Apoer2/Lrp8:the undercover cop of synaptic homeostasis

Apolipoprotein E receptor 2(ApoER2)is a receptor for the protein ApoE,the most common genetic risk factor for late-onset Alzheimer's disease(AD).It is also a key modulator of syna ptic homeostasis,in part through its effect on the expression of neuronal genes including those implicated in AD and other neuropsychiatric disorders.In this perspective,we highlight several genes affected by ApoER2 and its alternatively spliced forms and how aberrant expression can be rescued by the reintroduction of the ApoER2 intracellular domain in the mouse hippocampus.

Relationship of functional gastrointestinal disorders and psychiatric disorders: Implications for treatment

这篇文章重游在象急躁的肠症候群( IBS )那样的精神病理学和功能的胃肠的混乱之间的连接，讨论抗抑郁剂的合理使用以及非药理学来临到 IBS 的管理，并且从知识的现在的状态基于一个学科交差的观点为 IBS 的处理建议指南。精神病学的混乱上的相关出版文学，特别躯体化混乱在 IBS 的上下文，并且为管理的文学提供方向被考察，并且新方向在文学从调查结果被提供。IBS 是有为它的临床的演讲负责的各种各样的潜在的机制的异构的症候群。IBS 与在另外的机关系统的精神病学的问题， unexplained 症状，和功能的症候群典型地是复杂的。没有表明的原因，大多数 IBS 病人有多重抱怨，并且这些症状能包含除肠以外的系统，例如骨头和关节(fibromyalgia，颞下颌关节症候群) ，心(非心脏的胸痛) ，脉管(绝经后的症候群) ，并且大脑(焦虑，消沉) 。大多数 IBS 病人没有精神病学的病伴随他们的 somatoform (当医药混乱不在时的物理症状) 的精神分析形式(当精神病学的混乱不在时的心理抱怨) 的本身，而是一个范围症状抱怨。作为精神病学的病人把 IBS 病人标记不是正确的(除了有真躯体化的那些更困难的病人混乱) 。治疗的一个模式是不大可能的普遍有效或解决大多数症状。心理疗法或认知行为的治疗的技术能允许 IBS 病人与他们的病更乐意地处理。特定的事件压抑或焦虑混乱能为那些条件作为适当被管理。设计改进焦虑或消沉的药不为在 IBS 的精神病学的抱怨是一致地有用的，因为听起来类似于在精神病学的混乱看见的那些的精神分析形式症状不能与 IBS 在病人有一样的意义。

Pharmacotherapy for the management of achalasia: Current status, challenges and future directions

This article reviews currently available pharmacological options available for the treatment of achalasia, with a special focus on the role of botulinum toxin(BT) injection due to its superior therapeutic effect and side effect profile. The discussion on BT includes the role of different BT serotypes, better pharmacological formulations, improved BT injection techniques, the use of sprouting inhibitors, designer recombinant BT formulations and alternative substances used in endoscopic injections. The large body of ongoing research into achalasia and BT may provide a stronger role for BT injection as a form of minimally invasive, cost effective and efficacious form of therapy for patients with achalasia. The article also explores current issues and future research avenues that may prove beneficial in improving the efficacy of pharmacological treatment approaches in patients with achalasia.

Treatment of dyslipidemia in the elderly

Dyslipidemia 是为动脉粥样硬化的一个生长得很好的风险因素。在老病人对待 dyslipidemia 面对可能的多重 comorbidities 要求普通 dyslipidemias 的特定的知识和各种各样的 pharmacologic 代理人的相对安全。第一在 dyslipidemia 的治疗走的生活方式修正遗体；然而，支撑并且完成可接受的依从在能是困难的老并且它最好与药治疗在联合被使用。Statins 广泛地作为首要的治疗被接受。几最近的研究证明了 statins 在安全、有效老。然而，注意在超过 85 岁的病人关于病态和死亡上的 dyslipidemia 治疗的效果有很有限的数据是重要的。在摘要，临床医生必须认识到在老姿势的 dyslipidemia 的存在冠的事件和击的实质的风险。可得到的证据证明了在大多数，在的老病人为心血管的病态和死亡增加了风险，有适当治疗的 dyslipidemia 的治疗减少风险，并且当与为安全的靠近的监视小心地使用了时，治疗通常好容忍。与增加预期寿命，医生认出察觉的重要性和 dyslipidemia 的治疗在是批评的老。

The roles of MAPKs in disease

印射响应许多 ligands 和房间刺激涉及大量的细胞的小径和功能的家族 ases transduce 信号。MAPK 的异常或不恰当的功能现在在从癌症到煽动性的疾病到肥胖和糖尿病的疾病被识别了。在许多房间类型， MAPK ERK1/2 被连接到细胞增殖。因为在地岬和 B-Raf 的变化，能激活 ERK1/2 串联，在许多人的肿瘤被发现， ERK1/2 被认为在一些癌症起一个作用。发信号的反常 ERK1/2 也在 polycystic 肾疾病被发现了，并且象 cardio-facio-cutaneous 症候群那样的严肃的发展混乱在 ERK1/2 串联的部件从变化产生。ERK1/2 在区分得好的房间是必要的并且在神经原并且在上皮的极性的维护被连接了到长期的 potentiation。另外， ERK1/2 为在胰腺的贝它房间的胰岛素基因抄写是重要的，它响应传播葡萄糖的增加生产胰岛素在有机体允许有效葡萄糖利用和存储。导致或镇压的营养素和荷尔蒙胰岛素分泌物以在贝它房间上反映能分泌的需求的一种方式激活或禁止 ERK1/2。在这和另外的规章的小径的骚乱可以导致对某些人的混乱的病原学的 ERK1/2 的贡献。

A brief history of the DNA repair field

损坏脱氧核糖核酸的修理的历史能被跟踪到 mid-1930s。从那以后多重的脱氧核糖核酸修理机制，以及对脱氧核糖核酸的另外的生物回答损坏，被发现了，他们的规定被学习了。这篇文章简短描述这个领域的早历史。

Lymphocyte-to-monocyte ratio can predict mortality in pancreatic adenocarcinoma

AIM To determine if the lymphocyte-to-monocyte ratio(LMR) could be helpful in predicting survival in patients with pancreatic adenocarcinoma.METHODS We retrospectively reviewed the medical records of all patients diagnosed with pancreatic adenocarcinoma in the VA North Texas Healthcare System from January 2005 to December 2010. The LMR was calculated from peripheral blood cell counts obtained at the time of diagnosis of pancreatic cancer by dividing the absolute lymphocyte count by the absolute monocyte count. A Univariable Cox regression analysis was performed using these data, and hazard ratios(HR) and 95%CI were calculated. The median LMR(2.05) was used to dichotomize patients into high-LMR and low-LMR groups and the log rank test was used to compare survivalbetween the two groups.RESULTS We identified 97 patients with pancreatic adenocarcinoma(all men, 66% white, 30% African-American). The mean age and weight at diagnosis were 66.0 ± 0.9(SEM) years and 80.4 ± 1.7 kg respectively. Mean absolute lymphocyte and monocyte values were 1.50 ± 0.07 K/mL and 0.74 ± 0.03 K/mL respectively. Mean, median and range of LMR was 2.36, 2.05 and 0.4-12 respectively. In the univariable Cox regression analysis, we found that an increased LMR was a significant indicator of improved overall survival in patients with pancreatic adenocarcinoma(HR = 0.83; 95%CI: 0.70-0.98; P = 0.027). Kaplan-Meier analysis revealed an overall median survival of 128 d(95%CI: 80-162 d). The median survival of patients in the high-LMR(> 2.05) group was significantly greater than the low-LMR group(≤ 2.05)(194 d vs 93 d; P = 0.03), validating a significant survival advantage in patients with a high LMR.CONCLUSION The LMR at diagnosis is a significant predictor for survival and can provide useful prognostic information in the management of patients with pancreatic adenocarcinoma.

Assessing risks for gastric cancer: New tools for pathologists

Although the Sydney Systems (original and updated) for the classification of gastritis have contributed substantially to the uniformity of the reporting of gastric conditions, they lack immediacy in conveying to the user information about gastric cancer risk. In this review, we summarize the current understanding of the gastric lesions associated with an increased risk for cancer, and present the rationale for a proposal for new ways of reporting gastritis. In addition to the traditional histopathological data gathered and evaluated according to the Sydney System rules, pathologists could add an assessment expressed as grading and staging of the gastric inflammatory and atrophic lesions and integrate these findings with pertinent laboratory information on pepsinogens and gastrin levels. Such an integrated report could facilitate clinicians’ approach to the management of patients with gastric conditions.

Molecular mechanisms of cardiac aging

在心血管的结构 / 功能的联系年龄的变化在更老的人为心血管的疾病在显著地增加的风险被含有。老化不仅延长暴露到几另外的心血管的风险，而且导致内在的心脏的变化，它减少心脏的功能的保守，预先安排强调的心并且贡献增加的心血管的死亡在老。在鼠科的模型的内在的心脏的老化仔细在人概括年龄相关的心脏的变化，包括左室的肥大，纤维变性和心脏舒张的机能障碍。在老鼠的心脏的老化被 mitochondrial 蛋白质氧化，增加的 mitochondrial DNA 变化，增加的 mitochondrial 生物的续生说，以及减少的心脏的 SERCA2 蛋白质的累积伴随。所有显著地在指向到线粒体(mCAT ) 的老鼠 overexpressing 过氧化氢酶这些年龄相关的变化被稀释。这些调查结果表明 mitochondrial 的关键角色在心脏的老化和支持的反应的氧种类(ROS ) 到心脏的老化和年龄相关的心血管的疾病的 mitochondrial 抗氧化剂的潜在的申请。

Postcolonoscopy appendicitis in a patient with active ulcerative colitis

Complications due to diagnostic colonoscopy are uncommon and acute appendicitis is a very rare complication of colonoscopy.This poses a diagnostic challenge as the presentation of appendicitis is similar to that of other complications of colonoscopy such as perforation or postpolypectomy syndrome.It is hypothesized that postcolonoscopy appendicitis might be associated with obstruction of the appendiceal lumen with fecal matter during colonoscopy.None of the previous reports in the literature have described findings of appendicitis after colonoscopy in a patient with active ulcerative colitis.We present a case of a 28 yearold man with active ulcerative colitis who underwent colonoscopy and subsequently developed acute appendicitis.

钙调素参与离子通道和受体功能的调控

离子通道和受体是神经细胞信号发生及传递的结构基础.近年来的研究证明,离子通道和受体的功能受到细胞内及细胞外许多化学物质和信号分子的调控.越来越多的证据表明,正是这些以离子通道和受体为靶标的调控机制决定了中枢神经系统功能的复杂性和可塑性.在众多复杂的调控机制中,Ca^(2+)信号途径对于神经细胞的正常活动和病理改变均是至关重要的.经离子通道和受体内流的Ca^(2+)可对Ca^(2+)内流进行反馈调控,或是调控其他离子通道和受体的功能,它们的共同特点是都有Ca^(2+)/钙调素(CaM)的参与.Ca^(2+)/CaM通过对离子通道和受体进行反馈调控来保持通道之间的功能协调性和胞内的Ca^(2+)平衡.文中阐述了Ca^(2+)/CaM参与调控离子通道和受体功能的分子过程,进一步说明了细胞编码Ca^(2+)信号的机理.

Evidence of neurodegeneration in autism spectrum disorder

Autism spectrum disorder(ASD)is a neurological disorder in which a significant number of children experience a developmental regression characterized by a loss of previously-acquired skills and abilities.Loss of neurological function in ASD,as observed in affected children who have regressed,can be explained as neurodegeneration.Although there is research evidence of neurodegeneration or progressive encephalopathy in ASD,the issue of neurodegeneration in ASD is still under debate.Evidence of neurodegeneration in the brain in ASD includes:(1)neuronal cell loss,(2)activated microglia and astrocytes,(3)proinflammatory cytokines,(4)oxidative stress,and(5)elevated 8-oxo-guanosine levels.The evidence from this review suggests that neurodegeneration underlies the loss of neurological function in children with ASD who have experienced regression and loss of previously acquired skills and abilities,and that research into treatments to address the issue of neurodegeneration in ASD are warranted.

相对湿度变化对泪液蒸发变化的影响及其相关性研究

PURPOSE:To establish scientific relationship between relative humidity(RH)and aqueous tear evaporation to elucidate possible significance of this relationship in normals and aqueous tear deficiency patients.DESIGN:Prospective xperimental laboratory study.METHODS:Ocular surface evaporation was determined using evaporometry and calculated for two ranges of RH,25% to 35%,and 35% to 45% in a randomized clinical patient population.RESULTS:Average evaporative rate in the higher humidity range was between 0.029± 0.009 through 0.043± 0.016 μ l/cm2/min.At lower humidity,range was between 0.044± 0.013 through 0.058± 0.018 μ l/cm2/min.Differences in the corresponding evaporative rates were statistically significant(between P<.003 through P<.043)for each analysis.CONCLUSIONS:A decrease of 10% RH resulted in an average difference of between 28.33% to 59.42% increase in evaporation.The increase in evaporation at lower humidity has significant clinical implications for patients with aqueous deficient dry eyes,and possibly those undergoing laser-assisted in situ keratomileusis(LASIK).

利用组织培养的人羊膜上皮细胞的非外科移植术进行眼表重建

PURPOSE: To assess the effect of tissue-cultured human amniotic epithelial cells (AECs) in restoring the ocular surface, transplanted using a collagen shield seeded with AECs supported by a soft contact lens. DESIGN: Prospective interventional single-institutional case series with crossover controls. METHODS: Three eyes in three patients were identified with persistent corneal epithelial defects (PEDs) refractory to medical therapy. Two cases were secondary to neurotrophic keratopathy, while one case was attributable to longstanding alkali injury. AECs were isolated from serologically screened donor human placenta, seeded onto collagen corneal shields, and incubated in tissue culture medium for 7 days. These collagen shields were placed over the PED and supported by an overlying soft contact lens. The collagen shields dissolved by 72 hours, and the contact lenses were removed after this time. This cycle was repeated every week until healing was achieved. As a crossover control, collagen shields without AECs were placed in the same eye 1 week before placing collagen shields containing AECs. The PED was assessed by vital staining and slit-lamp color photography. RESULTS: The PEDs had a mean duration of 4 months and involved 20%to 37%of the corneal surface area, one case secondary to longstanding alkali injury and two cases attributable to neurotrophic keratopathy. No change in PED size was observed in those control eyes receiving collagen shields without AECs. Complete resolution of the PED was seen after two cycles of AEC-seeded collagen shield in one case, and four cycles in two cases, from 7 to 12 weeks following treatment in all patients. No loss of visual acuity was seen and clinical improvement was maintained in all cases, with a mean follow-up of 6.3 months. CONCLUSIONS: Nonsurgical transplantation of tissue-cultured AECs on a collagen shield provides a promising approach to restoring the ocular surface in cases of PED.

QUANTIFYING NANOP ARTICLE TRANSPORT IN VIVO USING HYP ERSPECTRAL IMA GING WITH A DORSAL SKINFOLD WINDOW CHAMBER

We have developed a noninv asive imaging method to quantify in viwo drug delivery pharmaco-kinetics without the need for blood or tissue collection to determine drug concentration.By combining the techniques of hy perspectral imaging and a dorsal skinfold window chamber,this method enabled the real-time monitoring of vascular transport and tissue deposition of nano-particles labeled with near infrared(NIR)dye.Using this imaging method,we quantified the delivery pharmacokinetics of the native high-density lipoprotein(HDL)and epidermal growth factor receptor(EGFR)-targeted HDL nanoparticles and demonstrated these HDLs had long circulation time in blood stream(half-life>12h).These HDL nanoparticles could eficiently carry cargo DiR-BOA to extravasate from blood vesels,difuse through extr acellular matrix,and penetrate and be retained in the tumor site.The EGFR targeting specificity of EGFR-targeted HDL(EGFR-specific peptide conjugated HDL)was also visualized in vivo by competitive inhi bition with excess EGFR specifc peptide.In summary,this imaging technology may help point the way toward the development of novel imaging based pharmacokinetic assays for preclinical drugs and evaluation of drug delivery eficiency,providing a dynamic window into the devel opment and application of novel drug delivery systems.

后天获得性耐甲氧苯青霉素金黄色葡萄球菌菌落感染在妊娠患者中的临床现状

The Abstract of this study was to review the presentation and management of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) in pregnant women. Methods: This was a chart review of pregnant patints who were diagnosed with MRSA between January 1, 2000, and July 30, 2004. Data collected included demographic characteristics, clinical presentation, culture results, and pathogen susceptibilities. Patients’ pregnancy outcomes were compared with the general obstetric population during the study period. Results: Fifty-seven charts were available for review. There were 2 cases in 2000, 4 in 2001, 11 in 2002, 23 in 2003, and 17 through July of 2004. Comorbid conditions included human immunodeficiency virus and acquired immunodeficiency syndrome (13% ), asthma (11% ), and diabetes (9% ). Diagnostic culture was most commonly obtained in the second trimester (46% ); however 18% of cases occurred in the postpartum period. Skin and soft tissue infections accounted for 96% of cases. The most common site for a lesion was the extremities (44% ), followed by the buttocks (25% ), and breast (mastitis)(23% ). Fifty-eight percent of patients had recurrent episodes. Sixty-three percent of patients required inpatient treatment. All MRSA isolates were sensitive to trimethoprim-sulfamethoxazole, vancomycin, and rifampin. Other antibiotics to which the isolates were susceptible included gentamicin (98% ) and levofloxacin (84% ). In comparison with the general obstetric population, patients with MRSA were more likely to be multiparous and to have had a cesarean delivery. Conclusion: Community-acquired MRSA is an emerging problem in our obstetric population. Most commonly, it presents as a skin or soft tissue infection that involves multiple sites. Recurrent skin abscesses during pregnancy should raise prompt investigation for MRSA.

拓扑替康应用于子宫癌肉瘤的二期评价:一项妇科肿瘤组研究

Objectives. To estimate the antitumor activity of topotecan in patients with persistent or recurrent carcinosarcoma (malignant mixed mullerian tumors) of the uterus and to determine the nature and degree of toxicity of topotecan in this cohort of patients. Materials and methods. Eligible patients had measurable advanced or recurrent carcinosarcoma of the uterus. Topotecan at a target dose of 1.5 mg/m2 was administered IV daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. Results. Twenty-seven member institutions entered 51 patients. Of the patients entered, 48 were eligible. Patient characteristics included a median age of 65, with 33% having prior radiation and 92% having prior chemotherapy. Twenty-six patients (54% ) had a performance status (PS) of 0, 18 (38% ) had a PS of 1, and four (8% ) had a PS of 2. Patients received from 1 to 21 (with a median of 2) courses of treatment. The most frequently observed grade 4 toxicities were neutropenia seen in 35 (73% ) patients, leukopenia in 14 (29% ), and thrombocytopenia in 10 (21% ). Three (6% )- patients developed neutropenic sepsis and died shortly after their first treatment cycle. There were five (10% ) complete responses; 13 (27% ) patients maintained stable disease, 26 (54% ) experienced increasing disease, and reassessment did not occur in four (8% ). Conclusion. Topotecan at this dose and schedule does not appear to have major activity in patients with advanced or recurrent uterine carcinosarcoma previously treated with chemotherapy.

The current trend and challenges of developing red yeast rice-based food supplements for hypercholesterolemia

Hypercholesterolemia is a risk factor of cardiovascular diseases,which have been managed using statin drugs.Red yeast rice(RYR)as a traditional food in the Eastern Asia countries has anti-hyperlipidemia activity.Recently,a variety of food supplement products containing RYR have been developed to lower blood cholesterol,which is attributed to the presence of monacolins,especially monacolin K(lovastatin,a statin drug).This review was aimed to summarize the clinical trials using RYR products to investigate their effects on lipid profiles in humans.Relevant articles of human clinical trials were retrieved from PubMed and discussed here.Results showed that RYR and its extracts have been included in commercially available products alone and in combinations with various other materials,which include bioactive compounds such as coenzyme Q10 and berberine,vitamins,extracts from other plants such as phytosterols,polyunsaturated fatty acids or even probiotics.The durations of the trials ranged from 4 weeks to 60 months.The content of monacolin K ranged from 0.32 mg/pack to 10 mg/pack.The data of these human clinical trials demonstrated that these RYR supplement products were sufficient to reduce blood cholesterol in different populations.However,the inclusions of certain materials might not have additive effect.Additionally,studies including a lovastatin only positive control group with the equivalent dose as that of monacolin K in the RYR products remain to be done.Furthermore,variations of monacolin K contents and presence of toxic citrinin are still concerns.Last,bioactivities of other components in RYR should be investigated as well.More future studies will certainly help to fully explore the potentials of this traditional food in the combat against cardiovascular and other metabolic diseases.

Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer's disease pathogenesis

Alzheimer disease(AD) is the most common neurodegenerative disorder worldwide and is at present,incurable.The accumulation of toxic amyloid-beta(Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline,an idea that underlies the'amyloid hypothesis'of AD etiology in both the familal(FAD) and sporadic forms of the disease.Genetic mutations causing FAD also result in the dysregulation of neuronal calcium(Ca2+) handling and may contribute to AD pathogenesis,an idea termed the'calcium hypothesis'of AD.Mutations in presenilin proteins account for majority of FAD cases.Presenilins function as catalytic subunit ofγ-secretase involved in generation of Aβ peptide Recently,we discovered that presenilns function as low-conductance,passive ER Ca2+ leak channels,independent of γ-secretase activity.We further discovered that many FAD mutations in presenilins result in loss of ER Ca2+ leak function activity and Ca2+ overload in the ER.These results provided potential explanation for abnormal Ca2+ signaling observed in FAD cells with mutations in presenilns.Our latest work on studies of ER Ca2+ leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.