Vitamine D et maladie cardiovasculaire: aspects épidémiologiques. [Vitamin D and cardiovascular disease: epidemiological aspects].

The quasi-ubiquitous distribution of vitamin D receptors in the human tissues and the high prevalence of vitamin D deficiency worldwide have generated much enthusiasm about the opportunity of cardiovascular disease prevention through vitamin D supplementation. However, reported associations between vitamin D and cardiovascular disease present important limitations and are prone to confounding and reverse causation. Results from ongoing randomized clinical trials testing the efficacy of vitamin D supplementation to reduce cardiovascular events will not be available before year 2015. This article reviews the epidemiology of vitamin D and provides a brief overview on the relationship between vitamin D and cardiovascular disease.

Steroid use in Crohn's disease.

The incidence and prevalence of Crohn's disease are increasing, particularly in the Western world and Asia. Corticosteroids have been used for decades to treat active Crohn's disease and remain the mainstay in the management of moderate-to-severe relapses in Crohn's disease. The use of corticosteroids, despite their efficacy, may be associated with several drawbacks. This review article provides a comprehensive account of the role of corticosteroids in inducing remission in adult patients with Crohn's disease, including aspects such as approaches to corticosteroid sparing and to minimize the risk of corticosteroid dependency, as well as the role of newer corticosteroids such as budesonide in reducing systemic adverse effects.

The role of the ubiquitin proteasome system in Alzheimer's disease.

Today, Alzheimer's disease (AD) is one of the most important age-related neurodegenerative diseases, but its etiology remains still unknown. Since the discovery that the hallmark structures of this disease i.e. the formation of amyloid fibers could be the product of ubiquitin-mediated protein degradation defects, it has become clear that the ubiquitin-proteasome system (UPS), usually essential for protein repair, turnover and degradation, is perturbed in this disease. Different aspects of normal and pathological aging are discussed with respect to protein repair and degradation via the UPS, as well as consequences of a deficit in the UPS in AD. Selective protein oxidation may cause protein damage, or protein mutations may induce a dysfunction of the proteasome. Such events eventually lead to activation of cell death pathways and to an aberrant aggregation or incorporation of ubiquitinated proteins into hallmark structures. Aggresome formation is also observed in other neurodegenerative diseases, suggesting that an activation of similar mechanisms must occur in neurodegeneration as a basic phenomenon. It is essential to discuss therapeutic ways to investigate the UPS dysfunction in the human brain and to identify specific targets to hold or stop cell decay.

Hepatitis E virus: a zoonosis adapting to humans.

Hepatitis E virus (HEV) infection is gaining global attention, not only because of the increasing burden of the disease in low endemicity countries, in terms of morbidity and mortality rates, but also due to recent advances in the molecular virology and epidemiology of this emerging pathogen. HEV infection spread can be described as the evolution of a zoonosis towards an established human infection. As known from other viruses, such as the human immunodeficiency virus or the influenza viruses, crossing the species barriers from animals to humans is a recurrent phenomenon. Albeit slow at the beginning, once the virus has adapted to humans, the person-to-person spread can proceed very quickly. Although an optimal cell culture system for HEV is not yet available, outstanding progress has been made with the in vitro expression of HEV-like particles. These new tools have fostered new research to understand the molecular, structural and immunological aspects of human HEV infection. Although some promising data from Phase II vaccine trials are available, recent discoveries will certainly open new avenues for HEV-specific prophylaxis and therapy.

Immunological mechanism of action and clinical profile of disease-modifying treatments in multiple sclerosis.

Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials.

Update on basic and clinical aspects of eosinophilic oesophagitis.

The identification of a distinct syndrome, designated eosinophilic oesophagitis (EoE), with its own clinical and histopathological characteristics, was first described in the early 1990s. Meanwhile intense research has uncovered many molecular, immunological and clinical aspects of this chronic-inflammatory disorder. This article focuses exclusively on basic and clinical insights of EoE gathered during the last few years. Regarding aetiopathogenesis it has become clear that EoE is a food-triggered disease with milk and wheat as the dominant culprit food categories. However, it is still debated whether a disturbed mucosal integrity allowing allergens to cross the mucosal barrier, or changes in wheat and milk manufacturing might induce these inflammatory responses. Furthermore, basic science and clinical studies have accordingly confirmed that a chronic eosinophilic inflammation leads to a remodelling of the oesophagus with micro- and macro-morphological alterations, ending in a strictured oesophagus with impaired function. Fortunately, long-term therapeutic trials, using either topical corticosteroids or dietary allergen avoidance, have demonstrated that this sequela can be prevented or even reversed. This finding is of clinical relevance as it supports the initiation of a consistent anti-inflammatory therapy. Nevertheless, EoE is still an enigmatic disease and the long list of unanswered questions will certainly stimulate further research.

La maladie de Fabry chez l'adulte: aspects cliniques et progrès thérapeutiques [Fabry disease in adulthood: clinical aspects and therapeutic progress].

INTRODUCTION: Fabry disease is an X-linked recessive abnormality of glycosphingolipid metabolism that is due to deficiency of the lysosomal enzyme alpha-galactosidase A. CURRENT KNOWLEDGE AND KEY POINTS: A majority of hemizygous men develop severe multisystemic disease (classic form), dominated by renal failure, progressive neurological and cardiac involvement. Nevertheless, some affected men retain sufficient enzyme activity and long remain asymptomatic (atypical form); their main manifestation is hypertrophic cardiomyopathy. Female heterozygous carriers are usually asymptomatic; 15% of them, however, have severe involvement of one or several organs. Laboratory, histologic and molecular diagnosis identifies 100% of hemizygous and over 80% of heterozygous subjects. FUTURE PROSPECTS AND PROJECTS: With developments in molecular genetics, it is now possible to produce the human recombinant enzyme alpha-galactosidase A. Two recent studies had proven that this therapeutic approach was able to be clinically and histologically effective in men. In addition, the results of a trial of gene therapy in a Fabry gene knocked-out mouse appear promising.

Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease.

With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t½) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t½ of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t½ of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t½ of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better clinical response to acetylcholinesterase inhibitors. However, confirmation studies in larger populations are necessary to establish evidence of which subgroups of patients will most likely benefit from anti-dementia drugs. The aim of this review is to summarize the pharmacodynamics and pharmacokinetics of the four commonly used anti-dementia drugs and to give an overview on the current knowledge of pharmacogenetics in this field.

Nouveaux aspects de la prise en charge de l'hypertension artérielle chez le patient insuffisant rénal chronique [New aspects of hypertension management in patients with chronic kidney disease].

Hypertension is a frequent finding in patients with chronic kidney disease. Whether primary or secondary to renal disease, hypertension remains an important risk factory for the progression of chronic kidney disease and the occurrence of cardiovascular events. The objective of this paper is to review different treatment strategies in hypertensive CKD patients, with the exclusion of patients with renal replacement therapy such as dialysis or renal transplantation.

Bloc atrioventriculaire complet sur borréliose de Lyme: aspects etectrocardiographiques, diagnostiques et microbiologiques [Atrioventricular heart block in Lyme disease]

Lyme disease is the most common tick-borne disease in Europe and in the United States. In comparison to dermatological, neurological and rheumatological manifestations, heart disease is quite rare. Atrioventricular heart block is nevertheless the most frequent cardiological manifestation. We hereby report the case of a patient with high degree heart block due to Lyme disease. We focus on the electrocardiographical evolution during antibiotic therapy, as well as on microbiological and diagnostic aspects. Lyme disease is a rare cause of conduction disturbances but it is treatable and potentially reversible.

Development of the First Disease Activity Index for Eosinophilic Esophagitis: Update on the EEsAI in 2011

Background a nd Aims: T he international E EsAI study g roupis currently developing the first activity index (EEsAI) specificfor Eosinophilic Esophagitis (EoE). Goal: To develop, evaluateand validate the EEsAI.Methods: T he d evelopment comprises three phases: 1.Selection of candidate items; 2. Evaluation of the activity indexin a f irst patient cohort; and 3. V alidation in a s econd EoEpatient cohort. Focus group interviews with patients were usedin p hase 1 to generate p atient r eported outcomes ( PRO)according to guidelines o f regulatory authorities ( FDA andEMA), whereas the section of biologic items was developed byDelphi r ounds of i nternational E oE experts from E urope andNorth America.Results: The EEsAI has a modular composition to assess thefollowing components o f EoE activity: p atient reportedoutcomes, endoscopic activity, histologic activity, laboratoryactivity, a nd quality of life. D efinitions f or all aspects o fendoscopic and histologic appearance were established byconsensus rounds among EoE experts. Symptom assessmenttools were created that take into account d ifferent foodconsistencies as w ell as f ood avoidance and specificprocessing strategies. T he EEsAI is evaluated in a c ohort ofadult EoE patients since March 2011.Conclusions: After successful validation, the EEsAI will allowto standardize outcome assessment in E oE t rials which w illlikely lead to its wide applicability.