Background. Central nervous system dysfunction continues to produce significant morbidity and ass... more Background. Central nervous system dysfunction continues to produce significant morbidity and associated mortality in patients undergoing cardiac surgery. Using a closed-chest canine cardiopulmonary bypass model, dogs underwent 2 h of hypothermic circulatory arrest (HCA) at 18°C, followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis, biochemically by analysis of microdialysis effluent, and by receptor autoradiography for N-methyl-D-aspartate (NMDA) glutamate receptor subtype expression.Results. Using a selective NMDA (glutamate) receptor antagonist (MK801) and an AMPA antagonist (NBQX), glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. A microdialysis technique was employed to evaluate the role of nitric oxide (NO) in neuronal cell death. Arginine plus oxygen is converted to NO plus citrulline (CIT) by the action of NO synthase (nNOS). CIT recovery in the cerebrospinal fluid and from canine cortical homogenates increased during HCA and reperfusion. These studies demonstrated that neurotoxicity after HCA involves a significant and early induction of nNOS expression, and neuronal processes leading to widespread augmentation of NO production in the brain.To further investigate the production of excitatory amino acids in the brain, we hypothesized the following scenario: HCA→ ↑ glutamate, ↑ aspartate, ↑ glycine→ ↑ intracellular Ca2+→ ↑ NO + CIT. Using the same animal preparation, we demonstrated that HCA caused increased intracerebral glutamate and aspartate that persists up to 20 h post-HCA. HCA also resulted in CIT (NO) production, causing a continued and delayed neurologic injury. Confirmatory evidence of the role of NO was demonstrated by a further experiment using a specific nNOS inhibitor, 7-nitroindazole. Animals underwent 2 h of HCA, and then were evaluated both physiologically and for NO production. 7-Nitroindazole reduced CIT (NO) production by 58.4 ± 28.3%. In addition, dogs treated with this drug had superior neurologic function compared with untreated HCA controls.Conclusions. These experiments have documented the role of glutamate excitotoxicity in neurologic injury and have implicated NO as a significant neurotoxin causing necrosis and apoptosis. Continued research into the pathophysiologic mechanisms involved in cerebral injury will eventually yield a safe and reliable neuroprotectant strategy. Specific interventional agents will include glutamate receptor antagonists and specific neuronal NO synthase inhibitors.
Applications to cardiothoracic surgery training programs have declined. Anecdotal evidence sugges... more Applications to cardiothoracic surgery training programs have declined. Anecdotal evidence suggests limited job availability for residents completing cardiothoracic training, which may contribute to this decline. This survey sought to document the experience of current, graduating residents.In June 2003, the Thoracic Surgery Residents Association surveyed residents completing accredited cardiothoracic training or additional subspecialization, utilizing a web-based survey hosted by CTSNet. Resident participation was voluntary and anonymous.Of the estimated 140 graduates, 89 responded. The majority were male (91.0%, n = 81), married (80.0%, n = 71), and had children (61.0%, n = 54). Average age was 36.2 years old, and mean educational debt was less than $50K. Of the 89 respondents, 77 initially sought jobs and 12 sought additional training. For residents seeking jobs, 19.5% (n = 15) received no offers and 13 of these ultimately pursued additional training. Acquired jobs were in private (53.0%, n = 34) or academic practice (47.0%, n = 30), with 73.4% (n = 47) involving general thoracic surgery. Most would again choose cardiothoracic surgery as a career (75.5%, n = 67), and 62.0% (n = 55) would again submit the same match list. However, 87.0% (n = 77) believed that the number of trainees should be decreased, 81.0% (n = 72) believed that reimbursement for cardiothoracic surgery is inadequate, and 77.5% (n = 69) believed that excessively low reimbursement will result in restricted access or decreased quality for patients.Most cardiothoracic residents were successful in finding employment after training. A substantial percentage, however, pursued additional training due to lack of job opportunities. Although most finishing residents were satisfied with training and career choice, significant concerns exist regarding job opportunities and compensation. These conditions may lead to difficulty in recruitment to the specialty.
Cardiovascular disease is the leading cause of death worldwide, accounting for 30% of all deaths,... more Cardiovascular disease is the leading cause of death worldwide, accounting for 30% of all deaths, with elevated blood pressure probably the most important modifiable risk factor. Worldwide, elevated blood pressure is estimated to cause 7.5 million deaths, about 12.8% of the total of all annual deaths. New drugs with different efficacy and effectiveness to control cardiovascular and renal disease are always welcomed. Adequate control of arterial hypertension is needed in order to reduce the consequences of cardiovascular and renal disease. A novel compound, LCZ696 , is currently in development based on the concept of comprising in the same entity a Neprilysin inhibitor, with a renin-angiotensin-aldosterone system inhibitor, in this case an angiotensin receptor blocker. This review, performed in PubMed including the last five years under the keywords cited below, presents the available data about LCZ696, the first-in-class angiotensin receptor Neprilysin inhibitor. Available data show that positive efficacy and a good tolerability profile of LCZ696 in the treatment of arterial hypertension as well as preliminary data indicate that it can also be useful in the treatment of cardiovascular disease. These data are particularly promising in the treatment of arterial hypertension.
Background. Central nervous system dysfunction continues to produce significant morbidity and ass... more Background. Central nervous system dysfunction continues to produce significant morbidity and associated mortality in patients undergoing cardiac surgery. Using a closed-chest canine cardiopulmonary bypass model, dogs underwent 2 h of hypothermic circulatory arrest (HCA) at 18°C, followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis, biochemically by analysis of microdialysis effluent, and by receptor autoradiography for N-methyl-D-aspartate (NMDA) glutamate receptor subtype expression.Results. Using a selective NMDA (glutamate) receptor antagonist (MK801) and an AMPA antagonist (NBQX), glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. A microdialysis technique was employed to evaluate the role of nitric oxide (NO) in neuronal cell death. Arginine plus oxygen is converted to NO plus citrulline (CIT) by the action of NO synthase (nNOS). CIT recovery in the cerebrospinal fluid and from canine cortical homogenates increased during HCA and reperfusion. These studies demonstrated that neurotoxicity after HCA involves a significant and early induction of nNOS expression, and neuronal processes leading to widespread augmentation of NO production in the brain.To further investigate the production of excitatory amino acids in the brain, we hypothesized the following scenario: HCA→ ↑ glutamate, ↑ aspartate, ↑ glycine→ ↑ intracellular Ca2+→ ↑ NO + CIT. Using the same animal preparation, we demonstrated that HCA caused increased intracerebral glutamate and aspartate that persists up to 20 h post-HCA. HCA also resulted in CIT (NO) production, causing a continued and delayed neurologic injury. Confirmatory evidence of the role of NO was demonstrated by a further experiment using a specific nNOS inhibitor, 7-nitroindazole. Animals underwent 2 h of HCA, and then were evaluated both physiologically and for NO production. 7-Nitroindazole reduced CIT (NO) production by 58.4 ± 28.3%. In addition, dogs treated with this drug had superior neurologic function compared with untreated HCA controls.Conclusions. These experiments have documented the role of glutamate excitotoxicity in neurologic injury and have implicated NO as a significant neurotoxin causing necrosis and apoptosis. Continued research into the pathophysiologic mechanisms involved in cerebral injury will eventually yield a safe and reliable neuroprotectant strategy. Specific interventional agents will include glutamate receptor antagonists and specific neuronal NO synthase inhibitors.
Applications to cardiothoracic surgery training programs have declined. Anecdotal evidence sugges... more Applications to cardiothoracic surgery training programs have declined. Anecdotal evidence suggests limited job availability for residents completing cardiothoracic training, which may contribute to this decline. This survey sought to document the experience of current, graduating residents.In June 2003, the Thoracic Surgery Residents Association surveyed residents completing accredited cardiothoracic training or additional subspecialization, utilizing a web-based survey hosted by CTSNet. Resident participation was voluntary and anonymous.Of the estimated 140 graduates, 89 responded. The majority were male (91.0%, n = 81), married (80.0%, n = 71), and had children (61.0%, n = 54). Average age was 36.2 years old, and mean educational debt was less than $50K. Of the 89 respondents, 77 initially sought jobs and 12 sought additional training. For residents seeking jobs, 19.5% (n = 15) received no offers and 13 of these ultimately pursued additional training. Acquired jobs were in private (53.0%, n = 34) or academic practice (47.0%, n = 30), with 73.4% (n = 47) involving general thoracic surgery. Most would again choose cardiothoracic surgery as a career (75.5%, n = 67), and 62.0% (n = 55) would again submit the same match list. However, 87.0% (n = 77) believed that the number of trainees should be decreased, 81.0% (n = 72) believed that reimbursement for cardiothoracic surgery is inadequate, and 77.5% (n = 69) believed that excessively low reimbursement will result in restricted access or decreased quality for patients.Most cardiothoracic residents were successful in finding employment after training. A substantial percentage, however, pursued additional training due to lack of job opportunities. Although most finishing residents were satisfied with training and career choice, significant concerns exist regarding job opportunities and compensation. These conditions may lead to difficulty in recruitment to the specialty.
Cardiovascular disease is the leading cause of death worldwide, accounting for 30% of all deaths,... more Cardiovascular disease is the leading cause of death worldwide, accounting for 30% of all deaths, with elevated blood pressure probably the most important modifiable risk factor. Worldwide, elevated blood pressure is estimated to cause 7.5 million deaths, about 12.8% of the total of all annual deaths. New drugs with different efficacy and effectiveness to control cardiovascular and renal disease are always welcomed. Adequate control of arterial hypertension is needed in order to reduce the consequences of cardiovascular and renal disease. A novel compound, LCZ696 , is currently in development based on the concept of comprising in the same entity a Neprilysin inhibitor, with a renin-angiotensin-aldosterone system inhibitor, in this case an angiotensin receptor blocker. This review, performed in PubMed including the last five years under the keywords cited below, presents the available data about LCZ696, the first-in-class angiotensin receptor Neprilysin inhibitor. Available data show that positive efficacy and a good tolerability profile of LCZ696 in the treatment of arterial hypertension as well as preliminary data indicate that it can also be useful in the treatment of cardiovascular disease. These data are particularly promising in the treatment of arterial hypertension.
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