The genetic basis of DOORS syndrome: an exome-sequencing study.

Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals

Evaluation of Nephroprotective and Immunomodulatory Activities of Antioxidants in Combination with Cisplatin against Murine Visceral Leishmaniasis

Leishmaniasis, a neglected tropical disease (NTD) caused by Leishmania, has been put on the World Health Organization agenda for eradication as a part of their Special Programme for Tropical Diseases Research. Visceral leishmaniasis (VL) is a life-threatening disease when no treatment is given. Most of the drugs still used to treat VL are often expensive, difficult to administer, have serious side effects, and several are becoming ineffective because of increasing parasite resistance. Cisplatin is a first-generation platinum-containing drug, used in the treatment of various solid tumors. We have for the first time characterized the in vivo effect of cisplatin in murine experimental visceral leishmaniasis, but at higher doses it is nephrotoxic. Considering the above findings, the present study was designed to evaluate the protective efficacy of the drug in combination with various antioxidants to reduce or prevent cisplatin-induced nephrotoxicity. Drug treatment induces a higher secretion of Th1 cytokines, diminution in parasite burden, and the supplementation of antioxidants which are antagonists of the toxicity helps in reducing the nephrotoxicity

Genome-Wide Analyses of Nkx2-1 Binding to Transcriptional Target Genes Uncover Novel Regulatory Patterns Conserved in Lung Development and Tumors

The homeodomain transcription factor Nkx2-1 is essential for normal lung development and homeostasis. In lung tumors, it is considered a lineage survival oncogene and prognostic factor depending on its expression levels. The target genes directly bound by Nkx2-1, that could be the primary effectors of its functions in the different cellular contexts where it is expressed, are mostly unknown. In embryonic day 11.5 (E11.5) mouse lung, epithelial cells expressing Nkx2-1 are predominantly expanding, and in E19.5 prenatal lungs, Nkx2-1-expressing cells are predominantly differentiating in preparation for birth. To evaluate Nkx2-1 regulated networks in these two cell contexts, we analyzed genome-wide binding of Nkx2-1 to DNA regulatory regions by chromatin immunoprecipitation followed by tiling array analysis, and intersected these data to expression data sets. We further determined expression patterns of Nkx2-1 developmental target genes in human lung tumors and correlated their expression levels to that of endogenous NKX2-1. In these studies we uncovered differential Nkx2-1 regulated networks in early and late lung development, and a direct function of Nkx2-1 in regulation of the cell cycle by controlling the expression of proliferation-related genes. New targets, validated in Nkx2-1 shRNA transduced cell lines, include E2f3, Cyclin B1, Cyclin B2, and c-Met. Expression levels of Nkx2-1 direct target genes identified in mouse development significantly correlate or anti-correlate to the levels of endogenous NKX2-1 in a dosage-dependent manner in multiple human lung tumor expression data sets, supporting alternative roles for Nkx2-1 as a transcriptional activator or repressor, and direct regulator of cell cycle progression in development and tumors

Adding content to contacts: measurement of high quality contacts for maternal and newborn health in Ethiopia, north east Nigeria, and Uttar Pradesh, India.

BACKGROUND: Families in high mortality settings need regular contact with high quality services, but existing population-based measurements of contacts do not reflect quality. To address this, in 2012, we designed linked household and frontline worker surveys for Gombe State, Nigeria, Ethiopia, and Uttar Pradesh, India. Using reported frequency and content of contacts, we present a method for estimating the population level coverage of high quality contacts. METHODS AND FINDINGS: Linked cluster-based household and frontline health worker surveys were performed. Interviews were conducted in 40, 80 and 80 clusters in Gombe, Ethiopia, and Uttar Pradesh, respectively, including 348, 533, and 604 eligible women and 20, 76, and 55 skilled birth attendants. High quality contacts were defined as contacts during which recommended set of processes for routine health care were met. In Gombe, 61% (95% confidence interval 50-72) of women had at least one antenatal contact, 22% (14-29) delivered with a skilled birth attendant, 7% (4-9) had a post-partum check and 4% (2-8) of newborns had a post-natal check. Coverage of high quality contacts was reduced to 11% (6-16), 8% (5-11), 0%, and 0% respectively. In Ethiopia, 56% (49-63) had at least one antenatal contact, 15% (11-22) delivered with a skilled birth attendant, 3% (2-6) had a post-partum check and 4% (2-6) of newborns had a post-natal check. Coverage of high quality contacts was 4% (2-6), 4% (2-6), 0%, and 0%, respectively. In Uttar Pradesh 74% (69-79) had at least one antenatal contact, 76% (71-80) delivered with a skilled birth attendant, 54% (48-59) had a post-partum check and 19% (15-23) of newborns had a post-natal check. Coverage of high quality contacts was 6% (4-8), 4% (2-6), 0%, and 0% respectively. CONCLUSIONS: Measuring content of care to reflect the quality of contacts can reveal missed opportunities to deliver best possible health care

Dose-Intensified Compared With Standard Chemotherapy for Nonmetastatic Ewing Sarcoma Family of Tumors: A Children's Oncology Group Study

The Ewing sarcoma family of tumors (ESFT) is a group of malignant tumors of soft tissue and bone sharing a chromosomal translocation affecting the EWS locus. The Intergroup INT-0091 demonstrated the superiority of a regimen of vincristine, cyclophosphamide, doxorubicin (VDC), and dactinomycin alternating with ifosfamide and etoposide (IE) over VDC for patients with nonmetastatic ESFT of bone. The goal of this study was to determine whether a dose-intensified regimen of VDC alternating with IE would further improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue