Thrombotic Occlusion of All Left Coronary Branches in a Young Woman with Severe Ulcerative Colitis

Background. The thrombosis risk is increased in active ulcerative colitis. The limited number of reported complications have predominantly been cerebrovascular but other vessel territories may also be affected. Patient. During a severe attack of ulcerative colitis a 37-year-old woman suffered occlusion of all left coronary artery branches. Serial angiographies showed progressive recanalisation of the coronary arteries during anticoagulation, but no atherosclerotic stenosis. The cause of infarction was thus considered to be an extensive coronary thrombosis. However, a large battery of blood tests failed to identify any procoagulant abnormality. Conclusion. Evidence is now accumulating that the increased thrombosis risk also may involve the coronary arteries, even in young patients. To the best of our knowledge this is the third reported case of myocardial infarction despite angiographically normal coronary arteries in a patient with active ulcerative colitis. The extent of affected myocardium was in this case exceptionally large

Back to the future:re-establishing guinea pig in vivo asthma models

Research using animal models of asthma is currently dominated by mouse models. This has been driven by the comprehensive knowledge on inflammatory and immune reactions in mice, as well as tools to produce genetically modified mice. Many of the identified therapeutic targets influencing airway hyper-responsiveness and inflammation in mouse models, have however been disappointing when tested clinically in asthma. It is therefore a great need for new animal models that more closely resemble human asthma. The guinea pig has for decades been used in asthma research and a comprehensive table of different protocols for asthma models is presented. The studies have primarily been focused on the pharmacological aspects of the disease, where the guinea pig undoubtedly is superior to mice. Further reasons are the anatomical and physiological similarities between human and guinea pig airways compared with that of the mouse, especially with respect to airway branching, neurophysiology, pulmonary circulation and smooth muscle distribution, as well as mast cell localization and mediator secretion. Lack of reagents and specific molecular tools to study inflammatory and immunological reactions in the guinea pig has however greatly diminished its use in asthma research. The aim in this position paper is to review and summarize what we know about different aspects of the use of guinea pig in vivo models for asthma research. The associated aim is to highlight the unmet needs that have to be addressed in the future

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Gender-Related Survival in Different Stages of Lung Cancer—A Population Study over 20 Years

Introduction: Tumour stage is the most important prognostic factor in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The aim of this study was to evaluate if female gender was a prognostic factor in different tumour stages in relation to histology and given therapy. Methods: From 1989-2008, 1497 patients in eastern Scania, in southern Sweden with 202,000 inhabitants, were referred and prospectively registered. Tumour stage, performance status, lung cancer type and primary therapy were registered. Results: In NSCLC, female patients in stages 1 and 2 who were treated with surgery had a better 5-year survival rate (79.4%), compared to males (60.6%; p = 0.0004). Female patients in stage 3 with active therapy (surgery and/or radiotherapy and/or chemotherapy) had a better 5-year survival than males (20.6% vs. 10.5%, respectively, p = 0.0006). Female patients with adenocarcinoma were favourable in stages 1-3. In stage 4, there was no survival difference between females and males. In SCLC, females with limited disease (LD) and active therapy (chemotherapy ± radiotherapy ± surgery) had a higher 5-year survival rate (28%) than males (5.6%); p = 0.001. Females with extensive disease (ED) and active therapy (chemotherapy ± radiotherapy) had a better 5-year survival (3.9%) compared to males (0.7%); p = 0.023. In multivariate analyses, patient performance status at diagnosis was also an independent prognostic factor in all tumour stages of lung cancer. Conclusions: This population-based study corroborates a female survival advantage in NSCLC stages 1-3, but not in metastatic stage 4, and this is also demonstrated for the adenocarcinoma subgroup. The study also confirms better prognosis in females with SCLC in both LD and ED. The study also demonstrates the importance of patient performance status as a prognostic factor in all stages of lung cancer

Prognostic factors in lung cancer in a defined geographical area over two decades with a special emphasis on gender.

Introduction: Many studies over recent decades report an increasing incidence of lung cancer in female patients. Female gender is often reported as a good prognostic factor. Objectives: The aim of the present study was to investigate prognostic factors with a special emphasis on gender. Methods: During 1989-2008, 1497 patients in eastern Scania, a part of southern Sweden with 202 000 inhabitants, were referred to one Central Hospital and prospectively registered. All patients were grouped into four 5-year periods and analysed for occurrence of lung cancer, patient performance status, types and stages of lung cancer and the relation to gender. Results: The incidence of lung cancer more than doubled in women. The proportion of adenocarcinomas increased in females and males to 57 % (p=0.028) and 42 % (p=0.001), respectively, while the frequency of small cell lung carcinomas (SCLCs) decreased in both genders to approximately 14 %. Females had significantly more frequent stage 1 (16.6 %) and higher surgery rate (23.1 %) than males (12 % and 18.2 %, respectively). Females showed a higher 5-year survival rate than males (20.1 % and 11.5 %, respectively; p<0.001). Patients with non-small cell lung carcinoma (NSCLC) had a higher 5-year survival rate than those with SCLC (16.5 % and 7.5 %, respectively; p<0.01); however there was no significant survival difference in females between NSCLC and SCLC. Conclusion: Female patients exhibited longer survival than males for both NSCLC and SCLC, and this was not explained by a higher frequency of stage 1 or surgery in NSCLC. © 2012 Blackwell Publishing Ltd

Nitric oxide gives maximal response after coronary artery bypass surgery

The dose-response to inhalation of nitric oxide (NO) after coronary artery bypass surgery was studied in seven patients with normal preoperative lung function and chest radiograms. During postoperative controlled ventilation with PEEP 5 and 10 cmH2O, the patients inhaled NO in concentrations of 2 to 25 ppm, in random order, for 6 to 10 minutes. Hemodynamic and oximetric data were analyzed before, 5 minutes after start of the NO inhalation, and 5 minutes after the cessation. The response was the same at all concentrations; mean pulmonary artery pressure decreased by 11 +/- 1% (P < 0.05) and pulmonary vascular resistance decreased by 22 +/- 2% (P < 0.05). Systemic hemodynamics did not change, but oximetric parameters tended to improve. Changes in PEEP did not affect the response. It is concluded that, in patients who have undergone coronary artery bypass grafting, inhalation of 2 to 25 ppm NO causes a dose-independent decrease in pulmonary artery pressure and pulmonary vascular resistance. In order to investigate the dose-response curve, concentrations lower than 2 ppm of NO must be used

Detection of mouth alcohol during breath alcohol analysis.

The presence of mouth alcohol (MA) during alcohol breath test for law enforcement is the most common cause of falsely high breath alcohol concentrations (BrAC). A fast and reliable test for detection of MA roadside at the scene of the act would facilitate the police efforts for proper prosecution. A tentative technique to use orally exhaled water vapour as a reference gas to position the origin of alcohol was validated. BrAC and water vapour concentration (WVC) were simultaneously measured as a known MA component was added to subjects with existing blood alcohol. In the absence of MA, water always precedes alcohol in a volumetric expirogram. In the presence of MA this relationship reversed. A scatterplot of WVC versus BrAC from similar fractional exhaled volumes illustrates how their relative positions change by MA. A deviation area (DA) between the scatterplot curve and a fictitious linear relationship was defined as a measurement of MA. The accuracy and cut-off level of the DA to detect MA were determined with receiver operating characteristic (ROC) curve analysis. The area under the ROC curve (AUC) was 0.95 (95% CI 0.90-1.0), indicating excellent discriminatory ability. The optimal cut-off for DA to discriminate between MA ≥0.010mg/L (1μg/100ml, 0.002g/210L) or lack of MA was -0.35, with a sensitivity of 0.91 and specificity of 0.95. Analysis of BrAC in relation to WVC is a practical method to detect and confirm MA contamination with high reliability