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Publication Record


Cardiovascular Disease Risk Factors in Ghana during the Rural-to-Urban Transition: A Cross-Sectional Study.
Kodaman N, Aldrich MC, Sobota R, Asselbergs FW, Poku KA, Brown NJ, Moore JH, Williams SM
(2016) PLoS One 11: e0162753
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Blood Glucose, Blood Pressure, Body Mass Index, Cardiovascular Diseases, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Ghana, Humans, Hypertension, Male, Middle Aged, Obesity, Plasminogen Activator Inhibitor 1, Prevalence, Risk Factors, Smoking, Surveys and Questionnaires, Tissue Plasminogen Activator, Triglycerides, Urbanization, Young Adult
Show Abstract · Added April 6, 2017
Populations in sub-Saharan Africa are shifting from rural to increasingly urban. Although the burden of cardiovascular disease is expected to increase with this changing landscape, few large studies have assessed a wide range of risk factors in urban and rural populations, particularly in West Africa. We conducted a cross-sectional, population-based survey of 3317 participants from Ghana (≥18 years old), of whom 2265 (57% female) were from a mid-sized city (Sunyani, population ~250,000) and 1052 (55% female) were from surrounding villages (populations <5000). We measured canonical cardiovascular disease risk factors (BMI, blood pressure, fasting glucose, lipids) and fibrinolytic markers (PAI-1 and t-PA), and assessed how their distributions and related clinical outcomes (including obesity, hypertension and diabetes) varied with urban residence and sex. Urban residence was strongly associated with obesity (OR: 7.8, 95% CI: 5.3-11.3), diabetes (OR 3.6, 95% CI: 2.3-5.7), and hypertension (OR 3.2, 95% CI: 2.6-4.0). Among the quantitative measures, most affected were total cholesterol (+0.81 standard deviations, 95% CI 0.73-0.88), LDL cholesterol (+0.89, 95% CI: 0.79-0.99), and t-PA (+0.56, 95% CI: 0.48-0.63). Triglycerides and HDL cholesterol profiles were similarly poor in both urban and rural environments, but significantly worse among rural participants after BMI-adjustment. For most of the risk factors, the strength of the association with urban residence did not vary with sex. Obesity was a major exception, with urban women at particularly high risk (26% age-standardized prevalence) compared to urban men (7%). Overall, urban residents had substantially worse cardiovascular risk profiles, with some risk factors at levels typically seen in the developed world.
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29 MeSH Terms
Plasminogen Activator Inhibitor-1 and Diagnosis of the Metabolic Syndrome in a West African Population.
Kodaman N, Aldrich MC, Sobota R, Asselbergs FW, Brown NJ, Moore JH, Williams SM
(2016) J Am Heart Assoc 5:
MeSH Terms: Adolescent, Adult, Antihypertensive Agents, Blood Glucose, Blood Pressure, Body Mass Index, Cholesterol, HDL, Cross-Sectional Studies, Diabetes Mellitus, Fasting, Female, Ghana, Humans, Hypertension, Hypoglycemic Agents, Male, Metabolic Syndrome, Middle Aged, Plasminogen Activator Inhibitor 1, Prevalence, Rural Population, Triglycerides, Urban Population, Young Adult
Show Abstract · Added April 6, 2017
BACKGROUND - Metabolic syndrome (MetS) is diagnosed by the presence of at least 3 of the following: obesity, hypertension, hyperglycemia, hypertriglyceridemia, and low high-density lipoprotein. Individuals with MetS also typically have elevated plasma levels of the antifibrinolytic factor, plasminogen activator inhibitor-1 (PAI-1), but the relationships between PAI-1 and MetS diagnostic criteria are not clear. Understanding these relationships can elucidate the relevance of MetS to cardiovascular disease risk, because PAI-1 is associated with ischemic events and directly involved in thrombosis.
METHODS AND RESULTS - In a cross-sectional analysis of 2220 Ghanaian men and women from urban and rural locales, we found the age-standardized prevalence of MetS to be as high as 21.4% (urban women). PAI-1 level increased exponentially as the number of diagnostic criteria increased linearly (P<10), supporting the conclusion that MetS components have a joint effect that is stronger than their additive contributions. Body mass index, triglycerides, and fasting glucose were more strongly correlated with PAI-1 than with canonical MetS criteria, and this pattern did not change when pair-wise correlations were conditioned on all other risk factors, supporting an independent role for PAI-1 in MetS. Finally, whereas the correlations between conventional risk factors did not vary significantly by sex or across urban and rural environments, correlations with PAI-1 were generally stronger among urban participants.
CONCLUSIONS - MetS prevalence in the West African population we studied was comparable to that of the industrialized West. PAI-1 may serve as a key link between MetS, as currently defined, and the endpoints with which it is associated. Whether this association is generalizable will require follow-up.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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24 MeSH Terms
Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial.
Ramirez CE, Nian H, Yu C, Gamboa JL, Luther JM, Brown NJ, Shibao CA
(2015) J Clin Endocrinol Metab 100: 4533-40
MeSH Terms: Adult, Albuminuria, Double-Blind Method, Endothelium, Vascular, Female, Fibrinolysis, Glucose, Glucose Clamp Technique, Glucose Tolerance Test, Hemodynamics, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Overweight, Phosphodiesterase 5 Inhibitors, Plasminogen Activator Inhibitor 1, Prediabetic State, Sildenafil Citrate
Show Abstract · Added November 30, 2015
CONTEXT - Sildenafil increases insulin sensitivity in mice. In humans, phosphodiesterase 5 inhibition improves disposition index, but the mechanism of this effect has not been elucidated and may depend on duration. In addition, increasing cyclic GMP without increasing nitric oxide could have beneficial effects on fibrinolytic balance.
OBJECTIVE - The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function.
DESIGN - This was a randomized, double-blind, placebo-controlled study.
SETTING - This trial was conducted at Vanderbilt Clinical Research Center.
PARTICIPANTS - Participants included overweight individuals with prediabetes.
INTERVENTIONS - Subjects were randomized to treatment with sildenafil 25 mg three times a day or matching placebo for 3 months. Subjects underwent a hyperglycemic clamp prior to and at the end of treatment.
MAIN OUTCOME MEASURES - The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion.
RESULT - Twenty-one subjects completed each treatment arm. After 3 months, the insulin sensitivity index was significantly greater in the sildenafil group compared to the placebo group by 1.84 mg/kg/min per μU/mL*100 (95% confidence interval, 0.01 to 3.67 mg/kg/min per μU/mL*100; P = .049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, there was no effect of 3-month treatment with sildenafil on acute- or late-phase glucose-stimulated insulin secretion (P > .30). Sildenafil decreased plasminogen activator inhibitor-1 (P = .01), without altering tissue-plasminogen activator. In contrast to placebo, sildenafil also decreased the urine albumin-to-creatinine ratio from 12.67 ± 14.67 to 6.84 ± 4.86 μg/mg Cr. This effect persisted 3 months after sildenafil discontinuation.
CONCLUSIONS - Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function.
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20 MeSH Terms
Genetics of Plasminogen Activator Inhibitor-1 (PAI-1) in a Ghanaian Population.
White MJ, Kodaman NM, Harder RH, Asselbergs FW, Vaughan DE, Brown NJ, Moore JH, Williams SM
(2015) PLoS One 10: e0136379
MeSH Terms: Adult, Cardiovascular Diseases, Circadian Rhythm, European Continental Ancestry Group, Female, Ghana, Humans, Male, N-Acetylgalactosamine-4-Sulfatase, Period Circadian Proteins, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide
Show Abstract · Added April 6, 2017
Plasminogen activator inhibitor 1 (PAI-1), a major modulator of the fibrinolytic system, is an important factor in cardiovascular disease (CVD) susceptibility and severity. PAI-1 is highly heritable, but the few genes associated with it explain only a small portion of its variation. Studies of PAI-1 typically employ linear regression to estimate the effects of genetic variants on PAI-1 levels, but PAI-1 is not normally distributed, even after transformation. Therefore, alternative statistical methods may provide greater power to identify important genetic variants. Additionally, most genetic studies of PAI-1 have been performed on populations of European descent, limiting the generalizability of their results. We analyzed >30,000 variants for association with PAI-1 in a Ghanaian population, using median regression, a non-parametric alternative to linear regression. Three variants associated with median PAI-1, the most significant of which was in the gene arylsulfatase B (ARSB) (p = 1.09 x 10(-7)). We also analyzed the upper quartile of PAI-1, the most clinically relevant part of the distribution, and found 19 SNPs significantly associated in this quartile. Of note an association was found in period circadian clock 3 (PER3). Our results reveal novel associations with median and elevated PAI-1 in an understudied population. The lack of overlap between the two analyses indicates that the genetic effects on PAI-1 are not uniform across its distribution. They also provide evidence of the generalizability of the circadian pathway's effect on PAI-1, as a recent meta-analysis performed in Caucasian populations identified another circadian clock gene (ARNTL).
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12 MeSH Terms
Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification.
Yuasa M, Mignemi NA, Nyman JS, Duvall CL, Schwartz HS, Okawa A, Yoshii T, Bhattacharjee G, Zhao C, Bible JE, Obremskey WT, Flick MJ, Degen JL, Barnett JV, Cates JM, Schoenecker JG
(2015) J Clin Invest 125: 3117-31
MeSH Terms: Animals, Fibrin, Fibrinogen, Fibrinolysis, Fracture Healing, Mice, Mice, Knockout, Ossification, Heterotopic, Plasminogen
Show Abstract · Added August 31, 2015
Bone formation during fracture repair inevitably initiates within or around extravascular deposits of a fibrin-rich matrix. In addition to a central role in hemostasis, fibrin is thought to enhance bone repair by supporting inflammatory and mesenchymal progenitor egress into the zone of injury. However, given that a failure of efficient fibrin clearance can impede normal wound repair, the precise contribution of fibrin to bone fracture repair, whether supportive or detrimental, is unknown. Here, we employed mice with genetically and pharmacologically imposed deficits in the fibrin precursor fibrinogen and fibrin-degrading plasminogen to explore the hypothesis that fibrin is vital to the initiation of fracture repair, but impaired fibrin clearance results in derangements in bone fracture repair. In contrast to our hypothesis, fibrin was entirely dispensable for long-bone fracture repair, as healing fractures in fibrinogen-deficient mice were indistinguishable from those in control animals. However, failure to clear fibrin from the fracture site in plasminogen-deficient mice severely impaired fracture vascularization, precluded bone union, and resulted in robust heterotopic ossification. Pharmacological fibrinogen depletion in plasminogen-deficient animals restored a normal pattern of fracture repair and substantially limited heterotopic ossification. Fibrin is therefore not essential for fracture repair, but inefficient fibrinolysis decreases endochondral angiogenesis and ossification, thereby inhibiting fracture repair.
0 Communities
5 Members
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9 MeSH Terms
Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3- and p53-dependent fibrotic responses.
Samarakoon R, Helo S, Dobberfuhl AD, Khakoo NS, Falke L, Overstreet JM, Goldschmeding R, Higgins PJ
(2015) J Pathol 236: 421-32
MeSH Terms: Animals, Apoptosis, Aristolochic Acids, Cell Cycle Checkpoints, Cell Line, Cell Proliferation, Disease Models, Animal, Enzyme Inhibitors, Fibrosis, Gene Expression Regulation, Humans, Kidney Diseases, Kidney Tubules, Male, Mice, Inbred C57BL, PTEN Phosphohydrolase, Plasminogen Activator Inhibitor 1, RNA Interference, Signal Transduction, Smad3 Protein, Streptozocin, Transfection, Transforming Growth Factor beta1, Tumor Suppressor Protein p53, Ureteral Obstruction
Show Abstract · Added April 19, 2016
Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis and diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ)-mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK-2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI-1, vimentin, α-SMA and fibronectin expression, compared to HK-2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53(Ser15) phosphorylation, with an accompanying decrease in population density and an increase in epithelial G1 cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI-1 rescued the PTEN loss-associated epithelial proliferative arrest. Moreover, TGFβ1-initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGFβ1 treatment and PTEN silencing potentiated epithelial cell death via p53-dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3- and p53-mediated fibrotic gene induction, with accompanying PAI-1-dependent proliferative arrest, and cooperates with TGFβ1 to induce the expression of profibrotic genes and tubular apoptosis.
Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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25 MeSH Terms
Management of portal vein thrombosis after liver transplantation with a combined open and endovascular approach.
Kensinger CD, Sexton KW, Baron CM, Lipnik AJ, Meranze SG, Gorden DL
(2015) Liver Transpl 21: 132-4
MeSH Terms: Aged, Fibrinolytic Agents, Humans, Infusions, Intravenous, Laparotomy, Liver Diseases, Alcoholic, Liver Transplantation, Male, Phlebography, Portal Vein, Thrombolytic Therapy, Tissue Plasminogen Activator, Tomography, X-Ray Computed, Treatment Outcome, Vascular Patency, Venous Thrombosis
Added February 12, 2015
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1 Members
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16 MeSH Terms
Rapid binding of plasminogen to streptokinase in a catalytic complex reveals a three-step mechanism.
Verhamme IM, Bock PE
(2014) J Biol Chem 289: 28006-18
MeSH Terms: Amino Acid Motifs, Bacterial Proteins, Binding Sites, Biocatalysis, Fibrinolysin, Humans, Kinetics, Plasminogen, Protein Binding, Protein Conformation, Streptococcal Infections, Streptococcus, Streptokinase, Substrate Specificity
Show Abstract · Added January 20, 2015
Rapid kinetics demonstrate a three-step pathway of streptokinase (SK) binding to plasminogen (Pg), the zymogen of plasmin (Pm). Formation of a fluorescently silent encounter complex is followed by two conformational tightening steps reported by fluorescence quenches. Forward reactions were defined by time courses of biphasic quenching during complex formation between SK or its COOH-terminal Lys(414) deletion mutant (SKΔK414) and active site-labeled [Lys]Pg ([5-(acetamido)fluorescein]-D-Phe-Phe-Arg-[Lys]Pg ([5F]FFR-[Lys]Pg)) and by the SK dependences of the quench rates. Active site-blocked Pm rapidly displaced [5F]FFR-[Lys]Pg from the complex. The encounter and final SK ·[5F]FFR-[Lys]Pg complexes were weakened similarly by SK Lys(414) deletion and blocking of lysine-binding sites (LBSs) on Pg kringles with 6-aminohexanoic acid or benzamidine. Forward and reverse rates for both tightening steps were unaffected by 6-aminohexanoic acid, whereas benzamidine released constraints on the first conformational tightening. This indicated that binding of SK Lys(414) to Pg kringle 4 plays a role in recognition of Pg by SK. The substantially lower affinity of the final SK · Pg complex compared with SK · Pm is characterized by a ∼ 25-fold weaker encounter complex and ∼ 40-fold faster off-rates for the second conformational step. The results suggest that effective Pg encounter requires SK Lys(414) engagement and significant non-LBS interactions with the protease domain, whereas Pm binding additionally requires contributions of other lysines. This difference may be responsible for the lower affinity of the SK · Pg complex and the expression of a weaker "pro"-exosite for binding of a second Pg in the substrate mode compared with SK · Pm.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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14 MeSH Terms
Emergence of the primary pediatric stroke center: impact of the thrombolysis in pediatric stroke trial.
Bernard TJ, Rivkin MJ, Scholz K, deVeber G, Kirton A, Gill JC, Chan AK, Hovinga CA, Ichord RN, Grotta JC, Jordan LC, Benedict S, Friedman NR, Dowling MM, Elbers J, Torres M, Sultan S, Cummings DD, Grabowski EF, McMillan HJ, Beslow LA, Amlie-Lefond C, Thrombolysis in Pediatric Stroke Study
(2014) Stroke 45: 2018-23
MeSH Terms: Adolescent, Child, Child, Preschool, Clinical Trials as Topic, Female, Fibrinolytic Agents, Hospitals, Pediatric, Humans, Male, Multicenter Studies as Topic, Quality of Health Care, Stroke, Tertiary Care Centers, Thrombolytic Therapy, Tissue Plasminogen Activator
Show Abstract · Added March 24, 2020
BACKGROUND AND PURPOSE - In adult stroke, the advent of thrombolytic therapy led to the development of primary stroke centers capable to diagnose and treat patients with acute stroke rapidly. We describe the development of primary pediatric stroke centers through preparation of participating centers in the Thrombolysis in Pediatric Stroke (TIPS) trial.
METHODS - We collected data from the 17 enrolling TIPS centers regarding the process of becoming an acute pediatric stroke center with capability to diagnose, evaluate, and treat pediatric stroke rapidly, including use of thrombolytic therapy.
RESULTS - Before 2004, <25% of TIPS sites had continuous 24-hour availability of acute stroke teams, MRI capability, or stroke order sets, despite significant pediatric stroke expertise. After TIPS preparation, >80% of sites now have these systems in place, and all sites reported increased readiness to treat a child with acute stroke. Use of a 1- to 10-Likert scale on which 10 represented complete readiness, median center readiness increased from 6.2 before site preparation to 8.7 at the time of site activation (P≤0.001).
CONCLUSIONS - Before preparing for TIPS, centers interested in pediatric stroke had not developed systematic strategies to diagnose and treat acute pediatric stroke. TIPS trial preparation has resulted in establishment of pediatric acute stroke centers with clinical and system preparedness for evaluation and care of children with acute stroke, including use of a standardized protocol for evaluation and treatment of acute arterial stroke in children that includes use of intravenous tissue-type plasminogen activator.
CLINICAL TRIAL REGISTRATION URL - http://www.clinicaltrials.gov. Unique identifier: NCT01591096.
© 2014 American Heart Association, Inc.
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MeSH Terms
Redox control of p53 in the transcriptional regulation of TGF-β1 target genes through SMAD cooperativity.
Overstreet JM, Samarakoon R, Meldrum KK, Higgins PJ
(2014) Cell Signal 26: 1427-36
MeSH Terms: Acetylation, Animals, Cell Line, DNA-Binding Proteins, Enzyme Activation, Epithelial Cells, Fibroblasts, Fibrosis, Gene Expression Regulation, Humans, Keratinocytes, Kidney Diseases, Kidney Tubules, Mice, Mice, Knockout, NADPH Oxidases, Phosphorylation, Plasminogen Activator Inhibitor 1, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Signal Transduction, Smad3 Protein, Transcriptional Activation, Transforming Growth Factor beta1, Tumor Suppressor Protein p53
Show Abstract · Added April 19, 2016
Transforming growth factor-β1 (TGF-β1) regulates the tissue response to injury and is the principal driver of excessive scarring leading to fibrosis and eventual organ failure. The TGF-β1 effectors SMAD3 and p53 are major contributors to disease progression. While SMAD3 is an established pro-fibrotic factor, the role of p53 in the TGF-β1-induced fibrotic program is not clear. p53 gene silencing, genetic ablation/subsequent rescue, and pharmacological inhibition confirmed that p53 was required for expression of plasminogen activator inhibitor-1 (PAI-1), a major TGF-β1 target gene and a key causative element in fibrotic disorders. TGF-β1 regulated p53 activity by stimulating p53(Ser15 and 9) phosphorylation and acetylation, promoting interactions with activated SMADs and subsequent binding of p53/SMAD3 to the PAI-1 promoter in HK-2 human renal tubular epithelial cells and HaCaT human keratinocytes. Immunohistochemistry revealed prominent co-induction of SMAD3, p53 and PAI-1 in the tubular epithelium of the obstructed kidney consistent with a potential in vivo role for p53 and SMADs in TGF-β1-driven renal fibrosis. TGF-β1-initiated phosphorylation of p53(Ser15) and up-regulation of expression of several pro-fibrotic genes, moreover, was dependent on the rapid generation of reactive oxygen species (ROS). shRNA silencing of the p22(Phox) subunit of NADP(H) oxidases in HK-2 cells partially attenuated (over 50%) p53(Ser15) phosphorylation and PAI-1 induction. These studies highlight the role of free radicals in p53 activation and subsequent pro-fibrotic reprogramming by TGF-β1 via the SMAD3-p53 transcriptional axis. Present findings provide a rationale for therapeutic targeting of SMAD3-p53 in aberrant TGF-β1 signaling associated with renal fibrosis.
Copyright © 2014 Elsevier Inc. All rights reserved.
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27 MeSH Terms