Saving, IDA Programs, and Effects of IDAs: A Survey of Participants

Saving, IDA Programs, and Effects of IDAs: A Survey of Participant

Rescue of the MERTK phagocytic defect in a human iPSC disease model using translational read-through inducing drugs.

Inherited retinal dystrophies are an important cause of blindness, for which currently there are no effective treatments. In order to study this heterogeneous group of diseases, adequate disease models are required in order to better understand pathology and to test potential therapies. Induced pluripotent stem cells offer a new way to recapitulate patient specific diseases in vitro, providing an almost limitless amount of material to study. We used fibroblast-derived induced pluripotent stem cells to generate retinal pigment epithelium (RPE) from an individual suffering from retinitis pigmentosa associated with biallelic variants in MERTK. MERTK has an essential role in phagocytosis, one of the major functions of the RPE. The MERTK deficiency in this individual results from a nonsense variant and so the MERTK-RPE cells were subsequently treated with two translational readthrough inducing drugs (G418 & PTC124) to investigate potential restoration of expression of the affected gene and production of a full-length protein. The data show that PTC124 was able to reinstate phagocytosis of labeled photoreceptor outer segments at a reduced, but significant level. These findings represent a confirmation of the usefulness of iPSC derived disease specific models in investigating the pathogenesis and screening potential treatments for these rare blinding disorders

Fatal progression of experimental visceral leishmaniasis is associated with intestinal parasitism and secondary infection by commensal bacteria, and is delayed by antibiotic prophylaxis.

Leishmania donovani causes visceral leishmaniasis (VL), which is typically fatal without treatment. There is substantial variation between individuals in rates of disease progression, response to treatment and incidence of post-treatment sequelae, specifically post-kala-azar dermal leishmaniasis (PKDL). Nevertheless, the majority of infected people are asymptomatic carriers. Hamsters and mice are commonly used as models of fatal and non-fatal VL, respectively. Host and parasite genetics are likely to be important factors, but in general the reasons for heterogeneous disease presentation in humans and animal models are poorly understood. Host microbiota has become established as a factor in cutaneous forms of leishmaniasis but this has not been studied in VL. We induced intestinal dysbiosis in mice and hamsters by long-term treatment with broad-spectrum antibiotics in their drinking water. There were no significant differences in disease presentation in dysbiotic mice. In contrast, dysbiotic hamsters infected with L. donovani had delayed onset and progression of weight loss. Half of control hamsters had a rapid progression phenotype compared with none of the ABX-treated animals and the nine-month survival rate was significantly improved compared to untreated controls (40% vs. 10%). Antibiotic-treated hamsters also had significantly less severe hepatosplenomegaly, which was accompanied by a distinct cytokine gene expression profile. The protective effect was not explained by differences in parasite loads or haematological profiles. We further found evidence that the gut-liver axis is a key aspect of fatal VL progression in hamsters, including intestinal parasitism, bacterial translocation to the liver, malakoplakia and iron sequestration, none of which occurred in non-progressing murine VL. Diverse bacterial genera were cultured from VL affected livers, of which Rodentibacter was specifically absent from ABX-treated hamsters, indicating this pathobiont may play a role in promoting disease progression. The results provide experimental support for antibiotic prophylaxis against secondary bacterial infections as an adjunct therapy in human VL patients

Integrated and Open Interpreter Education: The Open Educational Resource Reader and Workbook for Interpreters

https://digitalcommons.wou.edu/facbooks/1001/thumbnail.jp

A Randomized Controlled Trial of Changes in Fluid Distribution across Menstrual Phases with Creatine Supplementation

This study examined the effects of creatine (Cr) loading on body mass (BM) and fluid markers of total body water (TBW), extra-cellular fluid (ECF), and intra-cellular fluid (ICF) across the menstrual cycle (MC). Thirty moderately active females, either naturally-menstruating (NM) or using hormonal contraceptives (HC), were randomized to Cr (Cr; 4 × 5 g/day of creatine monohydrate for 5 days; n = 15) or a non-caloric placebo (PL; n = 15) using a double-blind, placebo-controlled design, with a menstrual phase crossover. BM, TBW, ECF, and ICF were measured at pre- and post-supplementation in randomized order of follicular phase (FP; NM: MC days 0–8, HC: inactive pill days) or luteal phase (LP; NM: ≤15 days from next projected cycle start date, HC: active pill days) using bioelectrical impedance spectroscopy. Acute hydration status and salivary estrogen were used as covariates. Change in BM was not different between groups across MC ([PL-Cr] Δ 0.40 ± 0.50 kg; p = 0.427) or between MC phase across groups ([FP-LP] Δ 0.31 ± 0.48 kg; p = 0.528). TBW (p = 0.802), ECF (p = 0.373), and ICF (p = 0.795) were not different between supplement groups at pre-supplementation/FP time points. There were no significant differences between the NM and HC subjects at any time point, for any outcome (p > 0.05). Following LP supplementation, significant changes were observed in TBW (Cr: Δ 0.83 ± 0.38 L, PL: Δ −0.62 ± 0.38 L; p = 0.021), ECF (Cr: Δ 0.46 ± 0.15 L, PL: Δ −0.19 ± 0.15 L; p = 0.013), and ICF (Cr: Δ 0.74 ± 0.23 L, PL: Δ −0.02 ± 0.23 L; p = 0.041). These data demonstrate an increase in all fluid compartments in the LP following Cr loading, without observed alterations in body weight for females

Dynamic two-axis curvature measurement using multicore fiber Bragg gratings interrogated by arrayed waveguide gratings

We describe the use of arrayed waveguide gratings (AWGs) in the interrogation of fiber Bragg gratings (FBGs) for dynamic strain measurement. The ratiometric AWG output was calibrated in a static deflection experiment over a ±200 με range. Dynamic strain measurement was demonstrated with a FBG in a conventional single-mode fiber mounted on the surface of a vibrating cantilever and on a piezoelectric actuator, giving a resolution of 0.5 με at 2.4 kHz. We present results of this technique extended to measure the dynamic differential strain between two FBG pairs within a multicore fiber. An arbitrary cantilever oscillation of the multicore fiber was determined from curvature measurements in two orthogonal axes at 1125 Hz with a resolution of 0.05 m-1. © 2006 Optical Society of America

Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada.

IntroductionWeight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).MethodsAdult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years.ResultsAmong 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI).ConclusionsPWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration

Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma

Mutations in the ALK tyrosine kinase receptor gene represent important therapeutic targets in neuroblastoma, yet their clinical translation has been challenging. The ALKF1174L mutation is sensitive to the ALK inhibitor crizotinib only at high doses and mediates acquired resistance to crizotinib in ALK-translocated cancers. We have shown that the combination of crizotinib and an inhibitor of downstream signaling induces a favorable response in transgenic mice bearing ALKF1174L/MYCN-positive neuroblastoma. Here, we investigated the molecular basis of this effect and assessed whether a similar strategy would be effective in ALK-mutated tumors lacking MYCN overexpression. We show that in ALK-mutated, MYCN-amplified neuroblastoma cells, crizotinib alone does not affect mTORC1 activity as indicated by persistent RPS6 phosphorylation. Combined treatment with crizotinib and an ATP-competitive mTOR inhibitor abrogated RPS6 phosphorylation, leading to reduced tumor growth and prolonged survival in ALKF1174L/MYCN-positive models compared to single agent treatment. By contrast, this combination, while inducing mTORC1 downregulation, caused reciprocal upregulation of PI3K activity in ALK-mutated cells expressing wild-type MYCN. Here, an inhibitor with potency against both mTOR and PI3K was more effective in promoting cytotoxicity when combined with crizotinib. Our findings should enable a more precise selection of molecularly targeted agents for patients with ALK-mutated tumors