Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women.

AIM: To quantify the effects of hormone-replacement therapy (HRT) on components of the metabolic syndrome in postmenopausal women. METHODS: Comprehensive searches of electronic databases were performed from April 1966 to October 2004. We included randomized controlled trials that were of at least 8 weeks duration and evaluated the effect of HRT on metabolic, inflammatory or thrombotic components. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Subgroup analysis evaluated the effects for transdermal and oral treatment and for diabetic and non-diabetic women. RESULTS: Pooled results of 107 trials showed that HRT reduced abdominal fat [-6.8% (CI, -11.8 to -1.9%)], HOMA-IR [-12.9% (CI, -17.1 to -8.6%)] and new-onset diabetes [relative risk 0.7 (CI, 0.6-0.9)] in women without diabetes. In women with diabetes, HRT reduced fasting glucose [-11.5% (CI, -18.0 to -5.1%)] and HOMA-IR [-35.8% (CI, -51.7 to -19.8%)]. HRT also reduced low-density lipoprotein/high-density lipoprotein cholesterol ratio [-15.7% (CI, -18.0 to -13.5%)], lipoprotein(a) [Lp(a)] [-25.0% [CI, -32.9 to -17.1%)], mean blood pressure [-1.7% (CI, -2.9 to -0.5%)], E-selectin [-17.3% (CI, -22.4 to -12.1%)], fibrinogen [-5.5% (CI, -7.8 to -3.2%)] and plasminogen activator inhibitor-1 [-25.1% (CI, -33.6 to -15.5%)]. Oral agents produced larger beneficial effects than transdermal agents, but increased C-reactive protein (CRP) [37.6% (CI, 17.4-61.3%)] and decreased protein S [-8.6% CI, -13.1 to -4.1%)], while transdermal agents had no effect. CONCLUSIONS: HRT reduces abdominal obesity, insulin resistance, new-onset diabetes, lipids, blood pressure, adhesion molecules and procoagulant factors in women without diabetes and reduced insulin resistance and fasting glucose in women with diabetes. Oral agents adversely affected CRP and protein S, while transdermal agents had no effects.

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.

BACKGROUND: Metformin is an oral anti-hyperglycemic agent used in the treatment of type 2 diabetes mellitus. The results of the UK Prospective Diabetes Study indicate that metformin treatment is associated with a reduction in total mortality compared to other anti-hyperglycemic treatments. Metformin, however, is thought to increase the risk of lactic acidosis, and is considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. OBJECTIVES: To assess the incidence of fatal and nonfatal lactic acidosis with metformin use compared to placebo and other glucose-lowering treatments in patients with type 2 diabetes mellitus. A secondary objective was to evaluate the blood lactate levels for those on metformin treatment compared to placebo or non-metformin therapies. SEARCH STRATEGY: A search was performed of The Cochrane Library (up to 8/2005), MEDLINE (up to 8/2005), EMBASE (up to 11/2000), OLD MEDLINE, and REACTIONS (up to 8/2005), in order to identify all studies of metformin treatment from 1966 to August 2005. The Cumulated Index Medicus was used to search relevant articles from 1959 to 1965. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Date of latest search: August 2005. SELECTION CRITERIA: Prospective trials in patients with type 2 diabetes that lasted longer than one month were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Observational cohort studies of metformin treatment lasting greater than one month were also included. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials to be included, assessed study quality and extracted data. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for placebo or other treatments. The upper limit for the true incidence of cases in the metformin and non-metformin groups were calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed effect model for continuous data. MAIN RESULTS: Pooled data from 206 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 47,846 patient-years of metformin use or in 38,221 patients-years in the non-metformin group. Using Poisson statistics with 95% confidence intervals the upper limit for the true incidence of metformin-associated lactic acidosis was 6.3 cases per 100,000 patient-years, and the upper limit for the true incidence of lactic acidosis in the non-metformin group was 7.8 cases per 100,000 patient-years. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to placebo or other non-biguanide therapies. The mean lactate levels were slightly lower for metformin treatment compared to phenformin (WMD -0.75 mmol/L, 95% CI -0.86 to -0.15). AUTHORS' CONCLUSIONS: There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments if prescribed under the study conditions.

Cardioselective beta-blockers for chronic obstructive pulmonary disease.

BACKGROUND: Beta-blocker therapy has a proven mortality benefit in patients with hypertension, heart failure and coronary artery disease, as well as during the perioperative period. These drugs have traditionally been considered contraindicated in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To assess the effect of cardioselective beta-blockers on respiratory function of patients with COPD. SEARCH STRATEGY: A comprehensive search of the Cochrane Airways Group Specialised Register (derived from systematic searches of CENTRAL, MEDLINE, EMBASE and CINAHL) was carried out to identify randomised blinded controlled trials from 1966 to May 2005. We did not exclude trials on the basis of language. SELECTION CRITERIA: Randomised, blinded, controlled trials of single dose or longer duration that studied the effects of cardioselective beta-blockers on the forced expiratory volume in 1 second (FEV1) or symptoms in patients with COPD. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data from the selected articles, reconciling differences by consensus. Two interventions studied were the administration of beta-blocker, given either as a single dose or for longer duration, and the use of beta2-agonist given after the study drug. MAIN RESULTS: Eleven studies of single-dose treatment and 9 of treatment for longer durations, ranging from 2 days to 12 weeks, met selection criteria. Cardioselective beta-blockers, given as a single dose or for longer duration, produced no change in FEV1 or respiratory symptoms compared to placebo, and did not affect the FEV1 treatment response to beta2-agonists. A subgroup analysis revealed no change in results for those participants with severe chronic airways obstruction or for those with a reversible obstructive component. AUTHORS' CONCLUSIONS: Cardioselective beta-blockers, given to patients with COPD in the identified studies did not produce adverse respiratory effects. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta-blockers should not be routinely withheld from patients with COPD.

Cardioselective beta-blockers for chronic obstructive pulmonary disease: a meta-analysis.

Beta-blocker therapy has a mortality benefit in patients with hypertension, heart failure and coronary artery disease, as well as during the perioperative period. These drugs have traditionally been considered contraindicated in patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to assess the effect of cardioselective beta-blockers on respiratory function of patients with COPD. Comprehensive searches were performed of the EMBASE, MEDLINE and CINAHL databases from 1966 to May 2001, and identified articles and related reviews were scanned. Randomised, blinded, controlled trials that studied the effects of cardioselective beta-blockers on the forced expiratory volume in 1 s (FEV1) or symptoms in patients with COPD were included in the analysis. Interventions studied were the administration of beta-blocker, given either as a single dose or for longer duration, and the use of beta2-agonist given after the study drug. Outcomes measured were the change in FEV1 from baseline and the number of patients with respiratory symptoms. Eleven studies of single-dose treatment and 8 of continued treatment were included. Cardioselective beta-blockers produced no significant change in FEV1 or respiratory symptoms compared to placebo, given as a single dose (-2.05% [95% CI, -6.05% to 1.96%]) or for longer duration (-2.55% [CI, -5.94% to 0.84]), and did not significantly affect the FEV1 treatment response to beta2-agonists. Subgroup analyses revealed no significant change in results for those participants with severe chronic airways obstruction or for those with a reversible obstructive component. In conclusion, cardioselective beta-blockers given to patients with COPD do not produce a significant reduction in airway function or increase the incidence of COPD exacerbations. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta-blockers should be considered for patients with COPD.

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.

BACKGROUND: Metformin is an oral anti-hyperglycemic agent used in the treatment of type 2 diabetes mellitus. The results of the UK Prospective Diabetes Study indicate that metformin treatment is associated with a reduction in total mortality compared to other anti-hyperglycemic treatments. Metformin, however, is thought to increase the risk of lactic acidosis, and is considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. OBJECTIVES: To assess the incidence of fatal and nonfatal lactic acidosis with metformin use compared to placebo and other glucose-lowering treatments in patients with type 2 diabetes mellitus. A secondary objective was to evaluate the blood lactate levels for those on metformin treatment compared to placebo or non-metformin therapies. SEARCH STRATEGY: A search was performed of the Cochrane Controlled Trials Register and the Database of Abstracts of Reviews of Effectiveness (up to 4/2000), Medline (up to 11/2000), Embase (up to 11/2000), Oldmedline, and Reactions (up to 5/2000), in order to identify all studies of metformin treatment from 1966 to November 2000. The Cumulated Index Medicus was used to search relevant articles from 1959 to 1965. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Date of latest search: November 2000. SELECTION CRITERIA: Prospective trials in patients with type 2 diabetes that lasted longer than one month were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Observational cohort studies of metformin treatment lasting greater than one month were also included. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials to be included, assessed study quality and extracted data. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for placebo or other treatments. The upper limit for the true incidence of cases in the metformin and non-metformin groups were calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed effects model for continuous data. MAIN RESULTS: Pooled data from 176 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 35,619 patient-years of metformin use or in 30,002 patients-years in the non-metformin group. Using Poisson statistics with 95% confidence intervals the upper limit for the true incidence of metformin-associated lactic acidosis was 8.4 cases per 100,000 patient-years, and the upper limit for the true incidence of lactic acidosis in the non-metformin group was 9 cases per 100,000 patient-years. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to placebo or other non-biguanide therapies. The mean lactate levels were slightly lower for metformin treatment compared to phenformin (WMD -0.75 mmol/L, 95% CI -0.86 to -0.15). REVIEWER'S CONCLUSIONS: There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments if prescribed under the study conditions, taking into account contra-indications.

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.

BACKGROUND: Metformin is an oral anti-hyperglycemic agent used in the treatment of type 2 diabetes mellitus. The results of the UK Prospective Diabetes Study indicate that metformin treatment is associated with a reduction in total mortality compared to other anti-hyperglycemic treatments. Metformin, however, is thought to increase the risk of lactic acidosis, and is considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. OBJECTIVES: To assess the incidence of fatal and nonfatal lactic acidosis with metformin use compared to placebo and other glucose-lowering treatments in patients with type 2 diabetes mellitus. A secondary objective was to evaluate the blood lactate levels for those on metformin treatment compared to placebo or non-metformin therapies. SEARCH STRATEGY: A search was performed of the Cochrane Controlled Trials Register and the Database of Abstracts of Reviews of Effectiveness (up to 4/2000), Medline (up to 11/2000), Embase (up to 11/2000), Oldmedline, and Reactions (up to 5/2000), in order to identify all studies of metformin treatment from 1966 to November 2000. The Cumulated Index Medicus was used to search relevant articles from 1959 to 1965. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Date of latest search: November 2000. SELECTION CRITERIA: Prospective trials in patients with type 2 diabetes that lasted longer than one month were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Observational cohort studies of metformin treatment lasting greater than one month were also included. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials to be included, assessed study quality and extracted data. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for placebo or other treatments. The upper limit for the true incidence of cases in the metformin and non-metformin groups were calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed effects model for continuous data. MAIN RESULTS: Pooled data from 176 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 35,619 patient-years of metformin use or in 30,002 patients-years in the non-metformin group. Using Poisson statistics with 95% confidence intervals the upper limit for the true incidence of metformin-associated lactic acidosis was 8.4 cases per 100,000 patient-years, and the upper limit for the true incidence of lactic acidosis in the non-metformin group was 9 cases per 100,000 patient-years. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to placebo or other non-biguanide therapies. The mean lactate levels were slightly lower for metformin treatment compared to phenformin (WMD -0.75 mmol/L, 95% CI -0.86 to -0.15). REVIEWER'S CONCLUSIONS: There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments if prescribed under the study conditions, taking into account contra-indications.

Cardioselective beta-blockers for chronic obstructive pulmonary disease.

BACKGROUND: Beta-blocker therapy has a proven mortality benefit in patients with hypertension, heart failure and coronary artery disease, as well as during the perioperative period. These drugs have traditionally been considered contraindicated in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To assess the effect of cardioselective beta-blockers on respiratory function of patients with COPD. SEARCH STRATEGY: A comprehensive search of EMBASE, MEDLINE and CINAHL was performed using the Cochrane Airways Group registry to identify randomised blinded controlled trials from 1966 to May 2001. The search was completed using the terms: asthma*, bronchial hyperreactivity*, respiratory sounds*, wheez*, obstructive lung disease* or obstructive airway disease*, and adrenergic antagonist*, sympatholytic* or adrenergic receptor block*. We did not exclude trials on the basis of language. SELECTION CRITERIA: Randomised, blinded, controlled trials of single dose or longer duration that studied the effects of cardioselective beta-blockers on the forced expiratory volume in 1 second (FEV1) or symptoms in patients with COPD. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data from the selected articles, reconciling differences by consensus. Two interventions studied were the administration of beta-blocker, given either as a single dose or for longer duration, and the use of beta2-agonist given after the study drug. MAIN RESULTS: Eleven studies of single-dose treatment and 8 of treatment for longer duration, ranging from 2 days to 12 weeks, met selection criteria. Cardioselective beta-blockers produced no statistically significant change in FEV1 or respiratory symptoms compared to placebo, given as a single dose (Weighted Mean Difference -2.05% [95% Confidence interval, -6.05 to 1.96%]) or for longer duration (WMD -2.55% [95% CI, -5.94 to 0.84]), and did not significantly affect the FEV1 treatment response to beta2-agonists. Exacerbations and hospitalizations were recorded in all trials, but none occurred during the periods of study, in either group. A subgroup analysis revealed no significant change in results for those participants with severe chronic airways obstruction or for those with a reversible obstructive component. REVIEWER'S CONCLUSIONS: The available evidence suggests that cardioselective beta-blockers, given to patients with COPD do not produce a significant short-term reduction in airway function or in the incidence of COPD exacerbations. However, the trials were small and of short duration. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta-blockers should be considered for patients with COPD, but administered with careful monitoring since data concerning long term administration and their effects during exacerbations are not available.

Cardioselective beta-blockers for reversible airway disease.

BACKGROUND: Beta-blocker therapy has mortality benefit in patients with hypertension, heart failure and coronary artery disease, as well as during the perioperative period. These drugs have traditionally been considered contraindicated in patients with reversible airway disease. OBJECTIVES: To assess the effect of cardioselective beta1-blockers on respiratory function of patients with reversible airway disease. Reversible airway disease was defined as asthma or chronic obstructive pulmonary disease with a reversible obstructive component. SEARCH STRATEGY: A comprehensive search of EMBASE, MEDLINE and CINAHL was performed using the Cochrane Airways Group registry to identify randomized blinded placebo-controlled trials from 1966 to May 2001. The search was completed using the terms: asthma*, bronchial hyperreactivity*, respiratory sounds*, wheez*, obstructive lung disease* or obstructive airway disease*, and adrenergic antagonist*, sympatholytic* or adrenergic receptor block*. We did not exclude trials on the basis of language. SELECTION CRITERIA: Randomized, blinded, placebo-controlled trials of single dose or longer duration that studied the effects of cardioselective beta1-blockers on the forced expiratory volume in 1 second (FEV1), symptoms and use of short-acting inhaled beta2-agonists, in patients with reversible airway disease. Reversible airway disease was documented by response to methacholine challenge, by an increase in FEV1 of at least 15% to beta2-agonist administration, or the presence of asthma as defined by the American Thoracic Society. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data from the selected articles, reconciling differences by consensus. Cardioselective beta1-blockers were divided into 2 groups, those with or without intrinsic sympathomimetic activity (ISA). Two interventions studied were the administration of beta1-blocker, given either as a single dose or for longer duration, and the use of beta2-agonist given after the study drug. MAIN RESULTS: Nineteen studies for single-dose treatment and 10 for treatment of longer duration met selection criteria. The patients had mild-moderate airways obstruction. For cardioselective beta1-blockers taken as a group, administration of a single dose was associated with a 7.98% (CI, 6.19 to 9.77%) reduction in FEV1, but with a 13.16% (CI, 10.76 to 15.56%) increase in beta2-agonist response, as compared to placebo. There was no increase in symptoms. After treatment lasting a few days to a few weeks, there was no decrement in FEV1 compared to placebo and no increase in symptoms or inhaler use. Regular use of cardioselective beta1-blockers without ISA produced a 13.13% (CI, 5.97 to 20.30) increase in beta2-agonist response compared to placebo, a response not seen with beta1-blockers containing ISA (-0.60% [CI, -11.7 to +10.5%]). REVIEWER'S CONCLUSIONS: Cardioselective beta1-blockers, given to patients with mild-moderate reversible airway disease, do not produce clinically significant adverse respiratory effects in the short term. It is not possible to comment on their effects in patient with more severe or less reversible disease, or on their effect on the frequency or severity of acute exacerbations. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta1-blockers should not be withheld from patients with mild-moderate reversible airway disease.

Cardioselective beta-blockers for reversible airway disease.

BACKGROUND: Beta-blocker therapy has mortality benefit in patients with hypertension, heart failure and coronary artery disease, as well as during the perioperative period. These drugs have traditionally been considered contraindicated in patients with reversible airway disease. OBJECTIVES: To assess the effect of cardioselective beta-blockers in patients with asthma or COPD. SEARCH STRATEGY: A search of EMBASE, MEDLINE and CINAHL was performed up to May 2002 using the terms: asthma*, bronchial hyperreactivity*, respiratory sounds*, wheez*, obstructive lung disease* or obstructive airway disease*, and adrenergic antagonist*, sympatholytic* or adrenergic receptor block*. SELECTION CRITERIA: Randomized, blinded, placebo-controlled trials of single dose or continued treatment of the effects of cardioselective beta-blockers in patients with reversible airway disease. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data from the selected articles, reconciling differences by consensus. Beta1-blockers were divided into those with or without intrinsic sympathomimetic activity (ISA). Interventions were: administration of single or continued beta1-blocker, and response to beta2-agonist given after the study drug. MAIN RESULTS: Nineteen studies on single-dose treatment and 10 studies on continued treatment met the inclusion criteria. Single dose cardioselective beta-blocker produced a 7.46% (95% CI 5.59, 9.32) reduction in FEV1, but with a 4.63% (95% CI 2.47, 6.78) increase in FEV1 with beta2-agonist, compared to placebo. Treatment lasting 3 - 28 days produced no change in FEV1 (-0.42%; 95% CI -3.74, 2.91), symptoms or inhaler use, whilst maintaining a 8.74% (95% CI 1.96, 15.52) response to beta2-agonist. There was no significant change in FEV1 treatment effect for those patients with COPD: single doses -5.28% (95% CI -10.03, -0.54%), continued treatment 1.07% (CI -3.3, 5.44. With continued treatment there was no significant difference in FEV1 response for beta1-blockers without ISA compared to those with IS: -3.22% (96%CI -7.79, 1.36) compared to 2.72% (95% CI -2.12, 7.59). Those without ISA produced a 12.0% increase in FEV1 after beta2-agonist administration compared to placebo (95%CI 4.12,19.87) while beta1-blockers with ISA produced no change compared to placebo (-0.60% [95%CI -13.93, 12.73). These results were obtained in a small number od studies of few patients. The difference was not significant. REVIEWER'S CONCLUSIONS: Cardioselective beta-blockers given in mild - moderate reversible airway disease or COPD, do not produce adverse respiratory effects in the short term. Given their demonstrated benefit in conditions such as heart failure, cardiac arrhythmias and hypertension, these agents should not be withheld from such patients, but long term safety (especially their impact during an acute exacerbation) still needs to be established.

Cardioselective beta-blocker use in patients with reversible airway disease.

BACKGROUND: Beta-blocker therapy has mortality benefit in patients with hypertension, heart failure and coronary artery disease, as well as during the perioperative period. These drugs have traditionally been considered contraindicated in patients with reversible airway disease. OBJECTIVES: To assess the effect of cardioselective beta-blockers on respiratory function of patients with reversible airway disease. Reversible airway disease was defined as asthma or chronic obstructive pulmonary disease with a reversible obstructive component. SEARCH STRATEGY: A comprehensive search of EMBASE, MEDLINE and CINAHL was performed using the Cochrane Airways Group registry to identify randomized blinded placebo-controlled trials from 1966 to February, 2000. The search was completed using the terms: asthma*, bronchial hyperreactivity*, respiratory sounds*, wheez*, obstructive lung disease* or obstructive airway disease*, and adrenergic antagonist*, sympatholytic* or adrenergic receptor block*. We did not exclude trials on the basis of language. SELECTION CRITERIA: Randomized, blinded, placebo-controlled trials of single dose or longer duration that studied the effects of cardioselective beta-blockers on the forced expiratory volume in 1 second (FEV1), symptoms and use of short-acting inhaled beta-agonists, in patients with reversible airway disease. Reversible airway disease was documented by response to methacholine challenge, by an increase in FEV1 of at least 15% to beta-agonist administration, or the presence of asthma as defined by the American Thoracic Society. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data from the selected articles, reconciling differences by consensus. Cardioselective beta-blockers were divided into 2 groups, those with or without intrinsic sympathomimetic activity (ISA). Two interventions studied were the administration of beta-blocker, given either as a single dose or for longer duration, and the use of beta-agonist given after the study drug. MAIN RESULTS: Nineteen studies for single-dose treatment and 10 for treatment of longer duration met selection criteria. The patients had mild-moderate airways obstruction. For cardioselective beta-blockers taken as a group, administration of a single dose was associated with a 7.98% (CI, 6.19 to 9.77%) reduction in FEV1, but with a 13.16% (CI, 10.76 to 15.56%) increase in beta-agonist response, as compared to placebo. There was no increase in symptoms. After treatment lasting a few days to a few weeks, there was no decrement in FEV1 compared to placebo and no increase in symptoms or inhaler use. Regular use of cardioselective beta-blockers without ISA produced a 13.13% (CI, 5.97 to 20.30) increase in beta-agonist response compared to placebo, a response not seen with beta-blockers containing ISA (-0.60% [CI, -11.7 to +10.5%]). REVIEWER'S CONCLUSIONS: Cardioselective beta-blockers, given to patients with mild-moderate reversible airway disease, do not produce clinically significant adverse respiratory effects in the short term. It is not possible to comment on their effects in patient with more severe or less reversible disease, or on their effect on the frequency or severity of acute exacerbations. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta-blockers should not be withheld from patients with mild-moderate reversible airway disease.

The temperature sensitivity of miniature endplate currents is mostly governed by channel gating: evidence from optimized recordings and Monte Carlo simulations.

The temperature dependence of miniature endplate current (MEPC) amplitude (A(c)), 20-80% rise time (t(r)), and 90-33% fall-time (t(f)) was determined for lizard (Anolis carolinensis) intercostal muscle using broadband extracellular (EC) and voltage clamp (VC) recordings. Voltage clamp methods were optimized for the fast MEPC rising phase using custom electronics. From 0-43 degrees C, A(c) increased by approximately 4.2-fold, while t(r) and t(f) decreased by approximately 3.6- and approximately 9.5-fold, respectively. Arrhenius plots were smoothly curved, with small apparent Q(10) (A(c)) or (Q(10))(-1) (t(r) and t(f)) values mostly well below 2.0. Nearly identical extracellular and voltage clamp results ruled out measurement artifacts, even for the shortest t(r) values (<60 microseconds). Monte Carlo simulation of MEPCs showed that a single underlying rate cannot determine the observed temperature dependence. To quantitatively reproduce the experimental t(f) results, a minimal model required activation energies of 46.0 (Q(10) approximately 2.0) and 63.6 (Q(10) approximately 2.5) kJ mol(-1) for channel opening and closing, respectively, and accounted for most of the observed changes in A(c) and t(r) as well. Thus, relatively large but offsetting temperature sensitivities of channel gating mostly govern and minimize the temperature dependence of MEPCs, preserving the safety factor for neuromuscular transmission. Additional temperature-sensitive parameters that could fine-tune the minimal model are discussed.

Mathematical model for the epidemiology of tuberculosis, with estimates of the reproductive number and infection-delay function.

The authors used epidemiologic data on tuberculosis to construct a model for the time delay from initial latent infection to active disease, when infection transmission occurs. They used case rate tables in the United States to calculate the fractional rate of change per annum (A) in the incidence of active tuberculosis. They then derived estimates for the effective reproductive number (R) and the cumulative transmission, defined as the number of people whom one infected person will infect in his or her lifetime and over many multiple successive transmissions, respectively. For A of -4 percent per year, the average US condition from 1930 to 1995, they estimate the reproductive number to be about 0.55 and the cumulative transmission to be about 1.2. The estimated rate of the new latent infections in the United States is 80,000 per year, the estimated prevalence of latent infections is 5 percent, and the number of transmissions of infection per active case is 3.5. From the model, the authors predicted active case rates in various age groups and compared them with published tables. The comparison suggests that the risk of activation decreases rapidly, then gradually, for the first 10 years after initial infection; the risk is relatively constant from 10 to 40 years and may decrease again after 40 years. The authors also discuss how this model can be used to help make decisions about tuberculosis control measures in the population.

Monitored isoniazid prophylaxis for low-risk tuberculin reactors older than 35 years of age: a risk-benefit and cost-effectiveness analysis.

BACKGROUND: Isoniazid chemoprophylaxis effectively prevents the development of active infectious tuberculosis. Current guidelines recommend withholding this prophylaxis for low-risk tuberculin reactors older than 35 years of age because of the risk for fatal isoniazid-induced hepatitis. However, recent studies have shown that monitoring for hepatotoxicity can significantly reduce the risk for isoniazid-related death. OBJECTIVE: To evaluate the effectiveness and cost-effectiveness of monitored isoniazid prophylaxis for low-risk tuberculin reactors older than 35 years of age. DESIGN: A Markov model was used to compare the health and economic outcomes of prescribing or withholding a course of prophylaxis for low-risk reactors 35, 50, or 70 years of age. Subsequent analyses evaluated costs and benefits when the effect of transmission of Mycobacterium tuberculosis to contacts was included. MEASUREMENTS: Probability of survival at 1 year, number needed to treat, life expectancy, and cost per year of life gained for individual persons and total population. RESULTS: Isoniazid prophylaxis increased the probability of survival at 1 year and for all subsequent years. For 35-year old, 50-year-old, and 70-year-old tuberculin reactors, life expectancy increased by 4.9 days, 4.7 days, and 3.1 days, respectively, and costs per person decreased by $101, $69, and $11, respectively. When the effect of secondary transmission to contacts was included, the gains in life expectancy per person receiving prophylaxis were 10.0 days for 35-year-old reactors, 9.0 days for 50-year-old reactors, and 6.0 days for 70-year-old reactors. Costs per person for these cohorts decreased by $259, $203, and $100, respectively. The magnitude of the benefit of isoniazid prophylaxis is moderately sensitive to the effect of isoniazid on quality of life. The hypothetical provision of isoniazid prophylaxis for all low-risk reactors older than 35 years of age in the U.S. population could prevent 35,176 deaths and save $2.11 billion. CONCLUSIONS: Monitored isoniazid prophylaxis reduces mortality rates and health care costs for low-risk tuberculin reactors older than 35 years of age, although reductions for individual patients are small. For the U.S. population, however, the potential health benefits and economic savings resulting from wider use of monitored isoniazid prophylaxis are substantial. We should consider expanding current recommendations to include prophylaxis for tuberculin reactors of all ages with no contraindications.

Miniature endplate current rise times less than 100 microseconds from improved dual recordings can be modeled with passive acetylcholine diffusion from a synaptic vesicle.

We recorded miniature endplate currents (mEPCs) using simultaneous voltage clamp and extracellular methods, allowing correction for time course measurement errors. We obtained a 20-80% rise time (tr) of approximately 80 micros at 22 degrees C, shorter than any previously reported values, and tr variability (SD) with an upper limit of 25-30 micros. Extracellular electrode pressure can increase tr and its variability by 2- to 3-fold. Using Monte Carlo simulations, we modeled passive acetylcholine diffusion through a vesicle fusion pore expanding radially at 25 nm x ms(-1) (rapid, from endplate omega figure appearance) or 0.275 nm x ms(-1) (slow, from mast cell exocytosis). Simulated mEPCs obtained with rapid expansion reproduced tr and the overall shape of our experimental mEPCs, and were similar to simulated mEPCs obtained with instant acetylcholine release. We conclude that passive transmitter diffusion, coupled with rapid expansion of the fusion pore, is sufficient to explain the time course of experimentally measured synaptic currents with trs of less than 100 micros.

Monte Carlo simulation of miniature endplate current generation in the vertebrate neuromuscular junction.

A Monte Carlo method for modeling the neuromuscular junction is described in which the three-dimensional structure of the synapse can be specified. Complexities can be introduced into the acetylcholine kinetic model used with only a small increase in computing time. The Monte Carlo technique is shown to be superior to differential equation modeling methods (although less accurate) if a three-dimensional representation of synaptic geometry is desired. The conceptual development of the model is presented and the accuracy estimated. The consequences of manipulations such as varying the spacing of secondary synaptic folds or that between the release of multiple quantal packets of acetylcholine, are also presented. Increasing the spacing between folds increases peak current. Decreased spacing of adjacent quantal release sites increases the potentiation of peak current.

Rate-amplitude correlation from single-channel records. A hidden structure in ion channel gating kinetics?

Lifetime probability density functions from single-channel recording are usually assumed to follow a multiexponential form. The amplitudes and rate constants for each exponential component are presumed to be independent. We have explored this assumption and have found a correlation between the amplitudes and the rate constants in certain cases. We examine this correlation and the possibility that other functional forms may also properly describe these distribution functions.

Diffusion models of ion-channel gating and the origin of power-law distributions from single-channel recording.

The lifetimes of the unitary currents from ion channels, as revealed from single-channel recording, are traditionally thought to follow exponential or multiexponential distributions. The interpretation of these event-time distributions is that the gating process follows Markov kinetics among a small number of states. There is recent evidence, however, that certain systems exhibit distributions that follow power laws or functions related to power laws. Likewise, it has been suggested that data sets that appear to be multiexponential may be fit to simple power laws as well. In this paper we propose a different view of ion-channel-gating kinetics that is consistent with these recent experimental observations. We retain the Markovian nature of the kinetics, but, in contrast to the traditional models, we suggest that ion-channel proteins have a very large number of states all of similar energy. Gating, therefore, resembles a diffusion process. We show that our simplest one-dimensional model exhibits single-channel distributions that follow power laws of the form t-a, where 1/2 less than or equal to a less than or equal to 3/2. Exponents determined from recent experiments approximately fall within this range. We believe that this model is consistent with modern views of protein dynamics and, thus, may provide a key to the molecular details of the gating process.

Resolution in EM autoradiography V: 45Ca (and 33P).

We devised a specimen to test EM autoradiographic resolution for calcium-45 (and phosphorous-33). A dry emulsion film was used for soluble compounds. We obtained a resolution (HD) value of 2300 +/- 500 A. This value is no larger than that previously obtained for Carbon -14, whose emission is about 1.6-fold lower. This result is as expected on theoretical grounds.

The galaxy luminosity function and the redshift-distance controversy (A Review).

The mean relation between distance and redshift for galaxies is reviewed as an observational question. The luminosity function for galaxies is an important ingredient and is given explicitly. We discuss various observational selection effects that are important for comparison of the linear and quadratic distance-redshift laws. Several lines of evidence are reviewed, including the distribution of galaxy luminosities in various redshift ranges, the luminosities of brightest galaxies in groups and clusters at various redshifts, and the Tully-Fisher correlation between neutral hydrogen velocity widths and luminosity. All of these strongly favor the linear law over the quadratic.