Progestin Receptor-Mediated Reduction of Anxiety-Like Behavior in Male Rats

BACKGROUND: It is well known progesterone can have anxiolytic-like effects in animals in a number of different behavioral testing paradigms. Although progesterone is known to influence physiology and behavior by binding to classical intracellular progestin receptors, progesterone's anxiety reducing effects have solely been attributed to its rapid non-genomic effects at the GABA A receptor. This modulation occurs following the bioconversion of progesterone to allopregnanolone. Seemingly paradoxical results from some studies suggested that the function of progesterone to reduce anxiety-like behavior may not be entirely clear; therefore, we hypothesized that progesterone might also act upon progestin receptors to regulate anxiety. METHODOLOGY/PRINCIPAL FINDINGS: To test this, we examined the anxiolytic-like effects of progesterone in male rats using the elevated plus maze, a validated test of anxiety, and the light/dark chamber in the presence or absence of a progestin receptor antagonist, RU 486. Here we present evidence suggesting that the anxiolytic-like effects of progesterone in male rats can be mediated, in part, by progestin receptors, as these effects are blocked by prior treatment with a progestin receptor antagonist. CONCLUSION/SIGNIFICANCE: This indicates that progesterone can act upon progestin receptors to regulate anxiety-like behavior in the male rat brain

Cardiac toxicity of trastuzumab in metastatic breast cancer patients previously treated with high-dose chemotherapy: a retrospective study

HER-2 overexpression is associated to a poor prognosis in high-risk and metastatic breast cancer (MBC) patients treated with high-dose chemotherapy (HDC). HER-2 status is also a predictive factor and when trastuzumab is administered in combination with or sequentially to chemotherapy, a significant disease-free and/or overall survival improvement has been observed in HER-2+ early and MBC. Unfortunately, in both settings, trastuzumab is associated with an increased risk of cardiac dysfunction (CD). We have reviewed the clinical charts of HER-2-overexpressing MBC patients treated with trastuzumab after HDC. Age, baseline left ventricular ejection fraction (LVEF), radiation therapy on cardiac area, exposure to anthracycline, single or multiple transplant, high-dose agents, trastuzumab treatment duration were recorded as potential risk factors. In total, 53 patients have been included in the analysis. Median LVEF at baseline was 60.5%; at the end of trastuzumab (data available for 28 patients only), it was 55% (P=0.01). Five out of the 28 (17.9%) patients experienced CD. Two out of 53 (3.8%) patients developed a congestive heart failure. Age ⩾50 years and multiple transplant procedure were potential risk factors for CD. The overall incidence of CD observed in this population of HER-2+ MBC patients treated with trastuzumab after HDC is not superior to that reported with concomitant trastuzumab and anthracyclines. However, patients with age ⩾50 years or receiving multiple course of HDC should be considered at risk for CD

Stage III and oestrogen receptor negativity are associated with poor prognosis after adjuvant high-dose therapy in high-risk breast cancer

We report on the efficacy and toxicity of a sequential high-dose therapy with peripheral blood stem cell (PBSC) support in 85 patients with high-risk stage II/III breast cancer. There were 71 patients with more than nine tumour-positive axillary lymph nodes. An induction therapy of two cycles of ifosfamide (total dose, 7.5 g m−2) and epirubicin (120 mg m−2) was given, and PBSC were harvested during G-CSF-supported leucocyte recovery following the second cycle. The PBSC-supported high-dose chemotherapy consisted of two cycles of ifosfamide (total dose, 12 000 mg m−2), carboplatin (900 mg m−2) and epirubicin (180 mg m−2). Patients were autografted with a median number of 3.7 × 106 CD34+ cells kg−1 (range, 1.9–26.5 × 106) resulting in haematological reconstitution within approximately 2 weeks following high-dose therapy. The toxicity was moderate in general, and there was no treatment-related toxic death. Twenty-one patients relapsed between 3 and 30 months following the last cycle of high-dose therapy (median, 11 months). The probability of disease-free and overall survival at 4 years were 60% and 83%, respectively. According to a multivariate analysis, patients with stage II disease had a significantly better probability of disease-free survival (74%) in comparison to patients with stage III disease (36%). The probability of disease-free survival was also significantly better for patients with oestrogen receptor-positive tumours (70%) compared to patients with receptor-negative ones (40%). Bone marrow samples collected from 52 patients after high-dose therapy were examined to evaluate the prognostic relevance of isolated tumour cells. The proportion of patients presenting with tumour cell-positive samples did not change in comparison to that observed before high-dose therapy (65% vs 71%), but a decrease in the incidence and concentration of tumour cells was observed over time after high-dose therapy. This finding was true for patients with relapse and for those in remission, which argues against a prognostic significance of isolated tumour cells in bone marrow. In conclusion, sequential high-dose chemotherapy with PBSC support can be safely administered to patients with high-risk stage II/III breast cancer. Further intensification of the therapy, including the addition of non-cross resistant drugs or immunological approaches such as the use of antibodies against HER-2/NEU, may be envisaged for patients with stage III disease and hormone receptor-negative tumours. © 1999 Cancer Research Campaig

The impact of different benefit packages of Medical Financial Assistance Scheme on health service utilization of poor population in Rural China

<p>Abstract</p> <p>Background</p> <p>Since 2003 and 2005, National Pilot Medical Financial Assistance Scheme (MFA) has been implemented in rural and urban areas of China to improve the poorest families' accessibility to health services. Local governments of the pilot areas formulated various benefit packages. Comparative evaluation research on the effect of different benefit packages is urgently needed to provide evidence for improving policy-making of MFA. This study was based on a MFA pilot project, which was one component of Health VIII Project conducted in rural China. This article aimed to compare difference in health services utilization of poor families between two benefit package project areas: H8 towns (package covering inpatient service, some designated preventive and curative health services but without out-patient service reimbursement in Health VIII Project,) and H8SP towns (package extending coverage of target population, covering out- patient services and reducing co-payment rate in Health VIII Supportive Project), and to find out major influencing factors on their services utilization.</p> <p>Methods</p> <p>A cross-sectional survey was conducted in 2004, which used stratified cluster sampling method to select poor families who have been enrolled in MFA scheme in rural areas of ChongQing. All family members of the enrolled households were interviewed. 748 and 1129 respondents from two kinds of project towns participated in the survey. Among them, 625 and 869 respondents were included (age≥15) in the analysis of this study. Two-level linear multilevel model and binomial regressions with a log link were used to assess influencing factors on different response variables measuring service utilization.</p> <p>Results</p> <p>In general, there was no statistical significance in physician visits and hospitalizations among all the respondents between the two kinds of benefit package towns. After adjusting for major confounding factors, poor families in H8SP towns had much higher frequency of MFA use (β = 1.17) and less use of hospitalization service (OR = 0.7 (H8SP/H8), 95%CI (0.5, 1.0)) among all the respondents. While calculating use of hospital services among those who needed, there was significant difference (p = 0.032) in percentage of hospitalization use between H8SP towns (46%) and H8 towns (33%). Meanwhile, the non-use but ought-to-use hospitalization ratio of H8SP (54%) was lower than that of H8 (67 %) towns. This indicated that hospitalization utilizations had improved in H8SP towns among those who needed. Awareness of MFA detailed benefit package and presence of physician diagnosed chronic disease had significant association with frequency of MFA use and hospitalizations. There was no significant difference in rate of borrowing money for illness treatment between the two project areas. Large amount of medical debt had strong association with hospitalization utilization.</p> <p>Conclusions</p> <p>The new extended benefit package implemented in pilot towns significantly increased the poor families' accessibility to MFA package in H8SP than that of H8 towns, which reduced poor families' demand of hospitalization services for their chronic diseases, and improved the poor population's utilization of out-patient services to some degree. It can encourage poor people to use more outpatient services thus reduce their hospitalization need. Presence of chronic disease and hospitalization had strong association with the presence of large amount of medical debt, which indicated that: although establishment of MFA had facilitated accessibility of poor families to this new system, and improved service utilization of poor families to some degree, but its role in reducing poor families' medical debt resulted from chronic disease and hospitalization was still very limited. Besides, the following requirements of MFA: co-payment for in-patient services, ceiling and deductibles for reimbursement, limitations on eligibility for diseases reimbursement, also served as most important obstacles for poor families' access to health care.</p> <p>Therefore, there is great need to improve MFA benefit package design in the future, including extending to cover out-patient services, raising ceiling for reimbursement, removing deductibles of MFA, reducing co-payment rate, and integrating MFA with New Rural Cooperative Medical Scheme more closely so as to provide more protection to the poor families.</p

Predictors of long-term outcome following high-dose chemotherapy in high-risk primary breast cancer

We report on a predictive model of long-term outcome in 114 high-risk breast cancer patients treated with high-dose chemotherapy between 1989 and 1994. Paraffin-blocks from 90 of the 114 primaries were assessed for the presence of five risk factors: grade, mitotic index, protein expression of p53, HER2/neu, and oestrogen/progesterone receptor status; we could analyse the effect of risk factors in 84 of these 90 tumours. Seven-year relapse-free and overall survival was 58% (95% confidence interval 44–74%) and 82% (95% confidence interval 71–94%) vs 33% (95% confidence interval 21–52%) and 41% (95% confidence interval 28–60%) for patients whose primary tumours displayed ⩾3 risk factors vs patients with ⩽2 risk factors. For the entire group of 168 high-risk breast cancer patients, inflammatory stage IIIB disease and involved post-mastectomy margins were associated with decreased relapse-free survival and overall survival; patients treated with non-doxorubicin containing standard adjuvant therapy experienced worse overall survival (RR, 2.08; 95% confidence interval 1.04 to 4.16; P=0.04), while adjuvant tamoxifen improved overall survival (RR, 0.65; 95% confidence interval 0.41–1.01; P=0.054). Future trial designs and patient selection for studies specific for high-risk breast cancer patients should include appropriate prognostic models. Validation of such models could come from recently completed randomised, prospective trials

Yes, I Am Ready Now: Differential Effects of Paced versus Unpaced Mating on Anxiety and Central Oxytocin Release in Female Rats

Sexual activity and partner intimacy results in several positive consequences in the context of stress-coping, both in males and females, such as reduced state anxiety in male rats after successful mating. However, in female rats, mating is a rewarding experience only when the estrous female is able to control sexual interactions, i.e., under paced-mating conditions. Here, we demonstrate that sex-steroid priming required for female mating is anxiolytic; subsequent sexual activity under paced mating conditions did not disrupt this anxiolytic priming effect, whereas mating under unpaced conditions increased anxiety-related behavior. In primed females, the release of the neuropeptide oxytocin (OT) within the hypothalamic paraventricular nucleus was found to be elevated and to further increase during paced, but not unpaced mating. Central administration of an OT receptor antagonist partly prevented priming/mating-induced anxiolysis indicating the involvement of brain OT in the anxiolysis triggered by priming and/or sexual activity