Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation.

Impaired gating of the auditory evoked P50 potential is one of the most pharmacologically well-characterized features of schizophrenia. This deficit is most commonly modeled in rodents by implanted electrode recordings from the hippocampus of the rodent analog of the P50, the P20-N40. The validity and effectiveness of this tool, however, has not been systematically reviewed. Here, we summarize findings from studies that have examined the effects of pharmacologic modulation on gating of the rodent hippocampal P20-N40 and the human P50. We show that drug effects on the P20-N40 are highly predictive of human effects across similar dose ranges. Furthermore, mental status (for example, anesthetized vs alert) does not appear to diminish the predictive capacity of these recordings. We then discuss hypothesized neuropharmacologic mechanisms that may underlie gating effects for each drug studied. Overall, this review supports continued use of hippocampal P20-N40 gating as a translational tool for schizophrenia research.

Beta2-agonists for acute bronchitis.

BACKGROUND: There are no clearly effective treatments for the cough of acute bronchitis, and beta2-agonists are often prescribed, perhaps because clinicians suspect many patients also have reversible airflow restriction contributing to the symptoms. OBJECTIVES: To determine whether beta2-agonists improve symptoms of acute bronchitis in patients who do not have underlying pulmonary disease. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2005), MEDLINE (January 1966 to November 2005) and EMBASE (1974 to November 2005). SELECTION CRITERIA: Trials in which patients (adults or children over two years of age) who were diagnosed with acute bronchitis or acute cough (without known pulmonary disease and without other cause) were randomized to beta2-agonist versus placebo, no treatment or alternative treatment. DATA COLLECTION AND ANALYSIS: Three authors independently selected outcomes and evaluated trial quality while blinded to study results, they then extracted data. Trials in children and in adults were analyzed separately. MAIN RESULTS: Two trials in children (n = 109) with acute cough and no evidence of airway obstruction did not find any benefits from beta2-agonists. Combined data did not show a significant difference in daily cough scores between patients given oral beta2-agonists and those in the control groups. Five trials in adults (n = 418) with acute cough or acute bronchitis had mixed results but overall summary statistics did not reveal any significant benefits from oral (three trials) nor inhaled (two trials) beta2-agonists. There were no significant differences in daily cough scores nor in the number of patients still coughing after seven days (control rate 73%; relative risks (RR) 0.77, 95% CI 0.54 to 1.09). Subgroups of patients with evidence of airflow limitation had lower symptom scores if given beta2-agonists, in one trial. Furthermore, the trials that did note quicker resolution of cough in patients given beta2-agonists were those that had a higher proportion of patients with wheezing at baseline. Patients given beta2-agonists were more likely to report tremor, shakiness or nervousness than patients in the control groups (for trials in children: control rate 0%; RR 6.76, 95% CI 0.86 to 53.12; number needed to harm (NNH) 9, 95% CI 5 to 100; for trials in adults: control rate 11%; RR 7.94, 95% CI 1.17 to 53.94; NNH 2.3, 95% CI 2 to 3). AUTHORS' CONCLUSIONS: There is no evidence to support the use of beta2-agonists in children with acute cough who do not have evidence of airflow obstruction. There is also little evidence that the routine use of beta2-agonists is helpful for adults with acute cough. These agents may reduce symptoms, including cough, in patients with evidence of airflow obstruction. However, this potential benefit is not well-supported by the available data and must be weighed against the adverse effects associated with beta2-agonists.

Antibiotics for acute bronchitis.

BACKGROUND: Antibiotic treatment of acute bronchitis, which is one of the most common illnesses seen in primary care, is controversial. Most clinicians prescribe antibiotics in spite of expert recommendations against this practice. OBJECTIVES: The objective of this review was to assess the effects of antibiotic treatment for patients with a clinical diagnosis of acute bronchitis. SEARCH STRATEGY: In this updated review, we searched the Cochrane Central Register of Controlled trials (CENTRAL) (The Cochrane Library Issue 2, 2004); MEDLINE (January 1966 to March 2004); EMBASE (January 2000 to December 2003); SciSearch from 1989 to 2004; reference lists of articles and the authors' personal collections up to 1996, and also wrote to study authors and drug manufacturers. EMBASE has previously been searched from 1974 to 2000). SELECTION CRITERIA: Randomised controlled trials comparing any antibiotic therapy with placebo in acute bronchitis or acute productive cough without other obvious cause in patients without underlying pulmonary disease. DATA COLLECTION AND ANALYSIS: At least two reviewers extracted data and assessed trial quality. Authors were contacted for missing data. MAIN RESULTS: Nine trials involving over 750 patients aged eight to over 65 and including smokers and non-smokers were included in the primary analysis. The quality of the trials was variable. A variety of outcome measures were assessed. Overall, patients receiving antibiotics had better outcomes than did those receiving placebo. At a follow-up visit, they were less likely to have a cough (relative risk (RR) 0.64, 95% confidence interval (CI) 0.49 to 0.85; number-needed-to-treat (NNT) 5; 95% CI 3 to 14), show no improvement on physician assessment (RR 0.52; 95% CI 0.31 to 0.87; NNT 14; 95% CI 8 to 50), or have abnormal lung findings (RR 0.48; 95% CI 0.26 to 0.89; NNT 11; 95% CI 6 to 50); and had shorter durations of cough (weighted mean difference 0.58 days; 95% CI 0.01 to 1.16 days), productive cough (weighted mean difference (WMD) 0.52 days; 95% CI 0.01 to 1.03 days), and feeling ill (WMD 0.58 days; 95% CI 0.00 to 1.16 days). There were no significant differences regarding the presence of night cough, productive cough, or activity limitations at follow up, or in the mean duration of activity limitations. The benefits of antibiotics were less apparent in a sensitivity analysis that included data from two other studies of patients with upper respiratory tract infections with productive cough. There was a non significant trend towards an increase in adverse effects in the antibiotic group, relative risk (RR) 1.22 (95% CI 0.94 to 1.58). REVIEWERS' CONCLUSIONS: Overall, antibiotics appear to have a modest beneficial effect in patients who are diagnosed with acute bronchitis. The magnitude of this benefit, however, is similar to that of the detriment from potential adverse effects.

Beta2-agonists for acute bronchitis.

BACKGROUND: The optimal treatment for acute bronchitis is not clear. Because many patients with acute bronchitis have airflow limitation as well as cough, beta2-agonists may be useful. OBJECTIVES: To determine whether beta2-agonists improve the symptoms of acute bronchitis in patients who do not have underlying pulmonary disease. SEARCH STRATEGY: The Cochrane Library (through August 2000), MEDLINE (1966 to 2000), EMBASE (1974 to 2000), and Conference Proceedings using "bronchodilator (exp)", "adrenergic beta-agonist (exp)", or "sympathomimetics (exp)" and "bronchitis" or "cough"; Science Citation Index for referenced publications; and letters to manufacturers of beta2-agonists. An updated search of the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 3, 2003); MEDLINE (January 2000 to July 2003); EMBASE (January 2000 to July 2003) was run in July 2003. SELECTION CRITERIA: Trials in which patients (adults or children over two years of age) without known pulmonary disease who were diagnosed with acute bronchitis or acute cough without other cause were randomized to beta2-agonist versus placebo, no treatment, or alternative treatment. DATA COLLECTION AND ANALYSIS: Three reviewers independently first selected outcomes and evaluated trial quality while blinded to study results, and then extracted data. Trials in children and in adults were analyzed separately. MAIN RESULTS: Two trials in children (n = 109) with acute cough and no evidence of airway obstruction did not find any benefits from beta2-agonists. Combined data did not show a significant difference in daily cough scores between patients given oral beta2-agonists and those in the control groups. Five trials in adults (n = 418) with acute cough or acute bronchitis had mixed results, but overall summary statistics did not reveal any significant benefits from oral (three trials) nor inhaled (two trials) beta2-agonists. There were no significant differences in daily cough scores nor in the number of patients still coughing after seven days (control rate 73%; RR = 0.77, 95% CI 0.54-1.09). Subgroups of patients with evidence of airflow limitation had lower symptom scores if given beta2-agonists in one trial; and the trials that did note quicker resolution of cough in patients given beta2-agonists were those that had a higher proportion of patients with wheezing at baseline. Patients given beta2-agonists were more likely to report tremor, shakiness, or nervousness than patients in the control groups (for trials in children control rate 0%; RR 6.76, 95% CI 0.86 to 53.12, NNH 9, 95% CI 5 to 100; for trials in adults, control rate 11%; RR 7.94, 95% CI 1.17 to 53.94, NNH 2.3, 95% CI 2 to 3). REVIEWER'S CONCLUSIONS: There is no evidence to support using beta2-agonists in children with acute cough who do not have evidence of airflow obstruction. There is also little evidence that the routine use of beta2-agonists for adults with acute cough is helpful. These agents may reduce symptoms, including cough, in patients with evidence of airflow obstruction; but this potential benefit is not well-supported by the available data and must be weighed against the adverse effects associated with beta2-agonists.

Are beta2-agonists effective treatment for acute bronchitis or acute cough in patients without underlying pulmonary disease? A systematic review.

OBJECTIVE: Our goal was to determine whether beta2-agonists improve the symptoms of acute bronchitis or acute cough in patients who do not have underlying pulmonary disease. STUDY DESIGN: We performed a systematic review including meta-analysis. DATA SOURCES: We included randomized controlled trials comparing beta2-agonists with placebo or alternative therapies identified from the Cochrane Library, MEDLINE, EMBASE, conference proceedings, Science Citation Index, the System for Information on Grey Literature in Europe, and letters to manufacturers of beta2-agonists. OUTCOMES MEASURED: We measured duration, persistence, severity or frequency of cough, productive cough, and night cough; duration of activity limitations; and adverse effects. RESULTS: Two trials in children with cough and no obvious airway obstruction did not find any benefits from beta2-agonists. Five trials in adults with cough and with or without airway obstruction had mixed results, but summary statistics did not reveal any significant benefits from beta2-agonists. Studies that enrolled more wheezing patients were more likely to show benefits from beta2-agonists, and in one study only patients with evidence of airflow limitation were more likely to benefit. Patients given beta2-agonists were more likely to report tremor, shakiness, or nervousness than those in the control groups. CONCLUSIONS: There is no evidence to support using beta2-agonists in children with acute cough and no evidence of airflow obstruction. There is little evidence that the routine use of beta2-agonists for adults with acute cough is helpful. These agents may reduce symptoms, including cough, in patients with evidence of airflow obstruction, but this potential benefit is not well-supported by the available data and must be weighed against the adverse effects associated with beta2-agonists.

Beta2-agonists for acute bronchitis.

BACKGROUND: The optimal treatment for acute bronchitis is not clear. Because many patients with acute bronchitis have airflow limitation as well as cough, beta2-agonists may be useful. OBJECTIVES: To determine whether beta2-agonists improve the symptoms of acute bronchitis in patients who do not have underlying pulmonary disease. SEARCH STRATEGY: Cochrane Library, MEDLINE, EMBASE, and Conference Proceedings using "bronchodilator (exp)", "adrenergic beta-agonist (exp)", or "sympathomimetics (exp)" and "bronchitis" or "cough"; Science Citation Index for referenced publications; and letters to manufacturers of beta2-agonists. SELECTION CRITERIA: Trials in which patients (adults or children age > 2 years) without known pulmonary disease who were diagnosed with acute bronchitis or acute cough without other cause were randomized to beta2-agonist vs. placebo, no treatment, or alternative treatment. DATA COLLECTION AND ANALYSIS: Three reviewers independently first selected outcomes and evaluated trial quality while blinded to study results, and then extracted data. Trials in children and in adults were analyzed separately. MAIN RESULTS: Two trials in children with acute cough and no evidence of airway obstruction did not find any benefits from beta2-agonists. Five trials in adults with acute cough or acute bronchitis had mixed results, but overall summary statistics did not reveal any significant benefits from beta2-agonists. Subgroups of patients with evidence of airflow limitation had lower symptom scores if given beta2-agonists in one trial; and the trials that did note quicker resolution of cough in patients given beta2-agonists were those that had a higher proportion of patients with wheezing at baseline. Patients given beta2-agonists (whether oral or inhaled) were more likely to report tremor, shakiness, or nervousness than patients in the control groups (NNH for children 9, 95% CI 5 to 100; NNH for adults 2.3, 95% CI 2 to 3). REVIEWER'S CONCLUSIONS: There is no evidence to support using beta2-agonists in children with acute cough who do not have evidence of airflow obstruction. There is also little evidence that the routine use of beta2-agonists for adults with acute cough is helpful. These agents may reduce symptoms, including cough, in patients with evidence of airflow obstruction; but this potential benefit is not well-supported by the available data and must be weighed against the adverse effects associated with beta2-agonists.

Antibiotics for acute bronchitis.

BACKGROUND: Antibiotic treatment of acute bronchitis, which is one of the most common illnesses seen in primary care, is controversial. Most clinicians prescribe antibiotics in spite of expert recommendations against this practice. OBJECTIVES: The objective of this review was to assess the effects of antibiotic treatment for patients with a clinical diagnosis of acute bronchitis. SEARCH STRATEGY: We searched MEDLINE, EMBASE, reference lists of articles and the authors' personal collections up to 1996, and Scisearch from 1989 to 1996; we also wrote to study authors and drug manufacturers. An updated search of the Cochrane Controlled Trials Register and MEDLINE was conducted in 2000. SELECTION CRITERIA: Randomised trials comparing any antibiotic therapy with placebo in acute bronchitis or acute productive cough without other obvious cause in patients without underlying pulmonary disease. DATA COLLECTION AND ANALYSIS: At least two reviewers extracted data and assessed trial quality. Authors were contacted for missing data. MAIN RESULTS: Nine trials involving over 750 patients aged eight to over 65 and including smokers and non-smokers were included. The quality of the trials was variable. A variety of outcome measures were assessed. Overall, patients receiving antibiotics had better outcomes than did those receiving placebo. At a follow-up visit, they were less likely to have a cough (relative risk 0.64, 95% confidence interval 0.49 to 0.85; number needed to treat 5, 95% CI 3 to 14), show no improvement on physician assessment (RR 0.52, 95% CI 0.31 to 0.87; NNT 14, 95% CI 8 to 50), or have abnormal lung findings (RR 0.48, 95% CI 0.26 to 0.89; NNT 11, 95% CI 6 to 50); and had shorter durations of cough (weighted mean difference 0.58 days, 95% CI 0.01 to 1.16 days), productive cough (WMD 0.52 days, 95% CI 0.01 to 1.03 days), and feeling ill (WMD 0.58 days, 95% CI 0.00 to 1.16 days). There were no significant differences regarding the presence of night cough, productive cough, or activity limitations at follow-up, or in the mean duration of activity limitations. The benefits of antibiotics were less apparent in a sensitivity analysis that included data from two other studies of patients with upper respiratory tract infections with productive cough. Antibiotic-treated patients reported significantly more adverse effects (RR 1.48, 95% CI 1.02 to 2.14; number needed to harm 17, 95% CI 9 to 100) such as nausea, vomiting, headache, skin rash or vaginitis. REVIEWER'S CONCLUSIONS: Overall, antibiotics appear to have a modest beneficial effect in patients who are diagnosed with acute bronchitis. The magnitude of this benefit, however, is similar to that of the detriment from potential adverse effects. Furthermore, patients with other symptoms of the common cold who have been ill for less than one week are not likely to have any benefit from antibiotics.

Safety and immunogenicity of NYVAC-JEV and ALVAC-JEV attenuated recombinant Japanese encephalitis virus--poxvirus vaccines in vaccinia-nonimmune and vaccinia-immune humans.

A controlled, randomized, double-blind clinical trial evaluated whether two attenuated recombinant poxviruses with identical Japanese encephalitis virus (JEV) gene insertions, NYVAC-JEV and ALVAC-JEV, were safe and immunogenic in volunteers. Groups of 10 volunteers distinguished by vaccinia immune status received two doses of each vaccine. The vaccines appeared to be equally safe and well tolerated in volunteers, but more reactogenic than licensed formalin-inactivated JE and placebo vaccines given as controls. NYVAC-JEV and ALVAC-JEV vaccine recipients had frequent occurrence of local warmth, erythema, tenderness, and/or arm pain after vaccination. There was no apparent effect of vaccinia immune status on frequency or magnitude of local and systemic reactions. NYVAC-JEV elicited antibody responses to JEV antigens in recipients but ALVAC-JEV vaccine poorly induced antibody responses. However, NYVAC-JEV vaccine induced neutralizing antibody responses only in vaccinia-nonimmune recipients while vaccinia-immune volunteers failed to develop protective antibodies (5/5 vs. 0/5 seroconversion, p<0.01). These data suggest that preexisting immunity to poxvirus vector may suppress antibody responses to recombinant gene products.

Antibiotics for acute bronchitis.

BACKGROUND: Antibiotic treatment of acute bronchitis, which is one of the most common illnesses seen in primary care, is controversial. Most clinicians prescribe antibiotics in spite of expert recommendations against this practice. OBJECTIVES: People with acute bronchitis may show little evidence of bacterial infection. If effective, antibiotics could shorten the course of the disease. However if they are not effective, the risk of antibiotic resistance may be increased. The objective of this review was to assess the effects of antibiotic treatment for patients with a clinical diagnosis of acute bronchitis. SEARCH STRATEGY: We searched Medline, Embase, reference lists of articles and the authors' personal collections up to 1996, and Scisearch from 1989 to 1996. SELECTION CRITERIA: Randomised trials comparing any antibiotic therapy with placebo in acute bronchitis. DATA COLLECTION AND ANALYSIS: At least two reviewers extracted data and assessed trial quality. MAIN RESULTS: Eight trials involving 750 patients aged eight to over 65 and including smokers and non-smokers were included. The quality of the trials was variable. A variety of outcome measures were assessed. In many cases, only outcomes that showed a statistically significant difference between groups were reported. Overall, patients receiving antibiotics had slightly better outcomes than did those receiving placebo. They were less likely to report feeling unwell at a follow up visit (odds ratio 0.42, 95% confidence interval 0.22 to 0.82), to show no improvement on physician assessment (odds ratio 0.43; 0.23 to 0.79), or to have abnormal lung findings (odds ratio 0.33, 95% confidence interval 0.13 to 0.86), and had a more rapid return to work or usual activities (weighted mean difference 0.7 days earlier, 95% confidence interval 0.2 to 1. 3). Antibiotic-treated patients reported significantly more adverse effects (odds ratio 1.64; 1.05 to 2.57) such as nausea, vomiting, headache, skin rash or vaginitis. REVIEWER'S CONCLUSIONS: Antibiotics appear to have a modest beneficial effect in the treatment of acute bronchitis, with a corresponding small risk of adverse effects. The benefits of antibiotics may be overestimated in this analysis because of the tendency of published reports to include complete data on only the outcomes found to be statistically significant.

Are antibiotics effective treatment for acute bronchitis? A meta-analysis.

BACKGROUND: Most clinicians prescribe antibiotics for acute bronchitis in spite of recommendations against this practice. Because the results of individual clinical trials have been mixed, we conducted a meta-analysis to determine whether antibiotics are effective treatment for acute bronchitis. METHODS: We conducted a comprehensive search to identify all trials in which patients who had a diagnosis of acute bronchitis were randomly assigned to treatment with an antibiotic or placebo. Patient-oriented outcomes of importance that were reported in at least 3 studies were quantitatively summarized. RESULTS: Nine studies met the inclusion criteria, but not all trials provided data for each outcome. Patients given antibiotics were less likely to have a cough (relative risk [RR] = 0.69; 95% confidence interval [CI], 0.49 -0.98) and be considered unimproved (RR = 0.51; 95% CI, 0.30-0.88) at a follow-up visit; but they were not less likely to have a productive cough (RR = 0.79; 95% CI, 0.60-1.03), activity limitations (RR = 0.59; 95% CI, 0.24-1.44), or feel ill (RR = 0.70; 95% CI, 0.31-1.58). Antibiotic-treated patients had a slightly shorter duration of productive cough (weighted mean difference [WMD] = -0.56 days; 95% CI, -1.09 to -0.04), but not of overall cough (WMD = -0.94; 95% CI, -2.08 to 0.21) or activity limitations (WMD = -0.49; 95% CI, -1.07 to 0.10). Patients treated with antibiotics did not report significantly more adverse effects (RR = 1.47; 95% CI, 0.82-2.65). CONCLUSIONS: Antibiotics may be modestly effective for a minority of patients with acute bronchitis. It is not clear which patient subgroups might benefit, and the failure of some studies to report negative findings may have resulted in overestimates of the benefits of antibiotics. Antibiotics are not necessary for every patient with acute bronchitis.

Induction of Japanese encephalitis virus-specific cytotoxic T lymphocytes in humans by poxvirus-based JE vaccine candidates.

Poxvirus-based recombinant Japanese encephalitis (JE) vaccine candidates, NYVAC-JEV and ALVAC-JEV, were examined for their ability to induce JE virus-specific cytotoxic T lymphocytes (CTLs) in a phase I clinical trial. These vaccine candidates encoded the JE virus premembrane (prM), envelope (E) and non-structural 1 (NS1) proteins. The volunteers received subcutaneous inoculations with each of these candidates on days 0 and 28, and blood was drawn 2 days before vaccination and on day 58. Anti-E and anti-NS1 antibodies were elicited in most vaccinees inoculated with NYVAC-JEV and in some vaccinees inoculated with ALVAC-JEV. Peripheral blood mononuclear cells (PBMCs) obtained from approximately one half of vaccines showed positive proliferation in response to stimulation with live JE virus. Cytotoxic assays demonstrated the presence of JE virus-specific CTLs in in vitro-stimulated PBMCs obtained from two NYVAC-JEV and two ALVAC-JEV vaccinees. Cell depletion tests using PBMCs from one NYVAC-JEV recipient indicated that the phenotype of CTLs was CD8+CD4-.

Murine immunoglobulin G subclass responses following immunization with live dengue virus or a recombinant dengue envelope protein.

Murine immunoglobulin G (IgG) subclass responses to immunization are restricted to certain subclasses depending on the nature of the immunogen. Immunization with live viruses generally leads to a predominant IgG2a response, which may be the most effective at resisting future challenge due to the unique effector functions of IgG2a. Knowledge of subclass responses following immunization with dengue vaccine candidates may be helpful in determining which candidates are most efficacious. We measured the dengue-specific IgG subclass responses of BALB/c mice following immunization with live dengue-2 virus or with a partially purified recombinant dengue-2 envelope (E) protein. Subclass responses following immunization with live virus were IgG2a > IgG1 > IgG2b > IgG3, as opposed to IgG1 > IgG2a > IgG2b > IgG3 after immunization with recombinant protein. Responses of all subclasses except IgG1 were greater following immunization with live dengue than with the recombinant E protein. Neutralizing antibody titers were also higher after immunization with live virus than with E protein and were positively correlated with dengue-specific IgG2a responses in mice immunized with recombinant E protein. Following separation of the four IgG subclasses by chromatography, the IgG2a fraction exhibited the greatest neutralizing activity. The results seen after immunization with live dengue virus or recombinant E protein in this study are in concordance with studies involving other viruses and viral proteins and may have implications for the development of an effective vaccine for dengue.

Risk factors for HIV infection in homosexual men: the Cleveland men's study of risks in a low-prevalence area.

Detailed questionnaires concerning alcohol and drug use, sexual practices, and medical history were completed by 301 homosexual men living in the Cleveland metropolitan area. Their sera were subsequently tested for antibodies to the human immunodeficiency virus. Fifty-six (18.6%) were seropositive. In a univariate analysis, age, drug use, and four specific sexual practices were associated with seropositivity. In a multiple logistic regression analysis, intravenous drug use and receptive anal-genital sex remained independent predictors of seropositivity.