The pancreas in human type 1 diabetes

Type 1 diabetes (T1D) is considered a disorder whose pathogenesis is autoimmune in origin, a notion drawn in large part from studies of human pancreata performed as far back as the 1960s. While studies of the genetics, epidemiology, and peripheral immunity in T1D have been subject to widespread analysis over the ensuing decades, efforts to understand the disorder through analysis of human pancreata have been far more limited. We have reviewed the published literature pertaining to the pathology of the human pancreas throughout all stages in the natural history of T1D. This effort uncovered a series of findings that challenge many dogmas ascribed to T1D and revealed data suggesting the marked heterogeneity in terms of its pathology. An improved understanding and appreciation for pancreatic pathology in T1D could lead to improved disease classification, an understanding of why the disorder occurs, and better therapies for disease prevention and management

Circulating Pneumolysin Is a Potent Inducer of Cardiac Injury during Pneumococcal Infection

Streptococcus pneumoniae accounts for more deaths worldwide than any other single pathogen through diverse disease manifestations including pneumonia, sepsis and meningitis. Life-threatening acute cardiac complications are more common in pneumococcal infection compared to other bacterial infections. Distinctively, these arise despite effective antibiotic therapy. Here, we describe a novel mechanism of myocardial injury, which is triggered and sustained by circulating pneumolysin (PLY). Using a mouse model of invasive pneumococcal disease (IPD), we demonstrate that wild type PLY-expressing pneumococci but not PLY-deficient mutants induced elevation of circulating cardiac troponins (cTns), well-recognized biomarkers of cardiac injury. Furthermore, elevated cTn levels linearly correlated with pneumococcal blood counts (r=0.688, p=0.001) and levels were significantly higher in non-surviving than in surviving mice. These cTn levels were significantly reduced by administration of PLY-sequestering liposomes. Intravenous injection of purified PLY, but not a non-pore forming mutant (PdB), induced substantial increase in cardiac troponins to suggest that the pore-forming activity of circulating PLY is essential for myocardial injury in vivo. Purified PLY and PLY-expressing pneumococci also caused myocardial inflammatory changes but apoptosis was not detected. Exposure of cultured cardiomyocytes to PLY-expressing pneumococci caused dose-dependent cardiomyocyte contractile dysfunction and death, which was exacerbated by further PLY release following antibiotic treatment. We found that high PLY doses induced extensive cardiomyocyte lysis, but more interestingly, sub-lytic PLY concentrations triggered profound calcium influx and overload with subsequent membrane depolarization and progressive reduction in intracellular calcium transient amplitude, a key determinant of contractile force. This was coupled to activation of signalling pathways commonly associated with cardiac dysfunction in clinical and experimental sepsis and ultimately resulted in depressed cardiomyocyte contractile performance along with rhythm disturbance. Our study proposes a detailed molecular mechanism of pneumococcal toxin-induced cardiac injury and highlights the major translational potential of targeting circulating PLY to protect against cardiac complications during pneumococcal infections

Antibiotic Treatment and Length of Hospital Stay in Relation to Delivery Mode and Prematurity.

To investigate how 1) maternal delivery mode and 2) prematurity in infants are associated to antibiotic treatment and length of hospital stay.Women having given birth and infants 0-12 months discharged from hospital between July 2005 and November 2011 were identified from the Swedish National Patient Register. Medical records were reviewed for 203 women and 527 infants. The risk ratio (RR) between antibiotic treatment and 1) delivery mode in women; 2) prematurity in infants was calculated. Length of stay and days of antibiotic therapy were compared by Wilcoxon rank-sum test.Women: There was an association between emergency caesarean section (CS) and antibiotic treatment (RR 5.0 95% confidence interval (CI) 2.2-11.5), but not for elective CS. Length of stay was longer for CS (emergency and elective) compared to vaginal delivery (p<0.01). Infants: RR for antibiotic treatment in preterm compared to term infants was 1.4 (95% CI 1.0-1.9). Length of stay (p<0.01), but not days of therapy (p = 0.17), was higher in preterm compared to term infants.We found that emergency CS increased the probability of maternal antibiotic treatment during hospitalisation, but no difference was found between term and preterm infants. The results are well aligned with current guidelines and may be considered in future studies on the effects of antibiotics

Use of Acid-Suppressive Drugs in Pregnancy and the Risk of Childhood Asthma:Bidirectional Crossover Study using the General Practice Research Database

<p>Background Recent studies have reported an association between maternal use of gastric acid-suppressive drugs during pregnancy and asthma in the offspring, but the association could have been confounded by unmeasured risk factors.</p><p>Objective We assessed the association between the use of acid-suppressive drugs during pregnancy and the risk of developing childhood asthma using a bidirectional crossover design.</p><p>Methods Mother-infant matched sets in the UK General Practitioners Research Database were used to identify children with a drug-treated asthma diagnosis during the years 2006-2010 who were matched to a sibling without asthma as controls. Primary exposure was use of any anti-suppressive drug during pregnancy, and subgroup analyses were conducted according to drug class (e.g. proton pump inhibitors or histamine 2 receptor antagonists) and trimester. Conditional logistic regression was used to estimate odds ratios (OR) with their corresponding 95 % confidence intervals (CIs).</p><p>Results A total of 1,874 children with asthma and 1,874 control siblings were included in the analysis. The exposure rate among case and control pregnancies was 22 and 20 %, respectively. After adjustments for gender, birth order, mother's age and general practice visits, the exposure to any gastric-acid suppressive drug during pregnancy slightly increased the risk for developing asthma (OR 1.23, 95 % CI 1.01-1.51; p = 0.042). A trend towards increased risks was observed for those who used proton pump inhibitors and/or histamine 2 receptor antagonists (adjusted OR 1.72, 95 % CI 1.00-2.98; p = 0.048).</p><p>Conclusion These findings lend support to the emerging evidence that exposure to acid-suppressive drugs during pregnancy is associated with childhood asthma. More basic research is now warranted to investigate the mechanisms.</p>