Genetic and physiological association of diabetes susceptibility with raised Na+/H+ exchange activity.

Insulin-dependent diabetes mellitus is a multigenic autoimmune disease, for which one of the best animal models is the nonobese diabetic (NOD) mouse strain. In both humans and NOD mice, major histocompatibility complex genes are implicated as risk factors in the disease process. Other susceptibility genes are also involved, and a number have been mapped in the mouse to specific chromosomal locations. To identify further susceptibility genes, diabetic backcross mice, produced after crossing NOD/Lt to the nondiabetic strains SJL and C57BL/6 (B6), were examined for markers not previously associated with disease susceptibility. Linkage was found to loci on chromosomes 4 and 14. Of the candidate loci on chromosome 4, the gene encoding the Na+/H+ exchanger-1, Nhe-1, was the most likely, since the NOD allele was different from that of both nondiabetic strains. NOD lymphocytes were found to have a higher level of Na+/H+ exchange activity than lymphocytes from either B6 or SJL mice. Since the chromosome 4 susceptibility gene is recessive, the B6 allele should prevent diabetes. This prediction was tested in fourth-generation backcross mice, selected for retention of the B6 allele at Nhe-1. Mice homozygous for Nhe-1 developed diabetes after cyclophosphamide treatment, but heterozygotes were largely protected from disease. These results implicate the Na+/H+ exchanger (antiporter) in the development of type 1 diabetes and may provide a screening test for at-risk individuals as well as offering prospects for disease prevention

Characterisation of urogenital ridge gene expression in the human embryonal carcinoma cell line NT2/D1

The study of the mammalian sex-determining pathway has been hampered by the lack of cell culture systems to investigate the underlying molecular relationships between sex-determining genes. Recent approaches using high-throughput genome-wide studies have revealed a number of sexually dimorphic genes expressed in the developing mouse gonad. Here, we investigated a human testicular cell line in terms of its expression of known sex-determining genes and newly identified candidates. The human embryonal carcinoma cell line NT2/D1 was screened for the expression of 46 genes with known or potential roles in the sex-determining and differentiation pathway. Forty genes tested were expressed in NT2/D1 cells including the testis-determining genes SRY, SOX9, SF-1, DHH and FGF9. Genes not expressed included WT1, DAX1 and the ovary-specific genes FOXL2 and WNT4. Cell-specific markers demonstrate that NT2/D1 cells reflect a number of cell types in the gonad including Sertoli, Leydig and germ cells. Our results suggest that male pathways initiated by SRY, SOX9 and SF-1 remain intact in these cells. Lack of expression of ovary-specific genes is consistent with a commitment of these cells to the male lineage. Manipulation of gene expression in this cell line could be an important new in vitro tool for the discovery of new human sex-determining genes

Effects of a program for coordinated care of advanced illness on patients, surrogates, and healthcare costs: a randomized trial

Objective: To evaluate the Advanced Illness Coordinated Care Program (AICCP), delivered by allied health personnel to improve care for patients coping with advanced illness and in need of preparation for end-of-life (EOL) care. Study design: Clinical trial involving 275 patients and 143 surrogates in 6 settings who were randomly assigned to the AICCP or usual care (UC). Methods: The AICCP participants met with a care coordinator for assistance with provider communication, care coordination, and support. The AICCP was evaluated for effects on satisfaction with care, advance planning, consistency of care with patient preferences, and healthcare costs. Results: The AICCP increased patient satisfaction with care and communication (P = .03), and AICCP surrogates reported fewer problems with provider support (P = .03). More AICCP than UC participants completed an advance directive (AD) (69.4% vs 48.4%; P = .006), and the AICCP group completed more ADs per participant (P = .01). Median time to AD documentation was 46 days for AICCP and 238 days for UC (P = .02). There was no difference in survival (AICCP 43% vs UC 42%). Six-month costs were lower with AICCP than with UC (12,123 US dollars vs 16,295 US dollars); however, the difference did not reach statistical significance. Conclusions: The AICCP improved satisfaction with care and helped patients develop and revise more ADs, sooner, without affecting mortality. This program may be delivered in a range of managed care, fee-for-service, and group-model settings