Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies.

The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARgamma and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARgamma(1/)- and RXRalpha(1/)- mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARgamma heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARgamma agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARgamma and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor alpha and interleukin 1beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARgamma and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARgamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARgamma ligands might hold promise in the clinic due to their synergistic effects.

Lymphomatoid granulomatosis in a renal transplant patient.

Lymphomatoid granulomatosis is a rare angiocentric and angiodestructive pulmonary angiitis considered as a variant of the lymphoproliferative disorder group. Patients with organ transplantation are at an increased risk for post-transplant lymphoproliferative disorders secondary to their immunosuppression. However, lymphomatoid granulomatosis has rarely been described in patients with renal transplantation. It often presents with severe pulmonary signs. We describe a case whose initial presentation was an isolated VIth nerve palsy. We review the radiological and pathological findings and discuss the etiopathogenesis and therapeutic options of this particular lymphoproliferative disorder. With careful and stepwise reduction in her immunosuppression, our patient showed a complete disappearance of her lymphomatoid granulomatosis, and she is clinically well more than 3 years after the diagnosis, with good kidney function.

Sexual protection behavior in HIV-positive gay men: testing a modified information-motivation-behavioral skills model.

This study on determinants of sexual protection behavior among HIV-positive gay men used the empirically tested information-motivation-behavioral skills (IMB) model. HIV-specific variables were added to the model to determine factors decisive for condom use with steady and casual partners. Data were collected using an anonymous, standardized self-administered questionnaire. Study participants were recruited at HIV outpatient clinics associated with the Eurosupport Study Group and the Swiss HIV Cohort Study. To identify factors associated with condom use, backward elimination regression analyses were performed. Overall, 838 HIV-infected gay men from 14 European countries were included in this analysis. About 53% of them reported at least one sexual contact with a steady partner; 62.5% had sex with a casual partner during the last 6 months. Forty-three percent always used condoms with steady partners and 44% with casual partners. High self-efficacy and subjective norms in favor of condom-use were associated with increased condom use with casual and steady partners, whereas feeling depressed was associated with decreased condom use with casual partners. Condoms were used less often with HIV-positive partners. Self-efficacy as an important behavioral skill to perform protection behavior was influenced by lower perceived vulnerability, higher subjective norms, and more positive safer sex attitudes. The IMB-model constructs appeared to be valid; however, not all the model predictors could be determined as hypothesized. Besides the original IMB constructs, HIV-specific variables, including sexual partners' serostatus and mental health, explained condom use. Such factors should be considered in clinical interventions to promote "positive prevention."

Gastric bypass in morbid obese patients is associated with reduction in adipose tissue inflammation via N-oleoylethanolamide (OEA)-mediated pathways.

Paradoxically, morbid obesity was suggested to protect from cardiovascular co-morbidities as compared to overweight/obese patients. We hypothesise that this paradox could be inferred to modulation of the "endocannabinoid" system on systemic and subcutaneous adipose tissue (SAT) inflammation. We designed a translational project including clinical and in vitro studies at Geneva University Hospital. Morbid obese subjects (n=11) were submitted to gastric bypass surgery (GBS) and followed up for one year (post-GBS). Insulin resistance and circulating and SAT levels of endocannabinoids, adipocytokines and CC chemokines were assessed pre- and post-GBS and compared to a control group of normal and overweight subjects (CTL) (n=20). In vitro cultures with 3T3-L1 adipocytes were used to validate findings from clinical results. Morbid obese subjects had baseline lower insulin sensitivity and higher hs-CRP, leptin, CCL5 and anandamide (AEA) levels as compared to CTL. GBS induced a massive weight and fat mass loss, improved insulin sensitivity and lipid profile, decreased C-reactive protein, leptin, and CCL2 levels. In SAT, increased expression of resistin, CCL2, CCL5 and tumour necrosis factor and reduced MGLL were shown in morbid obese patients pre-GBS when compared to CTL. GBS increased all endocannabinoids and reduced adipocytokines and CC chemokines. In morbid obese SAT, inverse correlations independent of body mass index were shown between palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA) levels and inflammatory molecules. In vitro, OEA inhibited CCL2 secretion from adipocytes via ERK1/2 activation. In conclusion, GBS was associated with relevant clinical, metabolic and inflammatory improvements, increasing endocannabinoid levels in SAT. OEA directly reduced CCL2 secretion via ERK1/2 activation in adipocytes.

Allergie aux beta-lactamines [Allergy to beta-lactam antibiotics].

Beta-lactam antibiotics allergies are common. Up to 10% of the population describe a former allergy to penicillins. However only 10 to 15% of these individuals are actually allergic. In most cases, beta-lactam antibiotics will be avoided and replaced by other antibiotics such as quinolones. This fear of a serious allergic reaction has an economic impact and may lead to the emergence of antibiotic resistance. A thorough allergic work-up can accurately determine true allergic patients. Most of the patients with a proven allergy will be able to tolerate other antibiotics belonging to the beta-lactam family. This article focuses on the management of beta-lactam allergic patients.

Consensus 2012 sur le diagnostic et le traitement des patients atteints de démence en Suisse [Consensus 2012--diagnosis and treatment of patients with dementia in Switzerland].

The 2012 Swiss consensus paper on diagnosis and management of patients suffering from dementia resulted from the work of an expert panel who met on March 23d to 25th in Luzem. Based on a literature review, panel members wrote a first draft that was subsequently circulated among multiple dementia experts in Switzerland. After adaptation and revisions according to comments, all consulted dementia specialists and panel members fully endorse the consensus content. The conference was financed by the Swiss Alzheimer Forum.

The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter.

Creatine transport has been assigned to creatine transporter 1 (CRT1), encoded by mental retardation associated SLC6A8. Here, we identified a second creatine transporter (CRT2) known as monocarboxylate transporter 12 (MCT12), encoded by the cataract and glucosuria associated gene SLC16A12. A non-synonymous alteration in MCT12 (p.G407S) found in a patient with age-related cataract (ARC) leads to a significant reduction of creatine transport. Furthermore, Slc16a12 knockout (KO) rats have elevated creatine levels in urine. Transport activity and expression characteristics of the two creatine transporters are distinct. CRT2 (MCT12)-mediated uptake of creatine was not sensitive to sodium and chloride ions or creatine biosynthesis precursors, breakdown product creatinine or creatine phosphate. Increasing pH correlated with increased creatine uptake. Michaelis-Menten kinetics yielded a Vmax of 838.8 pmol/h/oocyte and a Km of 567.4 µm. Relative expression in various human tissues supports the distinct mutation-associated phenotypes of the two transporters. SLC6A8 was predominantly found in brain, heart and muscle, while SLC16A12 was more abundant in kidney and retina. In the lens, the two transcripts were found at comparable levels. We discuss the distinct, but possibly synergistic functions of the two creatine transporters. Our findings infer potential preventive power of creatine supplementation against the most prominent age-related vision impaired condition.

The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

Postmortem angiography: review of former and current methods.

OBJECTIVE: Postmortem investigations are becoming more and more sophisticated. CT and MRI are already being used in pathology and forensic medicine. In this context, the impact of postmortem angiography increases because of the rapid evaluation of organ-specific vascular patterns, vascular alteration under pathologic and physiologic conditions, and tissue changes induced by artificial and unnatural causes. CONCLUSION: In this article, the advantages and disadvantages of former and current techniques and contrast agents are reviewed.

Colonic movements in healthy subjects as monitored by a Magnet Tracking System.

The Magnet Tracking System (MTS) is a minimally-invasive technique of continuous evaluation of gastrointestinal motility. In this study, MTS was used to analyse colonic propulsive dynamics and compare the transit of a magnetic pill with that of standard radio-opaque markers. MTS monitors the progress in real time of a magnetic pill through the gut. Ten men and 10 women with regular daily bowel movements swallowed this pill and 10 radio-opaque markers at 8 pm. Five hours of recordings were conducted during 2 following mornings. Origin, direction, amplitude and velocity of movements were analysed relative to space-time plots of the pill trajectory. Abdominal radiographs were taken to compare the progress of both pill and markers. The magnetic pill lay idle for 90% of its sojourn in the colon; its total retrograde displacement accounted for only 20% of its overall movement. Analysis of these movements showed a bimodal distribution of velocities: around 1.5 and 50 cm min(-1), the latter being responsible for 2/3 of distance traversed. There were more movements overall and more mass movements in males. Net hourly forward progress was greater in the left than right colon, and greater in males. The position of the magnetic pill correlated well with the advancement of markers. MTS showed patterns and propulsion dynamics of colonic segments with as yet unmet precision. Detailed analysis of slow and fast patterns of colonic progress makes it possible to specify the motility of colonic segments, and any variability in gender. Such analysis opens up promising avenues in studies of motility disorders.

Interstitial pregnancies' diagnosis and management: an eleven cases series.

PRINCIPLES: Interstitial pregnancy represents 2% of ectopic pregnancies, but it is a highly morbid condition with a 2.5% of maternal mortality. Its diagnostic and therapeutic management remains controversial. The aim of this review is to describe the management of interstitial pregnancy in our institution between 2001 and 2011 and to define some general rules for the clinical practice. METHODS: Single institution retrospective study. RESULTS: Eleven women were treated for interstitial pregnancy. The median age was 33 years and the median gestity was 4. Seven patients had a history of gynaecological surgery and four interstitial pregnancies followed in vitro fertilisation. The diagnosis was made at a median gestational age of seven weeks with a median beta-HCG level of 5,838 U/l. Six of the eleven patients received an initial treatment with intracornual methotrexate, three with intramuscular methotrexate and two with surgery. The median time to beta-HCG resolution was 58 days. Three of the eleven patients needed a second line treatment: two after intramuscular methotrexate and one after intracornual methotrexate. Six patients had further pregnancies and delivered by caesarean section. CONCLUSIONS: A high prevalence of previous ectopic pregnancies, gynaecological surgery and of pregnancies resulting from in vitro fertilisation was observed. The earliness of the diagnosis was the factor that allowed a conservative treatment in most cases. Beta-HCG level follow up was fundamental in allowing a second line therapy but beta-HCG can persist over a long period of time and this must be taken into account due to its possible psychological impact. Intracornual methotrexate seems to be more efficacious than intramuscular methotrexate in our series.

Daily smoking as a marker of weight control practices among female adolescents

Purpose: There is evidence indicating that adolescent females smoke as a way to control weight. The aim of our research is to assess whether daily smoking is a marker for weight control practices among adolescent females. Methods: Data were drawn from the 2002 Swiss Multicenter Adolescent Survey on Health (SMASH02) data base, a survey including 7,548 [3,838 females] in-school adolescents aged 16-20 years in Switzerland. Among females self-reporting BMI (N _ 3,761), two groups were drawn: daily smokers (DS, N _ 1,273) included all those smoking at least 1 cigarette/day and never smokers (NS, N _ 1,888) included all those having never smoked. Former (N _ 177) and occasional (N _ 423) smokers were not included. Groups were compared on weight control practices (being on a diet, self-induced vomiting, use of doctor-prescribed or over-the-counter appetite suppressors) controlling for possible confounding variables (age, BMI, feeling fat, body image, use of other substances, depression, sport practice, academic track and perceived advanced puberty). Analyses were performed with STATA 9. Bivariate analyses are presented as point-prevalence and multivariate analysis (using logistic regression) are presented as adjusted odds ratio (AOR) and [95% confidence interval]. Results: In the bivariate analysis, DS females were significantly more likely (p _ 0.001) than NS to be on a diet (DS: 33.2%, NS: 22.2%), to self-induce vomiting (DS: 9.0%, NS: 3.3%), and to use doctor prescribed (DS: 2.3%, NS: 0.9%) or over-the-counter (DS: 3.2%, NS: 1.2%) appetite suppressors. In the multivariate analysis, DS females were more likely than NS to be on a diet (AOR: 1.40 [1.17/1.68]), to self-induce vomiting (AOR: 2.07 [1.45/2.97]), and to use doctor-prescribed appetite suppressors (AOR: 1.99 [1.00/ 3.96]). Conclusions: Weight control practices are more frequent among female daily smokers than among never smokers. This finding seems to confirm cigarette smoking as a way to control weight among adolescent females. Health professionals should inquire adolescent female smokers about weight control practices, and this association must be kept in mind when discussing tobacco cessation options with adolescent females. Sources of Support: The SMASH02 survey was funded by the Swiss Federal Office of Public Health and the participating cantons.

Consensus 2012 sur le diagnostic et le traitement des patients atteints de démence en Suisse [Consensus 2012--diagnosis and treatment of patients with dementia in Switzerland].

The 2012 Swiss consensus paper on diagnosis and management of patients suffering from dementia resulted from the work of an expert panel who met on March 23d to 25th in Luzem. Based on a literature review, panel members wrote a first draft that was subsequently circulated among multiple dementia experts in Switzerland. After adaptation and revisions according to comments, all consulted dementia specialists and panel members fully endorse the consensus content. The conference was financed by the Swiss Alzheimer Forum.