Biomedical subjects
Publications and source records attributed to B S Chin.
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The use of hormone replacement therapy (HRT) for cardiovascular risk reduction remains uncertain. Although previous epidemiological surveys have suggested a clear benefit and nearly 50% mortality risk reduction with HRT in postmenopausal women, recent randomised trials have largely failed to support this. The epidemiological surveys may have been biased in a number of ways including the possibility that HRT users in these studies may have been healthier and taken a greater interest in modifying cardiovascular risks. The aim of the present study was to determine to what extent the revelations from all these trials have influenced HRT prescribing in general practice, in relation to cardiovascular disease. We reviewed 140 women on HRT and 140 age-matched controls from one city centre general practice in the west of Birmingham who were randomly selected by computer. The main indication for HRT use was presence of symptoms associated with oestrogen deficiency. The prevention of osteoporosis accounted for 7.1% of HRT indications, while the primary prevention of CHD was not an issue discussed by either the patient or the GP. Among non-users, 86.4% did not have a known contraindication and many did not have serum lipid measurements or estimations of cardiovascular risk. There was no difference between HRT users and non-users for smoking habits and presence of cardiovascular risk factors including diabetes, hypertension and coronary heart disease. HRT users were also less likely to undergo investigations, such as cervical smear tests and mammograms. In conclusion, this survey reflects the current uncertainty surrounding the use of HRT for cardiovascular risk prevention. Importantly, women on HRT may not be any healthier than non-users, nor do they seek more preventive care than non-users. This is contrary to previous presumptions that selection and prevention bias were the explanation for the apparent cardioprotective effects of HRT.
Heart failure still carries a high morbidity and mortality, necessitating new approaches for its management. Greater understanding of the pathophysiology of heart failure has opened the way for novel therapeutic approaches, including analogs of natriuretic peptides and drugs that modulate endothelin, cytokine release and endothelial vasoconstriction. Other drugs are undergoing laboratory and clinical trials that will eventually supersede or complement less optimal heart failure treatments. Clinical trials will ascertain if these new strategies in the treatment of heart failure will ultimately be successful in the management of these patients.
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The common acute lymphoblastic leukemia antigen [(CALLA) CD10, neutral endopeptidase 24.11 (NEP)] is a cell-surface zinc metalloprotease expressed by a subpopulation of early murine B-lymphoid progenitors and by bone marrow stromal cells that support the earliest stages of B lymphopoiesis. In previous in vitro studies in which uncommitted murine hematopoietic progenitors plated on a stromal cell layer differentiate into immature B cells, the inhibition of CD10/NEP increased early lymphoid colony numbers. To further characterize CD10/NEP function during lymphoid ontogeny in vivo, we utilized a Ly5 congenic mouse model in which the lymphoid differentiation of uncommitted hematopoietic progenitors from Ly5.1 donors was followed in sublethally irradiated Ly5.2 recipients treated with a specific long-acting CD10/NEP inhibitor (N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta- alanine (SCH32615)). The expression of Ly5.1, B220, and surface IgM (sIgM) was utilized to characterize donor-derived hematopoietic cells (Ly5.1+), B lymphocytes (B220+), and mature B cells (B220+ sIgM+) from the lymphoid organs of recipient animals treated with SCH32615 or vehicle alone. SCH32615-treated animals had higher percentages of Ly5.1+ donor splenocytes than animals treated with vehicle alone (16.9% vs. 10.4%, 63% increase, P = 0.013). Animals treated with the CD10/NEP inhibitor also had relatively more Ly5.1+ splenic B (B220+) cells than vehicle-treated animals (14.4% vs. 8.2%, 75% increase, P = 0.018). To more specifically characterize the effects of CD10/NEP inhibition on B-cell differentiation, Ly5.1+ splenocytes from animals treated with SCH32615 or vehicle alone were analyzed for coexpression of B220 and sIgM. Animals treated with the CD10/NEP inhibitor had a significantly higher percentage of mature donor B cells (Ly5.1+ B220+ sIgM+, 10.2% vs. 5.2%, 90% increase, P = 0.006) and a more modest relative increase in immature donor B cells (Ly5.1+ B220+ sIgM-, 4.7% vs. 3.4%, 38% increase, P = not significant). Taken together, these results suggest that CD10/NEP inhibition promotes the reconstitution and maturation of splenic B cells. Therefore, CD10/NEP may function to regulate B-cell ontogeny in vivo by hydrolyzing a peptide substrate that stimulates B-cell proliferation and/or differentiation.