The estrogen receptor is not essential for all estrogen neuroprotection: new evidence from a new analog

We synthesized an estrogen analog, ZYC-5, lacking activity at the classical estrogen receptor and examined its neuroprotective potential against necrosis induced by N-methyl-d-aspartate (NMDA) and apoptosis/necrosis induced by the NMDA receptor antagonist (+)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP). ZYC-5 protected cortical neurons in a dose-dependent manner, and the neuroprotection was more robust than with 17beta-estradiol. The effect of ZYC-5 was not mediated by the classical estrogen receptor, because it was unaffected by the antagonists 4-hydroxytamoxifen and ICI 182,780. The ZYC-5 protection against excitotoxicity was not directly mediated through the NMDA receptor, because there was no effect of ZYC-5 on NMDA current or the intracellular calcium increase induced by NMDA. Results obtained with the free-radical-sensitive dye, dihydroethidium, suggested that the neuroprotection of ZYC-5 was partly related to its radical scavenging properties. Although some of estrogen's neuroprotective effects may depend upon the estrogen receptor, our results suggest the possibility of neuroprotection without hormonal side effects.     

Impact of services,met needs,and service empowerment on consumer outcomes

The current study examined service characteristics, needs, and outcomes of consumers with severe mental disabilities served in a public mental health setting. The study utilized a longitudinal design with three yearly waves of measurement. Data were obtained from consumer interviews and case manager questionnaires. A model specifying relationships between service characteristics, needs, and outcomes was tested using structural equation modeling. This model incorporated service-related variables pertaining to service amounts, service empowerment, and needs in order to gain a better understanding of factors that mediate service effects and account for mental health outcomes. The model focused on consumers' perspectives, in order to highlight the importance of consumers' opinions about their mental health services and needs. The results suggested that consumers' perceptions that their needs are met were related to better symptomatology and quality of life outcomes. In addition, consumers' perceptions that they had some say in service-related decisions had an indirect effect on mental health outcomes by increasing the likelihood that needs were met according to consumers' perspectives. Results were mixed with regard to the effects of these variables on level of functioning outcomes. Service amount was unrelated to mental health outcomes. Furthermore, service amount was unrelated to consumers' perceptions of needs, suggesting that consumers' views regarding met and unmet needs may not be included sufficiently in decision-making surrounding the provision of services.     

Segregation analysis of prostate cancer in 1,719 white,African-American and Asian-American families in the United States and Canada

Some data suggest that brothers of prostate cancer patients have higher disease risk than their fathers, supporting an X-linked or recessive mode of inheritance. However, higher observed frequencies in brothers than fathers may merely reflect the strong temporal changes in US incidence rates. Objectives: (a) to evaluate the fit of X-linked, recessive, and dominant modes of inheritance to prostate cancer incidence, specific for calendar year, age, and race, in population-based samples of US and Canadian families; and (b) to evaluate a simple multifactorial model for familial aggregation of prostate cancer due to shared low-penetrance variants of many genes or shared lifestyle factors. Methods: The data consist of reported prostate cancer incidence in first-degree relatives of 1719 white, African-American, and Asian-American men with and without prostate cancer at ages < 70 years. Model parameters were estimated by maximizing a pseudo-likelihood function of the data, and goodness of model fit was assessed by evaluating discrepancies between observed and expected numbers of pairs of relatives with prostate cancer. Results: After adjusting for temporal trends in prostate cancer incidence rates we found that the X-linked model fit poorly, underpredicting the observed number of affected father–son pairs. This also was true of the recessive model, although the evidence for poor fit did not achieve statistical significance. In contrast, the dominant model provided adequate fit to the data. In this model the race-specific penetrance estimates for carriers of deleterious genotypes were similar among African-Americans and whites, but lower among Asian-Americans: risk by age 80 years for carriers born in 1900 was estimated as 75.3% for African-Americans and whites, and 44.4% for Asian-Americans. None of the Mendelian models fit the data better than did the simple multifactorial model. Conclusions: The good fit of the multifactorial model suggests that multiple genes, each having low penetrance, may be responsible for most inherited prostate cancer susceptibility, and that the contribution of rare highly penetrant mutations is small.     

Cytomegalovirus viremia during Campath-1H therapy for relapsed and refractory chronic lymphocytic leukemia and prolymphocytic leukemia

Campath-1H is effective therapy for patients with relapsed and refractory chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (PLL), but it is associated with profound lymphopenia and deficiencies in cell-mediated immunity. We report the incidence of cytomegalovirus (CMV) viremia in 34 patients treated with Campath-1H for relapsed or refractory CLL and PLL. All patients received infection prophylaxis during therapy and continuing for at least 2 months following Campath-1H. Five patients (15%) developed CMV viremia at a median of 28 days (range, 20-30 days) after the first dose of Campath-1H. The median CMV viral load was 860/mL (range, 420-2100/mL), as determined by quantitative plasma polymerase chain reaction (PCR). All 5 patients had a temperature > 38.5 degrees C, normal chest radiographs, normal liver function tests, and negative bacterial blood cultures with no clinical evidence of CMV disease at the time of presentation with CMV viremia. The median absolute neutrophil count (ANC) was 740/ microL (range, 340-1600/ microL), and the median absolute lymphocyte count (ALC) was 16/microL (range, 11-169/ microL) for the 5 patients at the time of CMV viremia. All 5 patients received ganciclovir therapy followed by prompt fever resolution and clearance of CMV viremia by plasma PCR. By univariate regression analysis, the following were not risk factors for CMV viremia: age, number of prior regimens, prior rituximab therapy, prior splenectomy, modified Rai stage at Campath-1H therapy (low/intermediate vs. high), ANC, and ALC; although, there was a trend towards significance for prior rituximab therapy (P = 0.07). Cytomegalovirus viremia may be a significant infectious complication during Campath-1H therapy and should be investigated further in future studies.     

Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis

To determine the impact of tumor progression on the reversibility of Neu-induced tumorigenesis, we have used the tetracycline regulatory system to conditionally express activated Neu in the mammary epithelium of transgenic mice. When induced with doxycycline, bitransgenic MMTV-rtTA/TetO-NeuNT mice develop multiple invasive mammary carcinomas, essentially all of which regress to a clinically undetectable state following transgene deinduction. This demonstrates that Neu-initiated tumorigenesis is reversible. Strikingly, extensive lung metastases arising from Neu-induced mammary tumors also rapidly and fully regress following the abrogation of Neu expression. However, despite the near universal dependence of both primary tumors and metastases on Neu transgene expression, most animals bearing fully regressed Neu-induced tumors ultimately develop recurrent tumors that have progressed to a Neu-independent state.     

The aging baboon: comparative demography in a non-human primate

Why do closely related primate genera vary in longevity, and what does this teach us about human aging? Life tables of female baboons (Papio hamadryas) in two wild populations of East Africa and in a large captive population in San Antonio, Texas, provide striking similarities and contrasts to human mortality patterns. For captive baboons at the Southwest Foundation for Biomedical Research, we estimate the doubling time of adult mortality rate as 4.8 years. Wild females in free-living populations in Tanzania and in Kenya showed doubling times of 3.5 and 3.8 years, respectively. Although these values are considerably faster than the estimates of 7-8 years for humans, these primates share a demographic feature of human aging: within each taxon populations primarily vary in the level of Gompertz mortality intercept (frailty) and vary little in the demographic rate of aging. Environmental and genetic factors within taxa appear to affect the level of frailty underlying senescence. In contrast, primate taxa are differentiated by rates of demographic aging, even if they cannot be characterized by species-specific lifespan.     

Performance parameters for screening and diagnostic mammography: specialist and general radiologists

PURPOSE: To evaluate performance parameters for radiologists in a practice of breast imaging specialists and general diagnostic radiologists who interpret a large series of consecutive screening and diagnostic mammographic studies. MATERIALS AND METHODS: Data (ie, patient age; family history of breast cancer; availability of previous mammograms for comparison; and abnormal interpretation, cancer detection, and stage 0-I cancer detection rates) were derived from review of mammographic studies obtained from January 1997 through August 2001. The breast imaging specialists have substantially more initial training in mammography and at least six times more continuing education in mammography, and they interpret 10 times more mammographic studies per year than the general radiologists. Differences between specialist and general radiologist performances at both screening and diagnostic examinations were assessed for significance by using Student t and chi(2) tests. RESULTS: The study involved 47,798 screening and 13,286 diagnostic mammographic examinations. Abnormal interpretation rates for screening mammography (ie, recall rate) were 4.9% for specialists and 7.1% for generalists (P <.001); and for diagnostic mammography (ie, recommended biopsy rate), 15.8% and 9.9%, respectively (P <.001). Cancer detection rates at screening mammography were 6.0 cancer cases per 1,000 examinations for specialists and 3.4 per 1,000 for generalists (P =.007); and at diagnostic mammography, 59.0 per 1,000 and 36.6 per 1,000, respectively (P <.001). Stage 0-I cancer detection rates at screening mammography were 5.3 cancer cases per 1,000 examinations for specialists and 3.0 per 1,000 for generalists (P =.012); and at diagnostic mammography, 43.9 per 1,000 and 27.0 per 1,000, respectively (P <.001). CONCLUSION: Specialist radiologists detect more cancers and more early-stage cancers, recommend more biopsies, and have lower recall rates than general radiologists.     

Medical audit of diagnostic mammography examinations: comparison with screening outcomes obtained concurrently

OBJECTIVE: We performed a medical audit of our diagnostic mammography practice and compared clinical outcomes with those of screening mammography examinations performed concurrently. MATERIALS AND METHODS: We analyzed 46,857 consecutive mammography examinations (10,007 diagnostic, 36,850 screening) from 1997 to 2000, including data on demographics, image interpretation, and biopsy (including size, nodal status, and cancer stage). RESULTS: The mean age at diagnostic mammography was 55.8 years (mean age at screening mammogram, 59.1 years; p < 0.0001). Among patients who underwent diagnostic examinations, 14.7% had a strong or very strong family history of breast cancer (screening, 11.6%; p < 0.0001). Examination findings were interpreted as abnormal in 14.4% (screening, 5.2%; p < 0.0001). Biopsy was performed in 11.9% (screening, 1.4%; p < 0.0001). Forty-six percent of the biopsies were positive for malignancy (screening, 38%; p < 0.0001). The cancer detection rate was 55 per 1000 (screening, 5/1000; p < 0.0001). Of cancers found, 74.4% were stage 0 or I (screening, 89.3%; p < 0.0001), average size was 18.0 mm (screening, 12.9 mm; p < 0.0001), and axillary nodes were positive for malignancy in 19.9% of invasive cancers (screening, 6.3; p < 0.0001). Differences between diagnostic and screening outcomes were attributable predominantly to the subgroup of diagnostic examinations performed for evaluation of palpable masses. CONCLUSION: Medical auditing of diagnostic mammography examinations yields substantially different results compared with those of screening examinations, including different patient demographics; higher number of positive biopsies; higher cancer detection rates; and larger, more advanced-stage cancers. Diagnostic and screening data should be segregated during auditing, or if this is not possible, analysis of combined results should be based on known differences between diagnostic and screening outcomes.