Thiomersal in vaccines: balancing the risk of adverse effects with the risk of vaccine-preventable disease.

A number of affluent countries are moving to eliminate thiomersal (thimerosal), an ethylmercury preservative, from vaccines as a precautionary measure because of concerns about the potential adverse effects of mercury in infants. The WHO advocates continued use of thiomersal-containing vaccines in developing countries because of their effectiveness, safety, low cost, wide availability and logistical suitability in this setting. The guidelines for long-term mercury exposure should not be used for evaluating risk from intermittent single day exposures, such as immunisation using thiomersal-containing vaccines. Similar or higher mercury exposures likely occur from breast feeding and the health benefit of eliminating thiomersal from a vaccine, if any, is likely to be very small. On the other hand, the benefits accrued from the use of thiomersal-containing vaccines are considerably greater but vary substantially between affluent and developing regions of the world. Because of the contribution to overall mercury exposure from breast milk and diet in later life, the removal of thiomersal from vaccines would produce no more than a 50% reduction of mercury exposure in infancy and <1% reduction over a lifetime. Different public policy decisions are appropriate in different settings to achieve the lowest net risk, viewed from the perspectives of the individual vaccinee or on a population basis. In developing regions of the world, at least over the next decade, far more benefit will accrue from protecting children against widely prevalent vaccine-preventable diseases by focusing efforts aimed at improving infant immunisation uptake by using current, inexpensive, domestically-manufactured, thiomersal-containing vaccines, than by investing in thiomersal-free alternatives.     

Physicians'' perceptions of the effect on clinical services of an alternative funding plan at an academic health sciences centre

BACKGROUND: In July 1994 an alternative funding plan for clinical services (global funding instead of fee-for-service payment) was established at the Southeastern Ontario Health Sciences Centre, Kingston, Ont. This study describes the perceptions of the referring physicians and consultants of the effects of the alternative funding plan 2.5 years after it was initiated. METHODS: A questionnaire was mailed to all physicians in the Kingston area in November 1996. Information was collected on demographics, referring physicians' perceptions of the funding plan's impact on their practices, consultants' perceptions of its impact on their activities, perceptions of referring and consultant physicians of its impact on services provided by consultants, and attitudes toward alternative funding in the context of the Ontario health care system. RESULTS: Of the 772 physicians 531 (68.8%) returned a completed questionnaire (323 referring physicians and 208 consultants). A sizeable proportion of the referring physicians (126 [39.0%]) indicated that they were referring fewer patients to consultants at the study centre. They did not think that their practice volume had increased, but they did report spending more time on complex cases and on patient care after referral or hospital stay, and more time coordinating community care after hospital stay. Of the consultants 81 (38.9%) believed that their time spent on patient care had increased. No consistent impact on time spent on research or teaching activities was perceived. A total of 54 (26.0%) of the consultants were concerned about the impact of the alternative funding plan on quality of care. A significant proportion of the respondents (399 [75.1%]) believed that outpatient waiting times had increased, and 116 (35.9%) of the referring physicians believed that consultants were not as available by telephone. Most (220 [68.1%]) of the referring physicians believed that the funding change had had a negative effect on health care services in the region, and 87 (41.8%) of the consultants agreed. Nevertheless, the respondents believed that other factors such as funding cuts, hospital bed closures and staff layoffs were much more responsible than the alternative funding plan for their negative perceptions. INTERPRETATION: The alternative funding plan appears to have had an impact on the practices of individual physicians. However, it was not the focus for significant opposition or support from either consultants participating in the funding plan or referring physicians.     

FcR blocking activity in serum of actively enhanced rat renal allograft recipients due to IgG anti-class II MHC alloantibody

In some rat strain combinations, pre-operative donor-specific blood transfusion produces long-term renal allograft survival, although the underlying mechanisms are unclear. This study has examined whether Fc receptor (FcR)-blocking activity could be detected in the serum of unmodified PVG strain recipients bearing a rejecting renal allograft and in recipients bearing an actively enhanced graft following pre-operative blood transfusion. Serum harvested on Day 5 from actively enhanced PVG recipients of DA rat renal allografts was shown to specifically inhibit erythrocyte-antibody (EA) rosette formation with donor strain, but not third-party, splenocytes, while the levels of EA rosette inhibition (EAI) in Day 5 serum from rejecting rats remained markedly lower. This FcR-blocking activity was present in enhanced serum fractions, prepared by discontinuous density gradient centrifugation, which corresponded to the 7 S peak. Purified IgG prepared from enhanced serum was also found to inhibit EA rosette formation with donor splenocytes, and absorption of the IgG preparations with donor strain erythrocytes failed to abrogate EA rosette inhibition. Further experiments, in which absorbed IgG from enhanced animals was tested for FcR blocking activity against splenocytes of defined major histocompatability complex (MHC) subregion specificities, established that FcR-blocking activity was mediated by IgG alloantibodies directed against donor MHC class II antigens. Whether the presence of such antibodies early after transplantation contributes to the beneficial effect of blood transfusion on graft survival remains to be determined.     

Complications associated with ileal pouch-anal anastomosis.

Seventy-three patients underwent total colectomy, rectal mucosectomy, creation of J or S ileal reservoir, and ileal pouch-anal anastomosis from 1982 to 1989. Mean follow-up was 38 months, with a minimum of 3 months in 15 patients being followed long-term at another institution. Forty-eight (66%) patients had histologically proven ulcerative colitis and 25 (34%) patients had familial polyposis. Thirty-eight J reservoirs and 35 S reservoirs were constructed. There were no perioperative deaths. The failure rate (loss of pouch) was 3%. Thirty-six complications in 34 (47%) patients were reported, 14 (19%) patients required surgery. Bowel obstruction was the most common postoperative complication (16%), followed by pouchitis (15%), and cuff infection (5%). Seventy-eight percent of the complications were associated with the J pouch. Average stool frequency at 1 year was 4 per 24-hour period. Other complications included postoperative pneumonia (1), peroneal nerve palsy (1), and temporary sexual dysfunction (1). Seven of 15 complications requiring surgical intervention occurred in the first 2 years of the study period, illustrating the learning curve associated with the procedure. Blood loss, transfusion requirements, and length of operation were not associated with higher complication rates. Use of the J pouch and experience of the individual surgeon affected morbidity.     

Effect of side-chain alteration on hormonal activity of nonsteroidal estrogen antagonists

Incorporation of novel side-chains in 3,4-diaryl chromans, an established nucleus present in the nonsteroidal estrogen antagonist centchroman, has been carried out. The effect of variation in the nature of the chain on relative binding affinity (RBA) to estrogen receptor, estrogenicity, and antiestrogenicity has been studied. Presence of hydrazide residue on cis- and trans-3,4-diaryl chromans led to relatively higher RBA and estrogenicity as compared with corresponding acids and esters.     

Activation of the aryl hydrocarbon receptor by TCDD inhibits senescence: A tumor promoting event?

Activation of the aryl hydrocarbon receptor (AHR) by the agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to promote tumor formation in both liver and skin. In the liver, but not the skin, the AHR-mediated events that contribute to TCDD’s tumor promoting activities have been studied in some detail and are thought to involve perturbation of cell fate processes. However, studies performed using cultured cells have often resulted in apparent contradictory results indicating that the impact of TCDD on cell fate processes may be cell context dependent. We and others have shown that in primary cultured keratinocytes TCDD increases post-confluent proliferation and increases late differentiation. Further, our studies performed in these cells indicate that TCDD can also inhibit culture-induced senescence. While senescence, a permanent cell cycle arrest, is emerging as an important process regulated by oncogenes and considered to be of therapeutic importance, its role with respect to TCDD/AHR mediated tumor promotion has not been fully considered. The intent of this article is to focus primarily on senescence as a cell process relevant to skin tumorigenesis and explore the idea that the inhibition of senescence by TCDD could be an important mechanism by which it may exert its tumor promoting effects in the skin.