Adult and juvenile dermatomyositis: are the distinct clinical features explained by our current understanding of serological subgroups and pathogenic mechanisms?

Adult and juvenile dermatomyositis share the hallmark features of pathognomic skin rash and muscle inflammation, but are heterogeneous disorders with a range of additional disease features and complications. The frequency of important clinical features such as calcinosis, interstitial lung disease and malignancy varies markedly between adult and juvenile disease. These differences may reflect different disease triggers between children and adults, but whilst various viral and other environmental triggers have been implicated, results are so far conflicting. Myositis-specific autoantibodies can be detected in both adults and children with idiopathic inflammatory myopathies. They are associated with specific disease phenotypes and complications, and divide patients into clinically homogenous subgroups. Interestingly, whilst the same autoantibodies are found in both adults and children, the disease features remain different within autoantibody subgroups, particularly with regard to life-threatening disease associations, such as malignancy and rapidly progressive interstitial lung disease. Our understanding of the mechanisms that underlie these differences is limited by a lack of studies directly comparing adults and children. Dermatomyositis is an autoimmune disease, which is believed to develop as a result of an environmental trigger in a genetically predisposed individual. Age-specific host immune responses and muscle physiology may be additional complicating factors that have significant impact on disease presentation. Further study into this area may produce new insights into disease pathogenesis.     

Multiple sclerosis: etiological mechanisms and future directions

Multiple sclerosis (MS) is a complex human autoimmune-type disease with a predominantly unknown etiology. Immunologic destruction of myelin basic protein (MBP) throughout the nervous system is the major pathology of multiple sclerosis. This review will attempt to update new information about basic mechanisms and therapeutic management of the disease. The significance of the structure of MBP is discussed with respect to the contribution of such structures to the disease process. A number of MBP peptides that serve as the immunodominant antigens in MS patients have been identified. These peptides have been studied in animal models for their antigenic characteristics and ability to induce disease. Evidence for genetic contributions is reviewed with multigenerational twin studies providing the best evidence for susceptible haplotypes. The role of microorganisms/viruses and environmental agents are discussed as potential etiological factors but are now thought to be of minor importance to the primary causal development of the disease. Of major consideration are immunological mechanisms that contribute to the development of autoimmunity. In particular, antigen expression, cytokine and leukocyte interactions, and regulatory T-cells are discussed. Particular attention is given to regulatory T-cells (Treg), which help balance/modulate other T-cells such as Th1 and Th2 cells, and how such Treg regulate autoimmunity is addressed. The importance of the role of Tregs is exemplified by the demonstration that administration of oral antigens can induce specific Tregs that counteract experimental autoimmune encephalomyelitis in animal models. The significance of animal studies to human multiple sclerosis is discussed. A potential role for natural antibodies and innate immune mechanisms to help provide resistance to disease development is also reviewed. Finally, a variety of therapeutic agents that have been and continue to be utilized for multiple sclerosis is reviewed. Trials with oral antigens, such as glatirmer acetate (copolymer 1) especially in combination with interferon-beta, have shown promise. Antibody therapy and bone marrow transplantation are also briefly discussed.     

Urine citrate and renal stone disease.

Calcium stone disease is attributable to supersaturation of the urine with calcium and other salts, the presence of substances that promote crystallization and a deficiency of inhibitors of crystallization. Citrate is a potent inhibitor of calcium oxalate and calcium phosphate stone formation whose excretion is diminished in some patients with stone disease owing to idiopathic causes or secondary factors such as bowel disease and use of thiazides. The pH within the proximal tubule cells is an important determinant of citrate excretion. Multivariate analysis has shown that the urine concentrations of calcium and citrate are the most important factors in stone formation. In uncontrolled studies potassium citrate, which increases urinary citrate excretion, appears to be promising as a therapeutic agent for patients with stone disease and hypocitraturia refractory to other treatment. On the other hand, there are potential drawbacks to sodium alkali therapy, such as the precipitation of calcium phosphates.     

神经变性构象病及其分子基础

构象病的概念被广泛用于命名与蛋白质的构象异常相关的疾病。随着生命科学的进步,人们对神经变性疾病发病的分子机制有了较好的认识,发现几乎所有的此类疾病,诸如阿尔采末病（AD）、帕金森病（PD）、亨廷顿病（HD）以及朊蛋白病（PrD）等都具有一个共同的特征,即病变细胞中蓄积有大量错误折叠并易于聚合的蛋白质,这符合构象病的特点,所以又派生了神经变性构象病的新概念。近年来,人们在神经变性构象病的蛋白质错误折叠和聚合以及其细胞毒性方面的认识越来越走向深入,这将对寻找有效的治疗方法起到极大的推动作用。     

Proteomics in asthma and COPD phenotypes and endotypes for biomarker discovery and improved understanding of disease entities

The application of proteomics to respiratory diseases, such as asthma and COPD, has been limited compared to other fields, like cancer. Both asthma and COPD are recognised to be multi-factorial and complex diseases, both consisting of clusters of multiple disease phenotypes. The complexity of these diseases combined with the inaccessibility and invasiveness of disease relevant samples have provided a hurdle to the progress of respiratory proteomics. Advances in proteomic instrumentation and methodology have led to the possibility to identify proteomes in much smaller quantities of biological material. This review focuses on the efforts in respiratory proteomics in relation to asthma and COPD, and the importance of identifying subgroups of disease entities to establish appropriate biomarkers, and to enhance the understanding of underlying mechanisms in each subgroup. Careful phenotype characterisation of patient subpopulations is required to make improvement in the field of heterogeneous diseases such as asthma and COPD, and the clusters of phenotypes are likely to encompass subgroups of disease with distinct molecular mechanisms; endotypes. The utilisation of modern advanced proteomics in endotypes of asthma and COPD will likely contribute to the increased understanding of disease mechanisms, establishment of biomarkers for these endotypes and improved patient care.     

Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function

The Hermansky-Pudlak syndrome (HPS) is a collection of related autosomal recessive disorders which are genetically heterogeneous. There are eight human HPS subtypes, characterized by oculocutaneous albinism and platelet storage disease; prolonged bleeding, congenital neutropenia, pulmonary fibrosis, and granulomatous colitis can also occur. HPS is caused primarily by defects in intracellular protein trafficking that result in the dysfunction of intracellular organelles known as lysosome-related organelles. HPS gene products are all ubiquitously expressed and all associate in various multi-protein complexes, yet HPS has cell type-specific disease expression. Impairment of specialized secretory cells such as melanocytes, platelets, lung alveolar type II epithelial cells and cytotoxic T cells are observed in HPS. This review summarizes recent molecular, biochemical and cell biological analyses together with clinical studies that have led to the correlation of molecular pathology with clinical manifestations and led to insights into such diverse disease processes such as albinism, fibrosis, hemorrhage, and congenital neutropenia.     

THE SIGNIFICANCE OF INFECTION IN ALLERGIC DISEASE-Its Influence on Diagnosis and Management

The presence of infection in allergic disease produces a confused picture in which two different causative factors must be clearly separated by the physician if he is to treat the patient successfully. The effects of infection are not consistent. There are situations, as seen in infectious diseases, where symptoms of allergic disease are temporarily relieved and others where the infection may intensify or precipitate the allergic condition. It is likewise important to recognize the complications superimposed upon allergic disease by infection. In such cases, control of the infection is as dependent upon control of the allergy as it is upon antibiotics.     

Update on: Shigella new serogroups/serotypes and their antimicrobial resistance

Shigellosis represents a major burden of disease in developing countries. A low infectious dose allows the disease to be spread effectively. Although shigellosis is mostly a self‐limiting disease, antibiotics are recommended to reduce deaths, disease symptoms and organism‐shedding time. However, in India, antimicrobial resistance among the genus Shigella is more common than among any other enteric bacteria. Notably, new serotypes or subserotypes in Shigella are reported from various parts of the world. Identification of new subserotypes of Shigella spp. is becoming a major issue as these strains are nontypeable by conventional serotyping. The commercially available antisera may not cover all possible epitopes of the O lipopolysaccharide antigen of Shigella serotypes. Therefore, molecular methods which most closely approach the resolution of full serotyping are necessary to identify such strains. In addition, the knowledge of a prevalent serotype in various geographic regions may assist in formulating strategies such as the development of a vaccine to prevent infection especially when the immunity to disease is serotype specific, and to understand the disease burden caused by new Shigella serotypes.     

Hermansky–Pudlak syndrome: a disease of protein trafficking and organelle function

The Hermansky–Pudlak syndrome (HPS) is a collection of related autosomal recessive disorders which are genetically heterogeneous. There are eight human HPS subtypes, characterized by oculocutaneous albinism and platelet storage disease; prolonged bleeding, congenital neutropenia, pulmonary fibrosis, and granulomatous colitis can also occur. HPS is caused primarily by defects in intracellular protein trafficking that result in the dysfunction of intracellular organelles known as lysosome‐related organelles. HPS gene products are all ubiquitously expressed and all associate in various multi‐protein complexes, yet HPS has cell type‐specific disease expression. Impairment of specialized secretory cells such as melanocytes, platelets, lung alveolar type II epithelial cells and cytotoxic T cells are observed in HPS. This review summarizes recent molecular, biochemical and cell biological analyses together with clinical studies that have led to the correlation of molecular pathology with clinical manifestations and led to insights into such diverse disease processes such as albinism, fibrosis, hemorrhage, and congenital neutropenia.     

Superantigens: the good, the bad, and the ugly

Increasing evidence suggests that superantigens play a role in immune-mediated diseases. Superantigens are potent activators of CD4+ T cells, causing rapid and massive proliferation of cells and cytokine production. This characteristic of superantigens can be exploited in diseases where strong immunologic responses are required, such as in the B16F10 animal model of melanoma. Superantigen administration is able to significantly enhance ineffective anti-tumor immune responses, resulting in potent and long-lived protective anti-tumor immunity. However, superantigens are more well-known for the role they play in diseases. Studies using an animal model for neurologic demyelinating diseases such as multiple sclerosis show that superantigens can induce severe relapses and activate autoreactive T cells not involved in the initial bout of disease. This may also involve epitope spreading of disease. Superantigens have also been implicated in acute diseases such as food poisoning and TSS, and in chronic diseases such as psoriasis and rheumatoid arthritis. Viral superantigens are also involved in the disease process, including superantigens derived from human immunodeficiency virus and mouse mammary tumor virus. Finally, immunotherapies that ameliorate the role played by superantigens in disease are discussed.     

Intracellular Cholesterol and Phospholipid Trafficking: Comparable Mechanisms in Macrophages and Neuronal Cells

During the past ten years considerable evidences have accumulated that in addition to monocytes/macrophages, that are implicated in innate immunity and atherogenesis, neuronal cells also exhibit an extensive cellular metabolism. The present study focuses on the major protein players that establish cellular distribution of cholesterol and phospholipids. Evidences are provided that neuronal cells and monocytes/macrophages are equipped with comparable intracellular lipid trafficking mechanisms. Selected examples are presented that trafficking dysfunctions lead to disease development, such as Tangier disease and Niemann-Pick disease type C, or contribute to the pathogenesis of diseases such as Alzheimer disease and atherosclerosis.     

Efficacy of the APimicos-B to control and prevent chalkbrood disease in honey bees

Chalkbrood disease in Apis mellifera is a fungal disease affecting developing brood, infested larvae become mummified. As it is a factorial disease, studies on this pathology are obstructed by the need of some predisposing conditions which must occur for such disease to develop. Thus, many questions are yet to be answered about which treatments to apply. The aim of this work is to evaluate the efficacy of the Apimicos-B, a treatment against chalk brood. To induce the disease, some pieces of combs containing susceptible worker brood both from infected and treated colonies and from infected and untreated colonies were cooled. No significant differences were registered (53.12% and 59.58% of mummification respectively).     

THE SIGNIFICANCE OF INFECTION IN ALLERGIC DISEASE—Its Influence on Diagnosis and Management

The presence of infection in allergic disease produces a confused picture in which two different causative factors must be clearly separated by the physician if he is to treat the patient successfully. The effects of infection are not consistent. There are situations, as seen in infectious diseases, where symptoms of allergic disease are temporarily relieved and others where the infection may intensify or precipitate the allergic condition. It is likewise important to recognize the complications superimposed upon allergic disease by infection. In such cases, control of the infection is as dependent upon control of the allergy as it is upon antibiotics.     

Parkinsonian tremor and simplification in network dynamics

We explore the behavior of richly connected inhibitory neural networks under parameter changes that correspond to weakening of synaptic efficacies between network units, and show that transitions from irregular to periodic dynamics are common in such systems. The weakening of these connections leads to a reduction in the number of units that effectively drive the dynamics and thus to simpler behavior. We hypothesize that the multiple interconnecting loops of the brain’s motor circuitry, which involve many inhibitory connections, exhibit such transitions. Normal physiological tremor is irregular while other forms of tremor show more regular oscillations. Tremor in Parkinson’s disease, for example, stems from weakened synaptic efficacies of dopaminergic neurons in the nigro-striatal pathway, as in our general model. The multiplicity of structures involved in the production of symptoms in Parkinson’s disease and the reversibility of symptoms by pharmacological and surgical manipulation of connection parameters suggest that such a neural network model is appropriate. Furthermore, fixed points that can occur in the network models are suggestive of akinesia in Parkinson’s disease. This model is consistent with the view that normal physiological systems can be regulated by robust and richly connected feedback networks with complex dynamics, and that loss of complexity in the feedback structure due to disease leads to more orderly behavior.     

Non-linear transmission and simple models for bovine tuberculosis

1.  A new model is presented for a possum–tuberculosis (TB) system ( Trichosurus vulpecula – Mycobacterium bovis ) that is both realistic and parsimonious. The model includes a phenomenological treatment of heterogeneity of risk for susceptible hosts, similar to that used in insect host–parasitoid systems.
2.  Parameter values for the model reflect current knowledge and differ significantly from those in other recent models of this system. Associated with these structural and parametric changes are substantially different predictions for the dynamics and control of TB in possums.
3.  The model predictions include (i) only limited host suppression due to the disease (< 10%, cf. several earlier simple models for TB in both possums and badgers); (ii) asymptotically stable disease dynamics (cf. homogeneous-mixing models that predict either extremely weak stability such that disease fails to recover when host density is temporarily reduced, or oscillatory behaviour and potential elimination of disease following such a perturbation); (iii) TB that is harder to control than in the homogeneous-mixing model equivalents, in line with practical experience; and (iv) a threshold host density for disease elimination that differs substantially from the host equilibrium density in the presence of disease.
4.  Homogeneous-mixing models are unable to reproduce this behaviour, whatever parameter values are chosen. Heterogeneous-mixing models with non-linear transmission may therefore be worth consideration in other endemic wildlife disease systems, as is now commonplace for insect–parasitoid and insect–pathogen ones.     

Dynamics of an SIQS epidemic model with transport-related infection and exit-entry screenings

Population dispersal, as a common phenomenon in human society, may cause the spreading of many diseases such as influenza, SARS, etc. which are easily transmitted from one region to other regions. Exit and entry screenings at the border are considered as effective ways for controlling the spread of disease. In this paper, the dynamics of an SIQS model are analyzed and the combined effects of transport-related infection enhancing and exit-entry screenings suppressing on disease spread are discussed. The basic reproduction number is computed and proved to be a threshold for disease control. If it is not greater than the unity, the disease free equilibrium is globally asymptotically stable. And there exists an endemic equilibrium which is locally asymptotically stable if the reproduction number is greater than unity. It is shown that the disease is endemic in the sense of permanence if and only if the endemic equilibrium exists. Exit screening and entry screening are shown to be helpful for disease eradication since they can always have the possibility to eradicate the disease endemic led by transport-related infection and furthermore have the possibility to eradicate disease even when the isolated cites are disease endemic.     

Dogs really are man's best friend--canine genomics has applications in veterinary and human medicine!

In 2003, the US National Human Genome Research Institute (NHGRI) agreed to fund a project to sequence the entire genome of a boxer dog named Tasha. Although the USA is a country of dog lovers, with approximately 38 million households owning one or more dogs, why did one of the National Institutes of Health countenance the use of 30 m dollars for such a purpose? The answer is that the NHGRI recognised the value of the dog as an unrivalled model for the study of human disease. In this paper, the reasons why the dog is such a good model are examined. Examples of where the study of disease in dogs is increasing the understanding of the genetic basis of human disease, of the development of improved diagnostic assays and of the evaluation of clinical therapies are provided.     

Atherosclerosis: from lesion formation to plaque activation and endothelial dysfunction

Atherosclerosis is an important source of morbidity and mortality in the developed world. Despite the fact that the association between LDL cholesterol and atherosclerosis has been evident for at least three decades, our understanding of exactly how LDL precipitates atherosclerosis is still in its infancy. At least three working hypotheses of atherosclerosis are now nearing the stage where their critical evaluation is possible through a combination of basic science investigation and murine models of atherosclerosis. As we move forward in our understanding of this disease, efforts will be increasingly focused on the molecular mechanisms of disease activation that precipitate the clinical manifestations of atherosclerosis such as heart attack and stroke. Two candidates for such investigation involve the events surrounding plaque activation and endothelial dysfunction. Further investigation in these fields should provide the necessary insight to develop the next generation of interventions that will reduce the clinical manifestations of this devastating disease. The purpose of this work is to review the major theories of atherogenesis, examine the aspects of atherosclerosis that lead to disease activation and discuss aspects of disease activation that are amenable to treatment.     

Escherichia coli serotyping and disease in man and animals.

Serotyping of Escherichia coli is useful, but complex, with 173 O antigens, 80 K antigens, and 56 H antigens, which can all be subdivided into partial antigens. The O, K, and H antigens can be found in nature in many of the possible combinations. The final number of E. coli serotypes is very high, 50,000-100,000 or more. The number of frequent pathogenic serotypes is, however, limited. Two main groups of such frequent serotypes are (i) serotypes from diarrhoeal disease and (ii) serotypes from extraintestinal disease. Serotypes from diarrhoeal diseases are mostly species specific, and could at present be used as epidemiological markers for bacterial clones equipped with special virulence markers, such as toxins and adhesins. Their O-antigen lipopolysaccharides may be regarded as virulence factors. These strains are not inhabitants of the normal intestine. Serotypes from extraintestinal diseases constitute a different set of clones, which are good colonizers of the intestinal tract, that under certain conditions succeed in invading host tissues. They are characterized by virulence factors different from those found in strains from diarrhoeal disease. Thus, the two groups of pathogenic E. coli are both composed of a limited number of clones for which the O:K:H serotypes are excellent, although not faultless, markers.     

SELDI-TOF-MS技术的改善和优化

表面增强激光解吸电离飞行时间质谱(Surface-enhanced laser desorption/ionization-time of flight,SELDI-TOF-MS)技术是目前蛋白质组学研究较为有效的手段之一,已被广泛的应用于肿瘤、传染性疾病、心血管病和神经系统等疾病的研究.然而SELDI-TOF-MS技术本身存在着一些问题,如分析结果有效性差和实验重复验证率低等,使其不能完全的应用于常规的临床诊断,现有许多研究致力于解决这些问题,如规范化实验室操作、预处理原始标本和数据、提高统计学方法等极大的改善和优化了这项技术.