Pancreatic islets under attack: cellular and molecular effectors

Abundant information is available on the involvement of various cellular and molecular mechanisms in beta cell apoptosis. The experimental evidence is controversial and difficult to reconcile, and the mechanisms of evasion of the autoreactive clones from immune surveillance are poorly understood. Multiple apoptotic pathways play a role in destructive insulitis, including perforin/granzyme, Fas/Fas-ligand (FasL), and other members of the necrosis factor superfamily. These pathways present redundant behaviors in both the initial and late stages of beta cell injury, and at the same time, each molecular mechanism is dispensable in the evolution of autoimmune diabetes. There may be a preferential use of perforin/granzyme in CD8(+) T cell-mediated lysis, which participates in onset of autoimmunity, and a predominance of FasL in CD4(+) T cell-mediated insulitis. Several cytokines released in the inflammatory infiltrate induce Fas expression in beta cells, priming them to FasL-mediated apoptosis. In this review, we focus on the possible participation of multiple cell subsets and molecular mechanisms in the pathogenesis of diabetes to the point where inflammation incites an irreversible vicious cycle that perpetuates beta cell death.     

Epigenetic silencing of the tumor suppressor klotho in human breast cancer

Klotho is a single pass transmembrane protein, associated with premature aging. We identified tumor suppressor activities for klotho, associated with reduced expression in breast cancer. We now aimed to analyze klotho expression in early stages of breast tumorigenesis and elucidate mechanisms leading to klotho silencing in breast tumors. We studied klotho expression, using immunohistochemistry, and found high klotho expression in all normal and mild hyperplasia samples, whereas reduced expression was associated with moderate and atypical ductal hyperplasia. Promoter methylation and histone deacetylation were studied as possible mechanisms for klotho silencing. Using bisulfite sequencing, and methylation-specific PCR, we identified KLOTHO promoter methylation in five breast cancer cell lines and in hyperplastic MCF-12A cells, but not in the non-tumorous mammary cell line HB2. Importantly, methylation status inversely correlated with klotho mRNA levels, and treatment of breast caner cells with 5-aza-2-deoxycytidine elevated klotho expression by up to 150-fold. KLOTHO promoter methylation was detected in 8/23 of breast cancer samples but not in normal breast samples. Chromatin immunoprecipitation revealed that in HB2 KLOTHO promoter was enriched with AcH3K9; however, in breast cancer cells, H3K9 was deacetylated, and treatment with the histone deacetylase inhibitor suberoylanilide bishydroxamide (SAHA) restored H3K9 acetylation. Taken together, these data indicate loss of klotho expression as an early event in breast cancer development, and suggest a role for DNA methylation and histone deacetylation in klotho silencing. Klotho expression and methylation may, therefore, serve as early markers for breast tumorigenesis.     

A Meta-Analysis of Sensory Modulation Symptoms in Individuals with Autism Spectrum Disorders

Sensory modulation symptoms are common in persons with autism spectrum disorders (ASD); however have a heterogeneous presentation. Results from 14 studies indicated a significant high difference between ASD and typical groups in the presence/frequency of sensory symptoms, with the greatest difference in under-responsivity, followed by over-responsivity and sensation seeking. Three moderators that reduced the variability in findings among studies were: chronological age, severity of autism, and type of control group. Sensory differences were highest for studies of children ages 6–9 years, samples with more than 80% with an autism diagnosis, and compared to a CA matched versus a MA or DD matched group. It is important to consider these moderators in the design of studies and interventions addressing sensory symptoms.     

Contagious caprine pleuropneumonia and Mannheimia haemolytica-associated acute respiratory disease of goats and sheep in Afar Region, Ethiopia

In April 2002, an investigation into an outbreak of acute respiratory disease in goats and sheep in Milae (Afar), Ethiopia was conducted. The investigation involved 4 flocks (722 sheep and 750 goats in total) and comprised the disease history, clinical and post-mortem examination, and microbiological analysis of nasal swabs, lung lesions, and pleural fluid samples. Clinically diseased animals exhibited severe respiratory distress, and necropsy of two of the goats demonstrated fibrinous pneumonia, lung sequestra, and excessive accumulation of straw coloured fluid in the thoracic cavity. Mannheimia haemolytica biotype T was isolated from nine (six goats and three sheep) out of 23 nasal swabs (39.1%). In the two necropsied animals Mycoplasma capricolum subsp. capripneumoniae (Mccp) was isolated from the lungs, and Mannheimia haemolytica biotype T was isolated from lung lesions and thoracic fluid. An unidentified Mycoplasma species was isolated from the thoracic fluid of one of the goats. Pseudomonas aeruginosa was isolated from a lung sequestrum of one of the necropsied goats. In vitro antimicrobial susceptibility test results indicated that two (33.3%) of the six M. haemolytica isolates that were tested were resistant to ampicillin and penicillin G, three (50%) to tetracycline, four (66.7%) to oxacillin, five (83.3%) to erythromycin, and six (100%) to clindamycin. Pseudomonas aeruginosa was resistant to all of the different classes of antimicrobials that were tested. Pleuropneumonia caused by Mccp, and secondary complications caused by M. haemolytica and the other unidentified Mycoplasma species, were confirmed as the cause of the outbreak. Morbidity was not associated with the species of animals affected (P > 0.05); however, mortality was significantly higher in goats than sheep (P < 0.05).