Edwardsiellosis in fish: a brief review

Edwardsiellosis is one of the most important bacterial diseases in fish. Scientific work on this disease started more than forty years ago and numerous workers around the world are continually adding to the knowledge of the disease. In spite of this, not a single article that reviews the enormous scientific data thus generated is available in the English language. This article briefly discusses some of the recent research on edwardsiellosis, describing the pathogen's interaction with the host and environment, its pathogenesis and pathology as well as diagnostic, preventive and control measures.     

Endpoints in the design of clinical trials for primary sclerosing cholangitis

Primary sclerosing cholangitis is an enigmatic disease affecting the bile ducts, eventually leading to liver failure necessitating liver transplantation in many cases. There is currently no therapy that has proven to halt disease progression. One of the reasons for this is the lack of proper endpoints to measure the effect of medical intervention on the course of the disease. Relevant clinical endpoints such as death or liver transplantation occur too infrequently in this orphan disease to be used as endpoints in phase 2 or 3 trials. It is therefore of utmost importance to identify appropriate surrogate endpoints that are reasonably likely to measure true clinical benefit. This article will discuss a number of surrogate endpoints that are likely candidates to serve this role. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

Myasthenia gravis: pathophysiology,diagnosis, differential diagnosis and management

Myasthenia gravis is an autoimmune disorder caused by impaired synaptic transmission at the neuromuscular junction. The characteristic signs and symptoms of this disease manifest as increasing muscle fatigue. This article reviews myasthenia gravis with an emphasis on the pathophysiology, systemic and ocular manifestations, diagnostic testing, and management of this disease.     

环氧合酶在神经变性疾病神经元进行性损伤中起重要作用

环氧合酶(COX)是非甾体抗炎药的主要作用靶点.自从上世纪90年代初被发现至今,COX已被证实广泛参与炎性反应过程.小胶质细胞是介导"神经炎性反应"的主要细胞类型,过去十年中,COX通路参与小胶质细胞激活及神经变性过程的机制取得了很大进展.本文对该领域的新近研究成果予以论述,并以三大神经变性疾病,即阿尔采末病(AD)、帕金森病(PD)和肌萎缩侧索硬化症(ALS)为例,对COX在其发病中的作用加以阐释,突出该领域的研究热点,为神经变性疾病发病机制及药物治疗研究提供新的思路.     

Blood-based protein biomarkers for diagnosis and classification of neurodegenerative diseases: current progress and clinical potential

Biomarker research is a rapidly advancing field in medicine. Recent advances in genomic, genetic, epigenetic, neuroscientific, proteomic, and metabolomic knowledge and technologies have opened the way to thriving research. In the most general sense, a biomarker refers to any useful characteristic that can be measured and used as an indicator of a normal biologic process, a pathogenic process, or a pharmacologic response to a therapeutic agent. Despite the extensive resources concentrated on this area, there are very few biomarkers currently available that qualify and are satisfactorily validated for mental disorders, and there is still a major lack of biomarkers for typifying neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. This article provides an overview of this field of research and focuses on recent advances in biomarker research in Alzheimer's disease and Parkinson's disease.     

Protective immune mechanisms against Theileria parva: evolution of vaccine development strategies.

Theileria parva is an intracellular sporozoan parasite that infects and transforms bovine lymphocytes, causing a severe lymphoproliferative disease known as East Coast fever in eastern, central and southern Africa. In this article, Declan McKeever and colleagues summarize the current understanding of immune mechanisms provoked by the parasite with regard to their role in both pathogenesis and protection. In particular, the influence of genomic polymorphism in parasite and host on the development of immunity is discussed, along with the evolution of current vaccine development strategies as a result of immunological research on the disease.     

Neuropsychological Aspects of Liver Disease and its Treatment

Liver disease can lead to serious impairment in cognitive functioning, through the development of a condition known as hepatic encephalopathy (HE). While gross impairment is clinically obvious, milder variants of the condition may escape detection at bedside examination and yet may have a significant impact on day-to-day activities. In this brief review article, the neuropsychology of liver disease is examined, focusing on nature, aetiology and significance. The possible contributory role of endogenous benzodiazepines in HE is described, as is the evidence regarding the effect of benzodiazepine antagonism on cognitive functioning in HE. The functional localisation of HE is briefly reviewed, as is the use of neuropsychological measures to evaluate treatment efficacy, e.g. following shunt procedures or liver transplantation. Finally, living donor liver transplantation is described, and the case is made for rigorous longitudinal neuropsychological evaluation of potential donors and recipients. Special issue article in honor of George Fink.     

Herpetic eye disease: immunopathogenesis and therapeutic measures

Infection of the cornea with herpes simplex virus (HSV) can result in a chronic disease called herpetic stromal keratitis (HSK). The disease represents one of the leading causes of infectious blindness in the Western world. Immune-mediated cellular damage is suspected in the pathogenesis of human HSK. The murine model has been pivotal in further establishing HSK as an immunopathological disease. This article reviews understanding of HSK, both in humans and in the mouse model, with an emphasis on possible future therapeutic strategies to counteract this blinding immunoinflammatory disease.     

Mechanisms of neuronal cell death in Huntington's disease

Huntington's disease (HD) is a genetically dominant neurodegenerative condition caused by an unique mutation in the disease gene huntingtin. Although the Huntington protein (Htt) is ubiquitously expressed, expansion of the polyglutamine tract in Htt leads to the progressive loss of specific neuronal subpopulations in HD brains. In this article, we will summarize the current understanding on mechanisms of how mutant Htt can elicit cytotoxicity, as well as how the selective sets of neuronal cell death occur in HD brains.     

Replication Proteins and Human Disease

In this article, we discuss the significance of DNA replication proteins in human disease. There is a broad range of mutations in genes encoding replication proteins, which result in several distinct clinical disorders that share common themes. One group of replication proteins, the MCMs, has emerged as effective biomarkers for early detection of a range of common cancers. They offer practical and theoretical advantages over other replication proteins and have been developed for widespread clinical use.Semiconservative replication of DNA is essential for cellular proliferation. Therefore, mutation of genes encoding the replication machinery could be thought to be fundamentally harmful to an organism. However, inherited and acquired mutations in such genes do occur, resulting in a broad spectrum of disease. The first half of this article outlines the phenotypes associated with several classes of replication disorders, before focusing on the pre-replicative complex (pre-RC) and its involvement in both inherited and acquired human disease. In the second half, we discuss the utility of replication proteins as oncological disease markers, again with emphasis on pre-RC components. The function and mechanism of action of the replication proteins described here are covered in depth in other articles in this collection (Holt and Reyes 2012; Bell and Botchan 2013; Siddiqui et al. 2013).     

Chromoblastomycosis in the Clinical Practice

Chromoblastomycosis is one of the most important implantation (subcutaneous) mycoses in the world. In recent years, the most significant advances against this disease have been made on the molecular taxonomy of the etiologic agents with an increase of the reported cases from Mainland China and South America. This article outlines the actual microbiologic, eco-epidemiologic and clinico-pathologic aspects of the disease, as well as recent therapeutic tolls to treat patients with different severity of chromoblasomycosis lesions.     

Alterations and molecular targeting of the GSK-3 regulator,PI3K,in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is a highly morbid, genetically unstable disease derived from the mucoepithelium of the upper aerodigestive tract. Recent characterization of this disease has implicated the PI3K-Akt-mTOR pathway as one of the most frequently dysregulated pathways. As such, there are several classes of PI3K inhibitors currently undergoing clinical trials. In this article, we review the PI3K pathway, mutations of this pathway in HNSCC, drugs that target PI3K, the impact of these agents on the PI3K and GSK-3 signaling axes, ongoing clinical trials evaluating PI3K inhibitors, and the challenges of using these drugs in the clinic. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.     

宠物犬黑热病的诊断与防控

黑热病（Kala-azar）又称内脏利什曼病（Visceral leishmaniasis,VL）,是由杜利什曼原虫（Leishmaniadonovani）引起,经白蛉（Phlebotomus species）传播所致人兽共患的一种慢性寄生虫性疾病。该病严重危害人类健康,是世界卫生组织的重要目标疾病之一。本文综述了人与宠物犬共患的黑热病的诊断与防控研究进展,为采取更具针对性的预防控制措施提供参考依据。     

Neoadjuvant Therapy for Prostate Cancer: An Oncologist's Perspective

With increasing use of prostate-specific antigen as a screening tool, diagnosis of prostate cancer has undergone a stage migration toward early-stage disease. Although this has increased the proportion of men who are candidates for definitive, potentially curative therapy, it has also made clear the limitations of our current standard of care. Specifically, despite adequate local therapy, a significant proportion of men go on to develop progressive disease. Neoadjuvant systemic therapy is one approach that continues to be studied as a way to maximize cure rates in the setting of early-stage disease. This article reviews the current data regarding neoadjuvant therapy, both hormonal and chemotherapy, and discusses which men are appropriate candidates for this option.     

Endometriosis: New concepts in the pathogenesis

Endometriosis is a gynaecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity. Though there are several theories, research scientists remain unsure as to the definitive cause(s) of endometriosis. Considering the relevant health problems caused by endometriosis, all new information on the pathogenesis of this disease, may have important clinical implications. Goal of this article is to summarize the latest advances in the pathogenesis of endometriosis, with particular emphasis on the embryological theory, that has been recently re-proposed. The possible clinical implications of these findings will be discussed.     

蛋白质组学在阿尔采末病中的研究进展

蛋白质组学是基因组时代产生的一门重要学科,是从整体水平对蛋白质的综合分析。阿尔采末病（Alzheimer’s disease,AD）是常见而复杂的神经退行性疾病之一。应用蛋白质组学对AD进行研究,不仅可在蛋白质水平上揭示疾病的本质,还有助于全面探讨AD的病理机制,建立诊断标准,发现药物治疗靶点。本文从病理机制（特别是蛋白质翻译后修饰）、发现临床生物标签及治疗药物三个方面,对蛋白质组学在AD中的研究进展进行了综替。     

Abeta,oxidative stress in Alzheimer disease: Evidence based on proteomics studies

The initiation and progression of Alzheimer disease (AD) is a complex process not yet fully understood. While many hypotheses have been provided as to the cause of the disease, the exact mechanisms remain elusive and difficult to verify. Proteomic applications in disease models of AD have provided valuable insights into the molecular basis of this disorder, demonstrating that on a protein level, disease progression impacts numerous cellular processes such as energy production, cellular structure, signal transduction, synaptic function, mitochondrial function, cell cycle progression, and proteasome function. Each of these cellular functions contributes to the overall health of the cell, and the dysregulation of one or more could contribute to the pathology and clinical presentation in AD. In this review, foci reside primarily on the amyloid β-peptide (Aβ) induced oxidative stress hypothesis and the proteomic studies that have been conducted by our laboratory and others that contribute to the overall understanding of this devastating neurodegenerative disease. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases.     

Why is there persistent disease despite biologic therapy? Importance of early intervention

This short article hypothesizes that the major reason for persistent disease despite biologic therapy is the inappropriately late timing of therapy with biologic agents. There is clear evidence to support this hypothesis. This short review will indicate that patients treated at an earlier phase of disease can achieve a clinical remission rate of 70% and a response rate of above 95%.The majority of studies of rheumatoid arthritis (RA) have shown that when patients with RA are treated with biologics, they achieve a remission rate of only 30% or less. There are many potential reasons why disease activity is incompletely suppressed by biologics. The most commonly used biologics are anti-cytokines, in particular those that block TNF alpha. Therefore, a logical reason for persistent disease activity is either incomplete blockade of the individual cytokine or the fact that multiple cytokines/alternative mechanisms are implicated in the pathogenesis. A pragmatic second reason is that the outcome measures used to measure response include elements other than disease activity/inflammation. Even when inflammation is completely switched off, these outcome measures may not normalize. An example of this is the reduced impact of inflammation-suppressive therapy on outcome measures in later disease, at a time when there is already extensive damage.This short article, representing a personal view, will examine the hypothesis that a major reason there is persistent disease activity is that anti-cytokine biologics are used inappropriately late in the disease. In patients with late disease, the disease activity score (DAS) reflects damage as well as inflammation and therapy has a large irreversible component. More controversially, the pathogenesis of the disease by this time may have evolved, so that the disease process is less reversible with the blockade of a single cytokine. For both of these reasons, TNF blockade will produce full benefits only when given early in the course of disease.     

A prospective on drug abuse-associated epigenetics and HIV-1 replication

Drugs of abuse serve as cofactors to susceptibility to HIV infection and disease progression. Although clinical reports indicate association between HIV/AIDS and drug use, the molecular mechanism of infection susceptibility and disease progression remains unclear. Drugs such as cocaine exert their addictive effects in part by epigenetic mechanisms. Given that epigenetic modifications play an important role in HIV-1 life cycle, it is essential to unravel whether drug abuse-associated epigenetic changes may contribute to HIV/AIDS. In this article we will provide a prospective on the impact of epigenetic mechanisms on HIV-1 life cycle.