The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene. Clinical characteristics and course of disease of 215 molecularly proven patients (146 index cases and 69 relatives) were analysed. We found 126 distincts variants that were divided into five groups: (1) Glycine substitutions (n=71), (2) splice-site and in-frame insertions-deletions (n=36), (3) variants leading to haplo-insufficiency (n=7), (4) non-glycine missense variants within the triple helix (n=4 variants), and (5) non-glycine missense variants or in-frame insertions-deletions, in the N- or C-terminal part of the protein (n=8). Overall, our cohort confirmed the severity of the disease with a median age at first complication of 29 years (IQR 22-39), the most frequent being arterial (48%) and digestive (24%) ruptures. Groups 2 and 1 were significantly more severe than groups 3-5, with extreme median ages at first major complication of 23-47 years. Patients of groups 3-5 had a less typical phenotype and remarkably absence of digestive events. The distribution of glycine-replacing amino acids was strongly biased towards more destabilizing residues of the collagen assembly. Thus the natural course of vEDS and the clinical phenotype of patients are influenced by the type of COL3A1 variant. This study also confirms that patients with variants located in the C- and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria. These findings may help refine diagnostic strategy, genetic counselling and clinical care.

[THROMBOANGIITIS OBLITERANS (BUERGER'S DISEASE)]. / Maladie de Buerger.

To day there appears to be a consensus to recognize thromboangiftis obliterans (Buerger's disease) as a distinct clinical and pathological entity, characterized by an inflammatory occlusive vasculitis of the small and medium-sized arteries and veins that affects young adult smokers. The strong link with smoking is one of the unique features of thromboangiitis obliterans. Once the disease has became established stepping smoking is the only effective way to prevent evolution of the disease and to reduce the risk of major amputations. Ischaemia of the lower and upper limbs and superficial thrombophlabitis are the essential features of the clinical presentation. However the diagnosis of thromboangiitis is rendered difficult by the lack of specific clinical, radiological, biological and histapathological features. Thus the diagnosis is funded on a probabilistic approach. Discontinuation of tobacco use and to day cannabis are the cornerstone of therapeutic management of patients with thromboangiitis. In patients with ischaemic lesions local care is the other main component of therapeutic management, infusion of iloprost had demonstrated some efficacy.

Efficacy and tolerance of infliximab in refractory Takayasu arteritis: French multicentre study.

OBJECTIVE: To analyse the efficacy and tolerance of infliximab in refractory Takayasu arteritis (TA). METHODS: French multicentre retrospective study that included patients with TA. Clinical disease activity was defined as new vascular and/or constitutional signs. RESULTS: Fifteen patients with TA [median age 41 (range 17-61) years; 13 women] were included. At initiation of infliximab therapy, 14 patients were treated with CSs [prednisone; median dose 20 (range 5-35) mg/day], MTX (n = 7) or AZA (n = 4). Infliximab was used at median 5 (range 3-5) mg/kg at a median of every 6 (range 4-8) weeks. A partial or good overall response was noted in 13 (87%) of the 15 cases, 10 (77%) of the 13 cases and 8 (73%) of the 11 cases at 3, 6 and 12 months, respectively. Clinical and biological activities significantly decreased within 3 months (from 11 at baseline to 4 patients at 12 months; P < 0.05), and similarly for CS dose [from median 20 (range 5-35) mg/day at baseline to median 6 (range 2.5-30) mg/day at 12 months; P < 0.05]. Only one patient was still steroid-dependent at 12 months (vs 8 cases before infliximab). CRP regressed from a median 30 (range 4-70) mg/l to 5 (range 0-57) mg/l and 6 (0-50) mg/l at 3 and 6 months, respectively (P < 0.05). Side effects were two infusion-related reactions, one pulmonary tuberculosis, one severe bacterial infection and EBV reactivation. CONCLUSION: This study confirms the interest of infliximab in terms of clinical and biological response, as well as the steroid-sparing effect in TA.

[Raynaud's phenomenon, disease or syndrome?]. / Phénomène de Raynaud, maladie ou syndrome?

Raynaud's phenomenon is a common symptom. More often it is usually an idiopathic and benign condition. But it can be an early manifestation of a connective tissue disease especially scleroderma and primary Sjogren's syndrom. Thus it is necessary to develop reasonable screening model. If the vasomotor symptoms are localized, a diagnosis of secondary Raynaud's phenomenon is highly probable and the main etiology is an arterial disease. Occupational arterial lesions are a particularly aspect of secondary Raynaud's phenomenon. Calcium channel blockers are the reference for the symptomatic treatment of Raynaud's phenomenon. In severe secondary forms, intravenous iloprost infusion is effective. New drugs as endothelin antagonist and phospodiesterase type 5 inhibitors are still to be evaluated.

Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial.

BACKGROUND: Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a ß(1)-adrenoceptor antagonist with a ß(2)-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. METHODS: Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptritrated by 100 mg steps every 6 months to a maximum of 400 mg per day. [DOSAGE ERROR CORRECTED]. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. FINDINGS: 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15-0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. INTERPRETATION: We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. FUNDING: French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

[New oral anticoagulants: prospects]. / Nouveaux antithrombotiques: perspectives.

Two new oral anticoagulants are licensed in France for prevention for venous thromboembolism in patients undergoing hip or knee arthroplasty. Dabigatran (Pradaxa) inhibits the active site of thrombin. The 220-mg dose is recommended for the majority of patients whereas the 150-mg dose is reserved for patients also taking amiodarone and for those at higher risk for bleeding (patients with moderate renal insufficiency). Rivaroxan (Xarelto) inhibits reversibly the active site of fXa, the 10 mg-dose once daily is recommended started 6 to 12 hours after wound closure. The two drugs are given once daily in fixed doses without coagulation monitoring. However the aim of the new anticoagulants is to replaced VKAs particularly for prevention of stroke in patients with auricular fibrillation and for the treatment of venous thrombo-embolism. Recently published results in these two indications with dabigatran are very promising.

Thromboangiitis obliterans and endothelial function.

BACKGROUND: Endothelial dysfunction may be involved in the pathophysiology of thromboangiitis obliterans (TAO). This study compares endothelial function and large artery stiffness between 10 TAO patients assessed during an exacerbation phase and 10 age- and sex-matched control subjects. MATERIAL AND METHODS: Flow-mediated vasodilation after gradual hand skin heating (from 28 degrees C to 44 degrees C) and endothelium-independent vasodilation after sublingual administration of 150 microg glyceryl trinitrate (GTN) were studied using a high-resolution echotracking system to simultaneously measure the brachial artery (BA) diameter and changes in wall shear stress. Aortic stiffness was assessed by carotid-to-femoral pulse wave velocity. RESULTS: The baseline BA diameter was significantly smaller in TAO patients (3599 +/- 668 microm) than in control subjects (4114 +/- 671, P = 0.04). Hand warming caused a linear increase in shear stress accompanied by a linear increase in BA diameter as a function of increasing temperature for TAO patients and control subjects. There was no significant difference between the two groups [relative increase in BA diameter: + 9.3% (-0.1 to 11.5) vs. + 4.8% (3.0 to 8.1), respectively; P = 0.63]. The slope of the BA diameter vs. shear stress relationship did not significantly differ between the two groups. The relative increase in the BA diameter after GTN was significantly greater in TAO patients than in controls [+ 30.8% (28.6 to 33.6) vs. + 16.2% (12.6 to 21.9) respectively; P = 0.02]. Finally, TAO patients had greater aortic stiffness than control subjects (9.81 +/- 1.72 m s(-1) vs. 7.82 +/- 0.84 m s(-1) respectively; P = 0.0052). CONCLUSIONS: Acute TAO is characterised by vasoconstriction and increased aortic stiffness in the absence of changes in flow-mediated dilation.

[Doctors to be have a lack of interest for general practice. Results from a national Poll in a population of 1 870 undergraduate french medical students concerning speciality choice]. / Désintérêt des futurs médecins pour la médecine générale. Résultats d'une enquête nationale sur les choix de spécialisation auprès de 1 870 externes français.

OBJECTIVES: Analyze the professional wishes of a large sample of medical students in their 6(th) year before the National Ranking Exam. MATERIALS AND METHODS: In March 2009, 3 215 students have participated in a National Practice Ranking Exam. Before getting their results on the Internet, they were invited to answer a questionnaire that included the choice of specialty within 37 choices and socio-demographics data. RESULTS: 1 870 students (59.8%) responded to the questionnaire. Two thirds of students were female (n=1 168; 62.5%) The ranking ranged from 3 to rank 3 215 (mean 1 529+/-20.9). A quarter of students (n=432; 23.1%) wanted to become general practitioners. Medical specialties were more often chosen than surgical specialties (excluding gynecology) (n=521, 27.9% vs. n=344; 18.4%). Gender sifnificantly influenced choice of a specialty (p<0.0001). Men were more attracted to anesthetics [11% (n=77/702) vs. 6% (n=82/1 168)] and surgery [29.9% (n=210) vs. 11.5% (n=134)] while women preferred gynecology [9.2% (n=107) vs. 3.3% (n=23)] and general medicine [28.1% (n=328) vs. 14.8% (n=104)]. On the ranking of mean grade of students, general medicine was last but one. Students wanted to take 74% of available residency offer in gynecology, 62% in surgery, 57% in medicine but only 14 % of general medicine. CONCLUSION: This study confirms the feminization of the medical population, the influence of gender on career choices and the lack of interest of students for general medicine.

Bone marrow-derived mononuclear cell therapy induces distal angiogenesis after local injection in critical leg ischemia.

Critical leg ischemia is associated with a high risk of amputation when revascularization is not possible. Cell therapy based on bone marrow-derived mononuclear cells or with peripheral mononuclear cells, collected after stimulation with G-CSF has been used in an attempt to stimulate angiogenesis. Although several studies have raised the hope that such cell therapy may be effective in critical leg ischemia, no direct demonstration of angiogenesis induced by bone marrow-derived mononuclear cell/peripheral mononuclear cell injection has been reported in man. The aim of this study was to identify and to evaluate the extent of the angiogenic process associated with cell therapy in critical leg ischemia in man. To address this question, this pathological study was conducted in patients enrolled in the OPTIPEC clinical trial (Optimization of Progenitor Endothelial Cells in the Treatment of Critical leg ischemia), an interventional cell therapy study in critical leg ischemia. Amputation specimens from these patients were submitted to a standardized dissection protocol. In three patients, an active angiogenesis was observed in the distal part of the ischemic limb but not in the gastrocnemius muscle, the site of bone marrow cell injection. All the newly formed vessels were positive for endothelial cell markers (CD31, CD34, von Willebrand factor) and negative for markers of lymphatic vessels (podoplanin). Immunohistochemical staining for Ki-67 and c-kit showed extensive endothelial cell proliferation within the new vessels. Bone marrow-derived mononuclear cell therapy in patients with critical leg ischemia induces an active, substained angiogenesis in the ischemic and distal parts of the treated limb, although this may not prevent amputation in some patients with very severe ischemia.