Effects of estradiol with oral or intravaginal progesterone on risk markers for breast cancer in a postmenopausal monkey model

OBJECTIVE: To evaluate the effects of oral estradiol given with either oral or intravaginal micronized progesterone (P4) on risk biomarkers for breast cancer in a postmenopausal monkey model. DESIGN: This experiment was a two-way crossover study in which 20 ovariectomized adult female cynomolgus macaques were treated (in equivalent doses for women) with oral estradiol (1 mg/d) + oral micronized P4 (200 mg/d) or intravaginal P4 delivered by Silastic rings (6- to 10-mg/d release rate). Hormone treatments lasted 2 months and were separated by a 1-month washout period. The primary outcome measure was breast epithelial proliferation. RESULTS: Serum P4 concentrations were significantly greater in subjects receiving oral P4 (10.9 ng/mL) compared with intravaginal P4 (3.8 ng/mL) at 2 to 3 hours after oral dosing (P<0.0001) but not at 24 to 28 hours after oral dosing (2.9 ng/mL for oral P4 vs 3.2 ng/mL for intravaginal P4 at 2 months, P=0.19). Serum estradiol concentrations were significantly lower after oral P4 than after intravaginal P4 (P<0.05 for all time points). Oral P4 resulted in significantly decreased body weight (-2.5%) compared with intravaginal P4 (+3.6%) (P=0.0001). Markers of breast proliferation, sex steroid receptor expression, and endometrial area did not differ significantly between oral P4 and intravaginal P4 treatments (P>0.1 for all). CONCLUSIONS: Despite different pharmacodynamic profiles, oral and intravaginal P4 had similar effects on biomarkers in the postmenopausal breast.     

Prognosis of AIDS-related systemic non-Hodgkin lymphoma treated with chemotherapy and highly active antiretroviral therapy depends exclusively on tumor-related factors

OBJECTIVES: To assess complete remission (CR) and survival in patients with systemic AIDS-related non-Hodgkin lymphoma (ARL) receiving highly active antiretroviral therapy (HAART). METHODS: We analyzed the Grupo de Estudio del SIDA register of systemic ARL, which started in Jan 1994, to collect cases diagnosed at 15 institutions prospectively and with active follow-up every 6 months. The date of censorship for this study was March 2005. RESULTS: During the study period, 210 consecutive patients were diagnosed with ARL, with a median age 39 of years, 75.7% of whom were male, and with a median baseline CD4 count of 160 cells/microL. Histologic subtypes were diffuse large B-cell lymphoma (DLCL; n = 153 [72.9%]), Burkitt and atypical Burkitt/Burkitt-like lymphoma (BL; n = 40 [19.0%]), T-cell lymphoma (TC; n = 8 [3.8%]), and miscellaneous (n = 9 [4.3%]). Chemotherapy with or without other modalities was administered to 186 (88.6%) patients. In an intent-to-treat analysis of 184 patients who received at least 1 chemotherapy course with adequate follow-up to assess their response, 119 (64.7%) achieved CR, and the median length of survival (Kaplan-Meier analysis) was 52 months (95% confidence interval [CI]: 23 to 82 months). Factors independently associated with CR were histologic subtype and International Prognostic Index (IPI) score. Factors independently associated with improved overall length of survival (OS) were CR, low IPI score, and histologic subtype. The single factor independently associated with disease-free survival was Ann Arbor stage. CONCLUSIONS: In patients with ARL treated with HAART, CR was associated exclusively with tumor-related factors. The CR rate was poorer in patients with BL and TC subtypes and was inversely correlated with IPI score. OS was independently associated with CR, IPI score, and the histologic subtype.     

Immune response in mice and swine to DNA vaccines derived from the Pasteurella multocida toxin gene

DNA vaccines were constructed with either a 5'-truncated or full-length, genetically detoxified toxin gene from Pasteurella multocida and two different DNA vaccine vectors, distinguished by the presence or absence of a secretion signal sequence. Optimal PMT-specific antibody responses and spleen cell secretion of interferon-gamma following immunization of mice were achieved with pMM4, the construct containing a signal sequence and encoding the entire toxin. Antibody responses were also induced in pigs immunized with pMM4 and levels increased significantly following booster injections and experimental infection with P. multocida. Significantly increased expression of interferon-gamma was detected in only a small subset of pMM4-immunized pigs. This report documents, for the first time, the ability of a DNA vaccine to elicit immune responses to the P. multocida toxin in both mice and swine.     

Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates

An association between reduced susceptibility to echinocandins and changes in the 1,3-beta-d-glucan synthase (GS) subunit Fks1p was investigated. Specific mutations in fks1 genes from Saccharomyces cerevisiae and Candida albicans mutants are described that are necessary and sufficient for reduced susceptibility to the echinocandin drug caspofungin. One group of amino acid changes in ScFks1p, ScFks2p, and CaFks1p defines a conserved region (Phe 641 to Asp 648 of CaFks1p) in the Fks1 family of proteins. The relationship between several of these fks1 mutations and the phenotype of reduced caspofungin susceptibility was confirmed using site-directed mutagenesis or integrative transformation. Glucan synthase activity from these mutants was less susceptible to caspofungin inhibition, and heterozygous and homozygous Cafks1 C. albicans mutants could be distinguished based on the shape of inhibition curves. The C. albicans mutants were less susceptible to caspofungin than wild-type strains in a murine model of disseminated candidiasis. Five Candida isolates with reduced susceptibility to caspofungin were recovered from three patients enrolled in a clinical trial. Four C. albicans strains showed amino acid changes at Ser 645 of CaFks1p, while a single Candida krusei isolate had a deduced R1361G substitution. The clinical C. albicans mutants were less susceptible to caspofungin in the disseminated candidiasis model, and GS inhibition profiles and DNA sequence analyses were consistent with a homozygous fks1 mutation. Our results indicate that substitutions in the Fks1p subunit of GS are sufficient to confer reduced susceptibility to echinocandins in S. cerevisiae and the pathogens C. albicans and C. krusei.     

Structuring a safer donor-replacement program

BACKGROUND: Replacement donors are more likely than volunteer donors to have positive or abnormal tests for transfusion-transmissible disease. In an effort to increase the donor pool, workers sought to identify a safer replacement-donor subgroup that may be acceptable for routine donations. STUDY DESIGN AND METHODS: In a retrospective review and cohort study, the replacement-donor effect was separated from the new- donor effect. The relative effect the replacement donor has on the risk of transfusion-transmissible diseases, donor retention, and frequency of returning donations was then quantified by comparison against the effect of repeat volunteer donors. RESULTS: The replacement donor had 3.1 times the risk and 0.72 times the donor retention rate and made 0.81 times as many returning donations as the repeat volunteer donor. The figures for the new-donor effect were similar. The two risks were additive, making a new replacement donor particularly hazardous. If replacement donations only from repeat replacement donors were considered, the donor risk and the number of donations per returning donor were made comparable to those for the general (combined) volunteer donor. CONCLUSION: The negative effect of the replacement donor is similar in magnitude to that of the new volunteer donor. A replacement-donation program targeting repeat replacement donors has an acceptable risk profile and may be a valuable adjunct to the collection of blood from general volunteer donors.     

Effect of race and genetics on vitamin D metabolism, bone and vascular health

The pathophysiology of chronic kidney disease-mineral and bone disorder accounts for an inverse relationship between bone mineralization and vascular calcification in progressive nephropathy. Inverse associations between bone mineral density (BMD) and calcified atherosclerotic plaque are also observed in individuals of European and African ancestry without nephropathy, suggesting a mechanistic link between these processes that is independent of kidney disease. Despite lower dietary calcium intake and serum 25-hydroxyvitamin D (25(OH)D) concentrations, African Americans have higher BMD and develop osteoporosis less frequently than do European Americans. Moreover, despite having more risk factors for cardiovascular disease, African Americans have a lower incidence and severity of calcified atherosclerotic plaque formation than do European Americans. Strikingly, evidence is now revealing that serum 25(OH)D and/or 1,25 dihydroxyvitamin D levels associate positively with atherosclerosis but negatively with BMD in African Americans; by contrast, vitamin D levels associate negatively with atherosclerosis and positively with BMD in individuals of European ancestry. Biologic phenomena, therefore, seem to contribute to population-specific differences in vitamin D metabolism, bone and vascular health. Genetic and mechanistic approaches used to explore these differences should further our understanding of bone-blood vessel relationships and explain how African ancestry protects from osteoporosis and calcified atherosclerotic plaque, provided that access of African Americans to health care is equivalent to individuals of European ethnic origin. Ultimately, in our opinion, a new mechanistic understanding of the relationships between bone mineralization and vascular calcification will produce novel approaches for disease prevention in aging populations.     

Defining and measuring construct of interprofessional professionalism

The Interprofessional Professionalism Collaborative (IPC), convened in 2006, currently consists of 11 national organizations representing health professions programs at the doctoral entry level, and is developing a framework of "interprofessional professionalism" (IPP) around observable behaviors that illustrate what professionalism looks like in the context of interprofessional collaborations focused on patient-, client-, and family-centered care. IPC's goal is to create tools to foster and measure these behaviors in health professionals and students. This paper describes the work of IPC to date and its future plans.     

Synergistic cytotoxic effect of azidothymidine and recombinant interferon alpha on normal human bone marrow progenitor cells

Azidothymidine (AZT) and interferon alpha (IFN-alpha) are among the drugs showing strong in vitro activity against the human immunodeficiency virus type-1 (HIV-1). Each drug, however, has significant toxicity against normal marrow progenitor cells that frequently proves dose-limiting in patients. In this study, AZT and recombinant IFN-alpha 2a (rIFN-alpha 2a) were tested as single agents and in combination against normal myeloid (CFU-GM) and erythroid (BFU- E) colony forming cells in a standard methylcellulose culture assay. The data were analyzed using a quantitative computerized analysis based on the median-effect principle and the isobologram equation as described by Chou and Talalay (Adv Enz Regul 22:27, 1984). The ED90 for BFU-E and CFU-GM inhibition was then compared with previously measured in vivo plasma levels of each drug and the ED90 for the anti-HIV-1 effect in vitro. We demonstrate that (a) the drugs are strongly synergistic in inhibiting marrow progenitor cell growth and that this synergism occurs at drug levels that are within the range of measured plasma levels in phase I clinical trials, (b) BFU-E are more sensitive than CFU-GM to the inhibiting effects of AZT, rIFN-alpha 2a or both drugs in combination, (c) the drug concentrations in combination that synergistically inhibit bone marrow progenitors are much higher than those required to inhibit HIV-1 replication in vitro, and (d) the anti- HIV-1 effect for the combination of AZT and rIFN-alpha 2a was clearly superior to the effect of AZT or rIFN-alpha 2a alone as indicated by the combination index and the dose-reduction index. These data suggest that substantially lower doses of AZT and rIFN-alpha than those currently being tested in clinical trials might not only maintain a strong synergistic anti-HIV-1 effect but might also avoid significant hematologic toxicity.