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Brier M.E.,University of Louisville | Brier M.E.,Robley Rex Veterans Administration Medical Center | Creed T.M.,University of Louisville | Gaweda A.E.,University of Louisville
Experimental Hematology | Year: 2013

We introduce a new, minimally invasive laboratory technique called reticulocyte-based estimation of lifespan (REBEL) of erythrocytes in humans. Its major advantage over existing techniques is its applicability to patients with both changing and steady-state erythropoiesis status. The feasibility of REBEL was tested in five patients with hemodialysis-dependent end-stage renal disease. The RNA degradation half-life was first determined for each subject on day 1 by flow cytometry measurement of the decay rate of thiazole orange stain. Reticulocyte age distribution was then measured from residual RNA content weekly for 2 months to estimate the RBC production rate time course. Mean RBC lifespan per subject was estimated by fitting the integrated RBC production rate over time to the measured RBC count and optimizing the integration limits. The mean reticulocyte RNA half-life was 0.71±0.11 days. The small coefficient of variation (15.6%) indicated that the degradation rate of RNA did not vary substantially between subjects. The mean RBC lifespan (TRBC=76.6±23.8 days) was comparable to the reported values for this patient population. © 2013.


Zhao C.,Jilin University | Zhao C.,University of Louisville | Zhao C.,Wenzhou University | Liu Y.,University of Louisville | And 10 more authors.
Journal of Lipid Research | Year: 2015

Alcohol consumption leads to adipose tissue lipoatrophy and mobilization of FFAs, which contributes to hepatic fat accumulation in alcoholic liver disease. This study aimed to investigate the role of fi broblast growth factor (FGF)21, a metabolic regulator, in the regulation of chronic-binge alcohol-induced adipose tissue lipolysis. FGF21 KO mice were subjected to chronic-binge alcohol exposure, and epididymal white adipose tissue lipolysis and liver steatosis were investigated. Alcohol exposure caused adipose intracellular cAMP elevation and activation of lipolytic enzymes, leading to FFA mobilization in both WT and FGF21 KO mice. However, alcohol-induced systemic elevation of catecholamine, which is known to be a major player in adipose lipolysis by binding to the β -adrenergic receptor, was markedly inhibited in KO mice. Supplementation with recombinant human FGF21 to alcohol-exposed FGF21 KO mice resulted in an increase in fat loss in parallel with an increase of circulating norepinephrine concentration. Furthermore, alcohol consumption-induced fatty liver was blunted in the KO mice, indicating an inhibition of fatty acid reverse transport from adipose to the liver in the KO mice. Taken together, our studies demonstrate that FGF21 KO mice are protected from alcohol-induced adipose tissue excess-lipolysis through a mechanism involving systemic catecholamine release.


Yang X.,Columbia University | Hondur G.,Columbia University | Li M.,University of Louisville | Cai J.,University of Louisville | And 4 more authors.
Investigative Ophthalmology and Visual Science | Year: 2015

PURPOSE. To better understand ocular hypertension–induced early molecular lterations that may determine the initiation of neurodegeneration in human glaucoma, this study analyzed retinal proteomic alterations in the ocular hypertensive human retina. METHODS. Retina samples were obtained from six human donors with ocular hypertension (without glaucomatous injury) and six age- and sex-matched normotensive controls. Retinal proteins were analyzed by two-dimensional LC-MS/MS (liquid chromatography and linear ion trap mass spectrometry) using oxygen isotope labeling for relative quantification of protein expression. Proteomics data were validated by Western blot and immunohistochemical analyses of selected proteins. RESULTS. Out of over 2000 retinal proteins quantified, hundreds exhibited over 2-fold increased or decreased expression in ocular hypertensive samples relative to normotensive controls. Bioinformatics linked the proteomics datasets to various pathways important for maintenance of cellular homeostasis in the ocular hypertensive retina. Upregulated proteins included various heat shock proteins, ubiquitin proteasome pathway components, antioxidants, and DNA repair enzymes, while many proteins involved in mitochondrial oxidative phosphorylation exhibited downregulation in the ocular hypertensive retina. Despite the altered protein expression reflecting intrinsic adaptive/protective responses against mitochondrial energy failure, oxidative stress, and unfolded proteins, no alterations suggestive of an ongoing cell death process or neuroinflammation were detectable. CONCLUSIONS. This study provides information about ocular hypertension–related molecular risk factors for glaucoma development. Molecular alterations detected in the ocular hypertensive human retina as opposed to previously detected alterations in human donor retinas with clinically manifest glaucoma suggest that proteome alterations determine the individual threshold to tolerate the ocular hypertension–induced tissue stress or convert to glaucomatous neurodegeneration when intrinsic adaptive/protective responses are overwhelmed. © 2015 The Association for Research in Vision and Ophthalmology, Inc.


Moffett B.K.,University of Louisville | Moffett B.K.,Robley Rex Veterans Administration Medical Center | Panchabhai T.S.,University of Louisville | Panchabhai T.S.,Robley Rex Veterans Administration Medical Center | And 13 more authors.
European Respiratory Journal | Year: 2011

Patients with parapneumonic effusions (PPE) measuring <1 cm by lateral decubitus radiograph (LDR) or <5 cm by lateral erect radiograph (LER) do not require thoracentesis. No such data exist for chest computed tomography (CCT). The objective of this study was to identify a PPE measurement by CCT that indicates the need for thoracentesis. A secondary data analysis of two pneumonia databases was conducted to identify patients with PPE. Measurements of PPE using LDR, LER and CCT were correlated by linear regression analysis. The clinical outcome of community-acquired pneumonia patients managed with the newly defined CCT measurement was evaluated. PPE was identified in 419 out of 1,460 patients with possible pneumonia. PPE measurements of 1 cm and 5 cm by LDR and LER, respectively, correlated with a measurement of 2.5 cm by CCT. Out of 95 patients with CCT measurements <2.5 cm, 31 poor clinical outcomes were reported: outcome was PPE related (n=1); outcome was PPE unrelated (n=26); and outcome was not evaluable (n=4). The single case of poor outcome also measured <1 cm by LDR. This study indicates that patients with community-acquired pneumonia and a PPE measuring <2.5 cm by CCT can be managed without the need for thoracentesis. Copyright©ERS 2011.


Beier J.I.,University of Louisville | Arteel G.E.,University of Louisville | McClain C.J.,University of Louisville | McClain C.J.,Robley Rex Veterans Administration Medical Center
Current Gastroenterology Reports | Year: 2011

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States. In studies from the Veterans Administration, patients with cirrhosis and superimposed alcoholic hepatitis had greater than 60% mortality over a 4-year period, with most of those deaths occurring in the first month. Thus, the prognosis for this disease is more ominous than for many common types of cancer (eg, breast, prostate, and colon). Moreover, ALD imposes a significant economic burden from lost wages, health care costs, and lost productivity. Unfortunately, there is still no Food and Drug Administration-approved or widely accepted drug therapy for any stage of ALD. Thus, a pressing need exists for a more detailed understanding of mechanisms of liver injury. This article reviews recent advances in mechanisms and therapy related to five major areas of direct relevance to ALD: oxidative stress; gut-liver axis and cytokine signaling; malnutrition; fibrin/clotting; and stellate cell activation/fibrosis. We also review why therapies related to these mechanisms have performed well in experimental animals and in vitro systems, but have not necessarily translated into effective therapy for humans with ALD. © 2010 Springer Science+Business Media, LLC (outside the USA).


Roberts A.M.,University of Louisville | Yu J.,University of Louisville | Yu J.,Robley Rex Veterans Administration Medical Center | Joshua I.G.,University of Louisville
Journal of Applied Physiology | Year: 2015

Activation of pulmonary C-fibers can reflexively decrease heart rate, blood pressure, and peripheral vascular resistance. However, the effects of these afferents on microvascular tone remain incompletely understood. In this study, we examined the effects of these afferents on microvascular tone in a striated muscle vascular bed. The right cremaster muscle in pentobarbital-anesthetized rats with intact circulation and innervation was suspended in a tissue bath, and diameters of small arterioles were measured by intravital video microscopy. Stimulation of pulmonary C-fibers by injecting capsaicin (5 μg/kg) or phenylbiguanide (20 μg/kg) into the right atrium dilated small arterioles and decreased blood pressure and heart rate. The effects persisted when the cervical vagus nerves were cooled to 5 to 7°C (blocking myelinated fibers), but were prevented by cooling to 0°C (blocking C-fibers and myelinated fibers), by cutting the genital femoral nerve (GFN) supplying the cremaster to block the nerve supply to the muscle, or by adding 6-hydroxydopamine to the bathing medium to selectively block sympathetic effects by depleting norepinephrine from adrenergic nerve terminals. Our results show that stimulation of pulmonary C-fibers reflexively dilates small arterioles in striated muscle by a mechanism that could involve withdrawal of sympathetic adrenergic tone. In conclusion, pulmonary C-fibers can exert an inhibitory influence on neural tone of the microcirculation at an important site where microvascular resistance and tissue blood flow are regulated. Copyright © 2015 the American Physiological Society.


PubMed | Robley Rex Veterans Administration Medical Center
Type: Journal Article | Journal: Current opinion in nephrology and hypertension | Year: 2011

This review will explore the basic assumptions needed to perform predictive modeling of hemoglobin response to erythropoiesis stimulating agents (ESAs) and summarize the current literature in the area so that the practitioner can incorporate these tools as part of an improved anemia management process.During the last year, several publications have demonstrated some advances in the field that may improve anemia management. The first of these was the publication of a randomized, controlled clinical trial of model predictive control in the dosing of erythropoietin. This work showed that hemoglobin variability can be decreased using predictive models of hemoglobin response. The second publication is potentially more interesting in the long run, as new markers of erythropoietin response were identified in a well-defined population of patients.Predictive models of hemoglobin response improve anemia management by decreasing hemoglobin variability. This will result in more patients within the target range. Coupling these tools with new biomarkers of hemoglobin response has the potential to dramatically improve anemia management.


Zhuang X.,University of Louisville | Teng Y.,University of Louisville | Samykutty A.,University of Louisville | Mu J.,University of Louisville | And 8 more authors.
Molecular Therapy | Year: 2016

The lack of access to the brain is a major obstacle for central nervous system drug development. In this study, we demonstrate the capability of a grapefruit-derived nanovector (GNV) to carry miR17 for therapeutic treatment of mouse brain tumor. We show that GNVs coated with folic acid (FA-GNVs) are enhanced for targeting the GNVs to a folate receptor-positive GL-26 brain tumor. Additionally, FA-GNV-coated polyethylenimine (FA-pGNVs) not only enhance the capacity to carry RNA, but the toxicity of the polyethylenimine is eliminated by the GNVs. Intranasal administration of miR17 carried by FA-pGNVs led to rapid delivery of miR17 to the brain that was selectively taken up by GL-26 tumor cells. Mice treated intranasally with FA-pGNV/miR17 had delayed brain tumor growth. Our results demonstrate that this strategy may provide a noninvasive therapeutic approach for treating brain-related disease through intranasal delivery. © 2016 The American Society of Gene & Cell Therapy.

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