Unsatisfactory outcomes in myasthenia gravis: influence by care providers.

Myasthenia gravis (MG) can be difficult to treat despite an available therapeutic armamentarium. Our aim was to analyze the factors leading to unsatisfactory outcome (UO). To this end we used the Myasthenia Gravis Foundation of America classification system. Forty one patients with autoimmune MG were followed prospectively from January 2003 to December 2007. Outcomes were assessed throughout follow-up and at a final visit. 'Unchanged', 'worse', 'exacerbation' and 'died of MG' post-intervention status were considered UOs. During follow-up, UO rates reached 54% and were related to undertreatment (41%), poor treatment compliance (23%), infections (23%), and adverse drug effects (13%). The UO rate at final study assessment was 20%. UO during follow-up was significantly (P = 0.004) predictive of UOs at final assessment. When care was provided by neuromuscular (NM) specialists, patients had significantly better follow-up scores (P = 0.01). At final assessment UO rates were 7% and significantly better in patients treated by NM specialists, compared to other physicians where UO rates reached 27%. UO was a frequent finding occurring in more than half our patients during follow-up. Nearly two-thirds of the UOs could have been prevented by appropriate therapeutic adjustments and improved compliance. The differential UO rates at follow-up, their dependency on the degree to which the management was specialized and their correlation with final outcomes suggest that specialized MG care improves outcomes.

Refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the Swiss HIV Cohort Study.

BACKGROUND: We aimed to assess the value of a structured clinical assessment and genetic testing for refining the diagnosis of abacavir hypersensitivity reactions (ABC-HSRs) in a routine clinical setting. METHODS: We performed a diagnostic reassessment using a structured patient chart review in individuals who had stopped ABC because of suspected HSR. Two HIV physicians blinded to the human leukocyte antigen (HLA) typing results independently classified these individuals on a scale between 3 (ABC-HSR highly likely) and -3 (ABC-HSR highly unlikely). Scoring was based on symptoms, onset of symptoms and comedication use. Patients were classified as clinically likely (mean score > or =2), uncertain (mean score > or = -1 and < or = 1) and unlikely (mean score < or = -2). HLA typing was performed using sequence-based methods. RESULTS: From 131 reassessed individuals, 27 (21%) were classified as likely, 43 (33%) as unlikely and 61 (47%) as uncertain ABC-HSR. Of the 131 individuals with suspected ABC-HSR, 31% were HLA-B*5701-positive compared with 1% of 140 ABC-tolerant controls (P < 0.001). HLA-B*5701 carriage rate was higher in individuals with likely ABC-HSR compared with those with uncertain or unlikely ABC-HSR (78%, 30% and 5%, respectively, P < 0.001). Only six (7%) HLA-B*5701-negative individuals were classified as likely HSR after reassessment. CONCLUSIONS: HLA-B*5701 carriage is highly predictive of clinically diagnosed ABC-HSR. The high proportion of HLA-B*5701-negative individuals with minor symptoms among individuals with suspected HSR indicates overdiagnosis of ABC-HSR in the era preceding genetic screening. A structured clinical assessment and genetic testing could reduce the rate of inappropriate ABC discontinuation and identify individuals at high risk for ABC-HSR.

Congenital diaphragmatic hernia: current status and review of the literature.

Treatment of congenital diaphragmatic hernia (CDH) challenges obstetricians, pediatric surgeons, and neonatologists. Persistent pulmonary hypertension (PPHT) associated with lung hypoplasia in CDH leads to a high mortality rate at birth. PPHT is principally due to an increased muscularization of the arterioles. Management of CDH has been greatly improved by the introduction of prenatal surgical intervention with tracheal obstruction (TO) and by more appropriate postnatal care. TO appears to accelerate fetal lung growth and to increase the number of capillary vessels and alveoli. Improvement of postnatal care over the last years is mainly due to the avoidance of lung injury by applying low peak inflation pressure during ventilation. The benefits of other drugs or technical improvements such as the use of inhaled nitric oxide or extracorporeal membrane oxygenation (ECMO) are still being debated and no single strategy is accepted worldwide. Despite intensive clinical and experimental research, the treatment of newborn with CDH remains difficult.

Thrombolyse intracoronarienne comme traitement de l'infarctus en constitution [Intracoronary thrombolysis as a treatment for evolving myocardial infarction].

Myocardial infarction is almost always the consequence of a thrombotic obstruction of one or more coronary arteries. We report our experience with the first 24 cases of intracoronary thrombolysis for recanalization of obstructed coronary arteries. 19 cases were successful, 1 case was partially successful and in 4 instances no reopening was observed. The amount of streptokinase used was 206 000 +/- 107 000 units, and reperfusion was achieved after 37 +/- 27.5 minutes. Recanalization of the vessel was accompanied by cessation of precordial pain and partial or complete normalization of the electrocardiogram. In one case bypass surgery was necessary because of reocclusion. Left ventricular function improvement after thrombolysis was dependent on the time-lag between occlusion and recanalization. These observations confirm others' experience that intracoronary thrombolysis appears to have favorable effects in patients with evolving myocardial infarction.

Effect of elective antibiotic therapy on resting energy expenditure and inflammation in cystic fibrosis.

Cystic fibrosis (CF) patients often present with malnutrition which may partly be due to increased resting energy expenditure (REE) secondary to inflammation. Both REE and tumour necrosis factor-alpha (TNF-alpha), as other markers of inflammation, are elevated during respiratory exacerbations and decrease after antibiotic treatment. However, the effect of antibiotic therapy on REE and inflammation in patients without respiratory exacerbation is not known. The aim of our study was to determine the effect of such an elective antibiotic therapy on REE, TNF-alpha, and other serum markers of inflammation. Twelve CF patients 5F/7M, age 15.9 +/- 6.1 years, weight for height ratio 89 +/- 8% without clinically obvious exacerbation and treated by intravenous antibiotics were studied. Both before (D0) and after (D14) treatment, pulmonary function tests were performed. REE was measured by indirect calorimetry and blood taken to measure inflammation parameters. Body weight increased by 1.1 kg from D0 to D14 (P < 0.001), composed of 0.3 kg fat mass and 0.8 kg fat-free mass (FFM). The forced expiratory volume at 1 s increased from 43 +/- 15% of predicted at D0 to 51 +/- 15% of predicted at D14 (P < 0.01). Mean REE was 41.1 +/- 7.6 kcal/kg FFM per day at D0 and did not change significantly at D14 (40.6 +/- 8.5 kcal/kg FFM per day). Serum markers of inflammation decreased from D0 to D14: C-reactive protein 17 +/- 17 mg/l to 4 +/- 7 mg/l (P < 0.05), elastase 62 +/- 29 microg/l to 45 +/- 18 microg/l (P < 0.02), orosomucoid acid 1.25 +/- 0.11 g/l to 0.80 +/- 0.15 g/l (P < 0.001), and TNF-alpha 37 +/- 14 pg/ml to 29 +/- 6 pg/ml (P = 0.05). Individual values showed a correlation between changes in REE and in TNF-alpha (P < 0.02). The contribution of inflammation to energy expenditure is possible but appears to be minimal in cystic fibrosis patients treated by antibiotics on a regular basis in the absence of clinically obvious exacerbation.

Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.

BACKGROUND: High-dose chemotherapy with autologous stem-cell transplantation is a standard treatment for young patients with multiple myeloma. Residual disease is almost always present after transplantation and is responsible for relapse. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide maintenance therapy after transplantation. METHODS: We randomly assigned 614 patients younger than 65 years of age who had nonprogressive disease after first-line transplantation to maintenance treatment with either lenalidomide (10 mg per day for the first 3 months, increased to 15 mg if tolerated) or placebo until relapse. The primary end point was progression-free survival. RESULTS: Lenalidomide maintenance therapy improved median progression-free survival (41 months, vs. 23 months with placebo; hazard ratio, 0.50; P<0.001). This benefit was observed across all patient subgroups, including those based on the β(2)-microglobulin level, cytogenetic profile, and response after transplantation. With a median follow-up period of 45 months, more than 70% of patients in both groups were alive at 4 years. The rates of grade 3 or 4 peripheral neuropathy were similar in the two groups. The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patient-years in the placebo group (P=0.002). Median event-free survival (with events that included second primary cancers) was significantly improved with lenalidomide (40 months, vs. 23 months with placebo; P<0.001). CONCLUSIONS: Lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival among patients with multiple myeloma. Four years after randomization, overall survival was similar in the two study groups. (Funded by the Programme Hospitalier de Recherche Clinique and others; ClinicalTrials.gov number, NCT00430365.).

Le diabète de type 2 est-il uniquement une affaire d'hyperglycémie? Entre science, humanisme et economie [Type 2 diabetes, is it just a case of hyperglycemia? Confusion between the interests of science, humanity and the economy]

The recommendations for the treatment of type 2 diabetic patients are often centered on the glycemia. These clinical trials based on this approach show only a beneficial effects on the prevention of microangiopathy. The coronary artery disease which is the main cause of mortality among these patients, is not reduced. These data should be interpreted with a systemic prospect. The diabetes vascular complications have multifactorial causes and these clinical trials are motivated for the promotion of hypoglycemic agents. Fortunately, the STENO study offers another glance on the treatment of the diabetes, associating multirisk approach and patients' accompaniment. It obliges to have a critical glance on the research often moved by economic issues and gives to the center a humanistic approach based on the therapeutic relation.

Self-reported non-adherence to antiretroviral therapy repeatedly assessed by two questions predicts treatment failure in virologically suppressed patients.

BACKGROUND: The aim of this study was to explore the predictive value of longitudinal self-reported adherence data on viral rebound. METHODS: Individuals in the Swiss HIV Cohort Study on combined antiretroviral therapy (cART) with RNA <50 copies/ml over the previous 3 months and who were interviewed about adherence at least once prior to 1 March 2007 were eligible. Adherence was defined in terms of missed doses of cART (0, 1, 2 or >2) in the previous 28 days. Viral rebound was defined as RNA >500 copies/ml. Cox regression models with time-independent and -dependent covariates were used to evaluate time to viral rebound. RESULTS: A total of 2,664 individuals and 15,530 visits were included. Across all visits, missing doses were reported as follows: 1 dose 14.7%, 2 doses 5.1%, >2 doses 3.8% taking <95% of doses 4.5% and missing > or =2 consecutive doses 3.2%. In total, 308 (11.6%) patients experienced viral rebound. After controlling for confounding variables, self-reported non-adherence remained significantly associated with the rate of occurrence of viral rebound (compared with zero missed doses: 1 dose, hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.72-1.48; 2 doses, HR 2.17, 95% CI 1.46-3.25; >2 doses, HR 3.66, 95% CI 2.50-5.34). Several variables significantly associated with an increased risk of viral rebound irrespective of adherence were identified: being on a protease inhibitor or triple nucleoside regimen (compared with a non-nucleoside reverse transcriptase inhibitor), >5 previous cART regimens, seeing a less-experienced physician, taking co-medication, and a shorter time virally suppressed. CONCLUSIONS: A simple self-report adherence questionnaire repeatedly administered provides a sensitive measure of non-adherence that predicts viral rebound.

Humoral and cellular rejection after combined liver-kidney transplantation in low immunologic risk recipients.

Combined liver-kidney transplantation is considered a low risk for immunologic complication. We report an unusual case of identical ABO liver-kidney recipient without preformed anti-human leukocyte antigen (HLA) antibodies, transplanted across a T- and B-cell-negative cross-match and complicated by early acute humoral and cellular rejection, first in the liver then in the kidney. While analyzing the immunologic complications in our cohort of 12 low-risk combined liver-kidney recipients, only one recipient experienced a rejection episode without detection of anti-HLA antibody over time. Although humoral or cellular rejection is rare after combined kidney-liver transplantation, our data suggest that even in low-risk recipients, the liver does not always systematically protect the kidney from acute rejection. Indeed, the detection of C4d in the liver should be carefully followed after combined liver-kidney transplantation.

Persistent hyperglycemia at 24-48 h in acute hyperglycemic stroke patients is not associated with a worse functional outcome.

BACKGROUND: Recently, it was shown that the relation between admission glucose and functional outcome after ischemic stroke is described by a J-shaped curve, with a glucose range of 3.7-7.3 mmol/l associated with a favorable outcome. We tested the hypothesis that persistence of hyperglycemia above this threshold at 24-48 h after stroke onset impairs 3-month functional outcome. METHODS: We analyzed all patients with glucose >7.3 mmol/l on admission from the Acute STroke Registry and Analysis of Lausanne (ASTRAL). Patients were divided into two groups according to their subacute glucose level at 24-48 h after last well-being time (group 1: ≤7.3 mmol/l, group 2: >7.3 mmol/l). A favorable functional outcome was defined as a modified Rankin Score (mRS) ≤2 at 3 months. A multiple logistic regression analysis of multiple demographic, clinical, laboratory and neuroimaging covariates was performed to assess predictors of an unfavorable outcome. RESULTS: A total of 1,984 patients with ischemic stroke were admitted between January 1, 2003 and October 20, 2009, within 24 h after last well-being time. In the 421 patients (21.2%) with admission glucose >7.3 mmol/l, the proportion of patients with a favorable outcome was not statistically significantly different between the two groups (59.2 vs. 48.7%, respectively). In multiple logistic regression analysis, unfavorable outcome was significantly associated with age (odds ratio, OR: 1.06, 95% confidence interval, 95% CI: 1.03-1.08 for every 10-year increase), National Institute of Health Stroke Score, NIHSS score, on admission (OR: 1.16, 95% CI: 1.11-1.21), prehospital mRS (OR: 12.63, 95% CI: 2.61-61.10 for patients with score >0), antidiabetic drug usage (OR: 0.36, 95% CI: 0.15-0.86) and glucose on admission (OR: 1.16, 95% CI: 1.02-1.31 for every 1 mmol/l increase). No association was found between persistent hyperglycemia at 24-28 h and outcome in either diabetics or nondiabetics. CONCLUSIONS: In ischemic stroke patients with acute hyperglycemia, persistent hyperglycemia (>7.3 mmol/l) at 24-48 h after stroke onset is not associated with a worse functional outcome at 3 months whether the patient was previously diabetic or not.

Céphalées pharmacorésistantes: nouvelles approches du casse-tête [Drug-resistant headache: is it the end?].

Chronic primary headache often cause significant interference with function and quality of life despite acute and preventive medicines. New treatments are emerging for pharmacologically intractable cluster headache and migraine. Occipital nerve stimulation in chronic cluster headache and botulinum toxin in chronic migraine represent the most promising therapies.

Effects of the PPAR-beta agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination.

BACKGROUND: Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-beta seems to play an important role in the regulation of central inflammation. In addition, PPAR-beta agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-beta agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-gamma and LPS. METHODS: Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-gamma and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-beta, PPAR-gamma, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling. RESULTS: GW 501516 decreased the IFN-gamma-induced up-regulation of TNF-alpha and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-beta agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression. CONCLUSION: Although GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-beta agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes.

La stratégie thérapeutique anti-VEGF améliore le pronostic visuel de la dégénérescence maculaire liée à l'âge exsudative [Intravitreal anti-VEGF injections improve the visual prognosis of wet age related macular degeneration].

Age related macular degeneration (AMD) is an ocular disease with high prevalence among elderly persons. Two different forms exist: dry AMD, usually slowly progressive, and neovascular AMD (wet form) more aggressive. Photodynamic therapy is used to treat the wet form and anti VEGF treatments recently became available and offer a real change in the prognostic of wet AMD. Two products are registered and used in Switzerland (Macugen and Lucentis), a third "off labels product", Avastin is also currently used in clinical practice. Nevertheless, both the duration of treatment and the number of injection requested to stabilise the disease were not defined in the studies. Ongoing studies are mainly evaluating combined treatments and long acting form of the drug.