Neonatal Androgenization Exacerbates Alcohol-Induced Liver Injury in Adult Rats, an Effect Abrogated by Estrogen

Alcoholic liver disease (ALD) affects millions of people worldwide and is a major cause of morbidity and mortality. However, fewer than 10% of heavy drinkers progress to later stages of injury, suggesting other factors in ALD development, including environmental exposures and genetics. Females display greater susceptibility to the early damaging effects of ethanol. Estrogen (E2) and ethanol metabolizing enzymes (cytochrome P450, CYP450) are implicated in sex differences of ALD. Sex steroid hormones are developmentally regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which controls sex-specific cycling of gonadal steroid production and expression of hepatic enzymes. The aim of this study was to determine if early postnatal inhibition of adult cyclic E2 alters ethanol metabolizing enzyme expression contributing to the development of ALD in adulthood. An androgenized rat model was used to inhibit cyclic E2 production. Control females (Ctrl), androgenized females (Andro) and Andro females with E2 implants were administered either an ethanol or isocalorically-matched control Lieber-DeCarli diet for four weeks and liver injury and CYP450 expression assessed. Androgenization exacerbated the deleterious effects of ethanol demonstrated by increased steatosis, lipid peroxidation, profibrotic gene expression and decreased antioxidant defenses compared to Ctrl. Additionally, CYP2E1 expression was down-regulated in Andro animals on both diets. No change was observed in CYP1A2 protein expression. Further, continuous exogenous administration of E2 to Andro in adulthood attenuated these effects, suggesting that E2 has protective effects in the androgenized animal. Therefore, early postnatal inhibition of cyclic E2 modulates development and progression of ALD in adulthood

A Computer Model for the Hydraulic Analysis of Open Channel Cross Sections

Irrigation and hydraulic engineers are often faced with the difficulty of tedious trial solutions of the Manning equation to determine the various geometric elements of open channels. This paper addresses the development of a computer model for the design of the most commonly used channel-sections. The developed model is intended as an educational tool. It may be applied to the hydraulic design of trapezoidal , rectangular, triangular, parabolic, round-concered rectangular, and circular cross sections. Two procedures were utilized for the solution of the encountered implicit equations; the Newton-Raphson and the Regula-Falsi methods.  In order to initiate the solution process , these methods require one and two initial guesses, respectively. Tge result revealed that the Regula-Flasi method required more iterations to coverage to the solution compared to the Newton-Raphson method, irrespective of the nearness of the initial guess to the actual solution. The average number of iterations for the Regula-Falsi method was approximately three times that of the Newton-Raphson method

A Computer Model for the Hydraulic Analysis of Open Channel Cross Sections

Irrigation and hydraulic engineers are often faced with the difficulty of tedious trial solutions of the Manning equation to determine the various geometric elements of open channels. This paper addresses the development of a computer model for the design of the most commonly used channel-sections. The developed model is intended as an educational tool. It may be applied to the hydraulic design of trapezoidal , rectangular, triangular, parabolic, round-concered rectangular, and circular cross sections. Two procedures were utilized for the solution of the encountered implicit equations; the Newton-Raphson and the Regula-Falsi methods.  In order to initiate the solution process , these methods require one and two initial guesses, respectively. Tge result revealed that the Regula-Flasi method required more iterations to coverage to the solution compared to the Newton-Raphson method, irrespective of the nearness of the initial guess to the actual solution. The average number of iterations for the Regula-Falsi method was approximately three times that of the Newton-Raphson method

The effect of estradiol on granulosa cell responses to FSH in women with polycystic ovary syndrome.

BackgroundThe influence of estradiol (E2) on granulosa cell (GC) function has not been tested clinically in women with polycystic ovary syndrome (PCOS). The objective of this study is to determine if E2 influences GC responses to FSH in women with PCOS.MethodsThis is a two phase, single cohort study conducted over a 2-year period at a single academic center. Nine women with PCOS according to NIH criteria. In Phase 1, FSH stimulation of GC responses as measured by E2 and Inhibin B (Inh B) were assessed before and at 5 and 6 weeks after GnRH agonist administration. In Phase 2, the same protocol was employed with the addition of an aromatase inhibitor (letrozole, LET) administered daily beginning at week 4 for 2 weeks.ResultsIn Phase 1, recovery of FSH, E2 and Inh B from ovarian suppression occurred at 5 and 6 weeks after GnRH agonist injection and preceded resumption of LH and androgen secretion. In Phase 2, hormone recovery after GnRH agonist was characterized by elevated FSH and suppressed E2 levels whereas recovery of LH and androgen levels were unchanged. In Phase 1, FSH stimulated E2 and Inh B responses were unaltered during recovery from ovarian suppression. In Phase 2, E2 and Inh B fold changes after FSH were significantly reduced at weeks 5 (p < 0.04) and 6 (p < 0.01), respectively.ConclusionIn anovulatory women with PCOS, chronic, unopposed E2 secretion may contribute, at least in part, to enhanced ovarian responsiveness to FSH.Trial registrationNCT02389088

Comparing febrile children presenting on and off antibiotics to the emergency department: a retrospective cohort study.

BACKGROUND: It is not yet known how antibiotics may affect Serious Bacterial Infections (SBI). Our aim is to describe the presentation, management, and serious bacterial infections (SBI) of febrile children on or off antibiotics. METHODS: Retrospective, cohort study of febrile Emergency Department patients, 0-36 months of age, at a single institution, between 2009 and 2012. RESULTS: Seven hundred fifty-three patients were included: 584 in the No-Antibiotics group and 169 (22%) in the Antibiotics group. Age and abnormal lung sounds were predictors for being on antibiotics (OR 2.00 [95% CI 1.23-3.25] and OR 1.04 [95% CI 1.02-1.06] respectively) while female gender, and lower temperatures were negative predictors (OR 0.68 [95%0.47-0.98] and OR 0.47 [95% CI 0.32-0.67] respectively). Antibiotics were prescribed by a physician 89% of the time; the most common one being Amoxicillin/Clavulanic Acid (39%). The antibiotic group got more blood tests (57% vs 45%) and Chest X-Rays (37% vs 25%). Overall, the percent of SBIs (and pneumonias) was statistically the same in both groups (6.5% in the No-antibiotic group VS 3.6%). CONCLUSIONS: Children presenting on antibiotics and off antibiotics were significantly different in their presentation and management, although the overall percentages of SBI were similar in each group. Further investigations into this subgroup of febrile children are needed

Decreased inhibin B responses following recombinant human chorionic gonadotropin administration in normal women and women with polycystic ovary syndrome.

ObjectiveTo determine whether granulosa cells contribute to excess androgen production, by assessing inhibin B (Inh B) responses to hCG in women with polycystic ovary syndrome (PCOS) and in normal women.DesignProspective study.SettingAcademic medical center.Patient(s)Twenty women with PCOS and 16 normal women.Intervention(s)Blood samples obtained before and 24 hours after injection of 25 μg recombinant hCG (r-hCG).Main outcome measure(s)Basal and stimulated Inh B, E2, androstenedione (A), and T responses after r-hCG administration.Result(s)In normal and PCOS women, r-hCG induced a significant reduction of Inh B levels. Lowered Inh B responses were not related to body mass index, PCOS status, or age by multivariate regression. Recombinant hCG significantly increased serum A and E2 in both normal and PCOS women.Conclusion(s)In normal and PCOS women, Inh B production was decreased following r-hCG administration. These findings strongly suggest that in PCOS women androgen excess is not enhanced by LH-stimulated Inh B production.Clinical trial registration numberNCT00747617

Decreased inhibin B responses following recombinant human chorionic gonadotropin administration in normal women and women with polycystic ovary syndrome.

ObjectiveTo determine whether granulosa cells contribute to excess androgen production, by assessing inhibin B (Inh B) responses to hCG in women with polycystic ovary syndrome (PCOS) and in normal women.DesignProspective study.SettingAcademic medical center.Patient(s)Twenty women with PCOS and 16 normal women.Intervention(s)Blood samples obtained before and 24 hours after injection of 25 μg recombinant hCG (r-hCG).Main outcome measure(s)Basal and stimulated Inh B, E2, androstenedione (A), and T responses after r-hCG administration.Result(s)In normal and PCOS women, r-hCG induced a significant reduction of Inh B levels. Lowered Inh B responses were not related to body mass index, PCOS status, or age by multivariate regression. Recombinant hCG significantly increased serum A and E2 in both normal and PCOS women.Conclusion(s)In normal and PCOS women, Inh B production was decreased following r-hCG administration. These findings strongly suggest that in PCOS women androgen excess is not enhanced by LH-stimulated Inh B production.Clinical trial registration numberNCT00747617

Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following experimental demyelination.

Chronic demyelination in the human CNS is characterized by an inhibitory microenvironment that impairs recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) leading to failed remyelination and axonal atrophy. By network-based transcriptomics, we identified sulfatase 2 (Sulf2) mRNA in activated human primary OPCs. Sulf2, an extracellular endosulfatase, modulates the signaling microenvironment by editing the pattern of sulfation on heparan sulfate proteoglycans. We found that Sulf2 was increased in demyelinating lesions in multiple sclerosis and was actively secreted by human OPCs. In experimental demyelination, elevated OPC Sulf1/2 expression directly impaired progenitor recruitment and subsequent generation of oligodendrocytes thereby limiting remyelination. Sulf1/2 potentiates the inhibitory microenvironment by promoting BMP and WNT signaling in OPCs. Importantly, pharmacological sulfatase inhibition using PI-88 accelerated oligodendrocyte recruitment and remyelination by blocking OPC-expressed sulfatases. Our findings define an important inhibitory role of Sulf1/2 and highlight the potential for modulation of the heparanome in the treatment of chronic demyelinating disease

Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia

SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell-autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters, SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (ORs) and of their signaling components. This non-cell-autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond