Hemoglobin variants and disease manifestations in severe falciparum malaria

Context  The geographical distributions of hemoglobin S (HbS), hemoglobin C (HbC), and ⁺-thalassemia (–) strongly suggest balancing selection with malaria. However, whereas several studies indicate that the HbS carrier state protects against all major forms of clinical malaria, malaria protection on clinical grounds has been more difficult to confirm for HbC and –, and questions remain as to whether it applies to all forms of the disease. Objective  To assess the association between major clinical forms of severe falciparum malaria and HbS, HbC, and –. Design, Setting, and Participants  Case-control study of 2591 children with severe falciparum malaria enrolled at a tertiary referral center in Ghana, West Africa, and 2048 age-, sex-, and ethnicity-matched control participants recruited by community surveys. Main Outcome Measures  Frequencies of HbS, HbC, and – in patients and controls, including stratifications of patients for signs of disease. Results  Patients presented with partly overlapping signs of disease, including severe anemia (64%), cerebral malaria (22%), respiratory distress (30%), hyperparasitemia (32%), prostration (52%), acidosis (59%), and hyperlactatemia (56%). Carrier states of HbS, HbC, and – were found in 1.4%, 9.4%, and 25.2% of the patients, respectively, and 14.8%, 8.7%, and 27.3% of controls. The HbS carrier state was negatively associated with all forms of the disease studied (overall odds ratio [OR], 0.08; 95% confidence interval [CI], 0.06-0.12). The HbC carrier state showed a negative association selectively with cerebral malaria (OR, 0.64; 95% CI, 0.45-0.91), and the – carrier state showed a negative association selectively with severe anemia (OR, 0.82; 95% CI, 0.69-0.96). Conclusion  Whereas the HbS carrier state was found to be negatively associated with all major forms of severe falciparum malaria, the negative associations of the carrier states of HbC and – appeared to be limited to cerebral malaria and severe anemia, respectively.      

Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease

Context  Alzheimer disease (AD) is characterized by pathological results at autopsy of amyloid plaques and tau-associated neurofibrillary tangles, but the clinical diagnosis of AD is determined on the basis of medical history, cognitive symptoms, and exclusionary criteria. The search for antemortem biomarkers is intense and has focused on cerebrospinal fluid (CSF) -amyloid_1-42 and tau proteins. Objectives  To compare CSF -amyloid and tau levels in a new population of AD patients and controls. To perform a meta-analysis of studies of CSF -amyloid and tau levels in AD patients and controls. Design  Cross-sectional study of the comparison of baseline CSF -amyloid_1-42 and tau levels in AD patients and controls. Meta-analysis involved 17 studies of CSF -amyloid and 34 studies of CSF tau. Setting  Clinical research unit of the National Institute of Mental Health, Bethesda, Md. Patients  The Geriatric Psychiatry Branch evaluated AD patients as inpatients at the National Institutes of Health Clinical Center between May 1985 and January 2001. A total of 203 patients participated in this study (131 with AD and 72 controls). None had other serious illnesses, and 31 of 131 AD cases had AD confirmed at autopsy. Meta-analysis provided an additional 3133 AD patients and 1481 controls. Main Outcome Measures  Levels of CSF -amyloid_1-42 were measured by a sandwich enzyme-linked immunoabsorbent assay with a polyclonal capture antibody and a monoclonal detection antibody. Levels of CSF tau were measured with a standard commercial immunoassay. Results  Levels of CSF -amyloid_1-42 were significantly lower in the AD patients vs controls (mean [SD], 183 [121] pg/mL vs 491 [245] pg/mL; P<.001). Levels of CSF tau were significantly higher in AD patients (mean [SD], 587 [365] pg/mL vs 244 [156] pg/mL; P<.001). The cutpoints of 444 pg/mL for CSF -amyloid_1-42 and 195 pg/mL for CSF tau gave a sensitivity and specificity of 92% and 89%, respectively, to distinguish AD patients from controls, which is comparable with rates with clinical diagnosis. Meta-analyses of studies comparing CSF -amyloid and tau levels in AD participants and controls confirmed an overall difference between levels in these 2 groups. Conclusions  Alzheimer disease is associated with a significant decrease in CSF -amyloid_1-42 levels along with an increase in CSF tau levels. These findings suggest that the 2 measures are biological markers of AD pathophysiology. While these CSF measures may have a potential clinical utility as biomarkers of disease, the preliminary and retrospective nature of the findings, the absence of assay standardization, and the lack of comparison patient populations must be addressed in future studies testing the usefulness of these CSF measures for predictive, diagnostic, or treatment evaluation purposes.      

Platelet activation in obese women: role of inflammation and oxidant stress

Context  Obesity, in particular abdominal adiposity, is associated with increased cardiovascular morbidity and mortality through mechanisms possibly linking the metabolic disorder to platelet and vascular abnormalities. Objective  To investigate the clinical and biochemical determinants of lipid peroxidation and platelet activation in obese women. Design, Setting, and Participants  Cross-sectional comparison, conducted between September 1999 and September 2001, of urinary 8-iso prostaglandin F₂ (8-iso PGF₂) and 11-dehydrothromboxane B₂ (11-dehyhdro-TxB₂) excretion levels in 93 women: 44 with a body mass index (BMI) higher than 28 and a waist-to-hip ratio (WHR) of 0.86 or higher, android obesity; 25 with a BMI higher than 28 and a WHR lower than 0.86, gynoid obesity; and 24 nonobese women with a BMI lower than 25. An additional study was conducted to determine the short-term effects of weight loss in 20 of the 44 women with android obesity. Intervention  During a 12-week period, 20 women with android obesity followed a weight loss program to reduce caloric intake to about 1200 kcal/d. Main Outcome Measures  Plasma C-reactive protein, insulin and leptin levels, and urinary 8-iso PGF₂ (marker of in vivo lipid peroxidation) and 11-dehyhdro-TxB₂ (marker of in vivo platelet activation) excretion. Weight loss was defined as successful when the initial body weight decreased by at least 5 kg after a 12-week period of caloric restriction. Results  Women with android obesity had higher levels of 8-iso PGF₂ (median [interquartile range {IQR}] 523 [393-685] vs 187 [140-225] pg/mg creatinine) and 11-dehyhdro-TxB₂ (median [IQR], 948 [729-1296] vs 215 [184-253] pg/mg creatinine) than nonobese women (P<.001). Both 8-iso PGF₂and 11-dehyhdro-TxB₂ were higher in women with android obesity than women with gynoid obesity (P<.001). Based on multiple regression analysis, C-reactive protein levels and WHRs of 0.86 or higher predicted the rate of 8-iso PGF₂ excretion independently of insulin and leptin levels. Of 20 women with android obesity, 11 achieved successful weight loss, which was associated with statistically significant reductions in C-reactive protein (median change, 23%; P<.05), 8-iso PGF₂ (median change, 32%; P = .04) and 11-dehydro-TxB₂ (median change, 54%; P = .005). Conclusions  Android obesity is associated with enhanced lipid peroxidation and persistent platelet activation. These abnormalities are driven by inflammatory triggers related to the degree of abdominal adiposity and are, at least in part, reversible with a successful weight-loss program.      

Beta2-adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome

Context  Previous data support an association between polymorphisms of the ₁- and ₂-adrenergic receptors (ADRB1 and ADRB2) and surrogate end points of response to -adrenergic blocker therapy. However, no associations between these polymorphisms and mortality have been demonstrated. Objective  To evaluate the effect of ADRB1 Arg389Gly (1165 CG), Ser49Gly (145 AG), and ADRB2 Gly16Arg (46 GA), Gln27Glu (79 CG) genotypes on survival among patients discharged with prescribed -blockers after an acute coronary syndrome (ACS). Design, Setting, and Patients  Prospective cohort study of 735 ACS patients admitted to 2 Kansas City, Mo, medical centers between March 2001 and October 2002; 597 patients were discharged with -blocker therapy. Main Outcome Measure  Multivariable-adjusted time to all-cause 3-year mortality. Results  There were 84 deaths during follow-up. There was a significant association between ADRB2 genotype and 3-year mortality among patients prescribed -blocker therapy. For the 79 CG polymorphism, Kaplan-Meier 3-year mortality rates were 16% (35 deaths), 11% (27 deaths), and 6% (4 deaths) for the CC, CG, and GG genotypes, respectively (P = .03; adjusted hazard ratios [AHRs], 0.51 [95% confidence interval {CI}, 0.30-0.87] for CG vs CC and 0.24 (95% CI, 0.09-0.68) for GG vs CC, P = .004). For the ADRB2 46 GA polymorphism, 3-year Kaplan-Meier mortality estimates were 10% (17 deaths), 10% (28 deaths), and 20% (20 deaths) for the GG, GA, and AA genotypes, respectively (P = .005; AHRs, 0.48 [95% CI, 0.27-0.86] for GA vs AA and 0.44 [95% CI, 0.22-0.85] for GG vs AA, P = .02). No mortality difference between genotypes was found among patients not discharged with -blocker therapy for either the 79 CG or 46 GA polymorphisms (P = .98 and P = .49, respectively). The ADRB2 diplotype and compound genotypes were predictive of survival in patients treated with -blockers (P = .04 and P = .002; AHRs, 5.36 [95% CI, 1.83-15.69] and 2.41 [95% CI, 0.86-6.74] for 46 A homozygous and composite heterozygous vs 79 G homozygous, respectively). No association of the ADRB1 variants with mortality was observed in either the -blocker or no -blocker groups. Conclusions  Patients prescribed -blocker therapy after an ACS have differential survival associated with their ADRB2 genotypes. Further assessment of the benefits of -blocker therapy in high-risk genotype groups may be warranted.      

Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes

Context  Glycemic disorders, one of the main risk factors for cardiovascular disease, are associated with activation of oxidative stress. Objective  To assess the respective contributions of sustained chronic hyperglycemia and of acute glucose fluctuations to oxidative stress in type 2 diabetes. Design, Setting, and Participants  Case-control study of 21 patients with type 2 diabetes (studied 2003-2005) compared with 21 age- and sex-matched controls (studied in 2001) in Montpellier, France. Main Outcome Measures  Oxidative stress, estimated from 24-hour urinary excretion rates of free 8-iso prostaglandin F₂ (8-iso PGF₂). Assessment of glucose fluctuations was obtained from continuous glucose monitoring system data by calculating the mean amplitude of glycemic excursions (MAGE). Postprandial contribution to glycemic instability was assessed by determining the postprandial increment of glucose level above preprandial values (mean postprandial incremental area under the curve [AUCpp]). Long-term exposure to glucose was estimated from hemoglobin A_1c, from fasting glucose levels, and from mean glucose concentrations over a 24-hour period. Results  Mean (SD) urinary 8-iso PGF₂ excretion rates were higher in the 21 patients with diabetes (482 [206] pg/mg of creatinine) compared with controls (275 [85] pg/mg of creatinine). In univariate analysis, only MAGE (r = 0.86; P<.001) and AUCpp (r = 0.55; P = .009) showed significant correlations with urinary 8-iso PGF₂ excretion rates. Relationships between 8-iso PGF₂ excretion rates and either MAGE or AUCpp remained significant after adjustment for the other markers of diabetic control in multiple linear regression analysis (multiple R² = 0.72 for the model including MAGE and multiple R² = 0.41 for the model including AUCpp). Standardized regression coefficients were 0.830 (P<.001) for MAGE and 0.700 (P = .003) for AUCpp. Conclusions  Glucose fluctuations during postprandial periods and, more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia. The present data suggest that interventional trials in type 2 diabetes should target not only hemoglobin A_1c and mean glucose concentrations but also acute glucose swings.      

Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial

Context  -Blockers have been shown to decrease cardiovascular risk in patients with hypertension and type 2 diabetes mellitus (DM); however, some components of the metabolic syndrome are worsened by some -blockers. Objective  To compare the effects of -blockers with different pharmacological profiles on glycemic and metabolic control in participants with DM and hypertension receiving renin-angiotensin system (RAS) blockade, in the context of cardiovascular risk factors. Design, Setting, and Participants  A randomized, double-blind, parallel-group trial (The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives [GEMINI]) conducted between June 1, 2001, and April 6, 2004, at 205 US sites that compared the effects of carvedilol and metoprolol tartrate on glycemic control. The 1235 participants were aged 36 to 85 years with hypertension (>130/80 mm Hg) and type 2 DM (glycosylated hemoglobin [HbA_1c], 6.5%-8.5%) and were receiving RAS blockers. Participants were followed up for 35 weeks. Interventions  Participants were randomized to receive a 6.25- to 25-mg dose of carvedilol (n = 498) or 50- to 200-mg dose of metoprolol tartrate (n = 737), each twice daily. Open-label hydrochlorothiazide and a dihydropyridine calcium antagonist were added, if needed, to achieve blood pressure target. Main Outcome Measures  Difference between groups in mean change from baseline HbA_1c following 5 months of maintenance therapy. Additional prespecified comparisons included change from baseline HbA_1c in individual treatment groups, treatment effect on insulin sensitivity, and microalbuminuria. Results  The 2 groups differed in mean change in HbA_1c from baseline (0.13%; 95% confidence interval [CI], –0.22% to –0.04%; P = .004; modified intention-to-treat analysis). The mean (SD) HbA_1c increased with metoprolol (0.15% [0.04%]; P<.001) but not carvedilol (0.02% [0.04%]; P = .65). Insulin sensitivity improved with carvedilol (–9.1%; P = .004) but not metoprolol (–2.0%; P = .48); the between-group difference was –7.2% (95% CI, –13.8% to –0.2%; P = .004). Blood pressure was similar between groups. Progression to microalbuminuria was less frequent with carvedilol than with metoprolol (6.4% vs 10.3%; odds ratio, 0.60; 95% CI, 0.36-0.97; P = .04). Conclusions  Both -blockers were well tolerated; use of carvedilol in the presence of RAS blockade did not affect glycemic control and improved some components of the metabolic syndrome relative to metoprolol in participants with DM and hypertension. The effects of the 2 -blockers on clinical outcomes need to be compared in long-term clinical trials.      

Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial

Context  Implantable cardioverter defibrillator (ICD) therapy is effective but is associated with high-voltage shocks that are painful. Objective  To determine whether amiodarone plus -blocker or sotalol are better than -blocker alone for prevention of ICD shocks. Design, Setting, and Patients  A randomized controlled trial with blinded adjudication of events of 412 patients from 39 outpatient ICD clinical centers located in Canada, Germany, United States, England, Sweden, and Austria, conducted from January 13, 2001, to September 28, 2004. Patients were eligible if they had received an ICD within 21 days for inducible or spontaneously occurring ventricular tachycardia or fibrillation. Intervention  Patients were randomized to treatment for 1 year with amiodarone plus -blocker, sotalol alone, or -blocker alone. Main Outcome Measure  Primary outcome was ICD shock for any reason. Results  Shocks occurred in 41 patients (38.5%) assigned to -blocker alone, 26 (24.3%) assigned to sotalol, and 12 (10.3%) assigned to amiodarone plus -blocker. A reduction in the risk of shock was observed with use of either amiodarone plus -blocker or sotalol vs -blocker alone (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.28-0.68; P<.001). Amiodarone plus -blocker significantly reduced the risk of shock compared with -blocker alone (HR, 0.27; 95% CI, 0.14-0.52; P<.001) and sotalol (HR, 0.43; 95% CI, 0.22-0.85; P = .02). There was a trend for sotalol to reduce shocks compared with -blocker alone (HR, 0.61; 95% CI, 0.37-1.01; P = .055). The rates of study drug discontinuation at 1 year were 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for -blocker alone. Adverse pulmonary and thyroid events and symptomatic bradycardia were more common among patients randomized to amiodarone. Conclusions  Despite use of advanced ICD technology and treatment with a -blocker, shocks occur commonly in the first year after ICD implant. Amiodarone plus -blocker is effective for preventing these shocks and is more effective than sotalol but has an increased risk of drug-related adverse effects. Clinical Trials Registration  ClinicalTrials.gov Identifier: NCT00257959      

Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial

Context  Low levels of cardiorespiratory fitness are associated with high risk of mortality, and improvements in fitness are associated with reduced mortality risk. However, a poor understanding of the physical activity–fitness dose response relation remains. Objective  To examine the effect of 50%, 100%, and 150% of the NIH Consensus Development Panel recommended physical activity dose on fitness in women. Design, Setting, and Participants  Randomized controlled trial of 464 sedentary, postmenopausal overweight or obese women whose body mass index ranged from 25.0 to 43.0 and whose systolic blood pressure ranged from 120.0 to 159.9 mm Hg. Enrollment took place between April 2001 and June 2005 in the Dallas, Tex, area. Intervention  Participants were randomly assigned to 1 of 4 groups: 102 to the nonexercise control group and 155 to the 4-kcal/kg, 104 to the 8-kcal/kg, and 103 to the 12-kcal/kg per week energy-expenditure groups for the 6-month intervention period. Target training intensity was the heart rate associated with 50% of each woman's peak O₂. Main Outcome Measure  The primary outcome was aerobic fitness assessed on a cycle ergometer and quantified as peak absolute oxygen consumption (O₂abs, L/min). Results  The mean (SD) baseline O₂abs values were 1.30 (0.25) L/min. The mean (SD) minutes of exercising per week were 72.2 (12.3) for the 4-kcal/kg, 135.8 (19.5) for the 8-kcal/kg, and 191.7 (33.7) for the 12-kcal/kg per week exercise groups. After adjustment for age, race/ethnicity, weight, and peak heart rate, the exercise groups increased their O₂abs compared with the control group by 4.2% in the 4-kcal/kg, 6.0% in the 8-kcal/kg, and 8.2% in the 12-kcal/kg per week groups (P<.001 for each vs control; P for trend <.001). There was no treatment x subgroup interaction for age, body mass index, weight, baseline O₂abs, race/ethnicity, or baseline hormone therapy use. There were no significant changes in systolic or diastolic blood pressure values from baseline to 6 months in any of the exercise groups vs the control group. Conclusion  In this study, previously sedentary, overweight or obese postmenopausal women experienced a graded dose-response change in fitness across levels of exercise training. Trial Registration  clinicaltrials.gov Identifier: NCT00011193      

Association of apolipoprotein E genotypes with lipid levels and coronary risk

Context  Previous reviews of associations of apolipoprotein E (apoE) genotype and coronary disease have been dominated by smaller studies that are liable to biases. Objective  To reassess associations of apoE genotypes with circulating lipid levels and with coronary risk. Data Sources  We conducted an updated meta-analysis including both published and previously unreported studies, using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database published between January 1970 and January 2007, reference lists of articles retrieved, and a registry of relevant studies. Study Selection  Eighty-two studies of lipid levels (86 067 healthy participants) and 121 studies of coronary outcomes (37 850 cases and 82 727 controls) were identified, with prespecified principal focus on studies with at least 1000 healthy participants for lipids and those with at least 500 coronary outcomes. Data Extraction  Information on genotype frequencies, lipid levels, coronary outcomes, and laboratory and population characteristics were recorded independently by 2 investigators and/or supplied by study investigators. Results  In the most extreme comparison, people with the 2/2 genotype had 1.14 mmol/L (95% confidence interval [CI], 0.87-1.40 mmol/L [44.0 mg/dL; 95% CI; 33.6-51.1 mg/dL]) or about 31% (95% CI, 23%-38%) lower mean low-density lipoprotein cholesterol (LDL-C) values than those with the 4/4 genotype. There were approximately linear relationships of apoE genotypes (when ordered 2/2, 2/3, 2/4, 3/3, 3/4, 4/4) with LDL-C and with coronary risk. The relationship with high-density lipoprotein cholesterol was inverse and shallow and that with triglycerides was nonlinear and largely confined to the 2/2 genotype. Compared with 3/3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in 2 carriers and was 1.06 (95% CI, 0.99-1.13) in 4 carriers. Conclusions  There are approximately linear relationships of apoE genotypes with both LDL-C levels and coronary risk. Compared with individuals with the 3/3 genotype, 2 carriers have a 20% lower risk of coronary heart disease and 4 carriers have a slightly higher risk.      

Mycobacterium tuberculosis infection in health care workers in rural India: comparison of a whole-blood interferon gamma assay with tuberculin skin testing

Context  Mycobacterium tuberculosis infection in health care workers has not been adequately studied in developing countries using newer diagnostic tests. Objectives  To estimate latent tuberculosis infection prevalence in health care workers using the tuberculin skin test (TST) and a whole-blood interferon (IFN-) assay; to determine agreement between the tests; and to compare their correlation with risk factors. Design, Setting, and Participants  A cross-sectional comparison study of 726 health care workers aged 18 to 61 years (median age, 22 years) with no history of active tuberculosis conducted from January to May 2004, at a rural medical school in India. A total of 493 (68%) of the health care workers had direct contact with patients with tuberculosis and 514 (71%) had BCG vaccine scars. Interventions  Tuberculin skin testing was performed using 1-TU dose of purified protein derivative RT23, and the IFN- assay was performed by measuring IFN- response to early secreted antigenic target 6, culture filtrate protein 10, and a portion of tuberculosis antigen TB7.7. Main Outcome Measures  Agreement between TST and the IFN- assay, and comparison of the tests with respect to their association with risk factors. Results  A large proportion of the health care workers were latently infected; 360 (50%) were positive by either TST or IFN- assay, and 226 (31%) were positive by both tests. The prevalence estimates of TST and IFN- assay positivity were comparable (41%; 95% confidence interval [CI], 38%-45% and 40%; 95% CI, 37%-43%, respectively). Agreement between the tests was high (81.4%;  = 0.61; 95% CI, 0.56-0.67). Increasing age and years in the health profession were significant risk factors for both IFN- assay and TST positivity. BCG vaccination had little impact on TST and IFN- assay results. Conclusions  Our study showed high latent tuberculosis infection prevalence in Indian health care workers, high agreement between TST and IFN- assay, and similar association between positive test results and risk factors. Although TST and IFN- assay appear comparable in this population, they have different performance and operational characteristics; therefore, the decision to select one test over the other will depend on the population, purpose of testing, and resource availability.      

Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline

Context  Alzheimer disease (AD) is characterized neuropathologically by the presence of amyloid -peptide (A)–containing plaques and neurofibrillary tangles composed of abnormal tau protein. Considerable controversy exists as to whether the extent of accumulation of A correlates with dementia and whether A alterations precede or follow changes in tau. Objectives  To determine whether accumulation of A correlates with the earliest signs of cognitive deterioration and to define the relationship between A accumulation and early tau changes. Design, Setting, and Patients  Postmortem cross-sectional study of 79 nursing home residents with Clinical Dementia Rating (CDR) scale scores of 0.0 to 5.0 who died between 1986 and 1997, comparing the levels of A variants in the cortices of the subjects with no (CDR score, 0.0 [n = 16]), questionable (CDR score, 0.5 [n = 11]), mild (CDR score, 1.0 [n = 22]), moderate (CDR score, 2.0 [n = 15]), or severe (CDR score, 4.0 or 5.0 [n = 15]) dementia. Main Outcome Measures  Levels of total A peptides with intact or truncated amino termini and ending in either amino acid 40 (Ax-40) or 42 (Ax-42) in 5 neocortical brain regions as well as levels of tau protein undergoing early conformational changes in frontal cortex, as a function of CDR score. Results  The levels of both Ax-40 and Ax-42 were elevated even in cases classified as having questionable dementia (CDR score = 0.5), and increases of both peptides correlated with progression of dementia. Levels of the more fibril-prone Ax-42 peptide were higher than those of Ax-40 in nondemented cases and remained higher throughout progression of disease in all regions examined. Finally, increases in Ax-40 and Ax-42 precede significant tau pathology at least in the frontal cortex, an area chosen for examination because of the absence of neuritic changes in the absence of disease. Conclusions  In this study, levels of total Ax-40 and Ax-42 were elevated early in dementia and levels of both peptides were strongly correlated with cognitive decline. Of particular interest, in the frontal cortex, A was elevated before the occurrence of significant tau pathology. These results support an important role for A in mediating initial pathogenic events in AD dementia and suggest that treatment strategies targeting the formation, accumulation, or cytotoxic effects of A should be pursued.      

Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up

Context  In the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, -tocopherol supplementation decreased prostate cancer incidence, whereas -carotene increased the risk of lung cancer and total mortality. Postintervention follow-up provides information regarding duration of the intervention effects and may reveal potential late effects of these antioxidants. Objective  To analyze postintervention effects of -tocopherol and -carotene on cancer incidence and total and cause-specific mortality. Design, Setting, and Participants  Postintervention follow-up assessment of cancer incidence and cause-specific mortality (6 years [May 1, 1993-April 30, 1999]) and total mortality (8 years [May 1, 1993-April 30, 2001]) of 25 563 men. In the ATBC Study, 29 133 male smokers aged 50 to 69 years received -tocopherol (50 mg), -carotene (20 mg), both agents, or placebo daily for 5 to 8 years. End point information was obtained from the Finnish Cancer Registry and the Register of Causes of Death. Cancer cases were confirmed through medical record review. Main Outcome Measures  Site-specific cancer incidence and total and cause-specific mortality and calendar time-specific risk for lung cancer incidence and total mortality. Results  Overall posttrial relative risk (RR) for lung cancer incidence (n = 1037) was 1.06 (95% confidence interval [CI], 0.94-1.20) among recipients of -carotene compared with nonrecipients. For prostate cancer incidence (n = 672), the RR was 0.88 (95% CI, 0.76-1.03) for participants receiving -tocopherol compared with nonrecipients. No late preventive effects on other cancers were observed for either supplement. There were 7261 individuals who died by April 30, 2001, during the posttrial follow-up period; the RR was 1.01 (95% CI, 0.96-1.05) for -tocopherol recipients vs nonrecipients and 1.07 (95% CI, 1.02-1.12) for -carotene recipients vs nonrecipients. Regarding duration of intervention effects and potential late effects, the excess risk for -carotene recipients was no longer evident 4 to 6 years after ending the intervention and was primarily due to cardiovascular diseases. Conclusions  The beneficial and adverse effects of supplemental -tocopherol and -carotene disappeared during postintervention follow-up. The preventive effects of -tocopherol on prostate cancer require confirmation in other trials. Smokers should avoid -carotene supplementation.      

Beta-blocker therapy and symptoms of depression,fatigue, and sexual dysfunction

Context  -Blocker therapy remains substantially underused in cardiac patientsdespite its proven mortality benefits. Reluctance to prescribe these agentsmay derive from concerns about their association with symptoms of depression,fatigue, and sexual dysfunction. Objective  To determine the association of -blockers with depressive symptoms,fatigue, and sexual dysfunction by performing a quantitative review of randomizedtrials that tested -blockers in myocardial infarction, heart failure,and hypertension. Data Sources  Randomized trials of -blockers used in the treatment of myocardialinfarction, heart failure, or hypertension were identified by searching theMEDLINE database for English-language articles (1966-2001). In addition, wesearched the reference lists of previously published trials and reviews of -blockersfor additional studies. Study Selection  Criteria for inclusion of trials in the review were: random allocationof study treatments, placebo control, noncrossover design, enrollment of atleast 100 patients, and a minimum of 6 months of follow-up. The initial searchproduced 475 articles, 42 of which met these criteria. Fifteen of these trialsreported on depressive symptoms, fatigue, or sexual dysfunction and were selectedfor inclusion. Data Extraction  For each trial, 1 author abstracted the frequency of adverse eventsin the -blocker and placebo groups and the numbers of patients randomizedto the treatment groups. Two other authors verified the counts of events,and all authors adjudicated any discrepancies. Two different types of informationon adverse events were abstracted: patient-reported symptoms and withdrawalof therapy due to a specified symptom. We categorized the tested -blockersby generation (early vs late) and lipid solubility (high vs low to moderate). Data Synthesis  The 15 trials involved more than 35 000 subjects. -Blockertherapy was not associated with a significant absolute annual increase inrisk of reported depressive symptoms (6 per 1000 patients; 95% confidenceinterval [CI], –7 to 19). -Blockers were associated with a smallsignificant annual increase in risk of reported fatigue (18 per 1000 patients;95% CI, 5-30), equivalent to 1 additional report of fatigue for every 57 patientstreated per year with -blockers. -Blockers were also associatedwith a small, significant annual increase in risk of reported sexual dysfunction(5 per 1000 patients; 95% CI, 2-8), equivalent to one additional report forevery 199 patients treated per year. None of the risks of adverse effectsdiffered significantly by degree of -blocker lipid solubility. The riskassociated with reported fatigue was significantly higher for early-generationthan for late-generation -blockers (P = .04). Conclusion  The conventional wisdom that -blocker therapy is associated withsubstantial risks of depressive symptoms, fatigue, and sexual dysfunctionis not supported by data from clinical trials. There is no significant increasedrisk of depressive symptoms and only small increased risks of fatigue andsexual dysfunction. The risks of these adverse effects should be put in thecontext of the documented benefits of these medications.      

beta-Blocker therapy in heart failure: scientific review

Context  Care of patients with heart failure has been revolutionized throughout the past decade. A paradigm shift in the strategy for treating heart failure caused by systolic dysfunction is in progress. Despite the initial perception about -blockers' safety, they are now the most extensively studied class of agents in the treatment of heart failure and have emerged as an important intervention to improve the clinical outcomes of heart failure patients. Objective  To provide scientific rationale for the use of -blockers for patients with heart failure. Data Sources  All English-language articles of large, randomized controlled clinical trials assessing the mortality benefits of -blockers in patients with heart failure were identified to provide the scientific rationale for the use of -blockers in heart failure. Basic science studies were reviewed to provide an overview of the potential physiologic role of -blockers in heart failure. Finally, clinical guidelines for the treatment of patients with heart failure were assessed to determine current recommendations for the use of these agents. Study Selection and Data Extraction  Randomized controlled clinical trials of -blockers that included more than 300 subjects and assessed mortality as a primary end point. Data Synthesis  Of the 4 -blockers tested in large randomized controlled clinical trials of patients with heart failure, 3 are available in the United States, bisoprolol, carvedilol, and metoprolol; 2 of these, carvedilol and metoprolol, have Food and Drug Administration indications for the treatment of heart failure. Compared with placebo treatment, -blocker use is associated with a consistent 30% reduction in mortality and a 40% reduction in hospitalizations in patients with class II and III heart failure. Conclusions  Tested in more than 10 000 patients, -blockers reduce morbidity and mortality in class II through IV heart failure. Along with angiotensin-converting enzyme inhibitors, digoxin, and diuretics, -blockers have strengthened the armamentarium to improve clinical outcomes of heart failure patients. The science supporting -blockers must be translated into practice safely and rationally if the agents are to achieve their full potential.      

Contemporary management of chronic obstructive pulmonary disease: scientific review

Context  The care of patients with chronic obstructive pulmonary disease (COPD) has changed radically over the past 2 decades, and novel therapies can not only improve the health status of patients with COPD but also modify its natural course. Objective  To systematically review the impact of long-acting bronchodilators, inhaled corticosteroids, nocturnal noninvasive mechanical ventilation, pulmonary rehabilitation, domiciliary oxygen therapy, and disease management programs on clinical outcomes in patients with COPD. Data Sources  MEDLINE and Cochrane databases were searched to identify all randomized controlled trials and systematic reviews from 1980 to May 2002 evaluating interventions in patients with COPD. We also hand searched bibliographies of relevant articles and contacted experts in the field. Study Selection and Data Extraction  We included randomized controlled trials that had follow-up of at least 3 months and contained data on at least 1 of these clinical outcomes: health-related quality of life, exacerbations associated with COPD, or death. For pulmonary rehabilitation, we included studies that had a follow-up of at least 6 weeks. Using standard meta-analytic techniques, the effects of interventions were compared with placebo or with usual care. In secondary analyses, the effects of interventions were compared against each other, where possible. Data Synthesis  Long-acting ₂-agonists and anticholinergics (tiotropium) reduced exacerbation rates by approximately 20% to 25% (relative risk [RR] for long-acting ₂-agonists, 0.79; 95% CI, 0.69-0.90; RR for tiotropium, 0.74; 95% CI, 0.62-0.89) in patients with moderate to severe COPD. Inhaled corticosteroids also reduced exacerbation rates by a similar amount (RR, 0.76; 95% CI, 0.72-0.80). The beneficial effects were most pronounced in trials enrolling patients with FEV₁ between 1 L and 2 L. Combining a long-acting ₂-agonist with an inhaled corticosteroid resulted in an approximate 30% (RR, 0.70; 95% CI, 0.62-0.78) reduction in exacerbations. Pulmonary rehabilitation improved the health status of patients with moderate to severe disease, but no material effect was observed on long-term survival or hospitalization rates. Domiciliary oxygen therapy improved survival by approximately 40% in patients with PaO₂ lower than 60 mm Hg, but not in those without hypoxia at rest. The data on disease management programs were heterogeneous, but overall no effect was observed on survival or risk of hospitalization. Noninvasive mechanical ventilation was not associated with improved outcomes. Conclusions  A significant body of evidence supports the use of long-acting bronchodilators and inhaled corticosteroids in reducing exacerbations in patients with moderate to severe COPD. Domiciliary oxygen therapy is the only intervention that has been demonstrated to prolong survival, but only in patients with resting hypoxia.      

A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke

Context  Myocardial infarction (MI) and ischemic stroke are thought to be caused by matrix digestion by metalloproteinases (MMPs) leading to rupture of atherosclerotic plaques. Production of macrophage MMP-2 and MMP-9 is induced by cyclooxygenase 2 (COX-2) and prostaglandin E₂ synthesis. Although COX-2 expression may be genetically determined, the relation between COX-2 polymorphisms and the risk of MI and stroke is unclear. Objective  To investigate the relationship between the –765GC polymorphism of the COX-2 gene and clinically evident plaque rupture. Design, Setting, and Participants  Prospective, matched case-control study conducted between March 2002 and October 2003 among 864 patients with first MI or atherothrombotic ischemic stroke and 864 hospitalized controls. The groups were matched for age, sex, body mass index, smoking, hypertension, hypercholesterolemia, and diabetes. The –765GC variant of the COX-2 gene was genotyped by restriction endonuclease digestion of polymerase chain reaction products. Main Outcome Measures  Presence of the –765GC polymorphism of the COX-2 gene; COX-2, MMP-2, and MMP-9 expression and activity in plaques and in peripheral monocytes; urinary 6-keto PGF₁ (marker of endothelial prostacyclin); and endothelium-dependent and -independent forearm blood flow vasodilation. Results  The prevalence of –765GC was 2.41 times higher among controls than among cases (43.3% vs 17.9%; P<.001). The prevalence of –765CC homozygosity was 5.81 times higher (6.4% vs 1.1%; P = .04). Among participants carrying the –765GC and –765CC genotypes, the prevalence ratios for MI or stroke were 0.48 (95% CI, 0.36-0.68) and 0.33 (95% CI, 0.24-0.55), respectively. Expression of COX-2 and MMPs was significantly lower in atherosclerotic plaques from participants carrying the –765C allele, while the –765GC polymorphism did not affect endothelial prostacyclin biosynthesis or endothelium-dependent vasodilation in vivo. In subgroup analyses (n = 224 cases), serum high-sensitivity C-reactive protein was significantly lower in patients carrying the –765C allele (mean [SD], 0.78 [0.1] vs 2.56 [0.4] mg/L; P = .04). Conclusions  We found that the –765GC polymorphism of the COX-2 gene is associated with a decreased risk of MI and stroke. Detection of this genotype may be useful for predicting genetic risk of MI and stroke.      

Discrepancy between the tuberculin skin test and the whole-blood interferon gamma assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country

Context  A recently developed whole-blood interferon (IFN-) assay based on stimulation with the Mycobacterium tuberculosis–specific antigens early secreted antigenic target 6 and culture filtrate protein 10 shows promise for the diagnosis of latent tuberculosis (TB) infection. Objective  To compare the tuberculin skin test (TST) and the whole-blood IFN- assay in the diagnosis of latent TB infection according to the intensity of exposure. Design and Setting  A prospective comparison between the whole-blood IFN- assay and the TST using a 2-TU dose of purified protein derivative RT23 in a population with intermediate TB burden was conducted sequentially between February 1, 2004, and February 28, 2005, in a Korean tertiary referral hospital. Participants  Of 273 participants, 220 (95.7%) had received BCG vaccine. Participants were grouped according to their risk of infection: group 1, no identifiable risk of M tuberculosis infection (n = 99); group 2, recent casual contacts (n = 72); group 3, recent close contacts (n = 48); group 4, bacteriologically or pathologically confirmed TB patients (n = 54). Main Outcome Measures  Levels of agreement between the TST and the IFN- assay and the likelihood of infection in the various groups. Results  For the TST with a 10-mm induration cutoff, the positive response rate in group 1 was 51%; group 2, 60%; group 3, 71%, and group 4, 78%. For the IFN- assay, the positive response rate in group 1 was 4%; group 2, 10%; group 3, 44%; and group 4, 81%. The overall agreement between the TST and the IFN- assay in healthy volunteers was = 0.16. The odds of a positive test result per unit increase in exposure across the 4 groups increased by a factor of 5.31 (95% confidence interval [CI], 3.62-7.79) for the IFN- assay and by a factor of 1.52 (95% CI, 1.20-1.91) for the TST (P<.001). Using a 15-mm induration cutoff for the TST did not make a substantial difference to the test results. Conclusion  The IFN- assay is a better indicator of the risk of M tuberculosis infection than TST in a BCG-vaccinated population.      

Pharmacological management to reduce exacerbations in adults with asthma: a systematic review and meta-analysis

Context  Over the last 2 decades, many new pharmacological agents have been introduced to reduce the growing morbidity associated with asthma, but the long-term effects of these agents on exacerbations are unclear. Objective  To systematically review and quantitatively synthesize the long-term effects of inhaled corticosteroids, long-acting ₂ agonists, leukotriene pathway modifiers/receptor antagonists, and anti-IgE therapies on clinical outcomes and particular clinically relevant exacerbations in adult patients with chronic asthma. Data Sources  MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant randomized controlled trials and systematic reviews published from January 1, 1980, to April 30, 2004. We identified additional studies by searching bibliographies of retrieved articles and contacting experts in the field. Study Selection and Data Extraction  Included trials were double-blind, had follow-up periods of at least 3 months, and contained data on exacerbations and/or forced expiratory volume in 1 second. The effects of interventions were compared with placebo, short-acting ₂ agonists, or each other. Data Synthesis  Inhaled corticosteroids were most effective, reducing exacerbations by nearly 55% compared with placebo or short-acting ₂ agonists (relative risk [RR], 0.46; 95% confidence interval [CI], 0.34-0.62; P<.001 for heterogeneity). Compared with placebo, the use of long-acting ₂ agonists was associated with 25% fewer exacerbations (RR, 0.75; 95% CI, 0.64-0.88; P = .43 for heterogeneity); when added to inhaled corticosteroids, there was a 26% reduction above that achieved by steroid monotherapy (RR, 0.74; 95% CI, 0.61-0.91; P = .07 for heterogeneity). Combination therapy was associated with fewer exacerbations than was increasing the dose of inhaled corticosteroids (RR, 0.86; 95% CI, 0.76-0.96; P = .65 for heterogeneity). Compared with placebo, leukotriene modifiers/receptor antagonists reduced exacerbations by 41% (RR, 0.59; 95% CI, 0.49-0.71; P = .44 for heterogeneity) but were less effective than inhaled corticosteroids (RR, 1.72; 95% CI, 1.28-2.31; P = .91 for heterogeneity). Use of monoclonal anti-IgE antibodies with concomitant inhaled corticosteroid therapy was associated with 45% fewer exacerbations (RR, 0.55; 95% CI, 0.45-0.66; P = .15 for heterogeneity). Conclusions  Inhaled corticosteroids are the single most effective therapy for adult patients with asthma. However, for those unable or unwilling to take corticosteroids, the use of leukotriene modifiers/receptor agonists appears reasonable. Long-acting ₂ agonists may be added to corticosteroids for those who remain symptomatic despite low-dose steroid therapy. Anti-IgE therapy may be considered as adjunctive therapy for young adults with asthma who have clear evidence of allergies and elevated serum IgE levels.      

beta-Blockers and reduction of cardiac events in noncardiac surgery: scientific review

Context  Recent studies suggest that perioperatively administered -blockers may reduce the risk of adverse cardiac events in patients undergoing major noncardiac surgery. Objective  To review the efficacy of perioperative -blockade in reducing myocardial ischemia, myocardial infarction, and cardiac or all-cause mortality from randomized trials. Data Sources  A MEDLINE and conventional search of English-language articles published since 1980 was performed to gather information related to perioperative cardiac complications and -blockade. Reference lists from all relevant articles and published recommendations for perioperative cardiac risk management were reviewed to identify additional studies. Study Selection and Data Extraction  Prospective randomized studies (6) were included in the analysis if they discussed the impact of -blockade on perioperative cardiac ischemia, myocardial infarction, and mortality for patients undergoing major noncardiac surgery. Articles were examined for elements of trial design, treatment protocols, important biases, and major findings. These elements were then qualitatively compared. Data Synthesis  We identified 5 randomized controlled trials: 4 assessed myocardial ischemia and 3 reported myocardial infarction, cardiac, or all-cause mortality. All studies sought to achieve -blockade before the induction of anesthesia by titrating doses to a target heart rate. Of studies reporting myocardial ischemia, numbers needed to treat were modest (2.5-6.7). Similarly modest numbers needed to treat were observed in studies reporting a significant impact on cardiac or all-cause mortality (3.2-8.3). The most marked effects were seen in patients at high risk; the sole study reporting a nonsignificant result enrolled patients with low baseline risk. As a group, studies of perioperative -blockade have enrolled relatively few carefully selected patients. In addition, differences in treatment protocols leave questions unanswered regarding optimal duration of therapy. Conclusions  Despite heterogeneity of trials, a growing literature suggests a benefit of -blockade in preventing perioperative cardiac morbidity. Evidence from these trials can be used to formulate an effective clinical approach while definitive trials are awaited.      

Apolipoprotein E and progression of chronic kidney disease

Context  Apolipoprotein E (APOE) genetic variation has been implicated in diabetic nephropathy with the 2 allele increasing and the 4 allele decreasing risk. APOE allelic associations with chronic kidney disease beyond diabetic nephropathy are unknown, with no studies reported in high-risk African American populations. Objective  To quantify the risk of chronic kidney disease progression associated with APOE in a population-based study including white, African American, diabetic, and nondiabetic individuals. Design, Setting, and Participants  Prospective follow-up (through January 1, 2003) of Atherosclerosis Risk in Communities (ARIC) study participants, including 3859 African American and 10 661 white adults aged 45 to 64 years without severe renal dysfunction at baseline in 1987-1989, sampled from 4 US communities. Main Outcome Measures  Incident chronic kidney disease progression, defined as hospitalization or death with kidney disease or increase in serum creatinine level of 0.4 mg/dL (35 µmol/L) or more above baseline, examined by APOE genotypes and alleles. Results  During median follow-up of 14 years, chronic kidney disease progression developed in 1060 individuals (incidence per 1000 person-years: 5.5 overall; 8.8 in African Americans and 4.4 in whites). Adjusting for major chronic kidney disease risk factors, 2 moderately increased and 4 decreased risk of disease progression (likelihood ratio test, P = .03). Further adjustment for low- and high-density lipoprotein cholesterol and triglycerides did not attenuate relative risks (RRs) (2: 1.08 [95% CI, 0.93-1.25] and 4: 0.85 [95% CI, 0.75-0.95] compared with 3; likelihood ratio test, P = .008). 4 decreased risk of end-stage renal disease (RR, 0.60 [95% CI, 0.43-0.84]). 2 was associated with a decline in renal function (RR, 1.25 [95% CI, 1.02-1.53]), though not with events, such as hospitalizations or end-stage renal disease. Risks were similar stratified by race, sex, diabetes, and hypertension (all P values for interaction >.05). Excess risk of chronic kidney disease in African Americans was not explained by APOE alleles. Conclusions  APOE variation predicts chronic kidney disease progression, independent of diabetes, race, lipid, and nonlipid risk factors. Our study suggests that nonlipid-mediated pathways, such as cellular mechanisms of kidney remodeling, may be involved in the association of APOE alleles and progression of chronic kidney disease.