Activities of beta-lactams and macrolides against Helicobacter pylori.

A continuous-culture system (chemostat) was used to study the activities of beta-lactam antimicrobial agents, clarithromycin, and 14-OH-clarithromycin against slowly growing Helicobacter pylori NCTC 11637. H. pylori was grown to steady state before exposure to these antimicrobial agents at x8 the MIC. The bactericidal actions of combinations of amoxicillin and clarithromycin were also studied. Viable counts (numbers of CFU per milliliter) were determined at 2-h intervals for 12 h and at 20 h after the addition of antibiotics. The effects of pH changes (6.5 to 7.4) on the activities of amoxicillin, clarithromycin, and the combination of these against H. pylori NCTC 11637 were also studied. Viable counts following exposure to ampicillin, cefixime, ceftazidime, cefuroxime, cefotaxime, azlocillin, and piperacillin at 20 h showed bacteriostatic activity. Imipenem, meropenem, amoxicillin, clarithromycin, and 14-OH-clarithromycin reduced the viable counts by 3 log10 CFU/ml (>/=99.9% killing). Imipenem was the most rapidly bactericidal against H. pylori NCTC 11637. Results of the pH experiments showed that amoxicillin was bactericidal at pHs 6.5 to 7. 4. Clarithromycin was bactericidal at pH 7.0 to 7.4 but was bacteriostatic at pH 6.5. The combination of amoxicillin and clarithromycin was bactericidal at pHs 6.5 and 7.0. A batch culture (flask system) was also used to investigate 12 strains of H. pylori for their susceptibilities to beta-lactams, clarithromycin, and/or 14-OH-clarithromycin in order to determine whether results from the chemostat model can be reproduced with batch cultures. Results of the chemostat time-kill kinetic study were reproducible in our batch culture flask system. The role of carbapenems in the eradication of H. pylori should be investigated.

Biofilm formation by Helicobacter pylori.

Helicobacter pylori NCTC 11637 produces a water-insoluble biofilm when grown under defined conditions with a high carbon:nitrogen ratio in continuous culture and in 10% strength Brucella broth supplemented with 3 g l-1 glucose. Biofilm accumulated at the air/liquid interface of the culture. Light microscopy of frozen sections of the biofilm material showed few bacterial cells in the mass of the biofilm. The material stained with periodic acid Schiff's reagent. Fucose, glucose, galactose, and glycero-manno-heptose, N-acetylglucosamine and N-acetylmuramic acid were identified in partially purified and in crude material, using gas chromatography and mass spectrometry. The sugar composition strongly indicates the presence of a polysaccharide as a component of the biofilm material. Antibodies (IgG) to partially purified material were found in both sero-positive and sero-negative individuals. Treatment of the biofilm material with periodic acid reduced or abolished immunoreactivity. Treatment with 5 mol l-1 urea at 100 degrees C and with phenol did not remove antigenic recognition by patient sera. The production of a water-insoluble biofilm by H. pylori may be important in enhancing resistance to host defence factors and antibiotics, and in microenvironmental pH homeostasis facilitating the growth and survival of H. pylori in vivo.

Absence of a post-antibiotic effect (PAE) of beta-lactams against Helicobacter pylori NCTC 11637.

A continuous culture system (chemostat) was used to study the post-antibiotic effect (PAE) of beta-lactams, against slowly-growing Helicobacter pylori NCTC 11637. H. pylori was grown at one quarter of its maximum specific growth rate (mu(max)) before exposure to ampicillin, amoxycillin, azlocillin, piperacillin or cefixime (8 x MIC). After 8 h, the antibiotics were inactivated. Viable counts were used to determine the rate of recovery of H. pylori. The recovery growth rate of H. pylori was similar to the maximum growth rate of H. pylori under antibiotic-free experimental conditions, so none of the beta-lactams studied showed a PAE against slowly-growing H. pylori.

Amino acid utilisation and deamination of glutamine and asparagine by Helicobacter pylori.

Helicobacter pylori can utilise amino acids as the sole carbon energy source. The present study demonstrated that H. pylori grown in continuous culture in a defined medium containing glucose and amino acids utilised alanine, arginine, asparagine, aspartate, glutamine, glutamate, proline and serine. Specific asparaginase and glutaminase enzymes deaminated asparagine and glutamine respectively to aspartate and glutamate, with the production of ammonia. The glutaminase activity was inhibited by 6-diazo-5-oxo-L-norleucine. All the 13 strains of H. pylori tested produced both glutaminase and asparaginase activities. Glutamine is important in the health of the gastric and intestinal mucosa and is a primary energy source for lymphocytes. Depletion of glutamine at the site of H. pylori infection may be of significance in the pathogenesis of H. pylori-associated diseases such as peptic ulcer and gastric cancer.

Review of the major intervention trials of lowering coronary artery disease risk through cholesterol reduction.

Results of primary and secondary prevention trials have shown that lowering total cholesterol and low-density lipoprotein (LDL) cholesterol leads to a reduction in both fatal and nonfatal ischemic events. The reduced coronary artery disease (CAD) risk associated with cholesterol lowering appears to be unrelated to the intervention used, whether it be a low-fat/low-cholesterol diet, partial ileal bypass surgery, or pharmacologic intervention with an agent such as a bile resin, a fibrate, or niacin. Data emerging on the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have shown that this newest class of cholesterol-lowering agents also reduces the risk for CAD. The studies provide increasing evidence that high LDL cholesterol levels not only contribute to atherosclerotic plaque formation but also interfere with normal endothelial control of arterial vasomotor tone. Because the small amount of plaque regression observed on angiographic studies is not sufficient to explain the magnitude of CAD risk reduction associated with lowered levels of LDL cholesterol, these studies suggest that vasomotor control and plaque stabilization may have a greater impact on clinical events than the stenosis caused by atherosclerotic plaques.

Physiology and biochemistry of Helicobacter pylori.

Since Helicobacter pylori was first isolated in 1982, a tremendous amount of work has been carried out on the pathogenic effects of the organism and latterly on its physiology, nutrition and biochemistry. It is a microaerophilic Gram-negative bacillus that is catalase- and oxidase-positive and expresses superoxide dismutase. High levels of urease are produced, the activity of which can be used in the identification of the organism and the infected state. Other noted features include the production of a cytotoxin and an associated protein (CagA). The bacterium is the major aetiological agent in the development of chronic active gastritis, gastric and duodenal ulcers, gastric adenocarcinomas and mucosa-associated lymphoid tissue lymphoma of the stomach. To gain a more complete understanding of how H. pylori causes disease a detailed knowledge of its biochemistry, physiology and nutrition is required.

Intercollegiate ice hockey injuries. A case for uniform definitions and reports.

The lack of agreement on definition of terms and consistent reporting strategies in sports epidemiology complicates the determination of injury rates in any sport. This study describes Canadian Intercollegiate ice hockey injuries over a 6-year period by following a standardized reporting strategy and clearly defined terminology. Overall, the data show that the knee is most susceptible to injury, that the forwards recorded the highest number of injuries, and that body contact caused the majority of injuries. Compared to other studies the results indicate a decreasing per game injury rate over the last 15 years and provide evidence that helmets and visors reduce the risk of head and facial injuries. Recommendations are propagated toward the adherence of standardized reporting strategies and uniform definitions to be used in future sports injury epidemiologic research.

High-dose epinephrine in adult cardiac arrest.

BACKGROUND: Recent studies suggest that doses of epinephrine of 0.1 mg per kilogram of body weight or higher may improve myocardial and cerebral blood flow as well as survival in cardiac arrest. Such studies have called into question the traditional dose of epinephrine (0.007 to 0.014 mg per kilogram) recommended for advanced cardiac life support. METHODS: We randomly assigned 650 patients who had had cardiac arrest either in or outside the hospital to receive up to five doses of high-dose (7 mg) or standard-dose (1 mg) epinephrine at five-minute intervals according to standard protocols for advanced cardiac life support. Patients who collapsed outside the hospital received no advanced-life-support measures other than defibrillation before reaching the hospital. RESULTS: There was no significant difference between the high-dose group (n = 317) and the standard-dose group (n = 333) in the proportions of patients who survived for one hour (18 percent vs. 23 percent, respectively) or who survived until hospital discharge (3 percent vs. 5 percent). Among the survivors, there was no significant difference in the proportions who remained in the best category of cerebral performance (90 percent vs. 94 percent) and no significant difference in the median Mini-Mental State score (36 vs. 37). The exploration of clinically important subgroups, including those with out-of-hospital arrest (n = 335) and those with in-hospital arrest (n = 315), failed to identify any patients who appeared to benefit from high-dose epinephrine and suggested that some patients may have worse outcomes after high-dose epinephrine. CONCLUSION: High-dose epinephrine was not found to improve survival or neurologic outcomes in adult victims of cardiac arrest.

Epinephrine in cardiopulmonary resuscitation.

This review assesses the role of epinephrine in cardiopulmonary resuscitation from the perspective of mechanisms of action, cardiac and cerebral effects, and use in human beings. We reviewed the literature from 1966 onward, using a Medline Search of the National Library of Medicine with the key words: "heart arrest," "resuscitation," and "epinephrine." Pertinent articles that represented original research were critically appraised by at least two authors. We concluded that the Advanced Cardiac Life Support recommended dose of epinephrine (1 mg or 0.007 to 0.014 mg/kg) has little scientific basis. Evidence from animal studies demonstrates that doses of 0.1 to 0.2 mg/kg are required to significantly improve myocardial and cerebral blood flow and resuscitation rates. Limited human data confirm the dose-dependent vasopressor response to epinephrine and the potential for improved immediate survival with higher doses. We suggest that randomized controlled human trials are needed to document the usefulness of higher doses of epinephrine in cardiopulmonary resuscitation.

Profile of sport/leisure injuries treated at emergency rooms of urban hospitals.

The main thrust of this study was to examine the nature and number of sport/leisure injuries treated in hospital emergency rooms in a large metropolitan city. A total of 244 respondents, or 4% of the total case load in six hospital emergency wards, were treated for sport/leisure injuries during the 1-week survey. The results show that 86.3% occurred to individuals 30 years of age or under, that injuries to males outnumbered those to females by a margin of 3:1, and that 57.5% of those injured were active on a regular basis (i.e., at least once a week). The highest number of sport/leisure injuries (71.5%) occurred from participation in noncontact recreational sports and 61.9% occurred during supervised activities, yet over 55% received no on-site or first-aid treatment. These data suggest a need to promote community oriented safety education and first-aid programs.

Severe exacerbations of COPD and asthma. Incremental benefit of adding ipratropium to usual therapy.

Single dose studies have assessed the utility of ipratropium bromide alone or with beta agonists in the short- and long-term management of chronic obstructive lung disease and asthma. We performed a randomized, double-blind trial to assess the incremental benefit over 24 hours of adding ipratropium vs placebo to a standardized regimen of medications commonly used in the acute and subsequent hospital management of COPD and asthma. Sixty-eight subjects received nebulized salbutamol, intravenous methylprednisolone, intravenous aminophylline, and antibiotics and were randomized to receive either 80 micrograms of ipratropium or placebo via metered dose inhaler and spacing device with each salbutamol treatment (6 to 8 times per day). Among the 50 patients who completed the study, there were no significant differences between ipratropium and placebo groups with respect to baseline FEV1, FVC, and PaCO2. The improvement of FEV1 from baseline to 24 hours was 294 (SD = 568) ml in the ipratropium group vs 393 (SD = 622) ml in placebo group. Adjusting FEV1 by age, gender, and smoking did not significantly alter the findings. Those with an admission diagnosis of asthma showed larger 24 hour FEV1 responses (487 ml in ipratropium vs 801 ml in placebo) than those with COPD (149 ml ipratropium vs 102 ml in placebo). However, within these two strata, there were no significant differences in FEV1 improvement between ipratropium and placebo groups. This study suggests that if ipratropium is used in the initial emergency treatment of COPD or asthma, it could safely be discontinued by 24 hours in order to reduce the cost and complexity of therapy.

Computed tomography to stage lung cancer. Approaching a controversy using meta-analysis.

The ability of computed tomography (CT) to detect mediastinal lymph node metastases from nonsmall cell bronchogenic lung cancer is highly controversial, as evidenced by reported accuracies ranging from 0.35 to 0.95 over the past eight years. We examined all studies on this matter published between January 1980 and April 1988, both to describe the overall experience and to identify characteristics (study design and methodology and CT scan techniques) that influenced reported accuracy. Of 79 relevant publications, 37 were excluded because they were review reports, assessed small cell lung cancer, or contained insufficient evidence to construct a contingency table (CT result versus node histology). The pooled, unweighted (weighted) results based on the remaining 42 studies were as follows: sensitivity, 0.79 (0.83); specificity, 0.78 (0.81); accuracy, 0.79 (0.81). Using a node size greater than 1.0 cm to define a "positive" CT result, as compared to a smaller diameter, was associated with significantly higher specificity, 0.89 versus 0.76, and accuracy, 0.86 versus 0.75 (p less than or equal to 0.005), but not sensitivity, 0.79 versus 0.75. The observed differences in accuracy between a fourth generation CT (0.83) and either a third or a second generation CT, (0.77 and 0.78, respectively) were not significant at p less than 0.05. No characteristics, either singly or in combination, resulted in accuracies exceeding 0.86. There exists random variation of individual study results around an overall mean accuracy of only 0.79, which is marginally improved by advances in CT technology and methods. Significant advances in the noninvasive detection of lymph node metastases must await an approach fundamentally different from CT-determined node size.

The atherogenic risk of antihypertensive therapy.

The past 20 years have demonstrated the unqualified success of antihypertensive therapy in reducing morbidity and mortality from cardiovascular and cerebrovascular disease. Evidence mounts, however, that certain antihypertensive agents may, themselves, have an adverse effect on the development and progression of cardiovascular disease. The dramatic reductions in the incidence of cerebrovascular events and congestive heart failure among patients receiving antihypertensive therapy have not been paralleled by similar reductions in cardiac morbidity or mortality. Several lines of evidence now point to the possibility that adverse metabolic changes are induced by certain antihypertensive drugs. These changes may offset, negate, or even reverse the potential benefit afforded by successful blood pressure control.

Vasodilator correction of hypotension in the postoperative period.

This case is unusual in that hypotension, as opposed to hypertension, was a consequence of increased sympathetic tone in the postoperative period, but it illustrates the well known fact that patients in compensated congestive heart failure do poorly when faced with an elevated myocardial oxygen need from either increased rate or afterload. Vasodilator therapy was effective in immediately reducing afterload and systolic regurgitant fraction, thereby increasing oxygen supply and lowering myocardial oxygen consumption.

Mutagenic effect of BUdR in diploid human fibroblasts.

It has only recently been possible to demonstrate the expected mutagenic effect of 5-bromodeoxyuridine (BUdR) in heteroploid hamster cells in culture. We have now extended this observation to diploid human fibroblasts utilizing techniques adapted from the work of Albertini and DeMars on X-ray mutagenesis at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus in these cells. In four separate experiments, fibroblasts from a female donor were exposed to 500 micrograms/ml ethylmethane sulfonate (EMS) or 3 micrograms/ml BUdR yielding survivals of 9% and 5%, respectively. After a 6-day expression period, survivors were plated in selection medium containing 0.3 micrograms/ml 8-azaguanine (8-AG). After 3-5 weeks, azaguanine-resistant colonies were isolated for characterization or stained for counting. The average spontaneous mutation rate/cell/generation was 0.6.10(-6). The average induced mutation rates for EMS and BUdR were 7.8.10(-6) and 6.3.10(-6)/cell/generation, respectively. Similar results were obtained in two experiments with an additional fibroblast line. Mutant colonies isolated following BUdR treatment demonstrated from 1.4 to 61.5% of the HGPRT activity of the parental line and showed at least 8% Barr bodies, excluding the possibility of contamination by Lesch-Nyhan cells. This demonstration of a BUdR effect comparable to that of an alkylating agent or X-irradiation opens the study of mutation due to base-analog substitution in diploid human cells.