Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium

OBJECTIVE: To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. DATA SOURCES: Forty research teams contributed data on APOE genotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. MAIN OUTCOME MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed for APOE genotypes epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon4, and epsilon4/epsilon4 relative to the epsilon3/epsilon3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. RESULTS: Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes epsilon2/epsilon4 (OR=2.6, 95% CI=1.6-4.0), epsilon3/epsilon4 (OR=3.2, 95% CI=2.8-3.8), and epsilon4/epsilon4 (OR=14.9, 95% CI= 10.8-20.6); whereas, the ORs were decreased for people with genotypes epsilon2/epsilon2 (OR=0.6, 95% CI=0.2-2.0) and epsilon2/epsilon3 (OR=0.6, 95% CI=0.5-0.8). The APOE epsilon4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03). The APOE epsilon4-AD association in Japanese subjects was stronger than in Caucasian subjects (epsilon3/epsilon4: OR=5.6, 95% CI=3.9-8.0; epsilon4/epsilon4: OR=33.1, 95% CI=13.6-80.5). The epsilon2/epsilon3 genotype appears equally protective across ethnic groups. We also found that among Caucasians, APOE genotype distributions are similar in groups of patients with AD whose diagnoses were determined clinically or by autopsy. In addition, we found that the APOE epsilon4 effect is evident at all ages between 40 and 90 years but diminishes after age 70 years and that the risk of AD associated with a given genotype varies with sex. CONCLUSIONS: The APOE epsilon4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association between APOE epsilon4 and AD in African Americans requires clarification, and the attenuated effect of APOE epsilon4 in Hispanics should be investigated further.     

The role of positron emission tomography in pharmacokinetic analysis

The physiological and biochemical measurements that can be performed noninvasively in humans with modern imaging techniques offer great promise for defining the precise state of a patient's disease and its response to therapy. In general, there are two critical points in drug development when PET measurements are likely to be particularly useful: (1) In preclinical studies, a new drug can be precisely compared to standard therapies or a series of analogs can be screened for further development on the basis of performance in appropriate animal models. (2) In phase I-II human studies, classic pharmacokinetic measurements can be coupled with imaging measurements (a) to define optimal dosing schedule; (b) to define the potential utility of interventions in particular clinical situations; and (c) to formulate the design of phase III studies that are crucial for drug licensure. In general, the types of measurements that are possible can be grouped into the following categories: 1. In those situations in which the drug can be radiolabeled, the time course of tissue delivery can be determined noninvasively in vivo in health and disease. Such information should be useful for determining dosing schedules, establishing efficacy, and predicting possible toxicity. 2. Ligand-receptor binding can be assessed in vivo in two ways. The ability of the drug to displace standard radiolabeled ligands from their receptors can be determined; alternatively, labeled drug can be used to more directly assess the distribution and time course of binding. These measurements are particularly useful for studying drugs that are active in the central nervous and cardiovascular systems. 3. Measurements of tissue metabolism will be useful in determining the effects of therapies aimed at particular metabolic abnormalities. In addition, these measurements may be useful in defining viability and function of tissues in such widely disparate clinical situations as cancer chemotherapy and cardiology. For example, effects of CNS or cardiovascular drugs can be monitored by observing 18FDG metabolism in brain and heart. We suggest that the joining of classic clinical pharmacology to exquisite imaging measurements will help form the basis for 21st-century clinical drug development.     

Immunoglobulin G responses against human papillomavirus type 16 virus-like particles in a prospective nonintervention cohort study of women with cervical intraepithelial neoplasia

BACKGROUND: Infection with cancer-linked human papillomavirus (HPV) types such as HPV type 16 (HPV16) is the most important risk factor in the development of cervical cancer. It has been shown that immunoglobulin G (IgG) antibody responses against HPV16 virus-like particles (VLPs) are specifically associated with genital HPV16 infection. PURPOSE: The aim of this study was to determine the temporal relationships between the presence of HPV16 VLP-specific IgGs, HPV16 infection patterns, and the course of premalignant cervical disease. METHODS: Plasma samples from 133 women who had been diagnosed originally with mild to moderate cervical dyskaryosis and enrolled in a prospective non-intervention cohort study conducted in Amsterdam, The Netherlands, from 1991 through 1996 were analyzed for the presence of HPV16 VLP-specific IgGs by use of an enzyme-linked immunosorbent assay. A detailed analysis was performed on 43 women with different HPV16 infection patterns during a follow-up period of 10-34 months. Progression or regression of cervical intraepithelial neoplasia (CIN) lesions was monitored by cytologic and colposcopic testing at intervals of 3-4 months. HPV typing in cervical smears was performed by use of a polymerase chain reaction-based assay. Statistical analysis of the serologic data was performed by use of the Mann-Whitney U test or 2 x 2 table analyses. RESULTS: The presence of HPV16 VLP-specific IgGs in the plasma of the patients was found to be associated with the presence of HPV16 DNA in the cervical smear. Significantly higher proportions of patients with persistent HPV16 infections (i.e., who were polymerase chain reaction positive in three to 11 consecutive tests) than of patients with cleared HPV16 infections were found to be positive for the presence of HPV16 VLP-specific IgGs (18 [69.2%] of 26 versus nine [28.1%] of 32, respectively; P = .003). HPV16 VLP-specific IgGs were consistently detected in all women (n = 11) who were persistently HPV16 DNA positive during follow-up and whose disease ultimately progressed to CIN III (histologically diagnosed severe dysplasia or carcinoma in situ). CONCLUSION: HPV16 VLP-specific IgG responses are present in the plasma of a majority of patients with persistent HPV16 infections and histologically confirmed high-grade lesions but only in a smaller subset of patients with cleared HPV16 infections and either normal cervical histology or low-grade CIN lesions. IMPLICATIONS: These results suggest that HPV16 VLP-specific antibodies are not responsible for the clearance of virally induced CIN lesions but that they might, in patients with persistent HPV16 infections, be indicative of an increased cervical cancer risk.     

A case of clofazimine enteropathy

A case of clofazimine enteropathy is described. A young male received clofazimine 200 mg daily for four years. He was admitted in a pigmented, emaciated state with abdominal pain, diarrhoea and weight loss. At laparotomy his abdominal organs were stained with dark brown-black pigment due to heavy infiltration with clofazimine crystals. Despite withdrawal of clofazimine his symptoms failed to settle. He developed oedema and hypoalbuminaemia. He died following a cerebral infarction.     

Self-care behaviors, self-efficacy, and social support effect on the glycemic control of patients newly diagnosed with non-insulin-dependent diabetes mellitus

The purpose of this study was to explore the glycemic control and influencing factors in outpatients newly diagnosed with non-insulin-dependent diabetes mellitus (NIDDM). By purposeful sampling, data were collected from 130 outpatients with NIDDM at one medical center in Kaohsiung. The results indicated: (1) the mean value for HbA1C was 7.12%; and 63.1% of the patients belonged to moderate to well controlled group; (2) male patient's HbA1C value was significantly lower than female patient's; patients with no religious belief also had a lower HbA1C value than patients with a religious background; (3) there were strongly negative correlations between self-care behaviors, social support, and self-efficacy and HbA1C; (4) using a multiple stepwise regression analysis, religious belief and self-care behaviors were found to explain 10.9% variance of HbA1C level. The results of this study could be used as a reference for diabetes health education program.     

Structure of the MscL homolog from Mycobacterium tuberculosis: a gated mechanosensitive ion channel

Mechanosensitive ion channels play a critical role in transducing physical stresses at the cell membrane into an electrochemical response. The MscL family of large-conductance mechanosensitive channels is widely distributed among prokaryotes and may participate in the regulation of osmotic pressure changes within the cell. In an effort to better understand the structural basis for the function of these channels, the structure of the MscL homolog from Mycobacterium tuberculosis was determined by x-ray crystallography to 3.5 angstroms resolution. This channel is organized as a homopentamer, with each subunit containing two transmembrane alpha helices and a third cytoplasmic alpha helix. From the extracellular side, a water-filled opening approximately 18 angstroms in diameter leads into a pore lined with hydrophilic residues which narrows at the cytoplasmic side to an occluded hydrophobic apex that may act as the channel gate. This structure may serve as a model for other mechanosensitive channels, as well as the broader class of pentameric ligand-gated ion channels exemplified by the nicotinic acetylcholine receptor.     

Low prevalence of coronary artery spasm in patients with normal coronary angiograms and unexplained ventricular fibrillation

AIMS: The aetiology of ventricular fibrillation in patients without identifiable structural heart disease is unknown. Recently, high prevalence of silent ischaemia due to coronary artery spasm has been reported in such patients. However, in at least one report, all patients had non-critical coronary artery lesions. Identification of coronary artery spasm as the underlying aetiology of ventricular fibrillation has important therapeutic implications. METHODS AND RESULTS: We performed ergonovine provocation tests in 18 patients (14 males, and four females; mean age, 36 years) with documented ventricular fibrillation in the absence of identifiable structural heart disease who had undergone aborted sudden death. In group I (n = 7) ergonovine provocation tests were performed at a mean interval of 31 months (range 21-42 months) after the index episode. These patients had already received an implantable cardioverter defibrillator, after failed electrophysiologically guided antiarrhythmic therapy. In group II (n = 11) the ergonovine provocation test was performed prospectively as part of the diagnostic evaluation. All patients were off antiarrhythmic drugs, calcium entry or beta-adrenoceptor blockers at the time of the ergonovine provocation test. Ergonovine was administered intravenously as a bolus injection, beginning with 0.05 mg followed every 3 min by incremental doses up to a cumulative maximum dose of 0.45 mg. Predefined end-points were (1) recording of ischaemic ST segment shifts of > or = 1 mm in at least two corresponding leads of the 12-lead electrocardiogram; (2) induction of ventricular tachycardia or ventricular fibrillation; and (3) administration of a cumulative dose of 0.45 mg. A positive response to ergonovine was seen in only one patient (5%) in group I in whom there developed ST segment elevation without angina and a short burst of rapid ventricular tachycardia. CONCLUSIONS: This study found a low prevalence of coronary artery spasm in patients with aborted sudden death resulting from documented ventricular fibrillation and non-apparent underlying heart disease. All patients had normal coronary angiograms and a negative history for spontaneous episodes of chest pain. The mechanism of arrhythmogenesis in such patients remains largely unknown.     

Immunodominance does not result from peptide competition for MHC class II presentation

Despite the fact that Ca2+ transport into the sarcoplasmic reticulum (SR) of muscle cells is electrogenic, a potential difference is not maintained across the SR membrane. To achieve electroneutrality, compensatory charge movement must occur during Ca2+ uptake. To examine the role of Cl- in this charge movement in smooth muscle cells, Ca2+ transport into the SR of saponin-permeabilized smooth muscle cells was measured in the presence of various Cl- channel blockers or when I-, Br-, or SO42- was substituted for Cl-. Calcium uptake was inhibited in a dose-dependent manner by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and by indanyloxyacetic acid 94 (R(+)-IAA-94), but not by niflumic acid or 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS). Smooth muscle SR Ca2+ uptake was also partially inhibited by the substitution of SO42- for Cl-, but not when Cl- was replaced by I- or Br-. Neither NPPB nor R(+)-IAA-94 inhibited Ca2+ uptake into cardiac muscle SR vesicles at concentrations that maximally inhibited uptake in smooth muscle cells. These results indicate that Cl- movement is important for charge compensation in smooth muscle cells and that the Cl- channel or channels involved are different in smooth and cardiac muscle cells.