Nebraska Western Iowa Health Care System

Omaha, NE, United States

Nebraska Western Iowa Health Care System

Omaha, NE, United States
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Cheng P.-W.,Nebraska Western Iowa Health Care System | Clemens D.L.,University of Nebraska Medical Center | Clemens D.L.,Nebraska Western Iowa Health Care System | Casey C.A.,University of Nebraska Medical Center | Casey C.A.,Nebraska Western Iowa Health Care System
Scientific Reports | Year: 2015

The hepatic asialoglycoprotein receptor (ASGP-R) is posttranslationally modified in the Golgi en route to the plasma membrane, where it mediates clearance of desialylated serum glycoproteins. It is known that content of plasma membrane-associated ASGP-R is decreased after ethanol exposure, although the mechanisms remain elusive. Previously, we found that formation of compact Golgi requires dimerization of the largest Golgi matrix protein giantin. We hypothesize that ethanol-impaired giantin function may be related to altered trafficking of ASGP-R. Here we report that in HepG2 cells expressing alcohol dehydrogenase and hepatocytes of ethanol-fed rats, ethanol metabolism results in Golgi disorganization. This process is initiated by dysfunction of SAR1A GTPase followed by altered COPII vesicle formation and impaired Golgi delivery of the protein disulfide isomerase A3 (PDIA3), an enzyme that catalyzes giantin dimerization. Additionally, we show that SAR1A gene silencing in hepatocytes mimics the effect of ethanol: dedimerization of giantin, arresting PDIA3 in the endoplasmic reticulum (ER) and large-scale alterations in Golgi architecture. Ethanol-induced Golgi fission has no effect on ER-to-Golgi transportation of ASGP-R, however, it results in its deposition in cis-medial-, but not trans-Golgi. Thus, alcohol-induced deficiency in COPII vesicle formation predetermines Golgi fragmentation which, in turn, compromises the Golgi-to-plasma membrane transportation of ASGP-R.


Petrosyan A.,Pamela Buffett Cancer Center | Casey C.A.,University of Nebraska Medical Center | Casey C.A.,Nebraska Western Iowa Health Care System | Cheng P.-W.,Pamela Buffett Cancer Center | Cheng P.-W.,Nebraska Western Iowa Health Care System
Scientific Reports | Year: 2016

Abnormalities in the Golgi apparatus function are important to the development of alcoholic liver injury. We recently reported that Golgi disorganization in ethanol (EtOH)-treated hepatocytes is caused by impaired dimerization of the largest Golgi matrix protein, giantin. However, little is known about the mechanism which forces fragmentation. Here, in both HepG2 cells overexpressing alcohol dehydrogenase and in rat hepatocytes, we found that EtOH administration reduces the complex between giantin and Rab6a GTPase and results in the S1943 phosphorylation of non-muscle Myosin IIA (NMIIA) heavy chain, thus facilitating NMIIA association with Golgi enzymes, as detected by biochemical approaches and 3D Structured Illumination Microscopy. We revealed that NMIIA-P-S1943 competes with giantin for the Rab6a dimer, which was converted to monomer after Golgi fragmentation. Therefore, Rab6a plays a dual role in the Golgi, serving as master regulator of Golgi organization and disorganization, and that NMIIA and giantin engage in a "tug-of-war". However, the inhibition of F-actin and downregulation of NMIIA or overexpression of NMHC-IIAδtailpiece, as well the overexpression of dominant negative Rab6a(T27N), preserved a compact Golgi phenotype. Thus, the actomyosin complex forces EtOH-induced Golgi disorganization, and the targeting of NMIIA-P-S1943 may be important for preventing the damaging effects of alcohol metabolism on the cell.


Neuman M.G.,Drug Safety and Biotechnology | Neuman M.G.,University of Toronto | French S.W.,University of California at Los Angeles | Casey C.A.,Nebraska Western Iowa Health Care System | And 13 more authors.
Experimental and Molecular Pathology | Year: 2013

Excessive alcohol consumption presents considerable health risks in humans. A variety of morphologic and functional changes contribute to hepatic injury produced by heavy drinking. The present review summarizes the current knowledge of alcohol-induced liver disease and describes preclinical experimental approaches used to understand alcoholic liver disease (ALD), with a particular emphasis on impaired protein and lipid trafficking, disruption of proteolysis and autophagy, alterations in methionine metabolism and perturbations in metabolic signaling that cause dysfunctional gene expression and the eventual formation of aggresomal Mallory-Denk bodies (MDB) in liver cells. These changes eventually lead to some of the more severe hepatic impairments, including alcoholic hepatitis and fibrosis. Moreover the misuse of alcohol contributes to immune dysfunction and inadequate immune response to viral infections. © 2013 Elsevier Inc.


Reidelberger R.D.,Nebraska Western Iowa Health Care System | Reidelberger R.D.,Creighton University | Haver A.C.,Nebraska Western Iowa Health Care System | Haver A.C.,Creighton University | And 3 more authors.
Obesity | Year: 2011

Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY3-36 (PYY 3-36). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY3-36 that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20pmol/h (0.15nmol/kg/day) produced a sustained 24 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY 3-36 produced a similar reduction in daily food intake for 10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY 3-36 on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY3-36 does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY 3-36 on food intake and body weight. © 2010 The Obesity Society.


Abuzaid A.S.,Creighton University | Birch N.,Nebraska Western Iowa Health Care System
Sultan Qaboos University Medical Journal | Year: 2015

Hyponatraemia is a common electrolyte disturbance, with moderate (serum sodium: 125–129 mmol/L) to severe (serum sodium: ≤125 mmol/L) forms of the disease occurring in 4–15% of hospitalised patients. While it is relatively common, determining the underlying cause of this condition can be challenging and may require extensive laboratory investigations. To this end, it is important to ascertain the efficacy of laboratory tests in determining the cause of hyponatraemia. Up to 10% of patients with hypothyroidism also have hyponatraemia. Routine evaluation of thyroid function is often advocated in cases of low serum sodium. A review and discussion of the available literature is presented here to examine this recommendation. © 2015 Sultan Qaboos University. All rights reserved.


Ramaswamy S.,Creighton University | Ramaswamy S.,Nebraska Western Iowa Health Care System | Driscoll D.,Nebraska Western Iowa Health Care System | Smith L.M.,University of Nebraska Medical Center | And 4 more authors.
Contemporary Clinical Trials Communications | Year: 2016

Background Post-traumatic stress disorder (PTSD) is a chronic anxiety disorder that is often difficult to treat. Patients suffering from PTSD often fail to respond to antidepressants and may have a high incidence of positive symptoms of psychosis, though antipsychotic medications have been minimally studied in this population. The aim of this study was to assess the impact of the atypical antipsychotic ziprasidone (Geodon) on PTSD symptom clusters, as well as comorbid major depressive disorder. To our knowledge, this is the first completed randomized controlled trial investigating the potential efficacy and tolerability of ziprasidone in patients with chronic PTSD. Methods We conducted a 9-week prospective, randomized, double-blind, placebo-controlled trial of ziprasidone in 30 patients diagnosed with PTSD and comorbid depression. After screening and randomization, patients completed nine weekly study visits at which treatment safety and efficacy were evaluated. Primary measures of efficacy included total and subscale scores from the Clinician-Administered PTSD Scale (CAPS), while the Hamilton Rating Scale for Depression (HAM-D), Hamilton Anxiety Scale (HAM-A), Clinical Global Impression (CGI), and Treatment Outcome PTSD Scale (TOP-8) were implemented as secondary efficacy measures. Results We observed no significant effect of treatment on reduction of PTSD or depression symptoms from pre- to post-treatment. Conclusions Our findings suggest that ziprasidone treatment may not significantly improve symptoms of PTSD or comorbid depression, though further study is needed.


PubMed | Nebraska Western Iowa Health Care System and Creighton University
Type: Journal Article | Journal: Sultan Qaboos University medical journal | Year: 2015

Hyponatraemia is a common electrolyte disturbance, with moderate (serum sodium: 125-129 mmol/L) to severe (serum sodium: 125 mmol/L) forms of the disease occurring in 4-15% of hospitalised patients. While it is relatively common, determining the underlying cause of this condition can be challenging and may require extensive laboratory investigations. To this end, it is important to ascertain the efficacy of laboratory tests in determining the cause of hyponatraemia. Up to 10% of patients with hypothyroidism also have hyponatraemia. Routine evaluation of thyroid function is often advocated in cases of low serum sodium. A review and discussion of the available literature is presented here to examine this recommendation.


Mikuls T.R.,University of Nebraska Medical Center | Mikuls T.R.,Nebraska Western Iowa Health Care System | Payne J.B.,University of Nebraska Medical Center | Deane K.D.,Aurora University | And 2 more authors.
Journal of Allergy and Clinical Immunology | Year: 2016

There is a growing body of evidence to suggest that autoimmunity in patients with rheumatoid arthritis (RA) is initiated outside the joint. This is supported by the observation that circulating autoantibodies, including both rheumatoid factor and anti-citrullinated protein antibody, can be detected in many subjects years before the development of initial joint symptoms leading to an RA diagnosis. Of the potential extra-articular sites implicated in disease initiation, mucosal tissues have garnered increasing attention. Several lines of investigation have separately implicated mucosal tissues from varying anatomic locations as possible initiating sites for RA, including those from the lung and oral cavity. In this review we summarize recent reports incriminating these mucosal tissues as the initial site of autoantibody generation and inflammation in patients with RA. © 2015 American Academy of Allergy, Asthma & Immunology.


Padala P.R.,University of Arkansas for Medical Sciences | Padala K.P.,University of Arkansas for Medical Sciences | Monga V.,Nebraska Western Iowa Health Care System | Ramirez D.A.,Nebraska Western Iowa Health Care System | Sullivan D.H.,University of Arkansas for Medical Sciences
Annals of Pharmacotherapy | Year: 2012

OBJECTIVE: To report 6 cases of selective serotonin reuptake inhibitor (SSRI)-associated apathy syndrome. CASE SUMMARIES: In all 6 cases, the patient reported loss of motivation while being treated with an SSRI. Loss of motivation was of new onset and temporally associated with the use of the SSRI. A trial of discontinuation of the SSRI was performed in all 6 patients and 2 were started on bupropion while cross-tapering from the SSRI. During the treatment trials, depression and apathy were monitored in all patients. Each case was assessed using the Apathy Evaluation Scale, Clinician version (AES-C), and by evaluating how the patient responded to discontinuation of the SSRI. DISCUSSION: Scores on the AES-C improved significantly in all 6 cases after the SSRI was discontinued. Improvement was also seen in the motivation, novelty, and persistence subdomain scores of the AES-C. A pretreatment AES-C score was available only in the first case. Based on the Naranjo probability scale, there was a probable cause of apathy syndrome with SSRI therapy in the first case and a possible association in the rest of the cases. CONCLUSIONS: In some patients SSRIs may cause an apathy syndrome that can be reversed through discontinuation of the agent. When evaluating patients being treated with an SSRI, clinicians should have a high degree of suspicion and specifically inquire for this iatrogenic form of apathy syndrome.


PubMed | University of British Columbia, University of Toronto, Cooperative Studies Program Coordinating Center, Health Economics Resource Center and the Center for Health Care Evaluation and Nebraska Western Iowa Health Care System
Type: | Journal: Trials | Year: 2015

A recent trial in rheumatoid arthritis found an inexpensive, but infrequently used, combination of therapies is neither inferior nor less safe than an expensive biologic drug. If the trial had been conducted over 10 years ago, arguably 100s of millions of dollars since spent on biologics could have been released to other, more effective treatments. Given the ever increasing number of trials proposed, this commentary uses the trial as an example to challenge payers and research funders to make smarter investments in clinical research to save potential future costs.NCT00405275 , registered 29 November 2006.

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