University of Nebraska Omaha

About: University of Nebraska Omaha is a education organization based out in Omaha, Nebraska, United States. It is known for research contribution in the topics: Population & Poison control. The organization has 4526 authors who have published 8905 publications receiving 213914 citations. The organization is also known as: UNO & University of Omaha.

Abnormal accumulation of desmin in gastrocnemius myofibers of patients with peripheral artery disease: associations with altered myofiber morphology and density, mitochondrial dysfunction and impaired limb function.

Abstract: Patients with peripheral artery disease (PAD) develop a myopathy in their ischemic lower extremities, which is characterized by myofiber degeneration, mitochondrial dysfunction and impaired limb function. Desmin, a protein of the cytoskeleton, is central to maintenance of the structure, shape and function of the myofiber and its organelles, especially the mitochondria, and to translation of sarcomere contraction into muscle contraction. In this study, we investigated the hypothesis that disruption of the desmin network occurs in gastrocnemius myofibers of PAD patients and correlates with altered myofiber morphology, mitochondrial dysfunction, and impaired limb function. Using fluorescence microscopy, we evaluated desmin organization and quantified myofiber content in the gastrocnemius of PAD and control patients. Desmin was highly disorganized in PAD but not control muscles and myofiber content was increased significantly in PAD compared to control muscles. By qPCR, we found that desmin gene transcripts were increased in the gastrocnemius of PAD patients as compared with control patients. Increased desmin and desmin gene transcripts in PAD muscles correlated with altered myofiber morphology, decreased mitochondrial respiration, reduced calf muscle strength and decreased walking performance. In conclusion, our studies identified disruption of the desmin system in gastrocnemius myofibers as an index of the myopathy and limitation of muscle function in patients with PAD.

Relationship Between Weight, Efavirenz Exposure, and Virologic Suppression in HIV-Infected Patients on Rifampin-Based Tuberculosis Treatment in the AIDS Clinical Trials Group A5221 STRIDE Study

Abstract: Tuberculosis is the leading cause of death in human immunodeficiency virus (HIV)–coinfected individuals worldwide. Concomitant treatment of HIV and tuberculosis is required to reduce the risk of death and HIV progression [1–3]. However, antiretroviral therapy (ART) can be complicated by drug–drug interactions with tuberculosis medications, particularly rifampin (RIF), which induces cytochrome (CYP) P450 enzymes. Efavirenz (EFV) is recommended as a component of first-line ART in HIV/tuberculosis coinfection [4] and is metabolized primarily through hepatic cytochrome P450 CYP2B6. EFV pharmacokinetic exposure is significantly increased by several genetic polymorphisms in CYP2B6 [5–9]. Slow-metabolizing CYP2B6 alleles are present in all populations at varying frequencies, with 516G→T (rs3745274) most frequent with African or Asian ancestry, 983T→C (rs28399499) most frequent with African ancestry, and 15582C→T (rs4803419) most frequent with Asian or European ancestry [6, 10–12]. In addition, patients taking multidrug therapy for tuberculosis also receive isoniazid, an inhibitor of CYP2A6 and other isoenzymes [13], potentially impacting EFV concentrations as well as rifampin. CYP2A6 is an alternative pathway for EFV elimination that may be of particular importance in patients with slow EFV metabolizer phenotypes [14, 15]. The appropriate EFV dose for HIV-infected patients receiving concomitant RIF continues to be debated because available data are conflicting. Traditional pharmacokinetic (PK) studies enrolling healthy volunteers in the United States combined with limited data from patients coinfected with HIV and tuberculosis have demonstrated a 30% decrease in plasma EFV area under the concentration time curve (AUC) with RIF coadministration [16–18]. In contrast, several larger, population-based studies in patients from primarily resource-limited settings indicate either that there is no effect of RIF on EFV concentrations [7, 19] or that RIF coadminstration increases EFV concentrations in African patients [20, 21]. Focusing on intensive PK data gathered primarily in developed settings, the US Food and Drug Administration (FDA) recently approved a revised EFV package insert to recommend that EFV be increased from a standard daily dose of 600 mg to 800 mg for patients taking concomitant RIF who weigh >50 kilograms [22], whereas the British HIV/tuberculosis treatment guidelines recommend EFV dose increase for those weighing >60 kg [23]. In contrast, based on clinical trial and observational data, the World Health Organization does not recommend increased EFV dosing based on weight in tuberculosis patients [4, 24]. Determining the appropriate dosing of EFV during tuberculosis treatment is essential because very high EFV concentrations may increase drug-related toxicity, while very low EFV concentrations may result in treatment failure with emergence of drug-resistant HIV [25, 26]. To evaluate the relationship between weight, EFV concentrations, and HIV RNA suppression, we conducted a population-based pharmacokinetic analysis in the STRIDE (A Strategy Study of Immediate Versus Deferred Initiation of Antiretroviral Therapy for AIDS Disease-Free Survival in HIV-Infected Persons Treated for Tuberculosis with CD4 < 250 Cells/mm3) study participants. The STRIDE study (A5221) was an open-label, randomized study comparing ART started earlier (within 2 weeks of tuberculosis treatment initiation) versus later (8–12 weeks after tuberculosis treatment initiation) in HIV-infected participants receiving RIF-based tuberculosis treatment [2]. The impact of weight ≥50 kg and ≥60 kg on EFV concentrations was evaluated, given the differing weight cutoffs for recommended EFV dose [22, 23, 27].

Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis

Abstract: DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for methylation of cytosine residues in mammals. DNA methylation contributes to the epigenetic control of gene transcription and is deregulated in virtually all human tumors. To better understand the generation of cancer-specific methylation patterns, we genetically inactivated Dnmt3b in a mouse model of MYC-induced lymphomagenesis. Ablation of Dnmt3b function using a conditional knockout in T cells accelerated lymphomagenesis by increasing cellular proliferation, which suggests that Dnmt3b functions as a tumor suppressor. Global methylation profiling revealed numerous gene promoters as potential targets of Dnmt3b activity, the majority of which were demethylated in Dnmt3b–/– lymphomas, but not in Dnmt3b–/– pretumor thymocytes, implicating Dnmt3b in maintenance of cytosine methylation in cancer. Functional analysis identified the gene Gm128 (which we termed herein methylated in normal thymocytes [Ment]) as a target of Dnmt3b activity. We found that Ment was gradually demethylated and overexpressed during tumor progression in Dnmt3b–/– lymphomas. Similarly, MENT was overexpressed in 67% of human lymphomas, and its transcription inversely correlated with methylation and levels of DNMT3B. Importantly, knockdown of Ment inhibited growth of mouse and human cells, whereas overexpression of Ment provided Dnmt3b+/+ cells with a proliferative advantage. Our findings identify Ment as an enhancer of lymphomagenesis that contributes to the tumor suppressor function of Dnmt3b and suggest it could be a potential target for anticancer therapies.

Long-term decline in intergenerational mobility in the United States since the 1850s

Abstract: We make use of newly available data that include roughly 5 million linked household and population records from 1850 to 2015 to document long-term trends in intergenerational social mobility in the United States. Intergenerational mobility declined substantially over the past 150 y, but more slowly than previously thought. Intergenerational occupational rank-rank correlations increased from less than 0.17 to as high as 0.32, but most of this change occurred to Americans born before 1900. After controlling for the relatively high mobility of persons from farm origins, we find that intergenerational social mobility has been remarkably stable. In contrast with relative stability in rank-based measures of mobility, absolute mobility for the nonfarm population-the fraction of offspring whose occupational ranks are higher than those of their parents-increased for birth cohorts born prior to 1900 and has fallen for those born after 1940.

The Infectious Nature of Patient-Generated SARS-CoV-2 Aerosol

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission causing coronavirus disease 2019 (COVID-19) may occur through multiple routes. We collected aerosol samples around six patients admitted into mixed acuity wards in April of 2020 to identify the risk of airborne SARS-CoV-2. Measurements were made to characterize the size distribution of aerosol particles, and size-fractionated, aerosol samples were collected to assess the presence of infectious virus in particles sizes of >4.1 µm, 1-4 µm, and 4.1 µm, 1-4 µm, and