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1.
J Card Surg ; 34(5): 305-311, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30908754

RESUMO

BACKGROUND: Cardiac surgery patients are at high risk for postoperative bleeding. Intravenous (IV) tranexamic acid (TxA) is a commonly used antifibrinolytic drug, but is associated with postoperative seizures. We conducted this pilot randomized controlled trial (RCT) to determine the feasibility of a larger trial that will be designed to investigate the impact of TxA administration route, intrapericardial (IP) vs IV, on postoperative bleeding and seizures. METHODS: In this single-center, double-blinded, pilot RCT we enrolled adult patients undergoing nonemergent on-pump cardiac operations through a median sternotomy. Participants were randomized to IP or IV TxA groups. The primary outcomes were cumulative chest tube drainage, transfusion requirements, and incidence of postoperative seizures. RESULTS: A total of 97 participants were randomized to the intervention and control groups. Baseline characteristics were similar in both groups. Most participants underwent a CABG and/or aortic valve replacement. There was no statistical difference. The IP TxA group was found to have a tendency for less chest tube drainage in comparison to the IV TxA group, 500.5 (370.0-700.0) and 540.0 (420.0-700.0) mL, respectively, which was not statistically significant (P = 0.2854). Fewer participants in the IP TxA group with cardiac tamponade and/or required a reoperation for bleeding and fewer packed red blood cell transfusions. None of the IP TxA group developed seizure vs one from the IV TxA group. CONCLUSION: This is the first known pilot RCT to investigate the role of TxA route of administration in open cardiac surgery. Intrapericardial TxA shows promising results with decreased bleeding, transfusion requirements, reoperations, and postoperative seizures. A larger RCT is needed to confirm these results and lead to a change in practice.


Assuntos
Antifibrinolíticos/administração & dosagem , Perda Sanguínea Cirúrgica/prevenção & controle , Procedimentos Cirúrgicos Cardíacos , Hemorragia Pós-Operatória/prevenção & controle , Ácido Tranexâmico/administração & dosagem , Administração Tópica , Idoso , Valva Aórtica/cirurgia , Ponte de Artéria Coronária , Método Duplo-Cego , Emulsões , Ácidos Graxos , Feminino , Implante de Prótese de Valva Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Fosfolipídeos , Projetos Piloto , Vitamina A , Vitamina D
2.
Europace ; 21(6): 856-863, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30875422

RESUMO

AIMS: Clinicians frequently pre-treat patients with amiodarone to increase the efficacy of electrical cardioversion for atrial fibrillation (AF). Our objective was to determine the precise effects of amiodarone pre- and post-treatment on conversion efficacy and sinus rhythm maintenance. METHODS AND RESULTS: We conducted a systematic review and meta-analysis of trials comparing pre- and post-treatment for electrical cardioversion with amiodarone vs. no therapy on (i) acute restoration and (ii) maintenance of sinus rhythm after 1 year. We searched MEDLINE and EMBASE from inception to July 2018 for randomized controlled trials. We evaluated the risk of bias for individual studies with the Cochrane tool and overall quality of evidence with the GRADE framework. We identified eight eligible studies (n = 1012). Five studies were deemed to have unclear or high risk of selection bias. We found the evidence to be of high quality based on GRADE. Treatment with amiodarone (200-800 mg daily for 1-6 weeks pre-cardioversion; 0-200 mg daily post-cardioversion) was associated with higher rates of acute restoration [relative risk (RR) 1.22, 95% confidence interval (CI) 1.07-1.39, P = 0.004, n = 1012, I2 = 65%] and maintenance of sinus rhythm over 13 months (RR 4.39, 95% CI 2.99-6.45, P < 0.001, n = 695, I2 = 0%). The effects of amiodarone for acute restoration were maintained when considering only studies at low risk of bias (RR 1.22, 95% CI 1.10-1.36, P < 0.001, n = 572, I2 = 0%). Adverse effects were typically non-serious, occurring in 3.4% (6/174) of subjects receiving amiodarone. CONCLUSION: High-quality evidence demonstrated that treatment with amiodarone improved the restoration and maintenance of sinus rhythm after electrical cardioversion of AF. Short-term amiodarone was well-tolerated.

3.
Breast Cancer Res Treat ; 172(2): 327-338, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30120700

RESUMO

PURPOSE: The methods (IHC/FISH) typically used to assess ER, PR, HER2, and Ki67 in FFPE specimens from breast cancer patients are difficult to set up, perform, and standardize for use in low and middle-income countries. Use of an automated diagnostic platform (GeneXpert®) and assay (Xpert® Breast Cancer STRAT4) that employs RT-qPCR to quantitate ESR1, PGR, ERBB2, and MKi67 mRNAs from formalin-fixed, paraffin-embedded (FFPE) tissues facilitates analyses in less than 3 h. This study compares breast cancer biomarker analyses using an RT-qPCR-based platform with analyses using standard IHC and FISH for assessment of the same biomarkers. METHODS: FFPE tissue sections from 523 patients were sent to a College of American Pathologists-certified central reference laboratory to evaluate concordance between IHC/FISH and STRAT4 using the laboratory's standard of care methods. A subset of 155 FFPE specimens was tested for concordance with STRAT4 using different IHC antibodies and scoring methods. RESULTS: Concordance between STRAT4 and IHC was 97.8% for ESR1, 90.4% for PGR, 93.3% for ERBB2 (IHC/FISH for HER2), and 78.6% for MKi67. Receiver operating characteristic curve (ROC) area under the curve (AUC) values of 0.99, 0.95, 0.99, and 0.85 were generated for ESR1, PGR, ERBB2, and MKi67, respectively. Minor variabilities were observed depending on the IHC antibody comparator used. CONCLUSION: Evaluation of breast cancer biomarker status by STRAT4 was highly concordant with central IHC/FISH in this blinded, retrospectively analyzed collection of samples. STRAT4 may provide a means to cost-effectively generate standardized diagnostic results for breast cancer patients in low- and middle-income countries.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , RNA Mensageiro/genética , Neoplasias da Mama/patologia , Proliferação de Células/genética , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Antígeno Ki-67/genética , Receptor ErbB-2/genética , Receptores de Progesterona/genética
4.
J Invasive Cardiol ; 30(1): 23-27, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29289947

RESUMO

OBJECTIVES: Patients with annular areas just above nominal S3 valve areas are at increased risk of over-sizing if a larger valve is implanted. We therefore evaluated the rate of permanent pacemaker (PPM) implantation associated with avoiding over-sizing by selective deployment balloon over-filling during transcatheter aortic valve replacement (TAVR) with the Sapien 3 (S3) valve. METHODS: We included consecutive patients treated with the S3 valve from January 2016 to May 2017. We identified computed tomography annular areas where the nominally deployed valve would be over-sized by >12%-15% (areas 340-360 mm² for 23 mm valve, 420-450 mm² for 26 mm valve, 530-580 mm² for 29 mm valve) as those at highest risk for valve over-sizing. In these situations, we used the smaller valve and over-filled the deployment balloon to achieve a predicted valve area/annular area ratio of approximately 1. For annular areas >650 mm², we over-filled the 29 mm valve to achieve a similar ratio. RESULTS: We evaluated 102 patients (59 males; mean age, 83.7 ± 6.5 years; mean STS score, 10.2). Over-filling of the deployment balloon was used in 35 cases (34%). We observed a post-TAVR PPM rate of 6.9% overall and 2.7% among the 75 patients without pre-TAVR right bundle-branch block (RBBB). Cases with valve over-filling vs nominal deployment had infrequent need for postdilation (14.3% vs 6.0%, respectively; P=.17) and similar postprocedure gradients (9.9 mm Hg vs 10.3 mm Hg, respectively; P=.59). CONCLUSION: A strategy to avoid S3 valve over-sizing by selective deployment balloon over-filling was associated with a low rate of PPM, especially in patients without pre-existing RBBB.


Assuntos
Estenose da Valva Aórtica/cirurgia , Arritmias Cardíacas/prevenção & controle , Marca-Passo Artificial/efeitos adversos , Complicações Pós-Operatórias , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/patologia , Valva Aórtica/cirurgia , Cateterismo Cardíaco/efeitos adversos , Cateterismo Cardíaco/instrumentação , Cateterismo Cardíaco/métodos , Análise de Falha de Equipamento , Feminino , Humanos , Masculino , Tamanho do Órgão , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Desenho de Prótese , Fatores de Risco , Substituição da Valva Aórtica Transcateter/efeitos adversos , Substituição da Valva Aórtica Transcateter/instrumentação , Substituição da Valva Aórtica Transcateter/métodos
6.
Lab Invest ; 97(12): 1521-1526, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28892092

RESUMO

Historically, mRNA measurements have been tested on several commercially available platforms, but none have gained broad acceptance for assessment of HER2. An mRNA measurement, as a continuous value, has the potential for use in adjudication of the equivocal category. Here we use a real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay in a closed, single-use cartridge, automated system. Multiple cores (1 mm in diameter) were retrospectively collected from 80 formalin-fixed paraffin-embedded (FFPE) tissue blocks with invasive breast cancer seen by Yale Pathology Labs between 1998 and 2011. Tissue cores were processed with a FFPE lysis kit to create lysates that were tested with the automated RT-qPCR assay. Results for IHC and FISH were extracted from the pathology reports and quantitative immunofluorescence (QIF) for each case was measured as previously described. Quality control testing showed that the GX platform RT-qPCR shows no case to case cross contamination on material from routine histology practices. Concordance between RT-qPCR and IHC/FISH was 91.25% (sensitivity=0.87; specificity=0.94; PPV=0.89; NPV=0.92) using a pre-defined delta Ct cut-off (dCt≥-1) for HER2. Concordance (OPA) between RT-qPCR and QIF was 94% (sensitivity=0.90; specificity=0.96; PPV=0.93; NPV=0.94) using dCt≥-1 and a previously defined cut-point for positivity by QIF. In conclusion, the closed system RT-qPCR assay shows >90% concordance with the ASCO/CAP HER2 IHC/FISH scoring. Additionally, the RT-qPCR assay is highly concordant (94%) with the continuous variable HER2 QIF assay, and may better reflect the true continuum of HER2 receptor status in invasive breast cancer. These initial results suggest that fast, closed system molecular assays may have future value for the adjudication of the ASCO/CAP HER2 equivocal category or possibly routine usage in time constrained or low resource settings.


Assuntos
Neoplasias da Mama , Imuno-Histoquímica , Hibridização in Situ Fluorescente , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Imunofluorescência , Humanos , RNA Mensageiro/análise , Receptor ErbB-2/metabolismo , Reprodutibilidade dos Testes , Estudos Retrospectivos
8.
Am J Cardiol ; 112(1): 100-3, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23561589

RESUMO

Transcatheter aortic valve implantation (TAVI) has become an option for patients with symptomatic severe aortic stenosis whose co-morbidities place them at high surgical risk. However, little is known regarding treatment allocation. From May 2008 to May 2011, all high-risk patients with symptomatic severe aortic stenosis referred to an experienced single-center TAVI clinic were reviewed. A total of 170 consecutive patients were evaluated. Of these, 58 (34%) were accepted for TAVI (mean age 81 ± 8 years). Thirty-three patients (19%) were accepted for conventional aortic valve replacement (AVR; mean age 83 ± 6 years). Sixty-two patients (37%) were treated conservatively (mean age 83 ± 6 years). Seventeen patients (10%) died awaiting complete assessment. At 30 days, all-cause mortality was 10% in the TAVI group, 3% in the conventional AVR group, and 32% in the conservatively treated group. Multivariate-adjustment identified the absence of chronic obstructive pulmonary disease (hazard ratio 0.30, 95% confidence interval 0.09 to 0.98, p <0.05) and the absence of frailty (hazard ratio 0.19, 95% confidence interval 0.07 to 0.55, p <0.01) as independent predictors of conventional AVR. In conclusion, of the high-risk patients with severe aortic stenosis referred for TAVI at a large single center, approximately 1/2 were accepted for intervention (conventional AVR or TAVI), and roughly 1/3 were treated conservatively.


Assuntos
Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Implante de Prótese de Valva Cardíaca/métodos , Próteses Valvulares Cardíacas , Idoso de 80 Anos ou mais , Cateterismo Cardíaco , Comorbidade , Ecocardiografia , Feminino , Humanos , Masculino , Estudos Prospectivos , Resultado do Tratamento
9.
J Am Coll Cardiol ; 60(19): 1864-75, 2012 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-23062535

RESUMO

OBJECTIVES: This study sought to evaluate the long-term outcomes after transcatheter aortic valve implantation (TAVI) in the Multicenter Canadian Experience study, with special focus on the causes and predictors of late mortality and valve durability. BACKGROUND: Very few data exist on the long-term outcomes associated with TAVI. METHODS: This was a multicenter study including 339 patients considered to be nonoperable or at very high surgical risk (mean age: 81 ± 8 years; Society of Thoracic Surgeons score: 9.8 ± 6.4%) who underwent TAVI with a balloon-expandable Edwards valve (transfemoral: 48%, transapical: 52%). Follow-up was available in 99% of the patients, and serial echocardiographic exams were evaluated in a central echocardiography core laboratory. RESULTS: At a mean follow-up of 42 ± 15 months 188 patients (55.5%) had died. The causes of late death (152 patients) were noncardiac (59.2%), cardiac (23.0%), and unknown (17.8%). The predictors of late mortality were chronic obstructive pulmonary disease (hazard ratio [HR]: 2.18, 95% confidence interval [CI]: 1.53 to 3.11), chronic kidney disease (HR: 1.08 for each decrease of 10 ml/min in estimated glomerular filtration rate, 95% CI: 1.01 to 1.19), chronic atrial fibrillation (HR: 1.44, 95% CI: 1.02 to 2.03), and frailty (HR: 1.52, 95% CI: 1.07 to 2.17). A mild nonclinically significant decrease in valve area occurred at 2-year follow-up (p < 0.01), but no further reduction in valve area was observed up to 4-year follow-up. No changes in residual aortic regurgitation and no cases of structural valve failure were observed during the follow-up period. CONCLUSIONS: Approximately one-half of the patients who underwent TAVI because of a high or prohibitive surgical risk profile had died at a mean follow-up of 3.5 years. Late mortality was due to noncardiac comorbidities in more than one-half of patients. No clinically significant deterioration in valve function was observed throughout the follow-up period.


Assuntos
Cateterismo Cardíaco/tendências , Desenho de Equipamento/tendências , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/cirurgia , Implante de Prótese de Valva Cardíaca/tendências , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Cateterismo Cardíaco/mortalidade , Desenho de Equipamento/mortalidade , Feminino , Seguimentos , Doenças das Valvas Cardíacas/mortalidade , Implante de Prótese de Valva Cardíaca/mortalidade , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia
10.
PLoS One ; 6(12): e28551, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22164304

RESUMO

HCV infection is a major cause of chronic liver disease and liver cancer in the United States. To address the pathogenesis caused by HCV infection, recent studies have focused on the direct cytopathic effects of individual HCV proteins, with the objective of identifying their specific roles in the overall pathogenesis. However, this approach precludes examination of the possible interactions between different HCV proteins and organelles. To obtain a better understanding of the various cytopathic effects of and cellular responses to HCV proteins, we used human hepatoma cells constitutively replicating HCV RNA encoding either the full-length polyprotein or the non-structural proteins, or cells constitutively expressing the structural protein core, to model the state of persistent HCV infection and examined the combination of various HCV proteins in cellular pathogenesis. Increased reactive oxygen species (ROS) generation in the mitochondria, mitochondrial injury and degeneration, and increased lipid accumulation were common among all HCV protein-expressing cells regardless of whether they expressed the structural or non-structural proteins. Expression of the non-structural proteins also led to increased oxidative stress in the cytosol, membrane blebbing in the endoplasmic reticulum, and accumulation of autophagocytic vacuoles. Alterations of cellular redox state, on the other hand, significantly changed the level of autophagy, suggesting a direct link between oxidative stress and HCV-mediated activation of autophagy. With the wide-spread cytopathic effects, cells with the full-length HCV polyprotein showed a modest antioxidant response and exhibited a significant increase in population doubling time and a concomitant decrease in cyclin D1. In contrast, cells expressing the non-structural proteins were able to launch a vigorous antioxidant response with up-regulation of antioxidant enzymes. The population doubling time and cyclin D1 level were also comparable to that of control cells. Finally, the cytopathic effects of core protein appeared to focus on the mitochondria without remarkable disturbances in the cytosol.


Assuntos
Autofagia , Carcinoma Hepatocelular/virologia , Hepacivirus/metabolismo , Neoplasias Hepáticas/virologia , Mitocôndrias/metabolismo , Animais , Anticorpos/química , Antioxidantes/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Genoma , Humanos , Imuno-Histoquímica/métodos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Transgênicos , Oxirredução , Fatores de Tempo , Regulação para Cima
11.
Transl Res ; 157(3): 128-38, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21316029

RESUMO

Radial artery (RA) graft spasm is a major cause of early graft failure in coronary artery bypass grafting surgeries. We explored the feasibility of thermal reduction of smooth muscle mass to attenuate vasoconstriction. Rat and rabbit femoral arteries were treated thermally in situ (45°C to 65°C; 0 s to 120 s) and then excised at various time points for histological and physiological study (pressure-diameter relationships). Human radial arteries were treated in vitro and studied in similar fashion. Weeks after thermal treatment, no overt indication was noted of vasospasm, thrombosis, or scarring in the arterial wall; however, this intervention led to a thermal dose-dependent reduction of vasoconstriction (to phenylephrine or potassium chloride) and to a conspicuous loss of smooth muscle. Pressure-diameter relationships showed no aneurismal dilation of these demuscularized arteries up to 200 mmHg. Qualitatively identical results were obtained in human radial arteries. Thermal ablation of RAs may provide a simple, safe, and effective solution to postsurgical vasospasm.


Assuntos
Artéria Femoral/anatomia & histologia , Artéria Femoral/fisiologia , Temperatura Alta/uso terapêutico , Músculo Liso Vascular/anatomia & histologia , Músculo Liso Vascular/fisiologia , Idoso , Animais , Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/métodos , Vasoespasmo Coronário/prevenção & controle , Artéria Femoral/transplante , Humanos , Técnicas In Vitro , Pessoa de Meia-Idade , Modelos Animais , Perfusão , Complicações Pós-Operatórias/prevenção & controle , Coelhos , Artéria Radial/anatomia & histologia , Artéria Radial/fisiologia , Artéria Radial/transplante , Terapia por Radiofrequência , Ratos , Grau de Desobstrução Vascular , Vasoconstrição
12.
J Am Coll Cardiol ; 55(11): 1080-90, 2010 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-20096533

RESUMO

OBJECTIVES: The aim of this study was: 1) to evaluate the acute and late outcomes of a transcatheter aortic valve implantation (TAVI) program including both the transfemoral (TF) and transapical (TA) approaches; and 2) to determine the results of TAVI in patients deemed inoperable because of either porcelain aorta or frailty. BACKGROUND: Very few data exist on the results of a comprehensive TAVI program including both TA and TF approaches for the treatment of severe aortic stenosis in patients at very high or prohibitive surgical risk. METHODS: Consecutive patients who underwent TAVI with the Edwards valve (Edwards Lifesciences, Inc., Irvine, California) between January 2005 and June 2009 in 6 Canadian centers were included. RESULTS: A total of 345 procedures (TF: 168, TA: 177) were performed in 339 patients. The predicted surgical mortality (Society of Thoracic Surgeons risk score) was 9.8 +/- 6.4%. The procedural success rate was 93.3%, and 30-day mortality was 10.4% (TF: 9.5%, TA: 11.3%). After a median follow-up of 8 months (25th to 75th interquartile range: 3 to 14 months) the mortality rate was 22.1%. The predictors of cumulative late mortality were peri-procedural sepsis (hazard ratio [HR]: 3.49, 95% confidence interval [CI]: 1.48 to 8.28) or need for hemodynamic support (HR: 2.58, 95% CI: 1.11 to 6), pulmonary hypertension (PH) (HR: 1.88, 95% CI: 1.17 to 3), chronic kidney disease (CKD) (HR: 2.30, 95% CI: 1.38 to 3.84), and chronic obstructive pulmonary disease (COPD) (HR: 1.75, 95% CI: 1.09 to 2.83). Patients with either porcelain aorta (18%) or frailty (25%) exhibited acute outcomes similar to the rest of the study population, and porcelain aorta patients tended to have a better survival rate at 1-year follow-up. CONCLUSIONS: A TAVI program including both TF and TA approaches was associated with comparable mortality as predicted by surgical risk calculators for the treatment of patients at very high or prohibitive surgical risk, including porcelain aorta and frail patients. Baseline (PH, COPD, CKD) and peri-procedural (hemodynamic support, sepsis) factors but not the approach determined worse outcomes.


Assuntos
Estenose da Valva Aórtica/mortalidade , Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Cateterismo Cardíaco , Implante de Prótese de Valva Cardíaca/métodos , Idoso , Idoso de 80 Anos ou mais , Canadá , Feminino , Humanos , Masculino , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
13.
Atherosclerosis ; 206(2): 405-10, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19394617

RESUMO

To evaluate the potential impact of using atherosclerotic radial artery (RA) conduits as grafts in coronary artery bypass surgery, we examined the vasoconstrictor and electrophysiological properties of mildly and severely atherosclerotic RAs. Vasoconstrictor responses were measured in cannulated and pressurized (85mmHg) RA segments and K(+) currents were measured in single smooth muscle cells. In the cannulated and pressurized vessel preparation, the pressure-induced dilation was attenuated in both the mildly and severely atherosclerotic RAs when compared to normal samples. Contractile responses to potassium chloride, thromboxane A(2) (TXA(2)) analog U-46619 and to E-ring and F-ring isoprostanes were also attenuated. Smooth muscle cells (SMCs) from atherosclerotic arteries manifested significantly greater K(+) current density (76.6+/-22.4pA/pF) when compared to normal SMCs (18.6+/-3.3pA/pF). Our results show that vasocontractile properties of both mildly and severely atherosclerotic arteries are reduced when compared to normal RAs. A possible explanation for this could be decreased vascular compliance due to arterial stiffening and a substantial augmentation of K(+) currents in sclerotic smooth muscle cells. We conclude that caution should be exercised when using RA grafts with atherosclerotic lesions since they could significantly impact the clinical outcome of CABG surgery.


Assuntos
Aterosclerose/patologia , Artéria Radial/fisiologia , Artéria Radial/transplante , Idoso , Aterosclerose/fisiopatologia , Ponte de Artéria Coronária/métodos , Elasticidade , Fenômenos Eletrofisiológicos , Humanos , Pessoa de Meia-Idade , Artéria Radial/patologia , Vasoconstrição/efeitos dos fármacos
14.
Proc Natl Acad Sci U S A ; 106(14): 5871-6, 2009 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-19321428

RESUMO

The coronavirus spike protein (S) plays a key role in the early steps of viral infection, with the S1 domain responsible for receptor binding and the S2 domain mediating membrane fusion. In some cases, the S protein is proteolytically cleaved at the S1-S2 boundary. In the case of the severe acute respiratory syndrome coronavirus (SARS-CoV), it has been shown that virus entry requires the endosomal protease cathepsin L; however, it was also found that infection of SARS-CoV could be strongly induced by trypsin treatment. Overall, in terms of how cleavage might activate membrane fusion, proteolytic processing of the SARS-CoV S protein remains unclear. Here, we identify a proteolytic cleavage site within the SARS-CoV S2 domain (S2', R797). Mutation of R797 specifically inhibited trypsin-dependent fusion in both cell-cell fusion and pseudovirion entry assays. We also introduced a furin cleavage site at both the S2' cleavage site within S2 793-KPTKR-797 (S2'), as well as at the junction of S1 and S2. Introduction of a furin cleavage site at the S2' position allowed trypsin-independent cell-cell fusion, which was strongly increased by the presence of a second furin cleavage site at the S1-S2 position. Taken together, these data suggest a novel priming mechanism for a viral fusion protein, with a critical proteolytic cleavage event on the SARS-CoV S protein at position 797 (S2'), acting in concert with the S1-S2 cleavage site to mediate membrane fusion and virus infectivity.


Assuntos
Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/fisiologia , Vírus da SARS/patogenicidade , Tripsina/metabolismo , Proteínas do Envelope Viral/metabolismo , Proteínas do Envelope Viral/fisiologia , Sítios de Ligação , Fusão Celular , Furina , Hidrólise , Mutagênese Sítio-Dirigida , Glicoproteína da Espícula de Coronavírus , Internalização do Vírus
15.
J Thorac Cardiovasc Surg ; 135(1): 131-8, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18179929

RESUMO

OBJECTIVES: Radial artery vasospasm remains a potential cause of early graft failure after coronary bypass graft surgery, despite pretreatment with alpha-adrenergic or calcium channel blockers. We examined the roles of isoprostanes and prostanoid receptors selective for thromboxane A2 in the vasoconstriction of human radial arteries. METHODS: Human radial arterial segments were pretreated intraoperatively with verapamil/papaverine or nitroglycerine/phenoxybenzamine, or not treated. In the laboratory, we measured isometric contractions in ring segments, vasoconstriction in pressurized segments, and changes in [Ca2+] and K+ currents in single cells. RESULTS: Although phenoxybenzamine eliminated adrenergic responses, the isoprostane 15-F(2t)-IsoP and 2 closely related E-ring molecules (15-E(1t)-IsoP and 15-E(2t)-IsoP) still evoked powerful contractions; 15-E(2t)-IsoP was approximately 10-fold more potent than the other 2 agents. Responses were mediated through thromboxane receptors because they were sensitive to ICI-192605. Furthermore, they were sensitive to the Rho-kinase inhibitors Y-27632 or H-1152 (both 10(-5) mol/L) or to cyclopiazonic acid (which depletes the internal Ca2+ pool), but not to nifedipine. In single cells, 15-E(2t)-IsoP elevated [Ca2+]i and suppressed K+ current. CONCLUSIONS: Isoprostanes accumulate after coronary artery bypass graft surgery, yet none of the currently available antispasm treatments for radial artery grafts is effective against isoprostane-induced vasoconstriction. It is imperative that more specific treatment strategies be developed. We found that isoprostane responses in radial arteries are mediated by prostanoid receptors selective for thromboxane A2 with activation of Rho-kinase and release of Ca2+. Pretreatment of radial artery grafts with Rho-associated kinase inhibitors may potentially reduce postoperative graft spasm. Clinical studies to test this are indicated.


Assuntos
Isoprostanos/farmacologia , Artéria Radial/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Cálcio/metabolismo , Humanos , Técnicas In Vitro , Artéria Radial/fisiopatologia , Receptores de Tromboxanos/efeitos dos fármacos , Receptores de Tromboxano A2 e Prostaglandina H2 , Transdução de Sinais , Coleta de Tecidos e Órgãos , Proteína rhoA de Ligação ao GTP/metabolismo
16.
Hawaii Dent J ; 39(5): 9-12; quiz 17, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19189512

RESUMO

Bisphosphonate related osteonecrosis of the jaw (BRONJ) is a recent discovery and has only been brought to the attention of health care professionals in since 2003. The purpose of this article is to describe this phenomenon and focus on preventive strategies to minimize the risk of patients developing this condition. Management and prevention will be broken down into patients taking IV bisphosphonates and patients taking oral bisphosphonates.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Doenças Maxilomandibulares/prevenção & controle , Procedimentos Cirúrgicos Bucais/efeitos adversos , Osteonecrose/prevenção & controle , Administração Oral , Idoso , Antibacterianos/uso terapêutico , Conservadores da Densidade Óssea/administração & dosagem , Desbridamento , Difosfonatos/administração & dosagem , Feminino , Humanos , Injeções Intravenosas , Doenças Maxilomandibulares/induzido quimicamente , Pessoa de Meia-Idade , Osteonecrose/induzido quimicamente , Osteoporose/prevenção & controle
17.
Can J Anaesth ; 54(6): 461-6, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17541075

RESUMO

PURPOSE: To describe the management of severe acute intracardiac thrombosis in a patient who underwent redo multiple valve replacement and valvular repair. The diagnostic features, associated risk factors, and anesthetic management are reviewed. CLINICAL FEATURES: A 67-yr-old woman undergoing redo mitral and aortic mechanical valve replacement and tricuspid annuloplasty under aprotinin prophylaxis exhibited severe refractory hypotension that began immediately after protamine reversal of intraoperative heparin anticoagulation following separation from cardiopulmonary bypass. Intraoperative transesophageal echocardiography revealed severe thrombosis in the right atrium, right ventricle and pulmonary artery. The patient was managed by immediate reheparinization and return to cardiopulmonary bypass (CPB), surgical thrombectomy, and intraoperative administration of recombinant tissue-plasminogen activator. After removal of the thrombi, and separation from CPB, no further protamine was given. One hundred units of blood products and two surgical re-explorations were required to manage subsequent massive postoperative bleeding. Acute heparin-induced thrombocytopenia (HIT) was ruled out using sensitive assays for HIT antibodies. After 16 days in the intensive care unit and 30 more days in hospital, the patient was subsequently transferred to a chronic care facility and succumbed several weeks later. CONCLUSION: Acute intraoperative thrombosis is a rare and potentially fatal complication of cardiac surgery. Intraoperative transesophageal echocardiography was essential for rapid diagnosis in this case. Multiple interacting prothrombotic factors (e.g., aprotinin use, acquired antithrombin deficiency, long pump time, post-protamine status, transfusion of blood components) were likely contributing factors related to this rare complication.


Assuntos
Ponte Cardiopulmonar , Trombose Coronária/terapia , Complicações Pós-Operatórias/terapia , Idoso , Pressão Sanguínea/fisiologia , Trombose Coronária/diagnóstico por imagem , Ecocardiografia Transesofagiana , Feminino , Frequência Cardíaca/fisiologia , Implante de Prótese de Valva Cardíaca , Humanos , Complicações Pós-Operatórias/diagnóstico por imagem , Reoperação , Cardiopatia Reumática/cirurgia
18.
Avian Dis ; 51(1): 45-51, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17461266

RESUMO

The avian coronavirus infectious bronchitis virus (IBV) strain Beaudette is an embryo-adapted virus that has extended species tropism in cell culture. In order to understand the acquired tropism of the Beaudette strain, we compared the S protein sequences of several IBV strains. The Beaudette strain was found to contain a putative heparan sulfate (HS)-binding site, indicating that the Beaudette virus may use HS as a selective receptor. To ascertain the requirements of cell-surface HS for Beaudette infectivity, we assayed for infectivity in the presence of soluble heparin as a competitor and determined infectivity in mutant cell lines with no HS or glycosaminoglycan expression. Our results indicate that HS plays a role as an attachment factor for IBV, working in concert with other factors like sialic acid to mediate virus binding to cells, and may explain in part the extended tropism of IBV Beaudette.


Assuntos
Heparitina Sulfato/metabolismo , Vírus da Bronquite Infecciosa/fisiologia , Receptores de Superfície Celular/metabolismo , Sequência de Aminoácidos , Animais , Bovinos , Linhagem Celular , Embrião de Galinha , Biologia Computacional , Cricetinae , Vírus da Bronquite Infecciosa/classificação , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Dados de Sequência Molecular , Ligação Proteica , Receptores de Superfície Celular/química , Glicoproteína da Espícula de Coronavírus , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo
19.
Virol J ; 4: 20, 2007 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-17324273

RESUMO

BACKGROUND: Coronaviruses are an important cause of infectious diseases in humans, including severe acute respiratory syndrome (SARS), and have the continued potential for emergence from animal species. A major factor in the host range of a coronavirus is its receptor utilization on host cells. In many cases, coronavirus-receptor interactions are well understood. However, a notable exception is the receptor utilization by group 3 coronaviruses, including avian infectious bronchitis virus (IBV). Feline aminopeptidase N (fAPN) serves as a functional receptor for most group 1 coronaviruses including feline infectious peritonitis virus (FIPV), canine coronavirus, transmissible gastroenteritis virus (TGEV), and human coronavirus 229E (HCoV-229E). A recent report has also suggested a role for fAPN during IBV entry (Miguel B, Pharr GT, Wang C: The role of feline aminopeptidase N as a receptor for infectious bronchitis virus. Brief review. Arch Virol 2002, 147:2047-2056. RESULTS: Here we show that, whereas both transient transfection and constitutive expression of fAPN on BHK-21 cells can rescue FIPV and TGEV infection in non-permissive BHK cells, fAPN expression does not rescue infection by the prototype IBV strain Mass41. To account for the previous suggestion that fAPN could serve as an IBV receptor, we show that feline cells can be infected with the prototype strain of IBV (Mass 41), but with low susceptibility compared to primary chick kidney cells. We also show that BHK-21 cells are slightly susceptible to certain IBV strains, including Ark99, Ark_DPI, CA99, and Iowa97 (<0.01% efficiency), but this level of infection is not increased by fAPN expression. CONCLUSION: We conclude that fAPN is not a functional receptor for IBV, the identity of which is currently under investigation.


Assuntos
Antígenos CD13/fisiologia , Vírus da Bronquite Infecciosa/fisiologia , Receptores Virais/fisiologia , Ligação Viral , Animais , Antígenos CD13/genética , Gatos , Linhagem Celular , Galinhas , Cricetinae , Vírus da Bronquite Infecciosa/crescimento & desenvolvimento
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