恩替卡韦与拉米夫定治疗HBeAg阴性慢性乙型肝炎的对照研究

Ⅱ期临床试验已经证实恩替卡韦是一种治疗HBeAg阴性慢性乙型肝炎有效和可选择的抗病毒药物。采用双盲法将648例未曾接受过核苷类药物治疗的HBeAg阴性慢性乙型肝炎随机分配进入恩替卡韦（0．5mg／d）治疗组或拉米夫定（100mg／d）治疗组，疗程至少52wk。     

Anterior, Total, and Two-Stage Corpus Callosum Section: Differential and Incremental Seizure Responses

Summary: Published reports suggest that control of generalized seizures is improved by callosotomy but do not necessarily indicate that completion of failed anterior callosotomy is beneficial. We studied 42 patients after anterior callosotomy and 22 after total callosotomy, of whom 14 underwent a two-stage procedure. Cure or marked diminution of seizures was most dramatic for atonic and tonic-clonic seizures after anterior callosotomy (100 and 83%), and for tonic-clonic and tonic seizures after total callosotomy (68 and 57%). For the 14 patients who failed to improve after anterior section and then underwent total section, incremental responses were noted for all seizure types, with cure or marked diminution of partial seizures in 2 of 14 patients, of tonic-clonic seizures in 6 of 10, of tonic seizures in 2 of 4, of atonic seizures in 2 of 5, and of myoclonic seizures in 1 of 1. More than two seizure types, verbal IQ <80, and diffuse ictal EEG patterns were significantly more common in the anterior callosotomy failures. Total callosotomy can be of benefit when anterior callosotomy fails, especially for persistent tonic- clonic and tonic seizures, and will most often be necessary in patients with diffuse cerebral abnormalities.     

Ictal EEG Changes with Corpus Callosum Section

Summary: Corpus collosum section diminishes but does not completely abolish secondary bilaterally synchronous interictal EEG discharges, yet often causes cessation of generalized seizures. The effects of corpus callosum section on ictal EEG patterns have not been described. We contrasted ictal EEG patterns before and after anterior callosotomy in 18 patients and before and after total callosotomy in 10 patients. Bilaterally synchronous seizure onset was disrupted in 5 of 11 anterior section patients and 5 of 5 total section patients. Seven of 18 anterior section patients and 5 of 10 total section patients had more localized seizure onset after the procedure; localization to the frontal lobe was observed after anterior or total section, but only total section patients had newly demonstrated posterior locations of seizure onset. These data suggest that the mechanisms by which bilaterally synchronous interictal and ictal discharges are generated differ. Although brainstem or diencephalic structures may contribute to formation of interictal bilateral synchrony, the corpus callosum may be the only pathway used in producing apparent bilateral synchronous seizure onset in patients with secondarily generalized seizures.     

Presenilins and APP in neuritic and synaptic plasticity: implications for the pathogenesis of Alzheimer's disease

A key neuropathological hallmark of Alzheimer’s disease (AD) is the loss of neocortical and hippocampal synapses, which is closely correlated with the degree of memory impairment. Mutations in the genes encoding the amyloid precursor protein (APP) and presenilins are responsible from some cases of early-onset autosomal-dominant AD. This article reviews the current understanding of how alterations in the cellular functions of APP and presenilins may result in the dysfunction and degeneration of synapses in AD. APP mutations result in increased production/aggregation of amyloid β-peptide (Aβ), which induces oxidative stress, resulting in the impairment of synaptic membrane ion, glutamate, and glucose transporters. APP mutations may also compromise the production and/or function of secreted forms of APP that are believed to play important roles in learning and memory processes. Presenilin (PS1) mutations result in a major defect in endoplasmic reticulum (ER) calcium regulation, which may perturb synaptic function in ways that lead to impaired synaptic plasticity and neuronal degeneration. Studies in transgenic mice that express APP and PS1 mutations have provided evidence that the mutations result in altered cellular calcium homeostasis and synaptic plasticity, and impaired learning and memory. This article provides a brief review of the pathophysiological interactions of APP and presenilins with synaptic proteins, and discusses how AD-linked mutations in APP and PS1 may disrupt synaptic processes that contribute to memory formation.     

Numb modifies neuronal vulnerability to amyloid beta-peptide in an isoform-specific manner by a mechanism involving altered calcium homeostasis: implications for neuronal death in Alzheimer's disease

Increased production of neurotoxic forms of amyloid beta-peptide (Abeta) and abnormalities in neuronal calcium homeostasis play central roles in the pathogenesis of Alzheimer's disease (AD). Notch, a membrane receptor that controls cell-fate decisions during development of the nervous system, has been linked to AD because it is a substrate for the gamma-secretase enzyme activity that involves the presenilin-1 (PS1) protein in which mutations cause early-onset inherited AD. The actions of Notch can be antagonized by Numb, an evolutionarily conserved protein that exists in four isoforms that differ in two functional domains: a phosphotyrosine-binding (PTB) domain and a proline-rich region (PRR). We now report that Numb isoforms containing a short PTB domain increase the vulnerability of PC12 cells to death induced by Abeta1-42 and by 4-hydroxynonenal, a lipid peroxidation product previously shown to mediate neurotoxic effects of Abeta. Dysregulation of cellular calcium homeostasis occurs in cells expressing Numb isoforms with a short PTB domain, and the death-promoting effect of Numb is abolished by pharmacological inhibition of calcium release. The levels of Numb are increased in cultured primary hippocampal neurons exposed to Abeta, suggesting a role for endogenous Numb in the neuronal death process. Furthermore, higher levels of Numb were detected in the cortex of mice expressing mutant amyloid precursor protein (APP) relative to age-matched wild-type mice. Our data identify a novel isoform-specific effect of Numb on neuronal life and death cell fate decisions potentially relevant to the pathogenesis of AD. Our findings also suggest that the effects of Numb on cell fate decisions, both during development of the nervous system and in neurodegenertive disorders, are mediated by changes in cellular calcium homeostasis.     

Concurrent LOH at multiple loci in human malignant mesothelioma with preferential loss of NF2 gene region

Human malignant mesothelioma (MM) is a highly aggressive neoplasm related to occupational asbestos exposure and characterised by a long latency period between the exposure and onset of disease. Previous studies indicate that losses at different genomic regions are present in MM. We examined allele loss at three known tumour suppressor gene regions (22q/NF2 gene, 9p/p16 gene, and 3p/FHIT gene) and at two other frequently deleted areas (14q and 6q) in MM. Loss of heterozygosity (LOH) was investigated in cell cultures and primary tumours with several highly polymorphic markers for each site. To study if LOH of the NF2 gene is a consistent feature in MM, we performed a more detailed analysis of chromosome 22q that included a NF2 marker (NF2CA3). We observed a high frequency of LOH occurring simultaneously at multiple loci. In particular, 100% of the cultured MM cells exhibited LOH at the NF2 gene region. From the other chromosomal sites analysed, recurrent allele loss was detected at 9p (5/7; 71%), 3p (4/7; 57%), 14q (3/7; 43%), and 6q (3/7; 43%). Of the 32 tumours, even those trimmed to exclude normal tissue, few showed LOH, suggesting consielment by normal cells within MM tumours, whereas tumour cells in primary cultures showed LOH already in passages 1-2. In conclusion, our present LOH data indicate that MM cells exhibit allele losses at multiple tumour suppressor gene sites concurrently, involving NF2 gene preferentially. This supports the view that the accumulation of multiple genetic hits is characteristic to malignant transformation of MM cells.