Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations

Additional file 1. Complementary data on primer sequences, SKI amplification and survival analyses

Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants

Background: The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. Objective: We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. Design: We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case–control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Results: Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Conclusions: Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD

Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant

Transplantation and immunomodulatio

Colony-stimulating factor 1-dependent resident macrophages play a regulatory role in fighting Escherichia coli fecal peritonitis

Osteopetrotic op/op mice have less than 5% of the normal number of macrophages in the peritoneal cavity (W. Wiktor-Jedrzejczak, A. Ahmed, C. Szczylik, and R.R. Skelly, J. Exp. Med. 156:1516-1527, 1982). Fecal peritonitis was induced by intraperitoneal injection of 0.5 ml of 5% autoclaved feces in saline along with Escherichia coli grown from feces of mice of the same colony and added in doses ranging between 10 and 10(6) CFU. Such infection led to a septic shock and either was lethal within 24 h or became cured without additional treatment of the mice. The op/op mice survived administration of 30-times-smaller doses of bacteria compared with their normal littermates. Analysis of the kinetics of cellular changes in the peritoneal cavity associated with such infection revealed that this increased susceptibility of macrophage-deficient mice cannot be explained by a direct role of macrophages in combating the infection. Instead, it appeared that the increased susceptibility to fatal fecal peritonitis was most likely due to delayed and impaired recruitment of neutrophils to the site of infection in mutant mice. The increased susceptibility of the op/op mice to E. coli fecal peritonitis was not due to their possible increased sensitivity to endotoxin, since the mutant mice tolerated lipopolysaccharide doses more than twice those tolerated by control littermates. On the other hand, their susceptibility to exogenous tumor necrosis factor alpha and interleukin-1 alpha was increased. Both mutant op/op and control mice were able to survive secondary challenge with 10(6) E. coli (administered along with feces) lethal for both types of mice on primary challenge. These data suggest that colony-stimulating factor 1-dependent resident peritoneal macrophages play a role in controlling primary infection by recruiting neutrophils and are not required for efficient response to secondary infection.</jats:p

Pheochromocytoma presenting as takotsubo-like cardiomyopathy following delivery

Item does not contain fulltextOBJECTIVE: Diagnosis of pheochromocytoma during pregnancy can be difficult, and the tumor carries an unfavorable prognosis if not diagnosed and treated in a timely manner. METHODS: To present a case of Takotsubo-like cardiomyopathy characterized by transient left ventricular apical ballooning due to pheochromocytoma following delivery. RESULTS: A few hours after Caesarean section, a 32-year-old Caucasian female presented with pulmonary edema followed by cardiac arrest with echocardiographic and ventriculographic evidence of reversible acute myocardial failure characteristic of Takotsubo-like cardiomyopathy. A previously unrecognized adrenal pheochromocytoma was found during her clinical work-up. Left ventricle (LV) function normalized after surgical removal of the tumor, which was carried out after implementing an alpha-adrenoreceptor blockade. Hemorrhagic necrosis of the pheochromocytoma was seen on histopathologic analysis; this may have triggered the sequence of events leading to the development of Takotsubo-like cardiomyopathy and hemodynamic collapse. CONCLUSION: To the best of our knowledge, this is the first reported case of Takotsubo-like cardiomyopathy related to pheochromocytoma following delivery. This emphasizes the increased cardiovascular risk if pheochromocytoma is not diagnosed and treated in a timely manner, especially during pregnancy