Investigational synthetic neuroactive steroid zuranolone in treatment of major depressive disorder with peripartum onset

Major depressive disorder with peripartum onset or peripartum depression is a common condition experienced by a large proportion of women and to some extent even in men. The current treatment strategies involve the use of conventional pharmacotherapeutic classes of drugs like selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) and psychotherapy methods in the management of this condition. In this article, we try to review and evaluate the pathophysiology of the condition along with the safety and efficacy of the novel investigational therapeutic drug zuranolone, which is a synthetic neuroactive steroid (NAS) that has shown promise in clinical trials for the management of conditions like major depressive disorder, peripartum depression and bipolar disorder. The synthetic NAS zuranolone is an orally bioavailable positive allosteric modulator of the gamma amino butyric acid (GABAA) receptor, which can regulate the action of the GABAergic pathway implicated in many depressive episodes and also affect the normal functioning of the hypothalmo pituitary-adrenal (HPA) axis which is the core pathophysiological cause behind major depressive disorder with peripartum onset

Development of the NASA/FLAGRO computer program for analysis of airframe structures

The NASA/FLAGRO (NASGRO) computer program was developed for fracture control analysis of space hardware and is currently the standard computer code in NASA, the U.S. Air Force, and the European Agency (ESA) for this purpose. The significant attributes of the NASGRO program are the numerous crack case solutions, the large materials file, the improved growth rate equation based on crack closure theory, and the user-friendly promptive input features. In support of the National Aging Aircraft Research Program (NAARP); NASGRO is being further developed to provide advanced state-of-the-art capability for damage tolerance and crack growth analysis of aircraft structural problems, including mechanical systems and engines. The project currently involves a cooperative development effort by NASA, FAA, and ESA. The primary tasks underway are the incorporation of advanced methodology for crack growth rate retardation resulting from spectrum loading and improved analysis for determining crack instability. Also, the current weight function solutions in NASGRO or nonlinear stress gradient problems are being extended to more crack cases, and the 2-d boundary integral routine for stress analysis and stress-intensity factor solutions is being extended to 3-d problems. Lastly, effort is underway to enhance the program to operate on personal computers and work stations in a Windows environment. Because of the increasing and already wide usage of NASGRO, the code offers an excellent mechanism for technology transfer for new fatigue and fracture mechanics capabilities developed within NAARP

Emotion Processing Deficit in Euthymic Bipolar Disorder: A Potential Endophenotype

Background: Emotion processing deficits have been described in patients with bipolar disorder (BD) and are considered one of the core cognitive abnormalities in BD with endophenotype potential. However, the literature on specific impairments in emotion processing cognitive strategies (directive/cortical/higher versus intuitive/limbic/lower) in euthymic adult BD patients and healthy first-degree relatives/high-risk (HR) subjects in comparison with healthy controls (HCs) is sparse. Methods: We examined facial emotion recognition deficits (FERD) in BD (N = 30), HR (N = 21), and HC (N = 30) matched for age (years), years of education, and sex using computer-administered face emotions–Matching And Labeling Task (eMALT). Results: The three groups were significantly different based on labeling accuracy scores for fear and anger (FA) (P \u3c 0.001) and sad and disgust (SD) (P \u3c 0.001). On post-hoc analysis, HR subjects exhibited a significant deficit in the labeling accuracy of FA facial emotions (P \u3c 0.001) compared to HC. The BD group was found to have significant differences in all FA (P = 0.004) and SD (P = 0.003) emotion matching as well as FA (P = 0.001) and SD (P \u3c 0.001) emotion labeling accuracy scores. Conclusions: BD in remission exhibits FERD in general, whereas specific labeling deficits of fear and anger emotions, indicating impaired directive higher order aspect of emotion processing, were demonstrated in HR subjects. This appears to be a potential endophenotype. These deficits could underlie the pathogenesis in BD, with possible frontolimbic circuitry impairment. They may have potential implications in functional recovery and prognosis of BD

Extended Hauser-Feshbach Method for Statistical Binary-Decay of Light-Mass Systems

An Extended Hauser-Feshbach Method (EHFM) is developed for light heavy-ion fusion reactions in order to provide a detailed analysis of all the possible decay channels by including explicitly the fusion-fission phase-space in the description of the cascade chain. The mass-asymmetric fission component is considered as a complex-fragment binary-decay which can be treated in the same way as the light-particle evaporation from the compound nucleus in statistical-model calculations. The method of the phase-space integrations for the binary-decay is an extension of the usual Hauser-Feshbach formalism to be applied to the mass-symmetric fission part. The EHFM calculations include ground-state binding energies and discrete levels in the low excitation-energy regions which are essential for an accurate evaluation of the phase-space integrations of the complex-fragment emission (fission). In the present calculations, EHFM is applied to the first-chance binary-decay by assuming that the second-chance fission decay is negligible. In a similar manner to the description of the fusion-evaporation process, the usual cascade calculation of light-particle emission from the highly excited complex fragments is applied. This complete calculation is then defined as EHFM+CASCADE. Calculated quantities such as charge-, mass- and kinetic-energy distributions are compared with inclusive and/or exclusive data for the $^{32}$S+$^{24}$Mg and $^{35}$Cl+$^{12}$C reactions which have been selected as typical examples. Finally, the missing charge distributions extracted from exclusive measurements are also successfully compared with the EHFM+CASCADE predictions.Comment: 34 pages, 6 Figures available upon request, Phys. Rev. C (to be published

Highly deformed 40^{40}Ca configurations in 28^{28}Si + 12^{12}C

The possible occurrence of highly deformed configurations in the $^{40}$Ca di-nuclear system formed in the $^{28}$Si + $^{12}$C reaction is investigated by analyzing the spectra of emitted light charged particles. Both inclusive and exclusive measurements of the heavy fragments (A $\geq$ 10) and their associated light charged particles (protons and $\alpha$ particles) have been made at the IReS Strasbourg {\sc VIVITRON} Tandem facility at bombarding energies of $E_{lab} (^{28}$Si) = 112 MeV and 180 MeV by using the {\sc ICARE} charged particle multidetector array. The energy spectra, velocity distributions, and both in-plane and out-of-plane angular correlations of light charged particles are compared to statistical-model calculations using a consistent set of parameters with spin-dependent level densities. The analysis suggests the onset of large nuclear deformation in $^{40}$Ca at high spin.Comment: 33 pages, 11 figure

Silencing of the Rotavirus NSP4 Protein Decreases the Incidence of Biliary Atresia in Murine Model

Biliary atresia is a common disease in neonates which causes obstructive jaundice and progressive hepatic fibrosis. Our previous studies indicate that rotavirus infection is an initiator in the pathogenesis of experimental biliary atresia (BA) through the induction of increased nuclear factor-kappaB and abnormal activation of the osteopontin inflammation pathway. In the setting of rotavirus infection, rotavirus nonstructural protein 4 (NSP4) serves as an important immunogen, viral protein 7 (VP7) is necessary in rotavirus maturity and viral protein 4 (VP4) is a virulence determiner. The purpose of the current study is to clarify the roles of NSP4, VP7 and VP4 in the pathogenesis of experimental BA. Primary cultured extrahepatic biliary epithelia were infected with Rotavirus (mmu18006). Small interfering RNA targeting NSP4, VP7 or VP4 was transfected before rotavirus infection both in vitro and in vivo. We analyzed the incidence of BA, morphological change, morphogenesis of viral particles and viral mRNA and protein expression. The in vitro experiments showed NSP4 silencing decreased the levels of VP7 and VP4, reduced viral particles and decreased cytopathic effect. NSP4-positive cells had strongly positive expression of integrin subunit α2. Silencing of VP7 or VP4 partially decreased epithelial injury. Animal experiments indicated after NSP4 silencing, mouse pups had lower incidence of BA than after VP7 or VP4 silencing. However, 33.3% of VP4-silenced pups (N = 6) suffered BA and 50% of pups (N = 6) suffered biliary injury after VP7 silencing. Hepatic injury was decreased after NSP4 or VP4 silencing. Neither VP4 nor VP7 were detected in the biliary ducts after NSP4. All together, NSP4 silencing down-regulates VP7 and VP4, resulting in decreased incidence of BA

Pneumonitis as A Consequence of (Peg)Interferon-Ribavirin Combination Therapy for Hepatitis C: a Review of the Literature

Combination of peginterferon and ribavirin is the current therapy for chronic hepatitis C infection (HCV). Interstitial pneumonitis is a rare side-effect of HCV therapy and is an important cause of dose reduction or discontinuation, impairing success of antiviral therapy. We performed a review of the literature in order to present diagnostic modalities and possible treatments for pneumonitis and to offer guidelines. We searched for cases where pneumonitis as a side-effect of HCV treatment was documented. First we performed a literature search via PubMed and Web of Science interface and second we searched three drug toxicity databases. We systematically analyzed all case reports with respect to clinical manifestations, type of treatment, and outcome. A literature search revealed 19 articles, containing 25 case descriptions, while we traced 33 cases from the drug toxicity databases. Pneumonitis presented with any of the combination of fever, dyspnea, and cough and can arise with any type of (conventional or pegylated) interferon. Mortality secondary to pneumonitis was seen in 7% of cases, exclusively with peginterferon α-2b. In most cases therapy was discontinued and steroids were started. Interferon-induced pneumonitis during HCV treatment is a severe complication and should be recognized in order to prevent further pulmonary damage and/or death

Resilience of the Eastern African electricity sector to climate driven changes in hydropower generation

Notwithstanding current heavy dependence on gas-fired electricity generation in the Eastern African Power Pool (EAPP), hydropower is expected to play an essential role in improving electricity access in the region. Expansion planning of electricity infrastructure is critical to support investment and maintaining balanced consumer electricity prices. Variations in water availability due to a changing climate could leave hydro infrastructure stranded or result in underutilization of available resources. In this study, we develop a framework consisting of long-term models for electricity supply and water systems management, to assess the vulnerability of potential expansion plans to the effects of climate change. We find that the most resilient EAPP rollout strategy corresponds to a plan optimised for a slightly wetter climate compared to historical trends. This study demonstrates that failing to climate-proof infrastructure investments can result in significant electricity price fluctuations in selected countries (Uganda & Tanzania) while others, such as Egypt, are less vulnerable

Resilience of the Eastern African electricity sector to climate driven changes in hydropower generation

Notwithstanding current heavy dependence on gas-fired electricity generation in the Eastern African Power Pool (EAPP), hydropower is expected to play an essential role in improving electricity access in the region. Expansion planning of electricity infrastructure is critical to support investment and maintaining balanced consumer electricity prices. Variations in water availability due to a changing climate could leave hydro infrastructure stranded or result in underutilization of available resources. In this study, we develop a framework consisting of long-term models for electricity supply and water systems management, to assess the vulnerability of potential expansion plans to the effects of climate change. We find that the most resilient EAPP rollout strategy corresponds to a plan optimised for a slightly wetter climate compared to historical trends. This study demonstrates that failing to climate-proof infrastructure investments can result in significant electricity price fluctuations in selected countries (Uganda & Tanzania) while others, such as Egypt, are less vulnerable

Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases

Mice lacking both PTEN and SHIP phosphatases develop spontaneous B cell lymphoma