RANTES gene polymorphisms (-403G>A and -28C>G) associated with hepatitis B virus infection in a Saudi population.

Besides the host immune response, genetic and environmental factors play crucial roles in the manifestation of hepatitis B virus (HBV) infection. "Regulated on activation normal T-cell expressed and secreted" factor (RANTES) plays a vital role in CD4(+), CD8(+) T-lymphocyte and dendritic cell activation and proliferation in inflammation. Single nucleotide polymorphisms (SNPs) in the RANTES gene are associated with several viral and non-viral diseases. Association studies have invariably indicated a lack of association between RANTES gene SNPs and HBV infection in ethnic populations, even though RANTES gene SNPs exhibit distinct ethnic distributions. Despite the high prevalence of HBV infections in Saudi Arabia, no studies have been made concerning a possible relationship between RANTES gene polymorphisms and susceptibility to and progression of HBV infection. We examined -403G>A and -28C>G RANTES gene variants in 473 healthy controls and 484 HBV patients in ethnic Saudi populations. Significant differences were found in the genotype and allele distributions of the SNPs between the controls and the HBV patients. Both SNPs were significantly linked to viral clearance in these subjects. Our data demonstrate for the first time in a Saudi population, a relationship between the RANTES gene polymorphisms and the clinical course of HBV infection and underscore the importance of evaluating the genetic background of the affected individual to determine how it may affect disease progression.

Nuclear BAG-1 expression inhibits apoptosis in colorectal adenoma-derived epithelial cells.

BAG-1 is an anti-apoptotic protein that is frequently deregulated in a variety of malignancies including colorectal cancer. There are three isoforms: BAG-1L is located in the nucleus, BAG-1M and BAG-1S are located both in the nucleus and the cytoplasm. In colon cancer, the expression of nuclear BAG-1 is associated with poorer prognosis and is potentially a useful predictive factor for distant metastasis. However, the function of BAG-1 in colonic epithelial cells has not been studied. Having previously shown a predominant nuclear localisation of BAG-1 in adenoma-derived cell lines, we wanted to determine the function of nuclear BAG-1 in these non-tumourigenic cells, to identify whether nuclear BAG-1 was implicated in tumour progression in the colon. In the current report we established that nuclear BAG-1 inhibits apoptosis in a colorectal adenoma-derived cell line. We demonstrate that apoptosis induced by gamma-radiation or the vitamin D analogue EB1089 in the non-tumourigenic human colorectal adenoma-derived S/RG/C2 cell line, was preceded by a decrease in nuclear and an increase in cytoplasmic BAG-1 expression. This change in subcellular localisation of BAG-1 was due to the redistribution of the BAG-1M isoform. In addition, we have shown that the maintenance of high nuclear BAG-1 through enforced expression of the nuclear localised BAG-1L isoform enhanced cellular survival after gamma-radiation or exposure to EB1089. Furthermore the expression of cytoplasmic BAG-1S isoform fused with a nuclear localisation signal protected against gamma-radiation induced apoptosis. This demonstrates that nuclear localisation of the BAG-1 protein confers a survival advantage in colorectal adenoma-derived cells and that nuclear BAG-1 could potentially be an important survival factor in colorectal carcinogenesis.

Histological changes in placental syncytiotrophoblasts of poorly controlled gestational diabetic patients.

It seems reasonable to expect that biochemical changes occurring in the pregnant woman with diabetes should be reflected in the placenta structure. However, it has not been possible to correlate placental morphology with glycemic control in a comparison between those with long life diabetes and poorly controlled gestational diabetes. In the present study we have histologically studied the syncytiotrophoblast of human placentae from overt diabetic and poorly controlled gestational diabetic patients. Using specific staining techniques and direct light microscopy we qualitatively studied these placentae and compared them with the normal placentae. We found fibrin thrombi, villous oedema, hyperplasia and thickening of basement membrane in the placentae of poorly controlled gestational diabetic mothers. Direct microscopy revealed that these various changes in syncytiotrophoblast structure were marked in the poorly controlled gestational placenta compared with overt diabetics, and could have been due to the presence of histochemical compounds e.g. general carbohydrates and lipids. These studies may indicate that poor control of diabetes during the gestation as indicated by high level HbAlc may result in the accummulation of carbohydrate compounds and fat droplets in the placental basement membrane, leading to structural changes in the placental cells.

Features of insulin receptor interaction in placenta from normal, overt and poorly controlled gestational diabetic patients.

Features of insulin binding to trophoblast plasma membranes were studied in six normal pregnant women (NP), six overt diabetes (ODP) and six poorly controlled glycemic gestational patients (PCDP) i.e. women who did not strictly follow the management of diabetes mellitus during pregnancy. A decreased maximum specific insulin receptor binding per 0.1 mg membrane protein in placenta from PCDP (12%) was found comparing with that from ODP or NP (17.5% and 36.2%, respectively, P < 0.01), The insulin binding in PCDP declined at a faster rate until it reached minimum when studied at a higher temperature (25-37 degrees C). The binding equilibrium was likewise attained faster at this temperature than that at lower temperature of 4 degrees C for all studied groups. The insulin receptor binding in all studied groups was pH dependent. The maximum binding in ODP and PCDP groups was attained at pH 7.8 while for NP maximum binding was at pH 7.4. The competitive binding assay was carried out with 14 concentrations of unlabelled insulin and the half maximal displacement of 125I-insulin was at 8 x 10(-9) M, 6 x 10(-9) M and 4 x 10(-9) M for NP, ODP and PCDP, respectively (P < 0.05) suggesting the differences in the effect of glycemic control on the insulin binding. Furthermore the binding yielded curvilinear Scatchard plots with the apparent affinity of the receptors being affected in the ODP and PCDP groups.(ABSTRACT TRUNCATED AT 250 WORDS)