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1.
Aesthetic Plast Surg ; 2024 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-38971925

RESUMO

INTRODUCTION: The rising use of soft tissue fillers for aesthetic procedures has seen an increase in complications, including vascular occlusions and neurological symptoms that resemble stroke. This study synthesizes information on central nervous system (CNS) complications post-filler injections and evaluates the effectiveness of hyaluronidase (HYAL) treatment. METHODS: A thorough search of multiple databases, including PubMed, EMBASE, Scopus, Web of Science, Google Scholar, and Cochrane, focused on publications from January 2014 to January 2024. Criteria for inclusion covered reviews and case reports that documented CNS complications related to soft tissue fillers. Advanced statistical and computational techniques, including logistic regression, machine learning, and Bayesian analysis, were utilized to dissect the factors influencing therapeutic outcomes. RESULTS: The analysis integrated findings from 20 reviews and systematic analyses, with 379 cases reported since 2018. Hyaluronic acid (HA) was the most commonly used filler, particularly in nasal region injections. The average age of patients was 38, with a notable increase in case reports in 2020. Initial presentation data revealed that 60.9% of patients experienced no light perception, while ptosis and ophthalmoplegia were present in 54.3 and 42.7% of cases, respectively. The statistical and machine learning analyses did not establish a significant linkage between the HYAL dosage and patient recovery; however, the injection site emerged as a critical determinant. CONCLUSION: The study concludes that HYAL treatment, while vital for managing complications, varies in effectiveness based on the injection site and the timing of administration. The non-Newtonian characteristics of HA fillers may also affect the incidence of complications. The findings advocate for tailored treatment strategies incorporating individual patient variables, emphasizing prompt and precise intervention to mitigate the adverse effects of soft tissue fillers. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

2.
Basic Res Cardiol ; 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38856733

RESUMO

Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and reperfusion injury with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in these patients. This review provides an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass, followed by a discussion of the specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and novel mechanical circulatory support technologies. Finally, translational strategies that investigate cardioprotection in the setting of cardiac surgery will be reviewed, with a focus on promising research in the areas of cell-based and gene therapy. Advances in this area will help cardiologists and cardiac surgeons mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery.

3.
Artigo em Inglês | MEDLINE | ID: mdl-38879117

RESUMO

INTRODUCTION: Sodium-glucose cotransporter-2 inhibitors are antidiabetic medications that have been shown to decrease cardiovascular events and heart failure-related mortality in clinical studies. We attempt to examine the complex interplay between metabolic syndrome and the sodium-glucose cotransporter-2 inhibitor canagliflozin (CAN) in a clinically relevant model of chronic myocardial ischemia. METHODS: Twenty-one Yorkshire swine were fed a high-fat diet starting at 6 weeks of age to induce metabolic syndrome. At 11 weeks, all underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce chronic myocardial ischemia. After 2 weeks, swine received either control (CON) (n = 11) or CAN 300 mg by mouth daily (n = 10) for 5 weeks, whereupon all underwent terminal harvest. RESULTS: There was a significant increase in cardiac output and heart rate with a decrease in pulse pressure in the CAN group compared with CON (all P values < .05). The CAN group had a significant increase in capillary density (P = .02). There was no change in myocardial perfusion or arteriolar density. CAN induced a significant increase in markers of angiogenesis, including Phospho-endothelial nitric oxide synthase, Endothelial nitric oxide synthase, vascular endothelial growth factor receptor-1, heat shock protein 70, and extracellular signal-regulated kinases (all P values < .05), plausibly resulting in capillary angiogenesis. CONCLUSIONS: CAN treatment leads to a significant increase in capillary density and augmented cardiac function in a swine model of chronic myocardial ischemia in the setting of metabolic syndrome. This work further elucidates the mechanism of sodium-glucose cotransporter-2 inhibitors in patients with cardiac disease; however, more studies are needed to determine if this increase in capillary density plays a role in the improvements seen in clinical studies.

4.
PLOS Glob Public Health ; 4(5): e0002758, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38709792

RESUMO

Community action is broadly recognised as central to comprehensive and effective system responses to pandemics. However, there is uncertainty about how and where communities can be best supported to bolster long-term resilience and preparedness. We applied a typology of community interventions (Community Informing, Consulting, Involving, Collaborating or Empowering-or CICICE) to cover the diverse range of interventions identified across the literature and used this to structure a scoping review addressing three linked topics: (i) how CICICE interventions have been understood and applied in the literature on epidemic and pandemic preparedness; (ii) the spectrum of interventions that have been implemented to strengthen CICICE and (iii) what evidence is available on their effectiveness in influencing preparedness for current and future emergencies. We drew on peer-reviewed and grey literature from the HIV (from 2000) and COVID-19 pandemics and recent public health emergencies of international concern (from 2008), identified through systematic searches in MEDLINE, Scopus, the Cochrane Collaboration database, supplemented by keyword-structured searches in GoogleScholar and websites of relevant global health organisations. Following screening and extraction, key themes were identified using a combined inductive/deductive approach. 130 papers met the criteria for inclusion. Interventions for preparedness were identified across the spectrum of CICICE. Most work on COVID-19 focused on informing and consulting rather than capacity building and empowerment. The literature on HIV was more likely to report interventions emphasising human rights perspectives and empowerment. There was little robust evidence on the role of CICICE interventions in building preparedness. Evidence of effect was most robust for multi-component interventions for HIV prevention and control. Much of the reporting focused on intermediate outcomes, including measures of health service utilisation. We put forward a series of recommendations to help address evidence shortfalls, including clarifying definitions, organising and stratifying interventions by several parameters and strengthening evaluation methods for CICICE.

5.
Surgery ; 176(2): 274-281, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38755032

RESUMO

BACKGROUND: We previously found that cardioplegic arrest and cardiopulmonary bypass are associated with altered coronary arteriolar response to serotonin in patients undergoing cardiac surgery. In this study, we investigated the effects of hypertension on coronary microvascular vasomotor tone in response to serotonin and alterations in serotonin receptor protein expression in the setting of cardioplegic arrest and cardiopulmonary bypass. METHODS: Coronary arterioles were dissected from harvested pre- and post-cardioplegic arrest and cardiopulmonary bypass right atrial tissue samples of patients undergoing cardiac surgery with normotension, well-controlled hypertension, and uncontrolled hypertension. Vasomotor tone was assessed by video-myography, and protein expression was measured with immunoblotting. RESULTS: Pre-cardioplegic arrest and cardiopulmonary bypass, serotonin induced moderate relaxation responses of coronary arterioles in normotension and well-controlled hypertension patients, whereas serotonin caused moderate contractile responses in uncontrolled hypertension patients. Post-cardioplegic arrest and cardiopulmonary bypass, serotonin caused contractile responses of coronary arterioles in all 3 groups. The post-cardioplegic arrest and cardiopulmonary bypass contractile response to serotonin was significantly higher in the uncontrolled hypertension group compared with the normotension or well-controlled hypertension groups (P < .05). Pre-cardioplegic arrest and cardiopulmonary bypass, expression of the serotonin 1A receptor was significantly lower in the uncontrolled hypertension group compared with the well-controlled hypertension and normotension groups (P = .01 and P < .001). Serotonin 1B receptor expression was higher in the uncontrolled hypertension group compared with the normotension or well-controlled hypertension groups post-cardioplegic arrest and cardiopulmonary bypass (P = .03 and P = .046). CONCLUSION: Uncontrolled hypertension is associated with an increased coronary contractile response of coronary microvessels to serotonin and altered serotonin receptor protein expression after cardioplegic arrest and cardiopulmonary bypass. These findings may contribute to a worse postoperative coronary spasm and worsened recovery of coronary perfusion in patients with uncontrolled hypertension after cardioplegic arrest and cardiopulmonary bypass and cardiac surgery.


Assuntos
Ponte Cardiopulmonar , Vasos Coronários , Hipertensão , Serotonina , Humanos , Ponte Cardiopulmonar/efeitos adversos , Masculino , Feminino , Serotonina/metabolismo , Serotonina/farmacologia , Hipertensão/fisiopatologia , Hipertensão/metabolismo , Hipertensão/etiologia , Pessoa de Meia-Idade , Idoso , Vasos Coronários/fisiopatologia , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Arteríolas/efeitos dos fármacos , Parada Cardíaca Induzida/efeitos adversos , Vasoconstrição/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Vasodilatação/efeitos dos fármacos
7.
Biomedicines ; 12(3)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38540200

RESUMO

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to be cardioprotective independent of glucose control, but the mechanisms of these benefits are unclear. We previously demonstrated improved cardiac function and decreased fibrosis in a swine model of chronic myocardial ischemia. The goal of this study is to use high-sensitivity proteomic analyses to characterize specific molecular pathways affected by SGLT-2 inhibitor canagliflozin (CAN) therapy in a swine model of chronic myocardial ischemia. METHODS: Chronic myocardial ischemia was induced in sixteen Yorkshire swine via the placement of an ameroid constrictor to the left circumflex coronary artery. After two weeks of recovery, swine received either 300 mg of CAN daily (n = 8) or a control (n = 8). After five weeks of therapy, the group of swine were euthanized, and left ventricular tissue was harvested and sent for proteomic analysis. RESULTS: Total proteomic analysis identified a total of 3256 proteins between the CAN and control groups. Three hundred and five proteins were statistically different. This included 55 proteins that were downregulated (p < 0.05, fold change <0.5) and 250 that were upregulated (p < 0.05, fold change >2) with CAN treatment. Pathway analysis demonstrated the upregulation of several proteins involved in metabolism and redox activity in the CAN-treated group. The CAN group also exhibited a downregulation of proteins involved in motor activity and cytoskeletal structure. CONCLUSIONS: In our swine model of chronic myocardial ischemia, CAN therapy alters several proteins involved in critical molecular pathways, including redox regulation and metabolism. These findings provide additional mechanistic insights into the cardioprotective effects of canagliflozin.

8.
Physiol Rep ; 12(5): e15976, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38472161

RESUMO

Small animal models have shown improved cardiac function with DPP-4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap by studying the DPP-4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Thirteen Yorkshire swine underwent the placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post-op, swine received either sitagliptin 100 mg daily (SIT, n = 5) or no drug (CON, n = 8). After 5 weeks of treatment, swine underwent functional measurements and tissue harvest. In the SIT group compared to CON, there was a trend towards decreased cardiac index (p = 0.06). The non-ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p < 0.01). This included proteins involved in fatty acid oxidation (FAO), myocardial contraction, and oxidative phosphorylation (OXPHOS). Sitagliptin treatment resulted in a trend towards decreased cardiac index and decreased expression of proteins involved in OXPHOS, FAO, and myocardial contraction in both ischemic and non-ischemic swine myocardium. These metabolic and functional changes may provide some mechanistic evidence for outcomes seen in clinical studies.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Isquemia Miocárdica , Suínos , Humanos , Animais , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Proteoma/metabolismo , Fosforilação Oxidativa , Fosfato de Sitagliptina/uso terapêutico , Proteômica/métodos , Miocárdio/metabolismo , Hipoglicemiantes/uso terapêutico , Modelos Animais de Doenças
9.
Bioengineering (Basel) ; 11(2)2024 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-38391611

RESUMO

INTRODUCTION: Patients with advanced coronary artery disease (CAD) who are not eligible for stenting or surgical bypass procedures have limited treatment options. Extracellular vesicles (EVs) have emerged as a potential therapeutic target for the treatment of advanced CAD. These EVs can be conditioned to modify their contents. In our previous research, we demonstrated increased perfusion, decreased inflammation, and reduced apoptosis with intramyocardial injection of hypoxia-conditioned EVs (HEVs). The goal of this study is to further understand the function of HEVs by examining their impact on oxidative stress using our clinically relevant and extensively validated swine model of chronic myocardial ischemia. METHODS: Fourteen Yorkshire swine underwent a left thoracotomy for the placement of an ameroid constrictor on the left circumflex coronary artery to model chronic myocardial ischemia. After two weeks of recovery, the swine underwent a redo thoracotomy with injection of either HEVs (n = 7) or a saline control (CON, n = 7) into the ischemic myocardium. Five weeks after injection, the swine were subjected to terminal harvest. Protein expression was measured using immunoblotting. OxyBlot analysis and 3-nitrotyrosine staining were used to quantify total oxidative stress. RESULTS: There was a significant increase in myocardial expression of the antioxidants SOD 2, GPX-1, HSF-1, UCP-2, catalase, and HO-1 (all p ≤ 0.05) in the HEV group when compared to control animals. The HEVs also exhibited a significant increase in pro-oxidant NADPH oxidase (NOX) 1, NOX 3, p47phox, and p67phox (all p ≤ 0.05). However, no change was observed in the expression of NFkB, KEAP 1, and PRDX1 (all p > 0.05) between the HEV and CON groups. There were no significant differences in total oxidative stress as determined by OxyBlot and 3-nitrotyrosine staining (p = 0.64, p = 0.32) between the groups. CONCLUSIONS: Administration of HEVs in ischemic myocardium induces a significant increase in pro- and antioxidant proteins without a net change in total oxidative stress. These findings suggest that HEV-induced changes in redox signaling pathways may play a role in increased perfusion, decreased inflammation, and reduced apoptosis in ischemic myocardium. Further studies are required to determine if HEVs alter the net oxidative stress in ischemic myocardium at an earlier time point of HEV administration.

10.
Methods Protoc ; 7(1)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38392691

RESUMO

The past several decades have borne witness to several breakthroughs and paradigm shifts within the field of cardiovascular medicine, but one component that has remained constant throughout this time is the need for accurate animal models for the refinement and elaboration of the hypotheses and therapies crucial to our capacity to combat human disease. Numerous sophisticated and high-throughput molecular strategies have emerged, including rational drug design and the multi-omics approaches that allow extensive characterization of the host response to disease states and their prospective resolutions, but these technologies all require grounding within a faithful representation of their clinical context. Over this period, our lab has exhaustively tested, progressively refined, and extensively contributed to cardiovascular discovery on the basis of one such faithful representation. It is the purpose of this paper to review our porcine model of chronic myocardial ischemia using ameroid constriction and the subsequent myriad of physiological and molecular-biological insights it has allowed our lab to attain and describe. We hope that, by depicting our methods and the insight they have yielded clearly and completely-drawing for this purpose on comprehensive videographic illustration-other research teams will be empowered to carry our work forward, drawing on our experience to refine their own investigations into the pathogenesis and eradication of cardiovascular disease.

11.
J Am Coll Surg ; 238(6): 1045-1055, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38288953

RESUMO

BACKGROUND: Although sodium-glucose cotransporter-2 inhibitors have been shown to improve cardiovascular outcomes in general, little is presently known about any sex-specific changes that may result from this therapy. We sought to investigate and quantify potential sex-specific changes seen with the sodium-glucose cotransporter-2 inhibitor canagliflozin (CAN) in a swine model of chronic myocardial ischemia. STUDY DESIGN: Eighteen Yorkshire swine underwent left thoracotomy with placement of an ameroid constrictor. Two weeks postop, swine were assigned to receive either control (F = 5 and M = 5) or CAN 300 mg daily (F = 4 and M = 4). After 5 weeks of therapy, swine underwent myocardial functional measurements, and myocardial tissue was sent for proteomic analysis. RESULTS: Functional measurements showed increased cardiac output, stroke volume, ejection fraction, and ischemic myocardial flow at rest in male swine treated with CAN compared with control male swine (all p < 0.05). The female swine treated with CAN had no change in cardiac function as compared with control female swine. Proteomic analysis demonstrated 6 upregulated and 97 downregulated proteins in the CAN female group compared with the control female group. Pathway analysis showed decreases in proteins in the tricarboxylic acidic cycle. The CAN male group had 639 upregulated and 172 downregulated proteins compared with control male group. Pathway analysis showed increases in pathways related to cellular metabolism and decreases in pathways relevant to the development of cardiomyopathy and to oxidative phosphorylation. CONCLUSIONS: Male swine treated with CAN had significant improvements in cardiac function that were not observed in female swine treated with CAN. Moreover, CAN treatment in male swine was associated with significantly more changes in protein expression than in female swine treated with CAN. The increased proteomic changes seen in the CAN male group likely contributed to the more robust changes in cardiac function seen in male swine treated with CAN.


Assuntos
Canagliflozina , Isquemia Miocárdica , Proteômica , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Feminino , Masculino , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Isquemia Miocárdica/metabolismo , Suínos , Fatores Sexuais , Modelos Animais de Doenças , Miocárdio/metabolismo , Doença Crônica
12.
J Am Heart Assoc ; 13(3): e031028, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38293916

RESUMO

BACKGROUND: Small conductance calcium-activated potassium (SK) channels are largely responsible for endothelium-dependent coronary arteriolar relaxation. Endothelial SK channels are downregulated by the reduced form of nicotinamide adenine dinucleotide (NADH), which is increased in the setting of diabetes, yet the mechanisms of these changes are unclear. PKC (protein kinase C) is an important mediator of diabetes-induced coronary endothelial dysfunction. Thus, we aimed to determine whether NADH signaling downregulates endothelial SK channel function via PKC. METHODS AND RESULTS: SK channel currents of human coronary artery endothelial cells were measured by whole cell patch clamp method in the presence/absence of NADH, PKC activator phorbol 12-myristate 13-acetate, PKC inhibitors, or endothelial PKCα/PKCß knockdown by using small interfering RNA. Human coronary arteriolar reactivity in response to the selective SK activator NS309 was measured by vessel myography in the presence of NADH and PKCß inhibitor LY333531. NADH (30-300 µmol/L) or PKC activator phorbol 12-myristate 13-acetate (30-300 nmol/L) reduced endothelial SK current density, whereas the selective PKCᵦ inhibitor LY333531 significantly reversed the NADH-induced SK channel inhibition. PKCß small interfering RNA, but not PKCα small interfering RNA, significantly prevented the NADH- and phorbol 12-myristate 13-acetate-induced SK inhibition. Incubation of human coronary artery endothelial cells with NADH significantly increased endothelial PKC activity and PKCß expression and activation. Treating vessels with NADH decreased coronary arteriolar relaxation in response to the selective SK activator NS309, and this inhibitive effect was blocked by coadministration with PKCß inhibitor LY333531. CONCLUSIONS: NADH-induced inhibition of endothelial SK channel function is mediated via PKCß. These findings may provide insight into novel therapeutic strategies to preserve coronary microvascular function in patients with metabolic syndrome and coronary disease.


Assuntos
Diabetes Mellitus , Forbóis , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Proteína Quinase C beta/metabolismo , Proteína Quinase C beta/farmacologia , Células Endoteliais/metabolismo , Miristatos/metabolismo , Miristatos/farmacologia , NAD/metabolismo , Vasodilatação/fisiologia , Diabetes Mellitus/metabolismo , Endotélio Vascular/metabolismo , RNA Interferente Pequeno/metabolismo , Acetatos/metabolismo , Acetatos/farmacologia , Forbóis/metabolismo , Forbóis/farmacologia
14.
J Surg Res ; 295: 442-448, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38070258

RESUMO

INTRODUCTION: Though marijuana use has been linked to an increase in heart failure admissions, no prior study has explored the association between its use and outcomes after coronary artery bypass grafting (CABG). This study examines the relationship between marijuana use and postoperative outcomes in CABG patients. METHODS: We utilized data from the National Inpatient Sample database from 2008 to 2018 for CABG patients ≥18 y old. Patients were divided into two groups based on marijuana use (abuse/dependency versus nonuse). Primary outcomes include in-hospital mortality, favorable discharge, and length of stay (LOS). Secondary outcomes include acute kidney injury (AKI), acute myocardial infarction (AMI), and transient ischemic attack (TIA)/stroke. A multivariable model, adjusted for confounding variables, was utilized for each outcome. RESULTS: A total of 343,796 patients met inclusion criteria for the study, 590 of which were marijuana users. In both marijuana user and nonuser groups, most patients were male and White with an average age of 56.0 and 66.3 y, respectively. There was a nonsignificant decreased odds of in-hospital mortality among marijuana users (odds ratio [OR] = 0.41, [0.141-1.124]). Marijuana users exhibited significantly decreased odds of home discharge (OR = 1.50, [1.24-1.81]), and increased odds of longer LOS (mean 10.4 d versus 9.8 d; OR = 1.14, [1.09-1.20]), AKI (OR = 1.40, [1.11-1.78]), AMI (OR = 1.56, [1.32-1.84]), and TIA/stroke (OR = 1.64, [1.21-2.22]). CONCLUSIONS: Marijuana use and dependency are associated with increased nonhome discharge, AKI, AMI, TIA/stroke, and longer LOS. Further studies are needed to delineate the pathophysiologic derangements that contribute to these unfavorable post-CABG outcomes.


Assuntos
Injúria Renal Aguda , Ataque Isquêmico Transitório , Uso da Maconha , Infarto do Miocárdio , Acidente Vascular Cerebral , Transtornos Relacionados ao Uso de Substâncias , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Uso da Maconha/efeitos adversos , Uso da Maconha/epidemiologia , Ataque Isquêmico Transitório/etiologia , Ponte de Artéria Coronária/efeitos adversos , Infarto do Miocárdio/etiologia , Transtornos Relacionados ao Uso de Substâncias/etiologia , Resultado do Tratamento , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Fatores de Risco , Estudos Retrospectivos
15.
Surgery ; 175(2): 265-270, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37940431

RESUMO

BACKGROUND: Inflammation and disruption of cardiac metabolism are prevalent in the setting of myocardial ischemia. Canagliflozin, a sodium-glucose costransporter-2 inhibitor, has beneficial effects on the heart, though the precise mechanisms are unknown. This study investigated the effects of canagliflozin therapy on metabolic pathways and inflammation in ischemic myocardial tissue using a swine model of chronic myocardial ischemia. METHODS: Sixteen Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. Two weeks later, pigs received either no drug (n = 8) or 300 mg canagliflozin (n = 8) daily. Five weeks later, pigs underwent terminal harvest and tissue collection. RESULTS: Canagliflozin treatment was associated with a trend toward decreased expression of fatty acid oxidation inhibitor acetyl-CoA carboxylase and decreased phosphorylated/inactivated acetyl-CoA carboxylase, a promotor of fatty acid oxidation, compared with control ischemic myocardium (P = .08, P = .03). There was also a significant modulation in insulin resistance markers p-IRS1, p-PKCα, and phosphoinositide 3-kinase in ischemic myocardium of the canagliflozin group compared with the control group (all P < .05). Canagliflozin treatment was associated with a significant increase in inflammatory markers interleukin 6, interleukin 17, interferon-gamma, and inducible nitric oxide synthase (all P < .05). There was a trend toward decreased expression of the anti-inflammatory cytokines interleukin 10 (P = .16) and interleukin 4 (P = .31) with canagliflozin treatment. CONCLUSION: The beneficial effects of canagliflozin therapy appear to be associated with inhibition of fatty acid oxidation and enhancement of insulin signaling in ischemic myocardium. Interestingly, canagliflozin appears to increase the levels of several inflammatory markers, but further studies are required to better understand how canagliflozin modulates inflammatory signaling pathways.


Assuntos
Isquemia Miocárdica , Inibidores do Transportador 2 de Sódio-Glicose , Simportadores , Suínos , Animais , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Canagliflozina/metabolismo , Miocárdio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Acetil-CoA Carboxilase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/complicações , Isquemia Miocárdica/metabolismo , Inflamação/metabolismo , Glucose/metabolismo , Simportadores/metabolismo , Ácidos Graxos/metabolismo , Modelos Animais de Doenças
16.
Braz. j. biol ; 84: e255916, 2024. tab, graf, mapas
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1364509

RESUMO

This study aims at reporting the indigenous knowledge of the medicinal flora from the inhabitants of surroundings of the World's largest artificial planted forest "Changa Manga", Pakistan. Data were collected by direct interviews and group meetings from 81 inhabitants including 32 local healers having information regarding the use of indigenous medicinal plants over a period of one year. Different statistical tools were applied to analyze the data including Frequency citation (FC), Relative frequency citation (RFC), Use Value, Factor of informants consensus and fidelity level. This study reported 73 plant species belonging to 37 plant families and 46 genera. The majority of plant species belong to compositae family. The most commonly used medicinal plants were P. hysterophorus L., P. dactylifera L., S. indicum L, P. harmala L., P. emblica L., and A. indica A.Juss. The greatest number of species was used to cure gastrointestinal disorders. The highest fidelity level (68.18%) was of E. helioscopia to cure gastrointestinal disorders. Maximum fresh uses (17) were reported by C. dactylon (L.) Pars. While the highest number of species reporting fresh uses in similar number was 13. In this study, five novel plants are being reported for the first time in Pakistan for their ethnomedicinal worth. Our data reflect unique usage of the medicinal plants in the study area. The statistical tools used in the study proved useful in pointing the most important and disease category specific plants. High use value plant and the new reported medicinal plants might prove an important source of the isolation of pharmacologically active compounds.


Este estudo tem como objetivo relatar o conhecimento indígena sobre a flora medicinal dos habitantes do entorno da maior floresta artificial plantada do mundo, a Changa Manga, no Paquistão. Os dados foram coletados por meio de entrevistas diretas e reuniões em grupo de 81 habitantes, incluindo 32 curandeiros locais, com informações sobre o uso de plantas medicinais indígenas durante o período de um ano. Diferentes ferramentas estatísticas foram aplicadas para analisar os dados, incluindo citação de frequência (FC), citação de frequência relativa (RFC), valor de uso, fator de consenso dos informantes e nível de fidelidade. Este estudo relatou 73 espécies de plantas pertencentes a 37 famílias de plantas e 46 gêneros. A maioria das espécies de plantas pertence à família Compositae. As plantas medicinais mais utilizadas foram P. hysterophorus L., P. dactylifera L., S. indicum L., P. harmala L., P. emblica L. e A. indica A. Juss. O maior número de espécies foi usado para curar distúrbios gastrointestinais. O maior nível de fidelidade (68,18%) foi de E. helioscopia para cura de distúrbios gastrointestinais. Os usos máximos em fresco (17) foram relatados por C. dactylon (L.) Pars. enquanto o maior número de espécies relatando usos frescos em número semelhante foi de 13. Neste estudo, cinco novas plantas estão sendo relatadas pela primeira vez no Paquistão por seu valor etnomedicinal. Nossos dados refletem o uso exclusivo das plantas medicinais na área de estudo. As ferramentas estatísticas utilizadas no estudo mostraram-se úteis para apontar as plantas mais importantes e específicas da categoria de doença. Plantas de alto valor de uso e as novas plantas medicinais relatadas podem ser uma importante fonte de isolamento de compostos farmacologicamente ativos.


Assuntos
Humanos , Plantas Medicinais , Florestas , Gastroenteropatias , Povos Indígenas , Medicina Tradicional , Paquistão
17.
J Surg Res ; 294: 249-256, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37925953

RESUMO

INTRODUCTION: Cardioplegia and cardiopulmonary bypass (CP/CPB) alters coronary arteriolar response to thromboxane A2 (TXA2) in patients undergoing cardiac surgery. Comorbidities, including hypertension (HTN), can further alter coronary vasomotor tone. This study investigates the effects of HTN on coronary arteriolar response to TXA2 pre and post-CP/CPB and cardiac surgery. MATERIALS AND METHODS: Coronary arterioles pre and post-CP/CPB were dissected from atrial tissue samples in patients with no HTN (NH, n = 9), well-controlled HTN (WC, n = 12), or uncontrolled HTN (UC, n = 12). In-vitro coronary microvascular reactivity was examined in the presence of TXA2 analog U46619 (10-9-10-4M). Protein expression of TXA2 receptor in the harvested right atrial tissue samples were measured by immunoblotting. RESULTS: TXA2 analog U46619 induced dose-dependent contractile responses of coronary arterioles in all groups. Pre-CPB contractile responses to U46619 were significantly increased in microvessels in the UC group compared to the NH group (P < 0.05). The pre-CP/CPB contractile responses of coronary arterioles were significantly diminished post-CP/CPB among the three groups (P < 0.05), but there remained an increased contractile response in the microvessels of the UC group compared to the WC and NH groups (P < 0.05). There were no significant differences in U46619-induced vasomotor tone between patients in the NH and WC groups (P > 0.05). There were no differences in expression of TXA2R among groups. CONCLUSIONS: Poorly controlled HTN is associated with increased contractile response of coronary arterioles to TXA2. This alteration may contribute to worsened recovery of coronary microvascular function in patients with poorly controlled HTN after CP/CPB and cardiac surgery.


Assuntos
Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos , Hipertensão , Humanos , Tromboxano A2/metabolismo , Tromboxano A2/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/metabolismo , Vasos Coronários , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ponte Cardiopulmonar , Hipertensão/complicações
18.
BMJ Glob Health ; 8(11)2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37931939

RESUMO

INTRODUCTION: Despite rapidly growing academic and policy interest in health system resilience, the empirical literature on this topic remains small and focused on macrolevel effects arising from single shocks. To better understand health system responses to multiple shocks, we conducted an in-depth case study using qualitative system dynamics. We focused on routine childhood vaccination delivery in Lebanon in the context of at least three shocks overlapping to varying degrees in space and time: large-scale refugee arrivals from neighbouring Syria; COVID-19; and an economic crisis. METHODS: Semistructured interviews were performed with 38 stakeholders working at different levels in the system. Interview transcripts were analysed using purposive text analysis to generate individual stakeholder causal loop diagrams (CLDs) mapping out relationships between system variables contributing to changes in coverage for routine antigens over time. These were then combined using a stepwise process to produce an aggregated CLD. The aggregated CLD was validated using a reserve set of interview transcripts. RESULTS: Various system responses to shocks were identified, including demand promotion measures such as scaling-up community engagement activities and policy changes to reduce the cost of vaccination to service users, and supply side responses including donor funding mobilisation, diversification of service delivery models and cold chain strengthening. Some systemic changes were introduced-particularly in response to refugee arrivals-including task-shifting to nurse-led vaccine administration. Potentially transformative change was seen in the integration of private sector clinics to support vaccination delivery and depended on both demand side and supply side changes. Some resilience-promoting measures introduced following earlier shocks paradoxically increased vulnerability to later ones. CONCLUSION: Flexibility in financing and human resource allocation appear key for system resilience regardless of the shock. System dynamics offers a promising method for ex ante modelling of ostensibly resilience-strengthening interventions under different shock scenarios, to identify-and safeguard against-unintended consequences.


Assuntos
Atenção à Saúde , Vacinação , Humanos , Líbano , Serviços de Saúde , Imunização
19.
Vessel Plus ; 72023.
Artigo em Inglês | MEDLINE | ID: mdl-37982029

RESUMO

Introduction: Research has shown epigenetic change via alternation of the methylation profile of human skeletal muscle DNA after Cardio-Pulmonary Bypass (CPB). In this study, we investigated the change in epigenome-wide DNA methylation profiles of porcine myocardium after ischemic insult in the setting of treatment with extracellular vesicle (EV) therapy in normal vs. high-fat diet (HFD) pigs. Methods: Four groups of three pigs underwent ameroid constrictor placement to the left circumflex artery (LCx) and were assigned to the following groups: (1) normal diet saline injection; (2) normal diet EV injection; (3) HFD saline injection; and (4) HFD EV injection. DNA methylation was profiled via reduced-representation bisulfite sequencing (RRBS) and compared using a custom bioinformatic pipeline. Results: After initial analysis, 441 loci had a nominal P value < 0.05 when examining the effect of ischemia vs. normal heart tissue on a normal diet in the absence of treatment. 426 loci at P value threshold < 0.05 were identified when comparing the ischemic vs. normal tissue from high-fat diet animals. When examining the effect of EV treatment in ischemic tissue in subjects on a normal diet, there were 574 loci with nominal P value < 0.05 with two loci Fructosamine 3 kinase related protein [(FN3KRP) (P < 0.001)] and SNTG1 (P = 0.03) significant after Bonferroni correction. When examining the effect of EV treatment in ischemic tissue in HFD, there were 511 loci with nominal P values < 0.05. After Bonferroni correction, two loci had P values less than 0.05, betacellulin [(BTC) (P = 0.008)] and [proprotein convertase subtilisin/kexin type 7 (PCSK7) (P = 0.01)]. Conclusions: Alterations in DNA methylation were identified in pig myocardium after ischemic insult, change in diet, and treatment with EVs. Hundreds of differentially methylated loci were detected, but the magnitude of the effects was low. These changes represent significant alterations in DNA methylation and merit further investigation.

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