Relative predictive value of intraventricular dysynchrony in determining long-term outcome in patients with known or suspected coronary disease

Improvement of intra-ventricular dysynchrony (IVD) in pts undergoing bi-ventricular pacing is associated with clinical improvementbut little isknownabout the relationship between IVD and prognosis.We sought whether IVD influences long-term outcome in pts with known or suspected coronary disease (CAD). Tissue Doppler imaging was performed in 184 pts (aged 61±10 years, 67% male) prior to dobutamine echo. From velocity curves the interval between QRS onset and max systolic velocity (Ts) was measured in basal septal, lateral, inferior and anterior segments. The maximal difference in Ts between segments (TsMax) was used as a measure of IVD. The standard deviation (TsSD) between all segments and the septal-lateral difference (TsSL) were also calculated. Pts were followed up for a median interval of 5 years and a Cox model used for survival analysis. The medianwall motion index (WMI) was 1.3 (IQR 1.0–1.8) at rest and 1.4 (IQR 1.3–1.9) at stress. The table shows IVD parameters. Forty-one deaths occurred during follow-up. Pts who died during follow-up, compared to survivors, showed greater IVD. WMI at rest (p = 0.03) and peak stress (p = 0.02), TsSD (p = 0.06), TsSL (p = 0.02) and TsMax (p = 0.05) but not QRS width were univariate predictors of mortality. TsSL was the only independent predictor of death (p = 0.01). Therefore, IVD is common in pts with known or suspected CAD. Pts with more IVD have reduced long-term survival, independent of WMI.

The Scientific Basis for High-Intensity Interval Training: Optimising Training Programmes and Maximising Performance in Highly Trained Endurance Athletes

While the physiological adaptations that occur following endurance training in previously sedentary and recreationally active individuals are relatively well understood, the adaptations to training in already highly trained endurance athletes remain unclear. While significant improvements in endurance performance and corresponding physiological markers are evident following submaximal endurance training in sedentary and recreationally active groups, an additional increase in submaximal training (i.e. volume) in highly trained individuals does not appear to further enhance either endurance performance or associated physiological variables [e.g. peak oxygen uptake (V-dot O2peak), oxidative enzyme activity]. It seems that, for athletes who are already trained, improvements in endurance performance can be achieved only through high-intensity interval training (HIT). The limited research which has examined changes in muscle enzyme activity in highly trained athletes, following HIT, has revealed no change in oxidative or glycolytic enzyme activity, despite significant improvements in endurance performance (p < 0.05). Instead, an increase in skeletal muscle buffering capacity may be one mechanism responsible for an improvement in endurance performance. Changes in plasma volume, stroke volume, as well as muscle cation pumps, myoglobin, capillary density and fibre type characteristics have yet to be investigated in response to HIT with the highly trained athlete. Information relating to HIT programme optimisation in endurance athletes is also very sparse. Preliminary work using the velocity at which V-dot O2max is achieved (Vmax) as the interval intensity, and fractions (50 to 75%) of the time to exhaustion at Vmax (Tmax) as the interval duration has been successful in eliciting improvements in performance in long-distance runners. However, Vmax and Tmax have not been used with cyclists. Instead, HIT programme optimisation research in cyclists has revealed that repeated supramaximal sprinting may be equally effective as more traditional HIT programmes for eliciting improvements in endurance performance. Further examination of the biochemical and physiological adaptations which accompany different HIT programmes, as well as investigation into the optimal HIT programme for eliciting performance enhancements in highly trained athletes is required.

Long-term potentiation of synaptic transmission in the avian hippocampus

The avian hippocampus plays a pivotal role in memory required for spatial navigation and food storing. Here we have examined synaptic transmission and plasticity within the hippocampal formation of the domestic chicken using an in vitro slice preparation. With the use of sharp microelectrodes we have shown that excitatory synaptic inputs in this structure are glutamatergic and activate both NMDA-and AMPA-type receptors on the postsynaptic membrane. In response to tetanic stimulation, the EPSP displayed a robust long-term potentiation (LTP) lasting >1 hr. This LTP was unaffected by blockade of NMDA receptors or chelation of postsynaptic calcium. Application of forskolin increased the EPSP and reduced paired-pulse facilitation: (PPF), indicating an increase in release probability. In contrast, LTP was not associated with a change in the PPF ratio. Induction of LTP did not occlude the effects of forskolin. Thus, in contrast to NMDA receptor-independent LTP in the mammalian brain, LTP in the chicken hippocampus is not attributable to a change in the probability of transmitter release and does not require activation of adenylyl cyclase, These findings indicate that a novel form of synaptic plasticity might underlie learning in the avian hippocampus.

Vaccine-induced Th1-type responses are dominant over Th2-type responses in the short term whereas pre-existing Th2 responses are dominant in the longer term

The effect of adjuvant on induction of human papillomavirus type 16 E7 protein-specific cytotoxic T lymphocytes (CTL) and immunoglobulin G (IgG)(2a) antibody was studied in C57BL/6 J mice immunized with various adjuvants and E7 protein. Quil-A adjuvant, but not complete Freund's adjuvant (CFA) or Algammulin, induced a T-helper 1 (Th1)-type response to E7, which was characterized by CTL activity against a tumour cell line transfected with E7 protein and by E7-specific IgG(2a). All tested adjuvants elicited comparable levels of E7-specific IgG(1). The longest duration and greatest magnitude of CTL response was seen following two immunizations with the highest dose of E7 and Quil-A. Simultaneous immunization with a Th1 and a T helper 2 (Th2)-promoting adjuvant gave a Th1-type response. However, E7 and Quil-A were unable to induce a Th1-type response (as measured by the inability to generate anti-E7 IgG(2a) antibody) in animals with a pre-existing Th2-type response to E7. These results suggest that saponin adjuvants may be suitable for immunotherapy in humans where a Th1-type response is sought, provided that there is no pre existing Th2-type response to the antigen.

Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala

Fear conditioning is a paradigm that has been used as a model for emotional learning in animals'. The cellular correlate of fear conditioning is thought to be associative N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity within the amygdala(1-3). Here we show that glutamatergic synaptic transmission to inhibitory interneurons in the basolateral amygdala is mediated solely by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast to AMPA receptors at inputs to pyramidal neurons, these receptors have an inwardly rectifying current-voltage relationship, indicative of a high permeability to calcium(4 5), Tetanic stimulation of inputs to interneurons caused an immediate and sustained increase in the efficacy of these synapses. This potentiation required a rise in postsynaptic calcium, but was independent of NMDA receptor activation. The potentiation of excitatory inputs to interneurons was reflected as an increase in the amplitude of the GABAA-mediated inhibitory synaptic current in pyramidal neurons. These results demonstrate that excitatory synapses onto interneurons within a fear conditioning circuit show NMDA-receptor independent long-term potentiation. This plasticity might underlie the increased synchronization of activity between neurons in the basolateral amygdala after fear conditioning(6).

Interval breast cancers in an Australian mammographic screening program

Objective: To determine the incidence of interval cancers which occurred in the first 12 months after mammographic screening at a mammographic screening service. Design: Retrospective analysis of data obtained by crossmatching the screening Service and the New South Wales Central Cancer Registry databases. Setting: The Central & Eastern Sydney Service of BreastScreen NSW. Participants: Women aged 40-69 years at first screen, who attended for their first or second screen between 1 March 1988 and 31 December 1992. Main outcome measures: Interval-cancer rates per 10 000 screens and as a proportion of the underlying incidence of breast cancer (as estimated by the underlying rate in the total NSW population). Results: The 12-month interval-cancer incidence per 10 000 screens was 4.17 for the 40-49 years age group (95% confidence interval [CI], 1.35-9.73) and 4.64 for the 50-69 years age group (95% CI, 2.47-7.94). Proportional incidence rates were 30.1% for the 40-49 years age group (95% CI, 9.8-70.3) and 22% for the 50-69 years age group (95% CI, 11.7-37.7). There was no significant difference between the proportional incidence rate for the 50-69 years age group for the Central & Eastern Sydney Service and those of major successful overseas screening trials. Conclusion: Screening quality was acceptable and should result in a significant mortality reduction in the screened population. Given the small number of cancers involved, comparison of interval-cancer statistics of mammographic screening programs with trials requires age-specific or age-adjusted data, and consideration of confidence intervals of both program and trial data.

Presynaptic long-term depression at a central glutamatergic synapse: a role for CaMKII

CaMKII is a calcium-activated kinase that is abundant in neurons and has been strongly implicated in memory and learning. Here we show that low-frequency stimulation of glutamatergic afferents in hippocampal slices from juvenile domestic chicks results in long-term depression of synaptic transmission. This reduction does not require activation of NMDA or metabotropic glutamate receptors and does not require a rise in postsynaptic calcium. However, buffering presynaptic calcium prevents the reduction of the excitatory postsynaptic potential or current that is induced by low-frequency stimulation. in addition, application of the calmodulin antagonist calmidazolium, or the specific CaMKII antagonist KN-93, completely blocks long-term depression. These findings demonstrate a newsy discovered form of long-term synaptic depression in the avian hippocampus.

Long-term risk of first recurrent stroke in the Perth Community Stroke Study

Background and Purpose-Few community-based studies have examined the long-term risk of recurrent stroke after an acute first-ever stroke. This study aimed to determine the absolute and relative risks of a first recurrent stroke over the first 5 years after a first-ever stroke and the predictors of such recurrence in a population-based series of people with first-ever stroke in Perth, Western Australia. Methods-Between February 1989 and August 1990, all people with a suspected acute stroke or transient ischemic attack of the brain who were resident in a geographically defined region of Perth, Western Australia, with a population of 138 708 people, were registered prospectively and assessed according to standardized diagnostic criteria. Patients were followed up prospectively at 4 months, 12 months, and 5 years after the index event. Results-Three hundred seventy patients with a first-ever stroke were registered, of whom 351 survived >2 days. Data were available for 98% of the cohort at 5 years, by which time 199 patients (58%) had died and 52 (15%) had experienced a recurrent stroke, 12 (23%) of which were fatal within 28 days. The 5-year cumulative risk of first recurrent stroke was 22.5% (95% confidence limits [CL], 16.8%, 28.1%). The risk of recurrent stroke was greatest in the first 6 months after stroke, at 8.8% (95% CL, 5.4%, 12.1%). After adjustment for age and sex, the prognostic factors for recurrent stroke were advanced, but not extreme, age (75 to 84 years) (hazard ratio [HR], 2.6; 95% CL, 1.1, 6.2), hemorrhagic index stroke (HR, 2.1; 95% CL, 0.98, 4.4), and diabetes mellitus (HR, 2.1; 95% CL, 0.95, 4.4). Conclusions-Approximately 1 in 6 survivors (15%) of a first-ever stroke experience a recurrent stroke over the next 5 years, of which 25% are fatal within 28 days. The pathological subtype of the recurrent stroke is the same as that of the index stroke in 88% of cases. The predictors of first recurrent stroke in this study were advanced age, hemorrhagic index stroke, and diabetes mellitus, but numbers of recurrent events were modest. Because the risk of recurrent stroke is highest (8.8%) in the first 6 months after stroke, strategies for secondary prevention should be initiated as soon as possible after the index event.

Characteristics of long-term cannabis users in Sydney, Australia

Two hundred long-term cannabis users (58% male) were interviewed on their characteristics and experience of use. Respondents had been regularly using cannabis for an average of 11 years and more than half used daily (56%). The most common route of administration was in a waterpipe, and nearly all (93%) smoked the flowering heads ot the plant. One in 5 (21%) had a cannabis-related conviction. The benefits of use were perceived to be its relaxing, mood-enhancing effects, and its ability to alter consciousness. The most commonly cited negative aspects of use were cost, negative psychological effects and legal status. Polydrug use was common, with alcohol and tobacco almost universally used on a regular basis. More than half the drinkers in the sample were consuming alcohol at hazardous or harmful levels.

Coronary events and exposure to environmental tobacco smoke: a case-control study from Australia and New Zealand

Objectives-To estimate the relative risk of coronary heart disease (CHD) associated with exposure to environmental tobacco smoke (ETS). Design-Population-based case-control study. Subjects-Cases were 953 people identified in a population register of coronary events, and controls were 3189 participants in independent community-based risk factor prevalence surveys from the same study populations. Setting-Newcastle, Australia and Auckland, New Zealand. Main outcome measures-Acute myocardial infarction or coronary death. Results-After adjusting for the effects of age, education, history of heart disease, and body mass index, women had a statistically significant increased risk of a coronary event associated with exposure to ETS (relative risk (RR) = 1.99; 95% confidence interval (CI)= 1.40-2.81). There was little statistical evidence of increased risk found in men (RR = 1.02, 95% CI = 0.81-1.28). Conclusion-Our study found evidence for the adverse effects of exposure to ETS on risk of coronary heart disease among women, especially at home. For men the issue is unclear according to the data from our study. Additional studies with detailed information on possible confounders and adequate statistical power are needed. Most importantly, they should use methods for measuring exposure to ETS that are sufficiently accurate to permit the investigation of dose-response relationships.