Integrating complementary and alternative medicine instruction into health professions education: organizational and instructional strategies.

A few years ago, the National Institutes of Health National Center for Complementary and Alternative Medicine funded a program called the Complementary and Alternative Medicine (CAM) Education Project. Grantees were 14 medical and nursing schools and the American Medical Student Association, which funded six additional medical schools. Grants were awarded in cohorts of five per year in 2000, 2001, and 2002-2003.The R25 grant recipients identified several major themes as crucial to the success of integrating CAM into health professions curricula. The rationale for integrating CAM curricula was in part to enable future health professionals to provide informed advice as patients dramatically increase the use of CAM. Success of new CAM education programs relied on leadership, including top-down support from institutions' highest administrators. Formal and informal engagement of key faculty and opinion leaders raised awareness, interest, and participation in programs. A range of faculty development efforts increased CAM-teaching capacity. The most effective strategies for integration addressed a key curriculum need and used some form of evidence-based practice framework. Most programs used a combination of instructional delivery strategies, including experiential components and online resources, to address the needs of learners while promoting a high level of ongoing interest in CAM topics. Institutions noted several benefits, including increased faculty development activities, the creation of new programs, and increased cross- and inter-university collaborations. Common challenges included the need for qualified faculty, crowded and changing curricula, a lack of defined best practices in CAM, and post-grant sustainability of programs.     

The diagnosis of male infertility--prospective time-specific study of conception rates related to seminal analysis and post-coital sperm--mucus penetration and survival in otherwise unexplained infertility

Infertile women without any inherent female infertility factorsand able to secrete normal cervical mucus were studied prospectivelyin relation to post-coital sperm—mucus penetration (PCT)and their partner's seminal analysis, excluding men with azoospermia.Time-specific cumulative conception rates calculated as forlife-table analysis were related to each measured seminal variableon routine analysis of 2–3 samples (volume, density, proportionwith progressive motility, and proportion with normal morphology);to various derivatives from combinations of these variables;to seminal findings after vital staining; and to the PCT results.The best seminal predictor of fertility was the motile normalsperm density (MNSD), the 18 month conception rates being 57.4%+ 4.6 (SE) and 30.2% + 5.9 (ratio 1.9, P < 0.001) above andbelow a derived threshold value of 4 x 10⁶/ml. The PCT led torates of 55.6% ± 4.3 and 14.9% ± 5.1 (ratio 3.73,P < 0.001) for positive and negative results, respectively.The PCT also gave rise to a significantly distinct intermediatepoor-psitive sub-group (conception rate 30.6% ± 9.0).Seminal analysis (the MNSD) did not affect the conception rateassociated with a positive PCT but helped to discriminate furtherwith a negative PCT (conception rates 22.5% ± 8.7 withan MNSD above 4 x 10⁶/ml versus 5.6% ± 4.8 below, P <0.05). The PCT was the single best predictor of fertility butseminal analysis (the MNSD) was of additional value after anegative PCT.     

Miscarriage rates following in-vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin

To assess the risk of miscarriage after in-vitro fertilization(IVF) with respect to age, cause of infertility, ovarian morphologyand treatment regimen, a retrospective analysis was performedof the first 1060 pregnancies conceived between June 1984 andJuly 1990 as a result of 7623 IVF cycles. Superovulation inductionwas achieved with human menopausal gonadotrophin (HMG) and/orpurified follicle stimulating hormone (FSH) together with eitherclomiphene citrate or the gonadotrophin hormone-releasing hormone(GnRH) agonist buserelin, the latter either as a short ‘flare’regimen or as a ‘long’ regimen to induce pituitarydesensitization. There were 282 spontaneous abortions (26.6%)and 54 ectopic pregnancies (5.1%). The mean age of women withongoing pregnancies was 32.2 (SD 3.9) years compared with 33.2(SD 4.1) years in those who miscarried, which were significantlydifferent (P = 0.008). There was no relation between the miscarriagerate and the indication for IVF. The miscarriage rate was 23.6%in women with normal ovaries compared with 35.8% in those withpolycystic ovaries [P = 0.0038, 95% confidence interval (CI)4.68–23.10%]. There was no difference in the miscarriagerate between treatment with HMG or FSH. Women whose ovarieswere normal on ultrasound were just as likely to miscarry ifthey were treated with clomiphene or with the long buserelinprotocol. Those with polycystic ovaries, however, had a significantreduction in the rate of miscarriage when treated with the longbuserelin protocol, 20.3% (15/74), compared with clomiphenecitrate, 47.2% (51/108) (P = 0.0003, 95% CI 13.82–40.09%).     

Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)

A cross-sectional survey in individuals affected with the lysosomal storage disease Mucopolysaccharidosis VI (MPS VI) was conducted to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of the disease. The survey evaluated 121 bona fide MPS VI-affected individuals over the age of 4 years from 15 countries across the Americas, Europe, and Australasia representing greater than 10% of the estimated world prevalence of the disease. A medical history, complete physical exam, urinary GAG determination, and assessment of several clinical measures related to physical endurance, pulmonary function, joint range of motion, strength, and quality of life were completed for each participant. Although a wide variation in clinical presentation was observed, several general findings were obtained reflecting progression of the disease. Impaired physical endurance, as measured by the distance achieved in a 6-min walk, could be demonstrated across all age groups of MPS VI-affected individuals. High urinary GAG values (>200 mug/mg creatinine) were associated with an accelerated clinical course comprised of age-adjusted short stature and low body weight, impaired endurance, compromised pulmonary function, and reduced joint range of motion. An unexpected result was the predominance of urinary GAG values <100 mug/mg creatinine for those participants over the age of 20 years. Pending the collection of longitudinal data, these results suggest that urinary GAG levels predict clinical morbidity, and longer-term survival is associated with urinary GAG levels below a threshold of 100 mug/mg creatinine.     

Alzheimer's disease: the relationship between the density of senile plaques, neurofibrillary tangles and A4 protein in human patients.

The numerical density of senile plaques (SP) and neurofibrillary tangles (NFT) as revealed by the Glees silver method was compared with SP and NFT revealed by the Gallyas method and with amyloid (A4) deposits in immunostained sections in 6 elderly cases of Alzheimer's disease. The density of NFT was generally greater and A4 lower in tissue from hippocampus compared with the neocortex suggesting that A4 deposition was less important than the degree of paired helical filament (PHF) related damage in the hippocampus. The density of Glees SP was positively correlated Gallyas SP weakly correlated with A4 deposit number. A stepwise multiple regression analysis which included A4 deposit and Gallyas SP density and accounted for 54% of the variation in Glees SP density. Hence, different populations of SP were revealed by the different staining methods. The results suggested that the Glees method may stain a population of SP in a region of cortex where both amyloid deposition and neurofibrillary changes have occurred.     

Interleukin-6 regulates the cytotoxic effect of tumour necrosis factor on U937 cells.

In this study, we demonstrate that low but not high concentrations of interleukin-6 (IL-6) potentiate the cytotoxic effect of tumour necrosis factor-alpha (TNF-alpha) on U937 cells, in a dose-dependent manner. Killing of U937 cells by 100 U/ml of TNF-alpha, was maximally potentiated by 50 U/ml of IL-6. No potentiation of cell killing was observed when the concentration of IL-6 was increased to 4000 U/ml. At a concentration of 50 U/ml, IL-6 up-regulated TNF receptor expression but no change in TNF receptor number was observed when the concentration of IL-6 was increased to 4000 U/ml. Low concentrations of IL-6 can also induce sub-cytotoxic doses of TNF-alpha (0.1 and 0.33 U/ml) to kill U937 cells. Up-regulation of TNF receptors by IL-6 is dependent on de novo protein synthesis since receptor induction is abolished in the presence of cycloheximide. Taken together the data suggest that the potentiation of cell killing observed by a combination of these lymphokines is mediated in part by IL-6-induced changes in TNF receptor expression.     

IL-12p40-overexpressing immature dendritic cells induce T cell hyporesponsiveness in vitro but accelerate allograft rejection in vivo: role of NK cell activation and interferon-gamma production

Infusion of genetically modified dendritic cells (DC) expressing immunosuppressive molecules is a potential therapy for organ rejection. IL-12p70, a cytokine produced mainly by DC and macrophages, consists of two subunits, p40 and p35. IL-12p70 is an activator of T cells, while the IL-12p40 subunit serves as a natural antagonist for IL-12p70 action. The primary aim of this study was to evaluate the effect of IL-12p40 gene-modification on both the T-cell stimulatory activity of immature DC (imDC) and their ability to prolong cardiac allograft survival. IL-12p40 gene-modified imDC (DC-p40) exhibited a phenotype characteristic of imDC and displayed impaired T-cell allostimulatory ability in vitro. However, to our surprise, for murine vascularized heterotopic heart transplantation (HHT), administration of donor-derived DC-p40 7 days prior to transplantation did not prolong allograft survival but instead significantly exacerbated cardiac allograft rejection. Further study showed that DC-p40 augmented NK cell activity both in vitro and in vivo and enhanced interferon-gamma (IFN-gamma) production in vivo, which might be due to the increased IL-23 production by DC-p40. Our data suggested that although IL-12p40 gene-modified immature DC can induce T cell hyporesponsiveness in vitro, their ability to activate NK cells and induce IFN-gamma production counterbalances this, exacerbating cardiac allograft rejection. The unexpected effects of DC-p40 limit their value in promoting allograft survival in vivo and likely reflect the complexity of IL-12p40 biology.     

Status of oral rabies vaccination in wild carnivores in the United States

Persistence of multiple variants of rabies virus in wild Chiroptera and Carnivora presents a continuing challenge to medical, veterinary and wildlife management professionals. Oral rabies vaccination (ORV) targeting specific Carnivora species has emerged as an integral adjunct to conventional rabies control strategies to protect humans and domestic animals. ORV has been applied with progress toward eliminating rabies in red foxes (Vulpes vulpes) in western Europe and southern Ontario, Canada. More recently since 1995, coordinated ORV was implemented among eastern states in the U.S.A. to prevent spread of raccoon (Procyon lotor) rabies and to contain and eliminate variants of rabies virus in the gray fox (Urocyon cinereoargenteus) and coyote (Canis latrans) in Texas. In this paper, we describe the current cooperative ORV program in the U.S.A. and discuss the importance of coordination of surveillance and rabies control programs in Canada, Mexico and the U.S.A. Specifically, several priorities have been identified for these programs to succeed, which include additional oral vaccines, improved baits to reach target species, optimized ORV strategies, effective communication and legal strategies to limit translocation across ORV barriers, and access to sufficient long-term funding. These key priorities must be addressed to ensure that ORV has the optimal chance of achieving long range programmatic goals of eliminating specific variants of rabies virus in North American terrestrial carnivores.     

Recombinant 25-kDa CD23 and interleukin 1 alpha promote the survival of germinal center B cells: evidence for bifurcation in the development of centrocytes rescued from apoptosis.

Germinal centers contain a proliferating pool of centroblasts which give rise to non-dividing centrocyte. Centrocytes are programmed to die by apoptosis unless they receive a positive signal for rescue. Rescue, in vivo, is likely to be dependent, initially, on interaction with antigen held on follicular dendritic cells (FDC). A subset of FDC located in that part of the germinal center furthest from centroblasts is particularly rich in CD23. Supernatants containing high levels of soluble CD23 were found not only to encourage the survival of germinal center B cells but also to promote their differentiation toward a plasmacytoid morphology; these activities were diminished following removal of CD23 from the supernatants. Recombinant 25-kDa CD23 was initially found to be incapable of providing the signal for germinal center cell development but on the addition of interleukin 1 alpha which, by itself, was inactive, rescue and differentiation of germinal center B cells were now achieved. Apoptosis in germinal center cells could also be prevented by the ligation of surface CD40 with monoclonal antibody: however, rescue via this pathway was not accompanied by plasmacytoid differentiation. These findings provide a functional rationale to the high level expression of CD23 found within a discrete subset of FDC and indicate a bifurcation in the development of germinal center B cells following their rescue from apoptosis.     

Safety and efficacy of a monomeric, functionally intact intravenous IgG preparation in patients with primary immunodeficiency syndromes

Results of an open, phase II clinical trial on therapy with an iv IgG preparation in patients with primary antibody-deficiency syndromes are reported. Three hundred infusions of the product, an intact monomeric IgG preparation, were given to 16 patients for an average of 14 (+/- 0.7) months, the dose being 220 (+/- 26.9) mg/kg/month. Only two minor adverse reactions occurred. This preparation did not produce transient leukopenia on infusion. Preinfusion serum IgG levels increased continuously in the course of treatment (average values: 325 +/- 51 at the beginning of therapy, 438 +/- 59 at 6 months, 568 +/- 75 at 12 months, 631 +/- 52 at the end of treatment). The infusions were well accepted and well tolerated by the patients, and the clinical efficacy was highly superior to intramuscular immunoglobulin.