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

This article revisits the links between psychopathology and functional gastrointestinal disorders such as irritable bowel syndrome （IBS）, discusses the rational use of antidepressants as well as non-pharmacological approaches to the management of IBS, and suggests guidelines for the treatment of IBS based on an interdisciplinary perspective from the present state of knowledge. Relevant published literature on psychiatric disorders, especially somatization disorder, in the context of [BS, and literature providing direction for management is reviewed, and new directions are provided from findings in the literature. IBS is a heterogeneous syndrome with various potential mechanisms responsible for its clinical presentations. IBS is typically complicated with psychiatric issues, unexplained symptoms, and functional syndromes in other organ systems. Most IBS patients have multiple complaints without demonstrated cause, and that these symptoms can involve systems other than the intestine, e.g. bones and joints （fibromyalgia, temporomandibular joint syndrome）, heart （non-cardiac chest pain）, vascular （post-menopausal syndrome）, and brain （anxiety, depression）. Host IBS patients do not have psychiatric illness per se, but a range of psychoform （psychological complaints in the absence of psychiatric disorder） symptoms that accompany their somatoform （physical symptoms in the absence of medical disorder） complaints. It is not correct to label IBS patients as psychiatric patients （except those more difficult patients with true somatization disorder）. One mode of treatment is unlikely to be universally effective or to resolve most symptoms. The techniques of psychotherapy or cognitive-behavioral therapy can allow IBS patients to cope more readily with their illness. Specific episodes of depressive or anxiety disorders can be managed as appropriate for those conditions. Medications designed to improve anxiety or depression are not uniformly useful for psychiatric complaints in IBS, because the psychoform symptoms that sound similar to those seen in psychiatric disorders may not have the same significance in patients with IBS.

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.

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

AIMTo determine if the lymphocyte-to-monocyte ratio (LMR) could be helpful in predicting survival in patients with pancreatic adenocarcinoma. METHODSWe 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 survival between the two groups. RESULTSWe 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/μL and 0.74 ± 0.03 K/μL 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. CONCLUSIONThe 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.

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.

Treatment of dyslipidemia in the elderly

Dyshpidemia is a well-established risk factor for atherosclerosis. Treating dyslipidemia in elderly patients requires specific knowledge and understanding of common dyslipidemias and the relative safety of various pharmacologic agents in the presence of possible multiple comorbidities. Lifestyle modification remains the first step in the treatment of dyslipidemia; however, it can be difficult to sustain and achieve acceptable compliance in the elderly and it is best used in combination with drug therapy. Statins are widely accepted as the first-line therapy. Several recent studies have demonstrated that statins are safe and effective in the elderly. However, it is important to note that there is very limited data regarding the effects of dyslipidemia treatment on morbidity and mortality in patients over 85 years of age. In summary, the clinicians must recognize that the presence of dyslipidemia in the elderly poses substantial risk of coronary events and stroke. The available evidence has demonstrated that in most elderly patients who are at increased risk for cardiovascular morbidity and mortality, treatment of dyslipidemia with appropriate therapy reduces the risk, and when used carefully with close monitoring for safety, the treatment is generally well tolerated. With increasing life expectancy, it is critical for physicians to recognize the importance of detection and treatment of dyslipidemia in the elderly.

Helical Repeats of Left-Handed DNA

DNA is generally assumed as a right-handed double helix and Z-DNA is a special kind of left-handed DNA infrequently found in nature. However, the finding of a zero linking number topoisomer supports a hypothesis that the two strands of DNA are winding ambidextrously, rather than plectonemically. It logically leads to a notion that the left-handed DNA is as common as right-handed DNA and the amount of left-handed DNA in a positively supercoiled plasmid prevails that of the right-handed DNA. In this report, the helical repeat of left-handed DNA, 12 bp per turn, was determined by a new method. How the positively supercoiled DNA was generated in hyperthermophiles and why their DNA can withstand the extreme high temperature are answered from an alternative theory.

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.

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.

Insulin-3基因敲除鼠生殖系统LGR8蛋白的表达

目的 Insulin-3(Insl3)和其唯一配体富含亮氨酸的G蛋白受体[LGR8(aka RXFP2)]系统在睾丸下降过程中起重要作用。本研究拟利用Insl3基因敲除鼠探讨Insl3与LGR8相互关系及其在生殖系统的表达情况。方法使用免疫共沉淀、Western blot及免疫组化法检测雄性野生型小鼠和Insl3基因敲除雄性小鼠各生殖器官LGR8蛋白的表达并比较分析。结果 LGR8蛋白在野生型小鼠睾丸、睾丸引带、附睾及输精管等多个雄性生殖器官均有表达。其表达程度在不同生殖器官不同,野生型小鼠睾丸LGR8的表达强于Insl3基因敲除鼠(P<0.05)。结论 LGR8蛋白在多个雄性生殖器官均有表达,Insl3-LGR8系统可能在男性多种生殖发育疾病中起作用。

脑型一氧化氮合成酶的钙调蛋白结合区的表达及活性鉴定

用ＰＣＲ法克隆出ｎＮＯＳ的ＣａＭ结合区基因（ｎＮＯＳ２４５５～２９８８ｂｐ），并在大肠杆菌中进行了高效表达。经金属离子螯合亲和层析得到纯度为９０％以上的重组蛋白，分子量为２２ｋＤａ，ＣａＭＯｖｅｒｌａｙａｓａｙ证实该蛋白具有ＣａＭ的结合活性。由于所表达的重组蛋白既具有序列特异性又具有ＣａＭ的结合活性，因此，可将它作为筛选ｎＮＯＳ特异性抑制肽的靶蛋白，亦可用于特异性抗体的制备。

NF-IL6对iNOS基因表达的负调控

诱生型一氧化氮合酶(iNOS)基因的调控序列中含有NF-IL6的识别元件,但NF-IL6对iNOS基因的调控功能目前尚不清楚。研究发现SP2/0骨髓瘤细胞能低剂量持续表达iNOS,并利用该模型将含有iNOS调控序列的报告基因质粒与NF-IL6的表达质粒共转染至SP2/0细胞,观察到NF-IL6的表达能抑制iNOS基因的表达,并呈剂量效应关系,初步认为NF-IL6是iNOS基因表达的负调控因子。

The roles of MAPKs in disease

MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.

A brief history of the DNA repair field

The history of the repair of damaged DNA can be traced to the mid-1930s. Since then multiple DNA repair mechanisms, as well as other biological responses to DNA damage, have been discovered and their regulation has been studied. This article briefly recounts the early history of this field.

Molecular mechanisms of cardiac aging

Age-associated changes in cardiovascular structure/ function are implicated in the markedly increased risk for cardiovascular disease in older persons. Aging not only prolongs exposure to several other cardiovascular risks, but also leads to intrinsic cardiac changes, which reduces cardiac functional reserve, predisposes the heart to stress and contributes to increased cardiovascular mortality in the elderly. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans, includ- ing left ventricular hypertrophy, fibrosis and diastolic dysfunction. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations, increased mitochondrial biogenesis, as well as decreased cardiac SERCA2 protein. All of these age-related changes are significantly attenu- ated in mice overexpressing catalase targeted to mitochondria （mCAT）. These findings demonstrate the critical role of rnitochondrial reactive oxygen species （ROS） in cardiac ag ing and support the potential antioxidants to cardiac aging lar diseases. application of mitochondrial and age-related cardiovascular diseases.

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.

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.

Mad revival of cancer

Aneuploidy （wrong numbers of chromosomes） is a hallmark of cancer cells and arises from chromosome missegregation in mitosis. To prevent aneuploidy, cells employ surveillance systems to monitor mitosis. The spindle checkpoint （also known as the mitotic checkpoint） is one such surveillance system conserved from yeast to man [1, 2]. During each. mitosis, this check- point detects aberrant kinetochore- microtubule attachments, inhibits the anaphase-promoting complex or cyclosome （APC/C）, stabilizes cyclin B 1 and securin, and delays anaphase onset until all sister chromatids reach proper microtubule attachment.

甲氨蝶呤与熊脱氧胆酸联合治疗原发性胆汁性肝硬化

This placebo-controlled, randomized, multicenter trial compared me effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopamy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig’ s histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopamy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.