Corticosteroids as an Adjuvant Treatment to Surgery in Chronic Subdural Hematomas: A Multi-Center Double-Blind Randomized Placebo-Controlled Trial.

Chronic subdural hematoma (CSDH) is a common condition necessitating surgery; however, recurrence occurs in 15-25% of cases despite surgical management. The HEMACORT trial was a prospective randomized, double-blind, placebo-controlled, multi-centric study (NCT01380028). The aim of this trial was to determine the effect of corticosteroids as an adjuvant treatment to surgery on CSDH recurrence at 6 months. After surgery, participants were assigned by block-randomization to receive either placebo or oral prednisone at a dose of 1 mg/kg/day followed by weekly stepwise tapering in steps of 10 mg/day. The primary outcome was CSDH recurrence, defined by the need for reoperation and/or radiological progression of CSDH. Secondary outcomes were one-year death, radiological changes, safety, neurological status, and quality of life. The trial was discontinued at midpoint of expected inclusions: 78 participants received prednisone and 77 received placebo controls. In an intention-to-treat analysis, CSDH clinicoradiological recurrence was not different between prednisone and placebo groups (21.8% vs. 35.1%, respectively; hazard ratio 0.56; 95% confidence interval 0.30-1.02; p = 0.06), although post hoc analyses concluded to statistical significance (p = 0.02). Earlier radiological resolution was observed after prednisone administration, but reoperation rates (reaching 5.8% overall) and functional outcomes were not different at 6 months. Among adverse events, sleep disorders occurred more often in the prednisone group (26.1% vs. 9.1%, p = 0.02). The HEMACORT trial data suggest that prednisone, as an adjuvant treatment to surgery, may reduce early radiological recurrence of CSDH, although clinical benefits are unclear. In view of these findings, the authors suggest that shorter treatment duration should be assessed for safety and efficacy in future trials.

Synovial-Fluid miRNA Signature for Diagnosis of Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatism in childhood; microRNAs (miRNAs) have been proposed as diagnostic biomarkers. Although joints are the primary targets for JIA, a synovial fluid-based miRNA signature has never been studied. We aim to identify miRNA biomarkers in JIA by comparing synovial fluid and serum samples from children with JIA and K.kingae septic arthritis (SA). With next-generation high-throughput sequencing, we measured the absolute levels of 2083 miRNAs in synovial fluid and serum from an exploratory cohort of children and validated differentially expressed miRNAs in a replication study by using RT-qPCR. We identified a 19-miRNA signature only in synovial fluid samples that was significantly deregulated, with at least 2-fold change in expression, in JIA versus SA (p < 0.01). The combination of miR-6764-5p, miR-155, and miR-146a-5p expression in synovial fluid yielded an area under the receiver operating characteristic curve of 1 (95% CI 0.978 to 1), thereby perfectly differentiating JIA from SA in children. We propose, for the first time, a synovial fluid-specific miRNA signature for JIA and associated signaling pathways that may indicate potential biomarkers to assist in the classification and differential diagnosis of JIA and help in understanding JIA pathogenesis.

A Molecular Predictor Reassesses Classification of Human Grade II/III Gliomas.

Diffuse gliomas are incurable brain tumors divided in 3 WHO grades (II; III; IV) based on histological criteria. Grade II/III gliomas are clinically very heterogeneous and their prognosis somewhat unpredictable, preventing definition of appropriate treatment. On a cohort of 65 grade II/III glioma patients, a QPCR-based approach allowed selection of a biologically relevant gene list from which a gene signature significantly correlated to overall survival was extracted. This signature clustered the training cohort into two classes of low and high risk of progression and death, and similarly clustered two external independent test cohorts of 104 and 73 grade II/III patients. A 22-gene class predictor of the training clusters optimally distinguished poor from good prognosis patients (median survival of 13-20 months versus over 6 years) in the validation cohorts. This classification was stronger at predicting outcome than the WHO grade II/III classification (P≤2.8E-10 versus 0.018). When compared to other prognosis factors (histological subtype and genetic abnormalities) in a multivariate analysis, the 22-gene predictor remained significantly associated with overall survival. Early prediction of high risk patients (3% of WHO grade II), and low risk patients (29% of WHO grade III) in clinical routine will allow the development of more appropriate follow-up and treatments.

Psychological and physiological effects of bupropion compared to methylphenidate after prolonged administration in healthy volunteers (NCT00285155).

PURPOSE: Bupropion is largely used as an antidepressant and smoking cessation therapy. The aim of this work was to compare pharmacodynamic properties of bupropion and the amphetamine-like methylphenidate after sustained administration in humans. METHODS: Twelve male volunteers completed this randomized, double-blind, placebo controlled, cross-over study. Bupropion and methylphenidate were administered separately for initial half-dose 6-day periods (150 and 10 mg respectively) followed by full-dose 8-day periods (300 and 20 mg respectively). Outcomes were subjective feelings, cognitive performances, autonomic and physiological parameters. RESULTS: Data are expressed as mean(SEM). After repeated administration, bupropion, like methylphenidate, decreased asthenia-fatigue [44(3.2) and 42(3.7), respectively vs. 53(4.1) for placebo; p = 0.034], despite an impairment of sleep onset [-4.3(3.32) and -1.9(3.76), respectively vs. +7.5(3.69); p = 0.016]. Both drugs increased resting diastolic blood pressure [67.9(1.23) and 65.7(0.98), respectively vs. 62.5(1.42) mm Hg; p = 0.001], body temperature [36.5(0.12) and 36.5(0.14) vs. 36.3(0.10) °C; p = 0.037] and decreased body weight [-0.7(0.23) and -0.6(0.22), respectively vs. +0.2(0.27) kg; p = 0.038]. No significant change could be observed on cognitive functions, appetite and energy consumption. CONCLUSION: Although it may not share all the properties of stimulant drugs, the effect profile of bupropion presents a number of similarities with that of methylphenidate over a 2-week treatment period.

Cell death and neuronal differentiation of glioblastoma stem-like cells induced by neurogenic transcription factors.

Glioblastoma multiform (GBM) are devastating brain tumors containing a fraction of multipotent stem-like cells which are highly tumorigenic. These cells are resistant to treatments and are likely to be responsible for tumor recurrence. One approach to eliminate GBM stem-like cells would be to force their terminal differentiation. During development, neurons formation is controlled by neurogenic transcription factors such as Ngn1/2 and NeuroD1. We found that in comparison with oligodendrogenic genes, the expression of these neurogenic genes is low or absent in GBM tumors and derived cultures. We thus explored the effect of overexpressing these neurogenic genes in three CD133(+) Sox2(+) GBM stem-like cell cultures and the U87 glioma line. Introduction of Ngn2 in CD133(+) cultures induced massive cell death, proliferation arrest and a drastic reduction of neurosphere formation. Similar effects were observed with NeuroD1. Importantly, Ngn2 effects were accompanied by the downregulation of Olig2, Myc, Shh and upregulation of Dcx and NeuroD1 expression. The few surviving cells adopted a typical neuronal morphology and some of them generated action potentials. These cells appeared to be produced at the expense of GFAP(+) cells which were radically reduced after differentiation with Ngn2. In vivo, Ngn2-expressing cells were unable to form orthotopic tumors. In the U87 glioma line, Ngn2 could not induce neuronal differentiation although proliferation in vitro and tumoral growth in vivo were strongly reduced. By inducing cell death, cell cycle arrest or differentiation, this work supports further exploration of neurogenic proteins to oppose GBM stem-like and non-stem-like cell growth.

Chronic use of benzodiazepines and latent cognitive decline in the elderly: results from the Three-city study.

We aimed to examine whether long-term use of benzodiazepines is associated with an accelerated decline of cognitive performances by using a statistical model specifically adapted to multivariate longitudinal bounded quantitative outcomes. The data came from the "Three-city" study, a French population based study. All the subjects were 65 years old or older at inclusion and had been followed-up for 7 years. The use of benzodiazepines and cognitive functioning were assessed at each examination phase (baseline, 2, 4 and 7 years). Cognitive decline was analyzed using a nonlinear multivariate mixed model with a latent process. This model makes it possible to assess change over time of the latent cognitive process underlying several neuropsychological tests: Mini Mental Status Examination, Isaacs Set test, Benton Visual Retention Test, and Trail Making Test (A and B), and to describe and account for their metrological properties. Analyses were adjusted for age, center, gender, education, socio-professional status, depression, insomnia, high blood pressure, hypercholesterolemia, alcohol, tobacco consumption and physical activity. Nine hundred and sixty nine subjects who reported taking benzodiazepines for 2, 4 or 7 consecutive years were compared to 4226 subjects who were non-benzodiazepine users. Chronic use of benzodiazepine was significantly associated with a lower latent cognitive level (ß=-1.79 SE=0.25 p=<0.001), but no association was found between chronic use and an acceleration of cognitive decline, neither on the latent cognitive process (ß × time=0.010 SE=0.04 p=0.81), nor on specific neuropsychological tests. Our results suggest that chronic benzodiazepine use is associated with poorer cognitive performance but not with accelerated cognitive decline with age.

Selecting healthy volunteers in specific populations: a retrospective analysis of clinical and laboratory screening.

Healthy volunteers must undergo a medical examination before enrollment in a clinical trial. An increasing number of trials include specific populations designed to match the target populations of the drugs tested. Our study aimed at evaluating which investigations are the most appropriate in different sub-populations of healthy volunteers. Data from 350 healthy volunteers who attended our Research Center from 1997 to 2004 were retrospectively analysed. Volunteers were distributed into five sub-populations: young men, senior men, overweight men, young women, postmenopausal women. The screening procedure comprised a review of medical history, physical examination, electrocardiogram and laboratory tests. Ineligibility criteria were classified as non-medical causes, protocol specific medical causes and non-specific medical causes. A total of 148 subjects (42%) were not-eligible, mainly because of non-specific medical causes (111 subjects), including abnormal medical history (34.5% of all ineligibilities). Blood pressure abnormalities were frequent in all sub-populations except young women. Electrocardiographic abnormalities led to ineligibility of only five overweight men and one menopausal woman. Abnormal laboratory tests accounted for 19.6% of ineligibilities. In senior subjects and overweight men, serologies, liver function tests and lipid profile contributed importantly to the selection process. Low red cells count was the most frequent laboratory abnormality in young women. Erythrocyte sedimentation rate, phosphocalcic metabolism and standard clotting tests led to frequent insignificant and non-contributive abnormalities. Our study confirms that a complete review of medical history is essential and determines the major part of ineligibilities. Complementary laboratory tests are always needed and may be adjusted to the population considered.