Autonomic Regulation of Voltage-Gated Cardiac Ion Channels

Altering voltage-gated ion channel currents, by changing channel number or voltage-dependent kinetics, regulates the propagation of action potentials along the plasma membrane of individual cells and from one cell to its neighbors. Functional increases in the number of cardiac sodium channels (Na_V1.5) at the myocardial sarcolemma are accomplished by the regulation of caveolae by β adrenergically stimulated G-proteins. We demonstrate that Na_V1.5, Ca_V1.2a, and K_V1.5 channels specifically localize to isolated caveolar membranes, and to punctate regions of the sarcolemma labeled with caveolin-3. In addition, we show that Na_V1.5, Ca_V1.2a, and K_V1.5 channel antibodies label the same subpopulation of isolated caveolae. Plasma membrane sheet assays demonstrate that Na_V1.5, Ca_V1.2a, and K_V1.5 cluster with caveolin-3. This may have interesting implications for the way in which adrenergic pathways alter the cardiac action potential morphology and the velocity of the excitatory wave.     

Ki67 LABELLING INDEX: AN INDEPENDENT PREDICTOR OF PROGRESSION IN PROSTATE CANCER TREATED BY RADICAL PROSTATECTOMY

The clinical course of prostate cancer is highly variable and cannot satisfactorily be predicted by histological criteria alone. Both tumour cell proliferation and neuroendocrine differentiation have been suggested as additional prognostic parameters, neuroendocrine differentiation being considered to enhance tumour cell proliferation. This study investigated the prognostic value of tumour cell proliferation [Ki67 labelling index (LI), MIB 1] and neuroendocrine differentiation and their relationship to each other. One hundred and thirty-seven paraffin-embedded radical prostatectomy specimens were examined. Neuroendocrine differentiation was found in 58 per cent of cases, but was not associated with pTN stage, Gleason score, Ki67 LI, or tumour progression. Ki67 LI was not significantly associated with pTN stage or with Gleason score. High grade ( P =0·0005), advanced local stage ( P =0·0004), positive lymph nodes ( P =0·02), and high Ki67 LI ( P =0·0203) were predictors of tumour progression if univariate analysis was performed, but Cox stepwise regression showed that only advanced local stage ( P =0·0025) and Ki67 LI ( P =0·0105) were independent predictors of tumour progression, the relative risk being 3·6 and 2·5, respectively. It is concluded that Ki67 is an important prognostic marker in prostate cancer with a potential for routine application.     

A new metric for quantifying performance impairment on the psychomotor vigilance test

We have developed a new psychomotor vigilance test (PVT) metric for quantifying the effects of sleep loss on performance impairment. The new metric quantifies performance impairment by estimating the probability density of response times (RTs) in a PVT session, and then considering deviations of the density relative to that of a baseline‐session density. Results from a controlled laboratory study involving 12 healthy adults subjected to 85 h of extended wakefulness, followed by 12 h of recovery sleep, revealed that the group performance variability based on the new metric remained relatively uniform throughout wakefulness. In contrast, the variability of PVT lapses, mean RT, median RT and (to a lesser extent) mean speed showed strong time‐of‐day effects, with the PVT lapse variability changing with time of day depending on the selected threshold. Our analysis suggests that the new metric captures more effectively the homeostatic and circadian process underlying sleep regulation than the other metrics, both directly in terms of larger effect sizes (4–61% larger) and indirectly through improved fits to the two‐process model (9–67% larger coefficient of determination). Although the trend of the mean speed results followed those of the new metric, we found that mean speed yields significantly smaller (～50%) intersubject performance variance than the other metrics. Based on these findings, and that the new metric considers performance changes based on the entire set of responses relative to a baseline, we conclude that it provides a number of potential advantages over the traditional PVT metrics.     

British Society for Haematology,slide session,annual scientific meeting,Glasgow, 2008

A morphology session is held each year at the Annual Scientific Meeting of the British Society of Haematology. Prior to the meeting this year, eight morphology cases were made available to BSH members as glass slides and also digitally as ‘virtual slides’. A panel of invited commentators who had no prior knowledge of the diagnosis discussed the eight cases. An initial limited history and blood count are given with representative images from the case material; this is followed by the discussants’ comments and suggested diagnosis. The actual clinical diagnosis is then given with other relevant information.     

Reports of alcohol‐related problems and alcohol dependence for demographic subgroups using interactive voice response versus telephone surveys: The 2005 US National Alcohol Survey

Introduction and Aims. Interactive voice response (IVR), a computer‐based interviewing technique, can be used within a computer‐assisted telephone interview (CATI) survey to increase privacy and the accuracy of reports of sensitive attitudes and behaviours. Previous research using the 2005 National Alcohol Survey indicated no overall significant differences between IVR and CATI responses to alcohol‐related problems and alcohol dependence. To determine if this result holds for demographic subgroups that could respond differently to modes of data collection, this study compares the prevalence rates of lifetime and last‐year alcohol‐related problems by gender, ethnicity, age and income subgroups obtained by IVR versus continuous CATI interviewing. Design and Methods. As part of the 2005 National Alcohol Survey, subsamples of English‐speaking respondents were randomly assigned to an IVR group that received an embedded IVR module on alcohol‐related problems (n = 450 lifetime drinkers) and a control group that were asked identical alcohol‐related problem items using continuous CATI (n = 432 lifetime drinkers). Results. Overall, there were few significant associations. Among lifetime drinkers, higher rates of legal problems were found for white and higher income respondents in the IVR group. For last‐year drinkers, a higher percentage of indicators of alcohol dependence was found for Hispanic respondents and women respondents in the CATI group. Discussion and Conclusion. Data on alcohol problems collected by CATI provide largely comparable results to those from an embedded IVR module. Thus, incorporation of IVR technology in a CATI interview does not appear strongly indicated even for several key subgroups.[Midanik LT, Greenfield TK. Reports of alcohol‐related problems and alcohol dependence for demographic subgroups using interactive voice response versus telephone surveys: The 2005 US National Alcohol Survey. Drug Alcohol Rev 2010]     

How does the pitch and pattern of a signal affect auditory arousal thresholds?

How arousal thresholds vary with different sounds is a critical issue for emergency awakenings, especially as sleepers are dying in fires despite having a working smoke alarm. Previous research shows that the current high-pitched (3000+ Hz) smoke alarm signal is significantly less effective than an alternative signal, the 520 Hz square wave, in all populations tested. However, as the number of sounds tested has been small further research is needed. Here we measured auditory arousal thresholds (AATs) across signals with a range of characteristics to determine the most effective waking signal. Thirty-nine young adults participated over three nights. In Part A, nine signals were presented in stage 4 sleep with ascending decibel levels. Signals were short beeps in the low- to mid-frequency range with different spectral complexities: square waves, pure tones, whoops and white noise. Part B manipulated temporal patterns, inserting silences of 0, 10 and 21 s after each 12 s of beeps. It was found that the low-frequency (400 and 520 Hz) square waves yielded significantly lower AATs than the alternatives. A trend was found across the three temporal manipulations, with a 10 s intervening silence showing some advantage. These findings support earlier research indicating that the best sound for awakening from deep sleep is a low-frequency square wave. It is argued that the signal with the lowest response threshold when awake may be the same as the most arousing signal when asleep, especially where the sleeper processes the signal as meaningful.     

Development of early postnatal peripheral nerve abnormalities in Trembler-J and PMP22 transgenic mice

Mutations in the gene for peripheral myelin protein 22 ( PMP22 ) are associated with peripheral neuropathy in mice and humans. Although PMP22 is strongly expressed in peripheral nerves and is localised largely to the myelin sheath, a dual role has been suggested as 2 differentially expressed promoters have been found. In this study we compared the initial stages of postnatal development in transgenic mouse models which have, in addition to the murine pmp22 gene, 7 (C22) and 4 (C61) copies of the human PMP22 gene and in homozygous and heterozygous Trembler-J ( Tr ^J ) mice, which have a point mutation in the pmp22 gene. The number of axons that were singly ensheathed by Schwann cells was the same in all groups indicating that PMP22 does not function in the initial ensheathment and separation of axons. At both P4 and P12 all mutants had an increased proportion of fibres that were incompletely surrounded by Schwann cell cytoplasm indicating that this step is disrupted in PMP22 mutants. C22 and homozygous Tr ^J animals could be distinguished by differences in the Schwann cell morphology at the initiation of myelination. In homozygous Tr ^J animals the Schwann cell cytoplasm had failed to make a full turn around the axon whereas in the C22 strain most fibres had formed a mesaxon. It is concluded that PMP22 functions in the initiation of myelination and probably involves the ensheathment of the axon by the Schwann cell, and the extension of this cell along the axon. Abnormalities may result from a failure of differentiation but more probably from defective interactions between the axon and the Schwann cell.