Baltimore Veterans Administration Medical Center

Baltimore, MD, United States

Baltimore Veterans Administration Medical Center

Baltimore, MD, United States
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Lee J.,Johns Hopkins University | Choi J.,Johns Hopkins University | Selen Alpergin E.S.,Johns Hopkins University | Zhao L.,Johns Hopkins University | And 6 more authors.
Cell Reports | Year: 2017

The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high-fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long-chain fatty acid β-oxidation (Cpt2L−/− mice). Paradoxically, Cpt2L−/− mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress, and systemic carnitine deficiency. Feeding an HFD induced hepatokines in mice, with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance. © 2017 The Author(s)

Deepak J.A.,University of Maryland Baltimore County | Deepak J.A.,Baltimore Veterans Administration Medical Center | Ng X.,University of Maryland, Baltimore | Feliciano J.,University of Maryland Baltimore County | And 2 more authors.
Annals of the American Thoracic Society | Year: 2015

Rationale: Up to 80% of patients with lung cancer have comorbid chronic obstructive pulmonary disease (COPD). Many of them are poor candidates for stage-specific lung cancer treatment due to diminished lung function and poor functional status, and many forego treatment. The negative effect of COPD may be moderated by pulmonologist-guided management. Objectives: This study examined the association between pulmonologist management and the probability of receiving the recommended stage-specific treatment modality and overall survival among patients with non-small cell lung cancer (NSCLC) with preexisting COPD. Methods: Early- and advanced-stage NSCLC cases diagnosed between 2002 and 2005 with a prior COPD diagnosis (3-24 months before NSCLC diagnosis) were identified in Surveillance, Epidemiology, and End Results tumor registry data linked to Medicare claims. Study outcomes included receipt of recommended stage-specific treatment (surgical resection for early-stage NSCLC and chemotherapy for advanced-stage NSCLC [advNSCLC]) and overall survival. Pulmonologist management was considered present if one or more Evaluation and Management visit claims with pulmonologist specialty were observed within 6 months after NSCLC diagnosis. Stage-specific multivariate logistic regression tested association between pulmonologist management and treatment received. Cox proportional hazard models examined the independent association between pulmonologist care and mortality. Two-stage residual inclusion instrumental variable (2SRI-IV) analyses tested and adjusted for potential confounding based on unobserved factors or measurement error. Measurements and Main Results: The cohorts included 5,488 patients with early-stage NSCLC and 6,426 patients with advNSCLC disease with preexisting COPD. Pulmonologist management was recorded for 54.9% of patients with early stage NSCLC and 35.7% of patients with advNSCLC. Of those patients with pulmonologist involvement, 58.5% of patients with early NSCLC received surgical resection, and 43.6% of patients with advNSCLC received chemotherapy. Pulmonologist management post NSCLC diagnosis was associated with increased surgical resection rates (odds ratio, 1.26; 95% confidence interval, 1.11-1.45) for early NSCLC and increased chemotherapy rates (odds ratio, 1.88; 95% confidence interval, 1.67-2.10) for advNSCLC. Pulmonologist management was also associated with reduced mortality risk for patients with early-stage NSCLC but not AdvNSCLC. Conclusions: Pulmonologist management had a positive association with rates of stage-specific treatment in both groups and overall survival in early-stage NSCLC. These results provide preliminary support for the recently published guidelines emphasizing the role of pulmonologists in lung cancer management. Copyright © 2015 by the American Thoracic Society.

Dipietro L.,Massachusetts Institute of Technology | Krebs H.I.,Massachusetts Institute of Technology | Krebs H.I.,University of Maryland, Baltimore | Volpe B.T.,Feinstein Institute for Medical Research | And 8 more authors.
IEEE Transactions on Neural Systems and Rehabilitation Engineering | Year: 2012

Both the American Heart Association and the VA/DoD endorse upper-extremity robot-mediated rehabilitation therapy for stroke care. However, we do not know yet how to optimize therapy for a particular patient's needs. Here, we explore whether we must train patients for each functional task that they must perform during their activities of daily living or alternatively capacitate patients to perform a class of tasks and have therapists assist them later in translating the observed gains into activities of daily living. The former implies that motor adaptation is a better model for motor recovery. The latter implies that motor learning (which allows for generalization) is a better model for motor recovery. We quantified trained and untrained movements performed by 158 recovering stroke patients via 13 metrics, including movement smoothness and submovements. Improvements were observed both in trained and untrained movements suggesting that generalization occurred. Our findings suggest that, as motor recovery progresses, an internal representation of the task is rebuilt by the brain in a process that better resembles motor learning than motor adaptation. Our findings highlight possible improvements for therapeutic algorithms design, suggesting sparse-activity-set training should suffice over exhaustive sets of task specific training. © 2006 IEEE.

Ma X.,University of Maryland, Baltimore | Holt D.,University of Maryland, Baltimore | Kundu N.,University of Maryland, Baltimore | Reader J.,University of Maryland, Baltimore | And 4 more authors.
OncoImmunology | Year: 2013

Cyclooxygenase-2 is frequently upregulated in epithelial tumors and contributes to poor outcomes in multiple malignancies. The COX-2 product prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on a family of four G protein-coupled receptors (EP 1-4). Using a novel small molecule EP 4 antagonist (RQ-15986) and a syngeneic murine model of metastatic breast cancer, we determined the effect of EP 4 blockade on innate immunity and tumor biology. Natural killer (NK)-cell functions are markedly depressed in mice bearing murine mammary tumor 66.1 or 410.4 cells owing to the actions of PGE2 on NK cell EP 4 receptors. The EP 4 agonist PGE1-OH inhibits NK functions in vitro, and this negative regulation is blocked by RQ-15986. Likewise, the treatment of tumor-bearing mice with RQ-15986 completely protected NK cells from the immunosuppressive effects of the tumor microenvironment in vivo. RQ-15986 also has direct effects on EP 4 expressed by tumor cells, inhibiting the PGE2-mediated activation of adenylate cyclase and blocking PGE2-induced tumor cell migration. The pretreatment of tumor cells with a non-cytotoxic concentration of RQ-15986 inhibited lung colonization, a beneficial effect that was lost in mice depleted of NK cells. The oral administration of RQ-15986 inhibited the growth of tumor cells implanted into mammary glands and their spontaneous metastatic colonization to the lungs, resulting in improved survival. Our findings reveal that EP 4 antagonism prevents tumor-mediated NKcell immunosuppression and demonstrates the anti-metastatic activity of a novel EP 4 antagonist. These observations support the investigation of EP 4 antagonists in clinical trials. © 2013 Landes Bioscience.

Bogan R.,Johns Hopkins University | Riddle R.C.,Johns Hopkins University | Riddle R.C.,Baltimore Veterans Administration Medical Center | Li Z.,Johns Hopkins University | And 7 more authors.
Journal of Bone and Mineral Research | Year: 2013

Osteogenesis imperfecta type VI (OI type VI) has recently be linked to a mutation in the SERPINF1 gene, which encodes pigment epithelium-derived factor (PEDF), a ubiquitously expressed protein originally described for its neurotrophic and antiangiogenic properties. In this study, we characterized the skeletal phenotype of a mouse with targeted disruption of Pedf. In normal mouse bone, Pedf was localized to osteoblasts and osteocytes. Micro-computed tomography (μCT) and quantitative bone histomorphometry in femurs of mature Pedf null mutants revealed reduced trabecular bone volume and the accumulation of unmineralized bone matrix. Fourier transform infrared microscopy (FTIR) indicated an increased mineral:matrix ratio in mutant bones, which were more brittle than controls. In vitro, osteoblasts from Pedf null mice exhibited enhanced mineral deposition as assessed by Alizarin Red staining and an increased mineral:matrix determined by FTIR analysis of calcified nodules. The findings in this mouse model mimic the principal structural and biochemical features of bone observed in humans with OI type VI and consequently provide a useful model with which to further investigate the role of PEDF in this bone disorder. Copyright © 2013 American Society for Bone and Mineral Research.

Zoch M.L.,Johns Hopkins University | Clemens T.L.,Johns Hopkins University | Clemens T.L.,Baltimore Veterans Administration Medical Center | Riddle R.C.,Johns Hopkins University | Riddle R.C.,Baltimore Veterans Administration Medical Center
Bone | Year: 2016

Osteocalcin is among the most abundant proteins in bone and is produced exclusively by osteoblasts. Initially believed to be an inhibitor of bone mineralization, recent studies suggest a broader role for osteocalcin that extends to the regulation of whole body metabolism, reproduction, and cognition. Circulating undercarboxylated osteocalcin, which is regulated by insulin, acts in a feed-forward loop to increase β-cell proliferation as well as insulin production and secretion, while skeletal muscle and adipose tissue respond to osteocalcin by increasing their sensitivity to insulin. Osteocalcin also acts in the brain to increase neurotransmitter production and in the testes to stimulate testosterone production. At least one putative receptor for osteocalcin, Gprc6a, is expressed by adipose, skeletal muscle, and the Leydig cells of the testes and appears to mediate osteocalcin's effects in these tissues. In this review, we summarize these new discoveries, which suggest that the ability of osteocalcin to function both locally in bone and as a hormone depends on a novel post-translational mechanism that alters osteocalcin's affinity for the bone matrix and bioavailability. This article is part of a Special Issue entitled Bone and diabetes. © 2015 Elsevier Inc.

Zhang Q.,Johns Hopkins University | Riddle R.C.,Johns Hopkins University | Riddle R.C.,Baltimore Veterans Administration Medical Center | Clemens T.L.,Johns Hopkins University | Clemens T.L.,Baltimore Veterans Administration Medical Center
Journal of Internal Medicine | Year: 2015

The skeleton, populated by large numbers of osteoblasts and long-lived osteocytes, requires a constant supply of energy-rich molecules to fuel the synthesis, deposition and mineralization of bone matrix during bone modelling and remodelling. When these energetic demands are not met, bone acquisition is suppressed. Recent findings suggest that key developmental signals emanating from Wnt low-density lipoprotein-related receptor 5 and hypoxia-inducible factor pathways impact osteoblast bioenergetics to accommodate the energy requirements for bone cells to fulfil their function. In vivo studies in several mutant mouse strains have confirmed a link between bone cells and global metabolism, ultimately leading to the identification of hormonal interactions between the skeleton and other tissues. The hormones insulin and leptin affect postnatal bone acquisition, whilst osteocalcin produced by the osteoblast in turn stimulates insulin secretion by the pancreas. These observations have prompted additional questions regarding the nature of the mechanisms of fuel sensing and processing in the osteoblast and their contribution to overall energy utilization and homeostasis. Answers to such questions should advance our understanding of metabolic diseases and may ultimately improve management of affected patients. In this review, we highlight recent studies in this field and offer a perspective on the evolutionary implications of bone as a metabolic endocrine organ. © 2015 The Association for the Publication of the Journal of Internal Medicine.

Kalaria C.,University of Maryland Baltimore County | Kittner S.,University of Maryland Baltimore County | Kittner S.,Baltimore Veterans Administration Medical Center
Neurologic Clinics | Year: 2015

Although screening for hypercoagulable states is commonly performed as part of the evaluation of first arterial ischemic stroke in young adults, available evidence does not support this as a routine practice, even in patients with cryptogenic stroke and a positive family history of early thrombotic events or in patients with a patent foramen ovale. Testing for antiphospholipid antibodies is a possible exception because persistent antibodies are associated with an increased risk of recurrent stroke. Despite the lack of supporting data, screening for hypercoagulable states in recurrent early-onset cryptogenic cerebral ischemia could be considered. © 2015.

Ivey F.M.,University of Maryland Baltimore County | Ivey F.M.,Baltimore Veterans Administration Medical Center | Ryan A.S.,University of Maryland Baltimore County | Ryan A.S.,Baltimore Veterans Administration Medical Center
Journal of Stroke and Cerebrovascular Diseases | Year: 2014

Background: Insulin resistance is highly prevalent after stroke, contributing to comorbid cardiovascular conditions that are the leading cause of death in the stroke population. This study determined the effects of unilateral resistive training (RT) of both the paretic and nonparetic legs on insulin sensitivity in stroke survivors. Methods: We studied 10 participants (mean age 65 ± 2 years; mean body mass index 27 ± 4 kg/m2) with hemiparetic gait after remote (>6 months) ischemic stroke. All subjects underwent 1-repetition maximum (1-RM) strength testing, 9 had an oral glucose tolerance test (OGTT), and 7 completed a 2-hour hyperglycemic clamp (with glucose elevation targeted at 98 mg/dL above baseline fasting level) before and after 12 weeks (3×/week) of progressive, high repetition, high-intensity RT. Body composition was assessed by dual-energy x-ray absorbtiometry in all participants. Results: Leg press and leg extension 1-RM increased in the paretic leg by 22% (P <.05) and 45% (P <.01), respectively. Fasting insulin decreased 23% (P <.05), with no change in fasting glucose. The 16% reduction in OGTT insulin area under the curve (AUC) across training was not statistically significant (P =.18). There was also no change in glucose AUC. First-phase insulin response during the hyperglycemic clamp (0-10 minutes) decreased 24% (P <.05), and second-phase insulin response (10-120 minutes) decreased 26% (P <.01). Insulin sensitivity increased by 31% after RT according to clamp calculations (P <.05). Conclusions: These findings provide the first preliminary evidence that RT may reduce hyperinsulinemia and improve insulin sensitivity after disabling stroke. © 2014 by National Stroke Association.

Blum K.,Inova Fairfax Heart and Vascular Institute | Gottlieb S.S.,University of Maryland Baltimore County | Gottlieb S.S.,Baltimore Veterans Administration Medical Center
Journal of Cardiac Failure | Year: 2014

Background Telemonitoring has been advocated as a way of decreasing costs and improving outcomes, but no study has looked at true Medicare payments and 30-day readmission rates in a randomized group of well treated patients. Objective The aim of this work was to analyze Medicare claims data to identify effects of home telemonitoring on medical costs, 30-day rehospitalization, mortality, and health-related quality of life. Methods A total of 204 subjects were randomized to usual-care and monitored groups and evaluated with the SF-36 and Minnesota Living With Heart Failure Questionnaire (MLHF). Hospitalizations, Medicare payments, and mortality were also assessed. Monitored subjects transmitted weight, blood pressure, and heart rate, which were monitored by an experienced heart failure nurse practitioner. Results Subjects were followed for 802 ± 430 days; 75 subjects in the usual-care group (316 hospitalizations) and 81 in the monitored group (327 hospitalizations) were hospitalized at least once (P =.51). There were no differences in Medicare payments for inpatient or emergency department visits, and length of stay was not different between groups. There was no difference in 30-day readmissions (P =.627) or mortality (P =.575). Scores for SF-36 and MLHF improved (P <.001) over time, but there were no differences between groups. The percentage of patients readmitted within 30 days was lower with telemonitoring for the 1st year, but this did not persist. Conclusions Telemonitoring did not result in lower total costs, decreased hospitalizations, improved symptoms, or improved mortality. A decrease in 30-day readmission rates for the 1st year did not result in decreased total cost or better outcomes. © 2014 Elsevier Inc. All rights reserved.

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