Angiotherapeutics from natural products: from bench to clinics?

Angiogenesis offers an enormous potentials for therapeutic intervention of many disorders afflicting mankind at present. With the identification of the major molecular players involved in the sequence of events leading to the formation of new blood vessels from pre-existing capillaries, inhibition or induction of the process may now be regulated. Bioactive compounds from natural sources may be used as regulatory agents. Inhibition of angiogenesis can control diseases characterized with excessive blood vessel growth like cancer, arthritis, psoriasis and diabetes retinopathy. Stimulation of angiogenesis would be favorable in the treatment of ischemic disorders and tissue engineering. An increasing number of bioactive compounds from natural sources and whose chemical structures have already been elucidated are reported as either potential inhibitors or inducers of angiogenesis. Drug development from natural products is a fast-emerging field that needs to be supported to provide people with more readily available and affordable healthcare.     

What we have learned from isolated cells from human ovary?

In the ovary, morphodynamics of follicles with cyclic maturation, ovulation and repair occur under the control of various tropic factors. The ovarian functions have been mostly studied by using subhuman primates and non-primate animals because of the limited availability of closely staged human specimens. We have recently established the in vitro culture systems of ovarian surface epithelium (OSE) and granulosa cells of humans, and subsequently developed the immortalization of each cell. The immortalized cell lines may supply us advanced studies on ovarian disorders as well as its physiological functions. On the embryologically putative müllerian potential of coelomic epithelium, endometriosis can be explained by coelomic metaplasia from the peritoneal mesothelium, including OSE. We can microscopically observe a continuity from flat epithelial cells on the ovarian surface or within the cortical inclusion cysts to endometriotic gland cells. The primary human OSE cells exhibited a glandular-stromal structure similar to endometriosis when they were co-cultured with endometrial stromal cells in an estrogen-rich environment. Primary and immortalized OSE cells converted the estrone to estradiol, and expressed the genes for steroidogenic factor-1 (SF-1), p450arom and 17beta-HSDs. This character of OSE was, in part, similar to the granulosa cells. One of the immortalized OSE clone produces disseminated tumors mimicking undifferentiated carcinomas in nude mice. Ovarian granulosa cells play a key role in the functional maturation of the entire follicle. The molecular pathways in granulosa cells responsible for the growth, differentiation, and nursing the oocyte are still largely unknown. Our immortalized human granulosa cell line, GC1a, obtained from developing follicles, showed no steroid hormone biosynthesis, and no detectable expression of the genes for StAR or cytochrome p450 enzymes due to the lack of SF-1. Transfected SF-1 elicited estradiol secretion in GC1a cells with concomitant expression of the genes encoding the proteins for gonadal steroidogenesis. The enzymatic activity of 17beta-HSD was also achieved by SF-1 transgene. These results indicate that SF-1 controls the gene expression required for steroidogenesis in the human developing follicle. Clinically, immortalized GC1a cells from human origin, with steroidogenic capacity, may serve as a feeder layer for in vitro oocyte maturation. Further investigations of our immortalized OSE and granulosa cells of humans will allow us to clarify whether they have a single progenitor cell.     

Stress from Uncertainty from Graduation to Retirement—A Population-Based Study of Swiss Physicians

BACKGROUND Uncertainty shapes many decisions made by physicians everyday. Uncertainty and physicians’ inability to handle it may result in substandard care and unexplained variations in patterns of care. OBJECTIVE To describe socio-demographic and professional characteristics of reactions to uncertainty among physicians from all specialties, including physicians in training. DESIGN Cross-sectional postal survey. PARTICIPANT All physicians practicing in Geneva, Switzerland (n = 1,994). MEASUREMENT Reaction to medical care uncertainty was measured with the Anxiety Due to Uncertainty and Concern About Bad Outcomes scales. The questionnaire also included items about professional characteristics and work-related satisfaction scales. RESULTS After the first mailing and two reminders, 1,184 physicians responded to the survey. In univariate analysis, women, junior physicians, surgical specialists, generalist physicians, and physicians with lower workloads had higher scores in both scales. In multivariate models, sex, medical specialty, and workload remained significantly associated with both scales, whereas clinical experience remained associated only with concern about bad outcomes. Higher levels of anxiety due to uncertainty were associated with lower scores of work-related satisfaction, while higher levels of concern about bad outcomes were associated with lower satisfaction scores for patient care, personal rewards, professional relations, and general satisfaction, but not for work-related burden or satisfaction with income-prestige. The negative effect of anxiety due to uncertainty on work-related satisfaction was more important for physicians in training. CONCLUSION Physicians’ reactions to uncertainty in medical care were associated with several dimensions of work-related satisfaction. Physicians in training experienced the greatest impact of anxiety due to uncertainty on their work-related satisfaction. Incorporating strategies to deal with uncertainty into residency training may be useful.     

New renin--angiotensin from plasma prorenin?

Within 24 h of binephrectomy in rats, plasma prorenin (activated by trypsin) rose well above normal levels while renin disappeared. This rise in prorenin may be attributed to enhanced secretion by an unidentified extrarenal source and the lack of any renin formation from it suggests that nephrectomy abolishes any systemic "convertase" mechanism that exists for its activation. Within 48 h of adrenalectomy in rats, plasma prorenin levels dropped below normal, while renin rose sharply, suggesting enhanced activation of prorenin to renin, resulting in prorenin depletion, and/or the release of a higher proportion of renin: prorenin by the kidneys. To test for enhanced convertase activity, we crosscirculated adrenalectomized (high convertase) and nephrectomized (low convertase) rats and observed a rapid drop in prorenin with an increase in renin in their shared blood. This was also observed after mixing their bloods in vitro, without crosscirculation, indicating that renal convertase activity was in the bloodstream and not just in the kidneys. Acute nephrectomy of previously adrenalectomized rats lowered renin and raised prorenin within 15 min suggesting a rapid loss of kidney-derived convertase. These results could not be attributed to changes in renin-substrate concentration. The new renin (from activated extrarenal prorenin) was blocked by a monoclonal antibody effective against normal rat plasma renin. It also generated immunoreactive angiotensin I, indicating immunological and biological coidentity with renal renin. The blood of normal control rats did not exhibit convertase activity in vivo or in vitro. These data point to a secretory (endocrine) source of extrarenal prorenin which is stimulated by nephrectomy and to a renal prorenin convertase mechanism which is abolished by nephrectomy and stimulated by adrenalectomy. Thus, in a high renin state, active renin may arise by activation of circulating prorenin (renal and extrarenal) as well as by direct renal release.     

What factors distinguish probands from multicase rheumatoid arthritis same sex sibships from sporadic disease?

Thirty-two of 243 same sex sibships in which the proband had rheumatoid arthritis (RA) had at least one same sex sibling with RA ("familial" RA) and 211 did not ("sporadic" RA). The most important factors accounting for familial RA were the sibship size, and the proportion of siblings sharing both HLA haplotypes with the proband. Demographic and clinical details, autoantibodies and HLA-DR status were similar between the 2 groups, with the exceptions of regular use of artificial teardrops, and involvement of distal interphalangeal joints, which were both more prevalent in familial RA. The extrapolation of results from familial to sporadic RA appears to be justified.