Vitamin D levels and associated factors: a population-based study in Switzerland.

QUESTIONS UNDER STUDY: To update the prevalence of vitamin D insufficiency and to identify factors associated with vitamin D status in the Swiss adult population. METHODS: Data from the 2010-2011 Swiss Study on Salt intake, a population-based study in the Swiss population, was used. Vitamin D concentration in serum was measured by liquid chromatography- tandem mass spectrometry. Major factors that influence vitamin D levels were taken into account. Survey statistical procedures were used to estimate means and prevalences of vitamin D levels and status. Monthly-specific tertiles of vitamin D and ordinal logistic regression were used to determine the associations of covariates of interest with vitamin D status. RESULTS: The prevalences of vitamin D insufficiency (serum 25-hydroxyvitamin D: 20-29.9 ng/ml) and deficiency (<20 ng/ml) were the highest in the January-March period; 26.4% (95%CI: 21.6-31.7) and 61.6% (95%CI: 56.0-67.0), respectively. In the same period, more than 9 of ten men were vitamin D insufficient or deficient. Each unit increase of Body Mass Index was associated with an 8% decreased likelihood of being in a higher vitamin D tertiles. Oral contraceptive, altitude, urinary excretion of calcium, use of vitamin D supplement or treatment, high wine consumption, physical activity were associated with vitamin D tertiles. Compared to the French-speaking region, the Italian-speaking region was independently associated with a higher likelihood of being in higher vitamin D tertiles (OR: 1.66, 95%CI: 1.14-2.43). CONCLUSIONS: Low levels of vitamin D are common among Swiss adults, in particular during winter months and outside the Italian-speaking region.

Traitement de la dépression résistante par l'association citalopram-lithium. Méthodologie d'une étude multicentrique en double aveugle et résultats préliminaires [Treatment of resistant depression with the citalopram-lithium combination. Methodology of a double-blind multicenter study and preliminary results].

Citalopram, a new bicyclic antidepressant, is the most selective serotonin reuptake inhibitor. In a number of double-blind controlled studies, citalopram was compared to placebo and to known tricyclic antidepressants. These studies have shown their efficacy and good safety. The inefficacy of a psychotropic treatment in at least 20% of depressives has led a number of authors to propose original drug combinations and associations, like antidepressant/lithium (Li), antidepressant/sleep deprivation (agrypnia), antidepressant/ECT, or antidepressant/LT3. The aim of this investigation is to evaluate the clinical effectiveness and safety of a combined citalopram/lithium treatment in therapy-resistant patients, taking account of serotonergic functions, as tested by the fenfluramine/prolactin test, and of drug pharmacokinetics and pharmacogenetics of metabolism. DESIGN OF THE STUDY: A washout period of 3 days before initiating the treatment is included. After an open treatment phase of 28 days (D) with citalopram (20 mg D1-D3; 40 mg D4-D14; 40 or 60 mg D15-D28; concomitant medication allowed: chloral, chlorazepate), the nonresponding patients [less than 50% improvement in the total score on the 21 item-Hamilton Depression Rating Scale (HDRS)] are selected and treated with or without Li (randomized in double-blind conditions: citalopram/Li or citalopram/placebo) during the treatment (D29-D35). Thereafter, all patients included in the double-blind phase subsequently receive an open treatment with citalopram/Li for 7 days (D36-D42). The hypothesis of a relationship between serotoninergic functions in patients using the fenfluramine/prolactin test (D1) and the clinical response to citalopram (and Li) is assessed. Moreover, it is evaluated whether the pharmacogenetic status of the patients, as determined by the mephenytoin/dextromethorphan test (D0-D28), is related to the metabolism of fenfluramine and citalopram, and also to the clinical response. CLINICAL ASSESSMENT: Patients with a diagnosis of major depressive disorders according to DSM III are submitted to a clinical assessment of D1, D7, D14, D28, D35, D42: HDRS, CGI (clinical global impression), VAS (visual analog scales for self-rating of depression), HDRS (Hamilton depression rating scale, 21 items), UKU (side effects scale), and to clinical laboratory examens, as well as ECG, control of weight, pulse, blood pressure at D1, D28, D35. Fenfluramine/prolactin test: A butterfly needle is inserted in a forearm vein at 7 h 45 and is kept patent with liquemine. Samples for plasma prolactin, and d- and l-fenfluramine determinations are drawn at 8 h 15 (base line). Patients are given 60 mg fenfluramine (as a racemate) at 8 h 30. Kinetic points are determined at 9 h 30, 10 h 30, 11 h 30, 12 h 30, 13 h 30. Plasma levels of d- and l-fenfluramine are determined by gas chromatography and prolactin by IRNA. Mephenytoin/dextromethorphan test: Patients empty their bladders before the test; they are then given 25 mg dextropethorphan and 100 mg mephenytoin (as a racemate) at 8 h 00. They collect all urines during the following 8 hours. The metabolic ratio is determined by gas chromatography (metabolic ratio dextromethorphan/dextrorphan greater than 0.3 = PM (poor metabolizer); mephenytoin/4-OH-mephenytoin greater than 5.6, or mephenytoin S/R greater than 0.8 = PM). Citalopram plasma levels: Plasma levels of citalopram, desmethylcitalopram and didesmethylcitalopram are determined by gas chromatography--mass spectrometry. RESULTS OF THE PILOT STUDY. The investigation has been preceded by a pilot study including 14 patients, using the abovementioned protocol, except that all nonresponders were medicated with citalopram/Li on D28 to D42. The mean total score (n = 14) on the 21 item Hamilton scale was significantly reduced after the treatment, ie from 26.93 +/- 5.80 on D1 to 8.57 +/- 6.90 on D35 (p less than 0.001). A similar patCitalopram, a new bicyclic antidepressant, is the most selective serotonin reu

Etude prospective sur l'utilité et valeur diagnostique du PET/CT au 18F-FDG pour le diagnostic d'infection sur cathéters veineux centraux permanents

Contexte Lié au vieillissement et à la sédentarisation de la population, ainsi qu'à la chronicisation du cancer, l'emploi de cathéters veineux centraux permanents (CVCP) n'a cessé d'augmenter. La complication majeure de ces dispositifs, induisant de forts taux de morbi-mortalité, est l'infection. Actuellement, le diagnostic de ces infections reste surtout basé sur la clinique et les hémocultures. Lorsque le doute persiste, une ablation chirurgicale suivie de la mise en culture des prélèvements chirurgicaux et du cathéter permettent de poser le diagnostic. En clinique, après ces examens, nous constatons que seule la moitié des cathéters retirés étaient réellement infectés. Alors que la tomographie par émission de positons fusionnée à la tomographie (PET/CT) a montré de bons résultats dans la détection des infections chroniques, la valeur diagnostique du PET/CT au fluorodeoxyglucose marqué au 18F (18F-FDG) pour les infections de CVCP n'a encore jamais été déterminée dans une étude prospective. Objectifs Au travers de cette étude prospective, ouverte et monocentrique, nous chercherons à connaître la valeur diagnostique du PET/CT au 18F-FDG dans la détection d'infections de CVCP et ainsi d'en déterminer son utilité. Nous essaierons aussi de déterminer la différence de valeur diagnostique du PET/CT au 18F-FDG par rapport aux méthodes conventionnelles (paramètres cliniques et culture du liquide d'aspiration), afin de se déterminer sur l'éventuelle utilité diagnostique de celui-ci. Méthodes Cadre : Etude prospective d'au moins 20 patients, avec 2 groupes contrôles d'au moins 10 patients ayant chacun respectivement une faible et une forte probabilité d'infection, soit au moins 40 patients au total. Population : patients adultes avec CVCP devant être retiré. Cette étude prévoit un examen PET/CT au 18F-FDG effectué auprès de patients nécessitant une ablation de CVCP sur suspicion d'infection, sans confirmation possible par les moyens diagnostiques non chirurgicaux. Deux acquisitions seront réalisées 45 et 70 minutes après l'injection de 5,5MBq/Kg de 18F-FDG. Le groupe contrôle à faible probabilité d'infection, sera formé de patients bénéficiant de l'ablation définitive d'un CVCP pour fin de traitement durant le laps de temps de l'étude, et ayant bénéficié au préalable d'un examen PET/CT pour raison X. Après avoir retiré chirurgicalement le CVCP, nous utiliserons la culture microbiologique des deux extrémités du CVCP comme étalon d'or (gold standard) de l'infection. Le groupe contrôle à forte probabilité d'infection sera formé de patients nécessitant une ablation de CVCP sur infection de CVCP confirmée par les moyens diagnostiques non chirurgicaux (culture positive du liquide de l'aspiration). Lors de l'examen PET/CT, ces patients auront aussi deux acquisitions réalisées 45 et 70 minutes après l'injection de 5,5MBq/Kg de 18F-FDG. Les résultats de ces examens seront évalués par deux spécialistes en médecine nucléaire qui détermineront le niveau de suspicion de l'infection sur une échelle de Likert allant de I à V, sur la base du nombre de foyers, de la localisation du foyer, de l'intensité de la captation de 18F-FDG au voisinage du cathéter et du rapport tissu/arrière-plan. Par la suite, nous retirerons chirurgicalement le CVCP. Nous utiliserons la culture microbiologique du pus (si présent), des deux extrémités du CVCP ainsi que l'histologie des tissus formant un tunnel autour du cathéter comme étalon d'or de l'infection. Les résultats seront analysés à l'aide de courbes ROC (Receiver Operating Characteristic) afin de déterminer la valeur diagnostique du PET/CT dans l'infection de CVCP. Les résultats des examens des patients avec suspicion clinique d'infection seront ensuite analysés séparément, afin de déterminer la différence de valeur diagnostique du PET/CT au 18F-FDG par rapport aux méthodes conventionnelles. Résultats escomptés Ce projet veut chercher à savoir si le PET/CT au 18F-FDG peut être un moyen diagnostique valide dans les infections de CVCP, s'avérer utile lorsque les autres moyens diagnostiques sont non conclusifs. Plus-value escomptée Actuellement, lors d'incertitude sur le diagnostic d'infection de CVCP, une opération chirurgicale est effectuée à titre préventif afin d'enlever le cathéter en cause, cependant seulement la moitié de ces cathéters sont réellement infectés en pratique. Le PET/CT au 18F-FDG, grâce à sa sensibilité élevée et probablement une bonne valeur prédictive négative, pourrait éviter à une partie des patients un retrait inutile du cathéter, diminuant ainsi les risques chirurgicaux et les coûts liés à de telles opérations, tout en préservant le capital d'accès vasculaire futur.

Psychiatric comorbidity and additional abuse of drugs in maintenance treatment with l- and d,l-methadone.

Sixty d,l- or l-methadone treated patients in maintenance therapy were interviewed for additional drug abuse and psychiatric comorbidity; 51.7% of the entire population had a comorbid Axis-I disorder, with a higher prevalence in females (P=0.05). Comorbid patients tended to have higher abuse of benzodiazepines, alcohol, cannabis, and cocaine, but not of heroin. They had received a significantly lower d,l- (P<0.05) and l-methadone dose than non-comorbid subjects. The duration of maintenance treatment showed an inverse relationship to frequency of additional heroin intake (P<0.01). Patients with additional heroin intake over the past 30 days had been treated with a significantly lower l-methadone dosage (P<0.05) than patients without. Axis-I comorbidity appears to be decreased when relatively higher dosages of d,l- (and l-methadone) are administered; comorbid individuals, however, were on significantly lower dosages. Finally, l-, but not d,l-methadone seems to be more effective in reducing additional heroin abuse.

Rôle de l'activation de c-Jun N-terminal kinase (JNK) dans un modèle de glaucome chez le rat et neuroprotection par inhibition de la voie de JNK

RESUME : Dans ce travail effectué chez le rat adulte, l'excitotoxicité rétinienne est élicitée par injection intravitréenne de NMDA. Les lésions en résultant sont localisées dans la rétine interne. Elles prennent la forme de pycnoses dans la couche des cellules ganglionnaires (corps cellulaires des cellules ganglionnaires et amacrines déplacées) et dans la partie interne de la couche nucléaire interne (cellules amacrines). Cette localisation est liée à la présence de récepteurs au glutamate de type NMDA sur ces cellules. L'activation de ces récepteurs entraîne un influx calcique et l'activation de diverses enzymes (phospholipase A, calpaïnes, calmoduline, synthase d'oxyde nitrique). La signalisation se poursuit en aval en partie par les voies des Mitogen Activated Protein Kinase (MAPK) : ERK, p38, ]NK. Dans les expériences présentées, toutes trois sont activées après l'injection de NMDA. Dans les cascades de signalisation de JNK, trois kinases s'ancrent sur une protéine scaffold. Les MAPKKK phosphorylent MKK4 et MKK7, qui phosphorylent JNK. JNK a de nombreuses cibles nucléaires (dont le facteur de transcription c-Jun) et cytoplasmiques. La voie de JNK est bloquée par l'inhibiteur peptidique D-JNKI-1 en empêchant l'interaction de la kinase avec son substrat. L'inhibiteur est formé de 20 acides aminés du domaine de liaison JBD et de 10 acides aminés de la partie TAT du virus HIV. L'injection intravitréenne de D-JNKI-1 permet une diminution des taux de JNK et c-Jun phosphorylés dans les lysats de rétine. L'effet prépondérant est la restriction importante des altérations histologiques des couches internes de la rétine. L'évaluation par électrorétinogramme met en sus en évidence une sauvegarde de la fonction cellulaire. Ce travail a ainsi permis d'établir la protection morphologique et fonctionnelle des cellules de la rétine interne par inhibition spécifique de la voie de JNK lors d'excitotoxicité. SUMMARY Excitotoxicity in the retina associates with several pathologies like retinal ischemia, traumatic optic neuropathy and glaucoma. In this study, excitotoxicity is elicited by intravitreal NMDA injection in adult rats. Lesions localise in the inner retina. They present as pyknotic cells in the ganglion cell layer (ganglion cells and displaced amacrines) and the inner nuclear layer (amacrine cells). These cells express NMDA glutamate receptors. The receptor activation leads to a calcium flow into the cell and hence enzyme activation (phospholipase, calpains, calmodulin, nitric oxide synthase). The subsequent signaling pathways can involve the Mitogen Activated Protein Kinases (MAPK): ERK, p38 end JNK. These were all activated in our experiments. The signaling cascade organises around several scaffold proteins. The various MAPKKK phosphorylate MKK4 and MKK7, which phosphorylate JNK. JNK targets are of nuclear (c-Jun transcription factor) or cytoplasmic localisation. The peptidic inhibitor D-JNKI-1, 20 amino acids from the JNK binding domain JBD coupled to 10 amino acids of the TAT transporter, disrupts the binding of JNK with its substrate. Intravitreal injection of the inhibitor lowers phosphorylated forms of JNK and c-Jun in retinal extracts. It protects strongly against histological lesions in the inner retina and allows functional rescue.

5-HT2A and alpha1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants.

Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of alpha1b-adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an alpha1-adrenergic antagonist. However, morphine-induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the alpha1b-adrenergic receptor (alpha1b-AR KO) and in wild-type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine-evoked DA release was completely blocked in alpha1b-AR KO mice by SR46349B (1 mg/kg), a 5-HT2A antagonist. SR46349B also completely blocked, in alpha1b-AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and D-amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5-HT2A and alpha1b-adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, D-amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or D-amphetamine were more than additive (160%) in naïve WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5-HT2A receptors for the genetic deletion of alpha1b-adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization.

Muscle recovery after repair of short and long peripheral nerve gaps using fibrin conduits.

Peripheral nerve injuries with loss of nervous tissue are a significant clinical problem and are currently treated using autologous nerve transplants. To avoid the need for donor nerve, which results in additional morbidity such as loss of sensation and scarring, alternative bridging methods have been sought. Recently we showed that an artificial nerve conduit moulded from fibrin glue is biocompatible to nerve regeneration. In this present study, we have used the fibrin conduit or a nerve graft to bridge either a 10 mm or 20 mm sciatic nerve gap and analyzed the muscle recovery in adult rats after 16 weeks. The gastrocnemius muscle weights of the operated side were similar for both gap sizes when treated with nerve graft. In contrast, muscle weight was 48.32 ± 4.96% of the contra-lateral side for the 10 mm gap repaired with fibrin conduit but only 25.20 ± 2.50% for the 20 mm gap repaired with fibrin conduit. The morphology of the muscles in the nerve graft groups showed an intact, ordered structure, with the muscle fibers grouped in fascicles whereas the 20 mm nerve gap fibrin group had a more chaotic appearance. The mean area and diameter of fast type fibers in the 20 mm gap repaired with fibrin conduits were significantly (P<0.01) worse than those of the corresponding 10 mm gap group. In contrast, both gap sizes treated with nerve graft showed similar fiber size. Furthermore, the 10 mm gaps repaired with either nerve graft or fibrin conduit showed similar muscle fiber size. These results indicate that the fibrin conduit can effectively treat short nerve gaps but further modification such as the inclusion of regenerative cells may be required to attain the outcomes of nerve graft for long gaps.

Differences in whole-body fat oxidation kinetics between cycling and running.

This study aimed to quantitatively describe and compare whole-body fat oxidation kinetics in cycling and running using a sinusoidal mathematical model (SIN). Thirteen moderately trained individuals (7 men and 6 women) performed two graded exercise tests, with 3-min stages and 1 km h(-1) (or 20 W) increment, on a treadmill and on a cycle ergometer. Fat oxidation rates were determined using indirect calorimetry and plotted as a function of exercise intensity. The SIN model, which includes three independent variables (dilatation, symmetry and translation) that account for main quantitative characteristics of kinetics, provided a mathematical description of fat oxidation kinetics and allowed for determination of the intensity (Fat(max)) that elicits maximal fat oxidation (MFO). While the mean fat oxidation kinetics in cycling formed a symmetric parabolic curve, the mean kinetics during running was characterized by a greater dilatation (i.e., widening of the curve, P < 0.001) and a rightward asymmetry (i.e., shift of the peak of the curve to higher intensities, P = 0.01). Fat(max) was significantly higher in running compared with cycling (P < 0.001), whereas MFO was not significantly different between modes of exercise (P = 0.36). This study showed that the whole-body fat oxidation kinetics during running was characterized by a greater dilatation and a rightward asymmetry compared with cycling. The greater dilatation may be mainly related to the larger muscle mass involved in running while the rightward asymmetry may be induced by the specific type of muscle contraction.

Efficacy and safety of various combination therapies based on a calcium antagonist in essential hypertension: results of a placebo-controlled randomized trial

We tested the efficacy and safety of different combination therapies in hypertensive patients with uncontrolled blood pressure (BP) on a monotherapy with a calcium antagonist: 1,647 hypertensive patients were enrolled to receive placebo for 4 weeks followed by isradipine (ISR) 2.5 mg twice daily (b.i.d.) for 4 weeks. Nonresponders [diastolic BP (DBP) > 90 mm Hg] were randomly assigned to receive either the beta-blocker bopindolol 0.5 or 1 mg/day, the diuretic metolazone 1.25 or 2.5 mg/day, the angiotensin-converting enzyme (ACE) inhibitor enalapril 10 or 20 mg/day, ISR 5 mg b.i.d., or placebo. One hundred seventy-five receiving placebo dropped out; 93% (n = 1,376) of the 1,472 patients finished 4-week monotherapy with ISR. Sixty percent (n = 826) reached target BP, and 40% (n = 550) remained uncontrolled and were randomized. Regardless of dosage, all drugs led to a comparable reduction in BP except for the lower dosage of bopindolol and ISR 5 mg b.i.d., which were less effective in lowering systolic BP (SBP). The BP decrease achieved by combination therapy ranged from 10 to 15 mm Hg SBP and from 7 to 11 mm Hg DBP but remained unchanged with placebo. Side effects were minor, and only 2.4% of patients discontinued therapy because of side effects. The side-effect score for edema was lower with ISR plus diuretics than with other combinations, whereas the ACE inhibitor was associated with a higher score for cough. Monotherapy with a calcium antagonist normalizes BP in about two-thirds of patients when used in general practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Performance of an ICU ventilator and two turbin-based ventilators dedicated to non invasive ventilation (NIV) in simulated high inspiratory effort and rate: a NIV-bench-study.

INTRODUCTION. The role of turbine-based NIV ventilators (TBV) versus ICU ventilators with NIV mode activated (ICUV) to deliver NIV in case of severe respiratory failure remains debated. OBJECTIVES. To compare the response time and pressurization capacity of TBV and ICUV during simulated NIV with normal and increased respiratory demand, in condition of normal and obstructive respiratory mechanics. METHODS. In a two-chamber lung model, a ventilator simulated normal (P0.1 = 2 mbar, respiratory rate RR = 15/min) or increased (P0.1 = 6 mbar, RR = 25/min) respiratory demand. NIV was simulated by connecting the lung model (compliance 100 ml/mbar; resistance 5 or 20 l/mbar) to a dummy head equipped with a naso-buccal mask. Connections allowed intentional leaks (29 ± 5 % of insufflated volume). Ventilators to test: Servo-i (Maquet), V60 and Vision (Philips Respironics) were connected via a standard circuit to the mask. Applied pressure support levels (PSL) were 7 mbar for normal and 14 mbar for increased demand. Airway pressure and flow were measured in the ventilator circuit and in the simulated airway. Ventilator performance was assessed by determining trigger delay (Td, ms), pressure time product at 300 ms (PTP300, mbar s) and inspiratory tidal volume (VT, ml) and compared by three-way ANOVA for the effect of inspiratory effort, resistance and the ventilator. Differences between ventilators for each condition were tested by oneway ANOVA and contrast (JMP 8.0.1, p\0.05). RESULTS. Inspiratory demand and resistance had a significant effect throughout all comparisons. Ventilator data figure in Table 1 (normal demand) and 2 (increased demand): (a) different from Servo-i, (b) different from V60.CONCLUSION. In this NIV bench study, with leaks, trigger delay was shorter for TBV with normal respiratory demand. By contrast, it was shorter for ICUV when respiratory demand was high. ICUV afforded better pressurization (PTP 300) with increased demand and PSL, particularly with increased resistance. TBV provided a higher inspiratory VT (i.e., downstream from the leaks) with normal demand, and a significantly (although minimally) lower VT with increased demand and PSL.

Long-term prognostic value of single-photon emission computed tomography myocardial perfusion imaging in diabetic patients with and without coronary artery disease

Keywords Diabetes mellitus; coronary artery disease; myocardial ischemia; prognostic value; single-photon emission computed tomography myocardial perfusion imaging Summary Aim: To determine the long-term prognostic value of SPECT myocardial perfusion imaging (MPI) for the occurrence of cardiovascular events in diabetic patients. Methods: SPECT MPI of 210 consecutive Caucasian diabetic patients were analysed using Kaplan-Meier event-free survival curves and independent predictors were determined by Cox multivariate analyses. Results: Follow-up was complete in 200 (95%) patients with a median period of 3.0 years (0.8-5.0). The population was composed of 114 (57%) men, age 65±10 years, 181 (90.5%) type 2 diabetes mellitus, 50 (25%) with a history of coronary artery disease (CAD) and 98 (49%) presenting chest pain prior to MPI. The prevalence of abnormal MPI was 58%. Patients with a normal MPI had neither cardiac death, nor myocardial infarction, independently of a history of coronary artery disease or chest pain. Among the independent predictors of cardiac death and myocardial infarction, the strongest was abnormal MPI (p<.0001), followed by history of CAD (Hazard Ratio (HR)= t 5.9, p=0.0001), diabetic retinopathy (HR=10.0, p=0.001) and inability to exercise (HR=7.7, p=0.02). Patients with normal 1VIPI had a low revascularisation rate of 2.4% during the follow-up period. Compared to normal MPI, cardiovascular events increased 5.2 fold for reversible defects, 8.5 fold for fixed defects and 20.1 fold for the association of both defects. Conclusion: Diabetic patients with normal MPI had an excellent prognosis independently of history of CAD. On the opposite, an abnormal MPI led to a > 5 fold increase in cardiovascular events. This emphasizes the value of SPECT MPI in predicting and risk-stratifying cardiovascular events in diabetic patients. Mots-Clés Diabète; maladie coronarienne; ischémie myocardique; valeur pronostique; tomoscintigraphie myocardique de perfusion par émission monophotonique Résumé Objectifs: Déterminer la valeur pronostique à long terme de la tomoscintigraphie myocardique de perfusion (TSMP) chez les patients diabétiques pour prédire les événements cardiovasculaires (ECV). Méthodes: Etude de 210 diabétiques caucasiens consécutifs référés pour une TSMP. Les courbes de survie ont été déterminées par Kaplan-Meier et les facteurs prédictifs indépendants par analyses multivariées de type Cox. Résultats: Le suivi a été complet chez 200 (95%) patients avec une durée médiane de 3.0 ans (0.8-50). La population était composée de 114 (57%) hommes, âge moyen 65±10 ans, avec 181 (90.5%) diabète de type 2, 50 (25%) antécédents de maladie coronarienne (AMC) et 98 (49%) patients connus pour un angor avant la TSMP. La prévalence de TSMP anormales était de 58%. Aucun décès d'origine cardiaque ou infarctus du myocarde n'est survenu chez les patients avec une TSMP normale, ceci indépendamment de leurs AMC et des douleurs thoraciques. Les facteurs prédictifs indépendants pour les ECV sont une TSMP anormale (p<.0001), les AMC (Hazard Ratio (HR)=15.9, p-0.0001), suivi de la rétinopathie diabétique (HR-10.0, p=0.001) et de l'incapacité à effectuer un exercice (HR=7.7, p=0.02). Les patients avec une TSMP normale ont présenté un taux de revascularisations de 2.4%. La présence de défauts mixtes accroît le risque d'ECV de 20.1 fois, les défauts fixes de 8.5 fois et les défauts réversibles de 5.2 fois comparés aux sujets avec une TSMP normale. Conclusion: Les patients diabétiques, coronariens ou non, avec une tomoscintigraphie myocardique de perfusion normale ont un excellent pronostique. A l'opposé, une TSMP anormale est associée à une augmentation du risque d'ECV de plus de 5 fois. Ceci confirme l'utilité de la TSMP dans la stratification du risque chez les patients diabétiques.

Calbindin D-28k- and substance P-immunoreactive primary sensory neurons: peripheral projections in chick hindlimbs.

The peripheral projections of two distinct subpopulations of primary sensory neurons, expressing either calbindin D-28k or substance P, were studied in chick hindlimbs by immunodetecting calbindin D-28k with a rabbit antiserum and substance P with a mouse monoclonal antibody. Calbindin D-28k-immunoreactive axons provided an innervation restricted to specific mechanoreceptors such as muscle spindles, Herbst and Merkel corpuscles, or collars of feather follicles but were absent from Golgi tendon organs. In contrast, substance P-positive axons spread out diffusely in muscles and skin, formed loose plexuses, and extended free branches to the endomysium, arteries, superficial dermis, or dermal pulp of feather follicles. The present results show that calbindin D-28k- and substance P-immunoreactive primary sensory neurons provide distinct modes of innervation to selective targets in peripheral tissues. The results suggest a possible correlation between CaBP-expressing nerve endings and rapidly adapting mechanoreceptors.

Comparisons of serum vitamin d levels, status, and determinants in populations with and without chronic kidney disease not requiring renal dialysis: a 24-hour urine collection population-based study.

OBJECTIVE: Vitamin D deficiency is frequent in the general population and might be even more prevalent among populations with kidney failure. We compared serum vitamin D levels, vitamin D insufficiency/deficiency status, and vitamin D level determinants in populations without chronic kidney disease (CKD) and with CKD not requiring renal dialysis. DESIGN AND METHODS: This was a cross-sectional, multicenter, population-based study conducted from 2010 to 2011. Participants were from 10 centers that represent the geographical and cultural diversity of the Swiss adult population (≥15 years old). INTERVENTION: CKD was defined using estimated glomerular filtration rate and 24-hour albuminuria. Serum vitamin D was measured by liquid chromatography-tandem mass spectrometry. Statistical procedures adapted for survey data were used. MAIN OUTCOME MEASURE: We compared 25-hydroxy-vitamin D (25(OH)D) levels and the prevalence of vitamin D insufficiency/deficiency (serum 25(OH)D < 30 ng/mL) in participants with and without CKD. We tested the interaction of CKD status with 6 a priori defined attributes (age, sex, body mass index, walking activity, serum albumin-corrected calcium, and altitude) on serum vitamin D level or insufficiency/deficiency status taking into account potential confounders. RESULTS: Overall, 11.8% (135 of 1,145) participants had CKD. The 25(OH)D adjusted means (95% confidence interval [CI]) were 23.1 (22.6-23.7) and 23.5 (21.7-25.3) ng/mL in participants without and with CKD, respectively (P = .70). Vitamin D insufficiency or deficiency was frequent among participants without and with CKD (75.3% [95% CI 69.3-81.5] and 69.1 [95% CI 53.9-86.1], P = .054). CKD status did not interact with major determinants of vitamin D, including age, sex, BMI, walking minutes, serum albumin-corrected calcium, or altitude for its effect on vitamin D status or levels. CONCLUSION: Vitamin D concentration and insufficiency/deficiency status are similar in people with or without CKD not requiring renal dialysis.

Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056.

Fragile X syndrome (FXS) is an X-linked condition associated with intellectual disability and behavioral problems. It is caused by expansion of a CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. This mutation is associated with hypermethylation at the FMR1 promoter and resultant transcriptional silencing. FMR1 silencing has many consequences, including up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. mGluR5 receptor antagonists have shown promise in preclinical FXS models and in one small open-label study of FXS. We examined whether a receptor subtype-selective inhibitor of mGluR5, AFQ056, improves the behavioral symptoms of FXS in a randomized, double-blind, two-treatment, two-period, crossover study of 30 male FXS patients aged 18 to 35 years. We detected no significant effects of treatment on the primary outcome measure, the Aberrant Behavior Checklist-Community Edition (ABC-C) score, at day 19 or 20 of treatment. In an exploratory analysis, however, seven patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA improved, as measured with the ABC-C, significantly more after AFQ056 treatment than with placebo (P < 0.001). We detected no response in 18 patients with partial promoter methylation. Twenty-four patients experienced an adverse event, which was mostly mild to moderately severe fatigue or headache. If confirmed in larger and longer-term studies, these results suggest that blockade of the mGluR5 receptor in patients with full methylation at the FMR1 promoter may show improvement in the behavioral attributes of FXS.