Activation of CD1d-restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets

CD1d-restricted invariant NKT (iNKT) cells are immunoregulatory cells whose loss exacerbates diabetes in nonobese diabetic (NOD) female mice. Here, we show that the relative numbers of iNKT cells from the pancreatic islets of NOD mice decrease at the time of conversion from peri-insulitis to invasive insulitis and diabetes. Conversely, NOD male mice who have a low incidence of diabetes showed an increased frequency of iNKT cells. Moreover, administration of alpha-galactosylceramide, a potent activating ligand presented by CD1d, ameliorated the development of diabetes in NOD female mice and resulted in the accumulation of iNKT cells and myeloid dendritic cells (DC) in pancreatic lymph nodes (PLN), but not in inguinal lymph nodes. Strikingly, injection of NOD female mice with myeloid DC isolated from the PLN, but not those from the inguinal lymph nodes, completely prevented diabetes. Thus, the immunoregulatory role of iNKT cells is manifested by the recruitment of tolerogenic myeloid DC to the PLN and the inhibition of ongoing autoimmune inflammation.     

Immune Reconstitution after Hematopoietic Stem Cell Transplantation in Immunodeficiency–Centromeric Instability–Facial Anomalies Syndrome Type 1

Journal of Clinical Immunology -     

Incidental Discovery of a Presacral Extradural Myxopapillary Ependymoma

Ependymoma is a malignant central nervous system tumor arising from the lining of the ventricles or central canal of the spinal cord. Extradural spinal ependymomas arise from heterotopic ependymal cells or the coccygeal medullary vestige and are extremely infrequent. We present a rare case of presacral extradural ependymoma. Extradural ependymomas typically demonstrate an extraneural spread and, thus, surveillance of the entire central nervous system is not typically recommended. A radiograph of the chest, liver profile, and attention to palpable lymphadenopathy (especially inguinal) on physical examination are vital for surveillance. Obtaining an R0 resection is the most important prognostic factor in survival and local recurrence.     

Molecular Detection of Malaria at Delivery Reveals a High Frequency of Submicroscopic Infections and Associated Placental Damage in Pregnant Women from Northwest Colombia

Plasmodium infection in pregnancy causes substantial maternal and infant morbidity and mortality. In Colombia, both P. falciparum and P. vivax are endemic, but the impact of either species on pregnancy is largely unknown in this country. A cross-sectional study was carried out with 96 pregnant women who delivered at their local hospital. Maternal, placental, and cord blood were tested for malaria infection by microscopy and real-time quantitative polymerase chain reaction (qPCR). A high frequency of infection was detected by qPCR (45%). These infections had low concentrations of parasite DNA, and 79% were submicroscopic. Submicroscopic infections were associated with placental villitis and intervillitis. In conclusion, the overall frequency of Plasmodium infection at delivery in Colombia is much higher than previously reported. These data prompt a re-examination of the local epidemiology of malaria using molecular diagnostics to establish the clinical relevance of submicroscopic infections during pregnancy as well as their consequences for mothers and newborns.     

Experiences in conducting multiple community-based HIV prevention trials among women in KwaZulu-Natal, South Africa

Background

South Africa, with its scientific capacity, good infrastructure and high HIV incidence rates, is ideally positioned to conduct large-scale HIV prevention trials. The HIV Prevention Research Unit of the South African Medical Research Council conducted four phase III and one phase IIb trials of women-initiated HIV prevention options in KwaZulu-Natal between 2003 and 2009. A total of 7046 women participated, with HIV prevalence between 25% and 45% and HIV incidence ranging from 4.5-9.1% per year. Unfortunately none of the interventions tested had any impact on reducing the risk of HIV acquisition; however, extremely valuable experience was gained, lessons learned and capacity built, while the communities gained associated benefits.

Experience

Our experience in conducting these trials ranged from setting up community partnerships to developing clinical research sites and dissemination of trial results. Community engagement included setting up community-based research sites with approval from both political and traditional leaders, and developing community advisory groups to assist with the research process. Community-wide education on HIV/sexually transmitted infection prevention, treatment and care was provided to over 90 000 individuals. Myths and misconceptions were addressed through methods such as anonymous suggestion boxes in clinic waiting areas and intensive education and counselling. Attempts were made to involve male partners to foster support and facilitate recruitment of women. Peer educator programmes were initiated to provide ongoing education and also to facilitate recruitment of women to the trials. Recruitment strategies such as door-to-door recruitment and community group meetings were initiated. Over 90% of women enrolled were retained. Community benefits from the trial included education on HIV prevention, treatment and care and provision of ancillary care (such as Pap smears, reproductive health care and referral for chronic illnesses). Social benefits included training of home-based caregivers and sustainable ongoing HIV prevention education through peer educator programmes.

Challenges

Several challenges were encountered, including manipulation by participants of their eligibility criteria in order to enroll in the trial. Women attempted to co-enroll in multiple trials to benefit from financial reimbursements and individualised care. The trials became ethically challenging when participants refused to take up referrals for care due to stigma, denial of their HIV status and inadequate health infrastructure. Lack of disclosure of HIV status to partners and family members was particularly challenging. Some of the ethical dilemmas put to the test our responsibility as researchers and our obligation to provide health care to research participants.

Conclusion

Conducting these five trials in a period of six years provided us with invaluable insights into trial implementation, community participation, recruitment and retention, provision of care and dissemination of trial results. The critical mass of scientists trained as clinical trialists will continue to address the relentless HIV epidemic in our setting and ensure our commitment to finding a biomedical HIV prevention option for women in the future.     

Metformin Treatment in the Period After Stroke Prevents Nitrative Stress and Restores Angiogenic Signaling in the Brain in Diabetes

Diabetes impedes vascular repair and causes vasoregression in the brain after stroke, but mechanisms underlying this response are still unclear. We hypothesized that excess peroxynitrite formation in diabetic ischemia/reperfusion (I/R) injury inactivates the p85 subunit of phosphoinositide 3-kinase (PI3K) by nitration and diverts the PI3K–Akt survival signal to the p38–mitogen-activated protein kinase apoptosis pathway. Nitrotyrosine (NY), Akt and p38 activity, p85 nitration, and caspase-3 cleavage were measured in brains from control, diabetic (GK), or metformin-treated GK rats subjected to sham or stroke surgery and in brain microvascular endothelial cells (BMVECs) from Wistar and GK rats subjected to hypoxia/reoxygenation injury. GK rat brains showed increased NY, caspase-3 cleavage, and p38 activation and decreased Akt activation. Metformin attenuated stroke-induced nitrative signaling in GK rats. GK rat BMVECs showed increased basal nitrative stress compared with controls. A second hit by hypoxia/reoxygenation injury dramatically increased the nitration of p85 and activation of p38 but decreased Akt. These effects were associated with impairment of angiogenic response and were restored by treatment with the peroxynitrite scavenger 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride or the nitration inhibitor epicatechin. Our results provide evidence that I/R-induced peroxynitrite inhibits survival, induces apoptosis, and promotes peroxynitrite as a novel therapeutic target for the improvement of reparative angiogenesis after stroke in diabetes.     

The Association Between Supportive High School Environments and Depressive Symptoms and Suicidality Among Sexual Minority Students

The purpose of this study was to determine if sexual minority students in supportive school environments experienced fewer depressive symptoms and lower rates of suicide ideation, plans and attempts (“suicidality”) than sexual minority students in less supportive school environments. In 2007, a nationally representative sample (N = 9,056) of students from 96 high schools in New Zealand used Internet tablets to complete a health and well-being survey that included questions on sexual attractions, depressive symptoms, and suicidality. Students reported their experience of supportive environments at school and gay, lesbian, bisexual, and transgender (GLBT) bullying, and these items were aggregated to the school level. Teachers (n = 2,901) from participating schools completed questionnaires on aspects of school climate, which included how supportive their schools were toward sexual minority students. Multilevel models were used to estimate school effects on depressive symptoms and suicidality controlling for background characteristics of students. Sexual minority students were more likely to report higher levels of depressive symptoms and suicidality than their opposite-sex attracted peers (p < .001). Teacher reports of more supportive school environments for GLBT students were associated with fewer depressive symptoms among male sexual minority students (p = .006) but not for female sexual minority students (p = .09). Likewise in schools where students reported a more supportive school environment, male sexual minority students reported fewer depressive symptoms (p = .006) and less suicidality (p < .001) than in schools where students reported less favorable school climates. These results suggest that schools play an important role in providing safe and supportive environments for male sexual minority students.     

Chronic pruritus associated withHelicobacter pylori

BACKGROUND: Helicobacter pylori is an established cause of gastritis and has been implicated in extradigestive diseases. OBJECTIVE: To investigate the role of H. pylori in patients with unexplained refractory pruritus. METHODS: Ten patients with severe pruritus unresponsive to conventional therapy were evaluated for active H. pylori infection by H. pylori serology followed by either esophagogastroduodenoscopy (EGD) or urea breath test. Of the 10 patients, 8 were found to have active infection. All 10 received anti-H. pylori antibiotic therapy and were reevaluated for relief of pruritus. RESULTS: Of 8 patients with active H. pylori infection, 87.5% (7/8) had some type of pruritus relief after triple therapy. Of these, 62.5% (5/8) had complete relief and 25% (2/8) had temporary relief of pruritus. The remaining 12.5% (1/8) did not respond. Two control patients without active H. pylori infection had no relief of pruritus with therapy. CONCLUSIONS: We have identified a population of patients with refractory pruritus and active H. pylori infection whose pruritus resolved after eradication of H. pylori.