Safety,Tolerability, and Pharmacokinetics of Single and Repeat Doses of Nemiralisib Administered via the Ellipta Dry Powder Inhaler to Healthy Subjects

Purpose

Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability.

HIV Sexual Risk and Syndemics among Women in Three Urban Areas in the United States: Analysis from HVTN 906

Limited data are available on the longitudinal occurrence of syndemic factors among women at risk for HIV infection in the USA and how these factors relate to sexual risk over time. HVTN 906 was a longitudinal study enrolling 799 HIV-uninfected women in three cities. Assessments were done at baseline, 6, 12, and 18 months to assess syndemic factors (low education, low income, unemployment, lack of health insurance, housing instability, substance use, heavy alcohol use, partner violence, incarceration) and sexual risk outcomes. For each sexual risk outcome, a GEE model was fit with syndemic factors or syndemic score (defined as sum of binary syndemics, ranging from 0 to 9), visit, study site, age and race/ethnicity as predictors to examine the multivariable association between syndemic factors and outcomes over time. Odds of unprotected sex while drunk or high were significantly higher when women reported lack of health insurance, substance and heavy alcohol use and partner violence. Housing instability, substance and heavy alcohol use, partner violence and recent incarceration were associated with higher odds of having multiple sexual partners. Odds of sex exchange were significantly higher in the presence of unemployment, housing instability, low education, lack of health insurance, substance and heavy alcohol use, partner violence and incarceration. Housing instability, substance and heavy alcohol use, and partner violence were significantly associated with higher odds of unprotected anal sex. Odds of having a recent STI were significantly higher when women reported housing instability and partner violence. There were significantly higher odds of the reporting of any risk outcomes during follow-up with higher syndemic score. This study highlights a group of women experiencing multiple poor social and health outcomes who need to be the focus of comprehensive interventions.     

Clinical presentations and outcomes in pulmonary embolism patients with cancer

Journal of Thrombosis and Thrombolysis - To study whether a diagnosis of cancer affects the clinical presentation and outcomes of patients with pulmonary embolism (PE). A retrospective analysis was...     

Exploring the fuzzy border between senolytics and senomorphics with chemoinformatics and systems pharmacology

Biogerontology - Senescent cells accumulate within tissues during aging and secrete an array of pro-inflammatory molecules known as senescent-associated secretory phenotype (SASP), which contribute...     

Compromised pontocerebellar and cerebellothalamocortical systems: speculations on their contributions to cognitive and motor impairment in nonamnesic alcoholism

BACKGROUND: Corticopontocerebellar and cerebellothalamocortical circuits underlie a wide range of neuropsychological processes compromised by alcoholism. The analyses herein tested whether abnormalities of volumes of brain structures forming nodes of these separate feed-forward and feedback systems are selectively related to each other and whether any of these noncortical regions can account for cognitive and motor deficits occurring as sequelae of chronic alcoholism. METHODS: Regional brain measures originated from our prior neuroimaging studies, showing in alcoholics significant volume deficits in the principal structures of interest: cerebellar hemispheres, vermis, pons, and thalamus as well as prefrontal, frontal, and parietal cortex. Neuropsychological functions targeted for analysis-problem solving, visuospatial ability, and static postural stability-showed 0.6 to 1.6 SD deficits in these alcoholic men. RESULTS: In alcoholics, the patterns of correlations were consistent with dissociation of thalamic and pontine circuitry. Pontine and thalamic volumes were not correlated with each other. Pontine volumes correlated with white matter volumes of anterior superior vermis and gray and white matter volumes of the cerebellar hemispheres but not with cortical regional volumes. Thalamic volumes correlated with gray matter volumes of the cerebellar hemispheres, parietal cortex, and inferior posterior vermian lobule, which itself correlated with parietal, prefrontal, and frontal cortical volumes. Controls did not show these correlational patterns. Brain structure-function relationships in alcoholics examined with multiple regression identified anterior vermian but not prefrontal or parietal volume as a unique predictor of balance scores; vermian and thalamic but not prefrontal cortical volumes as predictors of card sorting scores; and cerebellar hemispheric white matter but not parietal cortical volume as a predictor of visuospatial ability. CONCLUSIONS: Each major node of frontocerebellar circuitry shows volume deficits in alcoholics but can be independently compromised. Disruption of these circuits may underlie alcoholism-related neuropsychological deficits, either by abnormalities present in individual nodes or by disconnection via interruption of selective circuitry.     

Human vascular endothelial cells with extended life spans: in vitro cell response,protein expression,and angiogenesis

An in vitro angiogenesis system was designed for screening angiogenic agonists and antagonists. In order to obtain large quantities of cells and reproducibility, human endothelial cells with extended life spans were developed by retroviral transfection. The resulting cells grown in a serum-free medium containing endothelial cell growth supplement (ECGS) have a telomerase activity, extended life spans of at least 21 passages, and an endothelial cell phenotype (diI-acetylated-LDL upake, factor VIII-related antigen, VEGFR-1 and R-2, and tissue-type plasminogen activator (tPA)) that resembled that of unaltered primary endothelial cells. Exceptions were (i) a higher expression of tPA, and (ii) a non-significant growth response to FGF-2 or VEGF stimulation. Within three-dimensional fibrin gels, specific cell clones rapidly formed tubular structures in a more reproducible manner than those observed with low-passage primary cells. Tube formation by primary endothelial cells and those with extended life spans was dependent upon FGF-2 and ECGS, respectively. Both cell types produced FGF-2 and VEGF cytokines. Increasing doses of suramin significantly decreased the size of microvessels formed by both cell lines. These functional results indicate that a vascular matrix system containing human cells with extended life spans can be successfully utilized as an in vitro assay for antiangiogenic compounds.     

Inflammatory, abscess-forming foreign body reaction mimics a thrombus formation on an atrial septal defect closure device: A commented case report.

We are presenting a case of floating left and right atrial formations on an atrial septal defect occluder system (23mm StarFLEX)-Occluder) initially supposed to be thrombotic appositions in a 57-year-old man. The closure was performed on the background of left hemispheric stroke and atrial septal aneurysm (ASA) with patent foramen ovale (PFO). The suspect structures were detected in the 6-month follow-up by transesophageal echocardiography (TEE). The patient underwent a successful surgical explantation of the closure device and closure of the patent foramen ovale (PFO) using a pericardial patch. The pathological evaluation of the biatrial device associated appositions revealed hytrophic heart muscle tissue with perifocal scarring and purulent abscess-forming, granulating and foam-cell including inflammatory foreign body reaction instead of the expected thrombus formation.     

Longer Time Interval Between Completion of Neoadjuvant Chemoradiation and Surgical Resection Does Not Improve Downstaging of Rectal Carcinoma

PURPOSE: An interval of six to eight weeks between completion of preoperative chemoradiation therapy and surgical resection of advanced rectal cancer has been described. Our purpose was to determine whether a longer time interval between completion of therapy and resection increases tumor downstaging and affects perioperative morbidity. METHODS: Forty patients with advanced adenocarcinoma of the rectum underwent preoperative chemoradiation on a prospective trial with irinotecan (50 mg/m2), 5-fluorouracil (225 mg/m2), and concomitant external-beam radiation (45-54 Gy) followed by complete surgical resection of the tumor with total mesorectal excision. The time interval between completion of chemoradiation and surgical resection ranged from 28 to 97 days. The patients were divided into two groups with 33 eligible patients: Group A (4-week to 8-week time interval; 28-56 days) and Group B (10-week to 14-week interval; 67-97 days). Tumor downstaging was compared between these two groups. The number of patients downstaged by at least one T stage, those downstaged by at least one N stage, those with pathologic complete responses, and those with only residual microscopic tumor foci were compared. Postoperative length of stay, estimated blood loss, perioperative morbidity, and sphincter-sparing procedures were also compared. Chi-squared tests and Student's t-test were calculated. RESULTS: Group A had 19 patients, and Group B had 14 patients. Patient demographics were comparable. Mean age was 52 years, and 70 percent of patients were male. There were no deaths. There were no statistical differences in perioperative morbidity, with three anastomotic leaks in Group A. Tumors were downstaged in 58 percent of patients in Group A and 43 percent of those in Group B (P = 0.61). Nodal downstaging occurred in 78 percent of Group A and 67 percent of Group B (P = 0.9). The pathologic complete response rate was 21 percent in Group A and 14 percent in Group B (P = 0.97), and a residual microfocus of tumor was found in 33 percent of patients in Group A and 42 percent of those in Group B (P = 0.90). These differences were not statistically significant. CONCLUSIONS: Perioperative morbidity is not affected by longer intervals. A longer interval between completion of neoadjuvant chemoradiation and surgical resection may not increase the tumor response rate of advanced rectal cancer in this cohort.     

Brain Gray and White Matter Volume Loss Accelerates with Aging in Chronic Alcoholics: A Quantitative MRI Study

Magnetic resonance imaging (MRI) was used to study in vivo the brains of 49 patients with chronic alcoholism, 3 to 4 weeks post-withdrawal, and 43 normal healthy controls, all right-handed male veterans between the ages of 23 and 70 years. MRI scans were analyzed using a semi-automated procedure, which allowed the subcortical regions to be segmented into cerebrospinal fluid (CSF) and brain tissue and the cortical regions to be segmented into CSF, gray matter, and white matter. An age regression model was used to examine the effects of alcohol on brain structure, over and above that expected from the normal aging process. The alcoholics exhibited decreased tissue and increased CSF after correcting for aging. In the cortex, there was significant loss of both gray matter and white matter volume. In this sample of alcoholics, no particular cortical region was preferentially affected or spared. Furthermore, brain tissue volume loss increased with advanced age in the alcoholics. In this group of alcoholics there was no relationship between length of illness and age, i.e., the younger alcoholics had as heavy alcohol use histories as did the older alcoholics. Thus, the increased brain tissue loss with advanced age is interpreted as evidence for age-related increase in brain vulnerability to chronic alcohol abuse.