Novel genetic risk markers for ulcerative colitis in the IL2/IL21 region are in epistasis with IL23R and suggest a common genetic background for ulcerative colitis and celiac disease

OBJECTIVES: Recently, a genome-wide association study showed that single-nucleotide polymorphisms (SNPs) in the chromosome 4q27 region containing IL2 and IL21 are associated with celiac disease. Given the increased prevalence of inflammatory bowel disease (IBD) among celiac disease patients, we investigated the possible involvement of these SNPs in IBD. METHODS: Five SNPs strongly associated with celiac disease within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block on chromosome 4q27 and one coding SNP within the IL21 gene were analyzed in a large German IBD cohort. The study population comprised a total of 2,948 Caucasian individuals, including 1,461 IBD patients (ulcerative colitis (UC): n=514, Crohn's disease (CD): n=947) and 1,487 healthy unrelated controls. RESULTS: Three of the five celiac disease risk markers had a protective effect on UC susceptibility, and this effect remained significant after correcting for multiple testing: rs6840978: P=0.0082, P(corr)=0.049, odds ratio (OR) 0.77, 95% confidence interval (CI) 0.63-0.93; rs6822844: P=0.0028, P(corr)=0.017, OR 0.73, 95% CI 0.59-0.90; rs13119723: P=0.0058, P(corr)=0.035, OR 0.75, 95% CI 0.61-0.92. A haplotype consisting of the six SNPs tested was markedly associated with UC susceptibility (P=0.0025, P(corr)=0.015, OR 0.72, 95% CI 0.58-0.89). Moreover, in UC, epistasis was observed between the IL23R SNP rs1004819 and three SNPs in the KIAA1109/TENR/IL2/IL21 block (rs13151961, rs13119723, and rs6822844). CONCLUSIONS: Similar to other autoimmune diseases such as celiac disease, rheumatoid arthritis, type 1 diabetes, Graves' disease, and psoriatic arthritis, genetic variation in the chromosome 4q27 region predisposes to UC, suggesting a common genetic background for these diseases.

Cold-season temperatures in the European Alps during the past millennium: variability, seasonality and recent trends

This study presents a proxy-based, quantitative reconstruction of cold-season (mean October to May, TOct–May) air temperatures covering nearly the entire last millennium (AD 1060–2003, some hiatuses). The reconstruction was based on subfossil chrysophyte stomatocyst remains in the varved sediments of high-Alpine Lake Silvaplana, eastern Swiss Alps (46°27’N, 9°48′W, 1791 m a.s.l.). Previous studies have demonstrated the reliability of this proxy by comparison to meteorological data. Cold-season air temperatures could therefore be reconstructed quantitatively, at a high resolution (5-yr) and with high chronological accuracy. Spatial correlation analysis suggests that the reconstruction reflects cold season climate variability over the high- Alpine region and substantial parts of central and western Europe. Cold-season temperatures were characterized by a relatively stable first part of the millennium until AD 1440 (2σ of 5-yr mean values = 0.7 °C) and highly variable TOct–May after that (AD 1440–1900, 2σ of 5-yr mean values = 1.3 °C). Recent decades (AD, 1991-present) were unusually warm in the context of the last millennium (exceeding the 2σ-range of the mean decadal TOct–May) but this warmth was not unprecedented. The coolest decades occurred from AD 1510–1520 and AD 1880–1890. The timing of extremely warm and cold decades is generally in good agreement with documentary data representing Switzerland and central European lowlands. The transition from relatively stable to highly variable TOct–May coincided with large changes in atmospheric circulation patterns in the North Atlantic region. Comparison of reconstructed cold season temperatures to the North Atlantic Oscillation index (NAO) during the past 1000 years showed that the relatively stable and warm conditions at the study site until AD 1440 coincided with a persistent positive mode of the NAO. We propose that the transition to large TOct–May variability around AD 1440 was linked to the subsequent absence of this persistent zonal flow pattern, which would allow other climatic drivers to gain importance in the study area. From AD 1440–1900, the similarity of reconstructed TOct–May to reconstructed air pressure in the Siberian High suggests a relatively strong influence of continental anticyclonic systems on Alpine cold season climate parameters during periods when westerly airflow was subdued. A more continental type of atmospheric circulation thus seems to be characteristic for the Little Ice Age in Europe. Comparison of Toct–May to summer temperature reconstructions from the same study site shows that, as expected, summer and cold season temperature trends and variability differed completely throughout nearly the entire last 1000 years. Since AD 1980, however, summer and cold season temperatures show a simultaneous, strong increase, which is unprecedented in the context of the last millennium. We suggest that the most likely explanation for this recent trend is anthropogenic greenhouse gas (GHG) forcing.

Outcome of ventriculoperitoneal shunt implantation for treatment of congenital internal hydrocephalus in dogs and cats: 36 cases (2001-2009)

OBJECTIVE To examine outcome data for cats and dogs with congenital internal hydrocephalus following treatment via ventriculoperitoneal shunting to determine treatment-associated changes in neurologic signs, the nature and incidence of postoperative complications, and survival time. DESIGN Retrospective multicenter case series. ANIMALS 30 dogs and 6 cats with congenital internal hydrocephalus (confirmed via CT or MRI). PROCEDURES Medical records for dogs and cats with internal hydrocephalus that underwent unilateral ventriculoperitoneal shunt implantation from 2001 through 2009 were evaluated. Data collected included the nature and incidence of postoperative complications, change in clinical signs following surgery, and survival time. To compare pre- and postoperative signs, 2-way frequency tables were analyzed with a 1-sided exact McNemar test. RESULTS 8 of 36 (22%) animals developed postoperative complications, including shunt malfunction, shunt infection, and seizure events. Three dogs underwent shunt revision surgery. Thirteen (36%) animals died as a result of hydrocephalus-related complications or were euthanized. Following shunt implantation, clinical signs resolved in 7 dogs and 2 cats; overall, 26 (72%) animals had an improvement of clinical signs. After 18 months, 20 animals were alive, and the longest follow-up period was 9.5 years. Most deaths and complications occurred in the first 3 months after shunt placement. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that ventriculoperitoneal shunt implantation is a viable option for treatment of dogs or cats with congenital hydrocephalus. Because complications are most likely to develop in the first 3 months after surgery, repeated neurologic and imaging evaluations are warranted during this period.

Frequent sensitization to Candida albicans and profilins in adult eosinophilic esophagitis

BACKGROUND: Eosinophilic esophagitis (EoE) is often associated with atopic airway and skin diseases. More than 80% of EoE patients are sensitized to aero- and/or food allergens. Immunoglobulin (Ig)E-mediated immune responses to microbes have been reported to be deleterious in connection with atopic diseases. AIM: The aim of this study was to obtain a comprehensive overview about the sensitization spectrum of adult EoE patients. METHODS: IgE in sera of 35 patients with active EoE were analyzed for reactivity to Candida albicans, as well as to a panel of recombinant and purified natural allergen components, using a microarray. RESULTS: IgE sensitization to Candida albicans was found in 43% of EoE patients. More than 80% of EoE patients were sensitized to aeroallergens and 22% to food-specific allergen components, whereas 69% of the patients exhibited specific IgE to cross-reactive allergens. Among the latter, profilins were identified as most frequent IgE cross-reactive allergen components. Interestingly, dysphagia, the main symptom of adult EoE patients following rice and/or bread ingestion, was associated with sensitization to cross-reactive allergens such as profilins, pathogenesis-related (PR) 10 and lipid transfer proteins (LTP). Intolerance toward meat rarely correlated with sensitization to animal food allergens. CONCLUSION: Candida albicans and cross-reactive plant allergen components, in particular profilins, were identified as frequent sensitizers in adult EoE patients. Specific elimination therapies are suggested to reveal their actual roles in the pathogenesis of EoE.

A TEX 86 lake record suggests simultaneous shifts in temperature in Central Europe and Greenland during the last deglaciation

High-resolution quantitative temperature records from continents covering glacial to interglacial transitions are scarce but important for understanding the climate system. We present the first decadal resolution record of continental temperatures in Central Europe during the last deglaciation (similar to 14,60010,600cal. yrB.P.) based on the organic geochemical palaeothermometer TEX86. The TEX86-inferred temperature record from Lake Lucerne (Vierwaldstattersee, Switzerland) reveals typical oscillations during the Late Glacial Interstadial, followed by an abrupt cooling of 2 degrees C at the onset of Younger Dryas and a rapid warming of 4 degrees C at the onset of the Holocene, within less than 350years. The remarkable resemblance with the Greenland and regional stable oxygen isotope records suggests that temperature changes in continental Europe were dominated by large-scale reorganizations in the northern hemispheric climate system.

The EU’s Choice of Regulatory Venues for Trade Negotiations: A Tale of Agency Power?

This article focuses on the EU’s strategy for choosing regulatory venues to negotiate trade agreements. It analyses the existence of a clear venue hierarchy since the late 1990s and the recent change leading to a blurring of any clear preference for using bilateral, inter-regional or multilateral settings. The article challenges domestic explanations of the EU’s choice of venue, stressing the autonomy of the Commission as a major factor. Using a principal-agent framework, it shows that the Commission’s agenda-setting powers, the existence of interest divergence among principals (e.g. Member States, business groups) and the multi-level system facilitate agency.

Zum Freihandelsabkommen EU-USA: Auswirkungen auf die Schweiz

Seit Juli 2013 laufen die Verhandlungen über ein umfassendes Freihandels- und Investitionsschutzabkommen zwischen der EU und den USA. Die Verhandlungen laufen noch, und es ist zum heutigen Zeitpunkt wenig bekannt zum Ausgang und Umfang des Abkommens. Zwei der in der Öffentlichkeit breit diskutierten Streitpunkte sind das geplante Investor-Staat-Streitbeilegungsverfahren, sowie die sogenannten Chlor-Hühnchen. Das geplante Abkommen soll aber weit darüber hinaus greifen und nebst dem Zollabbau für Industrie- und Agrarprodukte auch die Beseitigung von nicht-tarifären Handelshemmnissen umfassen. Nicht-tarifäre Handelshemmnisse werden typischerweise durch eine Rechtsharmonisierung im Bereich der Produktionsstandards reduziert. Eine solche Harmonisierung könnte sich für die Schweizer Industrie als Herausforderung herausstellen. Auch strikte Ursprungsregeln könnten sich auf einzelne Schweizer Zwischenprodukte negativ auswirken. Potenziell negative Auswirkungen könnten aber durch verschiedene handelspolitische Massnahmen gemindert werden. Soweit minilaterale Abkommen wie das TTIP-Abkommen eine nicht-diskriminierende Rechtsharmonisierung vorsehen, wirken sie sich insgesamt primär positiv und wachstumsfördernd für Drittstaaten wie die Schweiz aus.

Assessment of Intramedullary Spinal Pressure in Small Breed Dogs With Thoracolumbar Disk Extrusion Undergoing Hemilaminectomy

OBJECTIVE To assess intramedullary spinal pressure (IMP) in small breed dogs with thoracolumbar disk extrusion. STUDY DESIGN Prospective cohort study. ANIMALS Small breed dogs (n = 14) with thoracolumbar disk extrusion undergoing hemilaminectomy and healthy chondrodystrophic laboratory dogs (control; n = 3) without spinal disease. METHODS Diagnosis was based on clinical and neurological examinations and magnetic resonance imaging (MRI) and was confirmed intraoperatively. A standardized anesthesia protocol and surgical procedure were used to minimize factors that could influence IMP. Intramedullary pressure was measured through a minidurotomy at the site of spinal cord compression using a fiber optic catheter inserted perpendicular to the longitudinal axis of the spinal cord. Measurements were taken after hemilaminectomy and again after removal of extruded disk material. RESULTS Affected dogs had significantly higher IMP compared to control dogs (P = .008) and IMP decreased significantly post-decompression compared with initial values (P < .001). No correlation was found between IMP and neurologic grade, degree of spinal cord compression on MRI, or signal intensity changes on MRI. CONCLUSION Acute thoracolumbar disk extrusion is associated with increased IMP in small breed dogs and surgical decompression results in an immediate decrease of IMP.

A retrospective study of 1- versus 2-cm excision margins for cutaneous malignant melanomas thicker than 2 mm.

BACKGROUND Most guidelines recommend at least 2-cm excision margin for melanomas thicker than 2 mm. OBJECTIVE We evaluated whether 1- or 2-cm excision margins for melanoma (>2 mm) result in different outcomes. METHODS This is a retrospective cohort study on patients with melanomas (>2 mm) who underwent tumor excision with 1-cm (228 patients) or 2-cm (97 patients) margins to investigate presence of local recurrences, locoregional and distant metastases, and disease-free and overall survival. RESULTS In all, 325 patients with mean age of 61.84 years and Breslow thickness of 4.36 mm were considered for the study with a median follow-up of 1852 days (1995-2012). There was no significant difference in the frequency of locoregional and distant metastasis between the 2 groups (P = .311 and .571). The survival analysis showed no differences for disease-free (P = .800; hazard ratio 0.948; 95% confidence interval 0.627-1.433) and overall (P = .951; hazard ratio 1.018; 95% confidence interval 0.575-1.803) survival. LIMITATIONS The study was not prospectively randomized. CONCLUSIONS Our study did not show any significant differences in important outcome parameters such as local or distant metastases and overall survival. A prospective study testing 1- versus 2-cm excision margin is warranted.

A meta-analysis of trabecular bone score in fracture risk prediction and its relationship to FRAX

Trabecular bone score (TBS) is a grey-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a BMD-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables and outcomes during follow up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% CI: 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR 1.32, 95%CI: 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95%CI: 1.65, 1.87 vs. 1.70, 95%CI: 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. This article is protected by copyright. All rights reserved.

Page du Cardinal de Brogny, Figurine, Profil, in: Fromental Halévy: La Juive

Signatur des Originals: S 36/G12630

Identification of genetic risk factors for cerebellar mutism in pediatric brain tumor patients

Following posterior fossa surgery for resection of childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET), cerebellar mutism (CM) may develop. This is a condition of absent or diminished speech in a conscious patient with no evidence of oral apraxia, which can be accompanied by other symptoms of the posterior fossa syndrome complex, which includes ataxia and hypotonia. Little is known about the etiology. Therefore, we conducted a SNP, gene, and pathway-level analysis to assess the role of host genetic variation on the risk of CM in M/PNET subjects following treatment. Cases (n= 20) and controls (n= 53) were recruited from the Childhood Cancer Epidemiology and Prevention Center, in Houston, TX. DNA samples were genotyped using the Illumina Human 1M Quad SNP chip. Ten pathways were identified from logistic regression used to identify the marginal effect of each SNP on CM risk. The minP test was conducted to identify associations between SNPs categorized to genes and CM risk. Pathways were assessed to determine if there was a significant enrichment of genes in the pathway compared to all other pathways. There were 78 genes that reached the threshold of min P ≤0.05 in 948 genes. The Neurotoxicity pathway was the most significant pathway after adjusting for multiple comparisons (q=0.040 and q=0.005, using Fisher's exact test and a test of proportions, respectively). Most genes within the Neurotoxicity pathway that reached a threshold of minP ≤0.05 were known to have an apoptosis function, possibly inducing neuronal apoptosis in the dentatothalamocortical pathway, and may be important in CM etiology in this population. This is the first study to assess the potential role of genetic risk factors on CM. As an exploratory study, these results should be replicated in a larger sample. ^