Regulation of interleukin 6 expression in murine bone marrow stromal cells.

The regulation of interleukin 6 (IL-6) expression in the B-lymphocyte-supporting murine stromal cell line BMS2 has been examined in response to exogenous cytokines and chemical agents. Kinetic analyses of IL-6 mRNA induction and decay are presented together with analysis of the IL-6 biological activity. The cytokines tumor necrosis factor, interleukin 1 (alpha and beta), and transforming growth factor beta, as well as forskolin and dibutyryl cyclic AMP, all induce a transient rise in the steady-state level of IL-6 mRNA and an increased release of IL-6 protein. To study its regulation at the chromatin level, the murine IL-6 genomic gene has been cloned. Induction of IL-6 expression correlates with increased DNA nicking, consistent with increased topoisomerase I and endogenous nuclease activity. This finding is supported by kinetic analyses using camptothecin, a topoisomerase I inhibitor. We conclude that IL-6 regulation in murine stromal cells capable of supporting B-lymphopoiesis is comparable to that observed in human diploid fibroblasts.     

Secretion of vascular endothelial growth factor/vascular permeability factor from human luteinized granulosa cells is human chorionic gonadotrophin dependent

Vascularization is a prominent event during corpus luteum formation, providing low density lipoproteins for steroid biosynthesis and enabling transport of secreted steroids. The process of vascularization is controlled by specific regulators. Vascular endothelial growth factor (VEGF), otherwise named vascular permeability factor (VPF), induces endothelial cell proliferation as well as angiogenesis in vivo and increases capillary permeability. Here we report the expression of VEGF/VPF mRNA by cultured human luteinized granulosa cells (GC) for at least 10 days. Without HCG VEGF/VPF expression declined after day 4 and by day 10 was reduced to approximately 30% of the value at day 4. However, after culture in the presence of 1 U/ml human chorionic gonadotrophin (HCG), expression of VEGF/VPF mRNA by GC was four times greater than control experiments by day 10, and increased 100% from day 4 to day 10. Simultaneously, HCG supplementation increased VEGF/VPF secretion by GC. Medium VEGF/VPF on day 3 was 13 pM without and 11 pM with HCG. Medium VEGF/VPF on day 10 was 6 pM without HCG and 29 pM with HCG. These results suggest that vascularization of the corpus luteum is induced by HCG-mediated effects of VEGF/VPF.      

Iron deficiency in sickle cell anaemia.

Thirty-seven patients with SCD were studied: 24 were diagnosed as homozygous Hb S on the basis of their haematological findings, and alpha:non-alpha globin chain ratios were found to be balanced in all. Thirteen patients were thought to have alpha or beta thalassaemia interaction with Hb S on the basis of low MCV and MCH, family history and/or presence of Hb A on electrophoresis. Six of them had abnormal alpha:non-alpha ratio (one had a ratio of 0.72 suggestive of alpha thalassaemia, and five had ratios between 1.4 and 1.9, compatible with beta thalassaemia interaction). The remaining seven patients with microcytosis had balanced globin chain synthesis and five were found to be iron deficient. Five additional patients (3 with Hb SS and 2 with Hb S/beta thalassaemia) had lower than normal serum ferritin concentration. The analysis of case histories disclosed that peptic ulceration, recurrent epistaxis and multiple pregnancies could account for iron loss in seven patients. These findings indicate that iron deficiency may be common in SCD and should be excluded as a cause of microcytosis. Microcytosis, in the absence of conclusive family studies and/or presence of Hb A on electrophoresis, is an unreliable indicator of alpha or beta thalassaemia interaction with Hb S.     

Canine X-linked severe combined immunodeficiency

Our laboratory has identified and characterized an X-linked severe combined immunodeficiency (XSCID) in dogs that is due to mutations in the common gamma (γc) subunit of the interleukin-2 (IL2), IL4, IL7, IL9, and IL 15 receptors. Canine XSCID, unlike genetically engineered γc-deficient mice, has a clinical and immunologic phenotype virtually identical to human XSCID. It appears that speciesspecific differences exist in the role of the γc and its associated cytokines in mice compared to their role in humans and dogs, suggesting γc-deficient dogs may be a more relevant model for studing the role of the γc in humans. We are utilizing this model for a variety of studies to address:

1. Fundamental questions concerning the role of the γc in cytokine regulation and lymphocyte development.
2. The pathogenesis of XSCID.
3. Strategies for improving bone marrow transplantation outcome.
4. Development and evaluation of strateies for gene therapy.
5. Human hematopoietic stem cell development.

     

Biological resurfacing of the knee: a review of surgical management

Lesions of the articular surfaces of the knee have been managed by various techniques over the last 50 years. Surgical management has involved: excising the damaged area, refashioning the underlying bone to produce a fibrous response, and introducing allograft, autograft and synthetic materials to encourage a repair matrix. The techniques and their pitfalls are reviewed and discussed, and suggestions made as to the direction of future studies for the repair of osteochondral lesions in the painful knee.     

RENAL TRANSPLANTATION – AN EARLY EXPERIENCE

Renal transplant (RT) is now a therapy of choice for end stage renal disease (ESRD). The Nephrology Unit, Asvini started functioning in Dec 90 and to date 1298 sittings of hemodialysis have been given to 45 patients. Of these, 35 were in ESRD and 11 patients underwent renal transplantation at this hospital during the period Jan 91 – Dec 93. One patient expired after 18 months of transplantation due to infection. Early experience in screening patients for RT, use of immunosuppression, management of rejection episodes and protocol are presented with special emphasis on its relevance to the Armed Forces.KEY WORDS: Transplantation, Renal Failure, Immunosuppression, Rejection