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.      

beta-Blockers and reduction of cardiac events in noncardiac surgery: clinical applications

Recent studies suggest that -blockers administered perioperatively may reduce the risk of adverse cardiac events and mortality in patients who have cardiac risk factors and undergo major noncardiac surgery. The objective of this article is to provide practicing physicians with examples of perioperative -blocker use in practice by using several hypothetical cases. Although current evidence describing the effectiveness of perioperative -blockade may not address all possible clinical situations, it is possible to formulate an evidence-based approach that will maximize benefit to patients. We describe how information from several sources can be used to guide management of patients with limited exercise tolerance, those at highest risk for perioperative cardiac events, patients who are taking -blockers long-term, and those with relative contraindications to -blockade. Even though fine points of their use remain to be elucidated, perioperative -blocker use is important and can be easily applied in practice by any physician involved with the care of patients perioperatively.      

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.      

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.      

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.      

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.      

Meta-analysis of Trials Comparing {beta}-Blockers, Calcium Antagonists, and Nitrates for Stable Angina

Context  Which drug is most effective as a first-line treatment for stable angina is not known. Objective  To compare the relative efficacy and tolerability of treatment with -blockers, calcium antagonists, and long-acting nitrates for patients who have stable angina. Data Sources  We identified English-language studies published between 1966 and 1997 by searching the MEDLINE and EMBASE databases and reviewing the bibliographies of identified articles to locate additional relevant studies. Study Selection  Randomized or crossover studies comparing antianginal drugs from 2 or 3 different classes (-blockers, calcium antagonists, and long-acting nitrates) lasting at least 1 week were reviewed. Studies were selected if they reported at least 1 of the following outcomes: cardiac death, myocardial infarction, study withdrawal due to adverse events, angina frequency, nitroglycerin use, or exercise duration. Ninety (63%) of 143 identified studies met the inclusion criteria. Data Extraction  Two independent reviewers extracted data from selected articles, settling any differences by consensus. Outcome data were extracted a third time by 1 of the investigators. We combined results using odds ratios (ORs) for discrete data and mean differences for continuous data. Studies of calcium antagonists were grouped by duration and type of drug (nifedipine vs nonnifedipine). Data Synthesis  Rates of cardiac death and myocardial infarction were not significantly different for treatment with -blockers vs calcium antagonists (OR, 0.97; 95% confidence interval [CI], 0.67-1.38; P=.79). There were 0.31 (95% CI, 0.00-0.62; P=.05) fewer episodes of angina per week with -blockers than with calcium antagonists. -Blockers were discontinued because of adverse events less often than were calcium antagonists (OR, 0.72; 95% CI, 0.60-0.86; P<.001). The differences between -blockers and calcium antagonists were most striking for nifedipine (OR for adverse events with -blockers vs nifedipine, 0.60; 95% CI, 0.47-0.77). Too few trials compared nitrates with calcium antagonists or -blockers to draw firm conclusions about relative efficacy. Conclusions  -Blockers provide similar clinical outcomes and are associated with fewer adverse events than calcium antagonists in randomized trials of patients who have stable angina.      

Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers

Context  Data on the efficacy of -blockers in the 3 most common genetic long QT syndrome (LQTS) loci are limited. Objective  To describe and assess outcome in a large systematically genotyped population of -blocker–treated LQTS patients. Design, Setting, and Patients  Consecutive LQTS-genotyped patients (n = 335) in Italy treated with -blockers for an average of 5 years. Main Outcome Measures  Cardiac events (syncope, ventricular tachycardia/torsades de pointes, cardiac arrest, and sudden cardiac death) while patients received -blocker therapy according to genotype. Results  Cardiac events among patients receiving -blocker therapy occurred in 19 of 187 (10%) LQT1 patients, 27 of 120 (23%) LQT2 patients, and 9 of 28 (32%) LQT3 patients (P<.001). The risk of cardiac events was higher among LQT2 (adjusted relative risk, 2.81; 95% confidence interval [CI], 1.50-5.27; P = .001) and LQT3 (adjusted relative risk, 4.00; 95% CI, 2.45-8.03; P<.001) patients than among LQT1 patients, suggesting inadequate protection from -blocker therapy. Other important predictors of risk were a QT interval corrected for heart rate that was more than 500 ms in patients receiving therapy (adjusted relative risk, 2.01; 95% CI, 1.16-3.51; P = .01) and occurrence of a first cardiac event before the age of 7 years (adjusted RR, 4.34; 95% CI, 2.35-8.03; P<.001). Conclusion  Among patients with genetic LQTS treated with -blockers, there is a high rate of cardiac events, particularly among patients with LQT2 and LQT3 genotypes.      

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.      

The APOE-{epsilon}4 Allele and the Risk of Alzheimer Disease Among African Americans, Whites, and Hispanics

Context.— Although the association between Alzheimer disease (AD) and the apolipoprotein E 4 (APOE-4) allele has been confirmed worldwide, it appears to be inconsistent among African Americans, Hispanics, and Nigerians. Objective.— To investigate the association between the APOE-4 allele and AD in elderly African Americans, Hispanics, and whites. Design.— Prospective, population-based, longitudinal study over a 5-year period (1991-1996). Setting.— The Washington Heights–Inwood community of New York City. Participants.— A total of 1079 Medicare recipients without AD or a related disorder at baseline. Main Outcome Measures.— Risk of clinically diagnosed AD in the 3 ethnic groups and among individuals with and without an APOE-4 allele. Results.— Compared with individuals with the APOE-3/3 genotype, the relative risk (RR) of AD associated with 1 or more copies of the APOE-4 allele was significantly increased among whites (RR, 2.5; 95% confidence interval [CI], 1.1-6.4), but not among African Americans (RR, 1.0; 95% CI, 0.6-1.6) or Hispanics (RR, 1.1; 95% CI, 0.7-1.6). In the absence of the APOE-4 allele, the cumulative risks of AD to age 90 years, adjusted for education and sex, were 4 times higher for African Americans (RR, 4.4; 95% CI, 2.3-8.6) and 2 times higher for Hispanics (RR, 2.3; 95% CI, 1.2-4.3) than for whites. In the presence of an APOE-4 allele, the cumulative risk of AD to age 90 years was similar for individuals in all 3 ethnic groups. Conclusion.— The presence of an APOE-4 allele is a determinant of AD risk in whites, but African Americans and Hispanics have an increased frequency of AD regardless of their APOE genotype. These results suggest that other genes or risk factors may contribute to the increased risk of AD in African Americans and Hispanics.      

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.      

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.      

Are {beta}-Blockers Efficacious as First-line Therapy for Hypertension in the Elderly?: A Systematic Review

Objective.— To assess antihypertensive efficacy of -blockers and their effects on cardiovascular morbidity and mortality and all-cause morbidity compared with diuretics in elderly patients with hypertension. Data Source.— A MEDLINE search of English-language articles published between January 1966 and January 1998 using the terms hypertension (drug therapy) and elderly or aged or geriatric, and cerebrovascular or cardiovascular diseases, and morbidity or mortality. References from identified articles were also reviewed. Data Selection.— Randomized trials lasting at least 1 year, which used as first-line agents diuretics and/or -blockers, and reported morbidity and mortality outcomes in elderly patients with hypertension. Data Synthesis and Results.— Ten trials involving a total of 16164 elderly patients (60 years) were included. Two thirds of the patients assigned to diuretics were well controlled on monotherapy, whereas less than a third of the patients assigned to -blockers were well controlled on monotherapy. Diuretic therapy was superior to -blockade with regard to all end points and was effective in preventing cerebrovascular events (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.51-0.72), fatal stroke (OR, 0.67; 95% CI, 0.49-0.90), coronary heart disease (OR, 0.74; 95% CI, 0.64-0.85), cardiovascular mortality (OR, 0.75; 95% CI, 0.64-0.87), and all-cause mortality (OR, 0.86; 95% CI, 0.77-0.96). In contrast, -blocker therapy only reduced the odds for cerebrovascular events (OR, 0.75; 95% CI, 0.57-0.98) but was ineffective in preventing coronary heart disease, cardiovascular mortality, and all-cause mortality (ORs, 1.01, 0.98, and 1.05, respectively). Conclusions.— In contrast to diuretics, which remain the standard first-line therapy, -blockers, until proven otherwise, should no longer be considered appropriate first-line therapy of uncomplicated hypertension in the elderly hypertensive patient.      

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      

Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression

Context  Pramipexole and levodopa are effective medications to treat motor symptoms of early Parkinson disease (PD). In vitro and animal studies suggest that pramipexole may protect and that levodopa may either protect or damage dopamine neurons. Neuroimaging offers the potential of an objective biomarker of dopamine neuron degeneration in PD patients. Objective  To compare rates of dopamine neuron degeneration after initial treatment with pramipexole or levodopa in early PD by means of dopamine transporter imaging using single-photon emission computed tomography (SPECT) with 2-carboxymethoxy-3(4-iodophenyl)tropane (-CIT) labeled with iodine 123. Design  Substudy of a parallel-group, double-blind randomized clinical trial. Setting and Patients  Eighty-two patients with early PD who were recruited at 17 clinical sites in the United States and Canada and required dopaminergic therapy to treat emerging disability, enrolled between November 1996 and August 1997. Interventions  Patients were randomly assigned to receive pramipexole, 0.5 mg 3 times per day with levodopa placebo (n = 42), or carbidopa/levodopa, 25/100 mg 3 times per day with pramipexole placebo (n = 40). For patients with residual disability, the dosage was escalated during the first 10 weeks, and subsequently, open-label levodopa could be added. After 24 months of follow-up, the dosage of study drug could be further modified. Main Outcome Measures  The primary outcome variable was the percentage change from baseline in striatal [¹²³I]-CIT uptake after 46 months. The percentage changes and absolute changes in striatal, putamen, and caudate [¹²³I]-CIT uptake after 22 and 34 months were also assessed. Clinical severity of PD was assessed using the Unified Parkinson Disease Rating Scale (UPDRS) 12 hours off anti-PD medications. Results  Sequential SPECT imaging showed a decline in mean (SD) [¹²³I]-CIT striatal uptake from baseline of 10.3% (9.8%) at 22 months, 15.3% (12.8%) at 34 months, and 20.7% (14.4%) at 46 months—approximately 5.2% per year. The mean (SD) percentage loss in striatal [¹²³I]-CIT uptake from baseline was significantly reduced in the pramipexole group compared with the levodopa group: 7.1% (9.0%) vs 13.5% (9.6%) at 22 months (P = .004); 10.9% (11.8%) vs 19.6% (12.4%) at 34 months (P = .009); and 16.0% (13.3%) vs 25.5% (14.1%) at 46 months (P = .01). The percentage loss from baseline in striatal [¹²³I]-CIT uptake was correlated with the change from baseline in UPDRS at the 46-month evaluation (r = - 0.40; P = .001). Conclusions  Patients initially treated with pramipexole demonstrated a reduction in loss of striatal [¹²³I]-CIT uptake, a marker of dopamine neuron degeneration, compared with those initially treated with levodopa, during a 46-month period. These imaging data highlight the need to further compare imaging and clinical end points of PD progression in long-term studies.      

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.      

Use of continuous quality improvement to increase use of process measures in patients undergoing coronary artery bypass graft surgery: a randomized controlled trial

Context  A rigorous evaluation of continuous quality improvement (CQI) in medical practice has not been carried out on a national scale. Objective  To test whether low-intensity CQI interventions can be used to speed the national adoption of 2 coronary artery bypass graft (CABG) surgery process-of-care measures: preoperative -blockade therapy and internal mammary artery (IMA) grafting in patients 75 years or older. Design, Setting, and Participants  Three hundred fifty-nine academic and nonacademic hospitals (treating 267 917 patients using CABG surgery) participating in the Society of Thoracic Surgeons National Cardiac Database between January 2000 and July 2002 were randomized to a control arm or to 1 of 2 groups that used CQI interventions designed to increase use of the process-of-care measures. Intervention  Each intervention group received measure-specific information, including a call to action to a physician leader; educational products; and periodic longitudinal, nationally benchmarked, site-specific feedback. Main Outcome Measure  Differential incorporation of the targeted care processes into practice at the intervention sites vs the control sites, assessed by measuring preintervention (January-December 2000)/postintervention (January 2001-July 2002) site differences and by using a hierarchical patient-level analysis. Results  From January 2000 to July 2002, use of both process measures increased nationally (-blockade, 60.0%-65.6%; IMA grafting, 76.2%-82.8%). Use of -blockade increased significantly more at -blockade intervention sites (7.3% [SD, 12.8%]) vs control sites (3.6% [SD, 11.5%]) in the preintervention/postintervention (P = .04) and hierarchical analyses (P<.001). Use of IMA grafting also tended to increase at IMA intervention sites (8.7% [SD, 17.5%]) vs control sites (5.4% [SD,15.8%]) (P = .20 and P = .11 for preintervention/postintervention and hierarchical analyses, respectively). Both interventions tended to have more impact at lower-volume CABG sites (for interaction: P = .04 for -blockade; P = .02 for IMA grafting). Conclusions  A multifaceted, physician-led, low-intensity CQI effort can improve the adoption of care processes into national practice within the context of a medical specialty society infrastructure.      

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.      

Association between licensure examination scores and practice in primary care

Context  Standards for licensure are designed to provide assurance to the public of a physician's competence to practice. However, there has been little assessment of the relationship between examination scores and subsequent practice performance. Objective  To determine if there is a sustained relationship between certification examination scores and practice performance and if licensing examinations taken at the end of medical school are predictive of future practice in primary care. Design, Setting, and Participants  A total of 912 family physicians, who passed the Québec family medicine certification examination (QLEX) between 1990 and 1993 and entered practice. Linked databases were used to assess physicians' practice performance for 3.4 million patients in the universal health care system in Québec, Canada. Patients were seen during the follow-up period for the first 4 years (1993 cohort of physicians) to 7 years (1990 cohort of physicians) of practice from July 1 of the certification examination to December 31, 1996. Main Outcome Measures  Mammography screening rate, continuity of care index, disease-specific and symptom-relief prescribing rate, contraindicated prescribing rate, and consultation rate. Results  Physicians achieving higher scores on both examinations had higher rates (rate increase per SD increase in score per 1000 persons per year) of mammography screening ( for QLEX, 16.8 [95% confidence interval {CI}, 8.7-24.9]; for Medical Council of Canada Qualifying Examination [MCCQE], 17.4 [95% CI, 10.6-24.1]) and consultation ( for QLEX, 4.9 [95% CI, 2.1-7.8]; for MCCQE, 2.9 [95% CI, 0.4-5.4]). Higher subscores in diagnosis were predictive of higher rates in the difference between disease-specific and symptom-relief prescribing ( for QLEX, 3.9 [95% CI, 0.9-7.0]; for MCCQE, 3.8 [95% CI, 0.3-7.3]). Higher scores of drug knowledge were predictive of a lower rate (relative risk per SD increase in score) of contraindicated prescribing for MCCQE (relative risk, 0.88; 95% CI, 0.77-1.00). Relationships between examination scores and practice performance were sustained through the first 4 to 7 years in practice. Conclusion  Scores achieved on certification examinations and licensure examinations taken at the end of medical school show a sustained relationship, over 4 to 7 years, with indices of preventive care and acute and chronic disease management in primary care practice.