Desmosomes and disease: pemphigus and bullous impetigo

Desmosomal cadherins are the pathophysiologic targets of autoimmune or toxin-mediated disruption in the human diseases pemphigus and bullous impetigo (including its generalized form, called staphylococcal scalded skin syndrome). Experiments exploiting the production of both pathogenic and nonpathogenic antidesmoglein antibodies in pemphigus patients' sera have afforded data that make an invaluable contribution towards identifying the functional domains of the desmogleins involved in intercellular adhesion. Conformational epitopes of antidesmoglein autoantibodies in pemphigus patients' sera and the specific cleavage site of desmoglein 1 by exfoliative toxin have been identified, implicating the N-terminal extracellular domains of the desmogleins as critical regions for controlling intercellular adhesion. Furthermore, the development of active autoimmune mouse models for pemphigus allows in vivo characterization of the disease and its pathogenesis. These studies offer new insight into the potential mechanisms of acantholysis in pemphigus and staphylococcal-associated blistering disease, with implications for the role of desmogleins in desmosomal structure and function.     

Congenital Chagas disease: an update

Congenital infection with Trypanosoma cruzi is a global problem, occurring on average in 5% of children born from chronically infected mothers in endemic areas, with variations depending on the region. This presentation aims to focus on and update epidemiological data, research methods, involved factors, control strategy and possible prevention of congenital infection with T. cruzi. Considering that etiological treatment of the child is always effective if performed before one year of age, the diagnosis of infection in pregnant women and their newborns has to become the standard of care and integrated into the surveillance programs of syphilis and human immunodeficiency virus. In addition to the standard tests, polymerase chain reaction performed on blood of neonates of infected mothers one month after birth might improve the diagnosis of congenital infection. Recent data bring out that its transmission can be prevented through treatment of infected women before they become pregnant. The role of parasite genotypes and host genetic factors in parasite transmission and development of infection in foetuses/neonates has to be more investigated in order to better estimate the risk factors and impact on health of congenital infection with T. cruzi.     

Desmosomes: emerging pathways and non-canonical functions in cardiac arrhythmias and disease

Desmosomes are critical adhesion structures in cardiomyocytes, with mutation/loss linked to the heritable cardiac disease, arrhythmogenic right ventricular cardiomyopathy (ARVC). Early studies revealed the ability of desmosomal protein loss to trigger ARVC disease features including structural remodeling, arrhythmias, and inflammation; however, the precise mechanisms contributing to diverse disease presentations are not fully understood. Recent mechanistic studies demonstrated the protein degradation component CSN6 is a resident cardiac desmosomal protein which selectively restricts cardiomyocyte desmosomal degradation and disease. This suggests defects in protein degradation can trigger the structural remodeling underlying ARVC. Additionally, a subset of ARVC-related mutations show enhanced vulnerability to calpain-mediated degradation, further supporting the relevance of these mechanisms in disease. Desmosomal gene mutations/loss has been shown to impact arrhythmogenic pathways in the absence of structural disease within ARVC patients and model systems. Studies have shown the involvement of connexins, calcium handling machinery, and sodium channels as early drivers of arrhythmias, suggesting these may be distinct pathways regulating electrical function from the desmosome. Emerging evidence has suggested inflammation may be an early mechanism in disease pathogenesis, as clinical reports have shown an overlap between myocarditis and ARVC. Recent studies focus on the association between desmosomal mutations/loss and inflammatory processes including autoantibodies and signaling pathways as a way to understand the involvement of inflammation in ARVC pathogenesis. A specific focus will be to dissect ongoing fields of investigation to highlight diverse pathogenic pathways associated with desmosomal mutations/loss.     

Toxicoproteomics in human health and disease: an update

Introduction: Toxicoproteomics is an emerging area of omics, intended to explore the changes in protein expression and modifications in biological samples exposed to toxicants. The development of techniques that utilize sophisticated instruments in proteomics has facilitated the exploration of a wide-range of protein coverage and assisted the quantitative and qualitative evaluation of protein changes as a result of the toxic effects of toxic substances.

Areas covered: Studies on toxicoproteomics have an immense potential to explore the molecular mechanism of action of a variety of toxic substances through deciphering the proteomic map altered as a result of toxicant exposure. Here, we provide an overview of toxicoproteomic approaches and the current paradigm of toxicoproteomics.

Expert commentary: Research in this area continues to increase our understanding of the role of toxicants in worsening human health and toxicity driven diseases. The progress in toxicoproteomics may realize the development of novel biomarkers, drug targets and personalized medicines by incorporating the advanced proteomic applications in this field.     

Charcot-Marie-Tooth (CMT) disease: an update

Charcot-Marie-Tooth (CMT) is the generic name given to a group of genetic disorders characterized by a relatively isolated dysfunction of peripheral nerves, with combined motor and sensory impairment. These CMT syndromes are the most frequent genetically-determined peripheral neuropathies, with a global prevalence between 4.7 and 36/100,000. Their clinical phenotype is predominantly motor, with a grossly symmetrical distal amyotrophy involving both lower and upper limbs. Mode of inheritance is variable: autosomal dominant, autosomal recessive or X-linked. Apparently sporadic forms can be a difficult diagnosis and they must be considered in all patients with a chronic polyneuropathy which is not clearly of acquired origin. During the last two decades, the identification of more than 25 genes mutated in CMT syndromes has complicated the classification of these disorders. Knowledge of the function of some of these genes has improved our understanding of the pathogenesis of myelinic or axonal dysfunction in CMT, but for some others their function remains elusive or unknown.     

Parkinson's disease in 1984: an update.

This update reviews several important topics in the field of Parkinson''s disease, including etiologic studies, the types and mechanisms of drug complications and their treatment, when and how to begin treatment, the association of dementia with Parkinson''s disease, and the development of the newer research tools. The recent discovery of a highly selective neurotoxin (MPTP) that causes parkinsonism in humans and other primates and the use of positron emission tomography in living patients should improve our understanding of the cause of cell death in Parkinson''s disease and assist in the development of more definitive treatment for this common, disabling neurologic condition.     

Alzheimer disease, the two-hit hypothesis: an update

Given the relative modality of single-insult models to accurately reflect Alzheimer disease pathogenesis, based on studies on mitogenic and oxidative stress signaling pathways, we proposed a two-hit hypothesis 2 years ago stating that both oxidative stress and mitogenic dysregulation are necessary and sufficient to cause the disease and suggested that it may be a common mechanism for other neurodegenerative diseases as well (X. Zhu, A.K. Raina, G. Perry, M.A. Smith, Alzheimer's disease: the two-hit hypothesis, Lancet Neurol. 3 (2004) 219-226). Recent developments in the field confirm some important predictions of the hypothesis and shed new lights on potential mechanisms regarding how steady state may be achieved in sporadic AD cases and therefore, in our opinion, strengthen the hypothesis, which will be the focus of this review.     

Newborn screening for Pompe disease: an update, 2011

There is mounting evidence in support of universal newborn screening for Pompe disease. Early treatment of children with infantile Pompe disease, prior to clinical diagnosis, is clearly of benefit in prolonging survival and improving cardiac and motor function. Several testing methods applicable to newborn screening using dried blood spots have been described and several are currently being tested in pilot screening programs. Although challenges remain, particularly in identification of the best strategy for follow-up and management of later onset Pompe disease, these challenges can surely be overcome as they have been with other disorders added to the newborn screening panel. It is anticipated that the results of the several pilot programs currently ongoing or in the planning stages in the United States will provide the data necessary to recommend universal newborn screening for Pompe disease for all infants.     

Epidemiology of Chagas disease in Mexico: an update.

With the continuing success of the Southern Cone Initiative against Chagas disease and steady progress of the Andean pact and Central American Initiatives, Mexico is among the last countries of Latin America to instigate a large-scale programme against Trypanosoma cruzi transmission. However, a national policy concerning Chagas disease control in Mexico has recently been developed. The Ministry of Health has approved a law about screening for anti-T. cruzi antibodies in the whole territory. Also, epidemiological surveillance and vector control programmes have started to inform regulation.     

Diagnosis of Hodgkin's disease: an update on histopathological and immunophenotypical features

The Hodgkin lymphoma (HL) is a B-cell lymphoma, as was proved by molecular studies with single-cell PCR. Histologically, it is characterized by a minority of neoplastic cells, Reed-Sternberg cells and its variants, related to a variable non-neoplastic inflammatory background. Nowadays, (WHO classification) the following types of HL are recognized: Nodular Paragranuloma and the Classical Hodgkin Lymphoma, the latter including Nodular Sclerosis, Mixed Cellularity, Lymphocyte-rich Classical Hodgkin Lymphoma and Lymphocyte Depletion. Morphology together with immunohistochemical studies allows to classify the different forms of Hodgkin lymphoma and to make a differential diagnosis with non-Hodgkin lymphomas. All classical Hodgkin lymphomas are treated similarly, and chances for remission and survival are currently good. Molecular parameters should be added to the current classification and patients could benefit from new therapeutic targets.     

Ivermectin: an update

Ivermecan was introduced as an antiparasitic agent in 1981. It is now registered for animal-health use in 35 countries and is being evaluated for possible use in man. This review summarises its antiparasitic efficacy and apparent mode of action. Additional information is given in previous review articles.     

Yersinia: an update

The 8th International Symposium on Yersinia was held in Turku, Finland, 4–8 September 2002.     

Clonorchiasis: an update

Clonorchis sinensis, the Chinese or oriental liver fluke, is an important human parasite and is widely distributed in southern Korea, China (including Taiwan), Japan, northern Vietnam and the far eastern part of Russia. Clonorchiasis occurs in all parts of the world where there are Asian immigrants from endemic areas. The human and animal reservoir hosts (dogs, pigs, cats and rats) acquire the infection from the ingestion of raw fish containing infectious metacercariae. The first intermediate snail hosts are mainly species of Parafossarulus and Bithynia. Numerous species of freshwater fish serve as the second intermediate hosts of C. sinensis. Extensive studies of clonorchiasis during several decades in Japan, Korea, China and other countries have shown much progress in proving its morphological features including ultrastructure, biology, pathogenesis, epidemiology, clinical manifestations and chemotherapy. The present review deals with mainly current results obtained on the epidemiological, pathological and clinical aspects, as well as control measures in endemic areas. As for the complications of clonorchiasis, formation of calculi in the intrahepatic biliary passages is one of the most characteristic pathological features. It is sometimes accompanied by suppurative cholangitis, cholecystitis, cholangiohepatitis and ultimately can cause cholangiocarcinoma. Experimental results on the relationship to the occurrence of cholangiocarcinoma are presented. Clinical diagnosis by radiological findings including cholangiography, sonography and computerized tomography as well as magnetic resonance imaging for biliary or pancreatic ducts are outlined. Current studies on immunology and molecular biology of C. sinensis were introduced. Praziquantel is the drug of choice for clonorchiasis. The most effective regimen is 25 mg kg(-1) three times daily (total dose, 75 mg kg(-1)) administered orally at 5- to 6-h intervals over a single day. Prevention and control measures are also discussed.     

Rendu-Osler disease: clinical and molecular update

The Rendu-Osler disease, also called Hereditary Hemorrhagic Telangiectasia (HHT) affects 1 in -5-8000 people. A french epidemiological study pointed out that it was particularly high in the Haut-Jura mountains in France. This pathology is characterized by frequent nosebleeds, mucocutaneous and visceral telangiectasia and hereditary autosomal-dominant trait. The mucocutaneous telangiectasia are hemorrhagic while the visceral telangiectasia, less frequent, lead to arteriovenous fistula in the lungs, the liver and the brain. HHT disease-causing genes (ENG, ACVRL1 and MADH4) encode proteins that modulate TGFβ superfamilly signaling in vascular endothelial cells. The recent discovery that BMP9 acts as the specific ligand of the receptor ALK1 and endoglin as its co-receptor shows that this signaling pathway is involved in the maturation phase of angiogenesis. Mice heterozygous for endoglin or ALK1 defects reproduce the HHT phenotype and further support the involvement of endothelial hyper proliferation in the pathogenesis of the disease. The medical management of patients remains mainly symptomatic, however the angiogenic trait of this disease should allow us to consider in the future new -therapeutic approaches using anti-angiogenic drugs.