O-Sullivan I.,University of Illinois at Chicago |
Zhang W.,University of Illinois at Chicago |
Wasserman D.H.,Vanderbilt Medical School |
Liew C.W.,University of Illinois at Chicago |
And 8 more authors.
Nature Communications | Year: 2015
FoxO proteins are major targets of insulin action. To better define the role of FoxO1 in mediating insulin effects in the liver, we generated liver-specific insulin receptor knockout (LIRKO) and IR/FoxO1 double knockout (LIRFKO) mice. Here we show that LIRKO mice are severely insulin resistant based on glucose, insulin and C-peptide levels, and glucose and insulin tolerance tests, and genetic deletion of hepatic FoxO1 reverses these effects. 13C-glucose and insulin clamp studies indicate that regulation of both hepatic glucose production (HGP) and glucose utilization is impaired in LIRKO mice, and these defects are also restored in LIRFKO mice corresponding to changes in gene expression. We conclude that (1) inhibition of FoxO1 is critical for both direct (hepatic) and indirect effects of insulin on HGP and utilization, and (2) extrahepatic effects of insulin are sufficient to maintain normal whole-body and hepatic glucose metabolism when liver FoxO1 activity is disrupted. © 2015 Macmillan Publishers Limited. All rights reserved.
PubMed | Albany Medical Center, University Utrecht, Stanford University, Albany Research Center and Vanderbilt Medical School
Type: Journal Article | Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology | Year: 2016
Protein phosphatase magnesium-dependent-1A (PPM1A) dephosphorylates SMAD2/3, which suppresses TGF- signaling in keratinocytes and during Xenopus development; however, potential involvement of PPM1A in chronic kidney disease is unknown. PPM1A expression was dramatically decreased in the tubulointerstitium in obstructive and aristolochic acid nephropathy, which correlates with progression of fibrotic disease. Stable silencing of PPM1A in human kidney-2 human renal epithelial cells increased SMAD3 phosphorylation, stimulated expression of fibrotic genes, induced dedifferentiation, and orchestrated epithelial cell-cycle arrest via SMAD3-mediated connective tissue growth factor and plasminogen activator inhibitor-1 up-regulation. PPM1A stable suppression in normal rat kidney-49 renal fibroblasts, in contrast, promoted a SMAD3-dependent connective tissue growth factor and plasminogen activator inhibitor-1-induced proliferative response. Paracrine factors secreted by PPM1A-depleted epithelial cells augmented fibroblast proliferation (>50%) compared with controls. PPM1A suppression in renal cells further enhanced TGF-1-induced SMAD3 phosphorylation and fibrotic gene expression, whereas PPM1A overexpression inhibited both responses. Moreover, phosphate tensin homolog on chromosome 10 depletion in human kidney-2 cells resulted in loss of expression and decreased nuclear levels of PPM1A, which enhanced SMAD3-mediated fibrotic gene induction and growth arrest that were reversed by ectopic PPM1A expression. Thus, phosphate tensin homolog on chromosome 10 is an upstream regulator of renal PPM1A deregulation. These findings establish PPM1A as a novel repressor of the SMAD3 pathway in renal fibrosis and as a new therapeutic target in patients with chronic kidney disease.-Samarakoon, R., Rehfuss, A., Khakoo, N. S., Falke, L. L., Dobberfuhl, A. D., Helo, S., Overstreet, J. M., Goldschmeding, R., Higgins, P. J. Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair.
Tep C.,Ohio State University |
Kim M.L.,Ohio State University |
Opincariu L.I.,Aurora University |
Limpert A.S.,Vanderbilt Medical School |
And 4 more authors.
Journal of Biological Chemistry | Year: 2012
Brain-derived neurotrophic factor (BDNF) was shown to play a role in Schwann cell myelination by recruiting Par3 to the axon-glial interface, but the underlying mechanism has remained unclear. Here we report that Par3 regulates Rac1 activation by BDNF but not by NRG1-Type III in Schwann cells, although both ligands activate Rac1 in vivo. During development, active Rac1 signaling is localized to the axon-glial interface in Schwann cells by a Par3-dependent polarization mechanism. Knockdown of p75 and Par3 individually inhibits Rac1 activation, whereas constitutive activation of Rac1 disturbs the polarized activation of Rac1 in vivo. Polarized Rac1 activation is necessary for myelination as Par3 knockdown attenuates myelination in mouse sciatic nerves as well as in zebrafish. Specifically, Par3 knockdown in zebrafish disrupts proper alignment between the axon and Schwann cells without perturbing Schwann cell migration, suggesting that localized Rac1 activation at the axon-glial interface helps identify the initial wrapping sites.Wetherefore conclude that polarization of Rac1 activation is critical for myelination. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Pharmacokinetic and pharmacodynamic study of tariquidar (XR9576), a P-glycoprotein inhibitor, in combination with doxorubicin, vinorelbine, or docetaxel in children and adolescents with refractory solid tumors
PubMed | Vanderbilt Medical School, Children's Hospital of Philadelphia, U.S. National Institutes of Health and U.S. National Cancer Institute
Type: Clinical Trial | Journal: Cancer chemotherapy and pharmacology | Year: 2016
P-glycoprotein (Pgp), an ATP-dependent transport protein, confers multidrug resistance in cancer cells. Tariquidar binds and inhibits Pgp. To assess the toxicity, pharmacokinetics (PK), and pharmacodynamics of tariquidar, we conducted a phase I trial of tariquidar in combination with doxorubicin, docetaxel, or vinorelbine in children and adolescents with recurrent or refractory solid tumors.Patients less than 19 years of age with refractory or recurrent solid tumors were eligible. Tariquidar (1, 1.5, or 2 mg/kg) was administered alone and in combination with doxorubicin, docetaxel, or vinorelbine. PK of tariquidar and cytotoxic drugs was performed. Pgp function was assessed by a rhodamine efflux assay and (99m)Tc-sestamibi scintigraphy. Tumor Pgp expression was assessed by immunohistochemistry. Response was assessed using Response Evaluation Criteria in Solid Tumors.Twenty-nine subjects were enrolled. No tariquidar-related dose-limiting toxicity (DLT) was observed. DLT related to cytotoxic drugs occurred in 12 % of subjects receiving tariquidar 2 mg/kg. When administered in combination with tariquidar, the clearance of docetaxel and vinorelbine was reduced compared to prior studies. Inhibition of rhodamine efflux was dose dependent. After tariquidar administration, (99m)Tc-sestamibi accumulation in tumor increased by 22 %. Objective responses (1 complete, 2 partial) were observed. There was no association between tumor Pgp expression and response.A tolerable and biologically active dose of tariquidar was established in children and adolescents. This trial demonstrates that modulators of resistance can be evaluated in combination with chemotherapy, and pharmacokinetic and pharmacodynamic endpoints can be useful in determination of recommended dose in children and adolescents.
Yuksel C.,McLean Hospital |
McCarthy J.,McLean Hospital |
McCarthy J.,University of Maryland University College |
Shinn A.,McLean Hospital |
And 8 more authors.
Schizophrenia Research | Year: 2012
There is growing evidence that schizophrenia (SZ) and bipolar disorder (BD) overlap significantly in risk factors, neurobiological features, clinical presentations, and outcomes. SZ is characterized by well documented gray matter (GM) abnormalities in multiple frontal, temporal and subcortical structures. Recent voxel-based morphometry (VBM) studies and meta-analyses in BD also report GM reductions in overlapping, albeit less widespread, brain regions. Psychosis, a hallmark of SZ, is also experienced by a significant proportion of BD patients and there is evidence that psychotic BD may be characterized by specific clinical and pathophysiological features. However, there are few studies comparing GM between SZ and psychotic BD. In this study we compared GM volumes in a sample of 58 SZ patients, 28 BD patients experiencing psychotic symptoms and 43 healthy controls using whole-brain voxel-based morphometry. SZ patients had GM reductions in multiple frontal and temporal regions compared to healthy controls and in the subgenual cortex compared to psychotic BD patients. GM volume was increased in the right posterior cerebellum in SZ patients compared to controls. However, psychotic BD patients did not show significant GM deficits compared to healthy controls or SZ patients. We conclude that GM abnormality as measured by VBM analysis is less pronounced in psychotic BD compared to SZ. This may be due to disease-specific factors or medications used more commonly in BD. © 2012 Elsevier B.V.
Armaghani S.J.,Vanderbilt University |
Lee D.S.,Vanderbilt University |
Bible J.E.,Vanderbilt University |
Shau D.N.,Vanderbilt Medical School |
And 4 more authors.
Journal of Spinal Disorders and Techniques | Year: 2016
Study Design: Prospective cohort analysis. Objective: To assess the effect of preoperative narcotic use on the incidence of 30- and 90-day postoperative complications, as well as length of hospital stay (LOS) in patients undergoing spine surgery. Summary of Background Data: Previous work has associated an increased incidence of complications and length of stay following surgery in patients with increased preoperative narcotic use. Despite this and recent national attention highlighting the negative effects of narcotics, they remain commonly used for the management of pain in patients undergoing spine surgery. Materials And Methods: A total of 583 patients undergoing spine surgery for a structural lesion were evaluated. Self-reported preoperative narcotic consumption was obtained and converted to morphine equivalents at the initial preoperative visit. LOS was recorded upon discharge and presence/type of a postoperative complication within 30/90 days was obtained. A multivariable logistic and linear regression analysis was performed for the incidence of complications and length of stay controlling for clinically important covariates. Results: Narcotic use was not associated with 30- or 90-day complications; however, smoking status was significantly associated with 30-day complications. Increased preoperative narcotic use was significantly associated with increased LOS, as was age, type of surgery, and depression. Conclusions: Increased preoperative narcotic use and depression are associated with increased LOS in patients undergoing spine surgery. We calculated that for every 100 morphine equivalents a patient is taking preoperatively; their stay is extended 1.1 days. Narcotic use was not associated with 30- or 90-day postoperative complications. As reimbursement is bundled before surgery, providing interventions for patients with treatable causes for increased length of stay can save cost overall. © 2014 Wolters Kluwer Health, Inc.
Trivedi H.K.,Vanderbilt Medical School |
Trivedi H.K.,Vanderbilt Psychiatric Hospital |
Pattison N.A.,Maine Medical Center |
Neto L.B.,Columbia University
Pediatric Clinics of North America | Year: 2011
The medical home concept has been in existence since the late 1960s and has recently been significantly broadened to encompass comprehensive primary care for all patient populations throughout the lifespan. This article provides (1) a review of the foundations and evolution of the medical home concept; (2) an analysis of patient/family, provider, and systemic challenges to developing an effective pediatric medical home particularly in relation to children's mental health needs; and (3) a discussion of future directions for its further adoption and successful implementation. © 2011 Elsevier Inc.
Bourne S.K.,Massachusetts General Hospital |
Sheth S.A.,Massachusetts General Hospital |
Neal J.,Massachusetts General Hospital |
Strong C.,Massachusetts General Hospital |
And 5 more authors.
Neurosurgery | Year: 2013
BACKGROUND: Anterior cingulotomy (AC) can be an effective therapy for patients with severe obsessive-compulsive disorder who are refractory to traditional medical therapy. For patients who do not respond to AC, the benefit of additional lesion procedures vs continued medical management remains unknown. OBJECTIVE: To determine whether a second lesion procedure is beneficial after unsuccessful initial AC. METHODS: In this retrospective cohort study, we reviewed the records of 31 patients who were nonresponders to initial AC. Full response was defined as at least a 35% decrease and partial response as a 25% to 34% decrease in Yale-Brown Obsessive-Compulsive Scale scores. Yale-Brown Obsessive-Compulsive Scale change was compared between patients who underwent additional surgery and those treated nonsurgically. In addition, for patients who underwent additional surgery, we compared the benefit of subcaudate tractotomy with repeat AC (extension of the initial lesion) as the second procedure. RESULTS: Nineteen patients underwent a second surgery and 12 patients continued nonsurgical therapy. Fifty-three percent of patients who received additional surgery were full responders and 21% were partial responders at the most recent follow-up compared with 17% full responders and 25% partial responders among those who continued conventional therapy (P = .02). Of the patients who underwent an additional surgery, there were 64% full and 9% partial responders in the subcaudate tractotomy group compared with 38% full and 38% partial responders in the repeat AC group (P = .04). CONCLUSION: Second lesion surgery can be a safe and effective therapy for patients who do not respond to initial AC. Subcaudate tractotomy may confer a higher response rate than repeat cingulotomy. Copyright © 2012 by the Congress of Neurological Surgeons.
Shi S.,Vanderbilt University |
Hida A.,Vanderbilt University |
McGuinness O.P.,Vanderbilt Medical School |
Wasserman D.H.,Vanderbilt Medical School |
And 2 more authors.
Current Biology | Year: 2010
Most of the central circadian clock genes in the mouse exist as paralog pairs (Per1 and Per2, Cry1 and Cry2, Clock and Npas2) in which each gene of the pair must be knocked out to confer arrhythmicity [1-3]. The only exception to this pattern is Bmal1 (also known as Mop3), the single knockout of which confers arrhythmicity, despite the presence of its paralog, Bmal2 (also known as Mop9) . The knockout of Bmal1 also has significant effects on longevity, metabolism, etc. [5, 6]. These results have led to the conclusion that Bmal1 is a singularly essential clock gene and that Bmal2 has a minimal role in the clock system. In contrast, we find that expression of Bmal2 from a constitutively expressed promoter can rescue the clock and metabolic phenotypes of Bmal1-knockout mice, including rhythmic locomotor activity, rhythmic metabolism, low body weight, and enhanced fat deposition. Combined with the data of Bunger and colleagues, who reported that knockout of Bmal1 downregulates Bmal2 , we conclude that Bmal1 and Bmal2 form a circadian paralog pair that is functionally redundant and that, in the mouse, Bmal2 is regulated by Bmal1 such that knockout of Bmal1 alone results in a functionally double Bmal1 and Bmal2 knockout. Therefore, the role(s) of Bmal2 may be more important than has been appreciated heretofore. © 2010 Elsevier Ltd. All rights reserved.
Ichida J.M.,Vanderbilt University |
Mavity-Hudson J.A.,Vanderbilt Medical School |
Casagrande V.A.,Vanderbilt University
Eye and Brain | Year: 2014
In primates, feedforward visual pathways from retina to lateral geniculate nucleus (LGN) are segregated to different layers. These layers also receive strong reciprocal feedback pathways from cortex. The degree to which feedforward streams in primates are segregated from feedback streams remains unclear. Here, we asked whether corticogeniculate cells that innervate the magnocellular (M), parvocellular (P), and koniocellular (K) layers of the LGN in the prosimian primate bush baby (Otolemur garnettii) can be distinguished based on either the laminar distribution or morphological characteristics of their axons and synaptic contacts in LGN, or on their cell body position, size, and dendritic distribution in cortex. Corticogeniculate axons and synapses were labeled anterogradely with biotinylated dextran injections in layer 6 of cortex. Corticogeniculate cell bodies were first labeled with fluorescent dextran injections limited to individual M, P, or K LGN layers and then filled with biotinylated Lucifer yellow. Results showed that feedback to the M or P LGN layers arises from cells with dendrites primarily confined to cortical layer 6 and axons restricted to either M or P LGN layers, but not both. Feedback to K LGN layers arises from cells: 1) whose dendrites distribute rather evenly across cortical layers 5 and 6; 2) whose dendrites always extend into layer 4; and 3) whose axons are never confined to K layers but always overlap with either P or M layers. Corticogeniculate axons also showed distributions that were retinotopically precise based on known receptive field sizes of layer 6 cells, and these axons mainly made synapses with glutamatergic projection neurons in the LGN in all layers. Taken together with prior physiological results, we argue that the morphological differences between the three corticogeniculate pathways show that the M and P feedback pathways could rapidly and specifically enhance local LGN activity, while we speculate that the K feedback pathway is organized to temporally synchronize activity between LGN and cortex. © 2014 Ichida et al.