In vitro growth and ovulation of follicles from ovaries of estrogen receptor (ER){alpha} and ER{beta} null mice indicate a role for ER{beta} in follicular maturation

Both estrogen receptor (ER) alpha and beta are expressed within the ovary and lack of either of these receptors affects ovarian function. In this study, the role of ERalpha and ERbeta in folliculogenesis and ovulation was further analyzed. Evaluation of ovarian follicle populations in wild-type and ERbeta knockout (betaERKO) ovaries revealed reduced late antral growth and ovulatory capacity of betaERKO follicles, indicated by reduced numbers of large antral follicles and corpora lutea and increased atresia of large antral follicles. An in vitro culture system was used to study growth, rupture, and luteinization of wild-type, ERalpha knockout (alphaERKO) and betaERKO ovarian follicles. alphaERKO follicles exhibited wild-type-like growth and ovulation rates but an increased capacity to synthesize estradiol. In contrast, betaERKO follicles showed a significant lack of progression from early antral to large antral stage, decreased estradiol production, and reduced ovulation. Expression patterns of several genes involved in follicle maturation and ovulation were analyzed in follicles grown in vitro. Ar, Pgr, and Has2 mRNA expression levels were the same among the three genotypes. However, betaERKO follicles showed reduced expression of Cyp19 mRNA during follicle maturation and reduced Lhcgr and Ptgs2 mRNA expression after human chorionic gonadotropin stimulus. Luteinization occurs normally in alphaERKO and betaERKO follicles, shown by increased progesterone secretion and increased cdkn1b mRNA expression after human chorionic gonadotropin. Collectively, these data indicate that ERbeta, but not ERalpha, plays a direct role in folliculogenesis. ERbeta appears to facilitate follicle maturation from the early antral to the preovulatory stage.     

Contribution of patient and physician factors to cardiac rehabilitation enrollment: a prospective multilevel study

BACKGROUND: Cardiac rehabilitation (CR) is an established means of reducing mortality, yet is grossly underutilized. This is due to both health system and patient-level factors; issues that have yet to be investigated concurrently. This study utilized a hierarchical design to examine physician and patient-level factors affecting verified CR enrollment. DESIGN: A prospective multisite study, using a multilevel design of 1490 coronary artery disease outpatients nested within 97 Ontario cardiology practices (mean 15 per cardiologist). METHODS: Cardiologists completed a survey regarding CR attitudes. Outpatients were surveyed prospectively to assess factors affecting CR enrollment. Patients were mailed a follow-up survey 9 months later to self-report CR enrollment. This was verified with 40 CR sites. RESULTS: Five hundred and fifty (43.4%) outpatients were referred, and 469 (37.0%) enrolled in CR. In mixed logistic regression analyses, factors affecting verified CR enrollment were greater strength of physician endorsement (P=0.005), shorter distance to CR (P=0.001), being married (P=0.01), and fewer perceived CR barriers (P=0.03). CONCLUSION: Both physician and patient factors play a part in CR enrollment. Patient CR barriers should be addressed during referral discussions, and reasons why physicians fail to uniformly endorse CR exploration. Although distance to CR was related to patient enrollment patterns, greater access to home-based CR services should be provided.     

A novel probiotic therapeutic in a murine model of Clostridioides difficile colitis

ABSTRACT

Clostridioides difficile infection (CDI) is a common cause of antimicrobial-associated diarrhea. Probiotics have shown variable results in decreasing its incidence and severity. We examined the efficacy of Lactobacillus reuteri administered using a novel probiotic biofilm delivery system in the treatment and prevention of CDI in a murine model.

For prophylactic therapy, mice received an oral antibiotic cocktail followed by clindamycin injection, followed by probiotic administration (planktonic vs. biofilm state), followed by C. difficile oral gavage. For treatment therapy, mice received antibiotics and C. difficile first, followed by probiotic administration. Clinical sickness scores (CSS) and intestinal histologic injury scores (HIS) were assigned.     

Screening,Treatment, and Prostate Cancer Mortality in the Seattle Area and Connecticut: Fifteen-year Follow-up

Background  Prior to introduction of the prostate-specific antigen (PSA) test, the Seattle–Puget Sound and Connecticut Surveillance, Epidemiology and End Results (SEER) areas had similar prostate cancer mortality rates. Early in the PSA era (1987–1990), men in the Seattle area were screened and treated more intensively for prostate cancer than men in Connecticut. Objective  We previously reported more intensive screening and treatment early in the PSA era did not lower prostate cancer mortality through 11 years and now extend follow-up to 15 years. Design  Natural experiment comparing two fixed population-based cohorts. Subjects  Male Medicare beneficiaries ages 65–79 from the Seattle (N = 94,900) and Connecticut (N = 120,621) SEER areas, followed from 1987–2001. Measurements  Rates of prostate cancer screening; treatment with radical prostatectomy, external beam radiotherapy, and androgen deprivation therapy; and prostate cancer-specific mortality. Main Results  The 15-year cumulative incidences of radical prostatectomy and radiotherapy through 2001 were 2.84% and 6.02%, respectively, for Seattle cohort members, compared to 0.56% and 5.07% for Connecticut cohort members (odds ratio 5.20, 95% confidence interval 3.22 to 8.42 for surgery and odds ratio 1.24, 95% confidence interval 0.98 to 1.58 for radiation). The cumulative incidence of androgen deprivation therapy from 1991–2001 was 4.78% for Seattle compared to 6.13% for Connecticut (odds ratio 0.77, 95% confidence interval 0.67 to 0.87). The adjusted rate ratio of prostate cancer mortality through 2001 was 1.02 (95% C.I. 0.96 to 1.09) in Seattle versus Connecticut. Conclusion  Among men aged 65 or older, more intensive prostate cancer screening early in the PSA era and more intensive treatment particularly with radical prostatectomy over 15 years of follow-up were not associated with lower prostate cancer-specific mortality.     

Comparison of apolipoprotein B metabolism in familial defective apolipoprotein B and heterogeneous familial hypercholesterolemia

Both defective LDL receptors (familial hypercholesterolaemia, FH) and mutations in apolipoprotein B (apoB) on LDL (familial defective apoB, FDB) give rise to a phenotype of elevated LDL cholesterol. We sought to compare the metabolic basis of the two conditions by examining apoB turnover in FDB and FH subjects. A group comprising three heterozygous and one homozygous FDB subjects were compared with five FH heterozygotes and 17 control subjects using a deuterated leucine tracer. Kinetic parameters were derived by multicompartmental modelling. FH heterozygotes had a reduced delipidation rate for VLDL, which led to a moderate increase in plasma triglyceride. Compared with controls and FH, the FDB subjects converted 44% less IDL to LDL. The LDL FCR was reduced to a similar extent in FDB and FH. In all subjects LDL plasma levels appeared to be regulated by the LDL FCR and the rate of production of small VLDL. We conclude that disturbances in IDL metabolism provide the basis for understanding why FDB is less severe than FH. Our findings suggest that an apoB-LDL receptor interaction is important in the IDL to LDL conversion.     

Cardiac presentation of ALK positive anaplastic large cell lymphoma

Cardiac involvement as an initial presentation of malignant lymphoma is a rare occurrence. We report the case of an immunocompetent 29-year-old male who presented with syncope and arrythmias secondary to a ventricular cardiac mass. Transcutaneous cardiac biopsy was non-diagnostic, therefore an open cardiac biopsy was performed from which a provisional diagnosis of a cardiac inflammatory pseudotumour was made. Six months after presentation, he developed several subcutaneous lesions with systemic symptoms. Histological and immunophenotypic review of the initial cardiac biopsy revealed features consistent with a diagnosis of CD30, ALK1 positive anaplastic large cell lymphoma (ALCL). Despite intensive treatment with combination chemotherapy, there was significant progression of disease, and he died 11 months after diagnosis. The overall prognosis of cardiac lymphoma remains poor, which may be due to the often late presentation of the tumour. To our knowledge, this is the first reported case of a cardiac ALK positive ALCL. Although rare, cardiac presentation of ALCL should be added to the list of differential diagnoses of cardiac lymphomas.     

Timing of the maternal drug dose and risk of perinatal HIV transmission in the setting of intrapartum and neonatal single-dose nevirapine

CONTEXT: Single-dose intrapartum and neonatal nevirapine (NVP) reduces perinatal HIV transmission and is in increasingly common use throughout the developing world. OBJECTIVE: We studied risk factors for perinatal transmission in the setting of NVP. DESIGN AND SETTING: A prospective cohort study at two public obstetrical clinics in Lusaka, Zambia. PATIENTS AND METHODS: In a volunteer sample of HIV-infected pregnant women and their newborns, the women received a 200 mg oral dose of NVP at the onset of labor; their infants received 2 mg/kg of NVP syrup within 24 h of birth. The main outcome measure was the infant HIV infection status at 6 weeks of life, determined by DNA polymerase chain reaction. RESULTS: Only 31 of 278 (11.2%) infants were infected at 6 weeks. In logistic regression, viral load exceeding the median [adjusted odds ratio (AOR), 3.1; 95% confidence interval (CI), 1.1-8.7] and 1 h or less elapsing between NVP ingestion and delivery (AOR, 5.0; 95% CI, 1.8-14) were associated with transmission. Women delivering within 1 h of NVP ingestion had a lower mean drug concentration (351 versus 942 ng/ml; P<0.001) and were more likely to have a 'sub-therapeutic' NVP level of less than 100 ng/ml (56 versus 20%; P<0.001) than those who delivered more than 1 h post-ingestion. However, concentrations <100 ng/ml were not more likely to be associated with transmission than concentrations > or = 100 ng/ml (12.9 versus 11.7%; P=0.8). We did not identify a threshold concentration below which risk of transmission increased. CONCLUSIONS: We confirmed low perinatal transmission rates with single-dose NVP. At least 1 h of pre-delivery NVP prophylaxis was a critical threshold for efficacy.     

Angiotensin II-induced non-alcoholic fatty liver disease is mediated by oxidative stress in transgenic TG(mRen2)27(Ren2) rats

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common health problem and includes a spectrum of hepatic steatosis, steatohepatitis and fibrosis. The renin-angiotensin system (RAS) plays a vital role in blood pressure regulation and appears to promote hepatic fibrogenesis. We hypothesized that increased RAS activity causes NAFLD due to increased hepatic oxidative stress. METHODS: We employed the transgenic TG(mRen2)27(Ren2) hypertensive rat, harboring the mouse renin gene with elevated tissue Angiotensin II (Ang II). RESULTS: Compared with normotensive Sprague-Dawley (SD) control rats, Ren2 developed significant hepatic steatosis by 9 weeks of age that progressed to marked steatohepatitis and fibrosis by 12 weeks. These changes were associated with increased levels of hepatic reactive oxygen species (ROS) and lipid peroxidation. Accordingly, 9-week-old Ren2 rats were treated for 3 weeks with valsartan, an angiotensin type 1 receptor blocker, or tempol, a superoxide dismutase/catalase mimetic. Hepatic indices for oxidative stress, steatosis, inflammation and fibrosis were markedly attenuated by both valsartan and tempol treatment. CONCLUSIONS: This study suggests that Ang II causes development and progression of NAFLD in the transgenic Ren2 rat model by increasing hepatic ROS. Our findings also support a potential role of RAS in prevention and treatment of NAFLD.     

Pregnant Women With Negative Alcohol Screens Do Drink Less: A Prospective Study

The authors examined the antepartum alcohol consumption of 100 women with negative alcohol screens as they initiated prenatal care. Subjects completed a comprehensive assessment of their alcohol use at 15.7 ± 4.9 weeks gestation and again 2 months after delivery, with 96% follow-up. The majority (87%) were abstinent in the 90-day period before study enrollment, while pregnant. Moreover, 92% drank no alcohol in the interval between study enrollment and delivery. These results are compared with the antepartum alcohol consumption of 250 women with positive alcohol screens. Routine prenatal screening can efficiently identify those at risk for alcohol consumption in the antepartum.