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Introdução. Frequência cardíaca (FC) elevada é reconhecida como um fator prognóstico de maior mortalidade na insuficiência cardíaca aguda descompensada (ICAD). Entretanto, pouco se conhece sobre os efeitos da redução da FC na evolução de pacientes com ICAD em ritmo sinusal, não havendo estudo clínico desenhado especificamente para o esclarecimento desta questão até o momento. Objetivos. Avaliar a eficácia e segurança da redução da FC através da inibição da corrente I(f) atrial em pacientes hospitalizados com ICAD em ritmo sinusal. Avaliar os efeitos de curto prazo da redução da FC nos parâmetros hemodinâmicos e de função ventricular por ecocardiografia e sobre os biomarcadores séricos de IC. Métodos. Estudo clínico randomizado, duplo-cego, controlado com placebo, unicêntrico. Os critérios de inclusão foram admissão por ICAD, fração de ejeção do ventrículo esquerdo (FEVE) < 40%, FC >80 bpm, INTERMACS >= 3 e ritmo sinusal. Os participantes do estudo (n=46, 48% feminino, idade média de 48±15 anos) receberam tratamento da ICAD orientado por diretriz e 5 mg de ivabradina (N = 23) ou placebo (N = 23) de 12/12 horas por 1 mês. Os desfechos estudados foram a variação em relação ao basal, aferida no quinto dia de intervenção, das seguintes variáveis: FC, pressão arterial sistêmica; volume sistólico (VS), índice cardíaco (Icar), FEVE, strain longitudinal global do VE (SLG-VE), índice de performance do miocárdio (IPM), relação E/A, tempo de desaceleração da onda E (TD onda E), relação E/e´, excursão sistólica máxima do anel tricúspide lateral (TAPSE), velocidade sistólica máxima do anel tricúspide lateral (s´), variação fracional da área do ventrículo direito (VFA), strain longitudinal global do ventrículo direito (SLG-VD), peptídeo natriurético tipo B (BNP), troponina, proteína C reativa (PCR), creatinina e NGAL (neutrophil gelatinase-associated lipocalin). Os pacientes foram acompanhados durante a internação e após a alta até o sexto mês, ou até a ocorrência de um evento cardiovascular pré-especificado. Resultados. A ivabradina reduziu significativamente a FC em comparação com o placebo (-14 ± 5 vs 0,2 ± 6 bpm, p < 0,001). A redução da FC acompanhou-se de melhora na FEVE (5,5 ± 15 vs -3,0 ± 11%, p = 0,03), no VS do VE (5,8 ± 11 vs -1,8 ± 10 mL, p = 0,02), no SLG-VD (2,0± 2,2 versus 0,3 ± 3,1%, p = 0,007), no TAPSE (1,6 ± 2,4 vs. -0,2 ± 1,7 mm, p = 0,004), na VFA (5,1 ± 7,8 vs -1,4 ± 4,5%, p = 0,001) e na s´ (0,5 ± 1,3 vs. -0.4 ± 1,0 cm/s, p = 0,009). Não houve diferença na pressão arterial sistêmica, Icar, IPM, TD onda E, BNP, troponina, PCR, NGAL e creatinina. Dos 46 pacientes, 24 (52%) apresentaram eventos adversos durante o acompanhamento, com 6 óbitos e 3 transplantes no grupo placebo e 5 óbitos e 2 transplantes no grupo tratado com ivabradina. A FC no quinto dia da intervenção foi um forte preditor de eventos de acordo com o modelo de risco proporcional de Cox (HR 1,08 [IC95% 1,03-1,12], p < 0.001), mesmo quando corrigida pela idade, tempo de diagnóstico de IC e gênero. Conclusão. Os dados sugerem que a inibição da I(f) reduz de forma segura a FC em pacientes admitidos por ICAD em ritmo sinusal, com benefício para a função cardíaca global. Nosso estudo sugere que a FC elevada pode ser considerada um potencial alvo terapêutico em pacientes com ICAD em ritmo sinusal, sendo necessário um estudo multicêntrico sobre o tema / Introduction. Elevated heart rate (HR) is a known prognostic factor of higher mortality in acute decompensated heart failure (ADHF). However, little is known about the effects of HR reduction on the progression of patients with ADHF in sinus rhythm, and there was no clinical study specifically designed to clarify this issue to date. Aims. To evaluate the efficacy and safety of HR reduction through inhibition of the atrial I(f) current in patients hospitalized with ADHF in sinus rhythm. To evaluate the short-term effects of HR reduction on hemodynamic and ventricular function parameters by echocardiography and on serum biomarkers of HF. Methods. Randomized, double-blind, placebo-controlled, single-center clinical trial. Inclusion criteria were ADHF, left ventricle ejection fraction (LVEF) <40%, HR >80 bpm, INTERMACS >= 3 and sinus rhythm. Participants in the study (n = 46, 48% female, mean age 48 ± 15 years) received guideline-guided treatment for ADHF and 5 mg ivabradine (N = 23) or placebo (N = 23) 12/12 hours for 1 month. Outcomes were change from baseline measured on the fifth day of intervention for the following variables: HR, systemic arterial pressure, LV stroke volume (LVSV), cardiac index (CI), LVEF, LV global longitudinal strain (LV-GLS), myocardial performance index (MPI), E/A, E wave deceleration time (E wave DT), E/e\' ratio, tricuspid annular plane systolic excursion (TAPSE), tricuspid annular plane peak-systolic velocity (s´), right ventricle (RV) fractional area change (FAC), RV global longitudinal strain (RV-GLS), B-type natriuretic peptide (BNP), troponin, reactive C protein (RCP), creatinine, and neutrophil gelatinase-associated lipocalin (NGAL). Patients were followed up during hospitalization and after discharge until the sixth month, or until the occurrence of a pre-specified cardiovascular event. Results. Ivabradine significantly reduced HR compared with placebo (-14 ± 5 vs 0.2 ± 6 bpm, p < 0.001). The HR reduction was accompanied by improvement in LVEF (5.5 ± 15 vs -3.0 ± 11%, p = 0.03), LVSV (5.8 ± 11 vs -1.8 ± 10 mL, p = 0.02), RV-GLS (2.0 ± 2.2 versus 0.3 ± 3.1%, p = 0.007), TAPSE (1.6 ± 2.4 vs. -0.2 ± 1,7 mm, p = 0.004), FAC (5.1 ± 7.8 vs -1.4 ± 4.5%, p = 0.001) and s´ (0.5 ± 1.3 vs. -0.4 ± 1.0 cm / s, p = 0.009). There was no difference in systemic arterial pressure, CI, MPI, E wave TD, BNP, troponin, RCP, NGAL and creatinine. Of the 46 patients, 24 (52%) presented events during follow-up, with 6 deaths and 3 transplants in placebo group and 5 deaths and 2 transplants in ivabradine group. HR on the fifth day of the intervention was a strong event predictor according to Cox proportional hazards model (HR 1.08 [95% CI 1.03-1.12], even when corrected for age, time from diagnosis of HF and gender. Conclusion. The data suggest that I(f) inhibition safely reduces HR in patients admitted with ADHF in sinus rhythm, with benefit to global cardiac function. Our study suggests that elevated HR may be considered a potential therapeutic target in patients with ADHF in sinus rhythm, requiring a multicenter study on the subject

Introdução. Frequência cardíaca (FC) elevada é reconhecida como um fator prognóstico de maior mortalidade na insuficiência cardíaca aguda descompensada (ICAD). Entretanto, pouco se conhece sobre os efeitos da redução da FC na evolução de pacientes com ICAD em ritmo sinusal, não havendo estudo clínico desenhado especificamente para o esclarecimento desta questão até o momento. Objetivos. Avaliar a eficácia e segurança da redução da FC através da inibição da corrente I(f) atrial em pacientes hospitalizados com ICAD em ritmo sinusal. Avaliar os efeitos de curto prazo da redução da FC nos parâmetros hemodinâmicos e de função ventricular por ecocardiografia e sobre os biomarcadores séricos de IC. Métodos. Estudo clínico randomizado, duplo-cego, controlado com placebo, unicêntrico. Os critérios de inclusão foram admissão por ICAD, fração de ejeção do ventrículo esquerdo (FEVE) < 40%, FC >80 bpm, INTERMACS >= 3 e ritmo sinusal. Os participantes do estudo (n=46, 48% feminino, idade média de 48±15 anos) receberam tratamento da ICAD orientado por diretriz e 5 mg de ivabradina (N = 23) ou placebo (N = 23) de 12/12 horas por 1 mês. Os desfechos estudados foram a variação em relação ao basal, aferida no quinto dia de intervenção, das seguintes variáveis: FC, pressão arterial sistêmica; volume sistólico (VS), índice cardíaco (Icar), FEVE, strain longitudinal global do VE (SLG-VE), índice de performance do miocárdio (IPM), relação E/A, tempo de desaceleração da onda E (TD onda E), relação E/e´, excursão sistólica máxima do anel tricúspide lateral (TAPSE), velocidade sistólica máxima do anel tricúspide lateral (s´), variação fracional da área do ventrículo direito (VFA), strain longitudinal global do ventrículo direito (SLG-VD), peptídeo natriurético tipo B (BNP), troponina, proteína C reativa (PCR), creatinina e NGAL (neutrophil gelatinase-associated lipocalin). Os pacientes foram acompanhados durante a internação e após a alta até o sexto mês, ou até a ocorrência de um evento cardiovascular pré-especificado. Resultados. A ivabradina reduziu significativamente a FC em comparação com o placebo (-14 ± 5 vs 0,2 ± 6 bpm, p < 0,001). A redução da FC acompanhou-se de melhora na FEVE (5,5 ± 15 vs -3,0 ± 11%, p = 0,03), no VS do VE (5,8 ± 11 vs -1,8 ± 10 mL, p = 0,02), no SLG-VD (2,0± 2,2 versus 0,3 ± 3,1%, p = 0,007), no TAPSE (1,6 ± 2,4 vs. -0,2 ± 1,7 mm, p = 0,004), na VFA (5,1 ± 7,8 vs -1,4 ± 4,5%, p = 0,001) e na s´ (0,5 ± 1,3 vs. -0.4 ± 1,0 cm/s, p = 0,009). Não houve diferença na pressão arterial sistêmica, Icar, IPM, TD onda E, BNP, troponina, PCR, NGAL e creatinina. Dos 46 pacientes, 24 (52%) apresentaram eventos adversos durante o acompanhamento, com 6 óbitos e 3 transplantes no grupo placebo e 5 óbitos e 2 transplantes no grupo tratado com ivabradina. A FC no quinto dia da intervenção foi um forte preditor de eventos de acordo com o modelo de risco proporcional de Cox (HR 1,08 [IC95% 1,03-1,12], p < 0.001), mesmo quando corrigida pela idade, tempo de diagnóstico de IC e gênero. Conclusão. Os dados sugerem que a inibição da I(f) reduz de forma segura a FC em pacientes admitidos por ICAD em ritmo sinusal, com benefício para a função cardíaca global. Nosso estudo sugere que a FC elevada pode ser considerada um potencial alvo terapêutico em pacientes com ICAD em ritmo sinusal, sendo necessário um estudo multicêntrico sobre o tema / Introduction. Elevated heart rate (HR) is a known prognostic factor of higher mortality in acute decompensated heart failure (ADHF). However, little is known about the effects of HR reduction on the progression of patients with ADHF in sinus rhythm, and there was no clinical study specifically designed to clarify this issue to date. Aims. To evaluate the efficacy and safety of HR reduction through inhibition of the atrial I(f) current in patients hospitalized with ADHF in sinus rhythm. To evaluate the short-term effects of HR reduction on hemodynamic and ventricular function parameters by echocardiography and on serum biomarkers of HF. Methods. Randomized, double-blind, placebo-controlled, single-center clinical trial. Inclusion criteria were ADHF, left ventricle ejection fraction (LVEF) <40%, HR >80 bpm, INTERMACS >= 3 and sinus rhythm. Participants in the study (n = 46, 48% female, mean age 48 ± 15 years) received guideline-guided treatment for ADHF and 5 mg ivabradine (N = 23) or placebo (N = 23) 12/12 hours for 1 month. Outcomes were change from baseline measured on the fifth day of intervention for the following variables: HR, systemic arterial pressure, LV stroke volume (LVSV), cardiac index (CI), LVEF, LV global longitudinal strain (LV-GLS), myocardial performance index (MPI), E/A, E wave deceleration time (E wave DT), E/e\' ratio, tricuspid annular plane systolic excursion (TAPSE), tricuspid annular plane peak-systolic velocity (s´), right ventricle (RV) fractional area change (FAC), RV global longitudinal strain (RV-GLS), B-type natriuretic peptide (BNP), troponin, reactive C protein (RCP), creatinine, and neutrophil gelatinase-associated lipocalin (NGAL). Patients were followed up during hospitalization and after discharge until the sixth month, or until the occurrence of a pre-specified cardiovascular event. Results. Ivabradine significantly reduced HR compared with placebo (-14 ± 5 vs 0.2 ± 6 bpm, p < 0.001). The HR reduction was accompanied by improvement in LVEF (5.5 ± 15 vs -3.0 ± 11%, p = 0.03), LVSV (5.8 ± 11 vs -1.8 ± 10 mL, p = 0.02), RV-GLS (2.0 ± 2.2 versus 0.3 ± 3.1%, p = 0.007), TAPSE (1.6 ± 2.4 vs. -0.2 ± 1,7 mm, p = 0.004), FAC (5.1 ± 7.8 vs -1.4 ± 4.5%, p = 0.001) and s´ (0.5 ± 1.3 vs. -0.4 ± 1.0 cm / s, p = 0.009). There was no difference in systemic arterial pressure, CI, MPI, E wave TD, BNP, troponin, RCP, NGAL and creatinine. Of the 46 patients, 24 (52%) presented events during follow-up, with 6 deaths and 3 transplants in placebo group and 5 deaths and 2 transplants in ivabradine group. HR on the fifth day of the intervention was a strong event predictor according to Cox proportional hazards model (HR 1.08 [95% CI 1.03-1.12], even when corrected for age, time from diagnosis of HF and gender. Conclusion. The data suggest that I(f) inhibition safely reduces HR in patients admitted with ADHF in sinus rhythm, with benefit to global cardiac function. Our study suggests that elevated HR may be considered a potential therapeutic target in patients with ADHF in sinus rhythm, requiring a multicenter study on the subject

This thesis is a socio-cultural study of the development of female stand-up comedy in the first decade of the twenty-first century within a multi-racial and multi-cultural Britain. It also engages with the theory and practice of performance and asks the question: ‘In what ways can it be said that female stand-up comics perform the comic side of bodily abjection?’ This question is applied to three groups of female case-studies which include: those who came into stand-up comedy in the 1980s; second-generation transnationals who became established at the end of the twentieth century; and twenty-first century newcomers to stand-up comedy. This third group also includes the author of this thesis who uses her own embodied experience as research, and Lynne Parker whose Funny Women organization was set up in 2002 to facilitate female entry into stand-up comedy. Alongside these three groups the subject of females as audience of female stand-up comedy is also explored. The issue of bodily abjection is explored in relation to seminal works on abjection by Julia Kristeva (1982) and Mary Douglas (1966) and regarding theories of the grotesque as posited by Mikhail Bakhtin (1984) and Mary Russo (1995). These texts are used in this thesis to argue that abjection is a significant aspect of both the context and content of contemporary female stand-up comedy and that the orifices, surfaces and processes of the body are still pertinent to twenty-first century female stand-up comedy.

Modulation of cardiac rate and contraction through calcium-dependent and independent means are of central import to the ability of an organism to adapt to its environment. Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent calcium-releasing second messenger across a broad range of tissues and organisms. In cardiac myocytes, NAADP is thought to stimulate calcium release from acidic stores which then bolsters filling and release during CICR. Questions remain: as to the potential need for amplification to generate the size of responses observed and the physiological role of the NAADP pathway. In contractile myocytes, photorelease of NAADP caused significant increase in calcium transient amplitude and velocity of transient upstroke and decay. Effects were absent during NAADP photorelease in the presence of Ned-19 or CaMKII inhibitors. Cellular calcium transient responses to &beta;-adrenergic stimulation were significantly reduced in the presence of inhibitors of the NAADP pathway. These data support the hypothesis that NAADP-induced calcium release is relevant during adrenergic stimulation and requires amplification through CaMKII. Rate modulation at the sino-atrial node can occur through the hyperpolarisation-activated current I_(f). Basal cardiac rate is a major determinant in cardiac mortality and compounds which specifically affect rate have clinical utility. A compound currently used to treat inflammatory conditions was found to have a significant rate-reducing effect in sino-atrial node preparations mediated by inhibition of I_(f). Apelin, an endogenous peptide, has been reported to potently generate improved contractility without development of hypertrophy. Study of its effects in single cells have provided conflicting information, at least in part because of the difficulty in working with the compound. A method for the consistent observation of apelin-mediated contractile responses is presented, focusing on the timecourse of cell contraction. These observations suggest a role for apelin in both inotropy and lusitropy and will enable further research.

The goal of this essay is to pursue a reading of ethnicity and sexuality in Shyam Selvadurai’s novel Funny Boy to show the importance of the interrelations between the two and how equally crucial both of these are in order to understand the protagonist Arjie’s journey and search for identity. To investigate the interrelation between ethnicity and sexuality, the analysis makes use of a method of simultaneous consideration that is similar to Mae Gwendolyn Henderson’s focus on “simultaneity of discourse” used by black women writers. The turning points in the protagonist’s life and search for an identity are crucial and influenced by issues of separation, and the theme of exile is prominent in the novel. Selvadurai uses the theme in several aspects on a number of levels, concerning both ethnicity and sexuality. However, the narrative also allows the protagonist to find an alternative route in exploring his identity as a “funny one”. These turning points are illustrated by a moving beyond the traditional gender roles and the idea of masculinity in areas of gendered and racialised spaces. Selvadurai shows a people that are ethnically and/or sexually divided while at the same time being linked through words and languages that can give and/or take away possibilities. Hence, a second aim of this essay is to show that the protagonist overcomes the limitations that society has set by choosing the path that is right for him, a path that allows him to be “funny”.

<p>The goal of this essay is to pursue a reading of ethnicity and sexuality in Shyam Selvadurai’s novel Funny Boy to show the importance of the interrelations between the two and how equally crucial both of these are in order to understand the protagonist Arjie’s journey and search for identity. To investigate the interrelation between ethnicity and sexuality, the analysis makes use of a method of simultaneous consideration that is similar to Mae Gwendolyn Henderson’s focus on “simultaneity of discourse” used by black women writers.</p><p>The turning points in the protagonist’s life and search for an identity are crucial and influenced by issues of separation, and the theme of exile is prominent in the novel. Selvadurai uses the theme in several aspects on a number of levels, concerning both ethnicity and sexuality. However, the narrative also allows the protagonist to find an alternative route in exploring his identity as a “funny one”.</p><p>These turning points are illustrated by a moving beyond the traditional gender roles and the idea of masculinity in areas of gendered and racialised spaces. Selvadurai shows a people that are ethnically and/or sexually divided while at the same time being linked through words and languages that can give and/or take away possibilities.</p><p>Hence, a second aim of this essay is to show that the protagonist overcomes the limitations that society has set by choosing the path that is right for him, a path that allows him to be “funny”.</p>

No description available.