Increased hepatobiliary clearance of unconjugated thyroxine determines DMP 904-induced alterations in thyroid hormone homeostasis in rats.

4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine (DMP 904) is a potent and selective antagonist of corticotropin releasing factor receptor-1 (CRF1 receptor) with an efficacious anxiolytic profile in preclinical animal models. In subchronic toxicity studies in Sprague-Dawley rats, DMP 904 produced thyroid follicular cell hypertrophy and hyperplasia, and a low incidence of follicular cell adenoma. The current investigations were designed to determine the mode of action by which DMP 904 disrupts thyroid homeostasis in male rats. Five-day treatment with DMP 904 (300 mg/kg/day) dramatically lowered serum thyroxine (T4) to levels below detectable limits (< 1 microg/dl) by 72 h, with concurrent decreases in triiodothyronine (T3, about a 70% decrease) and increases in thyroid stimulating hormone (TSH; about a three-fold increase). DMP 904 increased [125I]T4 total body clearance (Cl tb) (38.21 +/- 10.45 ml/h) compared to control (5.61 +/- 0.59 ml/h) and phenobarbital-treated rats (7.92 +/- 1.62 ml/h). This increase in Cl(tb) was associated with a significant increase in biliary clearance (Cl bile) of unconjugated [125I]T4 (nearly 80-times control rates) and increased liver:blood ratios of T4, suggestive of enhanced hepatic uptake of T4. A single dose of DMP 904 (200 mg/kg) increased mRNA levels of hepatic cytochrome P450s (CYP 3A1 and CYP 2B1) and UDP-glucuronosyltransferases (UGT 1A1 and UGT 1A2). DMP 904 also induced mRNAs of the canalicular transporter, multi-drug resistance protein-2 (Mrp2) and sinusoidal transporters, organic anion transporting proteins (Oatp1 and Oatp2) within 24 h. Western blot analysis confirmed DMP 904 related increases in Oatp2 protein expression. Collectively, these data suggest that DMP 904 is an agonist of the constitutive androstane receptor (CAR) and pregnane X receptor (PXR) and that the decreased serum levels of T4 and T3 resulted from increased hepatobiliary clearance. However, DMP 904 is distinguished from other compounds associated with similar effects on thyroid hormone homeostasis because its effects were primarily related to increased biliary excretion of unconjugated T4.     

Incidence and prognostic impact of amenorrhea during adjuvant therapy in high-risk premenopausal breast cancer: analysis of a National Cancer Institute of Canada Clinical Trials Group Study--NCIC CTG MA.5.

PURPOSE: To investigate the therapeutic impact of chemotherapy-induced amenorrhea in premenopausal patients with breast cancer. PATIENTS AND METHODS: We conducted a retrospective cohort study of a National Cancer Institute of Canada Clinical Trials Group phase III trial involving premenopausal patients randomized to receive cyclophosphamide, methotrexate, and fluorouracil (CMF), versus intensive cyclophosphamide, epirubicin, and fluorouracil (CEF). The objectives of our study were to describe the incidence of amenorrhea at 6 and 12 months post-random assignment and to determine the association of amenorrhea with relapse-free and overall survival. RESULTS: Data on 442 patients were used in our analyses. Despite the higher cumulative dose of cyclophosphamide in the CMF treatment arm, at 6 months post-random assignment, the rate of amenorrhea was higher in the CEF group (relative risk, 1.2; 95% CI, 1.0 to 1.3), with no difference at 12 months. In the receptor-positive subgroup, 6-month amenorrhea rates were not associated with prognosis. In contrast, amenorrhea at 12 months was significantly associated with relapse-free survival (hazard ratio, 0.51; 95% CI, 0.32 to 0.82; P = .005) and overall survival (hazard ratio, 0.40; 95% CI, 0.22 to 0.72; P = .002). CONCLUSION: Late chemotherapy-induced amenorrhea seems to be associated with improved outcome in patients with premenopausal, receptor-positive breast cancer.     

Modified Delphi Study on Nursing Practice and Science in Fetal Care

ObjectiveTo identify essential structures, processes, outcomes, and challenges of nursing practice in fetal care and to identify research priorities for nurses in fetal care.DesignWe used a modified Delphi method to achieve consensus.SettingA secure online survey platform.ParticipantsThe expert panel included nurses from the Fetal Therapy Nurse Network. In addition, a multidisciplinary research jury included members of the North American Fetal Therapy Network (NAFTNet).MethodsWe collected data in three consecutive rounds with online questionnaires that were e-mailed to panelists. We used content analysis to generate statements from an initial round of open-ended questions. Statements met consensus if 75% of the panelists ranked it as greater than or equal to 6 on a 1-to-7 Likert scale.ResultsThe 48 nurse panelists and 11 multidisciplinary jury members described a range of nursing processes. Consensus was reached on 96 statements related to the structure, processes, outcomes, and research priorities of nurses in fetal care.ConclusionThe participants agreed that an expert fetal care nursing team is necessary to provide care to women and families during fetal diagnosis and treatment. Ideally, these nurses should coordinate care and provide direct clinical care (e.g., patient counseling) in outpatient prenatal settings and inpatient settings when fetal surgery is involved. Nurses should be supported to take on leadership roles in program development, research, quality improvement, and professional development with relevant professional organizations.     

Aortic dilation, dissection, and rupture in patients with Turner syndrome

We report two patients with Turner syndrome who had aortic dissection and rupture, one with prior repair of coarctation. We also note the high incidence (8.8%) of unrecognized aortic root dilation in a group of 57 patients with Turner syndrome whom we prospectively evaluated by echocardiography. Our analysis and review of previously reported cases suggests that multiple risk factors may exist for aortic dissection, including coarctation, bicuspid aortic valve, and systemic hypertension, but that these need not be present. Aortic root dilation may be an additional finding that suggests the patient with Turner syndrome is also at risk. When it is present, magnetic resonance imaging visualizes the entire aorta and allows quantification of the site and degree of dilation. In patients with dissection, the aorta often exhibits pathologic evidence of cystic medial necrosis similar to the finding in patients with Marfan syndrome. Therapeutic methods to decrease risk, such as those directed toward prevention of bacterial endocarditis, blood pressure control, and perhaps prophylactic beta blockade or surgical reconstruction, may need to be considered. Patients with Turner syndrome, their families, and the physicians who care for them should be aware of the significance of unexplained chest pain, dyspnea, or hypotension as potential manifestations of aortic dissection or rupture.     

Is modified vestibulectomy for localized provoked vulvodynia an effective long-term treatment? A follow-up study

OBJECTIVE: To determine whether vestibulectomy is an effective long-term treatment and investigate the levels of patient satisfaction in women with localized provoked vulvodynia, and to provide long-term follow-up data from a cohort of women whose short-term success rates have been published previously. STUDY DESIGN: A retrospective case note review of 110 women with localized provoked vulvodynia and follow-up patient questionnaire. Patients were asked to quantify their pain scores before surgery, at 2 months after surgery and 1 year after surgery and score their satisfaction levels. RESULTS: Mean pain scores continued to improve throughout the first postoperative year. The mean score was 9.17 preoperatively, 5.24 at 2 months after surgery and 2.48 at 1 year after surgery. Eighty-three percent of patients would recommend the procedure as effective treatment of localized provoked vulvodynia. The overall mean satisfaction score was 7.96, and long-term success appears to be reflected by short-term results. CONCLUSION: Vestibulectomy is an effective long-term treatment for women with provoked localized vulvodynia; the procedure is associated with high levels of patient satisfaction and low complication rates. Shortterm success appears to be a good indicator of long-term improvement, and improve- ment continues throughout the first postoperative year.