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1.
Circulation ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31918577

RESUMO

Background: Diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury by incompletely understood mechanisms. Adipocyte dysfunction contributes to remote organ injury. However, the molecular mechanisms linking dysfunctional adipocytes to increased MI/R injury remain unidentified. The current study attempted to clarify whether and how small extracellular vesicles (sEV) may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating MI/R injury. Methods: Adult male mice were fed a normal or a high fat diet for 12 weeks. sEV (from diabetic serum, diabetic adipocytes, or high glucose/high lipid (HG/HL)-challenged non-diabetic adipocytes) were injected intramyocardially distal of coronary ligation. Animals were subjected to MI/R 48 hours after injection. Results: Intramyocardial injection of diabetic serum sEV in the non-diabetic heart significantly exacerbated MI/R injury, as evidenced by poorer cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. Similarly, intramyocardial or systemic administration of diabetic adipocyte sEV or HG/HL-challenged non-diabetic adipocyte sEV significantly exacerbated MI/R injury. Diabetic epididymal fat transplantation significantly increased MI/R injury in non-diabetic mice, whereas administration of a sEV biogenesis inhibitor significantly mitigated MI/R injury in diabetic mice. Mechanistic investigation identified that miR-130b-3p is a common molecule significantly increased in diabetic serum sEV, diabetic adipocyte sEV, and HG/HL-challenged non-diabetic adipocyte sEV. Mature (but not primary) miR-130b-3p was significantly increased in the diabetic and non-diabetic heart subjected to diabetic sEV injection. Whereas intramyocardial injection of a miR-130b-3p mimic significantly exacerbated MI/R injury in non-diabetic mice, miR-130b-3p inhibitors significantly attenuated MI/R injury in diabetic mice. Molecular studies identified AMPKα1/α2, Birc6, and Ucp3 as direct downstream targets of miR-130b-3p. Overexpression of these molecules (particularly AMPKα2) reversed miR-130b-3p induced pro-apoptotic/cardiac harmful effect. Finally, miR-130b-3p levels were significantly increased in plasma sEV from type 2 diabetic patients. Incubation of cardiomyocytes with diabetic patient sEV significantly exacerbated ischemic injury, an effect blocked by miR-130b-3p inhibitor. Conclusions: We demonstrate for the first time that miR-130b-3p enrichment in dysfunctional adipocyte-derived sEV, and its suppression of multiple anti-apoptotic/cardioprotective molecules in cardiomyocytes, is a novel mechanism exacerbating MI/R injury in the diabetic heart. Targeting miR-130b-3p mediated pathological communication between dysfunctional adipocytes and cardiomyocytes may be a novel strategy attenuating diabetic exacerbation of MI/R injury.

2.
Sci Rep ; 10(1): 23, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913350

RESUMO

Diabetes mellitus (DM) significantly increases myocardial ischemia/reperfusion (MI/R) injury. During DM, cardioprotection induced by conventional pre-conditioning (PreCon) is decreased due to impaired AMP-activated protein kinase (AMPK) signaling. The current study investigated whether PreCon with inhaled anesthetic sevoflurane (SF-PreCon) remains cardioprotective during DM, and identified the involved mechanisms. Normal diet (ND) and high-fat diet (HFD)-induced DM mice were randomized into control and SF-PreCon (3 cycles of 15-minute period exposures to 2% sevoflurane) groups before MI/R. SF-PreCon markedly reduced MI/R injury in DM mice, as evidenced by improved cardiac function (increased LVEF and ±Dp/dt), decreased infarct size, and decreased apoptosis. To determine the relevant role of AMPK, the effect of SF-PreCon was determined in cardiac-specific AMPKα2 dominant negative expressing mice (AMPK-DN). SF-PreCon decreased MI/R injury in AMPK-DN mice. To explore the molecular mechanisms responsible for SF-PreCon mediated cardioprotection in DM mice, cell survival molecules were screened. Interestingly, in ND mice, SF-PreCon significantly reduced MI/R-induced activation of p38, a pro-death MAPK, without altering ERK and JNK. In DM and AMPK-DN mice, the inhibitory effect of SF-PreCon upon p38 activation was significantly blunted. However, SF-PreCon significantly increased phosphorylation of ERK1/2, a pro-survival MAPK in DM and AMPK-DN mice. We demonstrate that SF-PreCon protects the heart via AMPK-dependent inhibition of pro-death MAPK in ND mice. However, SF-PreCon exerts cardioprotective action via AMPK-independent activation of a pro-survival MAPK member in DM mice. SF-PreCon may be beneficial compared to conventional PreCon in diabetes or clinical scenarios in which AMPK signaling is impaired.

3.
Circ Res ; 126(2): 212-228, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31694459

RESUMO

RATIONALE: Obstructive sleep apnea-hypopnea syndrome, a sleep breathing disorder in which chronic intermittent hypoxia (CIH) is the primary pathology, is associated with multiple cardiovascular diseases. However, whether and how CIH may affect cardiac remodeling following myocardial infarction (MI) remains unknown. OBJECTIVE: To determine whether CIH exposure at different periods of MI may exacerbate post-MI heart failure and to identify the mechanisms underlying CIH-exacerbated post-MI remodeling. METHODS AND RESULTS: Adult male mice were subjected to MI (4 weeks) with and without CIH (4 or 8 weeks). CIH before MI (CIH+MI) had no significant effect on post-MI remodeling. However, double CIH exposure (CIH+MI+CIH) or CIH only during the MI period (MI+CIH) significantly exacerbated pathological remodeling and reduced survival rate. Mechanistically, CIH activated TGF-ß (tumor growth factor-ß)/Smad (homologs of both the Drosophila protein MAD and the C. elegans protein SMA) signaling and enhanced cardiac epithelial to mesenchymal transition, markedly increasing post-MI cardiac fibrosis. Transcriptome analysis revealed that, among 15 genes significantly downregulated (MI+CIH versus MI), Ctrp9 (a novel cardioprotective cardiokine) was one of the most significantly inhibited genes. Real-time polymerase chain reaction/Western analysis confirmed that cardiomyocyte CTRP9 expression was significantly reduced in MI+CIH mice. RNA-sequencing, real-time polymerase chain reaction, and dual-luciferase reporter assays identified that microRNA-214-3p is a novel Ctrp9 targeting miRNA. Its upregulation is responsible for Ctrp9 gene suppression in MI+CIH. Finally, AAV9 (adeno-associated virus 9)-mediated cardiac-specific CTRP9 overexpression or rCTRP9 (recombinated CTRP9) administration inhibited TGF-ß/Smad and Wnt/ß-catenin pathways, attenuated interstitial fibrosis, improved cardiac function, and enhanced survival rate in MI+CIH animals. CONCLUSIONS: This study provides the first evidence that MI+CIH upregulates miR-214-3p, suppresses cardiac CTRP9 (C1q tumor necrosis factor-related protein-9) expression, and exacerbates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathological remodeling in MI patients with obstructive sleep apnea-hypopnea syndrome.

4.
Circ J ; 83(8): 1726-1736, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31217391

RESUMO

BACKGROUND: Withaferin A (WFA), an anticancer constituent of the plant Withania somnifera, inhibits tumor growth in association with apoptosis induction. However, the potential role of WFA in the cardiovascular system is little-studied and controversial.Methods and Results:Two different doses of WFA were tested to determine their cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury through evaluation of cardiofunction in wild-type and AMP-activated protein kinase domain negative (AMPK-DN) gentransgenic mice. Surprisingly, cardioprotective effects (improved cardiac function and reduced infarct size) were observed with low-dose WFA (1 mg/kg) delivery but not high-dose (5 mg/kg). Mechanistically, low-dose WFA attenuated myocardial apoptosis. It decreased MI/R-induced activation of caspase 9, the indicator of the intrinsic mitochondrial pathway, but not caspase 8. It also upregulated the level of AMP-activated protein kinase (AMPK) phosphorylation and increased the MI/R inhibited ratio of Bcl2/Bax. In AMPK-deficient mice, WFA did not ameliorate MI/R-induced cardiac dysfunction, attenuate infarct size, or restore the Bcl2/Bax (B-cell lymphoma2/Mcl-2-like protein 4) ratio. CONCLUSIONS: These results demonstrated for the first time that low-dose WFA is cardioprotective via upregulation of the anti-apoptotic mitochondrial pathway in an AMPK-dependent manner.

5.
Life Sci ; 211: 91-101, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30213729

RESUMO

Withaferin A (WFA), a withanolide derived from medicinal plant Withania somnifera, possesses anti-tumorigenic and immunomodulatory activities against various cancer cells. However, the role of WFA in myocardial ischemia reperfusion (MI/R) injury remains unclear. In the present study, we determined whether WFA may regulate cardiac ischemia reperfusion injury and elucidate the underlying mechanisms. We demonstrated that WFA enhanced H9c2 cells survival ability against simulated ischemia/reperfusion (SI/R) or hydrogen peroxide (H2O2)-induced cell apoptosis. In addition, the enhanced oxidative stress induced by SI/R was inhibited by WFA. Among the multiple antioxidant molecules determined, antioxidants SOD2, SOD3, Prdx-1 was obviously upregulated by WFA. When Akt inhibitor IV was administrated, WFA's suppression effect on oxidative stress was obviously abolished. Additional experiments demonstrated that WFA successfully inhibited H2O2 induced upregulation of SOD2, SOD3, and Prdx-1, ameliorated cardiomyocyte caspase-3 activity via an Akt dependent manner. Collectively, these results support the therapeutic potential of WFA against cardiac ischemia reperfusion injury and highlight the application of WFA in cardiovascular diseases holding great promise for the future.


Assuntos
Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vitanolídeos/farmacologia , Animais , Antioxidantes/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Indian J Ophthalmol ; 66(8): 1149-1153, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30038162

RESUMO

Purpose: The objective of this study was to determine the associations of strabismus surgery reoperation rates in a large national database of provider payments with geographic region, practice type and volume, and the availability of adjustable suture technique. Methods: Fee-for-service payments to providers for medicare beneficiaries having strabismus surgery between 2012 and 2015 were retrospectively analyzed to identify reoperations in the same calendar year. The adjustable-suture technique was considered to be available to the patient if the patient's surgeon billed for adjustable sutures. Predictors of reoperation in the same calendar year were determined by multivariable logistic regression. Results: Availability of the adjustable suture technique was not associated with reoperation rate in multivariable analysis among 5971 patients having horizontal muscle surgery (odds ratio, [OR] 0.86, P = 0.29), 2840 patients having vertical muscle surgery (OR 0.98, P = 0.93), or 1199 patients having surgery with scarring or restriction (OR 0.86, P = 0.61). For horizontal surgery, the reoperation rate was higher in academic practices (OR 1.67), as compared with community practices, and in the South (OR 2.85) and West (OR 1.92, all P < 0.001). The reoperation rate was unchanged with surgeons in the lowest-quartile of surgical volume. Among surgeons paid for horizontal surgery, 45% of surgeons in the Northeast, the West, or Florida coded for adjustable sutures, compared with 8% of surgeons elsewhere (P < 0.001). Conclusion: The availability of the adjustable-suture technique was not associated with reoperation rate after strabismus surgery in this large national database. Having surgery by a lower-volume surgeon was not associated with a higher reoperation rate. The reoperation rate was higher when surgery was conducted in an academic practice, or in certain regions of the country. Adjustable sutures are largely a bicoastal practice.


Assuntos
Gastos em Saúde , Medicare/economia , Procedimentos Cirúrgicos Oftalmológicos/economia , Estrabismo/cirurgia , Cirurgiões/provisão & distribução , Técnicas de Sutura/instrumentação , Suturas/economia , Idoso , Planos de Pagamento por Serviço Prestado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculos Oculomotores/cirurgia , Reoperação , Estudos Retrospectivos , Estrabismo/economia , Técnicas de Sutura/economia , Estados Unidos
7.
PLoS One ; 11(3): e0152247, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27023866

RESUMO

Clinical studies have identified hypoadiponectinemia as an independent hypertension risk factor. It is known that adiponectin (APN) can directly cause vasodilation, but the doses required exceed physiologic levels several fold. In the current study, we determine the effect of physiologically relevant APN concentrations upon vascular tone, and investigate the mechanism(s) responsible. Physiologic APN concentrations alone induced no significant vasorelaxation. Interestingly, pretreatment of wild type mouse aortae with physiologic APN levels significantly enhanced acetylcholine (ACh)-induced vasorelaxation (P<0.01), an endothelium-dependent and nitric oxide (NO)-mediated process. Knockout of adiponectin receptor 1 (AdipoR1) or caveolin-1 (Cav-1, a cell signaling facilitating molecule), but not adiponectin receptor 2 (AdipoR2) abolished APN-enhanced ACh-induced vasorelaxation. Immunoblot assay revealed APN promoted the AdipoR1/Cav1 signaling complex in human endothelial cells. Treatment of HUVECs with physiologic APN concentrations caused significant eNOS phosphorylation and nitric oxide (NO) production (P<0.01), an effect abolished in knockdown of either AdipoR1 or Cav-1. Taken together, these data demonstrate for the first time physiologic APN levels enhance the vasorelaxative response to ACh by inducing NO production through AdipoR1/Cav-1 mediated signaling. In physiologic conditions, APN plays an important function of maintaining vascular tone.


Assuntos
Acetilcolina/farmacologia , Adiponectina/farmacologia , Caveolina 1/metabolismo , Receptores de Adiponectina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Técnicas In Vitro , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos
8.
Free Radic Biol Med ; 89: 473-85, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26453924

RESUMO

Reduced levels of adiponectin (APN) contribute to cardiovascular injury in the diabetic population. Recent studies demonstrate elevated circulating APN levels are associated with endothelial dysfunction during pre-diabetes, suggesting the development of APN resistance. However, mechanisms leading to, and the role of, vascular APN resistance in endothelial dysfunction remain unidentified. The current study determined whether diabetes cause endothelial APN resistance, and by what mechanisms. Under high glucose/high lipids (HG/HL), APN-stimulated nitric oxide production by HUVEC was decreased, phosphorylation of eNOS, AMPK, and Akt was attenuated (P<0.01), and APN's anti-TNFα effect was blunted (P<0.01). APN receptor expression remained normal, whereas Cav1 expression was reduced in HG/HL cells (P<0.01). The AdipoR1/Cav1 signaling complex was dissociated in HG/HL cells. Knock-down of Cav1 inhibited APN's anti-oxidative and anti-inflammatory actions. Conversely, preventing HG/HL-induced Cav1 downregulation by Cav1 overexpression preserved APN signaling in HG/HL cells. Knock-in of a wild type Cav1 in Cav1 knock-down cells restored caveolae structure and rescued APN signaling. In contrast, knock-in of a mutated Cav1 scaffolding domain restored caveolae structure, but failed to rescue APN signaling in Cav1 knock-down cells. Finally, AdipoR1/Cav1 interaction was significantly reduced in diabetic vascular tissue, and the vasorelaxative response to APN was impaired in diabetic animals. The current study demonstrates for the first time the interaction between AdipoR1 and Cav1 is critical for adiponectin-mediated vascular signaling. The AdipoR1/Cav1 interaction is adversely affected by HG/HL, due largely to reduced Cav1 expression, supporting a potential mechanism for the development of APN resistance, contributing to diabetic endothelial dysfunction.


Assuntos
Adiponectina/metabolismo , Caveolina 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Receptores de Adiponectina/metabolismo , Transdução de Sinais , Animais , Glicemia/metabolismo , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Humanos , Immunoblotting , Imunoprecipitação , Lipídeos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , RNA Interferente Pequeno , Transdução de Sinais/fisiologia , Transfecção
9.
Am J Physiol Endocrinol Metab ; 308(10): E891-8, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25783894

RESUMO

Prevalence and severity of postmyocardial infarction heart failure continually escalate in type 2 diabetes via incompletely understood mechanisms. The discovery of the cardiac secretomes, collectively known as "cardiokines", has significantly enhanced appreciation of the local microenvironment's influence on disease development. Recent studies demonstrated that C1q-TNF-related protein-9 (CTRP9), a newly discovered adiponectin (APN) paralog, is highly expressed in the heart. However, its relationship with APN (concerning diabetic cardiovascular injury in particular) remains unknown. Plasma CTRP9 levels are elevated in APN knockout and reduced in diabetic mice. In contrast to APN, which circulates as full-length multimers, CTRP9 circulates in the plasma primarily in the globular domain isoform (gCTRP9). Recombinant full-length CTRP9 (fCTRP9) was cleaved when incubated with cardiac tissue extracts, generating gCTRP9, a process inhibited by protease inhibitor cocktail. gCTRP9 rapidly activates cardiac survival kinases, including AMPK, Akt, and endothelial NOS. However, fCTRP9-mediated kinase activation is much less potent and significantly delayed. Kinase activation by fCTRP9, but not gCTRP9, is inhibited by protease inhibitor cocktail. These results demonstrate for the first time that the novel cardiokine CTRP9 undergoes proteolytic cleavage to generate gCTRP9, the dominant circulatory and actively cardioprotective isoform. Enhancing cardiac CTRP9 production and/or its proteolytic posttranslational modification are of therapeutic potential, attenuating diabetic cardiac injury.


Assuntos
Adiponectina/química , Adiponectina/metabolismo , Cardiotônicos , Domínio Catalítico/genética , Glicoproteínas/química , Glicoproteínas/metabolismo , Proteólise , Células 3T3-L1 , Adiponectina/genética , Adiponectina/farmacologia , Animais , Cardiotônicos/química , Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/prevenção & controle , Dieta Hiperlipídica , Glicoproteínas/genética , Glicoproteínas/farmacologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dobramento de Proteína , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/farmacologia
10.
Acad Emerg Med ; 20(7): 724-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23782404

RESUMO

The Accreditation Council for Graduate Medical Education (ACGME) has outlined its "Next Accreditation System" (NAS) that will focus on resident and residency outcome measurements. Emergency medicine (EM) is one of seven specialties that will implement the NAS beginning July 2013. All other specialties will follow in July 2014. A key component of the NAS is the development of assessable milestones, which are explicit accomplishments or behaviors that occur during the process of residency education. Milestones describe competencies more specifically and identify specialty-specific knowledge, skills, attitudes, and behaviors (KSABs) that can be used as outcome measures within the general competencies. The ACGME and the American Board of Emergency Medicine (ABEM) convened an EM milestone working group to develop the EM milestones. This article describes the development, use within the NAS, and challenges of the EM milestones.


Assuntos
Acreditação/normas , Competência Clínica/normas , Medicina de Emergência/educação , Qualidade da Assistência à Saúde , Educação de Pós-Graduação em Medicina/normas , Feminino , Humanos , Internato e Residência/normas , Masculino , Estados Unidos
11.
Am J Physiol Endocrinol Metab ; 304(6): E661-7, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23360826

RESUMO

Recent clinical observations demonstrate adiponectin (APN), an adipocytokine with potent cardioprotective actions, is significantly reduced following myocardial ischemia/reperfusion (MI/R). However, mechanisms responsible for MI/R-induced hypoadiponectinemia remain incompletely understood. Adult male mice were subjected to 30-min MI followed by varying reperfusion periods. Adipocyte APN mRNA and protein expression and plasma APN and TNFα concentrations were determined. APN expression/production began to decline 3 h after reperfusion (reaching nadir 12 h after reperfusion), returning to control levels 7 days after reperfusion. Plasma TNFα levels began to increase 1 h after reperfusion, peaking at 3 h and returning to control levels 24 h after reperfusion. TNFα knockout significantly increased plasma APN levels 12 h after reperfusion but failed to improve APN expression/production 72 h after reperfusion. In contrast, TNF receptor-1 (TNFR1) knockout significantly restored APN expression 12 and 72 h after reperfusion, suggesting that other TNFR1 binding cytokines contribute to MI/R-induced APN suppression. Among many cytokines increased after MI/R, lymphotoxin-α (LTα) was the only cytokine remaining elevated 24-72 h after reperfusion. LTα knockout did not augment APN levels 12 h post-reperfusion, but did so by 72 h. Finally, in vitro treatment of adipocytes with TNFα and LTα at concentrations seen in MI/R plasma additively inhibited APN expression/production in TNFR1-dependent fashion. Our study demonstrates for the first time that LTα is a novel suppressor of APN expression and contributes to the sustained hypoadiponectinemia following MI/R. Combining anti-TNFα with anti-LTα strategies may achieve the best effects restoring APN in MI/R patients.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo Branco/metabolismo , Regulação para Baixo , Linfotoxina-alfa/metabolismo , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células 3T3-L1 , Adiponectina/sangue , Adiponectina/deficiência , Adiponectina/genética , Tecido Adiposo Branco/imunologia , Animais , Linfotoxina-alfa/sangue , Linfotoxina-alfa/genética , Masculino , Erros Inatos do Metabolismo/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isquemia Miocárdica/sangue , Isquemia Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Receptores Tipo I de Fatores de Necrose Tumoral/antagonistas & inibidores , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Regulação para Cima
13.
Arterioscler Thromb Vasc Biol ; 31(11): 2616-23, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21836066

RESUMO

OBJECTIVE: Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction. However, APN knockout animals manifest modest systemic dysfunction unless metabolically challenged. The protein family CTRPs (C1q/TNF-related proteins) has recently been identified as APN paralogs and some CTRP members share APN's metabolic regulatory function. However, the vasoactive properties of CTRPs remain completely unknown. METHODS AND RESULTS: The vasoactivity of currently identified murine CTRP members was assessed in aortic vascular rings and underlying molecular mechanisms was elucidated in human umbilical vein endothelial cells. Of 8 CTRPs, CTRPs 3, 5, and 9 caused significant vasorelaxation. The vasoactive potency of CTRP9 exceeded that of APN (3-fold) and is endothelium-dependent and nitric oxide (NO)-mediated. Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased NO production. AMPK knockdown completely blocked CTRP9-induced Akt/eNOS phosphorylation and NO production. Akt knockdown had no significant effect on CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1, but not receptor 2, knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, preincubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasorelaxative effects. CONCLUSION: We have provided the first evidence that CTRP9 is a novel vasorelaxative adipocytokine that may exert vasculoprotective effects via the adiponectin receptor 1/AMPK/eNOS dependent/NO mediated signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/farmacologia , Glicoproteínas/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Receptores de Adiponectina/metabolismo , Vasodilatação/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/farmacologia , Receptores de Adiponectina/antagonistas & inibidores , Receptores de Adiponectina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Vasodilatação/fisiologia
14.
Acad Emerg Med ; 18(5): 513-8, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21521403

RESUMO

The clerkship director (CD) serves as a faculty leader within a school of medicine and plays a vital role in the hierarchy of undergraduate medical education. Collectively, CDs across specialties serve a multitude of roles and are responsible for clerkship administration, curricular development, teaching, mentoring, and advising students. The emergency medicine (EM) CD has a vitally important role to play in the future development of medical students. EM CDs should be valued and supported, because they often represent our specialty within the medical school and play a vital role in training the physicians of tomorrow. Opportunities and resources must be made available to CDs to run and maintain a successful EM clerkship, while also balancing their clinical duties and academic endeavors. In addition, EM CDs need support from their respective medical schools and departments to run highly successful medical student rotations. This article was prepared with the objective of establishing the importance of the EM CD, defining the job description of the CD, explaining the importance of adequate release time to perform the role of the CD, and describing the necessary resources and support for the position. With EM becoming an increasingly popular and integral rotation for medical students, it is likely that additional emphasis will be placed on the role of the EM CD. This reference document serves as a template for the job description and expectations of an EM CD.


Assuntos
Estágio Clínico/organização & administração , Medicina de Emergência/educação , Docentes de Medicina , Descrição de Cargo , Humanos , Mentores , Diretores Médicos , Competência Profissional , Faculdades de Medicina , Sociedades Médicas
15.
Injury ; 42(5): 515-20, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20153857

RESUMO

OBJECTIVES: There exists no standard hospital emergency department (ED) triage procedure model for earthquake victims. This study provides an overview of the hospital triage procedure used for patients evaluated and treated at the West China Hospital of Sichuan University, Chengdu in the Sichuan province of China, following the May 12, 2008 Wenchuan earthquake. METHODS: Emergency triage and treatment teams were comprised of senior emergency medicine (EM) attending physician, junior EM attending physician, EM residents, and specialty surgeons. Retrospective analysis of the hospital medical records of 2283 earthquake victims was performed. Victims' demographic data, triage process and group assignments, diagnoses and dispositions were reviewed. RESULTS: In the 2 weeks following the Wenchuan earthquake, 2283 total patients with earthquake-related injuries were admitted to our hospital. 54 victims (2.4%) were lost to follow up. Patients were triaged into four main groups: resuscitation (n=6), urgent treatment (n=369), delayed treatment (n=1502), and minor injuries (n=406). 68.9% (1572/2283) of the patients were admitted to the hospital during the 15 days after the earthquake. The overall hospital mortality rate was 1.0% (15/1572). 1304 victims were transferred to nearby hospitals after initial treatment, stabilization, or surgery. CONCLUSIONS: Proper triage strategy should be established prior to the onset of a mass casualty event and should be appropriate to both the severity of the disaster and the accepting facility resource availability. Triage methods utilizing multi-specialty treatment teams and dynamic hospital-wide coordination are critical for efficient, efficacious patient management. Hopefully, sharing with the emergency medicine community the arduous challenges we faced in the wake of the Wenchuan earthquake will be useful for planning the response to future disasters.


Assuntos
Planejamento em Desastres/organização & administração , Terremotos/estatística & dados numéricos , Serviço Hospitalar de Emergência/organização & administração , Hospitalização/estatística & dados numéricos , Triagem/organização & administração , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China/epidemiologia , Planejamento em Desastres/normas , Terremotos/mortalidade , Serviço Hospitalar de Emergência/normas , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Incidentes com Feridos em Massa , Pessoa de Meia-Idade , Estudos Retrospectivos , Triagem/normas , Adulto Jovem
17.
J Emerg Med ; 39(2): 210-5, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20634023

RESUMO

BACKGROUND: The specialty of emergency medicine (EM) continues to experience a significant workforce shortage in the face of increasing demand for emergency care. SUMMARY: In July 2009, representatives of the leading EM organizations met in Dallas for the Future of Emergency Medicine Summit. Attendees at the Future of Emergency Medicine Summit agreed on the following: 1) Emergency medical care is an essential community service that should be available to all; 2) An insufficient emergency physician workforce also represents a potential threat to patient safety; 3) Accreditation Council for Graduate Medical Education/American Osteopathic Association (AOA)-accredited EM residency training and American Board of Medical Specialties/AOA EM board certification is the recognized standard for physician providers currently entering a career in emergency care; 4) Physician supply shortages in all fields contribute to-and will continue to contribute to-a situation in which providers with other levels of training may be a necessary part of the workforce for the foreseeable future; 5) A maldistribution of EM residency-trained physicians persists, with few pursuing practice in small hospital or rural settings; 6) Assuring that the public receives high quality emergency care while continuing to produce highly skilled EM specialists through EM training programs is the challenge for EM's future; 7) It is important that all providers of emergency care receive continuing postgraduate education.


Assuntos
Medicina de Emergência/educação , Serviço Hospitalar de Emergência/tendências , Medicina de Emergência/normas , Previsões , Humanos , Internato e Residência/normas , Profissionais de Enfermagem/educação , Assistentes Médicos/educação , Recursos Humanos
18.
J Emerg Nurs ; 36(4): 330-5, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20624567

RESUMO

Physician shortages are being projected for most medical specialties. The specialty of emergency medicine continues to experience a significant workforce shortage in the face of increasing demand for emergency care. The limited supply of emergency physicians, emergency nurses, and other resources is creating an urgent, untenable patient care problem. In July 2009, representatives of the leading emergency medicine organizations met in Dallas, TX, for the Future of Emergency Medicine Summit. This consensus document, agreed to and cowritten by all participating organizations, describes the substantive issues discussed and provides a foundation for the future of the specialty.


Assuntos
Medicina de Emergência , Enfermagem em Emergência , Serviço Hospitalar de Emergência/tendências , Necessidades e Demandas de Serviços de Saúde/tendências , Medicina de Emergência/educação , Medicina de Emergência/tendências , Enfermagem em Emergência/educação , Enfermagem em Emergência/tendências , Serviço Hospitalar de Emergência/organização & administração , Previsões , Humanos , Profissionais de Enfermagem/provisão & distribução , Enfermeiras e Enfermeiros/provisão & distribução , Assistentes Médicos/provisão & distribução , Médicos/provisão & distribução , Qualidade da Assistência à Saúde/normas , Estados Unidos , Recursos Humanos
20.
Am J Physiol Endocrinol Metab ; 299(2): E207-14, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20460580

RESUMO

Diabetes mellitus (DM) is closely related to cardiovascular morbidity and mortality, but the specific molecular basis linking DM with increased vulnerability to cardiovascular injury remains incompletely understood. Methylglyoxal (MG), a precursor to advanced glycation end products (AGEs), is increased in diabetic patient plasma, but its role in diabetic cardiovascular complications is unclear. Thioredoxin (Trx), a cytoprotective molecule with antiapoptotic function, has been demonstrated to be vulnerable to glycative inhibition, but whether Trx is glycatively inhibited by MG, thus contributing to increased cardiac injury, has never been investigated. Cultured H9c2 cardiomyocytes were treated with MG (200 muM) for 6 days. The following were determined pre- and post-simulated ischemia-reperfusion (SI-R; 8 h of hypoxia followed by 3 h of reoxygenation): cardiomyocyte death/apoptosis, Trx expression and activity, AGE formation, Trx-apoptosis-regulating kinase-1 (Trx-ASK1) complex formation, and p38 mitogen-activated protein kinase (MAPK) phosphorylation and activity. Compared with vehicle, MG significantly increased SI-R-induced cardiomyocyte LDH release and apoptosis (P < 0.01). Prior to SI-R, Trx activity was reduced in MG-treated cells, but Trx expression was increased moderately. Moreover, Trx-ASK1 complex formation was reduced, and both p38 MAPK activity and phosphorylation were increased. To investigate the effects of MG on Trx directly, recombinant human Trx (hTrx) was incubated with MG in vitro. Compared with vehicle, MG incubation markedly increased CML formation (a glycation footprint) and inhibited Trx activity. Finally, glycation inhibitor aminoguanidine administration during MG treatment of cultured cells reduced AGE formation, increased Trx activity, restored Trx-ASK1 interaction, and reduced p38 MAPK phosphorylation and activity, caspase-3 activation, and LDH release (P < 0.01). We demonstrated for the first time that methylglyoxal sensitized cultured cardiomyocytes to SI-R injury by posttranslational modification of Trx via glycation. Therapeutic interventions scavenging AGE precursors may attenuate ischemic-reperfusion injury in hyperglycemic state diseases such as diabetes.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Aldeído Pirúvico/farmacologia , Tiorredoxinas/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Células Cultivadas , Imuno-Histoquímica , L-Lactato Desidrogenase/metabolismo , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais/fisiologia , Tiorredoxinas/biossíntese , Tiorredoxinas/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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