26 research outputs found
Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 2. Tadalafil analogs
Author Posting. © The Author(s), 2012. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Bioorganic & Medicinal Chemistry Letters 22 (2012): 2582-2584, doi:10.1016/j.bmcl.2012.01.118.In this report we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1.This work was supported by the National Institutes of Health (R01AI082577), Boston University and Northeastern University
Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 1. Sildenafil analogs
Author Posting. © The Author(s), 2012. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Bioorganic & Medicinal Chemistry Letters 22 (2012): 2579-2581, doi:10.1016/j.bmcl.2012.01.119.Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this report we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.This work was supported by the National Institutes of Health (R01AI082577), Boston University and Northeastern University
Leveraging public health nurses for disaster risk communication in Fukushima City: a qualitative analysis of nurses' written records of parenting counseling and peer discussions
Experimental Characterization and Numerical Simulations of Surgical Knots
INTRODUCTION: Suture strength and knot topology are two of the several factors impacting the strength of surgical repairs in soft tissue such as a tendon and skin. The measurement and comparison of the strength of knotted suture is complicated by the lack of consensus test methods. Several prior studies assess FiberWire and others sutures, however, they evaluate or compare only the gross structural response of specific sutures or their knots without direct investigation of the governing mechanics. Little has been reported about the constituents of the suture, the core and jacket separately, nor their impact on the knot strength and failure mechanisms. PURPOSE: To develop a 3D finite element model of a surgical knot in order to determine the influence of knot topology and other factors governing the mechanics of surgical suture. MATERIAL & METHODS: An experimental study No.2 FiberWire was performed to observe the governing mechanics and to obtain data for finite element model validation. FiberWire suture is composed of a core covered with a jacket; each was tested separately and together as manufactured. A finite element model was created consisting of one knot throw. RESULTS: The maximum load of the core and jacket are approximately 65 N and 210 N respectively, and the maximum strain is 2.6% for the core and 9% for the jacket. The as-manufactured suture exhibited a failure mechanism akin to a child’s “finger trap” toy, that is, the core failed several times prior to complete failure of the suture. The finite element results were consistent with the experiments. They explain that the knot’s ~50% strength reduction relative to suture is due to the stresses from bending, twisting, and the stress concentrations from knot frictional contact. CONCLUSIONS: Under tension, the braided jacket lengthens and narrows while the angle between the warp and weft threads changes. Therefore, the circumference shrinks with increases in tension and “traps” the core with compression. This permits shear load transferred between the core and the jacket after core failure. The finite element of the knot is qualitatively consistent with experimental results. Thus, the model can be used in additional investigations
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The association of perceived stress and verbal memory is greater in HIV-infected versus HIV-uninfected women
In contrast to findings from cohorts comprised primarily of HIV-infected men, verbal memory deficits are the largest cognitive deficit found in HIV-infected women from the Women's Interagency HIV Study (WIHS), and this deficit is not explained by depressive symptoms or substance abuse. HIV-infected women may be at greater risk for verbal memory deficits due to a higher prevalence of cognitive risk factors such as high psychosocial stress and lower socioeconomic status. Here, we investigate the association between perceived stress using the Perceived Stress Scale (PSS-10) and verbal memory performance using the Hopkins Verbal Learning Test (HVLT) in 1009 HIV-infected and 496 at-risk HIV-uninfected WIHS participants. Participants completed a comprehensive neuropsychological test battery which yielded seven cognitive domain scores, including a primary outcome of verbal memory. HIV infection was not associated with a higher prevalence of high perceived stress (i.e., PSS-10 score in the top tertile) but was associated with worse performance on verbal learning (p < 0.01) and memory (p < 0.001), as well as attention (p = 0.02). Regardless of HIV status, high stress was associated with poorer performance in those cognitive domains (p's < 0.05) as well as processing speed (p = 0.01) and executive function (p < 0.01). A significant HIV by stress interaction was found only for the verbal memory domain (p = 0.02); among HIV-infected women only, high stress was associated with lower performance (p's < 0.001). That association was driven by the delayed verbal memory measure in particular. These findings suggest that high levels of perceived stress contribute to the deficits in verbal memory observed in WIHS women
Cognitive trajectories over 4 years among HIV-infected women with optimal viral suppression
To determine whether persistent viral suppression alters cognitive trajectories among HIV-infected (HIV+) women on combination antiretroviral therapy (cART) by investigating performance longitudinally in uninfected (HIV-) and 3 groups of HIV+ women: those with consistent viral suppression after continuous cART use (VS), those without consistent virologic suppression despite continuous cART use (NVS), and those without consistent virologic suppression after intermittent cART use (Int NVS).
Two hundred thirty-nine VS, 220 NVS, 172 Int NVS, and 301 HIV- women from the Women's Interagency HIV Study (WIHS) completed neuropsychological testing every 2 years for 3 visits between 2009 and 2013. Mixed-effects regressions were used to examine group differences on continuous T scores and categorical measures of impairment (T score <40).
On global function, VS women demonstrated lower scores and were more likely to score in the impaired range than HIV- women (
= 0.01). These differences persisted over time (group Ă— time,
> 0.39). VS women demonstrated lower learning and memory scores than HIV- women (
< 0.05) and lower attention/working memory and fluency scores than HIV- and NVS women (
< 0.05). Group differences in scores persisted over time. Categorically, VS women were more likely to be impaired on attention/working memory and executive function than HIV- women (
< 0.05). On motor skills, VS and NVS women showed a greater decline and were more likely to be impaired than HIV- women (
< 0.05).
Cognitive difficulties remain among HIV+ women despite persistent viral suppression. In some instances, VS women are worse than NVS women, reinforcing the need for novel adjunctive therapies to attenuate cognitive problems