Placental Protein Distribution in Maternal Diabetes Mellitus: An Immunocytochemical Study

Placentas associated with maternal diabetes are generally characterized by features of villous immaturity. We correlated the villous histology with the immunocytochemical distribution of four trophoblastic proteins: beta human chorionic gonadotropin (beta HCG), placental alkaline phosphatase (PLAP), pregnancy specific beta-1-glycoprotein (SP1), and human placental lactogen (HPL) in 14 third-trimester placentas associated with diabetes mellitus. Staining was increased for beta HCG and decreased for PLAP, SP1, and HPL in the diabetic placentas compared to control placentas of similar gestational age. This pattern was most prominent in areas of marked architectural villous immaturity within individual placentas and suggests concomitant functional immaturity.     

Self-reported sleep in postmenopausal women

OBJECTIVE: We aimed to find how self-reported sleep (measured by the St. Mary's Hospital Sleep Questionnaire) in postmenopausal women having hot flash activity was related to objective sleep (actigraphy), psychological and somatic symptoms [Women's Health Questionnaire (WHQ)], and cognitive test performance (computerized tests). A secondary aim was to find if self-reported sleep showed expected correlations with hyperarousal (Hyperarousal Scale). DESIGN: Drug trial baseline data from 88 healthy, postmenopausal women were retrospectively analyzed. Multivariate regression was used to adjust for confounder variables and test whether differences in self-reported sleep measures were systematically associated with differences in objective sleep, WHQ symptom measures, or cognitive test performance scores. RESULTS: Increased self-report scores for low sleep quality were associated with an increased risk of WHQ symptoms and reduced cognitive test performance. Self-reported sleep measures showed little correlation with their analogous objective measures. Self-reported low sleep quality proved most closely associated with the WHQ symptoms of tiredness, clumsiness, and difficulty concentrating. Women whose self-reported sleep-onset latency times were longer than the median overestimated their objective sleep onset time by 30 min, whereas the other women underestimated theirs by 15 min (P < 0.0001). Women whose self-reported total sleep was longer or shorter than the median, respectively, underestimated objective sleep times by 9 and 71 min (P < 0.0001). High hyperarousal scores were associated with underestimations of objective sleep. CONCLUSION: Self-reports of lower sleep quality were associated with increased WHQ psychological and somatic symptom measures and decreased cognitive test performance more than with differences in objective sleep. Self-reported trouble sleeping may signal problems independent from objectively low sleep quality, such as subjective distress or diminished cognitive function.     

Can autophagy protect against neurodegeneration caused by aggregate-prone proteins?

Protein conformation disorders or proteinopathies are a growing family of human diseases that are characterized by the accumulation of proteins in intracellular aggregates (also known as inclusions) in specific tissues/organs. The role of aggregates in these diseases has been a subject of vigorous debate. However, irrespective of the nature(s) of the toxic species, it is desirable for cells to be able to control the levels of these toxic proteins and restrict their accumulation. Here we discuss how the autophagy-lysosome pathway may regulate protein clearance in some of the protein conformation disorders and why this pathway may represent a possible therapeutic target in such conditions.     

Breastfeeding practices in a cohort of inner-city women: the role of contraindications

Background  

Little is known about the role of breastfeeding contraindications in breastfeeding practices. Our objectives were to 1) identify predictors of breastfeeding initiation and duration among a cohort of predominately low-income, inner-city women, and 2) evaluate the contribution of breastfeeding contraindications to breastfeeding practices.     

The pharmacokinetics of toborinone in subjects with congestive heart failure and concomitant renal impairment and/or concomitant hepatic impairment

The pharmacokinetics of toborinone was studied in subjects with congestive heart failure (CHF) and concomitant renal and/or hepatic disease. At the time of admission, subjects were grouped based on estimated creatinine clearance and serum bilirubin. Glomerular filtration rate was assessed using iothalamate clearance. Hepatic function was assessed using the caffeine metabolism test and indocyanine green clearance. No significant differences were observed in mean toborinone pharmacokinetic parameters among the four study groups. Positive correlations were observed between toborinone clearance and the measured indices of renal and hepatic function: creatinine clearance, iothalamate renal clearance, paraxanthine/caffeine ratio, and indocyanine green clearance. Toborinone clearance decreased with decreasing creatinine clearance, decreasing glomerular filtration rate, decreasing demethylation metabolic activity, and decreasing hepatic bloodflow, although no significant differences were observed in any mean toborinone pharmacokinetic parameters evaluated among the four study groups.     

The effects of concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6

This study investigated the effects of the concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6. In period 1, a single dose of 3.5 mg/kg theophylline was administered orally. In period 2, a single dose of 1.0 microg/kg/min toborinone was infused over 6 hours. In period 3, 3.5 mg/kg theophylline was coadministered with 1.0 microg/kg/min toborinone. Serial blood and pooled urine samples were collected before and after toborinone administration for the quantification of toborinone and its metabolites in plasma and urine. Serial blood samples were collected before and after theophylline administration for the quantification of theophylline and its metabolites in plasma. No significant differences were observed in toborinone pharmacokinetics between poor and extensive metabolizers via CYP2D6. Toborinone coadministration with theophylline did not result in a substantive effect on the disposition of theophylline and vice versa.     

STX6 rs1411478 is not associated with increased risk of Parkinson's disease

A variant in Syntaxin 6 (a soluble N-ethylmaleimide-sensitive factor attachment protein receptor STX6) (rs1411478) has been shown to be associated with progressive supranuclear palsy (PSP). Although Parkinson's disease (PD) and PSP are distinct neurodegenerative diseases, they share some clinical and genetic features. In this study, we evaluated STX6 genetic variability in PD susceptibility in ethnically matched case–control series from Canada, Norway, Taiwan and Tunisia and we evaluated the presence of pathogenic mutations within families. No pathogenic mutations were found in STX6. Similarly, statistical analysis of rs1411478 failed to identify differences in genotype or allelic frequencies between cases and controls. Our results do not support a role for STX6 in PD.     

Two distinct forms of the 64,000 Mr protein of the cleavage stimulation factor are expressed in mouse male germ cells

Polyadenylation in male germ cells differs from that in somatic cells. Many germ cell mRNAs do not contain the canonical AAUAAA in their 3' ends but are efficiently polyadenylated. To determine whether the 64,000 Mr protein of the cleavage stimulation factor (CstF-64) is altered in male germ cells, we examined its expression in mouse testis. In addition to the 64,000 Mr form, we found a related approximately 70,000 Mr protein that is abundant in testis, at low levels in brain, and undetectable in all other tissues examined. Expression of the approximately 70,000 Mr CstF-64 was limited to meiotic spermatocytes and postmeiotic spermatids in testis. In contrast, the 64,000 Mr form was absent from spermatocytes, suggesting that the testis-specific CstF-64 might control expression of meiosis-specific genes. To determine why the 64,000 Mr CstF-64 is not expressed in spermatocytes, we mapped its chromosomal location to the X chromosome in both mouse and human. CstF-64 may, therefore, be absent in spermatocytes because the X chromosome is inactivated during male meiosis. By extension, the testis-specific CstF-64 may be expressed from an autosomal homolog of the X chromosomal gene.     

Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose–response analysis

PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose–response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. The Disease Activity Score 28-4 calculated using C-Reactive Protein (DAS28-4 CRP) was the efficacy endpoint utilized in this dose–response model. For DAGR, the maximum effect (Emax) on DAS28-4 CRP was estimated to be ?1.2 points (95 % CI ?1.7, ?0.84), and the evaluated dose range provided 31–87 % of the Emax; for prednisone 5 and 10 mg, the estimated effects were ?0.27 (95 % CI ?0.55, 0.006) and ?0.94 point (95 % CI ?1.3, ?0.59), respectively. Stochastic simulations indicated that the DAGR 1, 5, 10 and 15 mg have probabilities of 0.9, 29, 54 and 62 %, respectively, to achieve efficacy greater than prednisone 10 mg at week 8. DAGR 9 mg estimated probability was 50 % suggesting that DAGR ≥9 mg QD has an effect on DAS28-4 CRP comparable to or greater than prednisone 10 mg QD. This work informs dose selection for late-stage confirmatory trials.