Outcome with calcium channel antagonists after myocardial infarction: A community-based study

Objectives. We sought to estimate the risk of death and recurrent myocardial infarction associated with the use of calcium antagonists after myocardial infarction in a population-based cohort study. Background. Calcium antagonists are commonly prescribed after myocardial infarction, but their long-term effects are not well established. Methods. Patients 25 to 69 years old with a suspected myocardial infarction were identified and followed up through a community-based register of myocardial infarction and cardiac death (part of the World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease [MONICA] Project in Newcastle, Australia). Data were collected by review of medical records, in-hospital interview and review of death certificates. Results. From 1989 to 1993, 3,982 patients with a nonfatal suspected myocardial infarction were enrolled in the study. At hospital discharge, 1,001 patients were treated with beta-adrenergic blocking agents, 923 with calcium antagonists, 711 with both beta-blockers and calcium antagonists and 1,346 with neither drug. Compared with patients given beta-blockers, patients given calcium antagonists were more likely to suffer myocardial infarction or cardiac death (adjusted relative risk [RR] 1.4, 95% confidence interval [CI] 1.0 to 1.9), cardiac death (RR 1.6, 95% CI 1.0 to 2.7) and death from all causes (RR 1.7, 95% CI 1.1 to 2.6). Compared with patients given neither beta-blockers nor calcium antagonists, patients given calcium antagonists were not at increased risk of myocardial infarction or cardiac death (RR 1.0, 95% CI 0.8 to 1.3), cardiac death (RR 0.9, 95% CI 0.6 to 1.2) or death from all causes (RR 1.0, 95% CI 0.7 to 1.3). No excess in risk of myocardial infarction or cardiac death was observed among patients taking verapamil (RR 0.9, 95% CI 0.6 to 1.6), diltiazem (RR 1.1, 95% CI 0.8 to 1.4) or nifedipine (RR 1.3, 95% CI 0.7 to 2.2) compared,vith patients taking neither calcium antagonists nor beta-blockers. Conclusions. These results are consistent with randomized trial data showing benefit from beta blockers after myocardial infarction and no effect on the risk of recurrent myocardial infarction and death with the use of calcium antagonists. Comparisons between beta-blockers and calcium antagonists favor beta blockers because of the beneficial effects of beta-blockers and not because of adverse effects of calcium antagonists. (C) 1998 by the American College of Cardiology.

Insulin-regulatable phosphoproteins in 3T3-L1 adipocytes form detergent-insoluble complexes not associated with caveolin

Whole body glucose homeostasis is dependent on the action of insulin. In muscle and adipose tissues, insulin stimulates glucose uptake by inducing the translocation of vesicles containing the glucose transporter GLUT4 to the cell surface. While the mechanisms of insulin-regulated GLUT4 translocation are not fully understood, some signaling intermediates have been implicated in this process. Interestingly, som: of these intermediates, including IRS-1 and PI3K, have been localised to the same intracellular membrane fraction as the GLUT4 storage pool, designated here as the high-speed pellet (HSP) fraction. This raises the possibility that many of the downstream insulin signaling intermediates may be located within close proximity to intracellular GLUT4. The goal of this study was to test this hypothesis in 3T3-L1 adipocytes. A large proportion of adipocyte phosphoproteins co-fractionated in the HSP fraction. In an attempt to resolve insulin-regulatable phosphoproteins, we subjected P-32-labeled subcellular fractions to two-dimensional gel electrophoresis (2-DE). Insulin reproducibly stimulated the phosphorylation of 12 spots in the HSP fraction. Most of the HSP phosphoproteins were insoluble in the nonionic detergent Triton X-100, whereas integral membrane proteins such as GLUT4 and intracellular caveolin were soluble under the same conditions. These results suggest that insulin-regulatable phosphoproteins in adipocytes may be organized in microdomains within the cell and that this assembly may act as an efficient conductor of the signaling proteins to rapidly facilitate downstream biological responses. Further study is required to establish the molecular basis for these detergent-insoluble signaling complexes.

Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis

Background & Aims: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that occasionally progresses to cirrhosis but usually has a benign course. The aim of this study was to investigate the role of the hemochromatosis mutation Cys282Tyr in development of the mild hepatic iron overload found in some patients with NASH and its association with hepatic damage in these patients. Methods: Fifty-one patients with NASH were studied. The presence of the Cys282Tyr mutation was tested in all patients, and the data were analyzed with respect to the histological grade of steatosis, inflammation, Perls' staining, hepatic iron concentration (HIC), and serum iron indices. Results: Thirty-one percent of patients with NASH were either homozygous or heterozygous for the Cys282Tyr mutation. This mutation was significantly associated with Perls' stain grade (P < 0.005), HIC (P < 0.005), and transferrin saturation percentage (P < 0.005) but not with serum ferritin levels. Linear regression analysis showed that increased hepatic iron (Perls' stain or HIC) had the greatest association with the severity of fibrosis (P < 0.0001). Conclusions: The Cys282Tyr mutation is responsible for most of the mild iron overload found in NASH and thus has a significant association with hepatic damage in these patients. Heterozygosity for the hemochromatosis gene mutation therefore cannot always be considered benign.

Delayed postural contraction of transversus abdominis in low back pain associated with movement of the lower limb

The temporal parameters of the response of the trunk muscles associated with movement of the lower limb were investigated in people with and without low back pain (LBP). The weight shift component of the task was completed voluntarily prior to a stimulus to move to allow investigation of the movement component of the response. In the control subjects the onset of electromyographic (EMG) activity of all trunk muscles preceded that of the muscle responsible for limb movement, thus contributing to the feed forward postural response. The EMG onset of transversus abdominis was delayed in the LBP subjects with movement in each direction, while the EMG onsets of rectus abdominis, erector spinae, and oblique abdominal muscles were delayed with specific movement directions. This result provides evidence of a change in the postural control of the trunk in people with LBP.

Relationship between peptide selectivities of human transporters associated with antigen processing and HLA class I molecules

Efficiency of presentation of a peptide epitope by a MHC class I molecule depends on two parameters: its binding to the MHC molecule and its generation by intracellular Ag processing. In contrast to the former parameter, the mechanisms underlying peptide selection in Ag processing are poorly understood. Peptide translocation by the TAP transporter is required for presentation of most epitopes and may modulate peptide supply to MHC class I molecules. To study the role of human TAP for peptide presentation by individual HLA class I molecules, we generated artificial neural networks capable of predicting the affinity of TAP for random sequence 9-mer peptides. Using neural network-based predictions of TAP affinity, we found that peptides eluted from three different HLA class I molecules had higher TAP affinities than control peptides with equal binding affinities for the same HLA class I molecules, suggesting that human TAP may contribute to epitope selection. In simulated TAP binding experiments with 408 HLA class I binding peptides, HLA class I molecules differed significantly with respect to TAP affinities of their ligands, As a result, some class I molecules, especially HLA-B27, may be particularly efficient in presentation of cytosolic peptides with low concentrations, while most class I molecules may predominantly present abundant cytosolic peptides.

Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta 1 subunit gene SCN1B

Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder(1). A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures(2). Segregation analysis suggests the majority of cases have complex inheritance(3) but rare families show apparent autosomal dominant: inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified(4,5). We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS(+)), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures(6). We now report linkage, in another large GEFS(+) family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta 1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Go-expression of the mutant pr subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.

Cohort trends in age of initiation to heroin use

This paper examines gender differences and trends over time in the age of initiation to heroin use. Data from two large surveys: the Sydney component of the ANAIDUS, conducted in 1989, and the ASHIDU, conducted in 1994, were used to examine this issue. Together, these studies contained information on 1,292 individuals who identified themselves as heroin users. Results indicated that, while there were no significant gender differences in age of initiation to heroin use, there was a significant (p < 0.001) time trend in the mean age at which heroin was first used. Specifically, the mean age of first heroin use among individuals born during the interval 1940-1949 was 20.5 years while among those born during 1970-1979 the mean age of first heroin use was 16.5 years. These findings were confirmed by analyses of the National Household Survey. Further analysis of the ASHIDU data indicated that younger age of initiation to heroin use was associated with polydrug use, overdose and crime after the effects of duration of heroin use had been statistically controlled. These findings suggest that there has been both an increase in the willingness of young people to experiment with heroin and an increased availability of the drug over this time. In combination with evidence that there has been an increase in the amount of heroin being imported into Australia, and an increased demand for treatment for opiate dependence, these data suggest that Australia is experiencing an increase in the use of heroin, particularly among youth.

The common tetratricopeptide repeat acceptor site for steroid receptor-associated immunophilins and Hop is located in the dimerization domain of hsp90

Structurally related tetratricopeptide repeat motifs in steroid receptor-associated immunophilins and the STI1 homolog, Hop, mediate the interaction with a common cellular target, hsp90, We have identified the binding domain in hsp90 for cyclophilin 40 (CyP40) using a two-hybrid system screen of a mouse cDNA library. All isolated clones encoded the intact carboxyl terminus of hsp90 and overlapped with a common region corresponding to amino acids 558-724 of murine hsp84, The interaction was confirmed in vitro with bacterially expressed CyP40 and deletion mutants of hsp90 beta and was delineated further to a 124-residue COOH-terminal segment of hsp90, Deletion of the conserved MEEVD sequence at the extreme carboxyl terminus of hsp90 precludes interaction with CyP40, signifying an important role for this motif in hsp90 function. We show that CyP40 and Hop display similar interaction profiles with hsp90 truncation mutants and present evidence for the direct competition of Hop and FK506-binding protein 52 with CyP40 for binding to the hsp90 COOH-terminal region. Our results are consistent with a common tetratricopeptide repeat interaction site for Hop and steroid receptor associated immunophilins within a discrete COOH-terminal domain of hsp90. This region of hsp90 mediates ATP-independent chaperone activity, overlaps the hsp90 dimerization domain, and includes structural elements important for steroid receptor interaction.

Jurisdictional trends in opioid overdose deaths, 1988-96

This report analysed data on opioid overdose mortality between 1988 and 1996 to: examine differences between jurisdictions in the rate of fatal opioid overdose and the rate of increase in overdose; and estimate the proportion of all deaths which were attributed to opioid overdose. Australian Bureau of Statistics (ABS) data were obtained on the number of deaths attributed to opioid dependence (ICD 9 codes 304.0, 304.7) and accidental opioid poisoning (ICD 9 codes E850.0, E850.1). The highest rate of fatal overdose occurred in NSW, followed by Victoria. The standardised mortality rate among other jurisdictions fluctuated quite markedly. While the rate of opioid overdose has increased throughout Australia, the rate of increase has been greater in some of the less-populous states and territories than it has in NSW or Victoria. In 1996, approximately 6.5% of all deaths among people aged 15-24 years and approximately 10% of all deaths among those aged 25-34 were due to opioid overdose. During the interval from 1988 to 1996, the proportion of deaths attributed to opioid overdose increased. From 1988 to 1996, the proportion of deaths attributed to opioid overdose among individuals aged 25-34 years was approximately one-third that attributed to suicide, but this proportion had increased to approximately one-half by 1996. The rate of increase in the proportion of deaths attributed to opioid overdose was higher than the rate of increase in the proportion of deaths attributed to suicide.

Fluctuations in heroin purity and the incidence of fatal heroin overdose

In order to determine the role played by heroin purity in fatal heroin overdoses, time series analyses were conducted on the purity of street heroin seizures in south western Sydney and overdose fatalities in that region. A total of 322 heroin samples were analysed in fortnightly periods between February 1993 to January 1995. A total of 61 overdose deaths occurred in the region in the study period. Cross correlation plots revealed a significant correlation of 0.57 at time lag zero between mean purity of heroin samples per fortnight and number of overdose fatalities. Similarly, there was a significant correlation of 0.50 at time lag zero between the highest heroin purity per fortnight and number of overdose fatalities. The correlation between range of heroin purity and number of deaths per fortnight was 0.40. A simultaneous multiple regression on scores adjusted for first order correlation indicated both the mean level of heroin purity and the range of heroin purity were independent predictors of the number of deaths per fortnight. The results indicate that the occurrence of overdose fatalities was moderately associated with both the average heroin purity and the range of heroin purity over the study period. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

A case-control study of employment status and mortality in a cohort of Australian youth

Recent studies have demonstrated a link in young populations between unemployment and ill health. The purpose of this study is to correlate mortality with employment status in two cohorts of young Australian males, aged 17-25 years, from 1984 to 1988. Two youth cohorts consisting of an initially unemployed sample (n = 1424 males) and a population sample (n = 4573 males), were surveyed annually throughout the study period. Those lost to follow-up during the survey period were matched with death registries across Australia. Employment status was determined from weekly diaries and death certificates and was designated as: employed or student; unemployed; not in the work force (excluding students). Conditional logistic regression, using age- and cohort- matched cases (deaths) and controls (alive), was used to estimate the odds ratio (OR) of dying with regard to employment status, taking into account potential confounders such as ethnicity, aboriginality, educational attainment, pre-existing health problems, socio-economic status of parents, and other factors. Twenty three male survey respondents were positively matched to death registry records. Compared to those employed or students (referent group), significantly elevated ORs were found to be associated with neither being in the workforce nor a student for all cause, external cause, and external cause mortality other than suicide. Odds ratios were adjusted for age, survey cohort, ethnicity, pre-existing physical and mental health status, education level, and socio-economic status of parent(s). A statistically significant increasing linear trend in odds ratios of male mortality for most cause groups was found across the employment categories, from those employed or student (lowest ORs), through those unemployed; to those not in the workforce (highest ORs). Suicide was higher, but not statistically significantly, in those unemployed or not in the workforce. Suicide also was associated, though not significantly, with the respondent not living with their parents when they were 14 years of age. No association was found between mortality and past unemployment experience, as measured by length of time spent unemployed, or the number of spells of unemployment experienced during the survey. The results of this study underscore the elevated risk to survival in young males as a consequence of being neither employed nor a student. (C) 1999 Elsevier Science Ltd. All rights reserved.

Leaking urine in Australian women: Prevalence and associated conditions

The paper aims to (1) assess the prevalence of leaking urine and to (2) explore associations between leaking urine and a variety of other symptoms, conditions, surgical procedures and life events in three large cohorts of Australian women, who are participants in the Australian Longitudinal Study on Women's Health. Young women aged 18-23 (N = 14,000), mid-age women, 45-50 (N 13,738) and older women, 70-75 (N = 12,417), were recruited randomly from the national HIC/Medicare database. Leaking urine was reported by approximately one in eight young women [estimated prevalence 12.8% (95% CI: 12.2-13.3)] and one in three mid-age women [36.1% (CI: 35.2-37.0)] and older women [35.0% (CI: 34.1-35.9)]. Leaking urine was significantly associated with parity, conditions which increase the pressure on the pelvic floor such as constipation and obesity, past gynecological surgery and conditions which can impact on bladder control. The study showed that fewer than half the women had sought help for the problem and that younger women were less likely to be satisfied with the help available for this problem. Strategies for continence promotion, including opportunistic raising of the issue at the time of cervical screening and pregnancy care are suggested, so that the health and social outcomes of untreated chronic incontinence in women might be improved.