Characterizing a rat Brca2 knockout model.

Evidence exists that BRCA2 carriers may have an elevated risk of breast, ovarian, colon, prostate, and pancreatic cancer. In general, carriers are defined as individuals with protein truncating mutations within the BRCA2 gene. Many Brca2 knockout lines have been produced and characterized in the mouse. We previously produced a rat Brca2 knockout strain in which there is a nonsense mutation in exon 11 between BRC repeats 2 and 3, and a truncated protein is produced. Interestingly, while such a mutation in homozygous mice would lead to limited survival of approximately 3 months, the Brca2-/- rats are 100% viable and the vast majority live to over 1 year of age. Brca2-/- rats show a phenotype of growth inhibition and sterility in both sexes. Aspermatogenesis in the Brca2-/- rats is due to a failure of homologous chromosome synapsis. Long-term phenotypes include underdeveloped mammary glands, cataract formation and lifespan shortening due to the development of tumors and cancers in multiple organs. The establishment of the rat Brca2 knockout model provides a means to study the role of Brca2 in increasing cancer susceptibility and inducing a novel ocular phenotype not previously associated with this gene.

The Mcs7 quantitative trait locus is associated with an increased susceptibility to mammary cancer in congenic rats and an allele-specific imbalance.

Identification of high-penetrance breast cancer genes such as Brca1 has been accomplished by analysing familial cases. However, these genes occur at low frequency and do not account for the majority of genetic risk. Identification of low-penetrance alleles that occur commonly in populations may benefit from unbiased genome-wide screening. One such approach uses linkage studies in rodent models to identify homologous human candidates. The Wistar Kyoto (WKy) rat is resistant to mammary carcinomas induced with 7,12-dimethybenz[a]anthracene (DMBA), whereas the Wistar Furth (WF) strain is susceptible. Previous genome-wide linkage studies in crosses of these strains identified three WKy resistance quantitative trait loci, Mcs5, Mcs6 and Mcs8, and one predicted to increase susceptibility, Mcs7. The Mcs7 region on rat chromosome 10 (RNO10) is orthologous to human 17q, a common site of genetic aberrations in breast cancer. Here, we establish the independent phenotype conferred by Mcs7 using congenic rats carrying the WKy Mcs7 locus on a WF background. Tumor multiplicity was significantly higher ( approximately 50%) in DMBA-treated congenics homozygous and heterozygous for the WKy allele at the Mcs7 locus, compared to controls. We also investigated allelic imbalance (AI) in mammary carcinomas from (WKy x WF)F1 rats and Mcs7 heterozygous congenics. Of the four known WKy Mcs loci tested, only Mcs7 displayed AI. The pattern of AI in carcinomas from both F1 and Mcs7 congenic rats was similar, suggesting a WF allelic loss. Together, these data suggest that one or more breast cancer-related genes are located within the dominantly acting WKy allele at the Mcs7 locus.

Pharmacologic, but not dietary, genistein supports endometriosis in a rat model.

Endometriosis is a disease in which uterine tissue proliferates in extrauterine sites. Using a surgical model to simulate endometriosis, we explored the potential for the phytoestrogen genistein, by injection and diet, to sustain endometriosis in rats. Uterine tissue was attached to intestinal mesentery of 8-week-old Sprague Dawley rats. After 3 weeks, the rats were ovariectomized and the implants measured. Following 3 weeks of daily injections or exposure to dietary genistein, animals were necropsied and implants located and measured. Injections of genistein (50 and 16.6 microg/g BW) or estrone (1 microg/rat) sustained the implants; injection of sesame oil (vehicle for estrone), dimethylsulfoxide (DMSO; vehicle for genistein), or genistein at 5.0 microg/g BW did not sustain implants. Dietary genistein (250 or 1000 mg genistein/kg AIN-76A diet) did not support the implants. In ovary-intact rats exposed to 250 mg genistein/kg AIN-76A diet, implant size was not altered, compared to control-fed animals. To assess estrogenic actions of genistein, we measured uterine estrogen receptor alpha (ER-alpha) and progesterone receptor (PR) isoforms A and B by Western blot analyses. Injections of estrone or genistein (50 or 16.6 microg/g BW) significantly reduced uterine ER-alpha compared to vehicle-treated animals. PR (B) was significantly increased by all injected doses of genistein or estrone and by the higher dietary dose (1000 mg genistein/kg AIN-76A). PR (A) was significantly increased by injected doses of genistein (16.6 and 5.0 microg/g BW). We conclude that pharmacologic injections, but not dietary physiological concentrations of genistein, support surgically induced endometriosis in rats. Our results suggest a critical role for ER modulation and genistein bioavailability in the maintenance of the implants.

Sex steroid receptor regulation by genistein in the prepubertal rat uterus.

We evaluated the mechanism of action by the phytoestrogen genistein in the prepubertal rat uterus, when administered pharmacologically or physiologically. Female rats were injected with genistein (500 microg/g body weight), estradiol benzoate (EB) (500 ng/g body weight) or vehicle, dimethylsulfoxide (DMSO), on days 16, 18, and 20 postnatal. In 21-day-old rats, both compounds increased circulating estradiol and decreased progesterone concentrations. Uterine estrogen receptor alpha (ER-alpha) and androgen receptor (AR) proteins were reduced, and progesterone receptors (PR) were increased, as measured by western blot analyses. Immunohistochemistry for ER-alpha was confirmatory. Reverse transcription-polymerase chain reaction (RT-PCR) analyses indicated a decrease in ER-alpha, but not in ER-beta, PR and AR mRNA levels following genistein treatment. In prepubertal rats exposed perinatally to 250 mg genistein per kg AIN-76A diet or 250 microg estradiol per kg diet, uterine ER-alpha, AR, and PR proteins were not altered significantly. We conclude that pharmacologic, but not physiologic concentrations of genistein can modulate sex steroid receptor expression in the rat uterus.

Psychiatric-mental health nursing at the interface: revisioning education for the specialty.

In the emerging health care environment, families and communities are facing a broad range of conditions that require more integrated views of wellness and illness, mind and body, and the biomedical and the behavioral. This also calls for an enhanced care delivery system. Three interfacing areas of practice have particular significance for the psychiatric-mental health nursing workforce: enhanced primary care, public health or population-focused health interventions, and managed care. This paper addresses the broad range of knowledge, skills, and competencies that are required for the future of advanced practice psychiatric-mental health nursing and describes interactive learning experiences and new pedagogies to deliver them.

[Suggestions for the health care system of the future: family-oriented primary health care]. / Vorschläge für das Gesundheitssystem der Zukunft: Familienorientierte Primary Health Care.

This paper will describe one of the major trends in health care delivery: family oriented primary care. Implications and future directions for practice, education and research in the United States and Germany will be described and contrasted. The paper is a result of an ongoing dialogue between the first author, a Fulbright Professor at the University of Witten/Herdecke, and the second and third authors. The authors believe that, contextualizing emerging trends in health care delivery in this way, helps to clarify both what is unique to each country and what is actually or potentially shared in common.

Genistein studies in rats: potential for breast cancer prevention and reproductive and developmental toxicity.

Asian women and men who consume a traditional diet high in soy products have low incidences of breast and prostate cancers, respectively. Yet Asians who immigrate to the United States and adopt a Western diet lose this protection. We investigated the potential of genistein, a component of soy, to protect against breast cancer and to cause reproductive and developmental toxicity. Our study showed that injections of genistein in rats during the prepubertal period resulted in a 50% reduction of chemically induced mammary tumorigenesis. Studies in mammary whole mounts revealed that prepubertal genistein exposure resulted in fewer terminal end buds and more lobules type II. Cell proliferation in the terminal end buds of adult rats treated prepubertally with genistein was less than that in animals treated with the vehicle (dimethyl sulfoxide). Reproductive and developmental toxicity studies did not find significant alterations to fertility, number of male and female offspring, body weight, anogenital distance, vaginal opening, testes descent, estrus cycle, or follicular development. We concluded that pharmacologic doses of genistein given to immature rats enhance mammary gland differentiation, resulting in a significantly less proliferative gland that is not as susceptible to mammary cancer. We speculate that breast cancer protection in Asian women consuming traditional soy-containing diets is, in part, derived from early exposure to genistein-containing soy. We believe that early programming events are essential for cancer protection benefits.

Prepubertal genistein treatment modulates TGF-alpha, EGF and EGF-receptor mRNAs and proteins in the rat mammary gland.

We have previously demonstrated that exposure to genistein early in life protects against chemically-induced mammary cancer in rats. To gain insight into the mechanism of action, we have investigated the expression of the EGF-signaling pathway in the mammary glands of 21 and 50 day old rats treated on days 16, 18, and 20 postpartum with 500 microg genistein/g body weight (B.W.) or an equivalent volume of the vehicle, dimethylsulfoxide (DMSO). This prepubertal genistein treatment up-regulated TGF-alpha and the EGF-receptor (EGFR), but not EGF, in mammary terminal ductal structures at day 21 postpartum. TGF-alpha, EGF and EGFR mRNA levels were similar in 21 day old control- and genistein-treated animals. At day 50 postpartum, mammary glands of genistein treated rats had more lobules and fewer terminal end buds (TEBs) and terminal ducts (TDs), i.e. they were more differentiated. TGF-alpha mRNA levels were down-regulated in TEB of proestrous and estrous females; EGF mRNA levels were down-regulated in TDs of proestrous, but not in estrous females; and EGFR mRNA levels were not altered in 50 day old proestrous or estrous female rats. EGFR immunostaining intensity was decreased in TEBs, but not in the total gland. EGF was increased in TEBs and TDs. TGF-alpha, EGF and EGFR were also observed in the stroma and fat pad, but genistein treatment did not alter the expression of these proteins in those locations. TGF-alpha, but not EGF and EGFR, immunostaining was observed in cell nuclei (not modulated by genistein), suggesting that this growth factor may act directly on nuclear events such as transcription and DNA replication. For comparative purposes, prepubertal diethylstilbestrol treatment was investigated and found to decrease EGFR immunostaining intensity and total IHC staining in all terminal ductal structures. We conclude that prepubertal genistein treatment directly stimulates TGF-alpha and EGFR to enhance mammary gland differentiation. This programs the differentiated cells for a down-regulated EGF-signaling pathway in TEBs and TDs of adult mammary glands. Reduced EGFR expression at time of carcinogen exposure may account for genistein programming against mammary cancer.

Advanced practice psychiatric-mental health nursing in a community-based nurse-managed primary care program.

In the evolving health care environment, advanced practice opportunities for psychiatric-mental health nurses may lie in managed care models of community oriented primary health care. As providers, care managers, health promoters and educators, and client advocates with family systems expertise, psychiatric-mental health advanced practice specialists are a necessary component of all primary health care. This article describes the development of a community-based primary care practice that integrates physical and mental health care on the same site.

Integrated primary health care. Opportunities for psychiatric-mental health nurses in a reforming health care system.

As changes in our health care system evolve, making the transition to greater parity of mental and physical health is paramount to move health care in the direction of prevention and health promotion. Although parity is the goal, the most feasible path to reaching it may lie in relinking mental health to physical health in managed care models of primary health care. This article identifies emerging directions in the mental health field and points to new opportunities for advancing the practice of psychiatric-mental health nurses.

Differences in bereavement reactions within couples following death of a child.

Differences in distress within couples who have experienced the sudden death of a child were examined. Results from two independent samples (N = 50 couples and N = 60 couples) were compared. The SCL-90-R and the BSI were used to measure global psychological distress and distress in nine symptom dimensions. Paired t tests revealed similar findings in the two samples: Within couples, women had significantly greater global distress than men and significantly greater distress than men in most symptom dimensions. Hostility scores within couples were similar and indicated a high level of hostility. The findings may explain relational problems observed within bereaved couples. Interventions designed to help couples cope with their differences and their hostility may decrease relational problems.

Uses and implications of the contextual approach to child custody decisions.

Child custody litigation signals parental conflicts that have serious implications for a child's long-term development. The authors describe a family systems approach to child custody decision making--the contextual approach, derived from contextual family theory. A case study analysis and pilot study illustrate the use of the approach with a small group of families who turn to the legal system to resolve custody or visitation disputes. The findings suggest the approach's usefulness in helping families create alternatives to continued disputation. The findings also reinforce the need for further research to test the preventive potential of the approach in reducing returns to court.

Pharmacokinetics and pharmacodynamics of ritodrine after intramuscular administration to pregnant women.

To define the pharmacokinetics and pharmacodynamics of ritodrine after intramuscular injection, we administered 5 or 10 mg ritodrine into the gluteus or deltoid muscles of 12 pregnant volunteers. Six women received 5 mg and six received 10 mg into each muscle group on different days. We withdrew blood samples before and 12 times in the 6 hours after ritodrine injection. Blood pressure and heart rate were recorded at each time. Ritodrine was measured by high-performance liquid chromatography. Peak ritodrine concentrations (mean +/- SD) after a single 5 mg injection in the deltoid or gluteus were 38 +/- 13 and 26 +/- 8 ng/ml, respectively. After a 10 mg dose in the deltoid or gluteus, peak concentrations were 59 +/- 30 and 47 +/- 22 ng/ml, respectively. Although higher, the peak plasma concentrations after injections into the deltoid were not significantly greater than those after injection into the gluteus. None of the pharmacokinetic parameters differed according to dose or injection site. The pharmacodynamic effects of ritodrine were unaffected by injection site, but ritodrine caused a dose-related increase in heart rate and systolic blood pressure and a dose-related decrease in diastolic blood pressure. After a 10 mg injection, the maximal changes in heart rate, systolic, and diastolic blood pressure were 22%, 10%, and 19%, respectively. However, mean blood pressure was not altered by either the 5 or 10 mg dose. These findings indicate that there are few differences in pharmacokinetic parameters between deltoid and gluteal injection of ritodrine. The single intramuscular injection of 5 or 10 mg ritodrine results in labor-inhibiting concentrations with clinically insignificant cardiovascular effects.

Pharmacokinetics of orally administered ritodrine.

The oral dosing regimen for ritodrine was based in large part on kinetic data obtained in nonpregnant subjects. There are limited kinetic data after oral administration of ritodrine in pregnancy. The purpose of the present study was to compare ritodrine kinetics in pregnant and nonpregnant women, evaluate the effect of feeding on ritodrine absorption in pregnant women, and determine if the plasma concentration of ritodrine is proportional to the dose administered in nonpregnant women. Plasma concentrations after a single 20 mg dose of ritodrine were significantly greater in fasting nonpregnant women than in fasting pregnant women. The area under the concentration time curve was 1372 +/- 385 and 1001 +/- 257 ng/ml/min, respectively. In pregnant women ingesting 20 mg of ritodrine, plasma concentrations were not significantly different in the fed or fasted state; plasma concentrations peaked at 11 ng/ml and were less than 3 ng/ml within 4 hours. In nonpregnant subjects the concentration of ritodrine in plasma was proportional to the dose. After ingestion of 10, 20, or 30 mg of ritodrine, the area under the curve was 751 +/- 253, 1372 +/- 385, and 2148 +/- 571 ng/ml/min, respectively. These data indicate that ritodrine concentrations in pregnant women after a 20 mg oral dose are low. Increases in dosage will probably result in proportional increases in plasma concentration. The maximal dose of ritodrine recommended for prevention of recurrent preterm labor should be increased.

All real living is meeting: the task of international education in a nursing curriculum.

Our experience suggests two significant benefits of shaping an international education focus in a nursing curriculum. First, a genuine understanding and appreciation of a foreign health care system is strengthened by identification of and confrontation with the socio-political context in which it is embedded. The second, and perhaps most fundamental benefit, is not so easy to verbalize. This involves the participant's personal confrontation with another culture. What is external, the experience of a foreign culture, translates into an encounter with the foreign territory of one's own thinking. The participant is challenged to overcome the traditional limitations of professional discipline, experience and vision and to move toward notions of world community and human solidarity. It seems to us that the development of concepts, resources and methods to move American nursing in the direction of greater solidarity with the world health care community is a legitimate task for nursing education.

A study of abortion and problems in decision-making.

PIP: This paper is directed to those individuals who are sufficiently disturbed by the complex realities of problem pregnancies and who are prepared to think beyond the confines of ideology. Rigid ideological positions tend to create distance from the hard complexities surrounding concrete human situations and to limit the realities of pain and helplessness that may exist for each of the parties to an unwanted pregnancy. Pregnancy is more than a biological condition or an isolated emotional entity giving rise to joy or grief. Pregnancy introduces a new relational component to an already existing relational network, and, conversely, abortion is neither simply the evacuation of the products of conception nor an endpoint to emotional stress. It is, in actuality, a broken relationship. In the clinical experience of these authors a sense of sadness frequently accompanies a woman's choice to undergo an abortion. Some problem pregnancy counselors maintain that they have never known a woman who terminated pregnancy without sadness. This information reinforces these authors' observations that facing a decision to have an abortion is not easy, often stressful, and an occasion when a woman should feel entitled to obtain the help of her total relationship system in arriving at a decision. The decision to continue or to terminate a problem pregnancy is rooted in a complex network of relationship factors that have an effect on the decision-making process. Repeated occurrences of unwanted pregnancies in the family are more than individual and disconnected events. Relational strategies that effect decision-making in problem pregnancies are effective in the hands of helping agents who value conjoint, intergenerational reciprocity as a therapeutic paradigm.^ieng