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No description available.

Despite intensive research on the neurobiological mechanisms of chronic pain, this therapeutic area remains one of the least satisfactorily covered by current drugs. Glutamate activates two major classes of receptors: ionotropic and metabotropic. Ionotropic receptors are classified into three major subclasses:a-amino-3- hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA). NMDA receptor activation, at the level of the spinal cord and peripheral tissue has been shown to play an important role in the facilitation of nociption in several animal models. Although the efficacy of NMDA receptor antagonists in various experimental and clinical pain situations has been well documented, their use as analgesics is limited by serious side effects such as memory impairment, psychotomimetic effects, ataxia and motor incoordination. Two promising current approaches to obtain effective analgesia devoid of side effects are by subtype-selective NMDA receptor antagonism in central nervous system (CNS) or peripheral use of NMDA receptor antagonist that do not interfere with central glutamate processing. NR2B subunit of NMDA receptor was predominantly found in the superficial dorsal horn of spinal cord. Recent discoveries have revealed that the transfection of small interfering RNAs (siRNAs) into animal cells results in the potent, long-lasting post-transcriptional silencing of specific genes. Thus, two approaches of antagonizing NMDA receptor in CNS and peripheral nervous system (PNS) for pain relief using siRNAs or pharmacological agents are investigated in this study. The first approach involves intrathecal administration of NR2B-siRNA into subarachnoid space and transfection of siRNA into cell of spinal cord by transfection agent of polyethylenimine (PEI). Formalin test was used to induce inflammatory pain in the hind paw of rats. Behavior response to formalin test was observed and recorded on 3rd, 7th, 14th, and 21th day after injection of siRNA. The spinal cords were dissected immediately after formalin test and used for analysis of mRNA and protein. The results revealed that the use of siRNA targeting the NR2B subunit could abolish formalin induced pain behaviors and not impair motor coordination in rat model. The expression of NR2B mRNA and its associated protein as demonstrated by real time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were decreased. Significant reduction of NR2B immunoreactivity in dorsal horn of spinal cord were detected after 7 days treated by NR2B siRNA. The peak effect of gene knockdown occurred on day 3 for mRNA and day 7 for its protein, following intrathecal injection of 5 µg of siRNA targeting NR2B subunit. The inhibition of NR2B mRNA and protein lasted about 14 days and recovered on 21th days after injection of siRNA. The nociceptive response induced by formalin was decreased during the period of downregulation of NR2B protein. A novel intrathecal delivery of siRNA transfected with PEI into cell of dorsal horn reduced formalin-induced pain. The second approach involves subcutaneous injection of NMDA receptor antagonist and topical use of alpha2-adrenergic agonist for abolishing surgical pain. Additionally, we proved the upregulation of glutamate receptors in human inflamed skin. The study examined whether the peripheral ionotropic glutamate receptors (iGluRs) increased in inflamed human skin taken from patients having inflammatory pain over inflamed skin and surrounding area. Real time RT-PCR and western blot were used for quantitation of mRNA and protein of iGluR in normal and inflamed human skin. A significant increase in mRNA and protein for the subunits of NMDA, AMPA, and kainate receptor were detected in inflamed skin when compared to normal skin. The results demonstrate that mRNA and protein level of iGluRs are increasingly expressed during states of persistent inflammation, and that this increased activity may be involved in mediating clinical inflammatory pain in human skin. To examine the postoperative analgesic effect and adverse effect of local NMDA receptor antagonist (ketamine), ketamine (0.3%, 3 ml) or saline was subcutaneous infiltrated pre-incisionally in 26 patients equally assigned to two groups undergoing circumcision surgery. The saline-infiltrated subjects also received 9-mg intramuscular ketamine into the upper arm to control for any related systemic analgesic effects. The postoperative analgesic and adverse effects were followed for 24 hours. For ketamine infiltrated patients, the time interval until first analgesic demand was prolonged and the incidence of pain free (pain score = 0) during movement and erection was significant higher than saline infiltrated patients. No significant differences were noted in the incidence of adverse effects between the two groups. Pre-incisional subcutaneous infiltration of ketamine acting via a peripheral mechanism can suppression postoperative pain after circumcision surgery. Apraclonidine hydrochloride (AH) is a topical, relatively selective alpha2-adrenergic agonist that has limited access to the CNS and exhibits fewer systemic (adverse) effects such as dizziness and hypotension. Eighty patients scheduled for arthroscopic knee surgery received either intraarticular (IA) normal saline, 50 ug IA AH, 150 ug IA AH, or 150 ug IA clonidine subsequent to surgery. The IA application of 150 ug apraclonidine and 150 ug clonidine provide similar degree of postoperative analgesia and similar incidence of adverse effect. The promise is that both approaches attenuating nociception state devoid of CNS adverse effects provide novel approach for the management of chronic pain.

A insuficiência cardíaca é uma síndrome clínica de mau prognóstico caracterizada por disfunção cardíaca associada à intolerância aos esforços, retenção de fluído e redução da longevidade. Dentre as serina/treonina quinases associadas às alterações funcionais e estruturais cardíacas observadas na progressão da insuficiência cardíaca, a família das proteínas quinase C (PKC) composta por 12 diferentes isoformas parece modular a contratilidade miocárdica e o remodelamento cardíaco. No presente estudo, caracterizamos o fenótipo cardíaco e o perfil de ativação das diferentes isoformas de PKC na progressão da insuficiência cardíaca de etiologia isquêmica em ratos. Além disso, estudamos o efeito da inibição sustentada da isoforma PKCβII sobre a sobrevida, o remodelamento cardíaco e a função ventricular em modelo de insuficiência cardíaca de etiologia isquêmica. Conseguinte, identificamos possíveis substratos cardíacos da PKCβII envolvidos na progressão da insuficiência cardíaca. Para isso, avaliamos os efeitos agudo e crônico da inibição da PKCβII sobre o transiente de cálcio e a contratilidade de cardiomiócito isolados de ratos adultos com insuficiência cardíaca. Por fim, testamos as inibições específicas das PKCβII e PKCβI na progressão da hipertrofia cardíaca compensada para a insuficiência cardíaca em modelo animal de hipertensão arterial sustentada. Nossos resultados sugerem que a inibição sustentada da PKCβII reverte o quadro de insuficiência cardíaca, melhorando a função ventricular, o remodelamento cardíaco e a sobrevida dos diferentes modelos de insuficiência cardíaca estudados, constituindose em uma estratégia terapêutica celular promissora / Heart failure is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality worldwide. Protein kinase C isozymes emerge as important potential therapeutic targets in chronic cardiovascular disease. However, individual PKC isozymes play different roles in the pathogenesis of cardiac diseases. Here, we characterized the cardiac phenotype as well as the different PKC isozyme activation profile during myocardial-induced heart failure progression in rat. Furthermore, we evaluated the role of selective PKCβ II inhibition on survival, left ventricle remodeling and cardiac function in myocardial-induced heart failure. Moreover, we identified the cardiac PKCβII substrates related to heart failure. Finally, PKCβII and PKCβI specific inhibitors were chronically delivered to hypertensive-induced heart failure rats and the cardiac phenotype was evaluated. Our data suggest that 6-wks of PKCβII inhibition, but not PKCβI, improved animal survival by restoring cardiac function and promoting cardiac anti-remodeling effect in both myocardial infarctioninduced heart failure and hypertensive-induced heart failure rats. The improved cardiac function and anti-remodeling effect of PKCβII inhibition seems to be associated with increased contractility of cardiac myocytes, improved miofilaments/Ca2+ sensitivity and decreased cardiac inflammatory response. Altogether, the results provide evidence for beneficial effects of PKCβII specific intracellular inhibition on cardiac function and remodeling, which may be a promising cellular therapy for heart failure treatment

A insuficiência cardíaca é uma síndrome clínica de mau prognóstico caracterizada por disfunção cardíaca associada à intolerância aos esforços, retenção de fluído e redução da longevidade. Dentre as serina/treonina quinases associadas às alterações funcionais e estruturais cardíacas observadas na progressão da insuficiência cardíaca, a família das proteínas quinase C (PKC) composta por 12 diferentes isoformas parece modular a contratilidade miocárdica e o remodelamento cardíaco. No presente estudo, caracterizamos o fenótipo cardíaco e o perfil de ativação das diferentes isoformas de PKC na progressão da insuficiência cardíaca de etiologia isquêmica em ratos. Além disso, estudamos o efeito da inibição sustentada da isoforma PKCβII sobre a sobrevida, o remodelamento cardíaco e a função ventricular em modelo de insuficiência cardíaca de etiologia isquêmica. Conseguinte, identificamos possíveis substratos cardíacos da PKCβII envolvidos na progressão da insuficiência cardíaca. Para isso, avaliamos os efeitos agudo e crônico da inibição da PKCβII sobre o transiente de cálcio e a contratilidade de cardiomiócito isolados de ratos adultos com insuficiência cardíaca. Por fim, testamos as inibições específicas das PKCβII e PKCβI na progressão da hipertrofia cardíaca compensada para a insuficiência cardíaca em modelo animal de hipertensão arterial sustentada. Nossos resultados sugerem que a inibição sustentada da PKCβII reverte o quadro de insuficiência cardíaca, melhorando a função ventricular, o remodelamento cardíaco e a sobrevida dos diferentes modelos de insuficiência cardíaca estudados, constituindose em uma estratégia terapêutica celular promissora / Heart failure is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality worldwide. Protein kinase C isozymes emerge as important potential therapeutic targets in chronic cardiovascular disease. However, individual PKC isozymes play different roles in the pathogenesis of cardiac diseases. Here, we characterized the cardiac phenotype as well as the different PKC isozyme activation profile during myocardial-induced heart failure progression in rat. Furthermore, we evaluated the role of selective PKCβ II inhibition on survival, left ventricle remodeling and cardiac function in myocardial-induced heart failure. Moreover, we identified the cardiac PKCβII substrates related to heart failure. Finally, PKCβII and PKCβI specific inhibitors were chronically delivered to hypertensive-induced heart failure rats and the cardiac phenotype was evaluated. Our data suggest that 6-wks of PKCβII inhibition, but not PKCβI, improved animal survival by restoring cardiac function and promoting cardiac anti-remodeling effect in both myocardial infarctioninduced heart failure and hypertensive-induced heart failure rats. The improved cardiac function and anti-remodeling effect of PKCβII inhibition seems to be associated with increased contractility of cardiac myocytes, improved miofilaments/Ca2+ sensitivity and decreased cardiac inflammatory response. Altogether, the results provide evidence for beneficial effects of PKCβII specific intracellular inhibition on cardiac function and remodeling, which may be a promising cellular therapy for heart failure treatment

No description available.

Summaries in Afrikaans and English / Text in Afrikaans / Tourettesindroom is 'n lewenslange versteuring wat gekenmerk word deur motoriese en vokale trekkings saam met moontlik ook komorbiede simptome soos aandagtekort-hiperaktiwiteitsversteuring, obsessief-kompulsiewe versteuring, aggressie en depressie. Die sindroom kom in hoe mate in Suid-Afrika voor en die pastor kan dus heel moontlik daarmee te doen kry. Die beste behandeling vir die sindroom is medikasie saam met gedrags- en gesinsterapie toegedien deur 'n multidissiplinere span. Die pastor het 'n rol om te vervul in hierdie span probleme het aangesien persone met Tourettesindroom dikwels in hulle verhoudings met God, hulleself en ander mense. Vir effektiewe pastorale berading aan sodanige persone, moet die pastor deeglike kennis he van die sindroom en die simptome daarvan, asook van sy of haar invalshoek as pastor. 'n Moontlike kernmoment van die sindroom wat deur die pastor aangespreek kan word, is die verlies aan beheer wat deur dje lyer ervaar word. Die sindroom kan as 'n verskoning gedrag en gebruik word vir negatiewe en onverantwoordelike die pastor sal die lyer dus moontlik eties moet konfronteer op 'n medemenslike wyse. / Tourette Syndrome is a lifelong disorder. Symptoms are motoric and vocalic tics with possible comorbid symptoms such as attention deficit disorder with hyperactivity, obsessive-compulsive disorder, and depression. It is frequent among South Africans and the pastor will probably be confronted with persons struggling with the syndrome. The best therapy for Tourette Syndrome is medication in conjunction with behaviour and family therapy administered by a multi-disciplinary team. Persons with Tourette Syndrome have problems maintaining relationships with God, themselves and others. The pastor therefore has a definite role to play in the team. Knowledge of the syndrome and its symptoms, and of pastoral care are essential for succesful pastoral counseling. A possible central theme of the syndrome is the loss of control experienced by the person with the syndrome. The syndrome can become an excuse for negative and irresponsible behaviour and ethical confrontation may be necessary. / Philosophy, Practical & Systematic Theology / M. Th. (Praktiese Teologie)

Background Rheumatoid arthritis (RA) is a systemic progressive destructive joint disease with an increased risk for co-morbidity and premature death if untreated. Cardiovascular disease (CVD) is the main cause of death but also other co-morbid conditions contribute to the patient’s shorter life expectancy. Inflammation is important for the development of CVD, but knowledge of its relationship with other co-morbidities is sparse. Early disease modifying anti rheumatic drugs (DMARDs) can suppress disease activity and improve the long-term outcome. The aim of this thesis was to evaluate prospectively aspects of disease activity and severity in a large cohort of patients with early RA. Predictive and prognostic markers, e.g., antibodies against citrullinated proteins/peptides (ACPAs), occurring in early disease and with implications for disease outcome and co-morbidity were evaluated. Methods Patients with early RA (i.e., symptomatic for ≤12 months) have, since December 1995, been consecutively included in a large survey of prospective and observational studies on the progression of RA and the development of co-omorbidity. Autoantibodies, inflammatory, genetic markers and radiographs have been analyzed. In paper I, 210 RA patients and 102 controls were followed regularly for two years. The predictive value of four different ACPAs in relation to disease activity and radiological progression was evaluated. In Paper II (n = 700) and in Papers III-IV (n =950), patients with early RA from the four northern-most counties of Sweden were followed regularly for 5 years. Data on risk factors and co-morbidity was collected, according to the study protocol, from clinical records and self-reported questionnaires from patients at inclusion into the study cohort and after five years. The predictive value of traditional and potential disease related risk factors for new cardiovascular events (CVE) was evaluated (II). In Paper III, the impact of age at the onset RA, stratified as being young onset RA (<58 years; YORA) and late onset RA (≥58 years; LORA) on disease activity, severity and chosen treatment, was evaluated. In Paper IV, the development of new co-morbidities after RA onset and their relation to inflammatory activity was assessed. Results The presence of anti-mutated citrullinated vimentin (MCV ) antibodies was associated with a more severe disease course, estimated by disease activity score, erythrocyte sedimentation rate (ESR) and swollen joint count after 24 months, compared with anti-CCP2, anti-CCP3, and anti CCP3.1 antibodies. In Paper II, the incidence of a new CVE during 5 years was explained by several of the traditional CV risk factors, and potentiated by a high disease activity. Treatment with DMARDs decreased the risk. In Paper III, LORA patients were associated with greater disease activity/severity at disease onset and over time compared with YORA who were more often ACPA positive. YORA patients were treated earlier with DMARDs, whilst LORA patients were more often treated with corticosteroids and less so with DMARDs early in the course of their disease. In Paper IV, 53%of patients already had one or more co-morbidities already at the onset of RA. After 5 years, 41% of the patients had developed at least one new co-morbidity. ESR at baseline and accumulated disease activity were associated with a new co-morbidity after five years. Conclusion Early RA patients sero-positive for anti- MCV antibodies appeared to have a higher disease activity over time. The occurrence of a new CVE in early RA patients was predicted by traditional risk factors for CVD which were potentiated by a high disease activity. Treatment with DMARDs decreased the risk. Patients with young onset of RA were associated with a higher frequency of ACPA. Late onset of RA was associated with higher disease activity/severity at inclusion and over time. However, LORA patients were more often treated with corticosteroids and less so with DMARDs early in the disease course. Development of a new co-morbidity during the five years following diagnosis was related to ESR.

Summaries in Afrikaans and English / Text in Afrikaans / Tourettesindroom is 'n lewenslange versteuring wat gekenmerk word deur motoriese en vokale trekkings saam met moontlik ook komorbiede simptome soos aandagtekort-hiperaktiwiteitsversteuring, obsessief-kompulsiewe versteuring, aggressie en depressie. Die sindroom kom in hoe mate in Suid-Afrika voor en die pastor kan dus heel moontlik daarmee te doen kry. Die beste behandeling vir die sindroom is medikasie saam met gedrags- en gesinsterapie toegedien deur 'n multidissiplinere span. Die pastor het 'n rol om te vervul in hierdie span probleme het aangesien persone met Tourettesindroom dikwels in hulle verhoudings met God, hulleself en ander mense. Vir effektiewe pastorale berading aan sodanige persone, moet die pastor deeglike kennis he van die sindroom en die simptome daarvan, asook van sy of haar invalshoek as pastor. 'n Moontlike kernmoment van die sindroom wat deur die pastor aangespreek kan word, is die verlies aan beheer wat deur dje lyer ervaar word. Die sindroom kan as 'n verskoning gedrag en gebruik word vir negatiewe en onverantwoordelike die pastor sal die lyer dus moontlik eties moet konfronteer op 'n medemenslike wyse. / Tourette Syndrome is a lifelong disorder. Symptoms are motoric and vocalic tics with possible comorbid symptoms such as attention deficit disorder with hyperactivity, obsessive-compulsive disorder, and depression. It is frequent among South Africans and the pastor will probably be confronted with persons struggling with the syndrome. The best therapy for Tourette Syndrome is medication in conjunction with behaviour and family therapy administered by a multi-disciplinary team. Persons with Tourette Syndrome have problems maintaining relationships with God, themselves and others. The pastor therefore has a definite role to play in the team. Knowledge of the syndrome and its symptoms, and of pastoral care are essential for succesful pastoral counseling. A possible central theme of the syndrome is the loss of control experienced by the person with the syndrome. The syndrome can become an excuse for negative and irresponsible behaviour and ethical confrontation may be necessary. / Philosophy, Practical and Systematic Theology / M. Th. (Praktiese Teologie)

O exercício resistido dinâmico é recomendado, em complemento ao aeróbico, para indivíduos hipertensos. O aumento da pressão arterial durante sua execução se faz, primordialmente, pelo aumento da resistência vascular periférica, porém o aumento do débito cardíaco também parece estar envolvido. A elevação da pressão arterial parece ser exacerbada em hipertensos não medicados. Entretanto, grande parte dos hipertensos está sob terapêutica medicamentosa e vários fazem uso de -bloqueadores, que reduzem o débito cardíaco pela diminuição da resposta taquicárdica e inotrópica à estimulação simpática. Assim, é possível supor que o uso de -bloqueadores reduza o aumento da pressão arterial nos exercícios resistidos. Porém, pelo nosso conhecimento, este efeito ainda não foi estudado. Assim, esta investigação teve por objetivo investigar o efeito do atenolol sobre a resposta da pressão arterial durante o exercício resistido de diferentes intensidades. Foram estudados 10 hipertensos essenciais com pressão arterial sistólica/diastólica sob placebo entre 140 e 160/90 e 105 mmHg. Os pacientes foram estudados após 6 semanas de uso de placebo e de atenolol, sendo que os indivíduos estavam cegos para a medicação. Em cada fase, os voluntários fizeram o exercício de extensão de joelhos na cadeira extensora até a exaustão, seguindo 3 protocolos realizados em ordem aleatória: a) uma série em 100% de 1RM (repetição máxima), b) três séries em 40% de 1RM e; c) três séries em 80% de 1RM. Antes, durante e após os exercícios, a pressão arterial foi medida diretamente na artéria radial. Os dados foram comparados pelo teste t student ou pela ANOVA de dois fatores para amostras repetidas. Quando necessário, foi utilizado o post-hoc de Newman-Keuls e aceito como significante o índice de P≤0,05. Verificou-se que o atenolol reduziu os valores absolutos atingidos pela pressão arterial sistólica durante a execução do exercício nas três intensidades (valores máximos: 100% = 186±4 vs. 215±7, 80% = 224±7 vs. 247±9 e 40% = 223±7 vs. 252±16, mmHg, P≤0,05). Além disso, ele reduziu o aumento desta pressão arterial na 1ª série do exercício nas 3 intensidades (100% = +38±5 vs. +54±9; 80% = +68±11 vs. +84±13 e 40% = +69±7 vs. +84±14, mmHg, P≤0,05). Em relação à pressão arterial diastólica, o atenolol diminuiu os valores máximos absolutos e o aumento desta pressão arterial (126±6 vs. 145±6 e +41±6 vs. +52±6, mmHg, P≤0,05) no exercício em 100% de 1RM, mas não a alterou nas demais intensidades. Dessa forma, é possível concluir que o atenolol foi eficaz em atenuar tanto o valor absoluto quanto a resposta da pressão arterial sistólica durante o exercício resistido de diferentes intensidades em hipertensos, conferindo-lhes uma certa proteção cardiovascular. Este achado reforça o conceito de que o aumento do débito cardíaco é um mecanismo importante para o aumento da pressão arterial sistólica durante este tipo de exercício / Dynamic resistance exercise is recommended in association to aerobic exercise for hypertensive patients. Blood pressure increase during this kind of exercise is mainly due to an increase in peripheral vascular resistance, however, an increase in cardiac output might also be involved. This blood pressure increase seems to be exacerbated in non-medicated hypertensives. Nevertheless, most of the hypertensives are taking medications, and some of them are receiving -blockers, which decreases cardiac output by the inhibition of sympathetic-induced increase on heart rate and cardiac contractility. Thus, -blockers might decrease blood pressure rise during resistance exercise which, to our knowledge, has not been studied yet. Hence, the aim of this study was to verify the effects of the selective -blocker atenolol on blood pressure increase during dynamic resistance exercise of different intensities. Ten essential hypertensives with systolic/diastolic blood pressures under placebo condition maintained among 140 and 160/90 and 105 mmHg were recruited. These volunteers were studied after 6 weeks of placebo and atenolol treatment, and they were blinded for the medication used. In each phase, the volunteers executed, in a random order, 3 protocols of knee extension exercise until fatigue: a) 1 set at 100% of 1 repetition maximum (1RM); b) 3 sets at 40% of 1RM; c) 3 sets at 80% of 1RM. Before, during and after the exercises, intra-arterial radial blood pressure was measured. Data were compared by paired student t-test and by two-way ANOVA for repeated measures. Newman-Keuls post-hoc test was applied when necessary. P≤0.05 was considered as significant. Atenolol decreased the absolute value achieved by systolic blood pressure during the exercise performed at the 3 intensities (maximum values: 100% = 186±4 vs. 215±7, 80%= 224±7 vs. 247±9 e 40% = 223±7 vs. 252±16, mmHg, P≤0.05). Moreover, atenolol also reduced systolic blood pressure increase in the first set of exercise at the 3 intensities (100% = +38±5 vs. +54±9; 80% = +68±11 vs. +84±13 e 40% = +69±7 vs. +84±14, mmHg, P≤0.05). In regard to diastolic blood pressure, atenolol decreased its absolute values and its increase during exercise performed at 100% of 1RM (126±6 vs. 145±6 e +41±6 vs. +52±6, mmHg, P≤0.05), but it did not change diastolic blood pressure at the other exercise intensities. In Conclusion, atenolol therapy was effective in reducing both, systolic blood pressure absolute values and increase during resistance exercise of different intensities in hypertensive subjects; given them some cardiovascular protection. This result enhances the belief that cardiac output increase is important for blood pressure enhancement during this kind of exercise