Investigation of microglial diversity in a LRRK2 G2019S mouse model of Parkinson's disease.

Microglia contribute to the outcomes of various pathological conditions including Parkinson's disease (PD). Microglia are heterogenous, with a variety of states recently identified in aging and neurodegenerative disease models. Here, we delved into the diversity of microglia in a preclinical PD model featuring the G2019S mutation in LRRK2, a known pathological mutation associated with PD. Specifically, we investigated the 'dark microglia' (DM) and the 'disease-associated microglia' (DAM) which present a selective enrichment of CLEC7A expression. In the dorsal striatum - a region affected by PD pathology - extensive ultrastructural features of cellular stress as well as reduced direct cellular contacts, were observed for microglia from old LRRK2 G2019S mice versus controls. In addition, DM were more prevalent while CLEC7A-positive microglia had extensive phagocytic ultrastructural characteristics in the LRRK2 G2019S mice. Furthermore, our findings revealed a higher proportion of DM in LRRK2 G2019S mice, and an increased number of CLEC7A-positive cells with age, exacerbated by the pathological mutation. These CLEC7A-positive cells exhibited a selective enrichment of ameboid morphology and tended to cluster in the affected animals. In summary, we provide novel insights into the occurrence and features of recently defined microglial states, CLEC7A-positive cells and DM, in the context of LRRK2 G2019S PD pathology.

Effectiveness of a secondary prevention protocol for occupational contact dermatitis.

BACKGROUND: Occupational skin diseases are often responsible for sick leave or job changes, affect mostly young subjects, are costly to society and have been reported as significant predictor of unemployment. OBJECTIVES: To assess, over time, the course of occupational hand dermatitis (OHD) after a specific training, by means of follow-up visits and TEWL measurement, to evaluate skin barrier integrity and if preventive measures for hand skin care provided may influence the course of the disease. METHODS: Workers with a diagnosis of OHD from January 2011 to December 2013 were contacted by telephone, filled in a questionnaire (NOSQ-2002) and were invited to a training course on prevention of skin dermatitis, and to a new clinical evaluation with TEWL measurement. Workers who joined the training programme were asked to undergo a new evaluation after 3 months. A total of 65 subjects without contact dermatitis were recruited as control group. RESULTS: One hundred and one subjects from 143 workers, who were contacted, filled in the questionnaire. Sixty-five of them followed the training course and underwent a new clinical evaluation withTEWL measurements. Ongoing symptoms of subjects decreased from 60.0% to 42.3% 3 months after the training, and the subgroup which strictly adhered to the recommendations given achieved better results (61.9% of symptoms improvement when compared to 29.0% obtained in subjects with partial adhesion to the protocol). TEWL values changed from 21.3 ± 9.6 to 18.6 ± 7.2 g/m²/h (P = 0.001) on the hands and from 16.6 ± 9.0 to 10.5 ± 4.6 g/m²/h (P = 0.001) on the forearm, confirming the skin barrier improvement. CONCLUSIONS: Our secondary prevention intervention was effective, leading to a reduction in clinical signs of dermatitis. TEWL measurement is a useful tool to evaluate skin integrity, mostly in apparently healthy skin, which may have a compromised barrier function, resulting in an exacerbation of the dermatitis.

[Physical activity adapted to the obese patients' needs: which assessments for what kind of prescription?]. / Activités physiques adaptées au patient obèse: quelles évaluations pour quelle prescription?

Physical activity is a key element for the obese patient willing to lose weight. The main aim of physical activity is to contribute to produce, and maintain, a negative energy balance. A recent approach suggests to focus on the intensity eliciting the maximal lipid oxidation rate. Physical activity prescription should however be adapted to the patient's physiological and metabolic profile. Determining the physical fitness of the patient during an incremental test and assessing body composition may be central elements determining physical activity prescription. Provided the activities are adapted to the patient's profile, numerous physical activities may be performed by the obese patient. A practical, clinical approach, based upon the metabolic profiling of the patient is proposed in this article.

[Bariatric surgery: what is the ideal length of the preoperative track?]. / Chirurgie bariatrique: queue est la durée idéale de l'itinéraire préopératoire?

Bariatric surgery not only has significant somatic implications but also imposes substantial behavioural and psychological changes. It is therefore essential to check previously that the potential candidate has not psychosomatic contraindications and its psychoocial context to allow adaptation to the changes requested by the intervention. After this preliminary phase the multidisciplinary support must provide a complete and adequate preparation for potential intervention, and ensure a follow-up to life in these patients. Bariatric support is therefore an ongoing process, which involves, in the preoperative phase, three steps: (1) to inform, (2) to assess and (3) prepare candidates.

[Role of the psychiatrist in the management of obesity]. / Rôle de l'approche psychologique dans la prise en charge des patients obèses.

The management of obese patients is complex and often generates a sense of powerlessness on the part of caregivers. Psychopathologies associated with obesity are omnipresent and require greater attention from the somaticians to better assist their patients in this chronic disease and to guide their care. Despite the often legitimate reluctance of patients, it remains fundamental to question the symptom, weight, beyond any prejudice. Obesity, with or without bypass project, requires support in the long term by a multidisciplinary team with an holistic approach in order to avoid creating a new failure as is the case with the methods of food restrictions perpetuate eating disorders.

[Prevalence of early and late dumping after gastric bypass]. / Prévalence des dumpings précoce et tardif après bypass gastrique.

Gastric bypass surgery is an effective treatment of obesity, bringing a significant weight loss and a major improvement of carbohydrate profile. However, in some patients, a deregulation in carbohydrate metabolism between insulin secretion and sensitivity is observed, whereupon early and late dumping happen. Their prevalence isn't well studied, although it seems that 10 to 20% of patients are affected. We've studied a cohort of 70 patients who undergone gastric bypass surgery at the CHUV. 18 (25.7%) patients have a positive anamnesis for early dumping and 10 (14.3%) for late dumping, being it superior as what is described in the literature.

Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS).

Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy.

[New guidelines for bariatric surgery care: practical implications]. / Nouvelles directives assécurologiques pour la prise en charge de la chirurgie bariatrique: conséquences pratiques.

From the 1st of January 2011, new conditions have been validated in which surgery for weight loss is borne by the basic insurance. These are very significant changes compared to the old criteria. Indeed, on one hand, patients with BMI > or = 35 kg/m2 may, without age limit and in the absence of comorbidities benefit from surgery without prior request to the medical council health insurance company concerned. On the other hand, the notion of a minimum casuistry is for the first time introduced in centers performing this type of intervention. In addition, certified centers are required to follow standard procedures for the patients' teaching and follow up.

[Management of hyperinsulinemic hypoglycemia post-gastric bypass surgery]. / Gestion des hypoglycémies après le bypass gastrique.

Gastric bypass surgery is an effective treatment for morbid obesity, allowing a substantial weight loss together with an improvement of the cardiovascular and metabolic comorbidities, particularly the glucose control. However, after gastric bypassing, an imbalance between sensitivity and insulin secretion may be observed. This disorder gives rise to hyperinsulinemic hypoglycemia (late dumping syndrome) and is characterized by a dizziness that can be disabling. This problem must be distinguished from conditions provoking similar symptoms, as for instance the early dumping syndrome and the food restriction-related hypoglycemia. Since all these conditions need a particular management, their distinction is essential.

[Anorexia: somatic assessment and management]. / Anorexie: évaluation et prise en charge somatiques.

Anorexia nervosa, which affects about 2-3% of the general population, is the psychiatric illness with the highest rate of mortality. The management is often complex, requiring multiple stakeholders on the patient's physical and psychiatric. The new specialized centre "abC" (anorexia-bulimia, Centre vaudois) was created with the objective of providing quality services to patients involved and to provide a network facilitating the interaction between physicians and specialized institutions. This is an inter-institutional and interdisciplinary collaboration born of the CHUV and the eHnv (Hospitalized Institutions in Nord Vaudois). The abC includes an outpatient pole (CHUV) and a hospital unit on the site of Saint Loup. At term, it will include a day centre (CHUV).

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential.

The purpose of this analysis was to assess the potential of BNCT, with L-boronophenylalanine (L-BPA), as first line radiotherapy for glioblastoma multiforme (GBM). The survival of patients with newly diagnosed GBM from a phase II BNCT study was compared with those from the two arms of a phase III study with conventional radiotherapy (RT) vs. RT plus concomitant and adjuvant medication with temozolomide (TMZ). A small subgroup, for which the methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) DNA-repair gene was known, was also considered. The results indicated that the use of BNCT with BPA should be explored in a stratified randomized phase II trial in which patients with the unmethylated MGMT DNA-repair gene are offered BNCT vs. RT plus TMZ.

[Anorexia and bulimia: the canton of Vaud's experience of an interdisciplinary approach]. / Anorexie mentale et boutimie: I'expérience vaudoise d'une prise en charge interdisciplinaire.

As psychiatric disorders attacking the body, anorexia and bulimia may have severe psychological, physical and social consequences, often requiring a long-standing interdisciplinary, coordinated and individualized approach. Recently the canton of Vaud has initiated and developed an interinstitutional structure--between the University Hospital (CHUV) and the hospitals of the Northern region of the canton (eHnv)--for the care of patients suffering from eating disorders. This structure, allowing the above mentioned approach for the treatment of eating disorders, consists of an outpatient facility located in the CHUV and an inpatient unit in the hospital of Saint Loup of the eHnv. Within this structure, the general practitioner plays a crucial role in the prevention of the chronification of these disorders by means of their early detection and management.

Independent contribution of parental migrant status and educational level to adiposity and eating habits in preschool children.

BACKGROUND/OBJECTIVE: Little is known about the precise role of parental migrant status (MS) and educational level (EL) on adiposity and various eating habits in young children. Therefore, we assessed their independent contribution in preschoolers. SUBJECTS/METHODS: Of 655 randomly selected preschoolers, 542 (5.1±0.6 years; 71% of parental MS and 37% of low parental EL) were analysed. Body composition was measured by bioelectrical impedance. Eating habits were assessed using a semiqualitative food frequency questionnaire and analysed according to five messages developed by the Swiss Society for Nutrition, based on factors implicated in childhood obesity: (1) 'Drinking water and decreasing sweetened drinks', (2) 'Eating fruit and vegetables', (3) 'Decreasing breakfast skipping', (4) 'Reducing fatty and sweet foods' and (5) 'Reducing the intake of meals and snacks in front of television'. RESULTS: Children of migrant and low EL parents had higher body fat, ate more meals and snacks while watching television and had more fruit and fatty foods compared with their respective counterparts (all P≤ 0.04). Children of low EL parents also consumed less water and vegetables compared with their counterparts (all P≤ 0.04). In most instances, we found an independent contribution of parental MS and EL to adiposity and eating habits. A more pronounced effect was found if both parents were migrants or of low EL. Differences in adiposity and eating habits were relatively similar to the joint parental data when assessed individually for maternal and paternal MS and EL. CONCLUSIONS: Parental MS and EL are independently related to adiposity and various eating habits in preschoolers.

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential.

The purpose of this study was to assess the potential of boron neutron capture therapy (BNCT), with a 6-h infusion of the boron carrier l-boronophenylalanine as a fructose preparation (BPA-f), as first-line radiotherapy for newly diagnosed glioblastoma multiforme (GBM). Patient survival data from a Phase II study using BNCT were compared with retrospective data from the two arms of a Phase III study using conventional radiotherapy (RT) in the reference arm and using RT plus concomitant and adjuvant medication with temozolomide (TMZ) in the experimental arm, and were also compared with small subgroups of these patients for whom the methylation status of the MGMT (O(6)-methylguanine-DNA methyltransferase) DNA repair gene was known. Differences in the baseline characteristics, salvage therapy after recurrence and levels of severe adverse events were also considered. The results indicate that BNCT offers a treatment that is at least as effective as conventional RT alone. For patients with an unmethylated MGMT DNA repair gene, a possible clinical advantage of BNCT over RT/TMZ was suggested. BNCT is a single-day treatment, which is of convenience to patients, with mild side effects, which would offer an initial 6 weeks of good-quality life during the time when patients would otherwise be undergoing daily treatments with RT and TMZ. It is suggested that the use of BNCT with a 6-h infusion of BPA-f should be explored in a stratified randomised Phase II trial in which patients with the unmethylated MGMT DNA repair gene are offered BNCT in the experimental arm and RT plus TMZ in the reference arm.

[The impact of obesity on fertility]. / Obésité et fertilité ne font pas bon ménage.

There are many negative impacts of obesity on fertility. Obese couples present decreased sperm count, decreased ovulation and conception rates, increased erectile dysfunction and spontaneous abortion rate as well as increased maternal and foetal complications of pregnancy. Moreover, obesity tends to decrease response to fertility treatments. Fortunately, intensive lifestyle modifications can restore fertility while decreasing pregnancy complications risk. With the increasing trend of obesity to affect young populations, taking care of these infertile couples rapidly is capital to restore fertility and decrease its related pregnancy complications.

[Surgery for diabetes: challenge or reality?]. / Chirurgie du diabète: provocation ou réalité?

Bariatric surgery techniques can usually increase either sensitivity or insulin resistance, acting on three different levels: decrease of food intake, malabsorption and modifications of entero-insulaire axis activity. This latter is taken into account in order to develop a new protocol to obtain diabetes remission without important weight loss and nutritional deficiencies. Preliminary results are interesting but they come from very short time studies with few patients. Moreover, complications rate is at present very high. Knowing better gastrointestinal mechanisms of diabetes control and especially incretins role is absolutely necessary before identifying surgery as a true metabolic treatment.

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.