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1.
Blood Cancer J ; 10(2): 16, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029705

RESUMO

Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 (RASSF2) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2-proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia.

2.
JACC Cardiovasc Interv ; 13(1): 86-93, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31918946

RESUMO

OBJECTIVES: This study sought to determine clinical outcomes between treatment groups over long-term follow-up. BACKGROUND: The safety and efficacy of a ridaforolimus-eluting stent (RES) was evaluated in the BIONICS (BioNIR Ridaforolimus-Eluting Coronary Stent System in Coronary Stenosis) and NIREUS (BioNIR Ridaforolimus Eluting Coronary Stent System [BioNIR] European Angiography Study) trials, demonstrating noninferiority of RES in comparison with a zotarolimus-eluting stent (ZES) regarding 1-year target lesion failure (TLF) and 6-month angiographic late lumen loss, respectively. METHODS: Patient-level data from the BIONICS (N = 1,919) and NIREUS (N = 302) randomized trials were pooled, and outcomes in patients implanted with RES and ZES compared. Broad inclusion criteria allowed enrollment of patients with acute coronary syndromes and complex lesions. The primary endpoint was the 2-year rate of TLF or clinically driven target lesion revascularization. RESULTS: A total of 2,221 patients (age 63.2 ± 10.3 years; 79.7% men) undergoing percutaneous coronary intervention with RES (n = 1,159) or ZES (n = 1,062) were included. Clinical and angiographic characteristics were similar between groups. At 2 years, the primary endpoint of TLF was similar among patients implanted with RES and ZES (7.0% vs. 7.2%; p = 0.94). Rates of target lesion revascularization (4.8% RES vs. 4.1% ZES; p = 0.41) and target vessel-related myocardial infarction (3.1% RES vs. 3.8% ZES; p = 0.52) did not differ between groups. The overall rate of stent thrombosis was also similar (0.5% RES vs. 0.9% ZES; p = 0.39). CONCLUSIONS: In a pooled analysis of 2 randomized trials, 2-year clinical outcomes were similar between patients undergoing percutaneous coronary intervention with RES and ZES. These results support the long-term safety and efficacy of RES for the treatment of a broad population of patients with coronary artery disease.

3.
Thromb Haemost ; 120(2): 348-362, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31820428

RESUMO

BACKGROUND: Individual randomized controlled trials (RCTs) of periprocedural anticoagulation with bivalirudin versus heparin during percutaneous coronary intervention (PCI) have reported conflicting results. Study-level meta-analyses lack granularity to adjust for confounders, explore heterogeneity, or identify subgroups that may particularly benefit or be harmed. OBJECTIVE: To overcome these limitations, we sought to develop an individual patient-data pooled database of RCTs comparing bivalirudin versus heparin. METHODS: We conducted a systematic review to identify RCTs in which ≥1,000 patients with acute myocardial infarction (AMI) undergoing PCI were randomized to bivalirudin versus heparin. RESULTS: From 738 identified studies, 8 RCTs met the prespecified criteria. The principal investigators of each study agreed to provide patient-level data. The data were pooled and checked for accuracy against trial publications, with discrepancies addressed by consulting with the trialists. Consensus-based definitions were created to resolve differing antithrombotic, procedural, and outcome definitions. The project required 3.5 years to complete, and the final database includes 27,409 patients (13,346 randomized to bivalirudin and 14,063 randomized to heparin). CONCLUSION: We have created a large individual patient database of bivalirudin versus heparin RCTs in patients with AMI undergoing PCI. This endeavor may help identify the optimal periprocedural anticoagulation regimen for patient groups with different relative risks of adverse ischemic versus bleeding events, including those with ST-segment and non-ST-segment elevation MI, radial versus femoral access, use of a prolonged bivalirudin infusion or glycoprotein inhibitors, and others. Adherence to standardized techniques and rigorous validation processes should increase confidence in the accuracy and robustness of the results.

4.
Am J Nephrol ; 50(6): 465-472, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31655801

RESUMO

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of adverse cardiovascular outcomes, in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). However, most studies used bare-metal stents or first-generation drug-eluting stents, and less guideline-directed therapy to reduce cardiovascular risk was reported in CKD patients. This study investigates the impact of moderate-CKD on patients undergoing PCI in the current era. METHODS: Patient level data were pooled from 2 multicenter randomized trials (BIONICS and NIREUS trials) with a near "all-comers" design, comparing PCI with ridaforolimus-eluting stents vs. zotarolimus-eluting stents in patients with CAD. Patients were classified according to the presence or absence of moderate-CKD, defined as creatinine clearance (CrCl) <60 mL/min. We compared baseline characteristics, angiographic findings, and clinical outcomes 1-year post-PCI. RESULTS: 236/2,201 (10.7%) patients had CKD, mean CrCl of 50.3 + 7.8 mL/min. These patients were generally older and more often with hypertension than non-CKD patients, but the use of guideline-directed therapy was similar between the groups. CKD was associated with an increased risk of cardiovascular death (hazard ratio [HR] 6.08; 95% CI 2.11-17.51; p < 0.001), but with a reduced occurrence of repeated revascularization, including ischemia-driven revascularization (HR 0.47; 95% CI 0.24-0.92; p < 0.05). The rate of repeated angiography per severe cardiovascular adverse event was significantly lower in the CKD than the non-CKD group (23/38 [61%] vs. 253/334 [76%], p < 0.05). CONCLUSIONS: Moderate-CKD in patients with CAD was associated with higher rates of all-cause and cardiovascular mortality, yet with a lower risk of revascularization 1-year following PCI. Lack of guideline-directed medical therapy does not explain the adverse outcome of CKD patients.

5.
JACC Cardiovasc Interv ; 12(19): 1941-1950, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31521646

RESUMO

OBJECTIVES: This study examined the smoker's paradox using patient-level data from 18 prospective, randomized trials of patients undergoing percutaneous coronary intervention (PCI) with stent implantation. BACKGROUND: Studies on the effects of smoking and outcomes among patients undergoing PCI have reported conflicting results. METHODS: Data from the RAVEL, E-SIRIUS, SIRIUS, C-SIRIUS, TAXUS IV and V, ENDEAVOR II to IV, SPIRIT II to IV, HORIZONS-AMI, COMPARE I and II, PLATINUM, and TWENTE I and II randomized trials were pooled. Patients were stratified by smoking status at time of enrollment. The 1- and 5-year ischemic outcomes were compared. RESULTS: Among 24,354 patients with available data on smoking status, 6,722 (27.6%) were current smokers. Smokers were younger and less likely to have diabetes mellitus; hypertension; hyperlipidemia; or prior myocardial infarction (MI), PCI, or coronary artery bypass grafting. Angiographically, smokers had longer lesions, more complex lesions, and more occlusions, but were less likely to have moderate or severe calcification or tortuosity. At 5 years, smokers had significantly higher rates of MI (7.8% vs. 5.6%; p < 0.0001) and definite or probable stent thrombosis (3.5% vs. 1.8%; p < 0.0001); however, there were no differences in the rates of death, cardiac death, target lesion revascularization, or composite endpoints (cardiac death, target vessel MI, or ischemic target lesion revascularization). After multivariable adjustment for potential confounders, smoking was a strong independent predictor of death (hazard ratio [HR]: 1.86; 95% confidence interval [CI]: 1.63 to 2.12; p < 0.0001), cardiac death (HR: 1.68; 95% CI: 1.38 to 2.05; p < 0.0001), MI (HR: 1.38; 95% CI: 1.20 to 1.58; p < 0.0001), stent thrombosis (HR: 1.60; 95% CI: 1.28 to 1.99; p < 0.0001), and target lesion failure (HR: 1.17; 95% CI: 1.05 to 1.30; p = 0.005). CONCLUSIONS: The present large, patient-level, pooled analysis with 5-year follow-up clearly demonstrates smoking to be an important predictor of adverse outcomes after PCI.

6.
JACC Cardiovasc Interv ; 12(16): 1580-1589, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31439338

RESUMO

OBJECTIVES: The study sought to determine the patterns of antithrombotic therapy and association with clinical outcomes in patients with atrial fibrillation (AF) and CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category) score ≥2 following transcatheter aortic valve replacement (TAVR). BACKGROUND: The impact of antithrombotic regimens on clinical outcomes in patients with AF and severe aortic stenosis treated with TAVR is unknown. METHODS: In the randomized PARTNER II (Placement of Aortic Transcatheter Valve II) trial and associated registries, 1,621 patients with prior AF and CHA2DS2-VASc score ≥2 comprised the study cohort. Outcomes were analyzed according to antithrombotic therapy. RESULTS: During the 5-year enrollment period, 933 (57.6%) patients were discharged on oral anticoagulant therapy (OAC). Uninterrupted antiplatelet therapy (APT) for at least 6 months or until an endpoint event was used in 544 of 933 (58.3%) of patients on OAC and 77.5% of patients not on OAC. At 2 years, patients on OAC had a similar rate of stroke (6.6% vs. 5.6%; p = 0.53) and the composite outcome of death or stroke (29.7% vs. 31.8%; p = 0.33), compared with no OAC. OAC with APT was associated with a reduced rate of stroke (5.4% vs. 11.1%; p = 0.03) and death or stroke (29.7% vs. 40.1%; p = 0.01), compared with no OAC or APT. Following adjustment, OAC with APT and APT alone were both associated with reduced rates of stroke compared with no OAC or APT (hazard ratio for OAC+APT: 0.43, 95% confidence interval: 0.22 to 0.85; p = 0.015; hazard ratio for APT alone: 0.32, 95% confidence interval: 0.16 to 0.65; p = 0.002), while OAC alone was not. CONCLUSIONS: Among patients with prior AF undergoing TAVR, antiplatelet with or without anticoagulant therapy was associated with a reduced risk of stroke at 2 years, implicating multifactorial stroke mechanisms in this population.

7.
Am Heart J ; 211: 68-76, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30897527

RESUMO

BACKGROUND: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) typically requires a greater number of stents and longer stent length than non-CTO PCI, placing these patients at greater risk for adverse ischemic events. We sought to determine whether the association between high platelet reactivity (HPR) and the risk of ischemic events is stronger after CTO than non-CTO PCI. METHODS: Patients undergoing successful PCI in the multicenter ADAPT-DES study were stratified according to whether they underwent PCI of a CTO. HPR was defined as VerifyNow platelet reaction units >208. The study primary endpoint was the 2-year risk target vessel failure ([TVF] defined as cardiac death, myocardial infarction, or target lesion revascularization). RESULTS: CTO PCI was performed in 400 of 8448 patients. HPR was present in 34.5% of CTO PCI patients and 43.1% of non-CTO PCI patients (P = .0007). Patients undergoing CTO PCI with versus without HPR had significantly higher 2-year rates of TVF (15.0% versus 8.3%, P = .04) without significant differences in bleeding. HPR was an independent predictor of 2-year TVF (adjusted HR 1.16, 95% CI 1.02-1.34, P = .03) whereas CTO PCI was not (adjusted HR 0.89, 95% CI 0.65-1.22, P = .48). There was a significant interaction between CTO versus non-CTO PCI and PRU as a continuous variable for 2-year TVF (Pinteraction = 0.02). CONCLUSIONS: In ADAPT-DES, HPR was associated with an increased 2-year risk of TVF after PCI, an association that was at least as strong after CTO PCI compared with non-CTO PCI.


Assuntos
Plaquetas/fisiologia , Oclusão Coronária/sangue , Oclusão Coronária/cirurgia , Stents Farmacológicos/efeitos adversos , Isquemia Miocárdica/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Idoso , Aspirina/uso terapêutico , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Complicações Pós-Operatórias , Estudos Prospectivos , Desenho de Prótese
8.
JACC Cardiovasc Interv ; 11(24): 2467-2476, 2018 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-30573057

RESUMO

OBJECTIVES: The authors sought to investigate the impact of diabetes mellitus (DM) on outcomes following contemporary drug-eluting stent (DES) implantation in the BIONICS (BioNIR Ridaforolimus Eluting Coronary Stent System in Coronary Stenosis) trial. BACKGROUND: Patients with DM are at increased risk for adverse events following percutaneous coronary intervention (PCI). METHODS: A prospective, multicenter, 1:1 randomized trial was conducted to evaluate in a noninferiority design the safety and efficacy of ridaforolimus-eluting stents versus zotarolimus-eluting stents among 1,919 patients undergoing PCI. Randomization was stratified to the presence of medically treated DM, and a pre-specified analysis compared outcomes according to the presence or absence of DM up to 2 years. RESULTS: The overall prevalence of DM was 29.1% (559 of 1,919). DM patients had higher body mass index, greater prevalence of hyperlipidemia and hypertension, and smaller reference vessel diameter. One-year target lesion failure (cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization) was significantly higher among diabetic patients (7.8% vs. 4.2%; p = 0.002), mainly due to higher target lesion revascularization (4.5% vs. 2.0%; p = 0.002). Rates of cardiac death, myocardial infarction, and stent thrombosis did not statistically vary. Among 158 patients undergoing 13-month angiographic follow-up, restenosis rates were 3 times higher in diabetic patients compared with nondiabetic patients (15.2% vs. 4.7%; p = 0.01). Clinical and angiographic outcomes were similar between ridaforolimus-eluting stent- and zotarolimus-eluting stent-treated patients. CONCLUSIONS: Despite advances in interventional therapies, and the implementation of new-generation DES, diabetic patients still have worse angiographic and clinical outcomes compared with nondiabetic patients undergoing PCI.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Doença da Artéria Coronariana/terapia , Estenose Coronária/terapia , Diabetes Mellitus/epidemiologia , Stents Farmacológicos , Intervenção Coronária Percutânea/instrumentação , Sirolimo/análogos & derivados , Idoso , Fármacos Cardiovasculares/efeitos adversos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/mortalidade , Reestenose Coronária/epidemiologia , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/mortalidade , Trombose Coronária/epidemiologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Prevalência , Estudos Prospectivos , Desenho de Prótese , Fatores de Risco , Método Simples-Cego , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
9.
BMJ Open ; 8(5): e019454, 2018 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-29730620

RESUMO

OBJECTIVES: Develop predictive models for a paediatric population that provide information for paediatricians and health authorities to identify children at risk of hospitalisation for conditions that may be impacted through improved patient care. DESIGN: Retrospective healthcare utilisation analysis with multivariable logistic regression models. DATA: Demographic information linked with utilisation of health services in the years 2006-2014 was used to predict risk of hospitalisation or death in 2015 using a longitudinal administrative database of 527 458 children aged 1-13 years residing in the Regione Emilia-Romagna (RER), Italy, in 2014. OUTCOME MEASURES: Models designed to predict risk of hospitalisation or death in 2015 for problems that are potentially avoidable were developed and evaluated using the C-statistic, for calibration to assess performance across levels of predicted risk, and in terms of their sensitivity, specificity and positive predictive value. RESULTS: Of the 527 458 children residing in RER in 2014, 6391 children (1.21%) were hospitalised for selected conditions or died in 2015. 49 486 children (9.4%) of the population were classified in the 'At Higher Risk' group using a threshold of predicted risk >2.5%. The observed risk of hospitalisation (5%) for the 'At Higher Risk' group was more than four times higher than the overall population. We observed a C-statistic of 0.78 indicating good model performance. The model was well calibrated across categories of predicted risk. CONCLUSIONS: It is feasible to develop a population-based model using a longitudinal administrative database that identifies the risk of hospitalisation for a paediatric population. The results of this model, along with profiles of children identified as high risk, are being provided to the paediatricians and other healthcare professionals providing care to this population to aid in planning for care management and interventions that may reduce their patients' likelihood of a preventable, high-cost hospitalisation.


Assuntos
Saúde do Adolescente , Saúde da Criança , Hospitalização , Modelos Biológicos , Adolescente , Criança , Pré-Escolar , Bases de Dados Factuais , Morte , Demografia , Feminino , Humanos , Lactente , Itália/epidemiologia , Masculino , Estudos Retrospectivos , Fatores de Risco
10.
BMJ Open ; 7(3): e012997, 2017 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-28363921

RESUMO

OBJECTIVES: A number of observational studies have reported that, in patients with chronic obstructive pulmonary disease (COPD), ß blockers (BBs) decrease risk of mortality and COPD exacerbations. To address important methodological concerns of these studies, we compared the effectiveness and safety of cardioselective BBs versus non-dihydropyridine calcium channel blockers (non-DHP CCBs) in patients with COPD and acute coronary syndromes (ACS) using a propensity score (PS)-matched, active comparator, new user design. We also assessed for potential unmeasured confounding by examining a short-term COPD hospitalisation outcome. SETTING AND PARTICIPANTS: We identified 22 985 patients with COPD and ACS starting cardioselective BBs or non-DHP CCBs across 5 claims databases from the USA, Italy and Taiwan. PRIMARY AND SECONDARY OUTCOME MEASURES: Stratified Cox regression models were used to estimate HRs for mortality, cardiovascular (CV) hospitalisations and COPD hospitalisations in each database after variable-ratio PS matching. Results were combined with random-effects meta-analyses. RESULTS: Cardioselective BBs were not associated with reduced risk of mortality (HR, 0.90; 95% CI 0.78 to 1.02) or CV hospitalisations (HR, 1.06; 95% CI 0.91 to 1.23), although statistical heterogeneity was observed across databases. In contrast, a consistent, inverse association for COPD hospitalisations was identified across databases (HR, 0.54; 95% CI 0.47 to 0.61), which persisted even within the first 30 days of follow-up (HR, 0.55; 95% CI 0.37 to 0.82). Results were similar across a variety of sensitivity analyses, including PS trimming, high dimensional-PS matching and restricting to high-risk patients. CONCLUSIONS: This multinational study found a large inverse association between cardioselective BBs and short-term COPD hospitalisations. The persistence of this bias despite state-of-the-art pharmacoepidemiologic methods calls into question the ability of claims data to address confounding in studies of BBs in patients with COPD.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Síndrome Coronariana Aguda/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Viés , Comorbidade , Bases de Dados Factuais , Progressão da Doença , Feminino , Hospitalização , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Taiwan/epidemiologia , Estados Unidos/epidemiologia
11.
J Virol ; 90(24): 11197-11207, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27707926

RESUMO

Murine leukemia virus (MLV) p12, encoded within Gag, binds the viral preintegration complex (PIC) to the mitotic chromatin. This acts to anchor the viral PIC in the nucleus as the nuclear envelope re-forms postmitosis. Mutations within the p12 C terminus (p12 PM13 to PM15) block early stages in viral replication. Within the p12 PM13 region (p12 60PSPMA65), our studies indicated that chromatin tethering was not detected when the wild-type (WT) p12 protein (M63) was expressed as a green fluorescent protein (GFP) fusion; however, constructs bearing p12-I63 were tethered. N-terminal truncations of the activated p12-I63-GFP indicated that tethering increased further upon deletion of p12 25DLLTEDPPPY34, which includes the late domain required for viral assembly. The p12 PM15 sequence (p12 70RREPP74) is critical for wild-type viral viability; however, virions bearing the PM15 mutation (p12 70AAAAA74) with a second M63I mutant were viable, with a titer 18-fold lower than that of the WT. The p12 M63I mutation amplified chromatin tethering and compensated for the loss of chromatin binding of p12 PM15. Rescue of the p12-M63-PM15 nonviable mutant with prototype foamy virus (PFV) and Kaposi's sarcoma herpesvirus (KSHV) tethering sequences confirmed the function of p1270-74 in chromatin binding. Minimally, full-strength tethering was seen with only p12 61SPIASRLRGRR71 fused to GFP. These results indicate that the p12 C terminus alone is sufficient for chromatin binding and that the presence of the p12 25DLLTEDPPPY34 motif in the N terminus suppresses the ability to tether. IMPORTANCE: This study defines a regulatory mechanism controlling the differential roles of the MLV p12 protein in early and late replication. During viral assembly and egress, the late domain within the p12 N terminus functions to bind host vesicle release factors. During viral entry, the C terminus of p12 is required for tethering to host mitotic chromosomes. Our studies indicate that the p12 domain including the PPPY late sequence temporally represses the p12 chromatin tethering motif. Maximal p12 tethering was identified with only an 11-amino-acid minimal chromatin tethering motif encoded at p1261-71 Within this region, the p12-M63I substitution switches p12 into a tethering-competent state, partially rescuing the p12-PM15 tethering mutant. A model for how this conformational change regulates early versus late functions is presented.


Assuntos
Cromatina/metabolismo , Produtos do Gene gag/genética , Interações Hospedeiro-Patógeno , Vírus da Leucemia Murina de Moloney/genética , Vírion/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cromatina/química , Cromatina/virologia , Regulação da Expressão Gênica , Produtos do Gene gag/química , Produtos do Gene gag/metabolismo , Células HEK293 , Humanos , Camundongos , Mitose , Vírus da Leucemia Murina de Moloney/crescimento & desenvolvimento , Vírus da Leucemia Murina de Moloney/metabolismo , Mutação , Ligação Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Vírion/crescimento & desenvolvimento , Vírion/metabolismo , Montagem de Vírus , Replicação Viral
12.
J Virol ; 90(24): 11208-11219, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27707931

RESUMO

The p12 protein of murine leukemia virus (MLV) Gag is associated with the preintegration complex (PIC), and mutants of p12 (PM14) exhibit defects in nuclear entry/retention. Mutants of the phosphorylated serine 61 also have been reported to have defects in the early life cycle. Here we show that a phosphorylated peptide motif derived from human papillomavirus 8 (HPV-8), the E2 hinge region including residues 240 to 255, can functionally replace the main phosphorylated motif of MLV p12 and can rescue the viral titer of a strain with the lethal p12-PM14 mutation. Complementation with the HPV-8 E2 hinge motif generated multiple second-site mutations in live viral passage assays. Additional p12 phosphorylation sites were detected, including the late domain of p12 (PPPY) as well as the late domain/protease cleavage site of matrix (LYPAL), by mass spectrometry and Western blotting. Chromatin binding of p12-green fluorescent protein (GFP) fusion protein and functional complementation of p12-PM14 occurred in a manner independent of the E2 hinge region phosphorylation. Replacement of serine 61 by alanine within the minimal tethering domain (61SPMASRLRGRR71) maintained tethering, but in the context of the full-length p12, mutants with substitutions in S61 remained untethered and lost infectivity, indicating phosphorylation of p12 serine 61 functions to temporally regulate early and late p12 functions. IMPORTANCE: The p12 protein, required for both early and late viral functions, is the predominant phosphorylated viral protein of Moloney MLV and is required for virus viability. Our studies indicate that the N terminus of p12 represses the early function of the chromatin binding domain and that deletion of the N terminus activates chromatin binding in the wild-type Moloney MLV p12 protein. Mass spectrometry and mutagenesis studies suggest that phosphorylation of both the repression domain and the chromatin binding domain acts to temporally regulate this process at the appropriate stages during infection.


Assuntos
Cromatina/metabolismo , Produtos do Gene gag/genética , Interações Hospedeiro-Patógeno , Vírus da Leucemia Murina de Moloney/genética , Serina/metabolismo , Vírion/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cromatina/química , Cromatina/virologia , Regulação da Expressão Gênica , Produtos do Gene gag/química , Produtos do Gene gag/metabolismo , Teste de Complementação Genética , Células HEK293 , Humanos , Camundongos , Mitose , Vírus da Leucemia Murina de Moloney/crescimento & desenvolvimento , Vírus da Leucemia Murina de Moloney/metabolismo , Mutação , Papillomaviridae/genética , Papillomaviridae/metabolismo , Fosforilação , Ligação Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Vírion/crescimento & desenvolvimento , Vírion/metabolismo , Montagem de Vírus , Replicação Viral
13.
Am J Med Qual ; 31(6): 526-535, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26228578

RESUMO

The objective was to evaluate the attitudes toward collaboration of nurses, general practitioners (GPs), and specialists practicing in newly established Medical Homes (MHs) in Parma Local Health Authority (LHA), Emilia-Romagna region, Italy. The 15-item Jefferson Scale of Attitudes Toward Physician-Nurse Collaboration was administered electronically to 172 physicians (66 GPs, 106 specialists) and 113 nurses practicing in 12 MHs. In all, 191 surveys (45 GPs, 59 specialists, 87 nurses) were completed (67% response rate). The mean total score among nurses (51.5, standard deviation [SD] = 3.7) reflected a significantly (P < .01) more positive attitude toward collaboration compared with GPs (47.8, SD = 4.6) and specialists (45.3, SD = 7.7). Discrepancies in attitudes are concerning because conflicting perceptions of professional roles may impede a successful transition to integrated care within MHs in Parma LHA. Internationally, further research into understanding interprofessional relationships within MHs is needed to inform policy and build a necessary culture of team-based care.


Assuntos
Atitude do Pessoal de Saúde , Clínicos Gerais , Enfermeiras e Enfermeiros , Equipe de Assistência ao Paciente , Assistência Centrada no Paciente/organização & administração , Adulto , Feminino , Clínicos Gerais/organização & administração , Clínicos Gerais/psicologia , Humanos , Relações Interprofissionais , Masculino , Medicina/organização & administração , Pessoa de Meia-Idade , Enfermeiras e Enfermeiros/organização & administração , Enfermeiras e Enfermeiros/psicologia , Equipe de Assistência ao Paciente/organização & administração , Relações Médico-Enfermeiro , Inquéritos e Questionários , Recursos Humanos
14.
BMJ Open ; 4(9): e005223, 2014 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-25231488

RESUMO

OBJECTIVES: Develop predictive models using an administrative healthcare database that provide information for Patient-Centred Medical Homes to proactively identify patients at risk of hospitalisation for conditions that may be impacted through improved patient care. DESIGN: Retrospective healthcare utilisation analysis with multivariate logistic regression models. DATA: A population-based longitudinal database of residents served by the Emilia-Romagna, Italy, health service in the years 2004-2012 including demographic information and utilisation of health services by 3,726,380 people aged ≥18 years. OUTCOME MEASURES: Models designed to predict risk of hospitalisation or death in 2012 for problems that are potentially avoidable were developed and evaluated using the area under the receiver operating curve C-statistic, in terms of their sensitivity, specificity and positive predictive value, and for calibration to assess performance across levels of predicted risk. RESULTS: Among the 3,726,380 adult residents of Emilia-Romagna at the end of 2011, 449,163 (12.1%) were hospitalised in 2012; 4.2% were hospitalised for the selected conditions or died in 2012 (3.6% hospitalised, 1.3% died). The C-statistic for predicting 2012 outcomes was 0.856. The model was well calibrated across categories of predicted risk. For those patients in the highest predicted risk decile group, the average predicted risk was 23.9% and the actual prevalence of hospitalisation or death was 24.2%. CONCLUSIONS: We have developed a population-based model using a longitudinal administrative database that identifies the risk of hospitalisation for residents of the Emilia-Romagna region with a level of performance as high as, or higher than, similar models. The results of this model, along with profiles of patients identified as high risk are being provided to the physicians and other healthcare professionals associated with the Patient Centred Medical Homes to aid in planning for care management and interventions that may reduce their patients' likelihood of a preventable, high-cost hospitalisation.


Assuntos
Morte , Hospitalização/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Adulto Jovem
15.
Artigo em Chinês | MEDLINE | ID: mdl-24741966

RESUMO

OBJECTIVE: To test the different contrctile responses of extracellular nucleotides, such as ATP, UTP and nucleotide uridine adenosine tetraphosphate (Up4A) in gastric longitudinal muscle (LM) and circular muscle (CM). Examined the effect of P2X and P2Y receptor antagonists (in this study, we used IP5I and suramin) and cyclooxygenase inhibitor (indomethacin) on Up4A induced contractile responses in LM and CM. METHODS: The rats were sacrificed and the stomachs were opened to gain LM and CM. Using organ bath system to assess contrctile responses of smooth muscle. RESULTS: Up4A could induce contractile responses in both CM and LM, which were similar with ATP and UTP. IP5 did not attenuate Up4A could induce contractions in both LM and CM, but suramin and indomethacin significantly inhibited Up4A contraction in CM, but not in LM. CONCLUSION: Our results suggest that extracellular nucleosides and their inhibitors induce different responses between LM and CM.


Assuntos
Fosfatos de Dinucleosídeos/farmacologia , Contração Muscular , Músculo Liso/fisiologia , Nucleotídeos/farmacologia , Trifosfato de Adenosina/farmacologia , Animais , Indometacina , Ratos , Suramina , Uridina Trifosfato/farmacologia
16.
AIDS Patient Care STDS ; 28(2): 47-55, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24491190

RESUMO

Eye disease is a well-documented complication of HIV infection. Opportunistic infections generally comprised the majority of pre-antiretroviral therapy (ART) eye complications. With the introduction of ART, opportunistic infections diminished. However, early ART regimens were cumbersome regarding side effects and pill burden, making patient compliance difficult. Newer ART regimens are better tolerated and consist of fewer pills, theoretically making compliance easier and therapy more effective. The aim of this chart review study is to examine eye disease epidemiology in HIV patients as ART has evolved. We reviewed 222 admissions at Thomas Jefferson University Hospitals for 188 patients. These cases were divided into two groups. The first group was comprised of patients admitted from 1995 through 2003, while the second group consisted of patients admitted from 2003 to 2010. Eye disease epidemiology was compared between the two groups. Our study did note a significant decrease in eye diseases caused by opportunistic infections in the 2003-2010 patient group. Noninfectious eye disease is a significant complication in this group.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Antirretrovirais/uso terapêutico , Oftalmopatias/epidemiologia , Infecções por HIV/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Pacientes Internados/estatística & dados numéricos , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Adulto , Antirretrovirais/efeitos adversos , Contagem de Linfócito CD4 , Oftalmopatias/diagnóstico , Oftalmopatias/tratamento farmacológico , Feminino , Infecções por HIV/complicações , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Carga Viral
17.
Int J Ment Health Nurs ; 16(2): 86-95, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17348959

RESUMO

The burden of providing care to a family member, who has a mental illness, has been investigated in the past. However, limited research has focused on how parents cope, as they attempt to maintain a functional family life, when they have a child with a mental illness. This study explored, using a descriptive correlational design, the: (i) differences between parents of a child with mental illness, regarding caregiver burden, coping patterns, and demographic characteristics; (ii) effect parental educational level, parental working status, educational level of the child, diagnosis of the child, and family economic status have on parental caregiver burden and coping patterns; (iii) relationships among caregiver burden and coping patterns; and (iv) demographic characteristics of parents and children that predict caregiver burden and parental coping patterns. Data were collected via interview using structured questionnaires, from 97 mainland Chinese parents who had a child with a mental illness. The findings revealed the parents perceived significant caregiver burden, while caring for their child with a mental illness, yet used limited coping patterns to maintain a functional family life. Also, a significant negative correlation was found between the parents' caregiver burden and the way of coping. Parental physical health and the child's educational level were the best predictors of caregiver burden, while parental physical health and educational levels were the best predictors of the way of coping. Findings suggest that effective nursing interventions should be instituted to help parents of a child with mental illness cope with caregiver burden, while maintaining a functional family life.


Assuntos
Grupo com Ancestrais do Continente Asiático , Cuidadores/psicologia , Efeitos Psicossociais da Doença , Transtornos Mentais/terapia , Pais , Adaptação Psicológica , Criança , China , Feminino , Humanos , Masculino , Relações Pais-Filho
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