) were screened for antimicrobial activity . All the crude extracts and fractions showed a broad spectrum of antibacterial activity, that was enhanced on fractionation . None of them showed activity against the tested moulds. Fitoterapia, 2001 Nov, 72(7), 822 - 4 Antimicrobial activity of Boswellia dalziellii stem bark; Adelakun EA et al.; The methanol and aqueous extracts of Boswellia dalziellii stem bark showed broad spectrum inhibiting activity against bacteria, both Gram-positive and Gram-negative, and fungi. Fitoterapia, 2001 Nov, 72(7), 818 - 21 Antimicrobial activity of Psychotria microlabastra; Khan MR et al.; The methanol extracts of leaves, root and stem barks of Psychotria microlabastra showed a broad spectrum of antibacterial activity, that was increased on fractionation (petrol, dichloromethane, ethyl acetate), particularly in the ethyl acetate fractions . None of the extractives showed activity against the tested moulds. Res Vet Sci, 2001 Jun, 70(3), 287 - 93 The effect of organic acids on the control of porcine post-weaning diarrhoea; Tsiloyiannis VK et al.; Post-weaning diarrhoea syndrome (PWDS) of piglets is caused mainly by Enterotoxigenic Escherichia coli (ETEC) strains . Six organic acids were tested for their efficacy in the control of PWDS, using a total of 384 weaned piglets, in eight groups, during a 28-day period . One group (negative control) was offered a diet free of antimicrobials, one group (positive control) was offered the same diet medicated with 44 p.p.m . of lincomycin and 44 p.p.m . spectinomycin (Lincospectin 22 premix, Upjohn), and six groups were offered feed supplemented with either 1.0 per cent propionic acid, 1.6 per cent lactic acid, 1.2 per cent formic acid, 1.2 per cent malic acid, 1.5 per cent citric acid or 1.5 per cent fumaric acid . Groups were compared with regard to the appearance of clinical signs, mortality, weight gain and feed conversion . All groups supplemented with organic acids had reduced incidence and severity of diarrhoea, and performed significantly better than the negative control group (P<0.05) . At the end of the trial, ETEC strains were detected in the control group not receiving antibiotics but not in the treated group . Organic acids and especially lactic acid are a useful tool in controlling PWDS. Res Vet Sci, 2001 Jun, 70(3), 281 - 5 The effect of organic acids on the control of post-weaning oedema disease of piglets; Tsiloyiannis VK et al.; Oedema disease usually occurs after weaning and is due to infection with Enterotoxaemic Escherichia coli strains . A total of 240 weaned piglets were used in five groups during a 28-day period . One group (a negative control) was offered feed free of antimicrobials ad libitum, three groups were offered the same diet ad libitum supplemented with either 1.6 per cent lactic acid, 1.5 per cent citric acid or 50 p.p.m . of enrotloxacin (ENR/Baytril I.E.R . 2 5 per cent, Bayer), respectively . Finally, one group was offered the same diet but the amount offered was restricted during the first 12 days post-weaning . Groups receiving acid or ENR additions to the diet had lower mortality than the negative control group (P<0.05) . The three groups on treated feed also showed significantly better growth performance and food conversion ratio than the control group (P<0.05) . Both organic acids and medication with 50 p.p.m . of ENR for a 10-day period are useful in controlling and/or preventing post-weaning oedema disease. Ann Pharmacother, 2001 Oct, 35(10), 1255 - 63 Antimicrobial-coated/bonded and -impregnated intravascular catheters; Pai MP et al.; OBJECTIVE: To review the literature regarding the prevention of catheter colonization and catheter-related bloodstream infections (CRBIs) with the use of antimicrobial-coated/bonded and -impregnated intravascular catheters . DATA SOURCES: Primary and review English-language literature were identified using MEDLINE (1966-September 2000) pertaining to the key terms antibiotic, antimicrobial, antiseptic, silver, and bonded, coated, Impregnated catheters . In addition, textbooks and relevant reference lists were reviewed . DATA EXTRACTION: All articles identified through the data sources were evaluated . Information deemed relevant to the objectives of the review was included . DATA SYNTHESIS: Significant morbidity and mortality are associated with the development of CRBIs . Preventative measures such as modification of these catheters with antimicrobial coating/bonding have produced varying results . Trials evaluating cefazolin, teicoplanin, vancomycin, silver, and chlorhexidine-silver sulfadiazine (C-SS) used for coated/bonded intravascular catheters have not demonstrated a consistent decrease in the incidence of CRBIs . However, a meta-analysis of trials evaluating C-SS intravascular catheters demonstrated a statistically significant reduction in CRBIs . A larger reduction in CRBIs has been reported with minocycline-rifampin (M-R) versus C-SS intravascular catheters . Use of the M-R and C-SS catheters may result in a cost savings of $100 million and reduce as many as 12,000 CRBI-related deaths annually when used short term (<7 d) . CONCLUSIONS: When used for short-term catheterization, M-R catheters appear to be superior to the currently available C-SS catheters at preventing CRBIs . Significant cost savings and reduction in mortality can be anticipated with the use of M-R catheters. Ann Pharmacother, 2001 Oct, 35(10), 1224 - 32 Antimicrobial cycling: the future or a fad? Hodges BM, White RL. OBJECTIVE: To assess the current evidence of the value of cycling of antimicrobials to control the emergence of resistance or to reverse existing resistance to antimicrobials . DATA SOURCES: Articles were obtained through a MEDLiNE search of the English-language literature from 1966 to January 2000 . Additionally, references from retrieved publications were reviewed to identify further articles . STUDY SELECTION AND DATA EXTRACTION: All investigations of switching between or cycling among antimicrobials were evaluated . Studies switching between or cycling among specific drugs or classes of drugs within institutional settings were included in this review . DATA SYNTHESIS: Studies involving cycling among different aminoglycosides suggest that, although temporary decreases in resistance can be documented, resistance usually rebounds rapidly on completion of the cycle and return to the original agent . Switching between classes of antimicrobials has produced inconsistent results and has been shown to replace resistance to one agent with resistance to another . Mathematical models using both in vitro and clinical data have suggested that, due to residual resistance in the population, cycling among drug classes is unlikely to yield long-term reductions in antimicrobial resistance, especially if a high level of antimicrobial resistance exists . CONCLUSIONS: Cycling among different antimicrobials to reverse resistance trends is currently not supported by published literature . Cycling to prevent the emergence of resistance may ultimately be more useful; however, no studies have evaluated this concept . Well-designed prospective studies are needed to evaluate the potential clinical value of antimicrobialcycling. J Biol Chem, 2002 Jan 4, 277(1), 416 - 23 Epub 2001 Oct 23. Lipoxygenase H1 gene silencing reveals a specific role in supplying fatty acid hydroperoxides for aliphatic aldehyde production; Leon J et al.; Lipoxygenases catalyze the formation of fatty acid hydroperoxide precursors of an array of compounds involved in the regulation of plant development and responses to stress . To elucidate the function of the potato 13-lipoxygenase H1 (LOX H1), we have generated transgenic potato plants with reduced expression of the LOX H1 gene as a consequence of co-suppression-mediated gene silencing . Three independent LOX H1-silenced transgenic lines were obtained, having less than 1% of the LOX H1 protein present in wild-type plants . This depletion of LOX H1 has no effect on the basal or wound-induced levels of jasmonates derived from 13-hydroperoxylinolenic acid . However, LOX H1 depletion results in a marked reduction in the production of volatile aliphatic C6 aldehydes . These compounds are involved in plant defense responses, acting as either signaling molecules for wound-induced gene expression or as antimicrobial substances . LOX H1 protein was localized to the chloroplast and the protein, expressed in Escherichia coli, showed activity toward unesterified linoleic and linolenic acids and plastidic phosphatidylglycerol . The results demonstrate that LOX H1 is a specific isoform involved in the generation of volatile defense and signaling compounds through the HPL branch of the octadecanoid pathway. J Biol Chem, 2002 Jan 4, 277(1), 148 - 54 Epub 2001 Oct 23. Escherichia coli produces phosphoantigens activating human gamma delta T cells; Feurle J et al.; Human Vgamma9delta2 T lymphocytes are suggested to play an important role in the immune response to various microbial pathogens . In contrast to alphabeta T cells, gammadelta T lymphocytes recognize small, non-protein, phosphate-bearing antigens (phosphoantigens) in a major histocompatibility complex-independent manner . Four different phosphoantigens termed TUBag1 to TUBag4 with a common 3-formyl-1-butyl-pyrophosphate moiety and isopentenyl-pyrophosphate have been isolated and identified from mycobacteria . However, natural occurring gammadelta T cell ligands from other bacterial species were not characterized so far . Here, we describe the structural identification of the two compounds responsible for the gammadelta T cell-stimulating capacity of Escherichia coli as similar to the mycobacterial phosphoantigens 3-formyl-1-butyl-pyrophosphate and its M(r) 275 homologue TUBag2 . In addition, E . coli phosphoantigens exert bioactivities on gammadelta T cells with similar potencies to the mycobacterial phosphoantigens at 5-15 nm concentration . Furthermore, our results clearly prove that the deoxyxylulose 5-phophate pathway (also referred to as Rohmer metabolic route of isoprenoid biosynthesis) is essential for the biosynthesis of the phosphoantigens in E . coli . Because this pathway is absent from human cells, it proves an ideal target for focusing efficiently the antimicrobial selectivity of human gammadelta T lymphocytes. Antiviral Res, 2001 Dec, 52(3), 225 - 39 Antiviral activities of lactoferrin; van der Strate BW et al.; Lactoferrin (LF) is an iron binding glycoprotein that is present in several mucosal secretions . Many biological functions have been ascribed to LF . One of the functions of LF is the transport of metals, but LF is also an important component of the non-specific immune system, since LF has antimicrobial properties against bacteria, fungi and several viruses . This review gives an overview of the present knowledge about the antiviral activities and, when possible, the antiviral modes of action of this protein . Lactoferrin displays antiviral activity against both DNA- and RNA-viruses, including rotavirus, respiratory syncytial virus, herpes viruses and HIV . The antiviral effect of LF lies in the early phase of infection . Lactoferrin prevents entry of virus in the host cell, either by blocking cellular receptors, or by direct binding to the virus particles. J Org Chem, 1999 Sep 3, 64(18), 6861 - 6869 DNA Binding by 4-Methoxypyrrolic Natural Products . Preference for Intercalation at AT Sites by Tambjamine E and Prodigiosin; Melvin MS et al.; The 4-methoxypyrrolic natural products contain a common 4-methoxy-2,2'-bipyrrole chromophore and exhibit promising anticancer, antimicrobial, and immunosuppressive activities . Herein, the ability of two representative members, tambjamine E (1) and prodigiosin (2), to bind calf thymus DNA (CT-DNA), polyd{G-C}(2), and polyd{A-T}(2) has been characterized using absorption and fluorescence spectroscopy . Scatchard plots showed that 1 occupies a site size (n) of ca . three base pairs and possesses affinity constants (K) ranging from 1 to 0.1 x 10(5) M(-)(1) . Prodigiosin (2) binds DNA by mixed modes, as isobestic points were not evident in titration experiments . The neutral aldehyde precursor 4 was found to possess no measurable DNA binding affinity, indicating that the enamine structure of 1 and the pyrromethene of 2 are essential elements for DNA binding affinity . The enamine of 1 was found to undergo hydrolysis to 4 with a half-life (t(1/2)) of 14.5 h at pH 7.4 and 37.5 degrees C . For the B-ring nitrogen atom of 1, a pK(a) value of 10.06 was also established . From fluorescence spectroscopy it was found that 1, 2, and 4 possess weak emission spectra in water that is increased in nonaqueous solvents . For 1 and 2, DNA binding also increased the emission yield . Energy-transfer measurements suggested an intercalative binding mode, with preference for AT sites . The ability of distamycin to displace 1 and 2 from the helix also suggested that they intercalate from the minor-groove . This specificity differs from other unfused aromatic cations that bind by a minor-groove mode at AT sequences and intercalate at GC sites . Reasons for the specificity displayed by 1 and 2, as well as the implications of our findings to their biological properties are discussed. J Org Chem, 1999 Jan 8, 64(1), 70 - 80 Vancomycin CD and DE Macrocyclization and Atropisomerism Studies; Boger DL et al.; Continued studies on the synthesis and atropisomerism of the vancomycin CD and DE ring systems based on aromatic nucleophilic substitution macrocyclization reactions for formation of the biaryl ethers are detailed in efforts that further define substituent effects, explore the impact of protecting groups, and establish the stereochemical integrity of peripheral substituents . These have led to the identification of a previously unrecognized site of epimerization within our original approach to the DE ring system and the introduction of significant improvements in the approach that will find utilization in syntheses of the vancomycin CDE ring system and of the natural product itself . The preparation of a complete set of DE ring system isomers bearing the unnatural stereochemistry at the labile C8, C11, and C14 sites was accomplished for comparison and established that C8 is prone to epimerization to the more stable, unnatural S versus R absolute stereochemistry if it bears an ester, but not a carboxamide, substituent . Additionally, an improved synthesis of the CD ring system, enlisting a C14 carboxamide versus ester substituent, is disclosed and establishes the stereochemical integrity of our prior approach which incorporated a C14 ester . A set of fully functionalized CD and DE ring systems were prepared and include the development of conditions for the final deprotections required for incorporation into efforts on the natural product . The examination of the antimicrobial activity of these key substructures of vancomycin is detailed. Br J Ophthalmol, 2001 Nov, 85(11), 1336 - 40 Detection of galectin-3 in tear fluid at disease states and immunohistochemical and lectin histochemical analysis in human corneal and conjunctival epithelium; Hrdlickova-Cela E et al.; BACKGROUND/AIM: Components of the tear fluid contribute to the biochemical defence system of the eye . To reveal whether the immune mediator and lipopolysaccharide binding galectin-3 is present in tears, tear samples were collected from eyes in healthy and pathological states . Investigation of expression of galectin-3 and galectin-3 reactive glycoligands in normal human conjunctival and corneal epithelia was also initiated as a step to understand the role of galectin-3 in ocular surface pathology . METHODS: Immunoblot analysis using either a rabbit polyclonal or a mouse monoclonal antibody against galectin-3 was employed to detect galectin-3 in tear fluid . Galectin-3 expression in tissue specimens was detected by immunocytochemistry employing A1D6 mouse monoclonal antibody, and galectin-3 reactive glycoligands were visualised by lectin histochemistry using labelled galectin-3 . RESULTS: Galectin-3 was found only in tears from patients with ocular surface disorders . It was expressed in normal corneal and conjunctival epithelia but not in lacrimal glands . Inflammatory leucocytes and goblet cells found in galectin-3 containing tear fluid also expressed galectin-3 . Galectin-3 binding sites were detected on the surface of conjunctival and corneal epithelial cells co-localising with desmoglein . CONCLUSIONS: This study revealed expression of galectin-3 in tear fluid obtained from patients with eye diseases . The role of this endogenous lectin (produced by inflammatory as well as epithelial cells) in antimicrobial action and inflammation modulation could be expected. Mutat Res, 2001 Nov 15, 498(1-2), 193 - 205 Ciprofloxacin: in vivo genotoxicity studies; Herbold BA et al.; The fluoroquinolone ciprofloxacin is widely used in antimicrobial therapy . It inhibits the bacterial gyrase and in high concentrations in vitro also the functionally related eukaryotic topoisomerase-II, which resulted in genotoxic effects in several in vitro tests . In order to evaluate the relevance of these findings, ciprofloxacin was tested in vivo for genotoxic activity using the following test systems: micronucleus test in bone marrow of mice, cytogenetic chromosome analysis in Chinese hamster, dominant lethal assay in male mice and UDS tests in primary rat and mouse hepatocytes in vivo . These results are compared with already published in vitro and in vivo studies with ciprofloxacin . All in vivo genotoxicity revealed no genotoxic effect for ciprofloxacin . In addition, ciprofloxacin was found to be non-carcinogenic in two rodent long-term bioassays . Therefore, ciprofloxacin is considered to be safe for therapeutic use. Int J Antimicrob Agents, 2001 Sep, 18(3), 283 - 6 The usage of antibiotics in Russia and some countries in Eastern Europe; Stratchounski L et al.; The patterns of antibiotic use in 1998 in Russia and some other countries in Eastern Europe (Belarus, Poland, Slovakia, Hungary) were studied . Poland, Slovakia and Hungary were "more modern" users of antibiotics, consuming new and expensive drugs . Russia and Belarus were "conservative" having a lower level of total consumption and using lesser quantities of penicillins, cephalosporins, macrolides, quinolones, carbapenems but greater amounts of aminoglycosides and chloramphenicol . It is essential for "conservative" countries to establish a national surveillance system of antibiotic consumption to monitor the development of bacterial resistance to antimicrobial agents and to monitor individual antibiotic use. Int J Antimicrob Agents, 2001 Sep, 18(3), 279 - 82 Antibiotic usage in Nordic countries; Bergan T; The consumption of antibacterials has remained relatively stable in Scandinavia and is low compared with most other countries . Measured as "Defined Daily Doses" (DDD), the highest consumption is found in Iceland and Finland, and the lowest in Denmark and Norway . The consumption in Iceland, Finland and Sweden is about twice that in Norway . The distribution of different classes of antimicrobials shows striking differences . Phenoxymethyl and benzylpenicillin make up about 55% of the DDDs in Sweden and 40% of the DDDs in Denmark and Norway, whereas the narrow-spectrum penicillins represent 20% of the DDDs in Iceland . Fluoroquinolones are little used except in Sweden where they account for about 10% of DDDs . The use of cephalosporins ranges from 1% (in Denmark) to 15% (in Finland) and between 3 and 5% in the other countries . The policy that narrow-spectrum penicillins may be used when necessary but broad-spectrum compounds should be avoided has the positive effect that there is greater susceptibility in the Nordic countries to these antibiotics than elsewhere. Eur J Med Chem, 2001 Sep, 36(9), 743 - 6 Synthesis and antitubercular activity of imidazo{2,1-b}thiazoles; Andreani A et al.; A number of selected imidazo{2,1-b}thiazoles entered the screening at the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) and one of these compounds, 2-chloro-6-phenylimidazo{2,1-b}thiazole, showed antitubercular activity . On this basis we planned the synthesis of new analogues bearing a substituted ring at the 6 position . For one compound only (2-chloro-6-p-chlorophenylimidazo{2,1-b}thiazole) the 5-nitroso derivative was also prepared . The antitubercular activity of these compounds was compared with the known analogues lacking the chlorine at the 2 position . 5-Nitroso-6-p-chlorophenylimidazo{2,1-b}thiazole showed potent antitubercular activity. Immunol Lett, 2001 Sep 3, 78(2), 103 - 11 Dendritic cell discoveries provide new insight into the cellular immunobiology of DNA vaccines; Coombes BK et al.; The evolution of increasingly virulent human pathogens, together with the rapid onset of antimicrobial resistance has created a need for new vaccination strategies . Nucleic acid vaccines, based on recombinant DNA technology are a promising new vaccine formulation capable of eliciting both humoral and cellular immune responses . This technology has been experimentally validated in animal models of pathogen challenge and tumor protection following administration of a DNA vaccine and has led to extensive research into the mechanisms of protective immunity . We focus here on the cellular and molecular mechanisms leading to cell-mediated immune responses to DNA vaccines and discuss these mechanisms in light of recent advances in the field of dendritic cell immunobiology . In particular, the potential involvement of: (i) the CpG pattern-recognition receptor, toll-like receptor-9; (ii) the dendritic cell-specific surface adhesion molecule, DC-SIGN; and (iii) the molecular interactions between CD40 and CD154 in the evolution of protective cell-mediated immunity to DNA vaccines are discussed . An improved understanding of the precise mechanisms leading to protective cellular immunity following DNA vaccination may help in the design of novel DNA constructs containing immunostimulatory features that target one or more of these mechanisms, with the aim of increasing the immunogenic potential and protective efficacy of DNA vaccines. Int J Environ Health Res, 2001 Sep, 11(3), 257 - 66 Thermal inactivation of antimicrobial-resistant Gram-positive cocci in chicken meat: D and Z value determinations; Bertolatti D et al.; Antimicrobial-resistance in Gram-positive bacteria is reported with increasing frequency in strains isolated from food animals . Their isolation from commercial poultry carcasses and meat products constitute a potential risk that resistant strains or resistance genes might spread to humans via the food chain . As bacterial inactivation by thermal process is a critical control point in the safe preparation of many ready-to-eat foods, it is important to determine the thermal resistance of these organisms . The present study was undertaken to investigate the thermal tolerance (D and Z values) of antimicrobial-resistant, Gram-positive cocci in ground chicken meat . The antimicrobial-resistant, Gram-positive cocci for this study were isolated from two poultry processing plants in Western Australia . D and Z value data indicate that these isolates do not exhibit enhanced thermal resistant characteristics . The estimated lethal effect of the cooking process for chicken meat indicates that an internal temperature of 70 degrees C for 2.1 min would provide a 7-log reduction of all cell suspensions tested. In Vitro Cell Dev Biol Anim, 2001 Sep, 37(8), 480 - 9 Isolation and culture of airway epithelial cells from chronically infected human lungs; Randell SH et al.; We describe procedures for isolating and culturing airway epithelial cells from chronically infected human lungs . Experience in our laboratory demonstrated the need to balance pathogen eradication against antibiotic toxicity to epithelial cells . To provide a logical basis for antibiotic selection and dose, we systematically analyzed the cytotoxicity of antibiotics useful against typical pathogens . Alone, colistin, ciprofloxacin, doxycycline, and tobramycin were moderately toxic at concentrations close to those used in cell culture, whereas amphotericin, ceftazidime, chloramphenicol, imipenem, meropenem, piperacillin, sulfamethoxazole/trimethoprim, and vancomycin were nontoxic even at concentrations many times the antimicrobial level . Epithelial cytotoxicity of combined antibiotics was additive, with no evidence of competition or synergism . Antibiotics had little effect on initial cell attachment and did not acutely lyse cells, but inhibited subsequent growth . Interestingly, cytotoxicity decreased markedly with increasing epithelial cell density . Cystic fibrosis (CF) and non-CF epithelial cells showed no differences in sensitivity to the antibiotics tested and initial exposure to antibiotics did not affect the electrophysiologic properties of resistance or short circuit current in well-differentiated cells . Tailored combinations of antibiotics at appropriate doses killed even multidrug-resistant bacteria . Thus, epithelial cells can usually be cultured from chronically infected CF airways. Respir Res, 2000, 1(3), 141 - 50 Epub 2000 Oct 20. Epithelial antimicrobial peptides in host defense against infection; Bals R; One component of host defense at mucosal surfaces seems to be epithelium-derived antimicrobial peptides . Antimicrobial peptides are classified on the basis of their structure and amino acid motifs . Peptides of the defensin, cathelicidin, and histatin classes are found in humans . In the airways, alpha-defensins and the cathelicidin LL-37/hCAP-18 originate from neutrophils . beta-Defensins and LL-37/hCAP-18 are produced by the respiratory epithelium and the alveolar macrophage and secreted into the airway surface fluid . Beside their direct antimicrobial function, antimicrobial peptides have multiple roles as mediators of inflammation with effects on epithelial and inflammatory cells, influencing such diverse processes as proliferation, immune induction, wound healing, cytokine release, chemotaxis, protease-antiprotease balance, and redox homeostasis . Further, antimicrobial peptides qualify as prototypes of innovative drugs that might be used as antibiotics, anti-lipopolysaccharide drugs, or modifiers of inflammation. Respir Res, 2000, 1(2), 87 - 92 Epub 2000 Aug 23. The role of secretory leukocyte proteinase inhibitor and elafin (elastase-specific inhibitor/skin-derived antileukoprotease) as alarm antiproteinases in inflammatory lung disease; Sallenave JM; Secretory leukocyte proteinase inhibitor and elafin are two low-molecular-mass elastase inhibitors that are mainly synthesized locally at mucosal sites . It is thought that their physicochemical properties allow them to efficiently inhibit target enzymes, such as neutrophil elastase, released into the interstitium . Historically, in the lung, these inhibitors were first purified from secretions of patients with chronic obstructive pulmonary disease and cystic fibrosis . This suggested that they might be important in controlling excessive neutrophil elastase release in these pathologies . They are upregulated by 'alarm signals' such as bacterial lipopolysaccharides, and cytokines such as interleukin-1 and tumor necrosis factor and have been shown to be active against Gram-positive and Gram-negative bacteria, so that they have joined the growing list of antimicrobial 'defensin-like' peptides produced by the lung . Their site of synthesis and presumed functions make them very attractive candidates as potential therapeutic agents under conditions in which the excessive release of elastase by neutrophils might be detrimental . Because of its natural tropism for the lung, the use of adenovirus-mediated gene transfer is extremely promising in such applications. J Org Chem, 1996 Nov 1, 61(22), 7764 - 7776 Role of the C(5)-C(5a) Exomethylene Group in Bicyclomycin: Synthesis, Structure, and Biochemical and Biological Properties; Park Hg H et al.; Thirty-two C(5)-C(5a) exomethylene-modified bicyclomycin derivatives were prepared to determine the effect of structural modification of this unit on bicyclomycin (1) function . The compounds were grouped into three categories: the C(5)-unsaturated bicyclomycins, the C(5a)-substituted C(5)-C(5a)-dihydrobicyclomycin derivatives, and the C(5)-modified norbicyclomycins . An efficient three-step procedure was developed to synthesize C(5a)-substituted C(5),C(5a)-dihydrobicyclomycins . Bicyclomycin was converted to bicyclomycin C(2'),C(3')-acetonide (36) and then treated with a nucleophile in 50% aqueous methanol ("pH" 10.5) to give the C(5a)-substituted C(5),C(5a)-dihydrobicyclomycin C(2'),C(3')-acetonide . Removal of the acetonide group (trifluoroacetic acid in 50% aqueous methanol) in the final step provided the desired bicyclomycin derivative . All the compounds were evaluated using the rho-dependent ATPase assay and their antimicrobial activities determined using a filter disc assay . Most of the compounds were also tested in the transcription termination assay . We observed that many of the C(5)-unsaturated bicyclomycins effectively inhibited ATP hydrolysis at 400 &mgr;M and inhibited the production of rho-dependent transcripts at 100 &mgr;M . The biochemical activities of C(5a)-bicyclomycincarboxylic acid (5), methyl C(5a)-bicyclomycincarboxylate (6), ethyl C(5a)-bicyclomycincarboxylate (7), and bicyclomycin C(5)-norketone O-methyloxime (11) were all similar to 1 . Compounds 6, 7, and 11 exhibited diminished antibiotic activity compared to 1, and 5 displayed no detectable activity . Several C(5a)-substituted C(5),C(5a)-dihydrobicyclomycins showed significant inhibition of rho-dependent ATPase and transcription termination activities . The inhibitory properties of C(5),C(5a)-dihydrobicyclomycin C(5a)-methyl sulfide (18), C(5),C(5a)-dihydrobicyclomycin C(5a)-phenyl sulfide (23), and C(5)-C(5a)-dihydrobicyclomycin-5,5a-diol (31) approached those of 1 . Compounds 18, 23, and 31 did not exhibit antibiotic activity . Two of the four C(5)-modified norbicyclomycin adducts showed moderate inhibitory activities in the ATPase assay, and none showed significant antibiotic activity . Our findings showed that the C(5)-C(5a) exomethylene unit retention in 1 was not essential for inhibition of in vitro rho activity . The structure-activity relationship data indicated that bicyclomycins that contained a small unsaturated C(5) unit or C(5),C(5a)-dihydrobicyclomycins that possessed a small, nonpolar C(5a) substituent effectively inhibited rho function in in vitro biochemical assays . We concluded that the C(5)-C(5a) unit in 1 was not a critical structural element necessary for drug binding to rho and that irreversible, inactivating units placed at this site would permit the bicyclomycin derivative to bind efficiently to rho. J Org Chem, 1996 Nov 1, 61(22), 7756 - 7763 Role of the {4.2.2} Bicyclic Unit in Bicyclomycin: Synthesis, Structure, Chemical, Biochemical, and Biological Properties; Santillan A Jr et al.; Twelve bicyclomycin derivatives were synthesized to determine the effect of modification of the {4.2.2} bicyclic unit in bicyclomycin (1) on drug function . Few bicyclomycin derivatives have been described in which the {4.2.2} ring system has been modified . The compounds evaluated were divided into two categories: the two N-methyl-modified bicyclomycins (2, 3) and the ten C(6)-substituted bicyclomycins (4-13) . Substituents introduced at the C(6) site included alkoxy, thioalkoxy, thiophenoxy, anilino, and hydrogen . A procedure was developed to synthesize select C(6)-substituted bicyclomycins . Bicyclomycin was first converted to bicyclomycin C(2'),C(3')-acetonide (16) and then treated with methanesulfonyl chloride to give in situ the corresponding C(6) mesylate 17 . Treatment of 17 with the appropriate nucleophile followed by removal of the C(2'),C(3')-acetonide group gave the desired C(6)-substituted bicyclomycin . The chemical properties of C(6) O-methylbicyclomycin (4) were examined . Treatment of THF-H(2)O mixtures of 4 with excess EtSH maintained at "pH" 8.0-9.0 led to no detectable reaction, while at more basic "pH" values 4 underwent stereospecific conversion to the bis-spiro derivative 33 and no appreciable EtSH addition to the C(5)-C(5a) exomethylene unit . These results were compared to the reactivity of 1 with EtSH . The stability (pH 7.4, 37 degrees C) of C(6)-substituted bicyclomycins 4, 6, and 10-13 in aqueous solutions were examined . We observed that most of these compounds (4, 6, 10-12) underwent near complete change (>75%) within 200 h . The {4.2.2} bicyclic-modified bicyclomycins were evaluated in the rho-dependent ATPase assay and their antimicrobial activities determined using a filter disc assay . Most of the compounds were also tested in the transcription termination assay . We observed that all structural modifications conducted within the {4.2.2} bicyclic unit led to a loss of rho-dependent ATPase (I(50) > 400 &mgr;M) and to transcription termination (I(50) > 100 &mgr;M) inhibitory activities, as well as a loss of antimicrobial activity (MIC > 32 mg/mL) . Only N(10)-methylbicyclomycin (2) displayed moderate inhibitory activities in these assays . These findings indicated that the {4.2.2} bicyclic unit played an important role in the antibiotic-rho recognition process . Potential factors that govern this interaction are briefly discussed . We concluded that placement of an irreversible inactivating unit at the N- and O-sites within the {4.2.2} bicyclic unit in 1 would likely prohibit the bicyclomycin derivative from efficiently binding to rho. J Org Chem, 1996 Nov 1, 61(22), 7750 - 7755 Role of the C(1) Triol Group in Bicyclomycin: Synthesis and Biochemical and Biological Properties; Park Hg H et al.; Bicyclomycin (1) is a commercial antibiotic whose primary site of action in Escherichia coli is the essential cellular protein transcription termination factor rho . The bicyclomycin binding domain in rho is unknown; however, enzyme irreversible inactivators that modify rho upon activation may identify the site . In this study, we investigated the importance for rho binding of the C(1) triol group in 1 . Twelve bicyclomycin derivatives were prepared, and the C(1) triol group was modified at the C(1'), the C(2'), and the C(3') sites . The compounds were evaluated by rho-dependent ATPase and transcription termination assays and their antimicrobial activities assessed using a filter disc assay . Bicyclomycin inhibited both rho-dependent ATPase (I(50) = 60 &mgr;M) and rho-dependent transcription termination (I(50) approximately 5 &mgr;M) processes and had a minimum inhibitory concentration value of 0.25 mg/mL against E . coli W3350 cells . None of the 12 C(1) triol bicyclomycin derivatives significantly inhibited rho-dependent ATPase (I(50) > 400 &mgr;M) and transcription termination (I(50) > 100 &mgr;M) activities or exhibited antibiotic activity at a 32 mg/mL concentration . These results indicated that there was a strong molecular complement between the C(1) triol group and its rho binding site . We concluded that the C(1) triol group in 1 is a critical structural element necessary for drug binding to rho and that an enzyme irreversible inactivating unit placed at this site would prohibit the bicyclomycin derivative from efficiently binding to rho. J Org Chem, 1996 Jun 14, 61(12), 4120 - 4124 Framework-Reactive Siderophore Analogs as Potential Cell-Selective Drugs . Design and Syntheses of Trimelamol-Based Iron Chelators; Ramurthy S et al.; Currently, the role of DNA-directed alkylating agents as potential anticancer/ antimicrobial drugs is of wide interest . Most of the alkylating agents used clinically as drugs damage DNA in cells without specificity, and this can lead to undesired toxicity problems . Minimizing serum residence time by targeting the drug to select pathogens or organs might diminish the effects of nonselective reactivity . This paper describes the syntheses and preliminary studies of analogs of siderophores (microbial iron chelators) 2 and 20 that incorporate centers within the siderophore framework capable of generating potent electrophiles (iminium ions), hopefully after directed cellular recognition and uptake . Formation of N-aminals from trimelamol (3) and substituted hydroxamic acid 4 or 5was critical for the design and synthesis of the targets . In preliminary biological testing, compound 2, a trimelamol-based siderophore analog, was active against Escherichia coli X580, illustrating the therapeutic potential of this new type of siderophore-mediated drug design and delivery. Arch Immunol Ther Exp (Warsz), 2001, 49 Suppl 2, S83 - 7 Effect of granulocyte-macrophage colony-stimulating growth factor on interferon and tumor necrosis factor production in whole blood cell cultures of patients with acute myelogenous leukemia; Kaminska T et al.; The effect of recombinat human granulocyte-macrophage colony-stimulating growth factor (rHuGM-CSF) treatment on in vitro interferon (IFN) and tumor necrosis factor (TNF) production in peripheral blood cells of 46 patients with acute myelogenous leukemia (AML) was examined . GM-CSF significantly enhanced virus-induced IFN-alpha production in blood cells (containing 68% of blasts) of 28 patients with M4-M5 AML according to the French-American-British (FAB) classification and also phytohemagglutinin (PHA)-induced IFN-gamma production in blood cells (containing 70% of blasts) of 18 patients with AML MO-M3 type . In control blood cells (25 healthy persons) GM-CSF enhanced PHA-induced IFN-gamma but did not influence IFN-alpha production . In the presence of GM-CSF, TNF-alpha titers induced with lipopolysaccharide were also higher in control blood cells but not in cells of patients with M0-M3 or M4-M5 type of AML . The significance of GM-CSF-enhanced IFN-alpha and IFN-gamma production in antimicrobial and anti-leukemic immune reactions which can develop during GM-CSF therapy is discussed. Pharmacotherapy, 2001 Oct, 21(10 Pt 2), 273S - 283S Integrating fluoroquinolones into the hospital formulary; Bertino JS Jr; With the increasing availability of new agents, selection of fluoroquinolones for formulary inclusion can be difficult . Appropriate evaluation of the important characteristics (pharmacokinetic and pharmacodynamic properties, antimicrobial activity, efficacy, tolerability, cost) of these agents should allow selection of the most cost-effective ones . Evidence from in vitro studies and clinical trials indicates differences exist among fluoroquinolones, especially in terms of activity against gram-positive, aerobic organisms . For selected clinical situations, it may be important to choose an agent that is available in both intravenous and oral formulations . Comparative drug costs, as well as costs associated with potential clinical failure and adverse events, should be evaluated carefully . Dosage regimens should be considered, as shorter durations of therapy and less frequent dose administration may lead to reduced labor costs and increased patient compliance, thereby improving effectiveness and economic efficiency. Pharmacotherapy, 2001 Oct, 21(10 Pt 2), 253S - 272S Fluoroquinolone adverse effects and drug interactions; Fish DN; Extensive pharmacologic and clinical development of quinolone antimicrobial agents has resulted in improved antimicrobial activity, pharmacokinetic features, toxicity, and drug-drug interaction profiles . Nalidixic acid and other early quinolones had limited use due to poor pharmacokinetics, relatively narrow antimicrobial spectrum of activity, and frequent adverse effects . Beginning with the development of fluoroquinolones, such as norfloxacin and ciprofloxacin, in the 1980s, the agents assumed a greatly expanded clinical role because of their broad antimicrobial spectrum of action, improved pharmacokinetic properties, and more acceptable safety profile . Although the pharmacokinetics and efficacy of the drugs have improved significantly, a major area of continued emphasis is to further reduce the frequency and severity of adverse events and drug-drug interactions . Older agents such as ciprofloxacin and ofloxacin are still extensively prescribed, but the focus of this article is on the newer fluoroquinolones (levofloxacin and other drugs that have been approved or have been under investigation since approximately 1997). An R Acad Nac Med (Madr), 2001, 118(2), 343 - 57; discussion 357-61 {The active efflux pump in antimicrobial resistance}; Piedrola Angulo G; Active efflux of antibiotics is one of the different resistance mechanisms of bacteria against antimicrobial agents . The rapid exit of the antibiotic from the bacteria prevents its interaction with target point . This mechanism, also known as active efflux pump, is very important since it can explain the simultaneous resistance to several antibiotic families . There are four main active efflux systems: MFS, RND, Smr and ABC . This review includes all of them, together with their transporting proteins, the bacteria that have those proteins and the phenotype of the antibiotics affected . The complex genotype regulation systems, including codifying genes, positive and negative regulators, chromosomal or plasmidic localization is also studied . Finally, the causes of marked resistance to antimicrobial agents of isolated strains in the clinic, especially in hospital areas are revised . The role of the European Antimicrobial Resistance Surveillance System (EARSS) in the evaluation of those resistances is discussed. Clin Infect Dis, 2001 Nov 15, 33(10), 1692 - 6 Epub 2001 Oct 12. Trends in the epidemiology of opportunistic fungal infections: predisposing factors and the impact of antimicrobial use practices; Singh N; In the past decade, the frequency of opportunistic fungal infections has increased, and the spectrum of fungal pathogens has changed . The increasing number of susceptible hosts, the introduction of newer modalities for hematopoietic stem cell transplantation, the evolution of organ transplantation practices, the use of novel immunosuppressive agents, and current antimicrobial prophylactic strategies have likely contributed to the changing epidemiology of invasive mycoses . The introduction of azoles more than a decade ago has had a profound impact on curtailing candidal infections . However, a dramatic increase in azole-resistant Candida species and mold infections has been documented . The trends in time of onset, spectrum, and frequency of infections due to invasive molds and opportunistic yeasts are unique for different fungi and vary between subsets of immunocompromised hosts . This review discusses the implications of these trends for guiding judicious use of antimicrobial prophylactics and for unraveling the pathophysiological basis of fungal infections. Proc Natl Acad Sci U S A, 1994 Mar 15, 91(6), 2329 - 33 Lipid-derived signals that discriminate wound- and pathogen-responsive isoprenoid pathways in plants: methyl jasmonate and the fungal elicitor arachidonic acid induce different 3-hydroxy-3-methylglutaryl-coenzyme A reductase genes and antimicrobial isoprenoids in Solanum tuberosum L; Choi D et al.; Induction of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR; EC 1.1.1.34) is essential for the synthesis of steroid derivatives and sesquiterpenoid phytoalexins in solanaceous plants following mechanical injury or pathogen infection . Gene-specific probes corresponding to different HMGR genes (hmg1 and hmg2) were used to study HMGR expression in potato tissue following treatment with methyl jasmonate, a lipoxygenase product of linolenic acid, or arachidonic acid, an elicitor present in the lipids of the potato late blight fungus Phytophthora infestans . Treatment of potato discs (2.2 cm in diameter) with low concentrations (0.45-45 nmol per disc surface) of methyl jasmonate nearly doubled the wound-induced accumulation of hmg1 transcripts and steroid-glycoalkaloid (SGA) accumulation, reduced the abundance of hmg2 transcripts, and did not induce phytoalexins . High concentrations of methyl jasmonate (2-4.5 mol per disc surface) suppressed hmg1 mRNA and SGA accumulation but did not affect hmg2 mRNA abundance or induce phytoalexins . In contrast, arachidonate treatment strongly suppressed hmg1 and strongly induced hmg2 mRNA in a concentration-dependent manner . There was a corresponding suppression of SGA accumulation and an induction of sesquiterpene phytoalexin accumulation by this elicitor . Lipoxygenase inhibitors reduced the wound-induced accumulation of hmg1 transcripts and suppressed SGA levels, effects that were overcome by exogenous methyl jasmonate (45 nmol per disc surface) . The results (i) suggest that methyl jasmonate can function as a signal for hmg1 expression and SGA induction following wounding and (ii) indicate that the arachidonate- and jasmonate-response pathways are distinct in relation to HMGR gene expression and isoprenoid product accumulation . The results also are consistent with placement of the HMGR activities encoded by hmg1 and hmg2 within discrete steroid and sesquiterpenoid biosynthetic channels. Cardiovasc Drug Rev, 2001 Fall, 19(3), 234 - 44 Cardiovascular actions of berberine; Lau CW et al.; Berberine, is an alkaloid from Hydrastis canadensis L., Chinese herb Huanglian, and many other plants . It is widely used in traditional Chinese medicine as an antimicrobial in the treatment of dysentery and infectious diarrhea . This manuscript describes cardiovascular effects of berberine and its derivatives, tetrahydroberberine and 8-oxoberberine . Berberine has positive inotropic, negative chronotropic, antiarrhythmic, and vasodilator properties . Both derivatives of berberine have antiarrhythmic activity . Some cardiovascular effects of berberine and its derivatives are attributed to the blockade of K+ channels (delayed rectifier and K(ATP)) and stimulation of Na+ -Ca(2+) exchanger . Berberine has been shown to prolong the duration of ventricular action potential . Its vasodilator activity has been attributed to multiple cellular mechanisms . The cardiovascular effects of berberine suggest its possible clinical usefulness in the treatment of arrhythmias and/or heart failure. Nature, 2001 Oct 18, 413(6857), 732 - 8 Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3; Alexopoulou L et al.; Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize molecular patterns associated with microbial pathogens, and induce antimicrobial immune responses . Double-stranded RNA (dsRNA) is a molecular pattern associated with viral infection, because it is produced by most viruses at some point during their replication . Here we show that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-kappaB and the production of type I interferons (IFNs) . TLR3-deficient (TLR3-/-) mice showed reduced responses to polyinosine-polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when sensitized with d-galactosamine (d-GalN), and reduced production of inflammatory cytokines . MyD88 is an adaptor protein that is shared by all the known TLRs . When activated by poly(I:C), TLR3 induces cytokine production through a signalling pathway dependent on MyD88 . Moreover, poly(I:C) can induce activation of NF-kappaB and mitogen-activated protein (MAP) kinases independently of MyD88, and cause dendritic cells to mature. Proc Natl Acad Sci U S A, 2001 Nov 6, 98(23), 13431 - 6 Epub 2001 Oct 23. A new class of oxidosqualene cyclases directs synthesis of antimicrobial phytoprotectants in monocots; Haralampidis K et al.; Many plants synthesize antimicrobial secondary metabolites as part of their normal program of growth and development, often sequestering them in tissues where they may protect against microbial attack . These include glycosylated triterpenoids (saponins), natural products that are exploited by man for a variety of purposes including use as drugs {Hostettmann, K . & Marston, A . (1995) Saponins (Cambridge Univ . Press, Cambridge, U.K.)} . Very little is known about the genes required for the synthesis of this important family of secondary metabolites in plants . Here we show the novel oxidosqualene cyclase AsbAS1 catalyzes the first committed step in the synthesis of antifungal triterpenoid saponins that accumulate in oat roots . We also demonstrate that two sodium azide-generated saponin-deficient mutants of oat, which define the Sad1 genetic complementation group, are defective in the gene encoding this enzyme and provide molecular genetic evidence indicating a direct link between AsbAS1, triterpenoid saponin biosynthesis, and disease resistance . Orthologs of AsbAS1 are absent from modern cereals and may have been lost during selection, raising the possibility that this gene could be exploited to enhance disease resistance in crop plants. Proc Natl Acad Sci U S A, 2001 Oct 23, 98(22), 12630 - 5 Epub 2001 Oct 16. Gambicin: a novel immune responsive antimicrobial peptide from the malaria vector Anopheles gambiae; Vizioli J et al.; A novel mosquito antimicrobial peptide, gambicin, and the corresponding gene were isolated in parallel through differential display-PCR, an expressed sequence tag (EST) project, and characterization of an antimicrobial activity in a mosquito cell line by reverse-phase chromatography . The 616-bp gambicin ORF encodes an 81-residue protein that is processed and secreted as a 61-aa mature peptide containing eight cysteines engaged in four disulfide bridges . Gambicin lacks sequence homology with other known proteins . Like other Anopheles gambiae antimicrobial peptide genes, gambicin is induced by natural or experimental infection in the midgut, fatbody, and hemocyte-like cell lines . Within the midgut, gambicin is predominantly expressed in the anterior part . Both local and systemic gambicin expression is induced during early and late stages of natural malaria infection . In vitro experiments showed that the 6.8-kDa mature peptide can kill both Gram-positive and Gram-negative bacteria, has a morphogenic effect on a filamentous fungus, and is marginally lethal to Plasmodium berghei ookinetes . An oxidized form of gambicin isolated from the cell line medium was more active against bacteria than the nonoxidized form from the same medium. Proc Natl Acad Sci U S A, 2001 Oct 23, 98(22), 12590 - 5 Epub 2001 Oct 16. Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays; De Gregorio E et al.; To identify new Drosophila genes involved in the immune response, we monitored the gene expression profile of adult flies in response to microbial infection by using high-density oligonucleotide microarrays encompassing nearly the full Drosophila genome . Of 13,197 genes tested, we have characterized 230 induced and 170 repressed by microbial infection, most of which had not previously been associated with the immune response . Many of these genes can be assigned to specific aspects of the immune response, including recognition, phagocytosis, coagulation, melanization, activation of NF-kappaB transcription factors, synthesis of antimicrobial peptides, production of reactive oxygen species, and regulation of iron metabolism . Additionally, we found a large number of genes with unknown function that may be involved in control and execution of the immune response . Determining the function of these genes represents an important challenge for improving our knowledge of innate immunity . Complete results may be found at http://www.fruitfly.org/expression/immunity/. Biophys J, 2001 Nov, 81(5), 2979 - 91 Comparison of the membrane association of two antimicrobial peptides, magainin 2 and indolicidin; Zhao H et al.; Interactions of two antimicrobial peptides, magainin 2 and indolicidin, with three different model biomembranes, namely, monolayers, large unilamellar vesicles (LUVs), and giant liposomes, were studied . Insertion of both peptides into lipid monolayers was progressively enhanced when the content of an acidic phospholipid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) in a film of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) was increased . Indolicidin and magainin 2 penetrated also into lipid monolayers containing cholesterol (mole fraction, X = 0.1) . Membrane association of magainin 2 attenuated lipid lateral diffusion in POPG-containing LUVs as revealed by the decrease in the excimer/monomer fluorescence ratio I(e)/I(m) for the pyrene fatty-acid-containing phospholipid derivative 1-palmitoyl-2-{10-(pyren-1-yl) decanoyl}-sn-glycero-3-phospho-rac-glycerol (PPDPG) . Likewise, an increase in steady-state fluorescence anisotropy of the membrane-incorporated diphenylhexatriene (DPH) was observed, revealing magainin 2 to increase acyl chain order and induce segregation of acidic phospholipids . Similar effects were observed for indolicidin . The topological effects of magainin 2 and indolicidin on phospholipid membranes were investigated using optical microscopy of giant vesicles . Magainin 2 had essentially no influence on either SOPC or SOPC:cholesterol (X = 0.1) giant liposomes . However, effective vesiculation was observed when acidic phospholipid (X(PG) = 0.1) was included in the giant vesicles . Indolicidin caused only a minor shrinkage of giant SOPC vesicles whereas the formation of endocytotic vesicles was observed when the giant liposome contained POPG (X(PG) = 0.1) . Interestingly, for indolicidin, vesiculation was also observed for giant vesicles composed of SOPC/cholesterol (X(chol) = 0.1) . Possible mechanisms of membrane transformation induced by these two peptides are discussed. J Pept Res, 2001 Oct, 58(4), 293 - 306 Conformation and other biophysical properties of cyclic antimicrobial peptides in aqueous solutions; Jelokhani-Niaraki M et al.; As a step towards understanding the mechanism of the biological activity of cyclic antimicrobial peptides, the biophysical properties and conformations of four membrane-active cyclic peptide antibiotics, based on gramicidin S (GS), were examined in aqueous environments . These cyclic peptides, GS10 {cyclo(VKLdYP)2}, GS12 {cyclo(VKLKdYPKVKLdYP)}, GS14 {cyclo(VKLKVdYPLKVKLdYP)} and {d-Lys}4GS14 {cyclo(VKLdKVdYPLKVKLdYP)} (d-amino acid residues are denoted by d and are underlined) had different ring sizes of 10, 12 and 14 residues, were different in structure and amphipathicity, and covered a broad spectrum of hemolytic and antimicrobial activities . GS10, GS12 and {d-Lys}4GS14 were shown to be monomeric in buffer systems with ionic strength biological environments . GS14 was also monomeric at low concentrations, but aggregated at concentrations > 50 microm . The affinity of peptides for self-assembly and interaction with hydrophobic surfaces was related to their free energy of intermolecular interaction . The effects of variations in salt and organic solvent (trifluoroethanol) concentration and temperature on peptide conformation were also examined . Similar to GS, GS10 proved to have a stable and rather rigid conformation in different environments and over a broad range of temperatures, whereas GS12, GS14 and {d-Lys}4GS14 had more flexible conformations . Despite its conformational similarity to GS10, GS14 had unique physicochemical properties due to its tendency to aggregate at relatively low concentrations . The biophysical data explain the direct relation between structure, amphipathicity and hydrophobicity of the cyclic peptides and their hemolytic activity . However, this relation with the antimicrobial activity of the peptides is of a more complex nature due to the diversity in membrane structures of microorganisms. Mol Plant Microbe Interact, 2001 Oct, 14(10), 1255 - 60 Wheat puroindolines enhance fungal disease resistance in transgenic rice; Krishnamurthy K et al.; Antimicrobial peptides play a role in the immune systems of animals and plants by limiting pathogen infection and growth . The puroindolines, endosperm-specific proteins involved in wheat seed hardness, are small proteins reported to have in vitro antimicrobial properties . Rice, the most widely used cereal crop worldwide, normally does not contain puroindolines . Transgenic rice plants that constitutively express the puroindoline genes pinA and/or pinB throughout the plants were produced . PIN extracts of leaves from the transgenic plants reduced in vitro growth of Magnaporthe grisea and Rhizoctonia solani, two major fungal pathogens of rice, by 35 to 50% . Transgenic rice expressing pinA and/or pinB showed significantly increased tolerance to M . grisea (rice blast), with a 29 to 54% reduction in symptoms, and R . solani (sheath blight), with an 11 to 22% reduction in symptoms . Puroindolines are effective in vivo in antifungal proteins and could be valuable new tools in the control of a wide range of fungal pathogens of crop plants. Anal Chem, 2001 Oct 1, 73(19), 4640 - 6 Analysis of trace levels of sulfonamide and tetracycline antimicrobials in groundwater and surface water using solid-phase extraction and liquid chromatography/mass spectrometry; Lindsey ME et al.; A method has been developed for the trace analysis of two classes of antimicrobials consisting of six sulfonamides (SAs) and five tetracyclines (TCs), which commonly are used for veterinary purposes and agricultural feed additives and are suspected to leach into ground and surface water . The method used solid-phase extraction and liquid chromatography/mass spectrometry (LC/MS) with positive ion electrospray . The unique combination of a metal chelation agent (Na2EDTA) with a macroporous copolymer resulted in quantitative recoveries by solid-phase extraction (mean recovery, 98 +/- 12%) at submicrogramper-liter concentrations . An ammonium formate/formic acid buffer with a methanol/water gradient was used to separate the antimicrobials and to optimize the signal intensity . Mass spectral fragmentation and ionization characteristics were determined for each class of compounds for unequivocal identification . For all SAs, a characteristic m/z 156 ion representing the sulfanilyl fragment was identified . TCs exhibited neutral losses of 17 amu resulting from the loss of ammonia and 35 amu from the subsequent loss of water . Unusual matrix effects were seen only for TCs in this first survey of groundwater and surface water samples from sites around the United States, requiring that TCs be quantitated using the method of standard additions. PDA J Pharm Sci Technol, 2001 Sep-Oct, 55(5), 278 - 85 Rapid methods for the microbiological surveillance of pharmaceuticals; Jimenez L; The use of rapid microbiological methods in pharmaceutical laboratories has improved the quality control analysis of water, products, raw materials, and enhanced the antimicrobial effectiveness testing of pharmaceutical finished products . Rapid release of samples has resulted in the optimization of manufacturing, product testing, and release allowing high throughput and simultaneous analysis of pharmaceutical formulations . ATP Bioluminescence, Impedance, Direct Viable Counts, and Flow Cytometry determine the total microbial content in a given pharmaceutical sample while PCR and Immunoassays detect the presence or absence of specific microbial species . Rapid methods provide reliable and cost effective analysis for the microbiological evaluation of pharmaceutical environments . The dramatic reduction in detection times and analysis, e.g., from 30 hours to 90 minutes, by using rapid methods will ultimately lead the pharmaceutical industry closer to real time monitoring of processes and samples. Eur J Obstet Gynecol Reprod Biol, 2001 Nov, 99(1), 85 - 9 Delayed interval delivery in multiple pregnancies; Van der Straeten FM et al.; Preterm delivery remains the most important complication of multiple pregnancies . We describe six cases of successful delay of the subsequent child(ren) after very preterm birth of the first-born, with intervals ranging between 14 and 117 days.Based on our findings and on the available literature, we propose a set of guidelines for the management of early preterm multiple birth deliveries, including tocolysis, antimicrobial therapy and corticosteroids. J Am Coll Nutr, 2001 Oct, 20(5 Suppl), 464S - 472S; discussion 473S-475S The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population; Salganik RI; Cellular oxidants, called reactive oxygen species (ROS), are constantly produced in animal and human cells . Excessive ROS can induce oxidative damage in cell constituents and promote a number of degenerative diseases and aging . Cellular antioxidants protect against the damaging effects of ROS . However, in moderate concentrations, ROS are necessary for a number of protective reactions . Thus, ROS are essential mediators of antimicrobial phagocytosis, detoxification reactions carried out by the cytochrome P-450 complex, and apoptosis which eliminates cancerous and other life-threatening cells . Excessive antioxidants could dangerously interfere with these protective functions, while temporary depletion of antioxidants can enhance anti-cancer effects of apoptosis . Experimental data are presented supporting these notions . The human population is heterogeneous regarding ROS levels . Intake of exogenous antioxidants (vitamins E, C, beta-carotene and others) could protect against cancer and other degenerative diseases in people with innate or acquired high levels of ROS . However, abundant antioxidants might suppress these protective functions, particularly in people with a low innate baseline level of ROS . Screening human populations for ROS levels could help identify groups with a high level of ROS that are at a risk of developing cancer and other degenerative diseases . It also could identify groups with a low level of ROS that are at a risk of down-r