The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration

The autoimmune model of multiple sclerosis (MS) pathogenesis provided for many years a useful but incomplete conceptual framework for understanding the complex array of factors that lead to the loss of immune homeostasis, myelin and axonal injury, and progressive neurological symptoms. The availability of novel tools in molecular neurogenetics and increasingly sophisticated neuroimaging technologies, together with the revitalization of MS neuropathology, has created a new paradigm for the multidisciplinary study of this disease. This is reflected by the growing resolution of the MS genomic map, discovery of delicate inflammatory networks that are perturbed in MS, identification of mediators of demyelination, and recognition that cumulative axonal loss and neuronal injury are the histological correlates of neurological disability. Together, these advances have set the stage for the development of therapeutic approaches designed to target the demyelinating and neurodegenerative components of the disease and promote repair.     

Genomics and the development of new diagnostics and anti-Candida drugs

Pathogenic Candida species remain a significant medical problem despite the availability of antifungal therapies. Two key issues must be addressed to improve the treatment of life-threatening systemic Candida infections. First, advanced diagnostic tools are required to facilitate the early identification of these infections, when therapeutic intervention is more likely to be effective. Second, improved antifungal therapies are needed. These therapies, which might include combinations of antifungals, need to be less toxic to the patient and more potent in killing a broader range of Candida species. Recent advances in unravelling the genomics of these species should facilitate efforts to achieve these goals. We discuss the contribution of genomics to the development of novel antifungals and new diagnostic tools.     

Protein array diagnostics for guiding therapy in rheumatoid arthritis

Early diagnosis and effective management of rheumatoid arthritis (RA) are pivotal, given the progressive, chronic, inflammatory, multi-systemic nature of the disease. Currently, proper initiation of adequate, individually tailored interventions in RA is delayed by the difficulty of early diagnosis and the limitations of disease activity and therapeutic response assessment tools. This is a significant challenge to rheumatologists, further complicated by the dynamic and progressively evolving autoimmune nature of RA, which is characterized by several immune mediators in a complex network that regulates the perpetuation of inflammation. Protein arrays constitute the most advanced current technology that can provide a comprehensive parallel analysis of this diverse network in RA, providing an individualized insight into immune status and host immune response. The last few years have seen significant transitions in the field of protein arrays, demonstrated by a technologic shift from the bench to the bedside, paving the way for the medical and scientific community to deliver patient-specific assessments and personalized management. Screening of protein arrays with sera or tissues from patients with RA enables the probing of immune responses and the identification of autoantibody signatures that can be used for the diagnosis and therapeutic management of patients. This article reviews the technology and the applications for protein arrays in the diagnosis and prognosis of RA. Clinical assessment tools could be derived from protein arrays, which may provide a means to continually track patients, allowing better evaluation of intervention strategies on a patient-specific basis and identification of diagnostic and disease activity biomarkers that could be used to guide optimal therapy in RA.     

Channelopathies - Emerging Trends in The Management of Inherited Arrhythmias

In spite of their relative rarity, inheritable arrhythmias have come to the forefront as a group of potentially fatal but preventable cause of sudden cardiac death in children and (young) adults. Comprehensive management of inherited arrhythmias includes diagnosing and treating the proband and identifying and protecting affected family members. This has been made possible by the vast advances in the field of molecular biology enabling better understanding of the genetic underpinnings of some of these disease groups, namely congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome. The ensuing knowledge of the genotype-phenotype correlations enables us to risk-stratify, prognosticate and treat based on the genetic test results. The various diagnostic modalities currently available to us, including clinical tools and genetic technologies, have to be applied judiciously in order to promptly identify those affected and to spare the emotional burden of a potentially lethal disease in the unaffected individuals. The therapeutic armamentarium of inherited arrhythmias includes pharmacological agents, device therapies and surgical interventions. A treatment strategy keeping in mind the risk profile of the patients, the local availability of drugs and the expertise of the treating personnel is proving effective. While opportunities for research are numerous in this expanding field of medicine, there is also tremendous scope for incorporating the emerging trends in managing patients and families with inherited arrhythmias in the Indian subcontinent.     

Advances in quantitative proteomics

Large-scale protein quantification has become a major proteomics application in many areas of biological and medical research. During the past years, different techniques have been developed, including gel-based such as differential in-gel electrophoresis (DIGE) and liquid chromatography-based such as isotope labeling and label-free quantification. These quantitative proteomics tools hold significant promise for biomarker discovery, diagnostic and therapeutic applications. They are also important for research in functional genomics and systems biology towards basic understanding of molecular networks and pathway interactions. In this review, we summarize current technologies in quantitative proteomics and discuss recent applications of the technologies.     

构建医患和谐：大型医院图书馆的医学信息服务的“三个面向”

针对临床医疗引发的医患矛盾,从医学信息服务角度提出了以面向医院管理层、临床医务人员和患者的医学信息服务来化解矛盾,阐述了大型医院图书馆以医学信息服务为纽带,构建医患和谐的工作要点。     

Fish oil: what the prescriber needs to know

There is a general belief among doctors, in part grounded in experience, that patients with arthritis need nonsteroidal anti-inflammatory drugs (NSAIDs). Implicit in this view is that these patients require the symptomatic relief provided by inhibiting synthesis of nociceptive prostaglandin E2, a downstream product of the enzyme cyclo-oxygenase (COX), which is inhibited by NSAIDs. However, the concept of 'safe' NSAIDs has collapsed following a multiplicity of observations establishing increased risk for cardiovascular events associated with NSAID use, especially but not uniquely with the new COX-2-selective NSAIDs. This mandates greater parsimony in the use of these agents. Fish oils contain a natural inhibitor of COX, reduce reliance on NSAIDs, and reduce cardiovascular risk through multiple mechanisms. Fish oil thus warrants consideration as a component of therapy for arthritis, especially rheumatoid arthritis, in which its symptomatic benefits are well established. A major barrier to the therapeutic use of fish oil in inflammatory diseases is ignorance of its mechanism, range of beneficial effects, safety profile, availability of suitable products, effective dose, latency of effects and instructions for administration. This review provides an evidence-based resource for doctors and patients who may choose to prescribe or take fish oil.     

Fish oil: what the prescriber needs to know

There is a general belief among doctors, in part grounded in experience, that patients with arthritis need nonsteroidal anti-inflammatory drugs (NSAIDs). Implicit in this view is that these patients require the symptomatic relief provided by inhibiting synthesis of nociceptive prostaglandin E₂, a downstream product of the enzyme cyclo-oxygenase (COX), which is inhibited by NSAIDs. However, the concept of 'safe' NSAIDs has collapsed following a multiplicity of observations establishing increased risk for cardiovascular events associated with NSAID use, especially but not uniquely with the new COX-2-selective NSAIDs. This mandates greater parsimony in the use of these agents. Fish oils contain a natural inhibitor of COX, reduce reliance on NSAIDs, and reduce cardiovascular risk through multiple mechanisms. Fish oil thus warrants consideration as a component of therapy for arthritis, especially rheumatoid arthritis, in which its symptomatic benefits are well established. A major barrier to the therapeutic use of fish oil in inflammatory diseases is ignorance of its mechanism, range of beneficial effects, safety profile, availability of suitable products, effective dose, latency of effects and instructions for administration. This review provides an evidence-based resource for doctors and patients who may choose to prescribe or take fish oil.     

DraGnET: Software for storing,managing and analyzing annotated draft genome sequence data

Background  

New "next generation" DNA sequencing technologies offer individual researchers the ability to rapidly generate large amounts of genome sequence data at dramatically reduced costs. As a result, a need has arisen for new software tools for storage, management and analysis of genome sequence data. Although bioinformatic tools are available for the analysis and management of genome sequences, limitations still remain. For example, restrictions on the submission of data and use of these tools may be imposed, thereby making them unsuitable for sequencing projects that need to remain in-house or proprietary during their initial stages. Furthermore, the availability and use of next generation sequencing in industrial, governmental and academic environments requires biologist to have access to computational support for the curation and analysis of the data generated; however, this type of support is not always immediately available.     

Practical Barriers to Implementation of Thyroid Cancer Guidelines in the Asia-Pacific Region

Objective: Numerous published guidelines have described the optimal management of thyroid cancer. However, these rely on the clinical availability of diagnostic and therapeutic modalities. We hypothesized that the availability of medical resources and economic circumstances vary in Asia-Pacific countries, making it difficult to implement guideline recommendations into clinical practice.Methods: We surveyed participants at the 2009 and 2013 Congresses of the Association of Southeast Asian Nations Federation of Endocrine Societies by distributing questionnaires to attendees at registration.Results: Responses were obtained from 268 respondents in 2009 and 163 respondents in 2013. Similar to the high prevalence of low-risk thyroid cancer observed in the Surveillance, Epidemiology, and End Results database, across the Asia-Pacific countries surveyed in 2009 and 2013, 50 to 100% of the respondents from the Philippines, Malaysia, Singapore, China, Taiwan, Thailand, Hong Kong, Korea, and Sri Lanka reported that more than 50% of the patients had low-risk thyroid cancer on follow-up. Importantly, there was much variation with regards to the perceived availability of investigation and treatment modalities.Conclusion: We found a wide variation in clinicians' perception of availability of diagnostic and therapeutic modalities in the face of a rise in thyroid cancer incidence and thyroid cancer management guidelines that emphasized their importance. The lack of availability of management tools and treatments will prove to be a major barrier to the implementation of thyroid cancer management guidelines in Southeast Asia, and likely in other parts of the world as well.Abbreviations: AFES = ASEAN Federation of Endocrine Societies ASEAN = Association of Southeast Asian Nations ATA = American Thyroid Association FNA = fine-needle aspiration PET = positron emission tomography RAI = radioactive iodine Tg = thyroglobulin TSH = thyroid-stimulating hormone     

Clinical and Molecular Attributes and Evaluation of Pancreatic Cystic Neoplasm

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are all considered “Pancreatic cystic neoplasms (PCNs)” and show a varying risk of developing into pancreatic ductal adenocarcinoma (PDAC). These lesions display different molecular characteristics, mutations, and clinical manifestations. A lack of detailed understanding of PCN subtype characteristics and their molecular mechanisms limits the development of efficient diagnostic tools and therapeutic strategies for these lesions. Proper in vivo mouse models that mimic human PCNs are also needed to study the molecular mechanisms and for therapeutic testing. A comprehensive understanding of the current status of PCN biology, mechanisms, current diagnostic methods, and therapies will help in the early detection and proper management of patients with these lesions and PDAC. This review aims to describe all these aspects of PCNs, specifically IPMNs, by describing the future perspectives.     

Head Injury and Early Signs of Tentorial Herniation: A Management Dilemma

In 100 patients intracranial exploration was done soon after severe head injury when signs of transtentorial herniation were present. A third of patients had extracerebral hematomas shown on initial burr hole examination. An additional 18 percent had parenchymal clots of clinical significance disclosed only by angiography after burr hole exploration or at autopsy. Half the patients in whom exploration was done did not have intracranial hematomas of sufficient size to warrant an operative approach. Detailed neurological examinations soon after injury and the availability of more rapid diagnostic tools may improve the accuracy of early diagnosis and allow more specific prognostication in patients with severe head injury.     

Sperm DNA damage and its role in IVF and ICSI

While the semen analysis has traditionally been relied upon to differentiate fertile and infertile men, its utility has been questioned in the current era of assisted reproductive technologies. The desire for more sophisticated diagnostic and predictive tools has led to increased use of sperm DNA damage in the management of male infertility. Despite the availability of numerous assays to measure sperm DNA damage, our understanding of the etiology, measurement, and clinical implications of sperm DNA damage remains incomplete. While the current evidence is fraught with heterogeneity that complicates attempts at comparison and meta-analysis, there does appear to be a role for sperm DNA damage in the development and maintenance of pregnancy in the era of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). However, as noted by the American Society for Reproductive Medicine, the routine and widespread use of sperm DNA damage testing is not yet supported. Further studies are needed to standardize the measurement of sperm DNA damage and to clarify the exact role of sperm DNA damage within the myriad of other male and female factors contributing to reproductive outcomes in IVF and ICSI.     

Regeneration in medicine: A plastic surgeons “tail” of disease,stem cells,and a possible future

Regeneration in medicine is a concept that has roots dating back to the earliest known records of medical interventions. Unfortunately, its elusive promise has still yet to become a reality. In the field of plastic surgery, we use the common tools of the surgeon grounded in basic operative principles to achieve the present day equivalent of regenerative medicine. These reconstructive efforts involve a broad range of clinical deformities, both congenital and acquired. Outlined in this review are comments on clinical conditions and the current limitations to reconstruct these clinical entities in the effort to practice regenerative medicine. Cleft lip, microtia, breast reconstruction, and burn reconstruction have been selected as examples to demonstrate the incredible spectrum and diverse challenges that plastic surgeons attempt to reconstruct. However, on a molecular level, these vastly different clinical scenarios can be unified with basic understanding of development, alloplastic integration, wound healing, cell–cell, and cell‐matrix interactions. The themes of current and future molecular efforts involve coalescing approaches to recapitulate normal development in clinical scenarios when reconstruction is needed. It will be a better understanding of stem cells, scaffolding, and signaling with extracellular matrix interactions that will make this future possible. Eventually, reconstructive challenge will utilize more than the current instruments of surgical steel but engage complex interventions at the molecular level to sculpt true regeneration. Immense amounts of research are still needed but there is promise in the exploding fields of tissue engineering and stem cell biology that hint at great opportunities to improve the lives of our patients. Birth Defects Research (Part C) 84:322–334, 2008. © 2008 Wiley‐Liss, Inc.     

Closing the translation gap: AI applications in digital pathology

Recent advances in artificial intelligence show tremendous promise to improve the accuracy, reproducibility, and availability of medical diagnostics across a number of medical subspecialities. This is especially true in the field of digital pathology, which has recently witnessed a surge in publications describing state-of-the-art performance for machine learning models across a wide range of diagnostic applications. Nonetheless, despite this promise, there remain significant gaps in translating applications for any of these technologies into actual clinical practice. In this review, we will first give a brief overview of the recent progress in applying AI to digitized pathology images, focusing on how these tools might be applied in clinical workflows in the near term to improve the accuracy and efficiency of pathologists. Then we define and describe in detail the various factors that need to be addressed in order to successfully close the “translation gap” for AI applications in digital pathology.     

Contemplating choice: attitudes towards intervening in human reproduction in Sri Lanka

To date, relatively little is known about the ethical, legal and social responses to recent advances in reproductive and genetic technology outside of Europe and North America. This article reports on a survey carried out among doctors (n?=?278) and medical students (n?=?1256) in Sri Lanka to find out more about their responses to novel interventions in human reproduction such as In-Vitro Fertilization, Pre-Implantation Genetic Diagnosis and genetic engineering. In the first part of the paper comparisons are drawn between this survey and a survey carried out in 1985 which also considered issues surrounding amniocentesis and therapeutic termination. The second part of the paper deals with more recent developments. The analysis reveals high levels of support for the use of new technologies in treating infertility and identifying genetic disorders. However, differences are apparent among the major religious communities represented in the sample and these are particularly in evidence in relation to pre-natal genetic diagnosis. An important theme throughout both surveys is the continuing tension surrounding State policy on termination of pregnancy and the implications this has for the development of screening and counseling services where genetic disorders are concerned.     

Contemplating choice: attitudes towards intervening in human reproduction in Sri Lanka

To date, relatively little is known about the ethical, legal and social responses to recent advances in reproductive and genetic technology outside Europe and North America. This article reports on a survey carried out among doctors (n=278) and medical students (n=1256) in Sri Lanka to find out more about their responses to novel interventions in human reproduction such as In-Vitro Fertilization, Pre-Implantation Genetic Diagnosis and genetic engineering. In the first part of the paper comparisons are drawn between this survey and a survey carried out in 1985 which also considered issues surrounding amniocentesis and therapeutic termination. The second part of the paper deals with more recent developments. The analysis reveals high levels of support for the use of new technologies in treating infertility and identifying genetic disorders. However, differences are apparent among the major religious communities represented in the sample and these are particularly in evidence in relation to prenatal genetic diagnosis. An important theme throughout both surveys is the continuing tension surrounding State policy and termination of pregnancy and the implications this has for the development of screening and counseling services where genetic disorders are concerned.     

Impact of the US Patent System on the Promise of Personalized Medicine

The biotechnology revolution promises unfathomable future scientific discovery. One of the potential benefits is the accelerated introduction of new diagnostics and treatments to the general public. The right medication for the right patient is the goal of personalized medicine, which directly benefits from many of biotechnology's biggest and most recent advances. The US patent system rewards innovation in medicine and other arts and sciences by granting innovators, for a period of time, the right to exclude others from using what was invented. One of the purposes of the patent system is to trade that right to exclude, and in its stead obtain the patent holder's obligation to fully and publicly disclose the essence of the innovations so that they can be improved, thus advancing the common welfare. A tension exists between personalized medicine's need for access to and use of scientific advances and the patent system's reward of exclusive use or nonuse to innovators. This tension may result in fewer diagnostic and therapeutic tools brought to the market and generally adopted. The risk seems particularly acute with respect to the diagnostic and therapeutic tools arising from genetic testing that hold specific value for a subset of the population. The judicial system has introduced ethical exceptions that overcome a patent holder's right to exclude; these judicial overrides relate to the provision of certain types of medical procedures and the development of certain types of new drugs, and not, apparently, to the use of diagnostic and therapeutic tools essential to the success of personalized medicine. A serious question exists as to whether legislative action is necessary to increase public access to genetic testing.