The Mexican consensus on the diagnosis and treatment of ulcerative colitis

The guidelines presented herein are an updated version of the recommendations published in 2007. Since then, there has been a rapid advance in the knowledge about the pathophysiology of ulcerative colitis and its therapeutic options. New drugs have been approved, novel targeted therapies have emerged, and new strategies have been developed to improve the previously available approaches to the disease.The aim of the present consensus is to promote the current knowledge of and Mexican perspective on the epidemiology, diagnosis, and medical and surgical treatment of chronic idiopathic ulcerative colitis.The final vote on the statements and their ultimate modifications were carried out at the consensus working group meeting. Evidence was evaluated through the GRADE classification. Resumen: Estas guías constituyen una actualización de las guías publicadas en 2007. Desde ese año, los conocimientos acerca de la fisiopatología, así como las opciones terapéuticas, han evolucionado rápidamente, con la aprobación de nuevos agentes, la aparición de nuevos blancos terapéuticos y nuevas estrategias para mejorar los abordajes disponibles previamente.El objetivo de este consenso es promover una actualización y perspectiva mexicana sobre la epidemiología, el diagnóstico así como el tratamiento médico y quirúrgico de la colitis ulcerosa crónica idiopática.Los enunciados fueron finalmente votados y se realizaron las modificaciones finales en la junta de consenso. La evaluación de la evidencia por la clasificación GRADE se realizó al momento del consenso. Keywords: Chronic idiopathic ulcerative colitis, Diagnosis, Treatment, Epidemiology, Colectomy, Pouchitis, Palabras clave: Colitis ulcerosa crónica idiopática, Diagnóstico, Tratamiento, Epidemiología, Colectomía, Pouchiti

Epidemiología, carga de la enfermedad y tendencias de tratamiento de la enfermedad inflamatoria intestinal en México

Introducción y objetivos: En México no existe información sistematizada para determinar/ monitorizar la carga de la enfermedad inflamatoria intestinal (EII). El objetivo del estudio fue estimar la carga anual de la EII en el Sistema Nacional de Salud por número de pacientes atendidos, hospitalizaciones y muertes y por grupos de edad. Material y métodos: Utilizando registros específicos de bases de datos del Sistema Nacional de Salud codificados por CIE-10: K50 y K51, obtuvimos y analizamos datos correspondientes a los pacientes atendidos y hospitalizados por grupo etario, así como muertes específicas durante el año 2015. Asimismo, se exploró la tendencia de tratamiento entre médicos. Resultados: En 2015, el número total de casos atendidos (prevalencia de casos atendidos) fue: enfermedad de Crohn en mujeres 5,009 (8.1), en hombres 4,944 (8.4). Los pacientes ≥ 50 años representaron el 35.1% del total; colitis ulcerosa crónica idiopática en mujeres 17,177 (27.7), en hombres 15,883 (26.9). Los ≥ 50 años representaron el 31.6% del total. Los casos hospitalizados fueron (prevalencia de casos hospitalizados): enfermedad de Crohn 1,097 (0.91). Los pacientes≥ 50 años representaron el 43.7% del total; colitis ulcerosa crónica idiopática 5,345 (4.42). Los enfermos ≥ 50 años representaron el 47.6% del total. Las defunciones fueron (tasa de muertes específicas): en enfermedad de Crohn: mujeres 32 (0.52), hombres 36 (0.50); colitis ulcerosacrónica idiopática en mujeres 267 (4.31), en hombres 186 (3.15).Conclusiones: La EII representa una carga para la salud de los adultos mexicanos y el Sistema de Salud, y se espera que aumente en los próximos 15 años

Inflammatory bowel disease in Mexico: Epidemiology, burden of disease, and treatment trends

Introduction and aims: There is no systematized information for determining/monitoring the burden of inflammatory bowel disease in Mexico. The aim of the present study was to estimate the annual burden of inflammatory bowel disease on the Mexican National Healthcare System, by number of patients seen, hospitalizations, and specific deaths, stratified into age groups. Materials and methods: Utilizing specific databases of the Mexican National Healthcare System registries coded as ICD-10: K50 and K51, we retrieved and analyzed the data corresponding to the patients seen and hospitalized in 2015, stratified by age group, as well as the specific deaths. Treatment trends among physicians were also examined. Results: In 2015, 5009 women (8.1) and 4944 men (8.4) with Crohn’s disease received medical attention (prevalence of cases seen) and 35.1% of those patients were ≥50 years of age. In that same period, 17,177 women (27.7) and 15,883 men (26.9) with ulcerative colitis wereseen and 31.6% of those patients were ≥50 years of age. The hospitalized cases (prevalence ofhospitalized cases) were 1097 patients (0.91) with Crohn’s disease and 43.7% of those patientswere ≥50 years of age; and 5345 patients (4.42) with ulcerative colitis and 47.6% of thosepatients were ≥50 years of age. Deaths (specific mortality rate) were: 32 women (0.52) and 36men (0.50) due to Crohn’s disease, and 267 women (4.31) and 186 men (3.15) due to ulcerativecolitis.Conclusions: Inflammatory bowel disease is a burden on the health of Mexican adults and theMexican National Healthcare System, and it is expected to increase over the next 15 year

Performance Verification of the Astro-E2 X-ray spectrometer in the flight configuration

The X-ray Spectrometer (XRS) is a high resolution, non-dispersive cryogenic detector on board the X-ray satellite, Astro-E2 (Suzaku), which was successfully launched on July 10, 2005. The XRS achieves an energy resolution of 6 eV at 6 keV (FWHM) and covers a broad energy range of {approx} 0.07-10 keV. The XRS will enable powerful plasma diagnostics of a variety of astrophysical objects such as the dynamics of gas in clusters of galaxies. The XRS was integrated to the spacecraft in September 2004, and took a series of spacecraft tests until April 2005. We describe results of the XRS performance verification in the spacecraft configuration. First, the noise level was extremely low on the spacecraft, and most of the pixels achieved an energy resolution of 5-6 eV at 5.9 keV. Microphonics from the mechanical cooler was one of the concerns, but they did not interfere with the detector, when the dewar was integrated to the spacecraft and filled with solid neon. To attain the best energy resolution, however, correction of gain drift is mandatory. The XRS has a dedicated calibration pixel for that purpose, and drift correction using the calibration pixel is very effective when the gain variation is due to changes in the {approx} 60-mK heat sink temperature. On the other hand, the calibration pixel and the other pixels do not respond in the same way to variations of the helium and neon bath temperatures, and this effect requires further study

Transcript levels of Toll-Like receptors 5, 8 and 9 correlate with inflammatory activity in Ulcerative Colitis

<p>Abstract</p> <p>Background</p> <p>Dysregulation of innate immune response by Toll-Like Receptors (TLRs) is a key feature in Ulcerative Colitis (UC). Most studies have focused on <it>TLR2, TLR3</it>, and <it>TLR4 </it>participation in UC. However, few studies have explored other TLRs. Therefore, the aim of this study was to evaluate the mRNA profiles of <it>TLR1 to 9 </it>in colonic mucosa of UC patients, according to disease activity.</p> <p>Methods</p> <p>Colonic biopsies were taken from colon during colonoscopy in 51 patients with Ulcerative Colitis and 36 healthy controls. mRNA levels of <it>TLR1 to 9, Tollip</it>, inflammatory cytokines <it>IL6 </it>and <it>TNF </it>were assessed by RT-qPCR with hydrolysis probes. Characterization of <it>TLR9 </it>protein expression was performed by Immunohistochemistry.</p> <p>Results</p> <p>Toll-like receptors <it>TLR8, TLR9</it>, and <it>IL6 </it>mRNA levels were significantly higher in the colonic mucosa from UC patients (both quiescent and active) as compared to healthy individuals (p < 0.04). In the UC patients group the <it>TLR2, TLR4, TLR8 </it>and <it>TLR9 </it>mRNA levels were found to be significantly lower in patients with quiescent disease, as compared to those with active disease (p < 0.05), whereas <it>TLR5 </it>showed a trend (p = 0.06). <it>IL6 </it>and <it>TNF </it>mRNA levels were significantly higher in the presence of active disease and help to discriminate between quiescent and active disease (p < 0.05). Also, <it>IL6 </it>and <it>TNF </it>mRNA positively correlate with TLRs mRNA with the exception for <it>TLR3</it>, with stronger correlations for <it>TLR5, TLR8</it>, and <it>TLR9 </it>(p < 0.0001). <it>TLR9 </it>protein expression was mainly in the lamina propria infiltrate.</p> <p>Conclusions</p> <p>This study demonstrates that <it>TLR2, TLR4, TLR8</it>, and <it>TLR9 </it>expression increases in active UC patients, and that the mRNA levels positively correlate with the severity of intestinal inflammation as well as with inflammatory cytokines.</p

TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation

NOD2, the nucleotide-binding domain and leucine-rich repeat containing gene family (NLR) member 2 is involved in mediating antimicrobial responses. Dysfunctional NOD2 activity can lead to severe inflammatory disorders, but the regulation of NOD2 is still poorly understood. Recently, proteins of the tripartite motif (TRIM) protein family have emerged as regulators of innate immune responses by acting as E3 ubiquitin ligases. We identified TRIM27 as a new specific binding partner for NOD2. We show that NOD2 physically interacts with TRIM27 via the nucleotide-binding domain, and that NOD2 activation enhances this interaction. Dependent on functional TRIM27, ectopically expressed NOD2 is ubiquitinated with K48-linked ubiquitin chains followed by proteasomal degradation. Accordingly, TRIM27 affects NOD2-mediated pro-inflammatory responses. NOD2 mutations are linked to susceptibility to Crohns disease. We found that TRIM27 expression is increased in Crohns disease patients, underscoring a physiological role of TRIM27 in regulating NOD2 signaling. In HeLa cells, TRIM27 is partially localized in the nucleus. We revealed that ectopically expressed NOD2 can shuttle to the nucleus in a Walker A dependent manner, suggesting that NOD2 and TRIM27 might functionally cooperate in the nucleus. We conclude that TRIM27 negatively regulates NOD2-mediated signaling by degradation of NOD2 and suggest that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases.Funding Agencies|German Research Foundation (DFG)|SFB670-NG01|Swedish Society of Medicine||Regional Research Council of South-East Sweden (FORSS)||Swedish Research Council division of Medicine||Gustav V 90th anniversary foundation||Italian Telethon Foundation||DFG|SE 1122/2-1|</p

Defining the Role of the MHC in Autoimmunity: A Review and Pooled Analysis

The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits – multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) – in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific pathogenetic mechanisms in autoimmunity

Benidipine reduces ischemia reperfusion-induced systemic oxidative stress through suppression of aldosterone production in mice

Aldosterone is implicated in the pathogenesis of several cardiovascular diseases, including ischemia reperfusion (I/R) and myocardial infarction, and also causes oxidative stress and inflammation in cardiovascular systems. Benidipine, a long-acting T-and L-type calcium channel blocker, reduces infarct size following myocardial I/R in rabbits. Benidipine also inhibits the production of aldosterone in vitro. However, the precise mechanism of this phenomenon in vivo remains unknown. We therefore evaluated whether benedipine has a beneficial role through the regulation of oxidative stress in myocardial I/R. C57BL/6J mice were subjected to 30 min of left ascending coronary I/R. Benidipine was administered orally at 3 mg kg -1daily for 3 weeks without any changes in hemodynamic variables. Benidipine significantly reduced infarction size (13.4±2.5%) compared with controls (25.5±3.6%). Urinary 8-hydroxy-2′ deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, increased significantly after I/R. I/R induced increases in 8-OHdG were significantly lower with benidipine. Local myocardial 8-OHdG was also elevated in I/R, but this augmentation was significantly suppressed with benidipine. The plasma aldosterone concentration (PAC) significantly increased 2 days after I/R and remained elevated at least 7 days after I/R. Treatment with benidipine significantly decreased I/R-induced elevation of the PAC. I/R-induced markers of fibrosis in hearts also reduced in benidipine. These results suggest that the administration of benidipine reduces myocardial infarct size as well as systemic oxidative stress after I/R. These phenomena are partially linked to reduced plasma aldosterone levels. © 2012 The Japanese Society of Hypertension All rights reserved

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all &gt;0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council