Dysregulation of dopamine signaling in the dorsal striatum inhibits feeding

Dopamine signaling is an important component of many goal-directed behaviors, such as feeding. Acute disruption of dopamine signaling using pharmacological agents tends to inhibit normal feeding behaviors in rodents. Likewise, genetically engineered dopamine-deficient (DD) mice are unable to initiate sufficient feeding and will starve by approximately 3 weeks of age if untreated. Adequate feeding by DD mice can be achieved by daily administration of L-3,4-dihydroxyphenylalanine (L-dopa), a precursor of dopamine, which can be taken up by dopaminergic neurons, converted to dopamine, and released in a regulated manner. In contrast, adequate feeding cannot be restored with apomorphine (APO), a mixed agonist that activates D1 and D2 receptors. Viral restoration of dopamine production in neurons that project to the dorsal striatum also restores feeding in DD mice. Administration of amphetamine (AMPH) or nomifensine (NOM), drugs which increase synaptic dopamine concentration, inhibits food intake in virally rescued DD mice (vrDD) as in control animals. These results indicate that the dysregulation of dopamine signaling in the dorsal striatum is sufficient to induce hypophagia and suggest that regulated release of dopamine in that brain region is essential for normal feeding and, probably, many other goal-directed behaviors.     

Locus of control, life events and treatment outcome in alcohol dependent patients

We investigated the relationship of locus of control and life events to outcome of treatment at 6 months in 67 patients with alcohol dependence. Outcome was less favourable in patients with pre-treatment scores indicating external locus of control than in those with internal locus of control. Furthermore, patients with relapse in the follow-up period experienced more independent life events with moderate to severe objective negative impact than those with more favourable outcome. These results suggest that locus of control may be of clinical use in formulating treatment and prognosis, and that the occurrence of life events may influence outcome. The results are discussed in relation to strategies for treatment and prevention of relapse.     

神经外科抗利尿激素分泌不当综合征的诊断与治疗

[目的]探讨神经外科抗利尿激素分泌不当综合征(SIADH)的可能发生机制、诊断思路、鉴别诊断及抢救治疗方法。[方法]回顾分析24例SIADH的临床诊治过程并进行文献复习。[结论]SIADH的特点为：①低血钠(血钠≤130mmol／L);②低血渗(血浆渗透压≤270mmol／L);③高尿钠(≥80mmol／L);④中心静脉压正常或稍升高;⑤肾功能正常。[结论]在神经外科低钠血症的诊治过程中,在经过补充钠盐后仍有低钠血症者,应考虑SIADH存在的可能,需进一步明确诊断,SIADH与脑性盐耗综合征的鉴别非常重要。     

Mutations and polymorphisms of the skeletal muscle α‐actin gene (ACTA1)

The ACTA1 gene encodes skeletal muscle α‐actin, which is the predominant actin isoform in the sarcomeric thin filaments of adult skeletal muscle, and essential, along with myosin, for muscle contraction. ACTA1 disease‐causing mutations were first described in 1999, when a total of 15 mutations were known. In this article we describe 177 different disease‐causing ACTA1 mutations, including 85 that have not been described before. ACTA1 mutations result in five overlapping congenital myopathies: nemaline myopathy; intranuclear rod myopathy; actin filament aggregate myopathy; congenital fiber type disproportion; and myopathy with core‐like areas. Mixtures of these histopathological phenotypes may be seen in a single biopsy from one patient. Irrespective of the histopathology, the disease is frequently clinically severe, with many patients dying within the first year of life. Most mutations are dominant and most patients have de novo mutations not present in the peripheral blood DNA of either parent. Only 10% of mutations are recessive and they are genetic or functional null mutations. To aid molecular diagnosis and establishing genotype–phenotype correlations, we have developed a locus‐specific database for ACTA1 variations ( http://waimr.uwa.edu.au ). Hum Mutat 30:1–11, 2009. © 2009 Wiley‐Liss, Inc.     

(−)Epigallocatechin-3-gallate inhibits the spontaneous firing of rat locus coeruleus neuron

(−)Epigallocatechin-3-gallate (EGCG), a tea catechin, has been known to cause many biological actions, such as anxiolytic and hypotensive effects in behavioral studies. However, to date, few reports investigate its neuronal modulation. In this study, intracellular recording was used to test the neuronal modulation of different catechins on locus coeruleus (LC) neuron, which has been demonstrated to be affected by cardiovascular function regulation and stressful events. Several catechins (1–1000 μM) were tested, including: (−)catechin (C), (−)catechingallate (CG), (−)epicatechin (EC), (−)epicatechin-3-gallate (ECG), (−)epigallocatechin (EGC) and EGCG. The results showed that catechins EC, ECG, EGC and EGCG could inhibit the spontaneous firing of the LC neurons; furthermore, these catechins show potency and efficacy in the order of EGCG > ECG > EC ≈ EGC. Among the tested catechins, EGCG was the most potent in inhibiting LC's spontaneous firing with IC₅₀ of 20.5 μM. This caused us to further examine the EGCG's desensitization and tolerance properties. When continuously administering EGCG at 1–300 μM for 20 min, no acute desensitization appeared. However, repeated applications of 300 μM EGCG at 5 min each time showed different results. The second and third applications induced less responses compared to that of the first application, suggesting a development of tolerance towards EGCG in inhibiting LC neuronal activity. Our data suggest that EGCG can inhibit LC neuron's spontaneous firing in a dose-dependent manner, with developed tolerance only when high concentration of EGCG is repeatedly applied.     

参松养心胶囊联合慢心律片治疗室性早搏的疗效观察

【目的】观察参松养心胶囊联合慢心律片治疗室性早搏的临床疗效。【方法】将103例室性早搏患者随机分为三组：对照组35例，口服慢心律片150mg，每日3次；单药组33例，口服参松养心胶囊4粒，每日3次；两药联用组35例，同时服用慢心律片和参松养心胶囊，剂量同前，用药4周后观察心电图及24h动态心电图、临床症状及肝肾功能、血脂、血糖等指标的变化。【结果】两药联用组、单药组、对照组控制室性早搏的总有效率分别为91．4％，72．7％和68．6％；症状改善率分别为94．3％，75．8％和71．4％。两药联用组控制室早的总有效率及症状改善率均优于单药组及对照组（P〈0．05），单药组与对照组控制室早的总有效率及症状改善率均差异无显著性（P〉0．05）。【结论】参松养心胶囊联合慢心律片治疗室性早搏疗效优于两药单独使用。     

Revealing the human mutome

Chen JM, Férec C, Cooper DN. Revealing the human mutome. The number of known mutations in human nuclear genes, underlying or associated with human inherited disease, has now exceeded 100,000 in more than 3700 different genes (Human Gene Mutation Database). However, for a variety of reasons, this figure is likely to represent only a small proportion of the clinically relevant genetic variants that remain to be identified in the human genome (the ‘mutome’). With the advent of next‐generation sequencing, we are currently witnessing a revolution in medical genetics. In particular, whole‐genome sequencing (WGS) has the potential to identify all disease‐causing or disease‐associated DNA variants in a given individual. Here, we use examples of recent advances in our understanding of mutational/pathogenic mechanisms to guide our thinking about possible locations outwith gene‐coding sequences for those disease‐causing or disease‐associated variants that are likely so often to have been overlooked because of the inadequacy of current mutation screening protocols. Such considerations are important not only for improving mutation‐screening strategies but also for enhancing the interpretation of findings derived from genome‐wide association studies, whole‐exome sequencing and WGS. An improved understanding of the human mutome will not only lead to the development of improved diagnostic testing procedures but should also improve our understanding of human genome biology.     

Studies on the hippocampal formation: From basic development to clinical applications: Studies on schizophrenia

The hippocampal formation plays a critical role in cognitive function. The developmental events that shape the hippocampal formation are continuing to be elucidated and their implications for brain function are emerging as well as applying those advances to interventions that have important possibilities for the treatment of brain dysfunction. The story told in this chapter is about the use of the in oculo transplant method to illuminate intrinsic and extrinsic features that underlie the development of the dentate gyrus and adjacent hippocampus and the role of one molecule in the hippocampus and schizophrenia. Schizophrenia, originally conceptualized as a dysfunction in dopaminergic neurotransmission, is now known to involve multiple neuronal systems. Dysfunction of hippocampal neurons is emerging as one of its signature pathological features. Basic insights into the development and function of hippocampal interneurons form the basis of a new treatment initiative for this illness. Evidence for the role of the alpha 7-nicotinic acetylcholine receptor in the development and function of these neurons in rodents has led to human trials of nicotinic agonists for cognitive dysfunction in schizophrenia and the possibility of improving hippocampal development in children at risk for schizophrenia by perinatal supplementation with choline, which can act as an alpha 7-nicotinic acetylcholine receptor agonist.