Defects in neurofibromatosis 2 protein function can arise at multiple levels

Neurofibromatosis 2 (NF2) is an inherited cancer syndrome resulting from mutations in the NF2 tumor suppressor gene. Analysis of NF2 mutations has revealed some general genotype-phenotype correlations. Severe disease has been associated with mutations that produce a premature termination while more mild disease has been associated with missense mutations. Here, we provide experimental proof for these genotype-phenotype correlations by demonstrating that nonsense mutations fail to produce stable merlin protein while missense mutations result in the generation of merlin proteins defective in negative growth regulation. This inability to suppress cell growth may result from defects in the function of merlin at several levels, including failure to form an intramolecular complex. Based on these findings, we propose a model for merlin growth suppression that provides a framework for analyzing NF2 patient mutations and merlin function.      

静息状态脑功能网络的研究及应用

目的:对静息状态网络的研究方法、初步的研究成果等作以介绍,并结合静息状态网络在阿尔茨海默病早期预警中的应用,介绍静息状态脑网络的应用。资料来源:应用计算机检索PubMed1980-01/2006-12与静息状态网络相关的文献,检索词“restingstate,functional connectivity”,并限定文献语言种类为“English”;同时计算机检索万方数据库1995-01/2006-12有关方面的文献,检索词为“静息,功能连接,阿尔茨海默病”,并限定语言种类为中文。资料选择:对资料进行初审,选取包括静息状态的相关文献,开始查找原文。纳入标准:①有关静息状态脑网络和功能连接的研究。②有关阿尔茨海默病的研究。排除标准:重复研究。资料提炼:共收集到53篇有关静息状态网络方面的研究,排除23篇重复性研究,30篇符合要求。资料综合:近年来,研究者发现大脑处于无任务的静息状态时,仍然存在着某种功能活动。这些现象表明大脑在静息状态时可能存在有组织的网络。这有助于对人脑高级意识和某些认知疾病的研究,因此,有关这方面的工作越来越受到人们的重视。结论:对静息状态网络的本质和规律的研究还很有限,对这个网络所支持的精确的功能还有待于进一步研究。     

Assessment of the effects of physical training in patients with chronic heart failure: the utility of effort-independent exercise variables

Traditionally, the effects of physical training in patients with chronic heart failure (CHF) are evaluated by changes in peak oxygen uptake (peak [(V)\dot]\textO₂ \dot{V}{\text{O}}_{2} ). The assessment of peak [(V)\dot]\textO₂ \dot{V}{\text{O}}_{2} , however, is highly dependent on the patients’ motivation. The aim of the present study was to evaluate the clinical utility of effort-independent exercise variables for detecting training effects in CHF patients. In a prospective controlled trial, patients with stable CHF were allocated to an intervention group (N = 30), performing a 12-week combined cycle interval and muscle resistance training program, or a control group (N = 18) that was matched for age, gender, body composition and left ventricular ejection fraction. The following effort-independent exercise variables were evaluated: the ventilatory anaerobic threshold (VAT), oxygen uptake efficiency slope (OUES), the [(V)\dot]_\textE /[(V)\dot]\textCO ₂ \dot{V}_{\text{E}} /\dot{V}{\text{CO}}_{ 2} slope and the time constant of [(V)\dot]\textO₂ \dot{V}{\text{O}}_{2} kinetics during recovery from submaximal constant-load exercise (τ-rec). In addition to post-training increases in peak [(V)\dot]\textO₂ \dot{V}{\text{O}}_{2} and peak [(V)\dot]_\textE , \dot{V}_{\text{E}} , , the intervention group showed significant within and between-group improvements in VAT, OUES and τ-rec. There were no significant differences between relative improvements of the effort-independent exercise variables in the intervention group. In contrast with VAT, which could not be determined in 9% of the patients, OUES and τ-rec were determined successfully in all patients. Therefore, we conclude that OUES and τ-rec are useful in clinical practice for the assessment of training effects in CHF patients, especially in cases of poor subject effort during symptom-limited exercise testing or when patients are unable to reach a maximal exercise level.     

Expression and regulation of vascular endothelial growth factor ligands and receptors during menstruation and post-menstrual repair of human endometrium

Regeneration and growth of the human endometrium after shedding of the functional layer during menstruation depends on an adequate angiogenic response. We analysed the mRNA expression levels of all known vascular endothelial growth factor (VEGF) ligands and receptors in human endometrium collected in the menstrual and proliferative phases of the menstrual cycle. In addition, we evaluated the expression of VEGF-A, VEGF-R2 and NRP-1 at the protein level. Two periods of elevated mRNA expression of ligands and receptors were observed, separated by a distinct drop at cycle days (CDs) 9 and 10. Immunohistochemical staining showed that VEGF and VEGF-R2 were expressed in epithelial, stromal and endothelial cells. NRP-1 was mainly confined to stroma and blood vessels; only in late-proliferative endometrium, epithelial staining was also observed. Except for endothelial VEGF-R2 expression in CDs 6-8, there were no significant differences in the expression of VEGF, VEGF-R2 or NRP-1 in any of the cell compartments. In contrast, VEGF release by cultured human endometrium explants decreased during the proliferative phase. This output was significantly reduced in menstrual and early-proliferative endometrium by estradiol (E2) treatment. Western blot analysis indicated that part of the VEGF-A was trapped in the extracellular matrix (ECM). Changes in VEGF ligands and receptors were associated with elevated expression of the hypoxia markers HIF1alpha and CA-IX in the menstrual and early proliferative phases. HIF1alpha was also detected in late-proliferative phase endometrium. Our findings indicate that VEGF-A exerts its actions mostly during the first half of the proliferative phase. Furthermore, VEGF-A production appears to be triggered by hypoxia in the menstrual phase and subsequently suppressed by estrogen during the late proliferative phase.     

Giant Asian honeybee or Bambara stings causing myocardial infarction,bowel gangrene and fatal anaphylaxis in Sri Lanka: a case series

The sting of Giant Asian honeybee (Apis dorsata) or Bambara in Sinhala and Karunge Kulavi in Tamil is a common environmental hazard in Sri Lanka known to cause immediate allergic reactions, which could be fatal in sensitized individuals. We reported myocardial infarction, bowel gangrene and fatal anaphylaxis in a prospectively proven case series and the association of these uncommon complications with delayed removal of stingers from the patients' skin.     

Induction of B cell apoptosis by co-cross-linking CD23 and sIg involves aberrant regulation of c-myc and is inhibited by bcl-2

A novel system to study the effects of co-cross-linking CD23/FceRII and sIg on murine B lymphocytes utilizes a highly multivalent form of anti- Ig prepared by covalently linking anti-Ig antibodies to a DNP-dextran backbone. CD23-sIg co-cross-linking is accomplished by the addition of DNP-specific monoclonal IgE. Previous studies demonstrated that co- cross-linking CD23 and sIg significantly inhibited mouse B cell proliferation, especially at high doses of the multivalent anti-Ig. Interestingly, examination of early activation signals reveals no difference in B cells subjected to co-cross-linking conditions as compared to B cells activated with anti-Ig alone. Total cellular protein tyrosine phosphorylation levels are unchanged by co-cross- linking. Analysis of B cell mRNA reveals that co-cross-linking the receptors does not alter the expression levels of ornithine decarboxylase 8 h after stimulation as compared to the controls. In contrast, levels of the proto-oncogene c-myc were significantly elevated 1 h after inducing B cell activation under co-cross-linking conditions. However, it remains unclear whether this aberrant c-myc regulation plays any role in inducing apoptosis. In addition, on day 3 after stimulation, the co-cross-linking of CD23 and sIg resulted in the formation of apoptotic B cells, determined by both photomicroscopy of the B cell cultures and FACS analysis of B cell nuclei. B cells obtained from bcl-2 transgenic mice proliferated as well as controls, and failed to undergo apoptosis when CD23 and sIg were co-cross-linked on their surface. These studies indicate that co-cross-linking of CD23 with B cell sIg inhibits B cell proliferation by a mechanism that is distinct from that seen by co-cross-linking of the Fc gamma RII and sIg. In addition, these results suggest a means by which antigen- specific IgE can down-regulate additional B cell activation and IgE synthesis.      

The effect of bed rest and an exercise countermeasure on leg venous function

This study was performed to assess the effect of resistive vibration exercise during bed rest deconditioning on venous vascular dimension and function, as measured with ultrasound in the popliteal vein. Sixteen men were assigned to bed rest (BR-Ctrl) or bed rest with resistive vibration exercise (BR-RVE). Before and at 25 and 52 days of bed rest, popliteal vein diameter was measured at increasing cuff pressures. Venous capacitance and compliance were calculated from the pressure–volume curve. After 52 days of bed rest, BR-Ctrl showed no change in baseline popliteal vein diameter or compliance, while venous capacitance decreased. Resistive vibration exercise had no effect on the response in venous diameter, capacitance or compliance to 52 days of bed rest. The decline in venous capacitance due to long-term bed rest is not effectively counteracted by resistive vibration exercise, indicating that an alternative factor during bed rest deconditioning is responsible for venous changes.     

Clearance of p-cresol sulfate and β-2-microglobulin from dialysate by commercially available sorbent technology

Dialysate regeneration by sorbents is an alternative to conventional single-pass dialysis. Little is known about the capacity of sorbents to clear dialysate of “middle molecules” and protein-bound uremic toxins. We studied p-cresol sulfate (PCS) and β-2-microglobulin (β2M) removal from dialysate by a sorbent: 1. PCS (40 mg PCS dissolved in 4 L of fresh dialysate) was recirculated through a sorbent cartridge (SORB Technology, Inc.) for analysis of PCS removal. 2. Spent peritoneal dialysate was recirculated on the “blood” side of a high-flux dialyzer. On the “dialysate” side of the membrane, bicarbonate dialysate was recirculated through a sorbent cartridge. β2M was measured in both streams. Two results are of particular importance for the use of regenerated fluid in chronic dialysis: 1. PCS was virtually completely removed from the dialysate. On average, PCS concentration was reduced to 1.4% of the starting concentration after 60 minutes. PCS extraction across the sorbent was nearly complete at any time. 2. β2M was on average reduced to 14.3% of the starting concentration after 60 minutes. Postsorbent concentrations were consistently below the validated range of the test method. We conclude that PCS and β2M are efficiently removed from the dialysate by commercially available sorbent technology. Spent peritoneal dialysis fluid can be cleared of β2M when circulated against sorbent-regenerated dialysate using a high-flux membrane.