Control of Aβ release from human neurons by differentiation status and RET signaling

Few studies have compared the processing of endogenous human amyloid precursor protein (APP) in younger and older neurons. Here, we characterized LUHMES cells as a human model to study Alzheimer's disease-related processes during neuronal maturation and aging. Differentiated LUHMES expressed and spontaneously processed APP via the secretase pathways, and they secreted amyloid β (Aβ) peptide. This was inhibited by cholesterol depletion or secretase inhibition, but not by block of tau phosphorylation. In vitro aged cells increased Aβ secretion without upregulation of APP or secretases. We identified the medium constituent glial cell line-derived neurotrophic factor (GDNF) as responsible for this effect. GDNF-triggered Aβ release was associated with rapid upregulation of the GDNF coreceptor “rearranged during transfection” (RET). Other direct (neurturin) or indirect (nerve growth factor) RET activators also increased Aβ, whereas different neurotrophins were ineffective. Downstream of RET, we found activation of protein kinase B (AKT) to be involved. Accordingly, inhibitors of the AKT regulator phosphatidylinositol-3-kinase completely blocked GDNF-triggered AKT phosphorylation and Aβ increase. This suggests that RET signaling affects Aβ release from aging neurons.     

Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation

A recurrent somatic activating mutation in the nonreceptor tyrosine kinase JAK2 (JAK2V617F) occurs in the majority of patients with the myeloproliferative disorders polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and, less commonly, chronic myelomonocytic leukemia. We do not understand the basis for the specificity of the JAK2V617F mutation in clonal disorders of the myeloid, but not lymphoid, lineage, nor has the basis for the pleiotropic phenotype of JAK2V617F-associated myeloproliferative disorders been delineated. However, the presence of the identical mutation in patients with related, but clinicopathologically distinct, myeloid disorders suggests that interactions between the JAK2V617F kinase and other signaling molecules may influence the phenotype of hematopoietic progenitors expressing JAK2V617F. Here, we show that coexpression of the JAK2V617F mutant kinase with a homodimeric Type I cytokine receptor, the erythropoietin receptor (EpoR), the thrombopoietin receptor, or the granulocyte colony-stimulating-factor receptor, is necessary for transformation of hematopoietic cells to growth-factor independence and for hormone-independent activation of JAK-STAT signaling. Furthermore, EpoR mutations that impair erythropoietin-mediated JAK2 or STAT5 activation also impair transformation mediated by the JAK2V617F kinase, indicating that JAK2V617F requires a cytokine receptor scaffold for its transforming and signaling activities. Our results reveal the molecular basis for the prevalence of JAK2V617F in diseases of myeloid lineage cells that express these Type I cytokine receptors but not in lymphoid lineage cells that do not.     

1294例女性高危型人乳头瘤病毒基因分型结果回顾性分析

目的了解北京地区妇科门诊就诊女性高危型人乳头瘤病毒(HPV)的感染及其基因亚型分布情况,为该市今后防治人乳头瘤病毒感染和宫颈癌提供参考依据。方法回顾性分析2013年1月至2014年5月该院妇科门诊就诊的1 294例女性宫颈拭子的13种高危型HPV基因分型检测结果,比较不同基因型的流行病学特点。采用SPSS17.0对数据进行统计学分析。结果 1 294例妇科门诊就诊女性中,以58型、16型和52型HPV最为常见,检出率分别为10.5%、9.2%和8.2%。各年龄段就诊女性中,30~40岁的HPV感染率最高(39.9%),其次为40~50岁、大于或等于60岁,差异无统计学意义(P0.05)。结论该地区妇科门诊就诊女性高危型HPV感染率较高,应加强HPV筛查力度,为今后HPV相关疾病的防治提供基础依据。     

晚清湖南刻印医籍研究

晚清时期,湖南各地出版机构和个人雕版刻印了大量医学书籍,尤其以方药、疫病以及传统畅销类医书多见,也包括部分清代湖南医家的学术著作.医籍刻印不仅适应晚清湖南社会各阶层对医学文本的需求,也扩展了地方医家学术成就的传播和影响力.     

Identification of signal transduction pathways involved in the formation of platelet subpopulations upon activation

Platelets are formed elements of blood. Upon activation, they externalize phosphatidylserine, thus accelerating membrane‐dependent reactions of blood coagulation. Activated platelets form two subpopulations, only one of which expresses phosphatidylserine. This study aimed to identify signalling pathways responsible for this segregation. Gel‐filtered platelets, intact or loaded with calcium‐sensitive dyes, were activated and labelled with annexin V and antibodies, followed by flow cytometric analysis. Calcium Green and Fura Red dyes were compared, and only the latter was able to detect calcium level differences in the platelet subpopulations. Phosphatidylserine‐positive platelets produced by thrombin had stably high intracellular calcium level; addition of convulxin increased and stabilized calcium level in the phosphatidylserine‐negative subpopulation. PAR1 agonist SFLLRN also induced calcium rise and subpopulation formation, but the resulting platelets were not coated with alpha‐granule proteins. Adenylatecyclase activator forskolin inhibited phosphatidylserine‐positive platelets formation several‐fold, while its inhibitor SQ22536 had no effect. This suggests that adenylatecyclase inactivation is necessary, but not rate‐limiting, for subpopulation segregation. Inhibition of mitogen‐activated protein kinase kinase (U0126) and glycoprotein IIb‐IIIa (Monafram^®) was without effect, whereas inhibitors of phosphatidylinositol 3‐kinase (wortmannin) and Src tyrosine kinase (PP2) decreased the procoagulant subpopulation threefold. These data identify the principal signalling pathways controlling platelet heterogeneity.     

The Push-Turn-Taptap Task Outperforms Measures of Executive Functioning in Predicting Declines in Functionality: Evidence-Based Approach to Test Validation

Performance on the Push-Turn-Taptap (PTT) task has been shown to be a strong predictor of concurrent everyday functioning. This study utilized a prospective, longitudinal design to evaluate the PTT task for predicting future performance on a behavioral assessment of everyday functioning. The PTT task was compared to other measures of executive functioning as well as general cognition in terms of administration time and ability to identify participants who evidenced functional decline. A total of 50 community-dwelling older adults (ages 58–87) completed the PTT task, Mattis Dementia Rating Scale, Geriatric Depression Scale, Behavioral Dyscontrol Scale, Delis-Kaplan Executive Function System, and Timed Instrumental Activities of Daily Living. Baseline PTT performance (a) was highly correlated with an objective measure of everyday functioning after approximately one year (r?=??.497, p?<?.001), (b) was associated with changes in follow-up functioning, F(3, 46)?=?3.15, p?=?.03, (c) was a better predictor of future functional status than a longer battery of EF, and (d) reliably identified individuals with the greatest magnitude of functional decline. The PTT tasks may provide a particularly advantageous method of predicting future changes in everyday functioning in older adults.     

Increased Neuronal Apoptosis in Medial Prefrontal Cortex is Accompanied with Changes of Bcl-2 and Bax in a Rat Model of Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by traumatic experience, which affects a patient’s quality of life and social stability. The objective of this study was to determine the apoptosis-related genes B-cell lymphoma 2 (Bcl-2) and BCL2-associated X (Bax) expressions and medial prefrontal cortex (mPFC) neuronal apoptosis after PTSD in rat model and therefore to provide experimental evidence to reveal PTSD pathogenesis. The single-prolonged stress (SPS) method was used to set up the rat PTSD models. Chemiluminescence was used to determine serum corticosterone levels. Neuronal apoptosis was detected using transmission electron microscopy, Hoechst staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Immunohistochemistry, immunofluorescence, RT-PCR, and Western blot were used to detect the expressions of Bcl-2 and Bax protein in mPFC. Our results showed an increased mPFC neuronal apoptosis after SPS stimulation. The number of apoptotic cells peaked on day 7. The expressions of Bcl-2 and Bax peaked on days 4 and 7. The Bcl-2/Bax ratio elevated on days 1 and 4 but decreased markedly on day 7. These results indicated that SPS stimulation increased the number of apoptotic neurons, up-regulated the expressions of Bcl-2 and Bax, and altered the Bcl-2/Bax ratio in the mPFC of PTSD rats.     

Utility of hospital admission for pediatric intussusceptions

Purpose

The standard practice in pediatric patients diagnosed with intussusception has been reduction via enema and admission for a period of nil per os and observation. Little data exists to support this practice. The objective of this study was to examine whether post-reduction admission to hospital is required.

Methods

A retrospective chart review was performed on all patients aged 0–18 years old with intussusception over a span of 20 years. Study included children treated for intussusception on first encounter with enema and subsequently admitted for observation. Study excluded those readmitted for recurrence after 48 h, patients whose intussusception did not reduce on first try, those lost to follow-up, and those who went to the operating room. Early recurrence was defined as recurrence within 48 h post-reduction.

Results

Out of 171 patients admitted, only one experienced an early recurrence (0.6 %). Median length of stay for all patients was 2 days. Average cost incurred per day for intussusception admission was $404.

Conclusion

Intussusception in a child that is successfully reduced via enema has a low recurrence rate and is usually followed by prompt resolution of symptoms. An abbreviated period of observation in the emergency department post-reduction may result in healthcare savings.

     

Effect of synthetic dermorphin analogues on tissue homeostasis in the myocardium of newborn albino rats

DNA synthesis and state of the nucleolar apparatus in myocardial cells of newborn albino rats receiving intraperitoneal injection of sedatin, a synthetic dermorphin analogue, were studied by means of autoradiography and silver impregnation. Labeling intensity significantly increased, while the number of nucleoli in nuclei decreased. Chemiluminescence study showed that the concentration of reactive oxygen metabolites significantly decreased in the myocardium of treated animals after sedatin administration. Non-arginine analogue of sedatin had little effect on tissue homeostasis in the myocardium. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 10, pp. 413–416, October, 2007