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.

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.

[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.

[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).

[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.

Selective effects of PPARgamma agonists and antagonists on human pre-adipocyte differentiation.

AIM: The insulin sensitizer rosiglitazone (RTZ) acts by activating peroxisome proliferator and activated receptor gamma (PPAR gamma), an effect accompanied in vivo in humans by an increase in fat storage. We hypothesized that this effect concerns PPARgamma(1) and PPARgamma(2) differently and is dependant on the origin of the adipose cells (subcutaneous or visceral). To this aim, the effect of RTZ, the PPARgamma antagonist GW9662 and lentiviral vectors expressing interfering RNA were evaluated on human pre-adipocyte models. METHODS: Two models were investigated: the human pre-adipose cell line Chub-S7 and primary pre-adipocytes derived from subcutaneous and visceral biopsies of adipose tissue (AT) obtained from obese patients. Cells were used to perform oil-red O staining, gene expression measurements and lentiviral infections. RESULTS: In both models, RTZ was found to stimulate the differentiation of pre-adipocytes into mature cells. This was accompanied by significant increases in both the PPARgamma(1) and PPARgamma(2) gene expression, with a relatively stronger stimulation of PPARgamma(2). In contrast, RTZ failed to stimulate differentiation processes when cells were incubated in the presence of GW9662. This effect was similar to the effect observed using interfering RNA against PPARgamma(2). It was accompanied by an abrogation of the RTZ-induced PPARgamma(2) gene expression, whereas the level of PPARgamma(1) was not affected. CONCLUSIONS: Both the GW9662 treatment and interfering RNA against PPARgamma(2) are able to abrogate RTZ-induced differentiation without a significant change of PPARgamma(1) gene expression. These results are consistent with previous results obtained in animal models and suggest that in humans PPARgamma(2) may also be the key isoform involved in fat storage.

Boron Neutron Capture Therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-f.

OBJECTIVES: To assess possible improved efficacy of Boron Neutron Capture Therapy (BNCT) for glioblastoma multiforme (GBM) using prolonged infusion and a correspondingly higher dose of l-boronophenylalanine, as the fructose complex (BPA-f). MATERIALS AND METHODS: The benefit of prolonged infusion was analyzed by comparing the results from a Phase II study using 6 h infusion of BPA-f with those obtained from a Phase I/II study using 2 h of infusion. Median survival time (MST) from diagnosis, patient baseline characteristics, salvage treatment and severe adverse events were considered in the comparison. RESULTS: MST increased significantly, from 12.8 (95% confidence interval or CI: 10.3-14.0) months with 2 h infusion to 17.7 (95% CI: 13.6-19.9) months with 6 h of infusion. The fraction of patients with WHO grade 3-4 adverse events was similar in the two studies at 13% and 14%, respectively. CONCLUSION: Prolonged infusion was found to be beneficial for the efficacy of BNCT and it is suggested that 6 h infusion of BPA-f should be used in future trials of BNCT for GBM. BNCT, which is a single-day treatment with mild side effects, should be assessed in a controlled trial, as an alternative to 30 daily fractions of conventional fractionated photon therapy over a period of 6 weeks.

[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.

[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.

A new type of internal hernia after laparoscopic Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass (RYGBP) is currently the most common bariatric procedure. One of its late complications is the development of internal hernia, which can lead to acute intestinal obstruction or recurrent colicky abdominal pain. The aim of this paper is to present a new, unusual, and so far not reported type of internal hernia. A common computerized database is maintained for all patients undergoing bariatric surgery in our departments. The charts of patients with the diagnosis of internal hernia were reviewed. Three patients were identified who developed acute intestinal obstruction due to an internal hernia located between the jejunojejunostomy and the end of the biliopancreatic limb, directly between two jejunal limbs with no mesentery involved. Another seven patients with intermittent colicky abdominal pain, re-explored for the suspicion of internal hernia, were found to also have an open window of the same location apart from a hernia at one of the typical hernia sites. Since this gap is systematically closed during RYGBP, no other patient has been observed with this problem. Even very small defects can lead to the development of internal hernias after RYGBP. Patients with suggestive symptoms must be explored. Closure of the jejunojejunal defect with nonabsorbable sutures prevents the development of an internal hernia between the jejunal loops at the jejunojejunostomy.

Contribution of mesothelial cells in the expression of inflammatory-related factors in omental adipose tissue of obese subjects.

OBJECTIVE: The objective of this study was to determine the contribution of mesothelial cells, present in human omental adipose tissue (OAT) but not in the subcutaneous depot (SAT), on the expression of inflammation-related factors. DESIGN: Comparison of the expression profiles of inflammation-related genes in mesothelial cells with those in the adipocyte-enriched (AEF) and stromal vascular fractions (SVF) and localization of interleukin-18 (IL-18) expression in adipose depots. SUBJECTS: Eleven obese Caucasian female subjects undergoing gastric bypass surgery (body mass index: 43.6+/-1.3 kg/m(2); age: 41.6+/-2.3 years). MEASUREMENTS: The expression profiles of cytokine and chemokine-related genes in mesothelial cells and in cell fractions prepared from OAT were assessed by the microarray technique. The differential expression of IL-18 was confirmed by real-time PCR and the protein was localized in adipose depots by immunohistochemistry. RESULTS: Microarray data analysis demonstrated that, of the 16 cytokine and chemokine-related genes that were upregulated in mesothelial cells compared with the AEF, IL-18 was the cytokine with the highest differential expression. IL-18 expression was similar in mesothelial cells and the SVF. In both SAT and OAT, IL-18 was immunolocalized in neutrophils and mast cells, but not in macrophages nor adipocytes. This cytokine was also detected in mesothelial cells in OAT. This additional source of expression may explain the higher IL-18 expression levels in OAT than SAT (+5.9-fold). CONCLUSION: By their capacity to express inflammatory-related factors, and in particular the proinflammatory cytokine IL-18 in OAT, mesothelial cells appear as a new player in the process of low-grade inflammation associated with obesity.

The positive inotropic effect of endothelin-1 is mediated by mitochondrial reactive oxygen species.

We have previously demonstrated the participation of reactive oxygen species (ROS) in the positive inotropic effect of a physiological concentration of Angiotensin II (Ang II, 1 nM). The objective of the present work was to evaluate the role and source of ROS generation in the positive inotropic effect produced by an equipotent concentration of endothelin-1 (ET-1, 0.4 nM). Isolated cat ventricular myocytes were used to measure sarcomere shortening with a video-camera, superoxide anion (()O(2)(-)) with chemiluminescence, and ROS production and intracellular pH (pH(i)) with epifluorescence. The ET-1-induced positive inotropic effect (40.4+/-3.1%, n=10, p<0.05) was associated to an increase in ROS production (105+/-29 fluorescence units above control, n=6, p<0.05). ET-1 also induced an increase in ()O(2)(-) production that was inhibited by the NADPH oxidase blocker, apocynin, and by the blockers of mitochondrial ATP-sensitive K(+) channels (mK(ATP)), glibenclamide and 5 hydroxydecanoic acid. The ET-1-induced positive inotropic effect was inhibited by apocynin (0.3 mM; 6.3+/-6.6%, n=13), glibenclamide (50 microM; 8.8+/-3.5%, n=6), 5 hydroxydecanoic acid (500 microM; 14.1+/-8.1, n=9), and by scavenging ROS with MPG (2 mM; 0.92+/-5.6%, n=8). ET-1 enhanced proton efflux (J(H)) carried by the Na(+)/H(+) exchanger (NHE) after an acid load, effect that was blocked by MPG. Consistently, the ET-induced positive inotropic effect was also inhibited by the NHE selective blocker HOE642 (5 microM; 9.37+/-6.07%, n=7). The data show that the effect of a concentration of ET-1 that induces an increase in contractility of about 40% is totally mediated by an intracellular pathway triggered by mitochondrial ROS formation and stimulation of the NHE.

An investigation of boron neutron capture therapy for recurrent glioblastoma multiforme.

Objectives - To explore the use of boron neutron capture therapy (BNCT) for patients with glioblastoma multiforme (GBM), recurring after surgery and conventional radiotherapy (photon radiotherapy). Materials and Methods - Boron uptake in recurrent GBM was measured for four patients. Twelve patients were subsequently treated by BNCT with boronophenylalanine-fructose (900 mg/kg body weight), administered by intravenous infusion for 6 h. Results - Median survival time from initial diagnosis was 22.2 months. Comparison with other BNCT studies indicates a clinical advantage of the prolonged infusion. BNCT was well tolerated and quality of life remained stable until tumor progression for all 12 patients. No correlation was found between survival times and minimum tumor dose and number of radiation fields. Conclusions - Boron neutron capture therapy, with the prolonged procedure for infusion, is at least as effective as other radiation therapies for recurrent GBM and is delivered in one treatment session, with low radiation dose to the healthy brain. Survival from diagnosis compares favorably with that obtained with conventional radiotherapy plus concomitant and adjuvant temozolomide (TMZ) and survival from recurrence compares favorably with that obtained with TMZ at first relapse. The results of the present investigation are encouraging and should be confirmed in a randomized trial.