Zhang W.-Y.,Phoenix VA Healthcare System |
Franco D.A.,Phoenix VA Healthcare System |
Schwartz E.,Phoenix VA Healthcare System |
D'Souza K.,Phoenix VA Healthcare System |
And 2 more authors.
Atherosclerosis | Year: 2017
Background and aims Peripheral insulin resistance is associated with several metabolic abnormalities, including elevated serum fatty acids that contribute to vascular injury and atherogenesis. Our goals were to examine whether saturated fatty acids can modify innate immune responses to subclinical concentrations of lipopolysaccharide (LPS) in endothelial cells, and to explore the underlying pathway and determine whether it is modified by high density lipoprotein (HDL) and other factors commonly altered in insulin resistance. Methods Physiologic concentrations of palmitic acid were added to human aortic endothelial cells with and without a variety of inhibitors or HDL and measures of cell inflammation and function assessed. Results Palmitic acid significantly amplified human aortic endothelial cell inflammatory responses to LPS. Similar results were obtained from lipolysis products of triglyceride rich lipoproteins. Metabolism of palmitic acid to ceramide and subsequent activation of PKC-ζ, MAPK and ATF3 appeared critical in amplifying LPS induced inflammation. The amplified response to palmitic acid/LPS was decreased by HDL, dose dependently, and this inhibition was dependent on activation of PI3K/AKT and reduction in ATF3. Conclusions These results indicate that endothelial cell innate immune responses are modified by metabolic abnormalities commonly present in insulin resistance and provide evidence for a novel mechanism by which HDL may reduce vascular inflammation. © 2016
Oh C.C.,Phoenix VA Healthcare System |
Nguy M.Q.,Phoenix VA Healthcare System |
Schwenke D.C.,Phoenix VA Healthcare System |
Migrino R.Q.,Phoenix VA Healthcare System |
And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2014
Rationale The mechanisms underlying lipotoxic/diabetic cardiomyopathy remain poorly understood. Saturated fatty acid (SFA) levels, elevated in obesity and type 2 diabetes, induce apoptosis in many cell types including cardiomyocytes. Signaling pathways, including the p38α mitogen-activated kinase (MAPK)-dependent pathway, have been implicated in apoptosis due to a diverse range of insults. Objective We tested the hypothesis that SFA-induced cardiomyocyte apoptosis is dependent on p38α activation. Methods and results Human adult ventricular cardiomyocytes (AC16 cells) were exposed to high physiological levels of palmitate (PA), a SFA. The apoptotic response was measured using annexin-V by flow cytometry, and the p38α-dependent pathway was evaluated using a p38 inhibitor PD169316, and by p38α small interfering RNA (siRNA) knockdown. PA exposure for 16 h dose-dependently increased apoptosis in AC16 cardiomyocytes (control: 2.6 ± 0.6%, 150 μM PA: 3.5 ± 0.9%, 300 μM PA: 11.5 ± 1.6%, n = 4, p < 0.01). PA did not change total p38α protein levels, but increased p38α phosphorylation dose-dependently (n = 5, p < 0.01). PD169316 tended to reduce PA-induced apoptosis (n = 4, p = 0.05). Specific p38α siRNA markedly reduced the expression of p38α but not p38β (n = 3, p < 0.0001), and dose-dependently attenuated PA-induced apoptosis (control siRNA: 7.7 ± 1.0%, 300 μM PA: 34.4 ± 5.0%, 300 μM PA + 30 pmol siRNA: 23.7 ± 4.4%, 300 μM PA + 60 pmol siRNA: 19.7 ± 2.6%, 300 μM PA + 120 pmol siRNA: 17.3 ± 2.8%, n = 4, p < 0.0001). Conclusions These results demonstrate that PA induces p38α activation, and reducing p38α expression attenuates PA-induced cardiomyocyte apoptosis. Our results support a potential mechanism by which high plasma SFA levels through p38α activation may lead to the development of lipotoxic/diabetic cardiomyopathy. © 2014 Elsevier Inc. All rights reserved.
PubMed | Phoenix VA HealthCare System, AZ Electronic and Oregon Health And Science University
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2014
The mechanisms underlying lipotoxic/diabetic cardiomyopathy remain poorly understood. Saturated fatty acid (SFA) levels, elevated in obesity and type 2 diabetes, induce apoptosis in many cell types including cardiomyocytes. Signaling pathways, including the p38 mitogen-activated kinase (MAPK)-dependent pathway, have been implicated in apoptosis due to a diverse range of insults.We tested the hypothesis that SFA-induced cardiomyocyte apoptosis is dependent on p38 activation.Human adult ventricular cardiomyocytes (AC16 cells) were exposed to high physiological levels of palmitate (PA), a SFA. The apoptotic response was measured using annexin-V by flow cytometry, and the p38-dependent pathway was evaluated using a p38 inhibitor PD169316, and by p38 small interfering RNA (siRNA) knockdown. PA exposure for 16 h dose-dependently increased apoptosis in AC16 cardiomyocytes (control: 2.60.6%, 150 M PA: 3.50.9%, 300 M PA: 11.51.6%, n=4, p<0.01). PA did not change total p38 protein levels, but increased p38 phosphorylation dose-dependently (n=5, p<0.01). PD169316 tended to reduce PA-induced apoptosis (n=4, p=0.05). Specific p38 siRNA markedly reduced the expression of p38 but not p38 (n=3, p<0.0001), and dose-dependently attenuated PA-induced apoptosis (control siRNA: 7.71.0%, 300 M PA: 34.45.0%, 300 M PA+30 pmol siRNA: 23.74.4%, 300 M PA+60 pmol siRNA: 19.72.6%, 300 M PA+120 pmol siRNA: 17.32.8%, n=4, p<0.0001).These results demonstrate that PA induces p38 activation, and reducing p38 expression attenuates PA-induced cardiomyocyte apoptosis. Our results support a potential mechanism by which high plasma SFA levels through p38 activation may lead to the development of lipotoxic/diabetic cardiomyopathy.
Deierhoi R.J.,The Surgical Center |
Deierhoi R.J.,University of Alabama at Birmingham |
Dawes L.G.,Phoenix VA Healthcare System |
Vick C.,University of Alabama at Birmingham |
And 2 more authors.
Journal of the American College of Surgeons | Year: 2013
Background The Surgical Care Improvement Program endorses mandatory compliance with approved intravenous prophylactic antibiotics; however, oral antibiotics are optional. We hypothesized that surgical site infection (SSI) rates may vary depending on the choice of antibiotic prophylaxis. Study Design A retrospective cohort study of elective colorectal procedures using Veterans Affairs Surgical Quality Improvement Program (VASQIP) and SSI outcomes data was linked to the Office of Informatics and Analytics (OIA) and Pharmacy Benefits Management (PBM) antibiotic data from 2005 to 2009. Surgical site infection rates by type of IV antibiotic agent alone (IV) or in combination with oral antibiotic (IV + OA) were determined. Generalized estimating equations were used to examine the association between type of antibiotic prophylaxis and SSI for the entire cohort and stratified by use of oral antibiotics. Results After 5,750 elective colorectal procedures, 709 SSIs (12.3%) developed within 30 days. Oral antibiotic + IV (n = 2,426) had a lower SSI rate than IV alone (n = 3,324) (6.3% vs 16.7%, p < 0.0001). There was a significant difference in the SSI rate based on type of preoperative IV antibiotic given (p ≤ 0.0001). Generalized estimating equations adjusting for significant covariates of age, body mass index, procedure work relative value units, and operation duration demonstrated an independent protective effect of oral antibiotics (odds ratio [OR] 0.37, 95% CI 0.29 to 0.46), as well as increased rates of SSI associated with ampicillin/sulbactam (OR 2.21, 95% CI 1.37 to 3.56) and second generation cephalosporins (cefoxitin, OR 2.50, 95% CI 1.83 to 3.42; cefotetan, OR 2.70, 95% CI 1.72 to 4.22) when compared with first generation cephalosporin/ metronidazole. Conclusions The choice of IV antibiotic was related to the SSI rate; however, oral antibiotics were associated with reduced SSI rate for every antibiotic class © 2013 by the American College of Surgeons.
Taylor S.E.,Barrow Neurological Institute |
Taylor S.E.,University of Arizona |
Taylor S.E.,University of Bath |
Morganti-Kossmann C.,Barrow Neurological Institute |
And 7 more authors.
PLoS ONE | Year: 2014
Brain microglial morphology relates to function, with ramified microglia surveying the micro-environment and amoeboid microglia engulfing debris. One subgroup of microglia, rod microglia, have been observed in a number of pathological conditions, however neither a function nor specific morphology has been defined. Historically, rod microglia have been described intermittently as cells with a sausage-shaped soma and long, thin processes, which align adjacent to neurons. More recently, our group has described rod microglia aligning end-to-end with one another to form trains adjacent to neuronal processes. Confusion in the literature regarding rod microglia arises from some reports referring to the sausage-shaped cell body, while ignoring the spatial distribution of processes. Here, we systematically define the morphological characteristics of rod microglia that form after diffuse brain injury in the rat, which differ morphologically from the spurious rod microglia found in uninjured sham. Rod microglia in the diffuse-injured rat brain show a ratio of 1.79±0.03 cell length:cell width at day 1 post-injury, which increases to 3.35±0.05 at day 7, compared to sham (1.17±0.02). The soma length:width differs only at day 7 post-injury (2.92±0.07 length:width), compared to sham (2.49±0.05). Further analysis indicated that rod microglia may not elongate in cell length but rather narrow in cell width, and retract planar (side) processes. These morphological characteristics serve as a tool for distinguishing rod microglia from other morphologies. The function of rod microglia remains enigmatic; based on morphology we propose origins and functions for rod microglia after acute neurological insult, which may provide biomarkers or therapeutic targets. © 2014 Taylor et al.
PubMed | Phoenix VA Healthcare System and Banner Good Samaritan Medical Center
Type: | Journal: Case reports in infectious diseases | Year: 2015
Ralstonia pickettii is a rare pathogen and even more rare in healthy individuals. Here we report a case of R. pickettii bacteremia leading to aortic valve abscess and complete heart block. To our knowledge this is the first case report of Ralstonia species causing infective endocarditis with perivalvular abscess.
Rogers L.C.,Valley Presbyterian Hospital |
Rogers L.C.,Western University of Health Sciences |
Frykberg R.G.,Phoenix VA Healthcare System
Medical Clinics of North America | Year: 2013
The Charcot foot or Charcot neuroarthropathy (CN) is a rare, but complex and often misdiagnosed complication of diseases causing peripheral neuropathy, like diabetes. Early recognition and treatment can prevent complications like ulcers and amputations. This article provides a review of the current evidence base and offers a pathway for treatment. © 2013 Elsevier Inc.
Frykberg R.G.,Phoenix VA Healthcare System |
Marston W.A.,University of North Carolina at Chapel Hill |
Advances in Skin and Wound Care | Year: 2015
OBJECTIVE: Diabetic foot ulcers (DFUs) are frequently recalcitrant and at risk for infection, which may lead to lower-extremity amputation or bone resection. Reporting the incidence of amputations/bone resections may shed light on the relationship of ulcer healing to serious complications. This study aimed to evaluate the incidence of amputations/bone resections in a randomized controlled trial comparing human fibroblast-derived dermal substitute plus conventional care with conventional care alone for the treatment of DFUs. DESIGN: Ulcer-related amputation/bone resection datawere extracted from data on all adverse events reported for the intent-to-treat population (N = 314), and amputations were categorized by type: Below the knee, Syme, Chopart, transmetatarsal, ray, toe, or partial toe. Data were analyzed retrospectively for the incidence of amputation/bone resection by treatment. SETTING: Randomized controlled trial. PATIENTS: Patients with full-thickness DFUs greater than 6 weeks' duration. INTERVENTIONS: Standard wound care plus human fibroblast-derived dermal substitute versus standard wound care alone. MAIN RESULTS: The incidence of amputation/bone resection in the study was 8.9% (28/314) overall, 5.5% (9/163) for patients receiving human fibroblast-derived dermal substitute, and 12.6% (19/151) for patients receiving conventional care (P = .031). Of the 28 cases of amputation/bone resection, 27 were preceded by ulcer-related infection. CONCLUSION: There were significantly fewer amputations/bone resections in patients who received human fibroblast-derived dermal substitute versus conventional care, likely related to the lower incidence of infection adverse events observed in the human fibroblast-derived dermal substitute treatment group.
Wukich D.K.,University of Pittsburgh |
Crim B.E.,University of Pittsburgh |
Frykberg R.G.,Phoenix VA Healthcare System |
Rosario B.L.,University of Pittsburgh
Journal of Bone and Joint Surgery - American Volume | Year: 2014
Background: This prospective study was designed to evaluate the frequency of surgical site infection in patients treated with foot and ankle surgery. Our hypothesis was that patients with complications of diabetes are at increased risk for surgical site infection compared with patients without diabetes and patients with diabetes who do not have diabetic complications. Another goal was to compare the association of neuropathy with surgical site infection in both nondiabetic and diabetic patients. Methods: Two thousand and sixty consecutive surgical cases were evaluated. Group 1 included nondiabetic patients without neuropathy, Group 2 included nondiabetic patients with neuropathy, Group 3 included patients with diabetes but no diabetic complications, and Group 4 included patients with diabetes who had at least one complication of diabetes. Results: The surgical site infection rate in this study was 3.1%. Patients with complicated diabetes had a 7.25-fold increased risk of surgical site infection compared with nondiabetic patients without neuropathy and a 3.72-fold increased risk compared with patients with uncomplicated diabetes. Patients with complicated diabetes had a nonsignificant 1.54-fold higher rate of surgical site infection compared with nondiabetic patients with neuropathy. Nondiabetic patients with neuropathy had a significant 4.72-fold increased risk of surgical site infection compared with nondiabetic patients without neuropathy. Despite this, nondiabetic patients with neuropathy did not have a significantly higher rate of surgical site infection than patients with uncomplicated diabetes, and the frequency of surgical site infection in the group with uncomplicated diabetes was not significantly different from that in the nondiabetic patients without neuropathy. Multivariable logistic regression analysis demonstrated that peripheral neuropathy and a hemoglobin A1c of ≥8% were independently associated with surgical site infection. Conclusions: Complicated diabetes increases the risk of surgical site infection after foot and ankle surgery. Patients who had diabetes without complications did not have a greater risk of surgical site infection compared with nondiabetic patients without neuropathy. The presence of neuropathy increases the risk of surgical site infection even in patients without diabetes. Poor long-term glycemic control is also associated with an increased risk of surgical site infection. Level of Evidence: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence. Copyright © 2014 by the Journal of Bone and Joint Surgery, Incorporated.
Holmberg M.,Phoenix VA Healthcare System
Pharmacy Times | Year: 2014
The FDA has approved AstraZeneca and Bristol-Myers Squibb Company's Farxiga (dapagliflozin) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The approval carries the limitation that Farxiga is not to be used for treatment of type 1 diabetes mellitus or diabetic ketoacidosis. More than 24 million Americans are affected by diabetes, and more than 90% of all new diabetes cases diagnosed are type 2. Farxiga has already been approved in 40 countries outside the United States, where it is marketed as Forxiga.