Novel features of retroviruses associated with human diseases.

The last decade has witnessed a new chapter in the history of retrovirology. As of now, four human retroviruses have been identified and molecularly characterized. They are associated with a wide spectrum of human diseases including cancer, immunodeficiency and neurological disorders. By virtue of their clinical relevance, their novel genes and regulatory mechanisms these viruses have become the focal point of research in retrovirology. The study of these viruses is of fundamental importance in understanding the mechanisms leading to transformation of human cells and distortion of the immunological state.     

The molecular basis of copper-transport diseases

Copper (Cu) is a potentially toxic yet essential element. MENKES DISEASE, a copper deficiency disorder, and WILSON DISEASE, a copper toxicosis condition, are two human genetic disorders, caused by mutations of two closely related Cu-transporting ATPases. Both molecules efflux copper from cells. Quite diverse clinical phenotypes are produced by different mutations of these two Cu-transporting proteins. The understanding of copper homeostasis has become increasingly important in clinical medicine as the metal could be involved in the pathogenesis of some important neurological disorders such as Alzheimer's disease, motor neurone diseases and prion diseases.     

Role of cognitive parameters in dengue hemorrhagic fever and dengue shock syndrome

Dengue is becoming recognized as one of the most important vector-borne human diseases. It is predominant in tropical and subtropical zones but its geographical distribution is progressively expanding, making it an escalating global health problem of today. Dengue presents with spectrum of clinical manifestations, ranging from asymptomatic, undifferentiated mild fever, dengue fever (DF), to dengue hemorrhagic fever (DHF) with or without shock (DSS), a life-threatening illness characterized by plasma leakage due to increased vascular permeability. Currently, there are no antiviral modalities or vaccines available to treat and prevent dengue. Supportive care with close monitoring is the standard clinical practice. The mechanisms leading to DHF/DSS remains poorly understood. Multiple factors have been attributed to the pathological mechanism, but only a couple of these hypotheses are popular in scientific circles. The current discussion focuses on underappreciated factors, temperature, natural IgM, and endotoxin, which may be critical components playing roles in dengue pathogenesis.     

Genetically Modified Pig Models for Human Diseases

Genetically modified animal models are important for understanding the pathogenesis of human disease and developing therapeutic strategies.Although genetically modified mice have been widely used to model human diseases,some of these mouse models do not replicate important disease symptoms or pathology.Pigs are more similar to humans than mice in anatomy,physiology,and genome. Thus,pigs are considered to be better animal models to mimic some human diseases.This review describes genetically modified pigs that have been used to model various diseases including neurological,cardiovascular,and diabetic disorders.We also discuss the development in gene modification technology that can facilitate the generation of transgenic pig models for human diseases.     

Modelling brain diseases in mice: the challenges of design and analysis

Genetically engineered mice have been generated to model a variety of neurological disorders. Several of these models have provided valuable insights into the pathogenesis of the relevant diseases; however, they have rarely reproduced all, or even most, of the features observed in the corresponding human conditions. Here, we review the challenges that must be faced when attempting to accurately reproduce human brain disorders in mice, and discuss some of the ways to overcome them. Building on the knowledge gathered from the study of existing mutants, and on recent progress in phenotyping mutant mice, we anticipate better methods for preclinical interventional trials and significant advances in the understanding and treatment of neurological diseases.     

Transglutaminase inhibition: A therapy to protect cells from death in neurodegeneration?

Transglutaminases(TGs;E.C.2.3.2.13)are ubiquitous enzymes which catalyze post-translational modifications of proteins.TGs and TG-catalyzed post-translational modifications of proteins have been shown to be involved in the molecular mechanisms responsible for several human diseases.In particular,TG activity has been hypothesized to also be involved also in the molecular mechanisms responsible for human neurodegenerative diseases.In support of this hypothesis,Basso et al recently demonstrated that the TG inhibition protects against oxidative stress-induced neuronal death,suggesting that multiple TG isoforms participate in oxidative stress-induced cell death and that nonselective TG isoform inhibitors will be most effective in fighting oxidative death in neurological disorders.In this commentary,we discuss the possible molecular mechanisms by which TG activity could be involved in the pathogenesis of neurological diseases,with particular reference to neurodegenerative diseases,and the possible involvement of multiple TG isoforms expressed simultaneously in the nervous system in these diseases.Moreover,therapeutic strategies based on the use of selective or nonselective TG inhibitors for the amelioration of thesymptoms of patients with neurological diseases,characterized by aberrant TG activity,are also discussed.     

Postsynaptic signaling at glutamatergic synapses as therapeutic targets

Dysregulation of glutamatergic synapses plays an important role in the pathogenesis of neurological diseases. In addition to mediating excitatory synaptic transmission, postsynaptic glutamate receptors interact with various membrane and intracellular proteins. They form structural and/or signaling synaptic protein complexes and thereby play diverse postsynaptic functions. Recently, several postsynaptic protein complexes have been associated with various neurological diseases and hence, have been characterized as important therapeutic targets. Moreover, novel small molecules and therapeutic peptides targeting and modulating the activities of these protein complexes have been discovered, some of which have advanced through preclinical translational research and/or clinical studies. This article describes the recent investigation of eight key protein complexes associated with the postsynaptic ionotropic and metabotropic glutamate receptors as therapeutic targets for central nervous system diseases.     

Recent advances in the manipulation of murine gene expression and its utility for the study of human neurological disease

Transgenic mouse models have vastly contributed to our knowledge of the genetic and molecular pathways underlying the pathogenesis of neurological disorders that affect millions of people worldwide. Not only have they allowed the generation of disease models mimicking the human pathological state but they have also permitted the exploration of the pathological role of specific genes through the generation of knock-out and knock-in models. Classical constitutive transgenic mice have several limitations however, due to behavioral adaptation process occurring and conditional mouse models are time-consuming and often lack extensive spatial or temporal control of gene manipulation. These limitations could be overcome by means of innovative methods that are now available such as RNAi, viral vectors and large cloning DNA vectors. These tools have been extensively used for the generation of mouse models and are characterized by the superior control of transgene expression that has been proven invaluable in the assessment of novel treatments for neurological diseases and to further investigate the molecular processes underlying the etiopathology of neurological disorders. Furthermore, in association with classical transgenic mouse models, they have allowed the validation of innovative therapeutic strategies for the treatment of human neurological disorders. This review describes how these tools have overcome the limitations of classical transgenic mouse models and how they have been of value for the study of human neurological diseases.     

A new type of anti-ganglioside antibodies present in neurological patients

High titers of anti-GA1 antibodies have been associated with neurological syndromes. In most cases, these antibodies cross-react with the structurally related glycolipids GM1 and GD1b, although specific anti-GA1 antibodies have also been reported. The role of specific anti-GA1 antibodies is uncertain since the presence of GA1 in the human nervous system has not been clarified. A rabbit was immunized with GD1a and its sera were screened for antibody reactivity by standard immunoassay methods (HPTLC-immunostaining and ELISA). Anti-GD1a antibodies were not detected but, unexpectedly, anti-GA1 IgG-antibodies were found. Antibody binding to GA1 was inhibited by soluble GA1 but also by GD1a. These results indicate that the rabbit produced antibodies that recognize epitopes present on the glycolipids, that are absent or not exposed on solid phase adsorbed GD1a. We investigated the presence of these unusual anti-ganglioside antibodies in normal and neurological patient sera. Approximately, 10% of normal human sera contained low titer of specific anti-GA1 IgG-antibodies but none of them recognized soluble GD1a. High titers of IgG-antibodies reacting only with GA1 were detected in 12 patient sera out of 325 analyzed. Of these, 6 sera showed binding that was inhibited by soluble GD1a and four of them also by GM1. This new type of anti-ganglioside antibodies should be considered important elements for understanding of the pathogenesis of these diseases as well as their diagnosis.     

Chronic viral diseases.

Until 20 years ago the only chronic viral diseases known were those considered to be confined to the nervous system. As a result of recent advances in epidemiology, molecular biology and immunology, new viral diseases have been recognized and their clinical features and pathogenesis elucidated. Chronic disease may result from infection with the hepatitis B and D viruses and whatever agent or agents cause hepatitis non-A, non-B, the herpesviruses, Epstein-Barr virus, cytomegalovirus and human T-lymphotropic virus type III. These diseases have common features, including long-term or even lifetime asymptomatic carriage, viremia, with virus free in the plasma or attached to circulating mononuclear cells, presence of virus in body secretions, irreversible tissue injury in target organs and oncogenic potential. New information on these diseases is reviewed. Other chronic diseases for which the cause is currently unknown may eventually prove to be due to viral infection. In addition, vaccines may be developed for prophylaxis of some chronic viral diseases and associated malignant diseases.     

Human bartonellosis: seroepidemiological and clinical features with an emphasis on data from Brazil - a review

Bartonellae are fastidious Gram-negative bacteria that are widespread in nature with several animal reservoirs (mainly cats, dogs, and rodents) and insect vectors (mainly fleas, sandflies, and human lice). Thirteen species or subspecies of Bartonella have been recognized as agents causing human disease, including B. bacilliformis, B. quintana, B. vinsonii berkhoffii, B. henselae, B. elizabethae, B. grahamii, B. washoensis, B. koehlerae, B. rocha-limaea, and B. tamiae. The clinical spectrum of infection includes lymphadenopathy, fever of unknown origin, endocarditis, neurological and ophthalmological syndromes, Carrion's disease, and others. This review provides updated information on clinical manifestations and seroepidemiological studies with an emphasis on data available from Brazil.     

Animal models of Parkinson's disease

Animal models are important tools in experimental medical science to better understand pathogenesis of human diseases. Once developed, these models can be exploited to test therapeutic approaches for treating functional disturbances observed in the disease of interest. On the basis of experimental and clinical findings, Parkinson's disease (PD) was the first neurological disease to be modeled and, subsequently, to be treated by neurotransmitter replacement therapy. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine have been used to develop PD models. Recently, it has been found that agricultural chemicals, such as rotenone and paraquat, when administered systemically, can reproduce specific features of PD in rodents, apparently via oxidative damage. Transgenic animals that over-express alpha-synuclein are used to study the role of this protein in dopaminergic degeneration. This review critically discusses animal models of PD and compares them with characteristics of the human disease.     

FORGE Canada Consortium: Outcomes of a 2-Year National Rare-Disease Gene-Discovery Project

Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGE’s impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally.     

Laminopathies: The molecular background of the disease and the prospects for its treatment

Laminopathies are rare human degenerative disorders with a wide spectrum of clinical phenotypes, associated with defects in the main protein components of the nuclear envelope, mostly in the lamins. They include systemic disorders and tissue-restricted diseases. Scientists have been trying to explain the pathogenesis of laminopathies and find an efficient method for treatment for many years. In this review, we discuss the current state of knowledge about laminopathies, the molecular mechanisms behind the development of particular phenotypes, and the prospects for stem cell and/or gene therapy treatments.     

5-羟甲基胞嘧啶及其TET氧合酶在神经系统发育和相关疾病中的研究进展

神经系统的正常发育是多种因素相互协调作用的结果,一旦特定因素失衡将引起相关疾病的发生。近年来不断有研究发现,DNA去甲基化过程的一类中间产物5-羟甲基胞嘧啶(5-hydroxymethylcytosine, 5hmC)作为一种新的表观遗传标记,在神经系统中高水平分布,并参与认知、记忆等重要的神经功能。5hmC的形成由氧合酶家族分子(ten-eleven translocation protein, TET)催化,在多种神经系统相关疾病中,5hmC水平和TETs分子的表达都发生改变,提示TET-5hmC表观遗传机制在复杂的神经系统发生发展过程中发挥了重要的调控作用。此外,作为基因表达调控的DNA标记物,5hmC的基因定位与基因表达水平的关系也是重要的研究方向。本文就近年来5hmC和TET家族蛋白分子在神经系统发育和相关疾病方面的重要研究发现进行了综述总结,希望为相关领域研究人员深入开展研究提供重要的思路,并为相关疾病设计治疗策略提供理论支持。     

Immunopathology of flavivirus infections

With the recent emergence of the flavivirus, West Nile virus (WNV), in particular, the New York strain of Lineage I WNV in North America in 1999, there has been a significant increase in activity in neurotropic flavivirus research. These viruses cause encephalitis that can result in permanent neurological sequelae or death. Attempts to develop vaccines have made progress, but have been variably successful, despite considerable commercial underwriting. Thus, the discovery of ways and means to combat disease is no less urgent. As such, most recent work has been directed towards dissecting and understanding the pathogenesis of disease, as a way of informing possible approaches to abrogation or amelioration of illness. Whether inherent to flaviviruses or because humans are incidental, dead-end hosts, it is clear that these viruses interact with their human hosts in extremely complex ways. This occurs from the cellular level, at which infection must be established to produce disease, to its interaction with the adaptive immune response, which may result in its eradication, with or without immunopathological and consequent neurological sequelae. As human proximity to and contact with flavivirus insect vectors and amplifying hosts cannot practically be eliminated, our understanding of the pathogenesis of flavivirus-induced diseases, especially with regard to possible targets for treatment, is imperative.     

Seminars in Virology: A Biological Perspective of Slow Virus Infection and Chronic Disease

Sequential events characterize the interaction of viruses with parenchymal cells, and acute lytic infections of tissues and organs have broad biological attributes. A knowledge of these permits a keener understanding of persistent, intermittent herpesvirus infections and persistent, continuous respiratory virus infections. In addition to unique biochemical mechanisms which may permit the latter chronic infections to evolve, the roles of defective and mutant strains of virus, viral interference, and the genetic, developmental and immunological expressions of the host are of considerable and provocative importance.The traditional view of viral infections embraces a broad spectrum of acute pathological and inflammatory events. The relationship of measles virus to subacute sclerosing panencephalitis, the elucidation of the latency of herpes simplex virus, and the slow unmasking of the pathogenesis of multiple sclerosis have illustrated the subtle elements of persistent viral infections of the human being. These chronic neurological diseases have provided the opportunity and stimulus for sharp dissection of the biological and biochemical processes which embellish the logical link of viral infections to other forms of chronic human illness.     

Immunoanatomic dissection of the human urinary tract by monoclonal antibodies

The immunoanatomy of the human kidney and urinary tract has been analyzed by a panel of mouse anti-human monoclonal antibodies that define specific domains and structures. The differentiation antigens detected by these monoclonal antibodies represent a series of glycoproteins characteristic of different cell types. They differ from the blood group antigens and appear to be distinct from other antigens previously described within the kidney or urinary tract. The antigens recognized by these monoclonal antibodies represent an immunohistologic dissection of the human nephron. These antibodies have a broad range of potential applications in studying embryogenesis and pathogenesis of nonneoplastic and neoplastic diseases of the human kidney and urothelium.