Clinical and Electrophysiological Characterization of Essential Tremor in 18 Children and Adolescents.

Background: Essential tremor (ET) is considered the most frequent abnormal movement in the general population, with childhood onset in 5 to 30% of the patients. Methods: A multicenter, descriptive cross-sectional study enrolled patients ⩽18 years with a definite diagnosis of ET according to the International Parkinson and Movement Disorders Society criteria. Demographic data, clinical and electrophysiological characteristics of the tremor, neurological examination and impact on quality of life were collected. Results: 9 males and 9 females were included (mean age of 13.9 years). Tremor was characterized by : upper limb onset at a mean age of 6.5 years; at enrollment, upper limbs localization, and involvement of an additional body region in 28% of the patients; kinetic tremor in all of the patients combined with postural tremor in 17 and rest tremor in 3; tremor mean frequency of 7.6 Hz, mean burst duration of 82.7 ms; identification of mild myoclonic jerks on the polymyographic recordings in 7 patients; altered quality of life with worse emotional outcomes in girls and when a disease duration >5 years was suggested. Discussion: Childhood-onset ET is associated with delayed diagnosis and remarkable functional impact. Electromyographic identification of additional mild myoclonus is a new finding whose significance is discussed. Highlights: ET onset involved upper limbs and at inclusion, 28% of the patients exhibited involvement of an additional body region.ET impacted quality of life for all patients.Girls and patients affected for >5 years reported worse emotional outcomes.Mild myoclonic jerks were identified on 7/17 polymyographic recordings.

[ECRIN standard requirements for good clinical practices-compliant data management in multinational clinical trials]. / Référentiel ECRIN pour la conformité aux bonnes pratiques de gestion des données des essais cliniques multinationaux.

CONTEXT: Clinical studies involve an increasing amount of data collection and management. However, there is no specific quality standard sufficiently practical, in free access, and open for data management and the underlying IT-infrastructure in academic units. European Clinical Research Infrastructures Network (ECRIN) published standard requirements for certified data management units. We present a French version of these standards. METHODS: A group of experts produced the standards, by consensus. The first version was revised after two pilot audits for data centre certification were performed. RESULTS: The revised version includes 21 lists of five to ten standards, in three groups: information technologies, data management (DM) and "general". CONCLUSIONS: These standards offer a clear description of DM and IT requirements for clinical studies. Initially created for ECRIN certification purposes, they offer a very useful reference for academic DM structures.

Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca2+) mishandling. Ca2+ release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca2+ release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca2+ concentration was increased, but RYR1-mediated Ca2+ release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca2+ concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca2+ concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca2+ leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.

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.

Differential Accumulation and Activation of Monocyte and Dendritic Cell Subsets in Inflamed Synovial Fluid Discriminates Between Juvenile Idiopathic Arthritis and Septic Arthritis.

Despite their distinct etiology, several lines of evidence suggest that innate immunity plays a pivotal role in both juvenile idiopathic arthritis (JIA) and septic arthritis (SA) pathophysiology. Indeed, monocytes and dendritic cells (DC) are involved in the first line of defense against pathogens and play a critical role in initiating and orchestrating the immune response. The aim of this study was to compare the number and phenotype of monocytes and DCs in peripheral blood (PB) and synovial fluid (SF) from patients with JIA and SA to identify specific cell subsets and activation markers associated with pathophysiological mechanisms and that could be used as biomarkers to discriminate both diseases. The proportion of intermediate and non-classical monocytes in the SF and PB, respectively, were significantly higher in JIA than in SA patients. In contrast the proportion of classical monocytes and their absolute numbers were higher in the SF from SA compared with JIA patients. Higher expression of CD64 on non-classical monocyte was observed in PB from SA compared with JIA patients. In SF, higher expression of CD64 on classical and intermediate monocyte as well as higher CD163 expression on intermediate monocytes was observed in SA compared with JIA patients. Moreover, whereas the number of conventional (cDC), plasmacytoid (pDC) and inflammatory (infDC) DCs was comparable between groups in PB, the number of CD141+ cDCs and CD123+ pDCs in the SF was significantly higher in JIA than in SA patients. CD14+ infDCs represented the major DC subset in the SF of both groups with potent activation assessed by high expression of HLA-DR and CD86 and significant up-regulation of HLA-DR expression in SA compared with JIA patients. Finally, higher activation of SF DC subsets was monitored in SA compared with JIA with significant up-regulation of CD86 and PDL2 expression on several DC subsets. Our results show the differential accumulation and activation of innate immune cells between septic and inflammatory arthritis. They strongly indicate that the relative high numbers of CD141+ cDC and CD123+ pDCs in SF are specific for JIA while the over-activation of DC and monocyte subsets is specific for SA.

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.

Effects of Nigella sativa seeds (black cumin) on insulin secretion and lipid profile: A pilot study in healthy volunteers.

It has been claimed that Nigella sativa seeds (NSS), also known as black cumin, have antidiabetic and lipid-lowering properties. Our pilot study investigated the effects of powdered NSS on insulin secretion and lipid profile in healthy male volunteers. We conducted a double-blind, randomized, placebo-controlled 4-week trial in 30 subjects, receiving NSS powder (1 g/day) or placebo orally (15 subjects/group). Insulin secretion as determined by the hyperglycaemic clamp technique, insulin sensitivity as well as cholesterol and triglycerides serum concentrations, were measured before and after treatment. NSS powder administration was clinically well tolerated. It did not modify fasting glycaemia and insulinaemia, and was ineffective on glucose-induced insulin secretion and insulin sensitivity. No significant changes on serum lipids were observed after treatment in any treatment groups, nor between the two treatment groups. However, in the treated group only, there was a significant correlation between total cholesterol change after treatment and its baseline level (r = -0.71, P = 0.006, n = 13), and between low-density lipoprotein (LDL) cholesterol change after treatment and its baseline level (r = -0.74, P = 0.004, n = 13). No such correlations were found for high-density lipoprotein (HDL) cholesterol, and for triglycerides. These results do not confirm any NSS effect on glucose regulation; however, they suggest that NSS powder may be of interest in lowering lipid concentrations in hyperlipidaemic subjects.

[Good professional practices of French CICs - version # 2]. / Manuel de bonnes pratiques professionnelles des CIC ­ version no2.

French clinical investigation centers (CICs) are academic platforms dedicated to clinical research. The QUALI-CIC working group helps to improve and harmonize practices within the CIC network. After some years of implementation, the manual of good professional practices of CICs (MGPP CIC) completed in 2010, needed to be revised to best fit with the large panel of CIC activities. The aim was also to make it more accurate and to reinforce requirements about participants safety and data security. In its second version published in the present article, the MGPP CIC includes 255 items divided into 15 chapters. An explanatory document, currently being drafted, will complete the manual to facilitate its implementation.

Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction.

OBJECTIVE: OPA1 mutations are responsible for more than half of autosomal dominant optic atrophy (ADOA), a blinding disease affecting the retinal ganglion neurons. In most patients the clinical presentation is restricted to the optic nerve degeneration, albeit in 20% of them, additional neuro-sensorial symptoms might be associated to the loss of vision, as frequently encountered in mitochondrial diseases. This study describes clinical and neuroradiological features of OPA1 patients. METHODS: Twenty two patients from 17 families with decreased visual acuity related to optic atrophy and carrying an OPA1 mutation were enrolled. Patients underwent neuro-ophthalmological examinations. Brain magnetic resonance imaging (T1, T2 and flair sequences) was performed on a 1.5-Tesla MR Unit. Twenty patients underwent 2-D proton spectroscopic imaging. RESULTS: Brain imaging disclosed abnormalities in 12 patients. Cerebellar atrophy mainly involving the vermis was observed in almost a quarter of the patients; other abnormalities included unspecific white matter hypersignal, hemispheric cortical atrophy, and lactate peak. Neurological examination disclosed one patient with a transient right hand motor deficit and ENT examination revealed hearing impairment in 6 patients. Patients with abnormal MRI were characterized by: (i) an older age (ii) more severe visual impairment with chronic visual acuity deterioration, and (iii) more frequent associated deafness. CONCLUSIONS: Our results demonstrate that brain imaging abnormalities are common in OPA1 patients, even in those with normal neurological examination. Lactate peak, cerebellar and cortical atrophies are consistent with the mitochondrial dysfunction related to OPA1 mutations and might result from widespread neuronal degeneration.

Chemical analysis and antihyperglycemic activity of an original extract from burdock root (Arctium lappa).

In the present study, we obtained a dried burdock root extract (DBRE) rich in caffeoylquinic acids derivatives. We performed the chemical characterization of DBRE and explored its antihyperglycemic potential in both in vitro and in vivo experiments. Chemical analysis of DBRE using LC-MS and GC-MS revealed the presence of a great majority of dicaffeoylquinic acid derivatives (75.4%) of which 1,5-di-O-caffeoyl-4-O-maloylquinic acid represents 44% of the extract. In the in vitro experiments, DBRE is able to increase glucose uptake in cultured L6 myocytes and to decrease glucagon-induced glucose output from rat isolated hepatocytes together with a reduction of hepatic glucose 6-phosphatase activity. DBRE did not increase insulin secretion in the INS-1 pancreatic ß-cell line. In vivo, DBRE improves glucose tolerance both after intraperitoneal and oral subchronic administration. In conclusion, our data demonstrate that DBRE constitutes an original set of caffeoylquinic acid derivatives displaying antihyperglycemic properties.

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.

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.

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.

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.

Closed-loop insulin delivery using a subcutaneous glucose sensor and intraperitoneal insulin delivery: feasibility study testing a new model for the artificial pancreas.

OBJECTIVE: Attempts to build an artificial pancreas by using subcutaneous insulin delivery from a portable pump guided by an subcutaneous glucose sensor have encountered delays and variability of insulin absorption. We tested closed-loop intraperitoneal insulin infusion from an implanted pump driven by an subcutaneous glucose sensor via a proportional-integral-derivative (PID) algorithm. RESEARCH DESIGN AND METHODS: Two-day closed-loop therapy (except for a 15-min pre-meal manual bolus) was compared with a 1-day control phase with intraperitoneal open-loop insulin delivery, according to randomized order, in a hospital setting in eight type 1 diabetic patients treated by implanted pumps. The percentage of time spent with blood glucose in the 4.4-6.6 mmol/l range was the primary end point. RESULTS During the closed-loop phases, the mean +/- SEM percentage of time spent with blood glucose in the 4.4-6.6 mmol/l range was significantly higher (39.1 +/- 4.5 vs. 27.7 +/- 6.2%, P = 0.05), and overall dispersion of blood glucose values was reduced among patients. Better closed-loop glucose control came from the time periods excluding the two early postprandial hours with a higher percentage of time in the 4.4-6.6 mmol/l range (46.3 +/- 5.3 vs. 28.6 +/- 7.4, P = 0.025) and lower mean blood glucose levels (6.9 +/- 0.3 vs. 7.9 +/- 0.6 mmol/l, P = 0.036). Time spent with blood glucose <3.3 mmol/l was low and similar for both investigational phases. CONCLUSIONS: Our results demonstrate the feasibility of intraperitoneal insulin delivery for an artificial beta-cell and support the need for further study. Moreover, according to a semiautomated mode, the features of the pre-meal bolus in terms of timing and amount warrant further research.

A fenugreek seed extract selectively reduces spontaneous fat intake in overweight subjects.

PURPOSE: Fenugreek seeds (Trigonella foenum-graecum L.) have long been used as a herbal medicine for treating metabolic and nutritive dysfunctions. They have been shown to modulate feeding behaviour in animals. We have recently observed a selective decrease in fat consumption in healthy normal weight volunteers treated with a hydro-alcoholic seed extract. However, strong clinical data on the effects of fenugreek seeds on energy intake are lacking, especially in overweight individuals. The aim of our study was to investigate the effects of a repeated administration of a fenugreek seed extract on the eating behaviour of overweight subjects. METHODS: Thirty-nine healthy overweight male volunteers completed a 6-week double-blind randomized placebo-controlled parallel trial of a fixed dose of a fenugreek seed extract. Main endpoints were energy intake (dietary records and meal test), weight, fasting and post-absorptive glucose and insulin, appetite/satiety scores and oxidative parameters. RESULTS: Daily fat consumption, expressed as the ratio fat reported energy intake/total energy expenditure (fat-REI/TEE), was significantly decreased in our overweight subjects administered the fenugreek seed extract relative to those receiving the placebo (fat-REI/TEE 0.26 +/- 0.02 vs. 0.30 +/- 0.01, respectively; P = 0.032). We also observed a significant decrease in the insulin/glucose ratio in subjects treated with fenugreek seed extract relative to the placebo group (0.89 +/- 0.09 vs. 1.06 +/- 0.10 mUI mmol(-1), respectively; P = 0.044). No significant effect was observed on weight, appetite/satiety scores or oxidative parameters. CONCLUSION: The repeated administration of a fenugreek seed extract slightly but significantly decreased dietary fat consumption in healthy overweight subjects in this short-term study.

A fenugreek seed extract selectively reduces spontaneous fat consumption in healthy volunteers.

PURPOSE: Fenugreek seeds (Trigonella foenum-graecum L.) are an old herbal remedy used to treat metabolic and nutritive dysfunctions. They have been shown to modulate feeding behaviour in animals, but strong clinical data are lacking. The aim of this study was to investigate the effects of a repeated administration of a fenugreek seed extract on energy intake and eating behaviour in healthy human volunteers. METHODS: Twelve healthy male volunteers completed a double-blind randomized placebo-controlled three-period cross-over trial of two different doses of a fenugreek seed extract (588 and 1176 mg). The three 14-day treatment periods were separated by a 14-day washout period. The main endpoints were energy intake, assessed in volunteers under normal ambulatory and free-living conditions by a 3-day detailed dietary record and during a meal test, weight, fasting glucose level, insulin and lipid profile, visual analogue scale scores of appetite/satiety and blood glucose and insulin levels measured repeatedly after a standardized breakfast. RESULTS: Daily fat consumption was significantly decreased by the higher dose of fenugreek seed extract [3.73 vs. 4.51 MJ day(-1), -17.3% vs. placebo, 95% confidence interval (CI) -1.51 to -0.05, n = 12, P = 0.038]. This specific reduction tended to lower the total energy intake (9.97 vs. 11.29 MJ day(-1), -11.7% vs. placebo, 95% CI -2.91 to 0.26, n = 12, P = 0.094). No significant effect was observed on the other nutrients or other endpoints. CONCLUSIONS: The repeated administration of a fenugreek seed extract specifically decreases dietary fat consumption in humans which, given the traditional use of the plant, constitutes a novel result.

Nigella sativa seed extracts enhance glucose-induced insulin release from rat-isolated Langerhans islets.

Nigella sativa L. 'Black cumin' (Ranunculaceae) is one of the plants commonly used in Moroccan folk medicine for treatment of various ailments including diabetes mellitus. The present study was undertaken to investigate the effect of different N. sativa seed extracts on insulin secretion. Different fractions of the seed were prepared: the defatted fraction (HR II), which was divided into two subfractions: the first (HR III) containing acidic and neutral compounds and the second (HR IV) containing basic compounds. The insulin secretory effects of these extracts were evaluated individually at different concentrations (0.01, 0.1, 1 and 5 mg/mL), in vitro in isolated rat pancreatic islets in the presence of 8.3 mmol/L glucose. The results show that addition of the defatted whole extract or of the basic subfraction of the seed in the incubation medium significantly increased glucose-induced insulin release from the islets. In the case of the acidic and neutral subfraction, the stimulatory effect was observed only for the higher concentration (5 mg/mL). However, a clear concentration-dependent increase in insulin release from isolated pancreatic islets was observed for the basic subfraction. Our data show that the antidiabetic properties of N. sativa seeds may be, at least partly, mediated by stimulated insulin release, and that the basic subfraction largely contributes to this stimulatory effect. Further phytochemical studies are underway in order to isolate the pharmacological compound(s) responsible for the insulinotropic effect of N. sativa seeds.

Assessment of single-dose benzodiazepines on insulin secretion, insulin sensitivity and glucose effectiveness in healthy volunteers: a double-blind, placebo-controlled, randomized cross-over trial [ISRCTN08745124].

BACKGROUND: The present study aimed at investigating in healthy volunteers the effects of diazepam and clonazepam on beta-cell function, insulin sensitivity and glucose effectiveness based on the frequently sampled intravenous (0.5 gkg-1) glucose tolerance test with minimal-model analysis. METHODS: The study was designed as a double-blind, placebo-controlled, cross-over clinical trial. Diazepam (10 mg) and clonazepam (1 mg) were infused during 30 min to 15 male subjects with a mean age of 22 years (range: 20-29), after informed consent was given. Benzodiazepines were assayed by capillary gas chromatography with electron capture, insulin by radioimmunoassay and glucose by the enzymatic glucose oxidase method. RESULTS: Both benzodiazepines induced significant psychotropic effects. The acute insulin responses (AIR) were significantly and negatively correlated with the clonazepam plasma concentrations (r = -0.609, P < 0.05, n = 14). However, the mean AIR was not significantly different between the benzodiazepine-treated subjects and the controls. In addition, the parameters of glucose assimilation were significantly decreased as compared with placebo in the subgroup of 7 subjects with plasma clonazepam concentrations higher than 6.0 ng ml-1 (median and lower limit of effective therapeutic concentrations): 1.37 +/- 0.3 versus 2.84 +/- 0.60 x 10(-2)min-1 (P = 0.028) for the coefficient of glucose tolerance (Kg), 2.18 +/- 0.29 versus 3.71 +/- 0.89 x 10(-4)microUml-1min-1 (P = 0.018) for insulin sensitivity (Si) and 1.80 +/- 0.39 versus 3.59 +/- 0.71 x 10(-2)min-1 (P = 0.028) for glucose effectiveness at basal insulin (Sg). These parameters were not significantly modified when diazepam was administered; plasma levels of this drug however, were below the effective therapeutic concentrations (300 ng ml-1) from min 15 after the end of the perfusion. CONCLUSION: The present results suggest that a benzodiazepine, in particular clonazepam, may alter insulin secretion and insulin sensitivity after a single administration in healthy volunteers.