Optimization of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives as inhibitors of monoamine oxidase

In recent studies, we have investigated the monoamine oxidase (MAO) inhibition properties of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives. Since numerous high potency MAO inhibitors are present among these chemical classes, the present study synthesizes 44 additional derivatives in an attempt to further derive structure-activity relationships (SARs) and to establish optimal substitution patterns for MAO inhibition. The results show that, with the exception of one compound, all indole-5,6-dicarbonitrile derivatives (10) exhibit submicromolar IC₅₀ values for the inhibition of MAO, with the most potent MAO-A inhibitor exhibiting an IC₅₀ value of 0.006 μM while the most potent MAO-B inhibitor exhibits an IC₅₀ value of 0.058 μM. Interestingly, an N-oxide derivative ( 4c ) also proved to be a potent and nonspecific MAO inhibitor. With the exception of one compound, all of the pyrrolo[3,4-f]indole-5,7-diones (28) also exhibit submicromolar IC₅₀ values for the inhibition of an MAO isoform. The most potent inhibitor exhibit an IC₅₀ value of 0.011 μM for MAO-A. This study proposes that high potency MAO inhibitors such as those investigated here, may act as lead compounds for the development of treatments for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression.     

Diagnostic performance of late-night salivary cortisol measured by automated electrochemiluminescence immunoassay in obese and overweight patients referred to exclude Cushing's syndrome

This study estimates diagnostic performance of late-night salivary cortisol (LNSC) as measured by automated electrochemiluminescence immunoassay (ECLIA), evaluates the clinical implication of two consecutive LNSC measurements, and compares its accuracy with enzyme-linked immunosorbent assay (ELISA) and serum cortisol after low-dose dexamethasone suppression test (DST) in obese and overweight patients referred for suspected Cushing's syndrome (CS). One hundred twenty three consecutive obese and overweight referred patients and 98 healthy volunteers provided two saliva samples collected at 23:00 using a Salivette (Sarstedt, Germany), assayed by ECLIA (Cobas e601) and ELISA. The patients underwent DST and were further evaluated until CS was pathologically confirmed (n?=?45) or excluded. Diagnostic performance of LNSC was evaluated by receiver operating characteristic (ROC) analysis. The total areas under the curve (AUC) were calculated to compare the different tests. We found that a cut-off value of 9.4?nmol/l can differentiate CS among obese and overweight patients with sensitivity of 84.4?% (95% CI 71.2-92.2), specificity of 92.3?% (95% CI 84.2-96.4), and diagnostic odds ratio of 65.1 (95% CI 20.4-207.6). No difference was found between AUCs from the first, second, and the mean from the two LNSC measurements (ECLIA), LNSC (ELISA), or DST. The single LNSC (ECLIA) and DST improved the sensitivity and specificity for concordant results up to 100 and 97.4?%, respectively. In conclusion, due to its automation and its comparable diagnostic performance, ECLIA is preferable as a first-line LNSC screening test for CS. The initial use of single LNSC followed by DST provides better diagnostic performance for concordant results.     

Safety and immunogenicity of the novel seasonal preservative‐ and adjuvant‐free influenza vaccine: Blind,randomized, and placebo‐controlled trial

The producers of influenza vaccines are not capable today to meet the global demand for an influenza vaccine in case of pandemic, so the World Health Organization recommends to develop the own influenza vaccine production in each country. A domestic preservative‐ and adjuvant‐free trivalent split vaccine against seasonal influenza was developed at the Research Institute for Biological Safety Problems. The paper presents the results of assessing safety and immunogenicity of the influenza split vaccine after single immunization of healthy volunteers aged 18‐50 years in the course of Phase I Clinical Trials. This study was randomized, blind, and placebo‐controlled. The volunteers were intramuscularly vaccinated with a dose of split vaccine or placebo. The study has shown that all local and systemic reactions had low degree of manifestation and short‐term character, so there was no need in medication. Serious side effects were not observed. On day 21 post vaccination the portion of vaccinated persons with fourfold seroconversions to influenza А/H1N1pdm09 virus was 100.0%, to influenza А/H3N2 virus—95.5%, to influenza B virus—81.8%, and in placebo group this index was 0%. Seroprotection rates against influenza А/H1N1pdm09, А/H3N2 and B viruses were 95.5, 86.3, and 72.7%, respectively. Geometric mean titers (GMT) of antibodies by day 21 post vaccination reached 175.7 for influenza А/H1N1pdm09 virus, 64.2 for influenza А/H3N2 virus, and 37.6 for influenza B virus; in placebo group GMT growth was not observed. So, the seasonal influenza split vaccine is well tolerated and fits all immunogenicity criteria for human influenza vaccines.     

αβ T Cell-Depleted Haploidentical Hematopoietic Stem Cell Transplantation without Antithymocyte Globulin in Children with Chemorefractory Acute Myelogenous Leukemia

We evaluated the outcome of αβ T cell-depleted haploidentical hematopoietic stem cell transplantation (HSCT) in a cohort of children with chemorefractory acute myelogenous leukemia (AML). Twenty-two patients with either primary refractory (n = 10) or relapsed refractory (n = 12) AML in active disease status received a transplant from haploidentical donors. The preparative regimen included cytoreduction with fludarabine and cytarabine and subsequent myeloablative conditioning with treosulfan and thiotepa. Antithymocyte globulin was substituted with tocilizumab in all patients and also with abatacept in 10 patients. Grafts were peripheral blood stem cells engineered by αβ T cell and CD19 depletion. Post-transplantation prophylactic therapy included infusion of donor lymphocytes, composed of a CD45RA-depleted fraction with or without a hypomethylating agent. Complete remission was achieved in 21 patients (95%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 18%, and the cumulative incidence of chronic GVHD was 23%. At 2 years, transplantation-related mortality was 9%, relapse rate was 42%, event-free survival was 49%, and overall survival was 53%. Our data suggest that αβ T cell-depleted haploidentical HSCT provides a reasonable chance of long-term survival in a cohort of children with chemorefractory AML and creates a solid basis for further improvement.     

Cortical blindness, a rare complication of pre-eclampsia

This is a case report of a previously undiagnosed pregnant teenager who presented to the emergency department with cortical blindness. She was found to be pre-eclamptic with the HELLP syndrome. She underwent immediate cesarean section, with delivery of a viable 32-week-old infant. Computed tomography and magnetic resonance imaging studies revealed abnormalities in the occipital lobes and a possible subarachnoid hemorrhage. Her vision improved immediately after the cesarean section, and returned to normal in a few days.     

Assessing Health Diagnosis Disclosure Decisions in Relationships: Testing the Disclosure Decision-Making Model

Illness affects millions of Americans each year, and the disclosure of health conditions can facilitate access to social support, in addition to other physical and physiological benefits. This article tests the Disclosure Decision-Making Model (DD-MM; Greene, 2009 Greene, K. 2009. “An integrated model of health disclosure decision-making”. In Uncertainty and information regulation in interpersonal contexts: Theories and applications, Edited by: Afifi, T. D. and Afifi, W. A. 226–253. New York, NY: Routledge.  [Google Scholar]) to predict factors that influence the likelihood of disclosing (and past disclosure of) nonvisible physical or mental health-related information. One hundred eighty-seven (n?=?187) people were recruited for a study to report on both disclosing and not disclosing a nonvisible health condition. Measured variables included information assessment, relational quality, anticipated reactions (support, relational consequences), confidence in response, disclosure efficacy, and disclosure (likelihood of disclosure and depth of disclosure). Structural equation modeling results supported many of the proposed hypotheses, with a great deal of similarity across models. Specifically, assessing information predicted efficacy, and to some extent relational outcomes. Closeness was related to response overall and to efficacy in one model. Response predicted outcome overall and likelihood of disclosure in one model. Finally, efficacy predicted likelihood of disclosure and depth of disclosure. The article discusses the implications of the findings for understanding information, relationship assessments, and efficacy in disclosing health diagnoses.     

Older Versus Newer Media and the Well-being of United States Youth: Results From a National Longitudinal Panel

PurposeTo determine the effects of both older and newer media use on academic, social, and mental health outcomes in adolescents and young adults.MethodsWe interviewed a nationally representative panel of youth ages 14–24 years (N = 719) twice 1 year apart to determine time spent with television, the Internet, videogames, and book reading, as well as the purpose of those uses. A cluster analysis identified major combinations of media use. Regression models tested hypotheses regarding changes in self-reported school grades, participation in clubs and sports, and symptoms of depression, as predicted by recent media use and differences in cluster membership.ResultsUse of older media was related to grades, with television inversely and book reading positively related to performance. Moderate use of the Internet was positively related to participation in both sports and clubs. Although heavy use of the Internet and videogames was associated with an increase in depression, increased depression also predicted greater use of these media as well as withdrawal from sports and clubs. Clusters that used media in moderation with an emphasis on information gathering were most associated with healthy outcomes.ConclusionsDespite concerns that excessive use of new media is harmful to adolescent development, the findings reinforce previous conclusions that television detracts from academic performance and book reading supports it. Heavy use of the Internet and video gaming may be more a symptom of mental health problems than a cause. Moderate use of the Internet, especially for acquiring information, is most supportive of healthy development.     

Multidonor bone marrow transplantation improves donor engraftment and increases the graft versus tumor effect while decreasing graft‐versus‐host disease

In partially matched donor transplantation, mandatory T‐cell depletion (TCD) increases the risks of rejection/graft failure, relapse, and post‐transplant infections. A multi‐donor approach was offered to resolve some of these drawbacks. This hypothesis was previously tested in a TCD fully mismatched murine model. However, the effect of multi‐donor transplantation (MDT) on graft‐versus‐host disease (GVHD) and graft versus tumor (GVT) effect were never tested. To assess the safety and efficacy of MDT, we used it in non‐TCD transplantation and murine breast carcinoma model. We found that when transplanting non‐TCD MDT composed by C57Bl/6 and C3H cells into BALB/c, a consistent trichimerism is established, dominated by C57Bl/6 cells. Following MDT the study animals experienced reduced GVHD compare with those transplanted from C57Bl/6 alone, while the GVT effect was superior. We conclude that MDT may serve as a technique that suppresses GVHD while maintaining the GVT effect.