Defective slow inactivation of sodium channels contributes to familial periodic paralysis

OBJECTIVE: To evaluate the effects of missense mutations within the skeletal muscle sodium (Na) channel on slow inactivation (SI) in periodic paralysis and related myotonic disorders. BACKGROUND: Na channel mutations in hyperkalemic periodic paralysis and the nondystrophic myotonias interfere with the normally rapid inactivation of muscle Na currents following an action potential. This defect causes persistent inward Na currents that produce muscle depolarization, myotonia, or onset of weakness. Distinct from fast inactivation is the process called SI, which limits availability of Na channels on a time scale of seconds to minutes, thereby influencing muscle excitability. METHODS: Human Na channel cDNAs containing mutations associated with paralytic and nonparalytic phenotypes were transiently expressed in human embryonic kidney cells for whole-cell Na current recording. Extent of SI over a range of conditioning voltages (-120 to +20 mV) was defined as the fraction of Na current that failed to recover within 20 ms at - 100 mV. The time course of entry to SI at -30 mV was measured using a conditioning pulse duration of 20 ms to 60 seconds. Recovery from SI at -100 mV was assessed over 20 ms to 10 seconds. RESULTS: The two most common hyperkalemic periodic paralysis (HyperPP) mutations responsible for episodic attacks of weakness or paralysis, T704M and M1592V, showed clearly impaired SI, as we and others have observed previously for the rat homologs of these mutations. In addition, a new paralysis-associated mutant, I693T, with cold-induced weakness, exhibited a comparable defect in SI. However, SI remained intact for both the HyperPP/paramyotonia congenita (PMC) mutant, A1156T, and the nonparalytic potassium-aggravated myotonia (PAM) mutant, V1589M. CONCLUSIONS: SI is defective in a subset of mutant Na channels associated with episodic weakness (HyperPP or PMC) but remains intact for mutants studied so far that cause myotonia without weakness (PAM).     

Clinical governance. Thin on the ground

Clinical governance is being led by two people, usually a GP and a nurse, in most of the PCGs that responded to the survey. A fifth of the leads for clinical governance had no experience of working on quality issues. Nearly a third of respondents felt that their health authority had provided poor support or none at all. Only 10 PCGs had identified a clinical governance budget. No PCG was working with a finance manager to develop clinical governance and only five were working with an information manager.     

Neuropsychological functioning and sleep patterns in the elderly.

OBJECTIVE: To discover whether reported sleep-wake disturbances in the elderly (more frequent nocturnal awakenings, earlier waking and more day time naps) are associated with neuropsychological dysfunction. DESIGN AND SETTING: A sample of 124 residents of a retirement village complex were interviewed about their sleep patterns and given neuropsychological assessments. Reported sleep-wake difficulties were combined to form two variables, "night sleep" and "day sleep". Additional sleep variables analysed were reported sleep duration and time of wakening. Principal components analysis of the neuropsychological test scores yielded four factors: "general ability", "memory", "motor", and "cerebral efficiency". MAIN OUTCOME MEASURES: A correlation analysis was performed for sleep variables, neuropsychological factors and age, mood scale and scores on indices of participation in physical and passive activities. RESULTS: There was no correlation between "night sleep" and the factor scores derived from the neuropsychological tests. "Day sleep" was correlated with "cerebral efficiency" only. Age was correlated with the "memory" and "motor" factors, the latter also being associated with participation in physical activities. CONCLUSION: Night sleep problems are not associated with neuropsychological deficits in a non-clinic population.     

Foetal cystic abdominal masses

Foetal abdominal cysts are frequently found on routine antenatal ultrasound. Various sonographic features might help in their differential diagnosis. However, a definitive diagnosis is often not made until postnatal life, and detection of an intra‐abdominal cyst antenatally rarely alters obstetric management. A review of possible causes of a foetal abdominal cyst is presented.     

Ifosfamide, carboplatin, and etoposide with midcycle vincristine versus standard chemotherapy in patients with small-cell lung cancer and good performance status: clinical and quality-of-life results of the British Medical Research Council multicenter randomized LU21 trial.

PURPOSE: Ifosfamide, carboplatin, etoposide, and vincristine, alone and in combination, are highly active against small-cell lung cancer (SCLC). This trial was designed to investigate whether survival could be improved by a regimen of all four drugs (ICE-V) compared with standard chemotherapy in patients with SCLC and good performance status, and to assess the patients' quality of life (QL). PATIENTS AND METHODS: Patients were randomly assigned to receive six cycles of either ICE-V at 4-week intervals without dose reduction or standard chemotherapy administered according to local practice. The recommended standard control regimens were cyclophosphamide, doxorubicin, and etoposide; and cisplatin and etoposide. RESULTS: A total of 402 patients were randomly assigned, and 350 (87%) patients have died. Overall survival was longer in the ICE-V group (hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P = .0049), median survival was 15.6 months in the ICE-V group and 11.6 months in the control group, and 2-year survival rates were 20% and 11%, respectively. There was no evidence that the relative survival benefit for ICE-V was less in extensive-stage than in limited-stage patients. An increased rate of septicemia was reported in the ICE-V group (15% v 7% in the control group), but this did not result in an increase in reported treatment-related deaths (four patients [2%] in both groups). The findings on QL were broadly similar in both groups, with some benefit in favor of ICE-V. CONCLUSION: Compared with standard chemotherapy, the ICE-V regimen improves overall survival without QL penalties, despite an increased but manageable level of toxicity.     

卒中医疗体系之急诊医疗服务的实施策略:美国心脏协会/美国卒中协会急诊医疗服务体系专家组和卒中委员会的政策声明

尽管卒中的预防、诊断、治疗和康复已取得一些进展,但卒中在美国仍然是第三大死亡原因和长期残疾的主要原因.每年约有70万人新发或复发卒中[1].在过去10年里,急性卒中诊治的一些进展,包括纤溶和其他短期疗法的引入,突出显示了急诊医疗服务(emergency medical services,EMS)机构和急诊医疗服务体系(emergency medical services systems,EMSS)在优化卒中医疗中的关键作用[2-7].     

Voice Hearing in Borderline Personality Disorder Across Perceptual,Subjective, and Neural Dimensions

BackgroundAuditory verbal hallucinations (AVH) commonly occur in the context of borderline personality disorder (BPD) yet remain poorly understood. AVH are often perceived by patients with BPD as originating from inside the head and hence viewed clinically as “pseudohallucinations,” but they nevertheless have a detrimental impact on well-being.MethodsThe current study characterized perceptual, subjective, and neural expressions of AVH by using an auditory detection task, experience sampling and questionnaires, and functional neuroimaging, respectively.ResultsPerceptually, reported AVH correlated with a bias for reporting the presence of a voice in white noise. Subjectively, questionnaire measures indicated that AVH were significantly distressing and persecutory. In addition, AVH intensity, but not perceived origin (i.e., inside vs outside the head), was associated with greater concurrent anxiety. Neurally, fMRI of BPD participants demonstrated that, relative to imagining or listening to voices, periods of reported AVH induced greater blood oxygenation level–dependent activity in anterior cingulate and bilateral temporal cortices (regional substrates for language processing). AVH symptom severity was associated with weaker functional connectivity between anterior cingulate and bilateral insular cortices.ConclusionIn summary, our results indicate that AVH in participants with BPD are (1) underpinned by aberrant perceptual-cognitive mechanisms for signal detection, (2) experienced subjectively as persecutory and distressing, and (3) associated with distinct patterns of neural activity that inform proximal mechanistic understanding. Our findings are like analogous observations in patients with schizophrenia and validate the clinical significance of the AVH experience in BPD, often dismissed as “pseudohallucinations.” These highlight a need to reconsider this experience as a treatment priority.     

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