Validation française de l'échelle d'expérience temporelle du plaisir [Validation of the Temporal Experience of Pleasure Scale (TEPS) in a French-speaking environment.]

INTRODUCTION: Anhedonia is defined as a diminished capacity to experience pleasant emotion and is commonly included among the negative symptoms of schizophrenia. However, if patients report experiencing a lower level of pleasure than controls, they report experiencing as much pleasure as controls with online measurements of emotion. OBJECTIVE: The Temporal Experience of Pleasure Scale (TEPS) measures pleasure experienced in the moment and in anticipation of future activities. The TEPS is an 18-item self-report measurement of anticipatory (10 items) and consummatory (eight items) pleasure. The goal of this paper is to assess the psychometric characteristics of the French translation of this scale. METHODS: A control sample was composed of 60 women and 22 men, with a mean age of 38.1 years (S.D.: 10.8). Thirty-six were without qualification and 46 with qualified professional diploma. A sample of 21 patients meeting DSM IV-TR criteria for schizophrenia was recruited among the community psychiatry service of the department of psychiatry in Lausanne. They were five women and 16 men; mean age was of 34.1 years (S.D.: 7.5). Ten obtained a professional qualification and 11 were without qualification. None worked in competitive employment. Their mean dose of chlorpromazine equivalent was 431mg (S.D.: 259). All patients were on atypical antipsychotics. The control sample fulfilled the TEPS and the Physical Anhedonia Scale (PAS). The patient sample fulfilled the TEPS and was independently rated on the Calgary Depression Scale and the Scale for Assessment of Negative Symptoms. For comparison with controls, patients were matched on age, sex and professional qualification. This required the supplementary recruitment of two control subjects. RESULTS: Results with the control sample indicate that the TEPS presents an acceptable internal validity with Crombach alphas of 0.84 for the total scale, 0.74 for the anticipatory pleasure scale and 0.79 for the consummatory pleasure scale. The confirmatory factor analysis indicated that the model is well adapted to our data (chi(2)/dl=1.333; df=134; p<0.0006; root mean square residual, RMSEA=0.064). External validity measured with the PAS showed R=-0.27 (p<0.05) for the consummatory scale and R=-0.26 for the total score. Comparisons between patients and matched controls indicated that patients were significantly lower than control on anticipatory pleasure (t=2.7, df(40), 2-tailed p=0.01; cohen's d=0.83) and on total score of the TEPS (t=2.8, df (40), 2-tailed p=0.01; cohen's d=0.87). The two samples did not differ on consummatory pleasure. The anticipatory pleasure factor and the total TEPS showed significant negative correlation with the SANS anhedonia, respectively R=-0.78 (p<0.01) for the anticipatory factor and R=-0.61 (p<0.01) for the total TEPS. There was also a negative correlation between the anticipatory factor and the SANS avolition of R=-0.50 (p<0.05). These correlations were maintained, with partial correlations controlling for depression and chlorpromazine equivalents. CONCLUSION: The results of this validation show that the French version of the TEPS has psychometric characteristics similar to the original version. These results highlight the discrepancy between results of direct or indirect report of experienced pleasure in patients with schizophrenia. Patients may have difficulties in anticipating the pleasure of future enjoyable activities, but not in experiencing pleasure once in an enjoyable activity. Medication and depression do not seems to modify our results, but this should be better controlled in a longitudinal study. The anticipatory versus consummatory pleasure distinction appears to be useful for the development of new psychosocial interventions, tailored to improve desire in patients suffering from schizophrenia. Major limitations of the study are the small size of patient sample and the under representation of men in the control sample.

Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study.

Huntington's disease (HD) is a monogenic neurodegenerative disease that affects the efferent neurons of the striatum. The protracted evolution of the pathology over 15 to 20 years, after clinical onset in adulthood, underscores the potential of therapeutic tools that would aim at protecting striatal neurons. Proteins with neuroprotective effects in the adult brain have been identified, among them ciliary neurotrophic factor (CNTF), which protected striatal neurons in animal models of HD. Accordingly, we have carried out a phase I study evaluating the safety of intracerebral administration of this protein in subjects with HD, using a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF. Six subjects with stage 1 or 2 HD had one capsule implanted into the right lateral ventricle; the capsule was retrieved and exchanged for a new one every 6 months, over a total period of 2 years. No sign of CNTF-induced toxicity was observed; however, depression occurred in three subjects after removal of the last capsule, which may have correlated with the lack of any future therapeutic option. All retrieved capsules were intact but contained variable numbers of surviving cells, and CNTF release was low in 13 of 24 cases. Improvements in electrophysiological results were observed, and were correlated with capsules releasing the largest amount of CNTF. This phase I study shows the safety, feasibility, and tolerability of this gene therapy procedure. Heterogeneous cell survival, however, stresses the need for improving the technique.

Fate of rubrospinal neurons after unilateral section of the cervical spinal cord in adult macaque monkeys: effects of an antibody treatment neutralizing Nogo-A.

The present study describes in primates the effects of a spinal cord injury on the number and size of the neurons in the magnocellular part of the red nucleus (RNm), the origin of the rubrospinal tract, and evaluates whether a neutralization of Nogo-A reduces the lesioned-induced degenerative processes observed in RNm. Two groups of monkeys were subjected to unilateral section of the spinal cord affecting the rubrospinal tract; one group was subsequently treated with an antibody neutralizing Nogo-A; the second group received a control antibody. Intact animals were also included in the study. Counting neurons stained with a monoclonal antibody recognizing non-phosphorylated epitopes on neurofilaments (SMI-32) indicated that their number in the contralesional RNm was consistently inferior to that in the ipsilesional RNm, in a proportion amounting up to 35%. The lesion also induced shrinkage of the soma of the neurons detected in the contralesional RNm. Infusing an anti-Nogo-A antibody at the site of the lesion did not increase the proportion of SMI-32 positive rubrospinal neurons in the contralesional RNm nor prevent shrinkage.

Efficacy and Safety of Canakinumab Vs Triamcinolone Acetonide in Patients with Gouty Arthritis Unable to Use Nonsteroidal Anti-Inflammatory Drugs and Colchicine, and On Stable Urate Lowering Therapy (ULT) or Unable to Use ULT

Background/Purpose: The primary treatment goals for gouty arthritis (GA) are rapid relief of pain and inflammation during acute attacks, and long-term hyperuricemia management. A post-hoc analysis of 2 pivotal trials was performed to assess efficacy and safety of canakinumab (CAN), a fully human monoclonal anti-IL-1_ antibody, vs triamcinolone acetonide (TA) in GA patients unable to use NSAIDs and colchicine, and who were on stable urate lowering therapy (ULT) or unable to use ULT. Methods: In these 12-week, randomized, multicenter, double-blind, double-dummy, active-controlled studies (_-RELIEVED and _-RELIEVED II), patients had to have frequent attacks (_3 attacks in previous year) meeting preliminary GA ACR 1977 criteria, and were unresponsive, intolerant, or contraindicated to NSAIDs and/or colchicine, and if on ULT, ULT was stable. Patients were randomized during an acute attack to single dose CAN 150 mg s.c. or TA 40 mg i.m. and were redosed "on demand" for each new attack. Patients completing the core studies were enrolled into blinded 12-week extension studies to further investigate on-demand use of CAN vs TA for new attacks. The subpopulation selected for this post-hoc analysis was (a) unable to use NSAIDs and colchicine due to contraindication, intolerance or lack of efficacy for these drugs, and (b) currently on ULT, or contraindication or previous failure of ULT, as determined by investigators. Subpopulation comprised 101 patients (51 CAN; 50 TA) out of 454 total. Results: Several co-morbidities, including hypertension (56%), obesity (56%), diabetes (18%), and ischemic heart disease (13%) were reported in 90% of this subpopulation. Pain intensity (VAS 100 mm scale) was comparable between CAN and TA treatment groups at baseline (least-square [LS] mean 74.6 and 74.4 mm, respectively). A significantly lower pain score was reported with CAN vs TA at 72 hours post dose (1st co-primary endpoint on baseline flare; LS mean, 23.5 vs 33.6 mm; difference _10.2 mm; 95% CI, _19.9, _0.4; P_0.0208 [1-sided]). CAN significantly reduced risk for their first new attacks by 61% vs TA (HR 0.39; 95% CI, 0.17-0.91, P_0.0151 [1-sided]) for the first 12 weeks (2nd co-primary endpoint), and by 61% vs TA (HR 0.39; 95% CI, 0.19-0.79, P_0.0047 [1-sided]) over 24 weeks. Serum urate levels increased for CAN vs TA with mean change from baseline reaching a maximum of _0.7 _ 2.0 vs _0.1 _ 1.8 mg/dL at 8 weeks, and _0.3 _ 2.0 vs _0.2 _ 1.4 mg/dL at end of study (all had GA attack at baseline). Adverse Events (AEs) were reported in 33 (66%) CAN and 24 (47.1%) TA patients. Infections and infestations were the most common AEs, reported in 10 (20%) and 5 (10%) patients treated with CAN and TA respectively. Incidence of SAEs was comparable between CAN (gastritis, gastroenteritis, chronic renal failure) and TA (aortic valve incompetence, cardiomyopathy, aortic stenosis, diarrohea, nausea, vomiting, bicuspid aortic valve) groups (2 [4.0%] vs 2 [3.9%]). Conclusion: CAN provided superior pain relief and reduced risk of new attack in highly-comorbid GA patients unable to use NSAIDs and colchicine, and who were currently on stable ULT or unable to use ULT. The safety profile in this post-hoc subpopulation was consistent with the overall _-RELIEVED and _-RELIEVED II population.

Neurorééducation précoce au Centre hospitalier universitaire vaudois: du rêve à la réalité [Early neurorehabilitation in an acute university hospital: from dream to reality].

The need for an early neurorehabilitation pathway was identified in an acute university hospital. A team was formed to draw up and implement it. A neuro-sensorial, interdisciplinary and coordinated therapy program was developed, focused on tracheostomised patients as soon as they were admitted to the intermediate care in neurology and neurosurgery. The impact of this care plan was evaluated by comparing the results obtained with that pertaining to patients treated previously in the same services. The comparison showed a reduction of 48% of the mean duration of tracheostomy, of 39% in the time to inscription in a neurorehabilitation centre and of 20% in the length of stay in the intermediate care. An early neurorehabilitation care program, with an interdisciplinary and coordinated team, reduces complications and lengths of stay.

MP2RAGE, a self bias-field corrected sequence for improved segmentation and T1-mapping at high field.

The large spatial inhomogeneity in transmit B(1) field (B(1)(+)) observable in human MR images at high static magnetic fields (B(0)) severely impairs image quality. To overcome this effect in brain T(1)-weighted images, the MPRAGE sequence was modified to generate two different images at different inversion times, MP2RAGE. By combining the two images in a novel fashion, it was possible to create T(1)-weighted images where the result image was free of proton density contrast, T(2) contrast, reception bias field, and, to first order, transmit field inhomogeneity. MP2RAGE sequence parameters were optimized using Bloch equations to maximize contrast-to-noise ratio per unit of time between brain tissues and minimize the effect of B(1)(+) variations through space. Images of high anatomical quality and excellent brain tissue differentiation suitable for applications such as segmentation and voxel-based morphometry were obtained at 3 and 7 T. From such T(1)-weighted images, acquired within 12 min, high-resolution 3D T(1) maps were routinely calculated at 7 T with sub-millimeter voxel resolution (0.65-0.85 mm isotropic). T(1) maps were validated in phantom experiments. In humans, the T(1) values obtained at 7 T were 1.15+/-0.06 s for white matter (WM) and 1.92+/-0.16 s for grey matter (GM), in good agreement with literature values obtained at lower spatial resolution. At 3 T, where whole-brain acquisitions with 1 mm isotropic voxels were acquired in 8 min, the T(1) values obtained (0.81+/-0.03 s for WM and 1.35+/-0.05 for GM) were once again found to be in very good agreement with values in the literature.

Couples contemporains - Cohésion, régulation et conflits. Une enquête sociologique

Comment peut-on caractériser les relations de couple aujourd'hui ? Sont-elles marquées par l'autonomie des conjoints ou au contraire par la valorisation du « nous-couple » ou du « nous-famille » ? Les couples se replient-ils sur eux-mêmes ou s'ouvrent-ils sur le monde qui les entoure ? Du point de vue des rôles et du pouvoir, l'égalité entre hommes et femmes est-elle désormais pratiquée ou au contraire les arrangements traditionnels perdurent-ils ?Ce livre montre que la situation est caractérisée par une grande diversité de styles d'interactions conjugales plutôt que par un modèle unique. Ces styles répondent à des logiques associées au statut social, à la position dans le parcours de vie et à la participation sociale des couples. De plus, ils génèrent des niveaux de problèmes et de satisfaction très differents.L'intérêt d'une analyse sociologique du fonctionnement des couples contemporains ne tient pas qu'à l'importance d'un groupe que l'on dit essentiel pour la construction de l'individu et pour l'intégration sociale, mais aussi à l'interrogation sociale et politique générée par les mutations familiales des trente dernières années.

Updated Swiss guidelines for the treatment and follow-up of cutaneous melanoma.

Melanoma is the most common lethal cutaneous neoplasm. In order to harmonize treatment and follow-up of melanoma patients, guidelines for the management of melanoma in Switzerland have been inaugurated in 2001. These have been approved by all Swiss medical societies involved in the care of melanoma patients. New data necessitated changes concerning the safety margins (reduction to maximally 2 cm) and modifications of the recommendations of follow-up.

The role of Notch signaling during hematopoietic lineage commitment.

Over the last few years a vast amount of progress has been made in identifying mechanisms controlling lineage commitment and plasticity of hematopoietic precursors to different lymphoid or myeloid lineages. This has been due largely to the ability to identify and isolate rare cell populations in order to investigate their developmental potential, together with the development of inducible and/or tissue specific targeting technology. One family of proteins that has been postulated to be involved in hematopoietic stem cell maintenance as well as in multiple commitment processes during T cell development is the Notch receptors and their ligands. In this review we will summarize recent findings and controversies regarding the role of Notch signaling in the myeloid and lymphoid systems.

Cell locations for AQP1, AQP4 and 9 in the non-human primate brain.

The presence of three water channels (aquaporins, AQP), AQP1, AQP4 and AQP9 were observed in normal brain and several rodent models of brain pathologies. Little is known about AQP distribution in the primate brain and its knowledge will be useful for future testing of drugs aimed at preventing brain edema formation. We studied the expression and cellular distribution of AQP1, 4 and 9 in the non-human primate brain. The distribution of AQP4 in the non-human primate brain was observed in perivascular astrocytes, comparable to the observation made in the rodent brain. In contrast with rodent, primate AQP1 is expressed in the processes and perivascular endfeet of a subtype of astrocytes mainly located in the white matter and the glia limitans, possibly involved in water homeostasis. AQP1 was also observed in neurons innervating the pial blood vessels, suggesting a possible role in cerebral blood flow regulation. As described in rodent, AQP9 mRNA and protein were detected in astrocytes and in catecholaminergic neurons. However additional locations were observed for AQP9 in populations of neurons located in several cortical areas of primate brains. This report describes a detailed study of AQP1, 4 and 9 distributions in the non-human primate brain, which adds to the data already published in rodent brains. This relevant species differences have to be considered carefully to assess potential drugs acting on AQPs non-human primate models before entering human clinical trials.

Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice.

Obesity and insulin resistance represent a problem of utmost clinical significance worldwide. Insulin-resistant states are characterized by the inability of insulin to induce proper signal transduction leading to defective glucose uptake in skeletal muscle tissue and impaired insulin-induced vasodilation. In various pathophysiological models, melatonin interacts with crucial molecules of the insulin signaling pathway, but its effects on glucose homeostasis are not known. In a diet-induced mouse model of insulin resistance and normal chow-fed control mice, we sought to assess the effects of an 8-wk oral treatment with melatonin on insulin and glucose tolerance and to understand underlying mechanisms. In high-fat diet-fed mice, but not in normal chow-fed control mice, melatonin significantly improved insulin sensitivity and glucose tolerance, as evidenced by a higher rate of glucose infusion to maintain euglycemia during hyperinsulinemic clamp studies and an attenuated hyperglycemic response to an ip glucose challenge. Regarding underlying mechanisms, we found that melatonin restored insulin-induced vasodilation to skeletal muscle, a major site of glucose utilization. This was due, at least in part, to the improvement of insulin signal transduction in the vasculature, as evidenced by increased insulin-induced phosphorylation of Akt and endoethelial nitric oxide synthase in aortas harvested from melatonin-treated high-fat diet-fed mice. In contrast, melatonin had no effect on the ability of insulin to promote glucose uptake in skeletal muscle tissue in vitro. These data demonstrate for the first time that in a diet-induced rodent model of insulin resistance, melatonin improves glucose homeostasis by restoring the vascular action of insulin.

Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.