Publications by authors named "Denise Cooper"

67 Publications

Documentation Sharing Deficiencies of Posthospitalized Skilled Nursing Facility Residents: A Retrospective Review.

J Nurs Care Qual 2021 Apr 29. Epub 2021 Apr 29.

School of Nursing, University of Michigan-Flint.

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http://dx.doi.org/10.1097/NCQ.0000000000000565DOI Listing
April 2021

A Retrospective Comparison of Guidelines to Assess Hospital-diagnosed Urinary Tract Infection in Nursing Home Residents.

Am J Infect Control 2021 Apr 16. Epub 2021 Apr 16.

Senior Associate Dean for Research and Strategic Initiatives, Interim Chair, Department of Physical Therapy, Martha V. and Wickliffe S. Lyne Professor of Health Administration, College of Health Professions, Virginia Commonwealth University, 900 E. Leigh Street, Box 980233, Richmond, VA 23298. Electronic address:

Background: Inappropriate antibiotic treatments for urinary tract infection (UTI) in nursing home (NH) residents are common and contribute to antibiotic resistance. Published guidelines aim to improve accurate assessment, diagnosis, and treatment of UTIs. This study assessed whether records from hospitalized NH residents diagnosed with UTI, while comparing the Cooper Tool and Stone criteria, supported appropriate treatment.

Methods: A retrospective chart review was conducted using electronic medical record (EMR) data from residents of 3 NHs who were diagnosed with UTI when hospitalized over a 3-year period. The Cooper Tool and Stone criteria were used to assess treatment appropriateness.

Results: Of 79 hospitalized residents treated for UTI, 11 (13.9%) were appropriately treated according to the Cooper Tool and 9 (11.4%) according to Stone. The two criteria agreed in 9 of the cases including 100% of those with catheters. Urinalysis was documented in 72% of residents and 24% had documentation of culture and sensitivity.

Conclusions: Appropriate UTI treatment rates using both tools were low but much higher in those with catheters. Future research is necessary to validate the use of these tools in the hospital setting which have the potential to improve treatment accuracy and reduce unnecessary antibiotics use.
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http://dx.doi.org/10.1016/j.ajic.2021.04.001DOI Listing
April 2021

Implementing Sleep Apnea Screening Prior to Conscious Sedation Procedures in a Rural Hospital: A Quality Improvement Project.

J Dr Nurs Pract 2020 11;13(3):243-248

University of Michigan-Flint School of Nursing, Flint, Michigan.

Background: Screening patients for obstructive sleep apnea (OSA) risk factors is an effective method for helping reduce adverse outcomes in conscious sedation. Patients receiving conscious sedation for endoscopy were not being screened for OSA at a rural hospital.

Objective: The purpose of this quality improvement project was to implement a nurse education program to improve OSA screening of endoscopy patients, using an evidence-based screening tool, and to increase nurse OSA knowledge and patient education.

Methods: This study was conducted in the outpatient perioperative section of a small rural hospital in northern Michigan. Data were obtained from pre/post chart review and nurse knowledge assessment. Twenty-eight nurses participated in an educational session that included OSA education and instructions on using the STOP-Bang questionnaire for OSA screening.

Results: Nurse OSA knowledge increased from 75% preeducation program to 89% posteducation program. Use of the STOP-Bang Questionnaire for patients presenting for outpatient endoscopy procedures requiring conscious sedation and patient OSA education increased from 43.5% to 81.2% pre- to posteducation program.

Conclusions: This study's educational session was successful in promoting use of the STOP-Bang questionnaire among perioperative nurses and increasing education for patients screened positive for OSA.

Implications For Nursing: Training nurses to use a brief OSA screening tool effectively improved the OSA screening of patients presenting for outpatient conscious sedation involving endoscopy.
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http://dx.doi.org/10.1891/JDNP-D-19-00078DOI Listing
November 2020

Development and Implementation of an Upper Respiratory Infection Treatment Protocol in a Primary Care Health Clinic.

J Prim Care Community Health 2020 Jan-Dec;11:2150132720966811

University of Michigan-Flint, Flint, MI, USA.

Background And Purpose: Acute viral respiratory infections (ARTIs) are among the most common reasons for a healthcare encounter throughout the industrialized world. Among the approximately100 million antibiotic prescriptions written every year for ARTI, half are prescribed inappropriately. Inappropriate antibiotic prescribing for viral illnesses poses a serious threat since many organisms have become resistant to commonly used antibiotics. The aim of this study was to develop an ARTI treatment protocol in accordance with current practice guidelines to decrease the number of inappropriately prescribed antibiotics in a primary care health clinic.

Methods: Patient subjects were obtained using convenience sampling and data collection was completed using ICD queries in the clinic's EHR system. A retrospective chart review analyzing antibiotic prescribing practices was conducted pre- and post- implementation of an educational session detailing current ARTI practice guidelines.

Conclusions: The results of this project showed clinical significance in that clinician education, focused on ARTI current practice guidelines and attentiveness in antibiotic prescription practices, reduced antibiotic use for viral ARTIs by 12.0%.

Implications For Practice: Clinician education and implementation of current practice guidelines for ARTI will assist clinicians decrease both the unnecessary adverse effects of antibiotics, as well as the threat of antibiotic resistance.
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http://dx.doi.org/10.1177/2150132720966811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649881PMC
November 2020

Preliminary Psychometrics of the Knowledge and Attitudes Toward SBAR Instrument (KA-SBAR).

J Dr Nurs Pract 2020 07 21;13(2):120-124. Epub 2020 Apr 21.

Georgia State University, Atlanta, Georgia.

Background: When measuring new practice approaches for improving patient safety in the clinical setting, researchers need instruments with evidence of reliability and validity.

Objective: The purpose of this analysis was to examine the reliability and validity of an instrument to assess knowledge and attitudes toward communication using situation-background-assessment-recommendation (SBAR; KA-SBAR).

Methods: This psychometric analysis was conducted with data from an interprofessional simulation-based learning experience with doctor of nursing practice students ( = 19) and physical therapy students ( = 52). Internal consistency reliability and construct validity tests including factor analysis for the KA-SBAR were conducted.

Results: The KA-SBAR instrument had adequate internal consistency reliability and evidence of construct validity, including identification of two factors that explained 70% of the instrument's variance. However, there may be a ceiling effect of scores, making it difficult to show change.

Conclusions: The KA-SBAR instrument may be useful in assessing clinicians' perceptions of SBAR communication in education and practice settings.

Implications For Nursing: When selecting data collection measures, nurses need to carefully consider the purpose of the measure and evidence of the instrument's reliability and validity. Educators need to consider the clinical expertise of the students in designing challenging simulations to advance learning.
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http://dx.doi.org/10.1891/JDNP-D-19-00058DOI Listing
July 2020

Improving Self-Care Outcomes in Ostomy Patients via Education and Standardized Discharge Criteria.

Home Healthc Now 2020 Jan/Feb;38(1):16-23

Rachel Millard, DNP, RN, FNP-C, CWON, is a Nurse Practitioner, Desert Regional Medical Center, Palm Springs, California. Denise Cooper, DNP, RN, ANP-BC, is an Associate Professor, School of Nursing, University of Michigan-Flint, Flint, Michigan. Mary Jo Boyle, DNP, RN, ACNP-BC, CCRN-K, is an Adjunct Faculty, School of Nursing, University of Michigan-Flint, Flint, Michigan.

Adjusting to life with a new ostomy is a daunting prospect for many patients. Without proper education, complications can occur, some requiring hospital readmission. Many home healthcare nurses also face the challenge of training new ostomy patients in self-care. The purpose of this quality improvement pilot study was to improve outcomes in a sample of new ostomy patients by implementing an intervention consisting of nurse and patient education. The study was conducted at a Southern California home healthcare agency with an average patient census of 270. The participants were 30 home healthcare nurses (6 licensed vocational nurses and 24 registered nurses). We followed the outcomes of four home healthcare patients with new ostomies. The nurse ostomy education session included both didactic and hands-on components to promote practice change. Patient education was guided by the use of an evidence-based ostomy skills checklist adapted from the Wound, Ostomy, and Continence Nurses Society's ostomy discharge criteria. Nurse's skills and competence were measured and compared via results from a 10-question pre- and postintervention nurse self-assessment survey. Patient outcomes were measured and compared via pre- and postintervention chart reviews examining three factors: number of weeks on service, number of visits to reach independence, and number of unscheduled visits. Statistical analysis of survey data showed a significant change in the scores for all questions, indicating the nurses felt more confident managing ostomies after the education session. After the intervention, the number of weeks patients were on service for a new ostomy diagnosis decreased by an average of 1.5 weeks; patients required 50% fewer visits to reach independence; and unscheduled visits decreased by 500%.
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http://dx.doi.org/10.1097/NHH.0000000000000816DOI Listing
November 2020

Measurement of Organ-Specific and Acute-Phase Blood Protein Levels in Early Lyme Disease.

J Proteome Res 2020 01 1;19(1):346-359. Epub 2019 Nov 1.

Institute for Systems Biology , Seattle , Washington 98109 , United States.

Lyme disease results from infection of humans with the spirochete . The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against . Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that (1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or (2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2, and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin, or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.
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http://dx.doi.org/10.1021/acs.jproteome.9b00569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981273PMC
January 2020

Co-infections in Persons with Early Lyme Disease, New York, USA.

Emerg Infect Dis 2019 04;25(4):748-752

In certain regions of New York state, USA, Ixodes scapularis ticks can potentially transmit 4 pathogens in addition to Borrelia burgdorferi: Anaplasma phagocytophilum, Babesia microti, Borrelia miyamotoi, and the deer tick virus subtype of Powassan virus. In a prospective study, we systematically evaluated 52 adult patients with erythema migrans, the most common clinical manifestation of B. burgdorferi infection (Lyme disease), who had not received treatment for Lyme disease. We used serologic testing to evaluate these patients for evidence of co-infection with any of the 4 other tickborne pathogens. Evidence of co-infection was found for B. microti only; 4-6 patients were co-infected with Babesia microti. Nearly 90% of the patients evaluated had no evidence of co-infection. Our finding of B. microti co-infection documents the increasing clinical relevance of this emerging infection.
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http://dx.doi.org/10.3201/eid2504.181509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433014PMC
April 2019

Human Adipose-Derived Stem Cell Conditioned Media and Exosomes Containing Promote Human Dermal Fibroblast Migration and Ischemic Wound Healing.

Adv Wound Care (New Rochelle) 2018 Sep 4;7(9):299-308. Epub 2018 Sep 4.

Research Service, James A. Haley Veterans Hospital, Tampa, Florida.

Chronically ill patients heal recalcitrant ulcerative wounds more slowly. Human adipose-derived stem cells (hADSCs) play an important role in tissue regeneration and exosomes secreted by hADSC contribute to their paracrine signaling. In addition to cytokines, lipids and growth factors, hADSC secrete mRNA, miRNA, and long noncoding (lnc) RNA into exosomes. In this study we examined the role of lncRNA (metastasis-associated lung adenocarcinoma transcript 1), an abundant lncRNA in exosomes from conditioned media (CM), on cell migration and ischemic wound healing. CM and isolated exosomes from hADSC were applied to human dermal fibroblast (HDF) in scratch assays and electric cell-substrate impedance sensing (ECIS) assays. CM was also applied to a rat model of ischemic wound healing and wound closure was followed. CM stimulated cell migration of HDFs by 48%. CM stimulated the closure of ischemic wounds in a rat model 50% faster than unconditioned media. The depletion of in adipose-derived stem cell (ADSC) CM significantly reduced cell migration. Since is secreted into exosomes, a purified population of exosomes was applied to HDF where they enhanced cell migration in a similar manner to FGF-2 or basic fibroblast growth factor (bFGF) in ECIS wound healing assays. The uptake of exosomes by HDF was shown using dynasore, an inhibitor that blocks clathrin- and caveolin-dependent endocytosis. Depletion of in hADSC with antisense oligonucleotides resulted in exosomes without . These exosomes had an effect similar to the unconditioned, control media in ECIS assays. Exosomes contain lncRNA and other factors that have the potential to stimulate HDF cell migration and angiogenesis involved in wound healing without applying stem cells to wounds. Our results show the potential of using topically applied ADSC-derived exosomes containing for treating ischemic wounds. This allows for harnessing the power of stem cell paracrine signaling capabilities without applying the cells.
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http://dx.doi.org/10.1089/wound.2017.0775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158770PMC
September 2018

Human Adipose-Derived Stem Cell Conditioned Media and Exosomes Containing Promote Human Dermal Fibroblast Migration and Ischemic Wound Healing.

Adv Wound Care (New Rochelle) 2018 Sep 4;7(9):299-308. Epub 2018 Sep 4.

Research Service, James A. Haley Veterans Hospital, Tampa, Florida.

Chronically ill patients heal recalcitrant ulcerative wounds more slowly. Human adipose-derived stem cells (hADSCs) play an important role in tissue regeneration and exosomes secreted by hADSC contribute to their paracrine signaling. In addition to cytokines, lipids and growth factors, hADSC secrete mRNA, miRNA, and long noncoding (lnc) RNA into exosomes. In this study we examined the role of lncRNA (metastasis-associated lung adenocarcinoma transcript 1), an abundant lncRNA in exosomes from conditioned media (CM), on cell migration and ischemic wound healing. CM and isolated exosomes from hADSC were applied to human dermal fibroblast (HDF) in scratch assays and electric cell-substrate impedance sensing (ECIS) assays. CM was also applied to a rat model of ischemic wound healing and wound closure was followed. CM stimulated cell migration of HDFs by 48%. CM stimulated the closure of ischemic wounds in a rat model 50% faster than unconditioned media. The depletion of in adipose-derived stem cell (ADSC) CM significantly reduced cell migration. Since is secreted into exosomes, a purified population of exosomes was applied to HDF where they enhanced cell migration in a similar manner to FGF-2 or basic fibroblast growth factor (bFGF) in ECIS wound healing assays. The uptake of exosomes by HDF was shown using dynasore, an inhibitor that blocks clathrin- and caveolin-dependent endocytosis. Depletion of in hADSC with antisense oligonucleotides resulted in exosomes without . These exosomes had an effect similar to the unconditioned, control media in ECIS assays. Exosomes contain lncRNA and other factors that have the potential to stimulate HDF cell migration and angiogenesis involved in wound healing without applying stem cells to wounds. Our results show the potential of using topically applied ADSC-derived exosomes containing for treating ischemic wounds. This allows for harnessing the power of stem cell paracrine signaling capabilities without applying the cells.
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http://dx.doi.org/10.1089/wound.2017.0775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158770PMC
September 2018

Academic Partnerships: Preparing Nurse Practitioners for Underserved Populations.

Nurs Educ Perspect 2018 Sep/Oct;39(5):324-326

About the Authors The authors are faculty and staff at the University of Michigan-Flint School of Nursing. Constance Creech, EdD, MSN, RN, ANP-BC, is director of graduate nursing affairs and associate professor. Janet Paulson, MPH, BSN, RN, is the grant program manager. Margaret Andrews, PhD, RN, CTN-A, FAAN, is interim dean and professor. Denise Cooper, DNP, RN, ANP-BC, is assistant professor. This project is supported by the Health Resources and Services Administration of the US Department of Health and Human Services under Grant DO9HP28677 Advanced Nursing Education University of Michigan-Flint Academic Partnership grant. For more information, contact Dr. Creech at

Medically underserved populations suffer disproportionately from disease and poor health, and nursing schools are challenged to prepare nurse practitioner students to effectively care for underserved patients. This article describes one university's endeavor to create and evaluate academic partnerships with HIV/hepatitis C virus primary care clinics in underserved settings. Designated preceptorships and specific preparation of students tailored for this population via online modules were strategies created to increase students' readiness to practice as primary care providers and increase clinical placements for nurse practitioner students. Outcomes include student readiness to practice and student satisfaction with clinics and preceptors.
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http://dx.doi.org/10.1097/01.NEP.0000000000000313DOI Listing
September 2019

Long noncoding RNA MALAT1 in exosomes drives regenerative function and modulates inflammation-linked networks following traumatic brain injury.

J Neuroinflammation 2018 Jul 12;15(1):204. Epub 2018 Jul 12.

James A Haley Veterans Hospital, Research Service, Tampa, FL, USA.

Background: Neuroinflammation is a common therapeutic target for traumatic brain injury (TBI) due to its contribution to delayed secondary cell death and has the potential to occur for years after the initial insult. Exosomes from adipose-derived stem cells (hASCs) containing the long noncoding RNA MALAT1 are a novel, cell-free regenerative approach to long-term recovery after traumatic brain injury (TBI) that have the potential to modulate inflammation at the genomic level. The long noncoding RNA MALAT1 has been shown to be an important component of the secretome of hASCs.

Methods: We isolated exosomes from hASC containing or depleted of MALAT1. The hASC-derived exosomes were then administered intravenously to rats following a mild controlled cortical impact (CCI). We followed the rats with behavior, in vivo imaging, histology, and RNA sequencing (RNA Seq).

Results: Using in vivo imaging, we show that exosomes migrate into the spleen within 1 h following administration and enter the brain several hours later following TBI. Significant recovery of function on motor behavior as well as a reduction in cortical brain injury was observed after TBI in rats treated with exosomes. Treatment with either exosomes depleted of MALAT1 or conditioned media depleted of exosomes showed limited regenerative effects, demonstrating the importance of MALAT1 in exosome-mediated recovery. Analysis of the brain and spleen transcriptome using RNA Seq showed MALAT1-dependent modulation of inflammation-related pathways, cell cycle, cell death, and regenerative molecular pathways. Importantly, our data demonstrates that MALAT1 regulates expression of other noncoding RNAs including snoRNAs.

Conclusion: We demonstrate that MALAT1 in hASC-derived exosomes modulates multiple therapeutic targets, including inflammation, and has tremendous therapeutic potential for treatment of TBI.
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http://dx.doi.org/10.1186/s12974-018-1240-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044101PMC
July 2018

Reducing Inappropriate Antibiotics for Urinary Tract Infections in Long-Term Care: A Replication Study.

J Nurs Care Qual 2019 Jan/Mar;34(1):16-21

School of Nursing, University of Michigan-Flint (Drs Cooper and McFarland); Impact Physician Group, Pontiac, Michigan (Dr Petrilli); and Michigan Health Specialists, Flint (Dr Shells).

Background: Nursing home providers face challenges in urinary tract infection assessment and treatment, often prescribing unnecessary antibiotics for asymptomatic bacteriuria, a practice that can result in adverse drug reactions, drug resistance, and an increase in antibiotic-associated diarrhea.

Purpose: The purpose of this project was to replicate the Cooper Urinary Tract Infection Program in another facility and measure its effectiveness.

Methods: Using a pre-post design, this project was implemented at a 120-bed, long-term care and rehabilitation facility located in the Midwest United States.

Interventions: This project used the multifaceted Cooper Urinary Tract Infection Program that includes the Cooper tool algorithm, didactic education for providers, and change champions.

Results: The results were significant improvements in nurse knowledge and reduced rates of urinary tract infections, inappropriate antibiotic treatments, and urinalyses.

Conclusions: These results add to the evidence for implementing the Cooper Urinary Tract Infection Program in long-term care facilities for effective reduction of inappropriate antibiotic usage for urinary tract infection.
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http://dx.doi.org/10.1097/NCQ.0000000000000343DOI Listing
February 2019

Examining Admission Factors Predicting Success in a Doctor of Nursing Practice Program.

J Nurs Educ 2018 Jan;57(1):49-52

Background: Graduate nursing programs are challenged to select students who are likely to succeed and who add to nursing workforce diversity.

Method: For this retrospective study, researchers examined 5 years of admission and retention data from a 4-year Bachelor-to-Doctor of Nursing Practice (DNP) program (n=144) at a large public midwestern university. Using a multinomial logistic regression analysis, four factors were examined to determine which predicted student success, delayed success, or failure: last 60-credit grade point average (GPA), admission essay score, average recommendation letter score, and demographic data (i.e., race, age, gender).

Results: GPA, age, and race were found to be significant predictors of student outcomes in this program. Writing and recommendation scores and gender did not predict student outcomes.

Conclusion: DNP admission committees should consider the weight given to the GPA in their admission formulas and be prepared to work with retention committees to support older and minority students. [J Nurs Educ. 2018;57(1):49-52.].
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http://dx.doi.org/10.3928/01484834-20180102-10DOI Listing
January 2018

Association Between Mental Health Staffing Level and Primary Care-Mental Health Integration Level on Provision of Depression Care in Veteran's Affairs Medical Facilities.

Adm Policy Ment Health 2018 01;45(1):131-141

Health Services Research & Development (HSR&D), Veteran Affairs (VA) Puget Sound Health Care System, 1660 Columbian Way, Seattle, WA, 98108, USA.

We examined the association of mental health staffing and the utilization of primary care/mental health integration (PCMHI) with facility-level variations in adequacy of psychotherapy and antidepressants received by Veterans with new, recurrent, and chronic depression. Greater likelihood of adequate psychotherapy was associated with increased (1) PCMHI utilization by recurrent depression patients (AOR 1.02; 95% CI 1.00, 1.03); and (2) staffing for recurrent (AOR 1.03; 95% CI 1.01, 1.06) and chronic (AOR 1.02; 95% CI 1.00, 1.03) depression patients (p < 0.05). No effects were found for antidepressants. Mental health staffing and PCMHI utilization explained only a small amount of the variance in the adequacy of depression care.
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http://dx.doi.org/10.1007/s10488-016-0775-9DOI Listing
January 2018

MALAT1 in Human Adipose Stem Cells Modulates Survival and Alternative Splicing of PKCδII in HT22 Cells.

Endocrinology 2017 01;158(1):183-195

James A. Haley Veterans Hospital, Tampa, Florida 33612; and.

Brain injury may be caused by trauma or may occur in stroke and neurodegenerative diseases. Because the central nervous system is unable to regenerate efficiently, there is utmost interest in the use of stem cells to promote neuronal survival. Of interest here are human adipose-derived stem cells (hASCs), which secrete factors that enhance regeneration and survival of neurons in sites of injury. We evaluated the effect of hASC secretome on immortalized mouse hippocampal cell line (HT22) after injury. Protein kinase C δ (PKCδ) activates survival and proliferation in neurons and is implicated in memory. We previously showed that alternatively spliced PKCδII enhances neuronal survival via B-cell lymphoma 2 Bcl2 in HT22 neuronal cells. Our results demonstrate that following injury, treatment with exosomes from the hASC secretome increases expression of PKCδII in HT22 cells and increases neuronal survival and proliferation. Specifically, we demonstrate that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA contained in the hASC exosomes mediates PKCδII splicing, thereby increasing neuronal survival. Using antisense oligonucleotides for MALAT1 and RNA immunoprecipitation assays, we demonstrate that MALAT1 recruits splice factor serine-arginine-rich splice factor 2 (SRSF2) to promote alternative splicing of PKCδII. Finally, we evaluated the role of insulin in enhancing hASC-mediated neuronal survival and demonstrated that insulin treatment dramatically increases the association of MALAT1 and SRSF2 and substantially increases survival and proliferation after injury in HT22 cells. In conclusion, we demonstrate the mechanism of action of hASC exosomes in increasing neuronal survival. This effect of hASC exosomes to promote wound healing can be further enhanced by insulin treatment in HT22 cells.
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http://dx.doi.org/10.1210/en.2016-1819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412980PMC
January 2017

Adipose-derived stem cells from lean and obese humans show depot specific differences in their stem cell markers, exosome contents and senescence: role of protein kinase C delta (PKCδ) in adipose stem cell niche.

Stem Cell Investig 2016 31;3. Epub 2016 Jan 31.

1 Department of Molecular Medicine, University of South Florida, Tampa, FL, USA ; 2 James A. Haley Veterans Hospital, Tampa, FL, USA ; 3 Honors College, University of South Florida, Tampa, FL, USA ; 4 Department of Surgery, University of South Florida, Tampa, FL, USA.

Background: Adipose-derived stem cells (ASC) and its exosomes are gaining utmost importance in the field of regenerative medicine. The ASCs tested for their potential in wound healing are predominantly derived from the subcutaneous depot of lean donors. However, it is important to characterize the ASC derived from different adipose depots as these depots have clinically distinct roles.

Methods: We characterized the ASC derived from subcutaneous and omental depots from a lean donor (sc-ASCn and om-ASCn) and compared it to the ASC derived from an obese donor (sc-ASCo and om-ASCo) using flow cytometry and real time qPCR.

Results: We show that stem cell markers Oct4, Sal4, Sox15, KLF4 and BMI1 have distinct expression patterns in each ASC. We evaluated the secretome of the ASC and characterized their secreted exosomes. We show long noncoding RNAs (lncRNAs) are secreted by ASC and their expression varied between the ASC's derived from different depots. Protein kinase C delta (PKCδ) regulates the mitogenic signals in stem cells. We evaluated the effect of silencing PKCδ in sc-ASCn, om-ASCn, sc-ASCo and om-ASCo. Using β-galactosidase staining, we evaluated the percentage of senescent cells in sc-ASCn, om-ASCn, sc-ASCo and om-ASCo. Our results also indicated that silencing PKCδ increases the percentage of senescent cells.

Conclusions: Our case-specific study demonstrates a role of PKCδ in maintaining the adipose stem cell niche and importantly demonstrates depot-specific differences in adipose stem cells and their exosome content.
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http://dx.doi.org/10.3978/j.issn.2306-9759.2016.01.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923648PMC
June 2016

Long-term Assessment of Post-Treatment Symptoms in Patients With Culture-Confirmed Early Lyme Disease.

Clin Infect Dis 2015 Dec 18;61(12):1800-6. Epub 2015 Sep 18.

Division of Infectious Diseases.

Background: Lyme disease patients with erythema migrans are said to have post-treatment Lyme disease symptoms (PTLDS) if there is persistence of subjective symptoms for at least 6 months following antibiotic treatment and resolution of the skin lesion. The purpose of this study was to characterize PTLDS in patients with culture-confirmed early Lyme disease followed for >10 years.

Methods: Adult patients with erythema migrans with a positive skin or blood culture for Borrelia burgdorferi were enrolled in a prospective study beginning in 1991 and followed up at 6 months and annually thereafter to determine the long-term outcome of this infection. The genotype of the infecting strain of B. burgdorferi was evaluated in subjects with PTLDS.

Results: One hundred twenty-eight subjects with culture-confirmed early Lyme disease, of whom 55% were male, were followed for a mean ± SD of 14.98 ± 2.71 years (median = 15 years; range = 11-20 years). Fourteen (10.9%) were regarded as having possible PTLDS, but only 6 (4.7%) had PTLDS documented at their last study visit. Nine (64.3%) had only a single symptom. None of the 6 with PTLDS at their last visit was considered to be functionally impaired by the symptom(s). PTLDS was not associated with a particular genotype of B. burgdorferi.

Conclusions: PTLDS may persist for >10 years in some patients with culture-confirmed early Lyme disease. Such long-standing symptoms were not associated with functional impairment or a particular strain of B. burgdorferi.
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http://dx.doi.org/10.1093/cid/civ735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657537PMC
December 2015

Response to Thomas E. Finucane, MD.

J Am Geriatr Soc 2015 Jan;63(1):203-4

Veteran Affairs Puget Sound Health Care System, Seattle, Washington; Department of Health Services, University of Washington, Seattle, Washington.

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http://dx.doi.org/10.1111/jgs.13209DOI Listing
January 2015

Long Non-Coding RNA NEAT1 Associates with SRp40 to Temporally Regulate PPARγ2 Splicing during Adipogenesis in 3T3-L1 Cells.

Genes (Basel) 2014 Nov 27;5(4):1050-63. Epub 2014 Nov 27.

Research Service, J. A. Haley Veterans Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL 33612, USA.

Long non-coding (lnc) RNAs serve a multitude of functions in cells. NEAT1 RNA is a highly abundant 4 kb lncRNA in nuclei, and coincides with paraspeckles, nuclear domains that control sequestration of paraspeckle proteins. We examined NEAT1 RNA levels and its function in 3T3-L1 cells during differentiation to adipocytes. Levels of NEAT1 transcript, measured by RT-PCR, fluctuated in a temporal manner over the course of differentiation that suggested its role in alternative splicing of PPARγ mRNA, the major transcription factor driving adipogenesis. When cells were induced to differentiate by a media cocktail of insulin, dexamethasone, and isobutylmethyxanthine (IBMX) on Day 0, NEAT1 levels dropped on Day 4, when the PPARγ2 variant was spliced and when terminal differentiation occurs The appearance of PPARγ2 coordinates with the PPARγ1 variant to drive differentiation of adipocytes. SiRNA used to deplete NEAT1 resulted in the inability of cells to phosphorylate the serine/arginine-rich splicing protein, SRp40. SiRNA treatment for SRp40 resulted in dysregulation of PPARγ1 and, primarily, PPARγ2 mRNA levels. SRp40 associated with NEAT1, as shown by RNA-IP on days 0 and 8, but decreased on day 4, and concentrations increased over that of IgG control. Overexpression of SRp40 increased PPARγ2, but not γ1. Although lncRNA MALAT1 has been investigated in SR protein function, NEAT1 has not been shown to bind SR proteins for phosphorylation such that alternative splicing results. The ability of cells to increase phosphorylated SR proteins for PPARγ2 splicing suggests that fluxes in NEAT1 levels during adipogenesis regulate alternative splicing events.
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http://dx.doi.org/10.3390/genes5041050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276926PMC
November 2014

Transformer 2β homolog (Drosophila) (TRA2B) regulates protein kinase C δI (PKCδI) splice variant expression during 3T3L1 preadipocyte cell cycle.

J Biol Chem 2014 Nov 26;289(46):31662-31672. Epub 2014 Sep 26.

Department of Molecular Medicine, University of South Florida, Tampa, Florida 33612; James A. Haley Veterans Hospital and University of South Florida, Tampa, Florida 33612. Electronic address:

Obesity is characterized by adipocyte hyperplasia and hypertrophy. We previously showed that PKCδ expression is dysregulated in obesity (Carter, G., Apostolatos, A., Patel, R., Mathur, A., Cooper, D., Murr, M., and Patel, N. A. (2013) ISRN Obes. 2013, 161345). Using 3T3L1 preadipocytes, we studied adipogenesis in vitro and showed that expression of PKCδ splice variants, PKCδI and PKCδII, have different expression patterns during adipogenesis (Patel, R., Apostolatos, A., Carter, G., Ajmo, J., Gali, M., Cooper, D. R., You, M., Bisht, K. S., and Patel, N. A. (2013) J. Biol. Chem. 288, 26834-26846). Here, we evaluated the role of PKCδI splice variant during adipogenesis. Our results indicate that PKCδI expression level is high in preadipocytes and decreasing PKCδI accelerated terminal differentiation. Our results indicate that PKCδI is required for mitotic clonal expansion of preadipocytes. We next evaluated the splice factor regulating the expression of PKCδI during 3T3L1 adipogenesis. Our results show TRA2B increased PKCδI expression. To investigate the molecular mechanism, we cloned a heterologous splicing PKCδ minigene and showed that inclusion of PKCδ exon 9 is increased by TRA2B. Using mutagenesis and a RNA-immunoprecipitation assay, we evaluated the binding of Tra2β on PKCδI exon 9 and show that its association is required for PKCδI splicing. These results provide a better understanding of the role of PKCδI in adipogenesis. Determination of this molecular mechanism of alternative splicing presents a novel therapeutic target in the management of obesity and its co-morbidities.
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http://dx.doi.org/10.1074/jbc.M114.592337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231647PMC
November 2014

Antidepressant adherence and risk of coronary artery disease hospitalizations in older and younger adults with depression.

J Am Geriatr Soc 2014 Jul 2;62(7):1238-45. Epub 2014 Jun 2.

Center of Innovation for Veteran-Centered and Value-Driven Care, Health Services Research and Development, Veteran Affairs Puget Sound Health Care System, Seattle, Washington; Department of Health Services, University of Washington, Seattle, Washington.

Objectives: To assess whether the relationship between antidepressant adherence and coronary artery disease (CAD) hospitalizations varied between older and younger adults with depression.

Design: Retrospective cohort study.

Setting: Department of Veterans Affairs outpatient clinics nationwide.

Participants: Chronically depressed individuals (n = 50,261; aged 20-97) who had been prescribed an antidepressant were identified from records indicating an outpatient clinic visit for depression (index depression visit) during fiscal years 2009 and 2010. Individuals were considered chronically depressed if they had had prior depression visits and treatment for depression within the previous 4 months. The sample was age-stratified into younger (<65) and older (≥ 65) groups.

Measurements: After the index depression visit, medication possession ratios were calculated from pharmacy refill data to determine whether participants had 80% or greater adherence to antidepressant refills during a 6-month treatment observation period. International Classification of Diseases, Ninth Revision, codes were used to derive CAD-related hospitalizations during the follow-up period. Mean follow-up was 24 months. Data were analyzed using Cox proportional hazard models.

Results: Older participants with 80% or greater antidepressant adherence had 26% lower risk of CAD hospitalizations (hazard ratio = 0.74, 95% confidence interval = 0.60-0.93). Antidepressant adherence was not significantly related to CAD hospitalizations in younger adults.

Conclusion: Older adults with chronic depression with 80% or greater antidepressant adherence had significantly lower risk of CAD hospitalizations at follow-up than those with less than 80% adherence. These preliminary results suggest that older adults with depression may derive cardiovascular benefits from clinical efforts to increase antidepressant adherence.
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http://dx.doi.org/10.1111/jgs.12849DOI Listing
July 2014

Comparison of Markers and Functional Attributes of Human Adipose-Derived Stem Cells and Dedifferentiated Adipocyte Cells from Subcutaneous Fat of an Obese Diabetic Donor.

Adv Wound Care (New Rochelle) 2014 Mar;3(3):219-228

Research Service, James A. Haley Veterans Hospital , Tampa, Florida. ; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida , Tampa, Florida.

Adipose tissue is a robust source of adipose-derived stem cells (ADSCs) that may be able to provide secreted factors that promote the ability of wounded tissue to heal. However, adipocytes also have the potential to dedifferentiate in culture to cells with stem cell-like properties that may improve their behavior and functionality for certain applications. ADSCs are adult mesenchymal stem cells that are cultured from the stromal vascular fraction of adipose tissue. However, adipocytes are capable of dedifferentiating into cells with stem cell properties. In this case study, we compare ADSC and dedifferentiated fat (DFAT) cells from the same patient and fat depot for mesenchymal cell markers, embryonic stem cell markers, ability to differentiate to adipocytes and osteoblasts, senescence and telomerase levels, and ability of conditioned media (CM) to stimulate migration of human dermal fibroblasts (HDFs). ADSCs and DFAT cells displayed identical levels of CD90, CD44, CD105, and were CD34- and CD45-negative. They also expressed similar levels of Oct4, BMI1, KLF4, and SALL4. DFAT cells, however, showed higher efficiency in adipogenic and osteogenic capacity. Telomerase levels of DFAT cells were double those of ADSCs, and senescence declined in DFAT cells. CM from both cell types altered the migration of fibroblasts. Despite reports of ADSCs from a number of human depots, there have been no comparisons of the ability of dedifferentiated DFAT cells from the same donor and depot to differentiate or modulate migration of HDFs. Since ADSCs were from an obese diabetic donor, reprogramming of DFAT cells may help improve a patient's cells for regenerative medicine applications.
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http://dx.doi.org/10.1089/wound.2013.0452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955970PMC
March 2014

Understanding the debate around regulation of support workers.

Br J Nurs 2014 Mar 13-26;23(5):260-3

Work-Based Education Facilitator, WBEF Network, University Hospital of South Manchester.

While much is written about the regulation of healthcare support workers (HCSWs), many authors and policy makers do not distinguish between assumption and evidence. As calls for compulsory regulation of HCSWs grow louder, it is crucial that the evidence underpinning the debate on both sides is considered carefully and critically. The authors reviewed journal articles and policy documents with the specific aim of clarifying the arguments for and against further regulation from an evidence-based perspective. The majority of material recommended HCSW regulation, however, the mechanisms by which regulation would deliver better patient care were often missing and were rarely evidence-based. This article provides clear definitions of the key terms and processes needed to engage in the debate, followed by a summary of the arguments for and against the regulation of support workers.
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http://dx.doi.org/10.12968/bjon.2014.23.5.260DOI Listing
April 2014

Dysregulated Alternative Splicing Pattern of PKCδ during Differentiation of Human Preadipocytes Represents Distinct Differences between Lean and Obese Adipocytes.

ISRN Obes 2013 10;2013:161345. Epub 2013 Apr 10.

James A. Haley Veterans' Hospital, Research Service VAR 151, 13000 Bruce B. Downs Boulevard, Tampa, FL 33612, USA ; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.

Obesity and its comorbidities affect millions of people. Here, we demonstrate that human preadipocytes are susceptible to programmed cell death (apoptosis) while mature adipocytes are resistant to apoptosis. The molecular mechanisms underlying the phenotype of apoptosis-resistant adipocytes are lesser known. To study the role of apoptosis and define molecular differences in the developmental process of adipogenesis, human preadipocytes were differentiated in vitro to mature adipocytes. Many genes in the apoptosis pathway are alternatively spliced. Our data demonstrates that during differentiation PKC δ , Bclx, and Caspase9 switch to their prosurvival splice variants along with an increase in Bcl2 expression when the cells terminally differentiate into mature adipocytes. Next we determined the expression pattern of these genes in obesity. Our data indicated high expression of PKC δ VIII in adipose tissue of obese patient in different depots. We demonstrate a shift in the in vitro expression of these splice variants in differentiating preadipocytes derived from obese patients along with a decrease in adipogenesis markers. Hence, the programmed splicing of antiapoptotic proteins is a pivotal switch in differentiation that commits adipocytes to a prosurvival pathway. The expression pattern of these genes is dysregulated in obesity and may contribute to adipose tissue dysfunction.
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http://dx.doi.org/10.1155/2013/161345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901959PMC
February 2014

Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats.

J Neurosci 2014 Jan;34(1):313-26

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair and School of Physical Therapy and Rehabilitation Sciences, University of South Florida Morsani College of Medicine, Tampa, Florida 33612, James A. Haley Veterans Affairs Hospital, Research Service, Tampa, Florida 33612, and Departments of Molecular Pharmacology and Physiology and Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612.

Traumatic brain injury (TBI) survivors exhibit motor and cognitive symptoms from the primary injury that can become aggravated over time because of secondary cell death. In the present in vivo study, we examined the beneficial effects of human adipose-derived stem cells (hADSCs) in a controlled cortical impact model of mild TBI using young (6 months) and aged (20 months) F344 rats. Animals were transplanted intravenously with 4 × 10(6) hADSCs (Tx), conditioned media (CM), or vehicle (unconditioned media) at 3 h after TBI. Significant amelioration of motor and cognitive functions was revealed in young, but not aged, Tx and CM groups. Fluorescent imaging in vivo and ex vivo revealed 1,1' dioactadecyl-3-3-3',3'-tetramethylindotricarbocyanine iodide-labeled hADSCs in peripheral organs and brain after TBI. Spatiotemporal deposition of hADSCs differed between young and aged rats, most notably reduced migration to the aged spleen. Significant reduction in cortical damage and hippocampal cell loss was observed in both Tx and CM groups in young rats, whereas less neuroprotection was detected in the aged rats and mainly in the Tx group but not the CM group. CM harvested from hADSCs with silencing of either NEAT1 (nuclear enriched abundant transcript 1) or MALAT1 (metastasis associated lung adenocarcinoma transcript 1), long noncoding RNAs (lncRNAs) known to play a role in gene expression, lost the efficacy in our model. Altogether, hADSCs are promising therapeutic cells for TBI, and lncRNAs in the secretome is an important mechanism of cell therapy. Furthermore, hADSCs showed reduced efficacy in aged rats, which may in part result from decreased homing of the cells to the spleen.
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http://dx.doi.org/10.1523/JNEUROSCI.2425-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866490PMC
January 2014

Protein kinase C delta (PKCδ) splice variant modulates senescence via hTERT in adipose-derived stem cells.

Stem Cell Investig 2014 19;1. Epub 2014 Jan 19.

1 James A Haley Veterans Hospital, Tampa, FL, USA ; 2 Department of Molecular Medicine and 3 Surgery, University of South Florida, Tampa, FL, USA.

Background: Adipose-derived stem cells (ADSC) were isolated and characterized from lean and obese subjects. We previously reported that distinct differences were observed in differentiating lean and obese preadipocytes. Protein kinase C delta (PKCδ) is alternatively spliced and has important roles in apoptosis. PKCδI promotes apoptosis and PKCδVIII promotes survival. Our previous data indicated an increase in the survival kinase, PKCδVIII in ADSC derived from an obese donor. We also determined that obese adipocytes were resistant to apoptosis. Here, we determine the relationship between a survival kinase PKCδVIII and hTERT expression in adipose derived stem cells from a lean and obese subject.

Methods: We evaluated the telomerase activity and human telomerase reverse transcriptase (hTERT) expression in lean and obese ADSC. The lean and obese ADSC were purchased as cryopreserved cells from ZenBio™ (Research Triangle Park, NC, USA). Analyses were performed using PRISM™ software and analyzed using two-tailed Student's t-test.

Results: We observed an increase in telomerase in differentiating obese ADSC using western blot analysis. We determined the levels of hTERT splice variants. hTERT α+/β+ splice variant was increased after transfected of PKCδVIII. We next determined whether PKCδVIII over-expression affected the levels of telomerase. The results indicate an increase in telomerase with PKCδVIII over-expression.

Conclusions: Over-expression of PKCδVIII in lean ADSC substantially increased expression of hTERT and telomerase. The decreased senescence seen in obese ADSC may in part be attributed to PKCδVIII. Obese ADSC undergo lower senescence and may have increased growth potential. These results propose a larger epigenetic modification in obese ADSC compared to lean ADSC.
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http://dx.doi.org/10.3978/j.issn.2306-9759.2014.01.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923498PMC
June 2016

Utility of serodiagnostics designed for use in the United States for detection of Lyme borreliosis acquired in Europe and vice versa.

Med Microbiol Immunol 2014 Feb 12;203(1):65-71. Epub 2013 Nov 12.

Division of Infectious Diseases, New York Medical College, Valhalla, NY, 10595, USA,

Although two-tier testing is standard practice in both the United States and Europe for the serologic diagnosis of Lyme borreliosis (LB), the test kits generally differ. The purpose of this study was to determine if the testing used in the United States will detect LB acquired in Europe and vice versa. Testing was performed on a convenience sample of archived sera from 40 LB patients from Austria and 39 from the United States, using first- and second-tier test kits from both the United States and Europe. The sensitivity of four first-tier tests from Europe and two first-tier tests from the United States was similar. Thus, two-tier testing was compared to the C6 ELISA as the first-tier test, since it is licensed in both the United States and Europe. The sensitivity of C6 two-tier testing with US assays was 9/40 (22.5 % [95 % CI 10.8-38.5 %]) for detection of LB acquired in Europe, and just 20.0 % (95 % CI 2.5-55.6 %) in the ten European patients with neurologic involvement. These results differed significantly from the sensitivity of European C6 two-tier testing that was 70.0 % (95 % CI 53.5-83.4 %) overall (p < 0.001) and 90.0 % (95 % CI 55.5-99.7 %) for the European patients with neurologic manifestations specifically (p = 0.016). In contrast, the sensitivity of European and US C6 two-tier testing was similar for detection of LB acquired in the United States. Two-tier serologic testing with the US test kits may be unsatisfactory for detection of LB acquired in Europe. First-tier testing with an assay such as the C6 ELISA should be considered as a stand-alone diagnostic strategy in such cases.
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http://dx.doi.org/10.1007/s00430-013-0315-0DOI Listing
February 2014

Sex Differences in Associations of Depressive Symptoms with Cardiovascular Risk Factors and Metabolic Syndrome among African Americans.

Cardiovasc Psychiatry Neurol 2013 16;2013:979185. Epub 2013 Sep 16.

Northwest HSR&D Center of Excellence, VA Puget Sound Health Care System, 1100 Olive Way, Suite 1400, Seattle, WA 98101, USA ; Department of Health Services, University of Washington, Seattle, WA 98195, USA.

Young to middle-aged women usually have notably lower rates of cardiovascular disease (CVD) than their male counterparts, but African American women lack this advantage. Their elevated CVD may be influenced by sex differences in associations between depressed mood and CVD risk factors. This cross-sectional study examined whether relations between scores on the Center for Epidemiologic Studies-Depression (CES-D) scale and a spectrum of CVD risk factors varied by sex among African Americans (n = 1076; ages 30-64) from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Sex-stratified multiple regressions and logistic regressions were conducted. Among women, CES-D scores correlated positively with systolic blood pressure and waist-to-hip ratio (P's < .05), but inversely with high-density lipoprotein cholesterol (HDL-C) (P < .01). Women had twice the odds for metabolic syndrome if CES-D scores ≥16 and had a ≥14% increase in odds of hypertension, abdominal obesity, and low HDL-C with each 5-unit increase in CES-D scores. Among men, CES-D scores correlated positively with high-sensitivity C-reactive protein (P < .05), and odds of hypertension increased by 21% with each 5-unit increase in CES-D scores. Depressive symptoms may promote premature CVD risk in African Americans, at least in part, via CVD risk factors and prevalent metabolic syndrome, particularly in African American women.
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http://dx.doi.org/10.1155/2013/979185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787626PMC
October 2013