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Zhu L.,Tennessee Valley Healthcare System | Brown W.C.,Tennessee Valley Healthcare System | Brown W.C.,Vanderbilt University | Cai Q.,Vanderbilt University | And 6 more authors.
Diabetes | Year: 2013

Pathway-selective insulin resistance where insulin fails to suppress hepatic glucose production but promotes liver fat storage may underlie glucose and lipid abnormalities after menopause. We tested the mechanisms by which estrogen treatment may alter the impact of a high-fat diet (HFD) when given at the time of ovariectomy (OVX) in mice. Female C57BL/6J mice underwent sham operation, OVX, or OVX with estradiol (E2) treatment and were fed an HFD. Hyperinsulinemic-euglycemic clamps were used to assess insulin sensitivity, tracer incorporation into hepatic lipids, and liver triglyceride export. OVX mice had increased adiposity that was prevented with E2 at the time of OVX. E2 treatment increased insulin sensitivity with OVX and HFD. In sham and OVX mice, HFD feeding induced fatty liver, and insulin reduced hepatic apoB100 and liver triglyceride export. E2 treatment reduced liver lipid deposition and prevented the decrease in liver triglyceride export during hyperinsulinemia. In mice lacking the liver estrogen receptor α, E2 after OVX limited adiposity but failed to improve insulin sensitivity, to limit liver lipid deposition, and to prevent insulin suppression of liver triglyceride export. In conclusion, estrogen treatment may reverse aspects of pathwayselective insulin resistance by promoting insulin action on glucose metabolism but limiting hepatic lipid deposition. © 2013 by the American Diabetes Association.


Pasek R.C.,Vanderbilt University | Gannon M.,Tennessee Valley Healthcare System | Gannon M.,Vanderbilt University
American Journal of Physiology - Endocrinology and Metabolism | Year: 2013

The maintenance of glucose homeostasis during pregnancy is critical to the health and well-being of both the mother and the developing fetus. Strikingly, approximately 7% of human pregnancies are characterized by insufficient insulin production or signaling, resulting in gestational diabetes mellitus (GDM). In addition to the acute health concerns of hyperglycemia, women diagnosed with GDM during pregnancy have an increased incidence of complications during pregnancy as well as an increased risk of developing type 2 diabetes (T2D) later in life. Furthermore, children born to mothers diagnosed with GDM have increased incidence of perinatal complications, including hypoglycemia, respiratory distress syndrome, and macrosomia, as well as an increased risk of being obese or developing T2D as adults. No single environmental or genetic factor is solely responsible for the disease; instead, a variety of risk factors, including weight, ethnicity, genetics, and family history, contribute to the likelihood of developing GDM, making the generation of animal models that fully recapitulate the disease difficult. Here, we discuss and critique the various animal models that have been generated to better understand the etiology of diabetes during pregnancy and its physiological impacts on both the mother and the fetus. Strategies utilized are diverse in nature and include the use of surgical manipulation, pharmacological treatment, nutritional manipulation, and genetic approaches in a variety of animal models. Continued development of animal models of GDM is essential for understanding the consequences of this disease as well as providing insights into potential treatments and preventative measures. © 2013 the American Physiological Society.


Pendergast J.S.,Vanderbilt University | Niswender K.D.,Tennessee Valley Healthcare System | Niswender K.D.,Vanderbilt University | Yamazaki S.,Vanderbilt University
PLoS ONE | Year: 2012

The mammalian circadian system is composed of multiple central and peripheral clocks that are temporally coordinated to synchronize physiology and behavior with environmental cycles. Mammals have three homologs of the circadian Period gene (Per1, 2, 3). While numerous studies have demonstrated that Per1 and Per2 are necessary for molecular timekeeping and light responsiveness in the master circadian clock in the suprachiasmatic nuclei (SCN), the function of Per3 has been elusive. In the current study, we investigated the role of Per3 in circadian timekeeping in central and peripheral oscillators by analyzing PER2::LUCIFERASE expression in tissues explanted from C57BL/6J wild-type and Per3-/- mice. We observed shortening of the periods in some tissues from Per3-/- mice compared to wild-types. Importantly, the periods were not altered in other tissues, including the SCN, in Per3-/- mice. We also found that Per3-dependent shortening of endogenous periods resulted in advanced phases of those tissues, demonstrating that the in vitro phenotype is also present in vivo. Our data demonstrate that Per3 is important for endogenous timekeeping in specific tissues and those tissue-specific changes in endogenous periods result in internal misalignment of circadian clocks in Per3-/- mice. Taken together, our studies demonstrate that Per3 is a key player in the mammalian circadian system.


Self W.H.,Vanderbilt University | Self W.H.,Tennessee Valley Healthcare System
Emergency Medicine Clinics of North America | Year: 2010

Acute human immunodeficiency virus (HIV) infection, also known as primary HIV infection, is the initial phase of infection, spanning from inoculation to the establishment of CD4 count and viral load set points. This phase is marked by dynamic changes in viral replication and host immune responses and contains 2 important clinical events: acute retroviral syndrome and seroconversion. Acute HIV infection is challenging to diagnose, but with recent improvements in diagnostic testing and a heightened awareness of acute HIV, the emergency physician is well positioned to make this diagnosis and initiate important interventions for the individual patient and public health. © 2010.


Ardestani S.,Vanderbilt University | Li B.,Vanderbilt University | Deskins D.L.,Vanderbilt University | Wu H.,Vanderbilt Ingram Cancer Center Cancer Biostatistics Center | And 4 more authors.
Cancer Research | Year: 2013

TNF-α, produced by most malignant cells, orchestrates the interplay between malignant cells and myeloid cells, which have been linked to tumor growth and metastasis. Although TNF-α can exist as one of two isoforms, a 26-kDa membrane tethered form (mTNF-α) or a soluble 17-kDa cytokine (sTNF-α), the vast majority of published studies have only investigated the biologic effects of the soluble form. We show for the first time thatmembrane and soluble isoforms have diametrically opposing effects on both tumor growth and myeloid content. Mouse lung and melanoma tumor lines expressing mTNF-α generated small tumors devoid of monocytes versus respective control lines or lines expressing sTNF-α. The lack of myeloid cells was due to a direct effect of mTNF-α on myeloid survival via induction of cell necrosis by increasing reactive oxygen species. Human non-small cell lung carcinoma expressed varying levels of both soluble and membrane TNF-α, and gene expression patterns favoring mTNF-α were predictive of improved lung cancer survival. These data suggest that there are significant differences in the role of different TNF-α isoforms in tumor progression and the bioavailability of each isoform may distinctly regulate tumor progression. This insight is critical for effective intervention in cancer therapy with the available TNF-α inhibitors, which can block both TNF-α isoforms. © 2013 American Association for Cancer Research.


Hassanein M.,Vanderbilt University | Hoeksema M.D.,Vanderbilt University | Shiota M.,Vanderbilt University | Qian J.,Vanderbilt University | And 8 more authors.
Clinical Cancer Research | Year: 2013

Purpose: We have previously identified solute-linked carrier family A1 member 5 (SLC1A5) as an overexpressed protein in a shotgun proteomic analysis of stage I non-small cell lung cancer (NSCLC) when compared with matched controls. We hypothesized that overexpression of SLC1A5 occurs to meet the metabolic demand for lung cancer cell growth and survival. Experimental Design: To test our hypothesis, we first analyzed the protein expression of SLC1A5 in archival lung cancer tissues by immunohistochemistry and immunoblotting (N = 98) and in cell lines (N = 36). To examine SLC1A5 involvement in amino acid transportation, we conducted kinetic analysis of L-glutamine (Gln) uptake in lung cancer cell lines in the presence and absence of a pharmacologic inhibitor of SLC1A5, gamma-L-Glutamyl-p-Nitroanilide (GPNA). Finally, we examined the effect of Gln deprivation and uptake inhibition on cell growth, cell-cycle progression, and growth signaling pathways of five lung cancer cell lines. Results: Our results show that (i) SLC1A5 protein is expressed in 95% of squamous cell carcinomas (SCC), 74% of adenocarcinomas (ADC), and 50% of neuroendocrine tumors; (ii) SLC1A5 is located at the cytoplasmic membrane and is significantly associated with SCC histology and male gender; (iii) 68% of Gln is transported in a Na +-dependent manner, 50% of which is attributed to SLC1A5 activity; and (iv) pharmacologic and genetic targeting of SLC1A5 decreased cell growth and viability in lung cancer cells, an effect mediated in part by mTOR signaling. Conclusions: These results suggest that SLC1A5 plays a key role in Gln transport controlling lung cancer cells' metabolism, growth, and survival. © 2012 American Association for Cancer Research.


McGrane S.,Vanderbilt University | Atria N.P.,Critical Care | Barwise J.A.,Tennessee Valley Healthcare System
Current Opinion in Anaesthesiology | Year: 2014

Purpose of Review: The autonomic nervous system functions to control heart rate, blood pressure, respiratory rate, gastrointestinal motility, hormone release, and body temperature on a second-to-second basis. Here we summarize some of the latest literature on autonomic dysfunction, focusing primarily on the perioperative implications. RECENT FINDINGS: The variety of autonomic dysfunction now extends to a large number of clinical conditions in which the cause or effect of the autonomic component is blurred. Methods for detecting dysautonomia can be as simple as performing a history and physical examination that includes orthostatic vital signs measured in both recumbent and vertical positions; however, specialized laboratories are required for definitive diagnosis. Heart rate variability monitoring is becoming more commonplace in the assessment and understanding of autonomic instability. Degenerative diseases of the autonomic nervous system include ParkinsonÊs disease and multiple system atrophy, with the most serious manifestations being postural hypotension and paradoxical supine hypertension. Other conditions occur in which the autonomic dysfunction is only part of a larger disease process, such as diabetic autonomic neuropathy, traumatic brain injury, and spinal cord injury. SUMMARY: Patients with dysautonomia often have unpredictable and paradoxical physiological responses to various perioperative stimuli. Knowledge of the underlying pathophysiology of their condition is required in order to reduce symptom exacerbation and limit morbidity and mortality during the perioperative period. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Ebesutani C.,Duksung Womens University | Kim E.,Tennessee Valley Healthcare System | Young J.,University of Mississippi
Child Psychiatry and Human Development | Year: 2014

Aggressive behaviors in youth tend to be relatively stable across the lifespan and are associated with maladaptive functioning later in life. Researchers have recently identified that both violence exposure and negative affective experiences are related to the development of aggressive behaviors. Children exposed to violence also often experience negative affect (NA) in the form of anxiety and depression. Bringing these findings together, the current study used a clinical sample of youth (N = 199; ages 7-17 years) referred to a psychiatric residential treatment facility to examine the specific contributions of NA and exposure to violence on the development of aggressive behaviors in youth. Using structural equation modeling, both NA and recent exposure to violence significantly predicted aggressive behaviors. More importantly, negative affect partially mediated the relationship between exposure to violence and aggression. Implications of these findings from a clinical perspective and future directions for research on aggression are discussed. © 2014 Springer Science+Business Media New York.


Randall M.J.,Tennessee Valley Healthcare System
Military Medicine | Year: 2012

This study examined the effectiveness of Public Law 110-181, "National Defense Authorization Act of Fiscal Year 2008, Title XVI-Wounded Warriors Matter," as it relates to health care for returning Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) combat veterans. Specifically, it examined the gap between the time an OEF/OIF combat service member left active service and subsequently obtained health care within the Veteran Affairs (VA) Healthcare System, and which factors influenced or impeded the veteran from obtaining health care sooner. Data were collected from 376 OEF/OIF combat veterans who sought health care at the Nashville or Murfreesboro VA Medical Centers. A questionnaire was designed exclusively for this study. The average time gap for an OEF/OIF combat veteran to transition from Department of Defense to VA health care was 3.83 months (SD 7.17). Twenty-six percent of respondents reported there were factors that impeded them from coming to the VA sooner. Factors included lack of knowledge about VA benefits, transportation/distance, perceptions of losing military career, seeking help as sign of weakness, and VA reputation. The study provided some evidence to support that Department of Defense and VA are meeting mandates for providing seamless transition of health care set forth by "Public Law 110-181, National Defense Authorization Act of Fiscal Year 2008". © Association of Military Surgeons of the U.S. All rights reserved.


McFarland M.S.,Tennessee Valley Healthcare System | Cripps R.,Tennessee Valley Healthcare System
Pharmacotherapy | Year: 2010

Type 2 diabetes mellitus has been associated with an increased risk of hepatic, pancreatic, colon, endometrial, breast, and bladder cancer. Although a mechanism of action for the increased risk has been postulated, no definitive evidence has been completely elucidated in the medical literature. Results of recently released studies documented the use of specific antidiabetic drugs with increased rates of cancer. The insulin analog glargine was the focus of four observational studies published in 2009 that outlined an increase in the rates of cancer associated with its use. In contrast, the use of metformin has been shown to possibly decrease the rate of specific cancers when used in the treatment of type 2 diabetes. These data regarding cancer risk and antidiabetic drugs are contradictory and at this time are inconclusive. Until results of long-term randomized prospective studies are available to elucidate a correlation with cancer and insulin, we must continue treating diabetes in order to avert the long-term complications of the disease.

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