Pharmacological inhibition of NOX reduces atherosclerotic lesions, vascular ROS and immune-inflammatory responses in diabetic Apoe(-/-) mice.

AIMS/HYPOTHESIS: Enhanced vascular inflammation, immune cell infiltration and elevated production of reactive oxygen species (ROS) contribute significantly to pro-atherogenic responses in diabetes. We assessed the immunomodulatory role of NADPH oxidase (NOX)-derived ROS in diabetes-accelerated atherosclerosis. METHODS: Diabetes was induced in male Apoe(-/-) mice with five daily doses of streptozotocin (55 mg kg(-1) day(-1)). Atherosclerotic plaque size, markers of ROS and immune cell accumulation were assessed in addition to flow cytometric analyses of cells isolated from the adjacent mediastinal lymph nodes (meLNs). The role of NOX-derived ROS was investigated using the NOX inhibitor, GKT137831 (60 mg/kg per day; gavage) administered to diabetic and non-diabetic Apoe(-/-) mice for 10 weeks. RESULTS: Diabetes increased atherosclerotic plaque development in the aortic sinus and this correlated with increased lesional accumulation of T cells and CD11c(+) cells and altered T cell activation in the adjacent meLNs. Diabetic Apoe(-/-) mice demonstrated an elevation in vascular ROS production and expression of the proinflammatory markers monocyte chemoattractant protein 1, vascular adhesion molecule 1 and IFNγ. Blockade of NOX-derived ROS using GKT137831 prevented the diabetes-mediated increase in atherosclerotic plaque area and associated vascular T cell infiltration and also significantly reduced vascular ROS as well as markers of inflammation and plaque necrotic core area. CONCLUSIONS/INTERPRETATION: Diabetes promotes pro-inflammatory immune responses in the aortic sinus and its associated lymphoid tissue. These changes are associated with increased ROS production by NOX. Blockade of NOX-derived ROS using the NOX inhibitor GKT137831 is associated with attenuation of these changes in the immune response and reduces the diabetes-accelerated development of atherosclerotic plaques in Apoe(-/-) mice.

Insulin and cardiovascular disease: biomarker or association?

In the 1980s prospective studies using whole populations suggested a relationship between insulin and cardiovascular disease, and these studies proposed that both metabolic and haemodynamic factors were associated with cardiovascular events. The initial analysis of the Paris Prospective Study (Diabetologia 19: 205-210), published in 1980, showed a positive correlation between insulin and cardiovascular events in healthy middle-aged policemen after a 5 year follow-up. In the Bedford Survey (Diabetologia 22: 79-84), also performed in the 1980s, a higher cardiovascular risk was demonstrated in diabetic patients and in those with borderline diabetes; however, in contrast to the Paris Prospective Study, insulin was negatively correlated to cardiovascular endpoints in the Bedford Survey. The initial enthusiasm for insulin as a cardiovascular risk marker was dampened when the 15 year follow-up data of the Paris Prospective Study (Diabetologia 34: 356-361) showed that the correlation between insulin and cardiovascular risk subsided with increased duration of follow-up. Despite the fact that hyperinsulinaemia was always strongly associated with other classical cardiovascular risk factors, univariate analyses usually failed to show a strong correlation between insulin and cardiovascular risk. The San Antonio Heart Study (Diabetologia 34: 416-422) performed in a bi-ethnic population that included a large proportion of Mexican-American participants again emphasised that insulin resistance may be the underlying factor associated with a cluster of metabolic and haemodynamic abnormalities. However, recently performed meta-analyses that included larger studies have not been able to confirm a critical role for insulin levels in cardiovascular risk. Indeed, it has been suggested that proinsulin or other factors may be better markers than insulin per se.

Linking RAGE and Nox in diabetic micro- and macrovascular complications.

Diabetes-associated micro- and macrovascular complications contribute to the increased morbidity and mortality observed in diabetes. Diabetes leads to accelerated generation of advanced glycation end products (AGEs) and activation of their receptor, RAGE, as well as activation of NAD(P)H oxidase (Nox), an enzyme dedicated to the production of reactive oxygen species, which ultimately leads to a pro-inflammatory environment characterised by oxidative stress. This review outlines the current evidence about the contribution of and interaction between the AGE-RAGE axis and Nox derived ROS formation in the development and progression of micro- and macrovascular diabetic complications (especially in atherosclerosis and nephropathy), and the mechanisms by which this occurs. We also outline novel treatments targeting the AGE-RAGE axis and specific Nox isoforms, which hold great promise in attenuating the development of diabetes-associated atherosclerosis and diabetic nephropathy.

Relation between postoperative antithrombin III concentrations and site of operation.

Antithrombin III concentrations were measured in 305 patients before and at intervals after operation for up to 12 days. The blood concentrations fell significantly after both major and minor surgery, but there was no relation between the expected degree of surgical trauma or the amount of blood transfused and the fall in concentration of antithrombin III. Some surgical procedures such as cholecystectomy, laparotomy, hernia repair, highly selective vagotomy, and transurethral resection of the prostate were associated with a greater depletion of antithrombin III than were other common operations and it is suggested that there are factors related to the actual site of the operation which affect the concentration of circulating antithrombin III in the postsurgical period.

Prediction of phenytoin dosage in epilepsy using multiple linear regression.

Analysis of plasma phenytoin in a group of patients treated for epilepsy showed that only 36% had values in the therapeutic range. The relationship between plasma phenytoin, body weight, and daily dosage of the drug were explored, and the data were analysed by multiple regression. The resultant equation, relating all three factors, were used to optimise drug dosage, and the importance of using the body weight of the patient before starting a phenytoin regimen is emphasised. An increase in the number of patients with plasma phenytoin in the therapeutic range was achieved, and the clinical value of being in that range is shown.

Abnormalities of the bony thorax causing tracheobronchial compression.

A number of intrathoracic and extrathoracic causes of airway obstruction have been well documented in the literature. At times, tracheal compression may be caused by abnormalities of the bony thorax whose previously unrecognized significance can result in unexpected difficulties when extubation is attempted following a routine intubation. Alternatively, patients may develop progressive distress secondary to their skeletal abnormalities. We report on cases illustrating anomalies of the manubrium, sternum and spine which have caused significant, occasionally life-threatening, tracheal and bronchial narrowing including pectus excavatum and scoliosis. A protocol is presented detailing the appropriate methods of diagnosis and treatment of these types of deformities.

Hospital laboratories as profit centers.

An aggressive business venture offers one solution to the growing competition and financial pressures hospital laboratories must overcome. For such a venture to be a success, a number of issues must be carefully considered. Properly met, today's challenges in the laboratory can become tomorrow's opportunities.

Alcohol exposure during late gestation: multiple developmental outcomes in sheep.

Alcohol consumption during pregnancy remains common in many countries. Exposure to even low amounts of alcohol (i.e. ethanol) in pregnancy can lead to the heterogeneous fetal alcohol spectrum disorders (FASD), while heavy alcohol consumption can result in the fetal alcohol syndrome (FAS). FAS is characterized by cerebral dysfunction, growth restriction and craniofacial malformations. However, the effects of lower doses of alcohol during pregnancy, such as those that lead to FASD, are less well understood. In this article, we discuss the findings of recent studies performed in our laboratories on the effects of fetal alcohol exposure using sheep, in which we investigated the effects of late gestational alcohol exposure on the developing brain, arteries, kidneys, heart and lungs. Our studies indicate that alcohol exposure in late gestation can (1) affect cerebral white matter development and increase the risk of hemorrhage in the fetal brain, (2) cause left ventricular hypertrophy with evidence of altered cardiomyocyte maturation, (3) lead to a decrease in nephron number in the kidney, (4) cause altered arterial wall stiffness and endothelial and smooth muscle function and (5) result in altered surfactant protein mRNA expression, surfactant phospholipid composition and pro-inflammatory cytokine mRNA expression in the lung. These findings suggest that fetal alcohol exposure in late gestation can affect multiple organs, potentially increasing the risk of disease and organ dysfunction in later life.

New technologies emerge.

Technology vendors continue to invent new devices, systems and processes to sell to the health care industry. Drugs, instruments and procedures continue to improve and address disease and injury treatment needs. In addition to these direct medical treatment innovations and enhancements, a number of new supporting systems and products have emerged. These support technologies hold significant promise for managers to make day-to-day execution of health care delivery more cost effective and customer friendly.