Jesse Brown Veterans Administration Medical Center

Chicago, IL, United States

Jesse Brown Veterans Administration Medical Center

Chicago, IL, United States
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Molokie R.E.,University of Illinois at Chicago | Molokie R.E.,Jesse Brown Veterans Administration Medical Center | Wilkie D.J.,University of Illinois at Chicago | Wittert H.,University of Illinois at Chicago | And 5 more authors.
European Journal of Pharmacology | Year: 2014

Recent evidence of neuropathic pain among adults with sickle cell disease (SCD) reveals a need for adjuvant analgesic treatments for these patients. Ca2+/calmodulin protein kinase IIα (CaMKIIα) has a known role in neuropathic pain and trifluoperazine is a potent CaMKIIα inhibitor. The study aim was to determine trifluoperazine's acute effects, primarily on adverse effects and secondarily on pain intensity reduction, in adults with SCD. In a phase I, open-label study of 6 doses of trifluoperazine (0.5, 1, 2, 5, 7.5, 10 mg), we obtained 7-hourly and 24-h repeated measures of adverse effects, pain intensity, and supplemental opioid analgesics in 18 adults with SCD (18 hemoglobin SS disease, 15 women, average age 35.8±8.9 years, ranged 23-53) each of whom received a single dose. Data were analyzed with descriptive statistics. Subjects reported moderate to severe sedative effects at 7.5 and 10 mg doses, respectively. Eight subjects reported 50% reduction in chronic pain without severe sedation or supplemental opioid analgesics; one of these subjects had dystonia 24.5 h after the 10 mg dose. The analgesic effect lasted for at least 24 h in 3 subjects. Sedation resolved with caffeine and dystonia resolved with diphenhydramine. Adults with SCD experienced minimal adverse effects at doses under 10 mg. In this molecular mechanism-driven translational study, trifluoperazine shows promise as an analgesic drug that is worthy of further testing in a randomized controlled study of adults with SCD starting at a dose of 1 mg in repeated doses to determine long-term adverse and analgesic effects.

Bishop J.R.,University of Illinois at Chicago | Reilly J.L.,Northwestern University | Harris M.S.H.,Jesse Brown Veterans Administration Medical Center | Patel S.R.,University of Illinois at Chicago | And 7 more authors.
Psychopharmacology | Year: 2015

Rationale: Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated. Objectives: The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment. Methods: Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients' level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions. Results: Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment. Conclusions: These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects. © Springer-Verlag 2014.

Keeton E.K.,Astrazeneca | McEachern K.,Astrazeneca | Dillman K.S.,Astrazeneca | Palakurthi S.,Astrazeneca | And 19 more authors.
Blood | Year: 2014

Upregulation of Pim kinases is observed in several types of leukemias and lymphomas. Pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor that effectively inhibits all three isoforms at <5 nM or <150 nM in enzyme and cell assays, respectively. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent reduction in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, andS6, aswell as increases in cleaved caspase 3 and p27. Inhibition of p4EBP1 and p-p70S6K and suppression of translation are the most representative effects of Pim inhibition in sensitive AML cell lines. AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bonemarrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant. These results underscore the therapeutic potential of Pim kinase inhibition for the treatment of AML. © 2014 by The American Society of Hematology.

Menon U.,Arizona State University | Belue R.,Pennsylvania State University | Wahab S.,Portland State University | Rugen K.,Jesse Brown Veterans Administration Medical Center | And 4 more authors.
Annals of Behavioral Medicine | Year: 2011

Background Early-stage diagnosis of colorectal cancer is associated with high survival rates; screening prevalence, however, remains suboptimal. Purpose This study seeks to test the hypothesis that participants receiving telephone-based tailored education or motivational interviewing had higher colorectal cancer screening completion rates compared to usual care. Methods Primary care patients not adherent with colorectal cancer screening and with no personal or family history of cancer (n=515) were assigned by block randomization to control (n=169), tailored education (n=168), or motivational interview (n=178). The response rate was 70%; attrition was 24%. Results Highest screening occurred in the tailored education group (23.8%, p<.02); participants had 2.2 times the odds of completing a post-intervention colorectal cancer screening than did the control group (AOR=2.2, CI=1.2-4.0). Motivational interviewing was not associated with significant increase in post-intervention screening. Conclusions Tailored education showed promise as a feasible strategy to increase colorectal cancer screening. © The Society of Behavioral Medicine 2011.

Huang W.,Northwestern University | Zhou W.,Northwestern University | Saberwal G.,Northwestern University | Saberwal G.,Jesse Brown Veterans Administration Medical Center | And 8 more authors.
Molecular and Cellular Biology | Year: 2010

The interferon consensus sequence binding protein (ICSBP) is an interferon regulatory transcription factor, also referred to as IRF8. ICSBP acts as a suppressor of myeloid leukemia, although few target genes explaining this effect have been identified. In the current studies, we identified the gene encoding growth arrest specific 2 (GAS2) as an ICSBP target gene relevant to leukemia suppression. We find that ICSBP, Tel, and histone deacetylase 3 (HDAC3) bind to a cis element in the GAS2 promoter and repress transcription in myeloid progenitor cells. Gas2 inhibits calpain protease activity, and β-catenin is a calpain substrate in these cells. Consistent with this, ICSBP decreases β-catenin protein and activity in a Gas2- and calpain-dependent manner. Conversely, decreased ICSBP expression increases β-catenin protein and activity by the same mechanism. This is of interest, because decreased ICSBP expression and increased β-catenin activity are associated with poor prognosis and blast crisis in chronic myeloid leukemia (CML). We find that the expression of Bcr/abl (the CML oncoprotein) increases Gas2 expression in an ICSBP-dependent manner. This results in decreased calpain activity and a consequent increase in β-catenin activity in Bcr/abl-positive (Bcr/abl +) cells. Therefore, these studies have identified a Gas2/calpain-dependent mechanism by which ICSBP influences β-catenin activity in myeloid leukemia. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Ming J.,University of Illinois at Chicago | Thulborn K.R.,University of Illinois at Chicago | Szlyk J.P.,University of Illinois at Chicago | Szlyk J.P.,Jesse Brown Veterans Administration Medical Center
Investigative Ophthalmology and Visual Science | Year: 2012

Purpose. To test the intra- and intersubject reproducibility of brain activation patterns that underlie visually guided saccades and word recognition in normally sighted subjects and patients with macular degeneration using functional magnetic resonance imaging (fMRI). Methods. Ten normally sighted subjects and five patients with macular degeneration were asked to perform two visually guided saccade tasks and two word-recognition tasks during fMRI with behavioral monitoring. The fMRI measurements were repeated three times at intervals of at least 4 weeks between sessions. The intrasubject reproducibility of the brain activation patterns was examined in a model-independent manner by comparing the distributions of activation across the frontal, parietal, temporal, and occipital brain lobes using Intraclass Correlation Coefficients (ICCs). Intersubject reproducibility was examined by repeated-measure ANOVA. Results. Control subjects showed overall higher intrasubject reproducibility of brain activation patterns (75% ICCs > 0.5) than that of patients with macular degeneration (56% ICCs > 0.5). The intrasubject reproducibility for the patients improved when the target location was fixed, as in the word-recognition tasks (75% ICCs > 0.5), compared with the visually saccade tasks (37% ICCs > 0.5). Intersubject variability of brain activation patterns was strikingly high for both the control and patient groups. Conclusions. The fMRI method can serve as a reliable within-subjects measure of brain activation that has potential for measuring longitudinal changes in brain networks associated with rehabilitation training. Striking intersubject variability reflected at the level of lobes of the brain among control subjects with similar behavioral performance, suggests individual analysis is necessary when implementing longitudinal brain activation studies. © 2012 The Association for Research in Vision and Ophthalmology, Inc.

Coccaro E.F.,University of Chicago | Fanning J.R.,University of Chicago | Phan K.L.,University of Illinois at Chicago | Phan K.L.,Jesse Brown Veterans Administration Medical Center | Lee R.,University of Chicago
CNS Spectrums | Year: 2015

Aggression is a behavior with evolutionary origins, but is often both destructive and maladaptive in today's society. Research over the past several decades has confirmed the involvement of neurotransmitter function in aggressive behavior. This research has centered around the serotonin hypothesis. As this literature continues to grow, guided by pre-clinical research and aided by the application of increasingly sophisticated neuroimaging methodology, a more complex picture has emerged. As current pharmacological and therapeutic interventions are effective but imperfect, it is hoped that new insights into the neurobiology of aggression will reveal novel avenues for treatment of this destructive and costly behavior. © 2015 Cambridge University Press.

Kessler C.S.,University of Illinois at Chicago | Kessler C.S.,Jesse Brown Veterans Administration Medical Center | McGuinn M.,University of Illinois at Chicago | McGuinn M.,Jesse Brown Veterans Administration Medical Center | And 4 more authors.
American Journal of Infection Control | Year: 2011

Background: It has been estimated that more than 8 million health care workers (HCWs) in the United States may be exposed to blood and body fluids via sharp and mucocutaneous exposures. Methods: An anonymous questionnaire was distributed among 505 HCWs. The target sample population included all the medical students; nursing professionals; dental professionals; and residents in internal medicine, emergency medicine, surgery, and obstetrics and gynecology at the University of Illinois Medical Center, Chicago, Illinois, a metropolitan tertiary care and referral center for Northern Illinois and Northwest Indiana. The sample was limited by the number of HCWs who were available to take the survey. The number and the characteristics of occupational exposures and reporting practices were recorded and compiled. Subsequently, a review of the English literature was performed using PubMed to analyze reasons for underreporting. Secondary and tertiary articles were located based on findings from the initial searches. Results: One hundred three of 455 (22.6%) HCWs reported a sharps exposure during their career, including their student years; thirty-four (33.0%) of these were not reported. One hundred five of 455 (23.1%) HCWs reported a mucocutaneous exposure during their career; 87 (82.9%) of these were not reported. The most common year of exposure was the intern year. The most common reason for not reporting was the belief that the exposure was not significant, followed by the combination of believing the exposure was not significant and being too busy. Conclusion: Underreporting of blood and body fluid exposures is common because of a belief that most exposures are not significant. More education of HCWs is needed to change this perspective.

Kuzmis A.,University of Illinois at Chicago | Lim S.B.,University of Illinois at Chicago | Desai E.,University of Illinois at Chicago | Jeon E.,University of Illinois at Chicago | And 4 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2011

Human neuropeptide Y (NPY) is an important biologics that regulates a multitude of physiological functions and could be amenable to therapeutic manipulations in certain disease states. However, rapid (within minutes) enzymatic degradation and inactivation of NPY precludes its development as a drug. Accordingly, we determined whether self-association of NPY with biocompatible and biodegradable sterically stabilized phospholipid micelles (SSM) improves its stability and bioactivity. We found that in saline NPY spontaneously aggregates; however, in the presence of SSM it self-associates with the micelles as monomers. Three NPY molecules self-associate with 1 SSM at saturation. This process stabilizes the peptide in α-helix conformation, abrogates its degradation by dipeptidyl peptidase-4 and potentiates NPY-induced inhibition of cAMP elaboration in SK-N-MC cells. Collectively, these data indicate that self-association of NPY with SSM stabilizes and protects the peptide in active monomeric conformation, thereby amplifying its bioactivity in vitro. We propose further development of NPY in SSM as a novel, long-acting nanomedicine. © 2011 Elsevier Inc.

Schwartz A.,University of Illinois at Chicago | Weiner S.J.,University of Illinois at Chicago | Weiner S.J.,Jesse Brown Veterans Administration Medical Center | Harris I.B.,University of Illinois at Chicago | Binns-Calvey A.,University of Illinois at Chicago
JAMA - Journal of the American Medical Association | Year: 2010

Context: A contextual error occurs when a physician does not identify elements of a patient's environment or behavior, such as access to care, that must be addressed to appropriately plan care. Research has demonstrated that contextual errors can be identified using standardized patients. Objective: To evaluate an educational intervention designed to increase physicians' skills in incorporating the patient's context in assessment and management of care and to thereby decrease the rate of contextual errors. Design, Setting, and Participants: Quasi-randomized controlled trial, with assessments by blinded observers. Fourth-year medical students (n=124) in internal medicine subinternships at the University of Illinois at Chicago or Jesse Brown Veterans Administration Medical Center between July 2008 and April 2009 and between August 2009 and April 2010 participated and were assessed. Intervention: A 4-hour course on contextualization. Main Outcome Measures: Probing for contextual issues in an encounter, probing for medical issues in an encounter, and developing an appropriate treatment plan. Outcomes were assessed using 4 previously validated standardized patient encounters performed by each participant and were adjusted for subinternship site, academic year, time of year, and case scenario. Results: Students who participated in the contextualization workshops were significantly more likely to probe for contextual issues in the standardized patient encounters than students who did not (90% [95% confidence interval {CI}, 87%-94% ] vs 62% [95% CI, 54%-69%], respectively) and significantly more likely to develop appropriate treatment plans for standardized patients with contextual issues (69% [95% CI, 57%-81%] vs 22% [95% CI, 12%-32%]. There was no difference between the groups in the rate of probing for medical issues (80% [95% CI, 75%-85%] vs 81% [95% CI, 76%-86%]) or developing appropriate treatment plans for standardized patients with medical issues (54% [95% CI, 42%-67%] vs 66% [95% CI, 53%-79%]). Conclusion: Medical students who underwent an educational intervention were more likely to contextualize care for individual standardized patients. ©2010 American Medical Association. All rights reserved.

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