Overexpression of Cannabinoid CB2 Receptor in the Brain Induces Hyperglycaemia and a Lean Phenotype in Adult Mice

t is well known that the endocannabinoid system, through cannabinoid CB1 receptor activation,has an important role in the main aspects of energy balance (i.e. food intake, energy expenditureand glucose and fat metabolism), orchestrating all the machinery involved in body weight con-trol and energy homeostasis. A number of studies have revealed a crucial role of brain CB1receptors in these processes. However, functional cannabinoid CB2 receptors have also beendescribed in the brain, with no studies addressing their putative role in body weight control andglucose homeostasis. We have tested this hypothesis by analysing fasting-induced feeding, bodyweight, some hypothalamic neuropeptides, glucose tolerance and plasma hormones in an animalmodel specifically overexpressing CB2 receptors in the central nervous system. We found thatspecific overexpression of CB2 receptors in the brain promoted higher basal glucose levels,decreased fasting-induced feeding and, eventually, led to a lean phenotype and glucose intoler-ance. These findings could not be attributed to decreased locomotor activity, increased anxietyor depressive-like behaviours. The expression of relevant neuropeptides such as pro-opiomelano-cortin and galanin in the arcuate nucleus of the hypothalamus was altered but not those of theCB1 receptor. Indeed, no changes in CB1 expression were found in the liver, skeletal muscle andadipose tissue. However, cannabinoid CB1 and CB2 receptor expression in the endocrine pan-creas and glucagon plasma levels were decreased. No changes in plasma adiponectin, leptin,insulin and somatostatin were found. Taken together, these results suggest a role for centralcannabinoid CB2 receptors in body weight control and glucose homeostasis

Henoch-Schönlein nephritis associated with streptococcal infection and persistent hypocomplementemia: a case report

<p>Abstract</p> <p>Introduction</p> <p>Henoch-Schönlein purpura is a systemic disease with frequent renal involvement, characterized by IgA mesangial deposits. Streptococcal infection can induce an abnormal IgA immune response like Henoch-Schönlein purpura, quite similar to typical acute post-infectious glomerulonephritis. Indeed, hypocomplementemia that is typical of acute glomerulonephritis has also been described in Henoch-Schönlein purpura.</p> <p>Case presentation</p> <p>We describe a 14-year-old Caucasian Spanish girl who developed urinary abnormalities and cutaneous purpura after streptococcal infection. Renal biopsy showed typical findings from Henoch-Schönlein purpura nephritis. In addition, she had low serum levels of complement (C4 fraction) that persisted during follow-up, in spite of her clinical evolution. She responded to treatment with enalapril and steroids.</p> <p>Conclusion</p> <p>The case described has, at least, three points of interest in Henoch-Schönlein purpura: 1) Initial presentation was preceded by streptococcal infection; 2) There was a persistence of low serum levels of complement; and 3) There was response to steroids and angiotensin-converting enzyme inhibitor in the presence of nephrotic syndrome. There are not many cases described in the literature with these characteristics. We conclude that Henoch-Schönlein purpura could appear after streptococcal infection in patients with abnormal complement levels, and that steroids and angiotensin-converting enzyme inhibitor could be successful treatment for the disease.</p

Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA)

Introduction: Currently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown.Methods: The aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24 months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1-4) to the individually highest tolerated dose of 2-4 g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5-104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4 g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician's and patient's global impression-change scales as well as the up-regulation of the frataxin protein level, safety and survival/death.Perspective: The NICOFA study represents one of the first attempts to assess the clinical efficacy of an epigenetic therapeutic intervention for this disease and will provide evidence of possible disease modifying effects of nicotinamide treatment in patients with Friedreich ataxia

Effect of sex in systemic psoriasis therapy: Differences in prescription, effectiveness and safety in the BIOBADADERM prospective cohort

The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be pre-scribed biologics. There were no differences between men and women in effectiveness of therapy, measur-ed in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness.The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall)

Calidad de las elecciones a titular del Ejecutivo en el Centro y Centro-occidente de México

Este libro, que tiene por objetivo analizar la calidad de las elecciones celebradas entre 2006 y 2011 para ocupar la titularidad del Poder Ejecutivo de las 14 entidades federativas de la República Mexicana que conforman las regiones Centro y Centro-occidente de este país, ha sido elaborado por investigadores pertenecientes a la Red Nacional de Investigación sobre la Calidad de la Democracia en México (Renicadem), la cual cuenta con un equipo de investigación en cada una de las entidades federativas del país. A su vez, esta Red constituye una de las cuatro líneas temáticas que componen la red temática del Conacyt “Sociedad civil y calidad de la democracia”. Con todo, la presente obra puede considerarse, en dos sentidos, como el resultado parcial de estudios realizados por investigadores que conforman la mencionada Renicadem. Por un lado, trata sólo de una de las varias dimensiones que esta Red ha establecido como necesarias para analizar la calidad de la democracia: la calidad electoral (otras dimensiones, que se encuentran en proceso de investigación, son calidad de vida, rendición de cuentas y Estado de derecho). También es parcial porque no abarca la totalidad de la República Mexicana, sino únicamente a las 14 entidades indicadas.UAE

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6&nbsp;years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P &lt; 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100&nbsp;years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes