Glutamate excitotoxicity is the predominant mechanism implicated in neuronal cell death associated with neurological disorders such as stroke, epilepsy, traumatic brain injury and ALS. Excessive stimulation of NMDA subtypes of glutamate receptors leads to protracted intracellular calcium elevations triggering calcium mediated neurotoxic mechanisms culminating in delayed neuronal cell death. In addition, glutamate excitotoxicity induces a NMDA dependent extended neuronal depolarization mediated by continuous calcium influx that correlates with delayed neuronal death. Attempts to prevent neuronal death by blocking calcium entry into the neurons using calcium channel blockers or NMDA receptor antagonists have failed to provide any beneficial effects in clinical trials. Thus, calcium continues to enter the neurons despite the presence of calcium entry blockers. This phenomenon is known as the "calcium paradox of stroke" and represents a major problem in developing effective therapies for treatment of stroke. Here employing a combination of patch clamp recordings, fluorescent calcium imaging and neuronal cell death assays in well-characterized in vivo and in vitro models of glutamate excitotoxicity, we report the discovery of a novel calcium permeable ion channel that is activated by excitotoxic glutamate injury and mediates a calcium current that is an early initiating step in causing neuronal death. Blocking this calcium permeable channel with high concentrations of Zn2+ or Gd3+ by removing extracellular calcium for a significant time period after the initial injury is effective in preventing calcium entry, apoptosis and neuronal death, thus accounting for the calcium paradox. This injury induced-calcium permeable channel provides a unique mechanism for calcium entry following stroke and offers a new target for extending the therapeutic window for preventing neuronal death after the initial excitotoxic (stroke) injury.

Objetivo: este estudo teve como objetivo avaliar as infecções por papilomavírus humano (HPV) e Chlamydia trachomatis (CT) em pacientes com artrite reumatoide (AR) pré e pós-terapia anti-TNF. Método: foram avaliadas 50 pacientes do sexo feminino com AR (preenchiam os critérios do Colégio Americano de Reumatologia) que eram elegíveis para terapia anti-TNF. Cinquenta pacientes foram incluídas no estudo de forma prospectiva. Destas, 45 pacientes foram reavaliadas após 6 meses de terapia anti-TNF. Inicialmente as 50 pacientes com AR foram comparadas com 50 controles saudáveis pareadas por idade. Foram avaliados dados demográficos, avaliação ginecológica (citologia cervical e avaliações histológicas), função sexual, parâmetros de doença e tratamento atual da AR. Os testes para detecções dos DNAs do HPV e CT nas espécimes cervicais foram realizados utilizando a captura híbrida II. Resultados: na avaliação inicial, a mediana da idade das pacientes com AR e controles foi de 49 (18-74) vs. 49 (18-74) anos, p = 1,0. Observou-se uma tendência de menor frequência de infecção por HPV nas pacientes com AR pré anti-TNF em relação aos controles (14% vs. 30%, p = 0,054). Adicionalmente, realizou-se avaliação das pacientes com AR com infecção positiva e negativa por HPV antes da terapia anti-TNF que demonstrou que o primeiro grupo apresentou maior frequência de relações sexuais (100% vs. 48%, p = 0,014), maior número de parceiros sexuais [1 (1-1) vs. 0 (0-1), p = 0,032] e maior frequência de citologia cervical anormal (43% vs. 7%, p = 0,029). A idade atual, a duração da doença, os parâmetros da doença e os tratamentos foram semelhantes em ambos os grupos (p > 0,05). Após 6 meses de terapia anti-TNF, a infecção por HPV permaneceu inalterada em cinco pacientes, enquanto que dois tornaram-se negativos e uma paciente adicional tornou-se positiva (p = 1,0). A infecção por CT foi uniformemente negativa nas pacientes com AR pré e pós-TNF, assim como nas controles. Conclusões: a infecção por HPV observada nas pacientes sexualmente ativas com AR antes da terapia anti-TNF foi leve, sem evidência de infecção por CT. A terapia anti-TNF não aumentou o risco de exacerbação e/ou progressão das infecções por HPV e CT em pacientes com AR / Objective: to evaluate human papillomavirus (HPV) and Chlamydia trachomatis (CT) infections in rheumatoid arthritis (RA) patients pre- and post-TNF blocker. Methods: fifty female RA patients (American College of Rheumatology criteria), who were eligible to anti-TNF therapy, [n = 50 at baseline (BL) and n = 45 after 6 months of treatment (6M)] and 50 agematched healthy controls were prospectively enrolled. They were assessed for demographic data, gynecologic, sexual, cervical cytology and histological evaluations, disease parameters and current treatment. HPV DNA and CT DNA testing in cervical specimens were done using Hybrid Capture II assays. Results: at BL, the median current age of RA patients and controls was 49(18-74) vs. 49(18-74) years, p = 1.0. A trend of lower frequency of HPV infection was observed in AR patients pre anti-TNF compared to controls (14% vs. 30%, p = 0.054). Further evaluation of AR patients with and without HPV infection before anti-TNF therapy showed that the former group had higher frequency of sexual intercourses (100% vs. 48%, p = 0.014), higher median number of sexual partners [1(1-1) vs. 0(0-1), p=0.032] and higher frequency of abnormal cervical cytology (43% vs. 7%, p = 0.029). Current age, disease duration, disease parameters and treatments were alike in both groups (p > 0.05). At 6M after TNF blockage, HPV infection remained unchanged in five patients, whereas two became negative and one additional patient turn out to be positive (p = 1.0). CT infection was uniformly negative in RA patients pre- and post-TNF blockage and in controls. Conclusions: anti-TNF does not seem to increase short-term risk of exacerbation and/or progression of HPV and CT infections in RA patients

Os anti-hipertensivos bloqueadores de canais de cálcio, por interferirem no transporte de cálcio através das membranas celulares, podem afetar muitos processos metabólicos, incluindo o metabolismo ósseo. O objetivo deste estudo foi avaliar, de forma radiográfica, histológica e bioquímica, os efeitos do bloqueador de canais de cálcio amlodipina no processo de reparo de um defeito ósseo, simulando fratura, no ramo mandibular de ratos. Foram utilizados 50 ratos machos Wistar, que foram submetidos ao mesmo procedimento cirúrgico unilateral simulando fratura mandibular, e distribuídos em dois grupos de 25 animais: grupo experimental, que receberam amlodipina, via oral, na dosagem de 0,04 mg / rato / dia, iniciando 12 dias antes do procedimento e continuando até o sacrifício; grupo controle, que permaneceu não tratado. Os animais foram sacrificados nos períodos de 1, 7, 14, 30 e 90 dias pós-operatórios. Foram realizados testes bioquímicos de fosfatase alcalina e cálcio séricos. Exame radiográfico foi obtido para mensuração da área radiolúcida do defeito ósseo. O estudo histológico compreendeu a análise descritiva do processo de reparo ósseo e a avaliação histomorfométrica da quantidade de osso neoformado. Os valores numéricos foram submetidos a análises estatísticas. A análise radiográfica demonstrou maior área radiolúcida no interior do defeito ósseo para o grupo experimental, nos períodos de 14 (p=0,016), 30 (p=0,009) e 90 (p=0,028) dias. Na análise histológica não se observaram atrasos no processo de reparo ósseo para ambos os grupos. Porém, na análise histomorfométrica, o grupo da amlodipina apresentou redução significante do volume de osso neoformado nos períodos de 7 e 14 dias (p=0,049), não havendo diferenças significativas no período de 30 dias. Houve redução significante nos níveis de fosfatase alcalina para o grupo da amlodipina nos períodos iniciais (p=0,049). Não houve alterações para os níveis de cálcio sérico. Concluiu-se que o uso crônico da amlodipina prejudicou a neoformação óssea no processo de reparo do defeito cirúrgico no ramo mandibular de ratos, porém não impediu a consolidação da fratura. / Antihypertensive, calcium channel blockers, which interfere on calcium transport across the cell membrane, may affect many metabolic processes, including bone metabolism. The aim of this study was to evaluate by radiographic, histologic and biochemical analyses the effects of calcium channel blocker amlodipine on bone healing of a defect simulating a fracture in mandibular ramus of rats. Fifty male Wistar rats were used, and submitted to the same unilateral surgical procedure simulating a mandibular fracture, distributed into two groups of 25 animals: experimental group, which received oral doses of 0.04 mg / rat / day starting 12 days before of procedure and continuing until sacrifice; control group, which remained untreated. Animals were sacrificed at 1, 7, 14, 30 and 90 days postoperatively. Blood biochemical tests of alkaline phosphatase and serum calcium were made. Radiographic examination was obtained in order to mensurate the radiolucent area of bone defect. Histological study comprised descriptive analysis of bone healing and histomorphometric analysis of the amount of newly formed bone. Numerical values were submitted to statistical analyses. Radiographic analysis showed larger radiolucent area into bone defect to the experimental group at the periods of 14 (p=0.016), 30 (p=0.009) and 90 (p=0.028) days. In the histological analysis there was no delay in the bone repair stages in both groups. However, in the histomorphometric analysis, the experimental group presented significative lowering of newly formed bone volume at 7 and 14 days periods (p=0.049), with no significant differences at 30 days period. There was significative decrease of alkaline phosphatase levels in experimental group in the initial periods (p=0.049). There was no change in the serum calcium levels. It was concluded that chronic use of amlodipine compromised bone neoformation in the repairing process of surgical defect in the mandibular ramus of rats, but no precluded occurrence of fracture consolidation.

L’hypertension artérielle pulmonaire (HTAP) est une maladie rare caractérisée par un remodelage des artères pré-capillaires pulmonaires lié à une dysfonction des cellules endothéliales (CE) conduisant à une prolifération cellulaire vasculaire. Cette prolifération conduit à une obstruction progressive du lit artériel et à l’augmentation des résistances vasculaires. L’hypertension pulmonaire (HTP) qui en résulte provoque une hypertrophie du ventricule droit aboutissant à la défaillance cardiaque et à la mort du patient. Actuellement le seul recours possible est la transplantation pulmonaire. Les mécanismes responsables de ce remodelage vasculaire sont encore peu connus. Les premiers travaux présentés mettent en évidence in situ un nouveau mécanisme impliqué dans ce remodelage. Au cours de ce processus, appelé transition endothélio-mésenchymateuse (EndoMT), les CE se désolidarisent de l’endothélium vasculaire et envahissent l’espace sous endothélial. Ce mécanisme s’accompagne d’une perte progressive du phénotype endothélial et du gain d’un phénotype mésenchymateux invasif et proliférant. L’EndoMT est impliquée dans la formation des lésions intimale et plexiforme. L’inhibition de l’EndoMT a donné des résultats prometteurs dans des modèles in vivo et in vitro d’HTAP. Cette découverte ouvre une nouvelle voie pour le traitement de la maladie. Dans un second projet nous avons confirmé le lien suspecté entre les chimiothérapies et la maladie veino-occlusive pulmonaire (MVOP), une forme d’HTP touchant les veines et veinules pulmonaires. L’étude des cas rapportés de MVOP consécutive à une chimiothérapie indiquent une forte incidence des agents alkylants, notamment du cyclophosphamide (CP), sur le développement de la MVOP. L’exposition au CP a provoqué une HTP associée à des lésions post-capillaires chez 3 espèces animales (souris, rat et lapin) confirmant ce lien. Nous espérons que nos travaux aboutiront à une plus grande vigilance concernant cette complication rare et sévère de l’exposition aux agents alkylants. De plus, nos travaux in vivo ont permis de mettre au point le tout premier modèle expérimental de MVOP. Au cours du dernier projet présenté, nous avons démontré que le nebivolol, un β-bloquant (β1 antagoniste β2 et β3 agoniste ayant un effet vasodilatateur) de 3ème génération, permettait d’améliorer les paramètres hémodynamiques et morphologiques, ainsi que la dysfonction endothéliale, liés à l’HTAP dans les modèles in vivo et in vitro. Ces travaux suggèrent la nécessité de réévaluer les recommandations actuelles, basées sur l’étude de β-bloquants non spécifiques de 1ère génération, qui proscrivent leur utilisation dans l’HTAP. En revisitant plusieurs aspects du remodelage vasculaire, ma thèse contribue ainsi à l’innovation thérapeutique dans l’HTAP. / Pulmonary arterial hypertension (PAH) is a rare disease characterized by a severe modeling of the precapillary pulmonary arteries related to an endothelial cells (EC) dysfunction leading to vascular cell proliferation. This proliferation leads to a progressive obstruction of the distal pulmonary arterial bed and increases pulmonary vascular resistance. The resulting pulmonary hypertension (PH) leads to a progressive right ventricular hypertrophy, and subsequent right heart failure and death unless the patient receives a lung transplantation. The primary mechanisms that trigger the vascular remodeling remain poorly understood. In the first presented study, we discovered in situ a new pathological process involved in vascular remodeling in PAH. During this process called endothelial-to-mesenchymal transition (EndoMT), the EC lose their cell-junctions to leave the endothelium and invade the subendothelial space. This phenomenon involves the progressive loss of the endothelial phenotype and the gain of a pro-invasive and pro-proliferative mesenchymal phenotype. This process is implicated in the pathogenesis of intimal and plexiform lesions. The inhibition of EndoMT gave promising results in experimental in vivo and in vitro models of PAH. This finding may have therapeutic implications for PAH. During a second project presented, we confirmed the suspected potential link between chemotherapies and the pulmonary veino-occlusive disease (PVOD). PVOD is a PH with vein and venular lesions. The systematic review of cases of chemotherapy induced PVOD cases suggests that alkylating agents, and cyclophosphamide (CP) in particular, represents a risk factor for the development of PVOD. In experimental models, CP exposure induced PH in three different animal models (mouse, rat, and rabbit). We hope that our findings will allow achieving greater vigilance against this rare and severe complication after alkylating agents exposure. Moreover our in vivo results lead to the development of the 1st experimental model of PVOD. In the last part, we demonstrated that nebivolol, a 3rd generation β-blocker (β1 antagonist, β2 & β3 agonist with vasodilator effect), improved PAH in in vitro and in vivo models. The actual guidelines, based on results obtained with non-specific 1st generation β-blockers, advice against the use of β-blockers in PAH. Our results suggest that the recommendation against β-blockers might be reevaluated taking into consideration their generation and specificity. By revisiting many aspects of vascular remodeling, my thesis contributes to therapeutic innovation in PAH.

Background: Calcium channel blockers are mainly divided into antihypertensive and antianginal treatment agents. In 2000 it was estimated that 972 million adults worldwide were living with hypertension and it is expected to affect 1.56 billion patients by 2025. The incremental expenditure for the antihypertensive therapeutic group in the United States of America was estimated at $US 55 billion per annum in 2006. It was stated that around seven million people in the United States of America suffered from angina, with around 400 000 new reports every year. Objective: To determine the prescribing patterns of calcium channel blocker medicine items during 2005 to 2008 in a section of the private health care sector of South Africa. Methods: A retrospective quantitative drug utilisation review was done using a medicine claims database ranging over four years from 1 January 2005 to 31 December 2008. The total medicine claims database was divided into cardiovascular medicine items and then into calcium channel blockers. These were analysed according to age as well as gender. Further analysis included adherence of calcium channel blockers as well as an analysis of prescribers of these items during the study period. Results: The total number of patients on the medicine claims database consisted of 1 509 621 patients in 2005. This number decreased to 974 497 patients in 2008. The most medicine items were dispensed in 2006 (n = 21 113 422) with an average cost of R 92.82 (SD = 196.42) per medicine item. It was noted that 16.05% (n = 242 264) of patients used at least one cardiovascular item in 2005. The percentage of cardiovascular medicine item users increased by 4.36% during the study period to 20.41% (n = 198 847) in 2008. In 2008 the cardiovascular medicine items dispensed were responsible for 19.18% (R 342 565 308.41) of the total cost of all medicine items claimed. In 2005 the results revealed that 1.63% (n = 318 258) of all medicine items dispensed were calcium channel blocker medicine items. The percentage of calcium channel blockers increased to 2.24% (n = 367 437) of the total number of medicine items in 2008. The cost prevalence index was calculated for the calcium channel blockers and the value declined from 1.5 in 2005 to 1.22 in 2008, which indicated that the items dispensed were relatively expensive, but less than in 2005. An increase of 16.17% in the usage of generic medicine items were noted from 2005 to 2008. More female patients than male patients claimed medicine items during the study period. A higher percentage of male patients used a cardiovascular medicine item as well as calcium channel blockers during the study period compared to females and a larger percentage of their medicine expenditure was used on cardiovascular medicine items as well as calcium channel blockers compared to females. The usage of cardiovascular medicine items as well as calcium channel blocker medicine items increased with patient age. In 2008, 17.98% of patients older than 65 years of age used a calcium channel blocker compared to 0.97% of patients aged > 25 <= 35 years. Only 60.34% of calcium channel blockers items were used with acceptable refill adherence rates during the study. More than a third of the calcium channel blockers medicine items used had unacceptable low adherence rates from 2005 to 2008. In each of the study years the highest potential saving with generic substitution was seen with amlodipine containing items. It was also observed that some generic substitutions could be relatively more expensive than the innovator products and an increased cost instead of a saving through generic substitution may have occurred. Conclusion: This study highlighted the prescribing patterns and cost implications of calcium channel blockers in the private health care sector of South Africa. It is recommended that a more in–depth study of the adherence of calcium channel blockers be done. This study should also include the cost strategies of generic substitution of calcium channel blockers in South Africa. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Background: Calcium channel blockers are mainly divided into antihypertensive and antianginal treatment agents. In 2000 it was estimated that 972 million adults worldwide were living with hypertension and it is expected to affect 1.56 billion patients by 2025. The incremental expenditure for the antihypertensive therapeutic group in the United States of America was estimated at $US 55 billion per annum in 2006. It was stated that around seven million people in the United States of America suffered from angina, with around 400 000 new reports every year. Objective: To determine the prescribing patterns of calcium channel blocker medicine items during 2005 to 2008 in a section of the private health care sector of South Africa. Methods: A retrospective quantitative drug utilisation review was done using a medicine claims database ranging over four years from 1 January 2005 to 31 December 2008. The total medicine claims database was divided into cardiovascular medicine items and then into calcium channel blockers. These were analysed according to age as well as gender. Further analysis included adherence of calcium channel blockers as well as an analysis of prescribers of these items during the study period. Results: The total number of patients on the medicine claims database consisted of 1 509 621 patients in 2005. This number decreased to 974 497 patients in 2008. The most medicine items were dispensed in 2006 (n = 21 113 422) with an average cost of R 92.82 (SD = 196.42) per medicine item. It was noted that 16.05% (n = 242 264) of patients used at least one cardiovascular item in 2005. The percentage of cardiovascular medicine item users increased by 4.36% during the study period to 20.41% (n = 198 847) in 2008. In 2008 the cardiovascular medicine items dispensed were responsible for 19.18% (R 342 565 308.41) of the total cost of all medicine items claimed. In 2005 the results revealed that 1.63% (n = 318 258) of all medicine items dispensed were calcium channel blocker medicine items. The percentage of calcium channel blockers increased to 2.24% (n = 367 437) of the total number of medicine items in 2008. The cost prevalence index was calculated for the calcium channel blockers and the value declined from 1.5 in 2005 to 1.22 in 2008, which indicated that the items dispensed were relatively expensive, but less than in 2005. An increase of 16.17% in the usage of generic medicine items were noted from 2005 to 2008. More female patients than male patients claimed medicine items during the study period. A higher percentage of male patients used a cardiovascular medicine item as well as calcium channel blockers during the study period compared to females and a larger percentage of their medicine expenditure was used on cardiovascular medicine items as well as calcium channel blockers compared to females. The usage of cardiovascular medicine items as well as calcium channel blocker medicine items increased with patient age. In 2008, 17.98% of patients older than 65 years of age used a calcium channel blocker compared to 0.97% of patients aged > 25 <= 35 years. Only 60.34% of calcium channel blockers items were used with acceptable refill adherence rates during the study. More than a third of the calcium channel blockers medicine items used had unacceptable low adherence rates from 2005 to 2008. In each of the study years the highest potential saving with generic substitution was seen with amlodipine containing items. It was also observed that some generic substitutions could be relatively more expensive than the innovator products and an increased cost instead of a saving through generic substitution may have occurred. Conclusion: This study highlighted the prescribing patterns and cost implications of calcium channel blockers in the private health care sector of South Africa. It is recommended that a more in–depth study of the adherence of calcium channel blockers be done. This study should also include the cost strategies of generic substitution of calcium channel blockers in South Africa. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Critical illness associated muscle weakness and muscle dysfunction in intensive care unit (ICU) patients lead to severe morbidity and mortality as well as significant adverse effect on quality of life. Immobilization, mechanical ventilation, neuromuscular blocking agents, corticosteroids, and sepsis have been implicated as important risk factors, but the underlying molecular and cellular mechanisms remain unclear.  A unique porcine ICU model was employed to investigate the effect of these risk factors on the expression profiles, gene expression and contractile properties of limb and diaphragm muscle, in the early phase of ICU stay. This project has focused on unraveling the underlying molecular and cellular pathways or networks in response to ICU and critical illness interventions. Upregulation of heat shock proteins indicated to play a protective role despite number of differentially transcribed gene groups that would otherwise have a negative effect on muscle fiber structure and function in response to immobilization and mechanical ventilation.  Mechanical ventilation appears to play a critical role in development of diaphragmatic dysfunction. Impaired autophagy, chaperone expression and protein synthesis are indicated to play a pivotal role in exacerbating muscle weakness in response to the combined effect of risk factors in ICU. These results may be of therapeutic importance in alleviating critical illness associated muscle weakness.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Les anticorps monoclonaux (AcM) anti-CD20 sont essentiels pour le traitement du lymphome non hodgkinien et de la leucémie lymphoïde chronique (LLC). Les AcM agissent soit en activant directement la signalisation apoptotique dans les cellules cibles, soit via le système immunitaire. Dans une étude préclinique, nous avons montré que le traitement avec AcM anti-CD20, rituximab et GA101, induit l'expression de la protéine early growth response 1 (EGR-1) (Dalle et al., 2011). EGR-1 est un facteur de transcription régulé par le calcium (Ca2+) et CD20 est impliqué dans la régulation du flux calcique transmembranaire. Nous avons donc étudié le rôle d'EGR-1 et du flux Ca2+ dans l'activité cytotoxique des AcM anti-CD20. Nous avons montré qu'EGR-1 est rapidement induit suite à l'exposition au rituximab et à GA101. La baisse de l'expression d'EGR-1 par shRNA a supprimé l'effet cytotoxique du GA101 à la fois in vitro et in vivo, indiquant qu'EGR-1 est requis pour la mort cellulaire médiée par CD20. De plus, la surexpression d'EGR-1 augmente la sensibilité au GA101 in vitro et in vivo. En outre, nos résultats indiquent que les AcM anti-CD20 induisent un flux Ca2+. Le blocage du flux Ca2+ par inhibiteurs de canaux calciques (ICC) a aboli l'induction d'EGR-1 ainsi que l'efficacité du GA101 in vivo et ex vivo dans des échantillons de LLC. Plus important, nos données indiquent que les patients recevant des ICC ont une moins bonne réponse au traitement par les AcM anti-CD20. En conclusion, nous avons identifié EGR-1 comme potentiel biomarqueur pour prédire la réponse à la thérapie anti-CD20 et démontré que les ICC ont un impact négatif sur l'efficacité des AcM anti-CD20 chez les patients / Anti-CD20 monoclonal antibodies (mAbs) are an essential component of the treatment of patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL). They mediate their antitumor effects by activating the immune system or by direct apoptotic signaling in target cells. In a previous preclinical study, we showed that treatment with anti-CD20 mAbs, rituximab and GA101, resulted in upregulated expression of early growth factor 1 (EGR-1) (Dalle et al. 2011). EGR-1 is a calcium (Ca2+) regulated transcription factor and CD20 is hypothesized to regulate transmembrane Ca2+ flux. Therefore, we aimed to assess the role of EGR-1 and Ca2+ flux in the cytotoxic activity of anti-CD20 mAbs. We have shown that EGR-1 expression is rapidly upregulated in CD20+ cells following rituximab and GA101 exposure. Decreasing EGR-1 expression by shRNA abolishes the direct cytotoxic effect of GA101 both in vitro and in vivo, indicating that EGR-1 is required for CD20-mediated cell death. Additionally, the overexpression of EGR-1 enhances the cytotoxic activity of GA101 both in vitro and in vivo. Furthermore, our results indicate that anti-CD20 mAbs induce calcium influx. Blocking the Ca2+ flux with calcium channel blockers (CCB) abolishes EGR-1 induction and impaires the GA101 efficacy in vivo and ex vivo in CLL blood samples. More importantly, our data indicate that patients receiving CCBs and anti-CD20 therapy have worst progression free survival and overall survival. In conclusion we have identified EGR-1 as a potential biomarker to predict response to anti-CD20 therapy. We demonstrated that co-treatement with CCBs negatively impacts the outcome of patients receiving anti-CD20 mAbs

Made available in DSpace on 2016-06-02T20:18:14Z (GMT). No. of bitstreams: 1 3660.pdf: 12159654 bytes, checksum: e4bf1704d730c95175def3dbe81e9d83 (MD5) Previous issue date: 2011-03-18 / Financiadora de Estudos e Projetos / Myocardial infarction (MI) and chronic heart failure (CHF) are among the cardiovascular diseases with high morbidity and mortality and both conditions are characterized by reduced ability to perform dynamic exercise. In CHF, the mechanisms responsible for exercise intolerance has been most widely investigated. There is a complex interaction between central and peripheral factors, including changes in lung function, reduced respiratory muscle strength and impaired autonomic modulation. However, little is known about their capacity to exercise at high altitude. The responsible factors to the functional capacity reduction in IM are unclear, especially in the early phase of recovery after hospital discharge. In this sense, two studies were developed with the purpose of assessing ventilatory limitation and cardiorespiratory efficiency in subjects with recent myocardial infarction and chronic heart failure. The first was developed in two stages and involved eight men (49 ± 8 years) with uncomplicated recent MI (RMI) and ten men (48 ± 9 years) apparently healthy subjects (CG). All patients underwent pulmonary function (PF), cardiopulmonary exercise testing on a ramp (CPX) and constant load (TECC) protocol. TECC was applied at three intensities, identified in CPET, corresponding to ventilatory anaerobic threshold, plus 25% and minus 25%. At the initial step we investigated the ventilatory limitation, with exercise tidal flow-volume loop, the breathing strategy and ventilatory efficiency during exercise (VE/VCO2 slope and OUES). The RMI group presented lower expiratory reserve volume (0.9±0.3 vs. 1.8±0.5 L; p<0.05) and OUES (1836±470 vs. 2695±258; p<0.01) when compared to the CG. RMI group also demonstrated EFL during all three CWETs, whereas the CG presented EFL only during the higher intensity. In the second step we evaluated the heart rate (HR) and oxygen uptake (VO2) responses at the beginning of dynamic exercise at three intensities, through the kinetics analysis. The RMI time constants (_) of HR (_HR) and VO2 (_VO2) showed different response, because the _VO2 was slower than _HR. When compared to the CG, RMI presented slower _VO2 at moderate workload. In conclusion, recent uncomplicated MI is associated with reduction in oxygen uptake ventilatory efficiency, slowing of _VO2 and ventilatory limitation at dynamic exercise, even when there is no reduction in PF and respiratory muscle strength. In the second study, thirty CHF patients (NYHA I-III, 25M/5F; 59±10 years, LVEF=39.6±7.1%) treated with carvedilol were underwent to CPET and CWET. CWET was applied at 50% of the peak workload reached at CPET, in normoxia and hypoxia, to simulate a 2000 meters altitude. To identify the effect of carvedilol on the response to moderate exercise in hypoxia, we evaluated the kinetics of HR and VO2 at the initial stage of dynamic exercise and the response of these variables during the CWET. The VO2 was 20% higher in hypoxia, the _VO2 was faster in hypoxia and the _HR was faster in normoxia. Ten patients, who lowered _VO2 in hypoxia had greater HR increase during maximal CPET, suggesting lower functional betablockade. The faster _VO2 in hypoxia is likely due to a peripheral effect of carvedilol mediated either by _- or _-receptor. / O infarto do miocárdio (IM) e a insuficiência cardíaca (IC) crônica estão entre as doenças cardiovasculares com maior morbidade e mortalidade e caracterizam-se por redução da capacidade de realização de exercício dinâmico. Na IC crônica, os mecanismos responsáveis pela intolerância ao exercício têm sido mais amplamente investigados e apresentam complexa interação entre fatores centrais e periféricos, incluindo alterações da função pulmonar, redução da força dos músculos respiratórios e comprometimento da modulação autonômica. Contudo, pouco se sabe em relação à capacidade de exercício em altitude elevada. No IM, principalmente na fase precoce da recuperação pós-alta hospitalar, os fatores responsáveis pela redução da capacidade funcional são pouco conhecidos. Com o propósito de avaliar a limitação ventilatória e a eficiência cardiorrespiratória de indivíduos com IM recente e IC crônica, foram desenvolvidos dois estudos. O primeiro foi realizado em duas etapas e contou com oito homens (49±8 anos) com IM recente (RMI) não complicado e dez homens (48±9 anos) aparentemente saudáveis (CG). Todos realizaram prova de função pulmonar (FP), teste de exercício cardiopulmonar em rampa (TECP) e em carga constante (TECC). O TECC foi aplicado em três intensidades, identificadas no TECP, correspondentes ao limiar de anaerobiose ventilatório, 25% acima e 25% abaixo. Inicialmente investigou-se a limitação ventilatória, com emprego da alça fluxo-volume corrente durante o exercício, a estratégia ventilatória e a eficiência ventilatória durante o exercício (VE/VCO2 slope e OUES). O grupo RMI apresentou menor volume de reserva expiratório em repouso (0,9±0,3 vs. 1,8±0,5 L; p<0,05) e OUES (1836±470 vs. 2695±258; p<0,01). Além disso, o RMI apresentou limitação ao fluxo expiratório nas três intensidades estudadas, enquanto no CG esteve presente apenas na maior intensidade. Na segunda etapa avaliou-se o comportamento da frequência cardíaca (FC) e do consumo de oxigênio (VO2) no início do exercício dinâmico, em três intensidades, por meio da análise da cinética da resposta destas variáveis. As constantes de tempo (_) da FC (_FC) e do VO2 (_VO2) apresentaram comportamento distinto no RMI, sendo que a _VO2 foi mais lenta nas três intensidades. Além disso, a _VO2 do RMI foi mais lenta que a do CG na intensidade moderada. Em conclusão, IM recente não complicado está associado com redução da eficiência ventilatória para o consumo de oxigênio, lentificação do consumo de oxigênio e limitação ao fluxo expiratório durante exercício dinâmico, mesmo quando não há redução da FP e da força dos músculos respiratórios. No segundo estudo foram realizados TECP e TECC em trinta pacientes com IC crônica (NYHA I-III, 25M/5F; 59±10 anos; FEVE=39,6±7,1%) em uso de carvedilol. O TECC foi aplicado em intensidade equivalente a 50% da máxima do TECP em condições de normóxia e hipóxia, a fim de simular altitude de 2000 metros. Com o propósito de identificar o efeito do carvedilol sobre a resposta da FC e do VO2 ao exercício moderado em normóxia e hipóxia, avaliou-se a cinética destas variáveis na fase inicial do exercício dinâmico, bem como a resposta das mesmas durante o TECC. O VO2 foi 20% maior em hipóxia, a _VO2 foi mais rápida em hipóxia e a _FC foi mais rápida em normóxia. Dez pacientes que apresentaram _VO2 mais lenta em hipóxia mostraram maior incremento da FC no TECP, o que sugere menor bloqueio funcional dos receptores beta. A _VO2 mais rápida em hipóxia pode estar relacionada ao efeito periférico do carvedilol, mediado pelos receptores alfa e beta.