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INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is often associated with ischaemia despite lack of focal epicardial coronary stenosis. Our aim was to assess invasive coronary microvascular circulation and correlate findings with echocardiography. METHODS: We prospectively enrolled patients with HCM and controls who were referred for diagnostic coronary angiography. A pressure-temperature sensor coronary guidewire was used with intracoronary injections of room-temperature saline to measure mean coronary transit time during rest and hyperaemia induced with intravenous adenosine. The index of microvascular resistance (IMR) was calculated. Left ventricular mass was calculated during echocardiographic studies. RESULTS: Patients with HCM (n=12) and controls (n=7), had similar demographics. Left ventricular ejection fraction was higher in HCM (76.7%±11.0% vs 55.0%±15.9%, p=0.003). IMR was non-significantly higher in HCM (21.7±10.2 vs 15.3±4.8, p=0.16). Only patients with HCM had abnormal IMR (>25). Coronary flow reserve was non-significantly higher in HCM (2.7±1.6 vs 2.1±1.2, p=0.34). IMR correlated with left ventricular mass in hypertrophic cardiomyopathy subjects (Pearson r=0.68, p=0.02). CONCLUSIONS: Microvascular dysfunction as assessed by IMR may be abnormal in HCM and is correlated with left ventricular mass.
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Cardiomiopatia Hipertrófica , Função Ventricular Esquerda , Cardiomiopatia Hipertrófica/diagnóstico , Circulação Coronária , Ecocardiografia , Humanos , Volume SistólicoRESUMO
CONTEXT: Making a diagnosis can be difficult for learners as they must integrate multiple clinical variables. Diagnostic schemes can help learners with this complex task. A diagnostic scheme is an algorithm that organises possible diagnoses by assigning signs or symptoms (e.g. systolic murmur) to groups of similar diagnoses (e.g. aortic stenosis and aortic sclerosis) and provides distinguishing features to help discriminate between similar diagnoses (e.g. carotid pulse). The current literature does not identify whether scheme layouts should guide learners to reason one step at a time in a terminally branching scheme or weigh multiple variables simultaneously in a hybrid scheme. We compared diagnostic accuracy, perceptual errors and cognitive load using two scheme layouts for cardiac auscultation. METHODS: Focused on the task of identifying murmurs on Harvey, a cardiopulmonary simulator, 86 internal medicine residents used two scheme layouts. The terminally branching scheme organised the information into single variable decisions. The hybrid scheme combined single variable decisions with a chart integrating multiple distinguishing features. Using a crossover design, participants completed one set of murmurs (diastolic or systolic) with either the terminally branching or the hybrid scheme. The second set of murmurs was completed with the other scheme. A repeated measures manova was performed to compare diagnostic accuracy, perceptual errors and cognitive load between the scheme layouts. RESULTS: There was a main effect of the scheme layout (Wilks' λ = 0.841, F3,80 = 5.1, p = 0.003). Use of a terminally branching scheme was associated with increased diagnostic accuracy (65 versus 53%, p = 0.02), fewer perceptual errors (0.61 versus 0.98 errors, p = 0.001) and lower cognitive load (3.1 versus 3.5/7, p = 0.023). CONCLUSIONS: The terminally branching scheme was associated with improved diagnostic accuracy, fewer perceptual errors and lower cognitive load, suggesting that terminally branching schemes are effective for improving diagnostic accuracy. These findings can inform the design of schemes and other clinical decision aids.
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Simulação por Computador , Tomada de Decisões , Sopros Cardíacos/diagnóstico , Medicina Interna/educação , Internato e Residência , Estenose da Valva Aórtica , Estudos Cross-Over , Avaliação Educacional/métodos , Auscultação Cardíaca , Doenças das Valvas Cardíacas , HumanosRESUMO
BACKGROUND AIMS: Cellular immunotherapy relies on several highly variable patient-specific parameters, such as (i) cell number before and after expansion, (ii) targeting of cells to tumors, (iii) cell survival and function after infusion, and (iv) on- and off-target adverse events. Cellular approaches such as the specific expansion of γδ T cells as opposed to αß T cells are being pursued. γδ T cells are reasonable candidates for immunotherapy because they (i) possess intrinsic anti-tumorigenicity, (ii) require no priming, (iii) direct tumor killing via recognition of stress-responsive ligands, and (iv), as we now show, can be expanded to clinical cell doses in current Good Manufacturing Practice serum-free media (SFM). METHODS: γδ T-cell expansion was evaluated in several SFMs. Additionally, the expanded γδ T cells were evaluated for their transduction efficiency using lentiviral vectors (LV). RESULTS: Of the SFM cultures, robust expansion was only observed in OpTmizer supplemented with high-dose interleukin-2. γδ T-cell percentages and numbers were sufficient for clinical use. Using cells from several donors, transduction efficiencies ranged from 13 to 33%, which is similar to transduction levels observed using αß T cells with similar multiplicity of infection. DISCUSSION: An optimized method of γδT-cell expansion and transduction was developed that can be tested in early-phase clinical trials. With appropriate elimination of the αßT cell-component, the absence of MHC-restriction affords the opportunity for use in the allogeneic setting with limited risk of graft versus host disease. Finally, the use of SFM provides clinically safer, widely applicable and potentially more efficacious cellular immunotherapy.
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Bioengenharia/métodos , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/citologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultura Livres de Soro , Difosfonatos/farmacologia , Relação Dose-Resposta a Droga , Engenharia Genética , Vetores Genéticos/metabolismo , Humanos , Imidazóis/farmacologia , Imunoterapia , Interleucina-2/farmacologia , Células K562 , Contagem de Linfócitos , Receptores de LDL/metabolismo , Linfócitos T/efeitos dos fármacos , Doadores de Tecidos , Ácido ZoledrônicoRESUMO
BACKGROUND: Sevoflurane is an inhalation anesthetic that has cardioprotective effects. There is limited information regarding its use outside of the operating room and its potential protective effect for patients presenting with myocardial infarction. METHODS: In the Sevoflurane In Acute Myocardial Infarction trial, patients with a first acute ST-elevation myocardial infarction (STEMI) who were treated by primary percutaneous coronary intervention were randomized to inhalation of sevoflurane or oxygen (control). From the time of the patient's arrival for cardiac catheterization, the anesthesia team administered sevoflurane or oxygen for 30 min using a tight-fitting mask. In this substudy, we report the one-year outcomes. Patients were followed clinically for one year; they underwent a thallium cardiac viability study at six months and an echocardiogram at one year. RESULTS: Forty-six patients completed follow-up. One patient in the sevoflurane group died. The mean [standard deviation (SD)] ejection fraction by single-photon emission computed tomography at six months was 51.7 (7.7)% in the sevoflurane group and 51 (9.1)% in the control group (mean difference, 0.7%; 95% confidence interval [CI], -5.9 to 7.3; P = 0.831). The median [interquartile range] amount of scarring at six months was 0% [0 - 8] in the sevoflurane group and 2.5% [0 - 7.1] in control group (mean difference, -0.1%; 95% CI, -4.6 to 4.4; P = 0.700). The mean (SD) percentage of hibernating myocardium was similar in both groups 0% [0, 5] (mean difference, -1.3%; 95% CI, -3.4 to 0.9; P = 0.259). The mean (SD) ejection fraction at one year increased compared with baseline by 8.0 (9.1)% (P < 0.001). CONCLUSIONS: In this study, we did not find an effect of sevoflurane on left ventricular function or myocardial injury at one year post STEMI. This trial was registered at www.clinicaltrials.gov ; identifier: NCT00971607.
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Anestésicos Inalatórios/administração & dosagem , Éteres Metílicos/administração & dosagem , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/métodos , Idoso , Anestésicos Inalatórios/farmacologia , Método Duplo-Cego , Ecocardiografia , Feminino , Seguimentos , Humanos , Masculino , Éteres Metílicos/farmacologia , Pessoa de Meia-Idade , Oxigênio/administração & dosagem , Sevoflurano , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
PURPOSE: This study aims to assess the association between excessive daytime sleepiness (EDS) and variables extracted from the pulse-oximetry signal obtained during overnight polysomnography. METHODS: A cross-sectional design was used to study the relation between four hypoxemia variables and EDS as determined by Epworth Sleepiness Scale scores (ESSS) in 200 consecutive patients, newly diagnosed with obstructive sleep apnea (OSA), as defined by an apnea-hypopnea index (AHI)≥ 15. Hypoxemia measurements were compared between sleepy (ESSS ≥ 10) and nonsleepy (ESSS<10) patients before and after dichotomizing the cohort for each hypoxemia variable (and for AHI) such that there were 35 (165) patients in each of the corresponding higher (lower) subcohorts. The hypoxemia variables were combined into a biomarker, and its accuracy for predicting sleepiness in individual patients was evaluated. We planned to interpret prediction accuracy above 80 % as evidence that hypoxemia predicted EDS. RESULTS: Hypoxemia was unassociated with sleepiness in OSA patients with AHI in the range of 15 to 50. In patients with AHI>50, the hypoxemia biomarker (but not individual hypoxemia variables) predicted sleepiness with 82 % accuracy. CONCLUSION: Nocturnal hypoxemia as determined by a polyvariable biomarker reliably predicted EDS in patients with severe OSA (AHI>50), indicating that oxygen fluctuation had a direct role in the development of EDS in patients with severe OSA.
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Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Hipóxia/diagnóstico , Polissonografia , Apneia Obstrutiva do Sono/diagnóstico , Idoso , Estudos de Coortes , Colorado , Distúrbios do Sono por Sonolência Excessiva/epidemiologia , Feminino , Humanos , Hipóxia/epidemiologia , Masculino , Pessoa de Meia-Idade , Oximetria , Valor Preditivo dos Testes , Apneia Obstrutiva do Sono/epidemiologia , Estatística como AssuntoRESUMO
Background: Hospital admission due to breathlessness carries a significant burden to patients and healthcare systems, particularly impacting people in low-income countries. Prompt appropriate treatment is vital to improve outcomes, but this relies on accurate diagnostic tests which are of limited availability in resource-constrained settings. We will provide an accurate description of acute breathlessness presentations in a multicentre prospective cohort study in Malawi, a low resource setting in Southern Africa, and explore approaches to strengthen diagnostic capacity. Objectives: Primary objective: Delineate between causes of breathlessness among adults admitted to hospital in Malawi and report disease prevalence. Secondary objectives : Determine patient outcomes, including mortality and hospital readmission 90 days after admission; determine the diagnostic accuracy of biomarkers to differentiate between heart failure and respiratory infections (such as pneumonia) including brain natriuretic peptides, procalcitonin and C-reactive protein. Methods: This is a prospective longitudinal cohort study of adults (≥18 years) admitted to hospital with breathlessness across two hospitals: 1) Queen Elizabeth Central Hospital, Blantyre, Malawi; 2) Chiradzulu District Hospital, Chiradzulu, Malawi. Patients will be consecutively recruited within 24 hours of emergency presentation and followed-up until 90 days from hospital admission. We will conduct enhanced diagnostic tests with robust quality assurance and quality control to determine estimates of disease pathology. Diagnostic case definitions were selected following a systematic literature search. Discussion: This study will provide detailed epidemiological description of adult hospital admissions due to breathlessness in low-income settings, which is currently poorly understood. We will delineate between causes using established case definitions and conduct nested diagnostic evaluation. The results have the potential to facilitate development of interventions targeted to strengthen diagnostic capacity, enable prompt and appropriate treatment, and ultimately improve both patient care and outcomes.
BACKGROUND: People admitted to hospital with symptoms of breathlessness are often severely ill and need quick, accurate assessment to facilitate timely initiation of appropriate treatments. In low resource settings, such as Malawi, limited access to diagnostic equipment impedes patient assessment. Failure to identify and treat the underlying diagnosis may lead to preventable death. AIMS: This cohort study aims to delineate between common, treatable causes of breathlessness among adult patients admitted to hospital in Malawi and measure survival. We will also evaluate the performance of blood markers to diagnose and differentiate between conditions. The results will help us develop context-appropriate diagnostic and treatment algorithms based on resources available in the health system Methods in brief: We will recruit adult patients who present to hospital with breathlessness in a central national referral hospital (Queen Elizabeth Central Hospital, Blantyre), and a district hospital (Chiradzulu District Hospital, Chiradzulu). We will conduct enhanced diagnostic tests to determine causes of breathlessness against internationally accepted diagnostic guidelines. Patients will be followed up throughout their hospital admission and after discharge, until 90 days. INTERPRETATION: This study aligns with World Health Assembly resolutions on 'Strengthening diagnostics capacity' and on 'Integrated emergency, critical and operative care for universal health coverage and protection from health emergencies'. The results of this study will have the potential to facilitate development of interventions targeted to strengthen diagnostic capacity, enable prompt and appropriate treatment, and ultimately improve care and outcomes for acutely unwell patients.
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The application of immunotherapies such as chimeric antigen receptor (CAR) T therapy or bi-specific T cell engager (BiTE) therapy to manage myeloid malignancies has proven more challenging than for B-cell malignancies. This is attributed to a shortage of leukemia-specific cell-surface antigens that distinguish healthy from malignant myeloid populations, and the inability to manage myeloid depletion unlike B-cell aplasia. Therefore, the development of targeted therapeutics for myeloid malignancies, such as acute myeloid leukemia (AML), requires new approaches. Herein, we developed a ligand-based CAR and secreted bi-specific T cell engager (sBite) to target c-kit using its cognate ligand, stem cell factor (SCF). c-kit is highly expressed on AML blasts and correlates with resistance to chemotherapy and poor prognosis, making it an ideal candidate for which to develop targeted therapeutics. We utilize γδ T cells as a cytotoxic alternative to αß T cells and a transient transfection system as both a safety precaution and switch to remove alloreactive modified cells that may hinder successful transplant. Additionally, the use of γδ T cells permits its use as an allogeneic, off-the-shelf therapeutic. To this end, we show mSCF CAR- and hSCF sBite-modified γδ T cells are proficient in killing c-kit+ AML cell lines and sca-1+ murine bone marrow cells in vitro. In vivo, hSCF sBite-modified γδ T cells moderately extend survival of NSG mice engrafted with disseminated AML, but therapeutic efficacy is limited by lack of γδ T-cell homing to murine bone marrow. Together, these data demonstrate preclinical efficacy and support further investigation of SCF-based γδ T-cell therapeutics for the treatment of myeloid malignancies.
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Leucemia Mieloide Aguda , Camundongos , Animais , Ligantes , Receptores Proteína Tirosina Quinases , Proteínas Proto-Oncogênicas c-kit/genética , Imunoterapia Adotiva , Fator de Células-TroncoRESUMO
BACKGROUND AND AIM OF THE STUDY: Mitral regurgitation (MR) is frequently present in patients with calcific aortic stenosis (AS). Yet, the issue of whether to surgically correct the MR during aortic valve replacement (AVR) remains uncertain. The study aim was to define the outcome of MR after transcatheter aortic valve implantation (TAVI) in the TRanscatheter EndoVascular Implantation of VALves (REVIVAL) II trial. METHODS: Echocardiography was performed before and at 24 h, and three and six months after valve implantation. The degree of MR was evaluated by expert readers and by the vena contracta (VC) method. Significant MR was defined as at least mild to moderate MR. Those patients with a 30% reduction in VC were classified as good responders (GR group), and the remainder as poor responders (PR group). RESULTS: The study comprised 35 subjects with at least mild to moderate MR before TAVI. The mean VC of the whole group declined from 0.5 +/- 0.2 cm initially to 0.32 +/- 0.2 cm and 0.38 +/- 0.2 cm at 24 h and three months, respectively (p < 0.05). At three months, 12 patients had > 30% VC reduction; these constituted the GR group, while the remainder constituted the PR group. The percentage of patients with mitral annular calcification with restriction (MACr), defined as calcification encroaching onto the leaflets and restricting leaflet motion, was significantly lower in the GR group compared to the PR group (17% versus 61%, respectively; p < 0.05). The remaining pre-specified parameters did not differ significantly between the GR and PR groups, including age, gender, mitral valve tethering height and area (6 +/- 2 mm versus 5 +/- 3 mm and 10 +/- 4 mm2 versus 13 +/- 9 and 10 +/- 4 mm2, respectively), change in the aortic valve area (336 +/- 130% versus 285 +/- 180%), change in mean systolic aortic valve pressure (-20 +/- 8% versus - 23 +/- 10%), and left ventricular ejection fraction (47 +/- 15% versus 45 +/- 18%). CONCLUSION: MR is improved significantly after TAVI for AS. MACr was the only variable associated with a reduction in MR improvement. These results suggest that a careful echocardiographic evaluation of the mitral valve prior to TAVI may help to predict which patients should experience an improvement in their MR.
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Estenose da Valva Aórtica/terapia , Cateterismo Cardíaco , Implante de Prótese de Valva Cardíaca/métodos , Insuficiência da Valva Mitral/complicações , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/fisiopatologia , Cateterismo Cardíaco/instrumentação , Distribuição de Qui-Quadrado , Ecocardiografia Doppler em Cores , Ecocardiografia Transesofagiana , Feminino , Próteses Valvulares Cardíacas , Implante de Prótese de Valva Cardíaca/instrumentação , Humanos , Masculino , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/fisiopatologia , Desenho de Prótese , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
OBJECTIVE: We sought direct evidence that acute exposure to environmental-strength electromagnetic fields (EMFs) could induce somatic reactions (EMF hypersensitivity). METHODS: The subject, a female physician self-diagnosed with EMF hypersensitivity, was exposed to an average (over the head) 60-Hz electric field of 300 V/m (comparable with typical environmental-strength EMFs) during controlled provocation and behavioral studies. RESULTS: In a double-blinded EMF provocation procedure specifically designed to minimize unintentional sensory cues, the subject developed temporal pain, headache, muscle twitching, and skipped heartbeats within 100 s after initiation of EMF exposure (p < .05). The symptoms were caused primarily by field transitions (off-on, on-off) rather than the presence of the field, as assessed by comparing the frequency and severity of the effects of pulsed and continuous fields in relation to sham exposure. The subject had no conscious perception of the field as judged by her inability to report its presence more often than in the sham control. DISCUSSION: The subject demonstrated statistically reliable somatic reactions in response to exposure to subliminal EMFs under conditions that reasonably excluded a causative role for psychological processes. CONCLUSION: EMF hypersensitivity can occur as a bona fide environmentally inducible neurological syndrome.
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Campos Eletromagnéticos/efeitos adversos , Exposição Ambiental/efeitos adversos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/etiologia , Adulto , Telefone Celular , Computadores , Método Duplo-Cego , Feminino , Humanos , Doenças do Sistema Nervoso/fisiopatologia , Polissonografia/métodos , SíndromeRESUMO
The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
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Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Dilatada/mortalidade , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Hipertrófica/mortalidade , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Ventrículos do Coração/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Função Ventricular Esquerda/genéticaRESUMO
BACKGROUND: Major complications with respect to the development of gene therapy treatments for hemophilia A include low factor VIII (fVIII) expression and humoral immune responses resulting in inhibitory anti-fVIII antibodies. We previously achieved sustained curative fVIII activity levels in hemophilia A mice after nonmyeloablative transplantation of genetically-modified hematopoietic stem cells (HSCs) encoding a B-domain deleted porcine fVIII (BDDpfVIII) transgene with no evidence of an immune response. METHODS: Mouse HSCs were transduced using MSCV-based recombinant virus encoding BDDpfVIII and transplanted into hemophilia A mice. Transplanted mice were followed for donor cell engraftment, fVIII expression and activity, and generation of anti-fVIII immune response. RESULTS: We now show that: (i) the protein expressed by hematopoietic cells has a specific activity similar to that of purified protein; (ii) BDDpfVIII expressed from hematopoietic cells effectively induces thrombus formation, which is shown using a new method of in vivo analysis of fVIII function; (iii) naïve and pre-immunized mice receiving HSC gene therapy are nonresponsive to challenges with recombinant human fVIII; (iv) nonresponsiveness is not broken after stringent challenges with BDDpfVIII; and (v) T cells from these mice are unresponsive to BDDpfVIII presentation. Furthermore, stem cells isolated from donors with high titer anti-human fVIII antibodies show no defects in donor cell engraftment or the ability to express BDDpfVIII. CONCLUSIONS: These results demonstrate that HSC gene therapy can be an effective alternative treatment for individuals with hemophilia A and may benefit patients by inducing immunological nonresponsiveness to fVIII replacement products.
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Fator VIII/metabolismo , Terapia Genética/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Hemofilia A/terapia , Animais , Humanos , Ativação Linfocitária/imunologia , Camundongos , Linfócitos T/imunologiaRESUMO
Establishment of immunocompetent cell mediated anti-tumor immunity is often mitigated by the myelosuppressive effects during administration of chemotherapy. We hypothesized that protecting these immune cells from drug induced toxicities may allow for the combined administration of immunotherapy and chemotherapy. Using a SIV-based lentiviral gene transfer system we delivered the drug-resistant variant P140KMGMT into the immunocompetent cell lines NK-92 and TALL-104, and the myelogenous leukemia cell line, K562, which is a target for both NK-92 and TALL-104 cells. Genetically engineered immunocompetent cells developed significant resistance to temozolomide compared to non-modified cells, and genetic modification of these cells did not affect their ability to kill K562 cells. We then evaluated the effectiveness of drug-resistant immunocompetent cell mediated killing of tumor cells in the presence and absence of chemotherapy. During a chemotherapy challenge the cytotoxic activity of non-modified immunocompetent cells was dramatically impaired. However, when combined with chemotherapy, genetically-modified immune cells retained their cytotoxic activities and efficiently killed non-modified target cells. These results show that engineering immunocompetent cells to withstand chemotherapy challenges can enhance tumor cell killing when chemotherapy is applied in conjunction with cell-based immunotherapy.
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Citotoxicidade Imunológica , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Engenharia Genética , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Proteínas Supressoras de Tumor/genética , Animais , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/transplante , Camundongos , Neoplasias/tratamento farmacológico , Vírus da Imunodeficiência Símia/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/transplante , Temozolomida , Transdução GenéticaRESUMO
BACKGROUND: Ergot-derived dopamine agonists are associated with increased risk of valvular dysfunction in Parkinson's disease. The risk of valvular disease associated with lower doses of cabergoline used to treat prolactinomas remains controversial. OBJECTIVE: To determine whether there is an association of cabergoline and valvular function in patients with hyperprolactinaemia according to gender. DESIGN: Case-record retrospective study. SETTING: Outpatient neuroendocrine clinical centre at a tertiary care hospital. STUDY PARTICIPANTS: One hundred patients (48 men and 52 women) with hyperprolactinaemia who had an echocardiogram while receiving cabergoline for at least 6 months. CONTROLS: One hundred controls (48 men and 52 women) selected from Massachusetts general hospital (MGH) database of echocardiograms without clinically significant findings, matched to patients for age, gender, body mass index (BMI) and hypertension. MAIN OUTCOME MEASURE: Echocardiogram. RESULTS: There were no significant differences in valvular function in patients compared with controls. However, women patients had a higher prevalence of mild tricuspid regurgitation (TR) than female controls (15.4%vs. 1.9%, P = 0.03). Among men only, patients had more trace TR than controls (68.8%vs. 45.8%, P = 0.02). The mild valvular regurgitation in patients was not clinically significant and did not correlate with dose, duration or cumulative dose. CONCLUSIONS: Overall cabergoline was not associated with valvulopathy. However, subdivided by gender, hyperprolactinaemic men and women had higher prevalence of trace or mild TR, respectively, compared with gender matched controls. There may be gender differences in valvular dysfunction associated with cabergoline. Longer term, larger studies are necessary to evaluate definitively an effect of cabergoline on valvular function in hyperprolactinaemic patients.
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Ergolinas/uso terapêutico , Valvas Cardíacas/efeitos dos fármacos , Valvas Cardíacas/fisiopatologia , Hiperprolactinemia/tratamento farmacológico , Caracteres Sexuais , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cabergolina , Estudos de Casos e Controles , Ecocardiografia , Ergolinas/efeitos adversos , Ergolinas/farmacologia , Feminino , Valvas Cardíacas/diagnóstico por imagem , Antagonistas de Hormônios/efeitos adversos , Antagonistas de Hormônios/farmacologia , Antagonistas de Hormônios/uso terapêutico , Humanos , Hiperprolactinemia/diagnóstico por imagem , Hiperprolactinemia/etiologia , Hiperprolactinemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/fisiopatologia , Prolactina/antagonistas & inibidores , Prolactinoma/complicações , Prolactinoma/diagnóstico por imagem , Prolactinoma/tratamento farmacológico , Prolactinoma/fisiopatologia , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Rapid ventricular pacing (RP) during percutaneous balloon aortic valvuloplasty (BAV) facilitates balloon positioning by preventing the "watermelon seeding" effect during balloon inflation. The clinical consequences of RP BAV have never been compared with standard BAV in which rapid pacing in not used. We evaluated the immediate results and in-hospital adverse events of patients with severe aortic stenosis (AS) undergoing BAV with and without RP. METHODS: This is a retrospective study of patients with severe AS undergoing retrograde BAV. Patients who underwent BAV with RP were compared to those who did not receive RP during BAV. Procedural outcomes, complications, and in-hospital adverse events were compared between both groups. Stratified analyses were performed to evaluate RP in pre-specified subsets for confounding and effect modification. RESULTS: Between January 2005 and December 2008, 111 consecutive patients underwent retrograde BAV at Massachusetts General Hospital. Sixty-seven patients underwent BAV with RP. Nearly 90% of patients were NYHA class III or IV and the mean AVA was 0.64 cm(2). Baseline characteristics and balloon sizes were similar in the two groups. The average post-BAV AVA was smaller in the RP group compared to the no-RP group (0.87 v. 1.02 cm(2), p = 0.02). Pre and post-cardiac output, in-hospital mortality, myocardial infarction, stroke, frequency of cardiopulmonary arrest, vasopressor use, and major complications were similar in the two groups. CONCLUSIONS: 1) RP allows precise balloon placement during BAV. 2) RP BAV is associated with lower post-BAV AVA. 3) RP BAV may be safely performed in patients with high-risk cardiac features.
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Estenose da Valva Aórtica/terapia , Estimulação Cardíaca Artificial , Cateterismo , Idoso , Idoso de 80 Anos ou mais , Cateterismo Cardíaco , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIMS: It remains unclear whether cardiac resynchronization therapy (CRT) device implantation during inpatient (IP) hospitalization affords the same benefit as elective outpatient (OP) implantation. We hypothesized that IPs undergoing CRT device implantation during acute hospitalization may have worse outcomes compared with elective OP implantation. METHODS AND RESULTS: We retrospectively separated patients undergoing CRT implants at Massachusetts General Hospital into OP (n= 196) and IP (n = 105) cohorts. Long-term outcomes, measured as heart failure (HF) hospitalization, all-cause mortality, ventricular assist device placement, or heart transplant over a 2-year follow-up period, were estimated by the Kaplan-Meier method. Propensity scores were generated to balance the baseline co-morbidities between IP and OP. Baseline age, gender, left ventricular ejection fraction, and aetiology of cardiomyopathy were comparable between OP and IP (66.8 ± 11.8 vs. 67.5 ± 13.4 years, 78 vs. 84% males, 24 vs. 23%, and 39 vs. 50% ischaemic, P = NS). Inpatients had greater burden of diabetes mellitus (40 vs. 27%, P = 0.028), renal insufficiency (47 vs. 25%, P< 0.001), and right ventricular dysfunction (54 vs. 39%, P = 0.026) compared with OPs. At 2-year follow-up, IP implant was associated with greater risk of HF hospitalization (HR 1.6, 95% CI 1.03-2.48, P = 0.038) compared with elective OP implants. After propensity score adjustment, there was no statistically significant difference in HF hospitalization between the IP and OP groups (HR 1.031, 95% CI 0.61-1.78, P = 0.91). CONCLUSION: Compared with OP CRT implants, IPs are at increased risk for recurrent HF hospitalization; however, the increased risk is attributable to greater co-morbidities in the IP population.
Assuntos
Dispositivos de Terapia de Ressincronização Cardíaca , Terapia de Ressincronização Cardíaca/métodos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Pacientes Internados , Pacientes Ambulatoriais , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Both anatomic interlead separation and left ventricle lead electrical delay (LVLED) have been associated with outcomes following cardiac resynchronization therapy (CRT). However, the relationship between interlead distance and electrical delay in predicting CRT outcomes has not been defined. METHODS: We studied 61 consecutive patients undergoing CRT for standard clinical indications. All patients underwent intraprocedural measurement of LVLED. Interlead distances in the horizontal (HD), vertical (VD), and direct (DD) dimensions were measured from postprocedure chest radiographs (CXR). Remodeling indices [percent change in left ventricle (LV) ejection fraction, end-diastolic, end-systolic dimensions] were assessed by transthoracic echocardiogram. RESULTS: There was a positive correlation between corrected LVLED and HD on lateral CXR (r = 0.361, P = 0.004) and a negative correlation between LVLED and VD on posteroanterior (PA) CXR (r =-0.281, P = 0.028). To account for this inverse relationship, we developed a composite anatomic distance (defined as: lateral HD-PA VD), which correlated most closely with LVLED (r = 0.404, P = 0.001). Follow-up was available for 48 patients. At a mean of 4.1 +/- 3.2 months, patients with optimal values for both corrected LVLED (>or=75%) and composite anatomic distance (>or=15 cm) demonstrated greater reverse LV remodeling than patients with either one or neither of these optimized values. CONCLUSIONS: We identified a significant correlation between LV-right ventricular interlead distance and LVLED; additionally, both parameters act synergistically in predicting LV anatomic reverse remodeling. Efforts to optimize both interlead distance and electrical delay may improve CRT outcomes.
Assuntos
Insuficiência Cardíaca/terapia , Ventrículos do Coração/fisiopatologia , Remodelação Ventricular/fisiologia , Idoso , Idoso de 80 Anos ou mais , Estimulação Cardíaca Artificial/métodos , Eletrodos Implantados , Feminino , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Marca-Passo Artificial , Estudos Prospectivos , Volume Sistólico/fisiologia , Resultado do Tratamento , UltrassonografiaRESUMO
Human coagulation factor VIII (fVIII) is inefficiently biosynthesized in vitro and has proven difficult to express at therapeutic levels using available clinical gene-transfer technologies. Recently, we showed that a porcine and certain hybrid human/porcine fVIII transgenes demonstrate up to 100-fold greater expression than human fVIII. In this study, we extend these results to describe the use of a humanized, high-expression, hybrid human/porcine fVIII transgene that is 89% identical to human fVIII and was delivered by lentiviral vectors (LVs) to hematopoietic stem cells for gene therapy of hemophilia A. Recombinant human immunodeficiency virus-based vectors encoding the fVIII chimera efficiently transduced human embryonic kidney (HEK)-293T cells. Cells transduced with hybrid human/porcine fVIII encoding vectors expressed fVIII at levels 6- to 100-fold greater than cells transduced with vectors encoding human fVIII. Transplantation of transduced hematopoietic stem and progenitor cells into hemophilia A mice resulted in long-term fVIII expression at therapeutic levels despite <5% genetically modified blood mononuclear cells. Furthermore, the simian immunodeficiency virus (SIV) -derived vector effectively transduced the human hematopoietic cell lines K562, EU1, U.937, and Jurkat as well as the nonhematopoietic cell lines, HEK-293T and HeLa. All cell lines expressed hybrid human/porcine fVIII, albeit at varying levels with the K562 cells expressing the highest level of the hematopoietic cell lines. From these studies, we conclude that humanized high-expression hybrid fVIII transgenes can be utilized in gene therapy applications for hemophilia A to significantly increase fVIII expression levels compared to what has been previously achieved.
Assuntos
Terapia Genética/métodos , Hemofilia A/terapia , Transgenes/genética , Animais , Linhagem Celular , Modelos Animais de Doenças , Fator VIII/genética , Vetores Genéticos/genética , Humanos , Lentivirus/genética , Camundongos , SuínosRESUMO
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant-negative fashion. However loss-of-function (haploinsufficiency) is the most common disease mechanism for pathogenic variants in MYBPC3, suggesting that MYBPC3 complete deletion may play a role in HCM pathogenesis. Here, we investigate MYBPC3 complete deletion as a disease mechanism in HCM by analyzing two unrelated patients with confirmed diagnosis of HCM that tested negative by Sanger sequencing analysis. METHODS: MYBPC3 complete deletion was investigated by Multiplex ligation-dependent probe amplification (MLPA) and microarray analyses. The mechanism of deletion was investigated by interrogating the SINEBase database. RESULTS: Patient-1 was diagnosed with nonobstructive HCM in his mid-40s while undergoing assessment for palpitations, and patient-2 with obstructive HCM in his late-20s while undergoing systolic heart murmur assessment for an unrelated illness. MLPA testing revealed a heterozygous deletion of all MYBPC3 exons in both patients. Subsequent microarray testing confirmed these deletions which extended beyond the 5' and 3' ends of MYBPC3. Genomic assessment suggested that these deletions resulted from Alu/Alu-homologous recombination. CONCLUSION: Our results demonstrate that haploinsufficiency resulting from MYBPC3 complete deletion, potentially mediated by Alu recombination, is an important disease mechanism in cardiomyopathy and emphasizes the importance of copy number variation analysis in patients clinically suspected of HCM.
Assuntos
Elementos Alu , Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Cardiomiopatia Hipertrófica/patologia , Deleção de Genes , Recombinação Homóloga , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The dynamical complexity of brain electrical activity manifested in the EEG is quantifiable using recurrence analysis (RA). Employing RA, we described and validated an originative method for automatically classifying epochs of sleep that is conceptually and instrumentally distinct from the existing method. NEW METHOD: Complexity in single overnight EEGs was characterized second-by-second using four RA variables that were each averaged over consecutive 30-sec epochs to form four-component vectors. The vectors were staged using four-component cluster analysis. Method validity and utility were established by showing: (1) inter- and intra-subject consistency of staging results (method insusceptible to nonstationarity of the EEG); (2) use of method to eliminate costly and arduous visual staging in a binary classifications task for detecting a neurogenic disorder; (3) ability of method to provide new physiological insights into brain activity during sleep. RESULTS: RA of sleep-acquired EEGs yielded four continuous measures of complexity and its change-rate that allowed automatic classification of epochs into four statistically distinct clusters ("stages"). Matched subjects with and without mental distress were accurately classified using biomarkers based on stage designations. COMPARISON WITH EXISTING METHODS: For binary-classification purposes, the method was cheaper, faster, and at least as accurate as the existing staging method. Epoch-by-epoch comparison of new versus existing methods revealed that the latter assigned epochs having widely different dynamical complexities into the same stage (dynamical incoherence). CONCLUSIONS: Sleep can be automatically staged using an originative method that is fundamentally different from the existing method.