Effectiveness of a shared team approach between nurses and doctors for improved risk factor management in survivors of stroke: a cluster randomized controlled trial.

BACKGROUND AND PURPOSE: Limited evidence exists on the benefits of organized care for improving risk factor control in patients with stroke or transient ischaemic attack. The effectiveness of an individualized management programme in reducing absolute cardiovascular disease risk in this high-risk population was determined. METHODS: This was a prospective, multicentre, cluster-randomized controlled trial with blinded assessment of outcomes and intention-to-treat analysis. Patients hospitalized for stroke/transient ischaemic attack and aged ≥18 years were recruited from four hospitals. General practices treating recruited patients were randomized to provide either usual care or an individualized management programme comprising nurse-led education and review of care plans by stroke specialists in addition to usual care. The primary outcome was a change in cardiovascular Framingham Risk Score between baseline and 12 months. RESULTS: From January 2010 to November 2013, 156 general practices (280 patients) were randomly assigned to usual care (control) and 159 (283 patients) to the intervention. The median age was 70.1 years; 65% were male. Overall, >80% of participants were prescribed recommended secondary prevention therapies at baseline. The primary efficacy analysis comprised 533 participants, with 30 either dying or lost to follow-up. In adjusted analyses, no significant between-group difference was found in the cardiovascular risk score at 12 months (0.04, 95% confidence interval -1.7, 1.8). CONCLUSIONS: The effectiveness of an organized secondary prevention programme for stroke may be limited in patients from high-performing hospitals with regular post-discharge follow-up and communication with general practices.

ASPREE-D: Aspirin for the prevention of depression in the elderly.

BACKGROUND: Not only is depression associated with increased inflammation but inflammation is a risk factor for the genesis of depression. Many of the environmental risk factors for depression are transduced through inflammatory signaling. Anti-inflammatory agents show promise for the management of depression in preclinical, epidemiological, and early clinical studies. This opens the door to the potential for anti-inflammatory agents to treat and prevent depression. There are no evidence-based pharmacotherapies for depression prevention. METHOD: ASPREE-D, aspirin in the prevention of depression in the elderly, is a sub study of ASPREE, which explores the potential of aspirin to prevent a range of inflammation related disorders in the elderly. With a sample size of 19,114, and a duration of 5 years, this placebo controlled study will be one of the largest randomized controlled trials in psychiatry and will provide definitive evidence on the ability of aspirin to prevent depression. RESULTS: This paper presents the rationale for the study and presents a summary of the study design. CONCLUSIONS: ASPREE-D may not only define novel therapy but will provide mechanistic proof of concept of the role of inflammation in depression.

Transient hypertension and sustained tachycardia in mice housed individually in metabolism cages.

The novel environment of a metabolic cage can be stressful for rodents, but few studies have attempted to quantify this stress-response. Therefore, we determined the effects on mean arterial pressure (MAP) and heart rate (HR), of placing mice of both sexes in metabolism cages for 2 days. After surgical implantation of a carotid artery catheter mice recovered individually in standard cages for 5 days. Mice then spent 2 days in metabolism cages. MAP and HR were monitored in the standard cage on Day 5 and in metabolism cages on Days 6-7. MAP increased by 18+/-3 and 22+/-4 %, while HR increased by 27+/-4 and 27+/-6 %, in males and females, respectively, during the first hours after cage switch. MAP decreased to baseline in the fourth and eighth h following metabolism cage switch in males and females, respectively. However, HR remained significantly elevated in both sexes during the entire two-day period in metabolism cages. Females had lower MAP than males both pre- and post-metabolism cage switch, but there were no sex differences in HR. These results demonstrate sustained changes in cardiovascular function when mice are housed in metabolism cages, which could potentially affect renal function.

The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects.

AIMS: Rosiglitazone, a thiazolidinedione antidiabetic medication used in the treatment of Type 2 diabetes mellitus, is predominantly metabolized by the cytochrome P450 (CYP) enzyme CYP2C8. The anti-infective drug trimethoprim has been shown in vitro to be a selective inhibitor of CYP2C8. The purpose of this study was to evaluate the effect of trimethoprim on the CYP2C8 mediated metabolism of rosiglitazone in vivo and in vitro. METHODS: The effect of trimethoprim on the metabolism of rosiglitazone in vitro was assessed in pooled human liver microsomes. The effect in vivo was determined by evaluating rosiglitazone pharmacokinetics in the presence and absence of trimethoprim. Eight healthy subjects (four men and four women) completed a randomized, cross-over study. Subjects received single dose rosiglitazone (8 mg) in the presence and absence of trimethoprim 200 mg given twice daily for 5 days. RESULTS: Trimethoprim inhibited rosiglitazone metabolism both in vitro and in vivo. Inhibition of rosiglitazone para-hydroxylation by trimethoprim in vitro was found to be competitive with apparent K(i) and IC(50) values of 29 microm and 54.5 microm, respectively. In the presence of trimethoprim, rosiglitazone plasma AUC was increased by 31% (P = 0.01) from 2774 +/- 645 microg l(-1) h to 3643 +/- 1051 microg l(-1) h (95% confidence interval (CI) for difference 189, 1549), and half-life was increased by 27% (P = 0.006) from 3.3 +/- 0.5 to 4.2 +/- 0.8 h (95% CI for difference 0.36, 1.5). Trimethoprim reduced the para-O-sulphate rosiglitazone/rosiglitazone and the N-desmethylrosiglitazone/rosiglitazone AUC(0-24) ratios by 22% and 38%, respectively. CONCLUSIONS: These results indicate that trimethoprim is a competitive inhibitor of CYP2C8-mediated rosiglitazone metabolism in vitro and that trimethoprim administration increases plasma rosiglitazone concentrations in healthy subjects.

Rapid hypotensive response to fasting in spontaneously hypertensive rats.

This study examined changes in renal function and mean arterial pressure (MAP) in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats during 48 h of fasting, independent of changes in sodium intake. Spontaneously hypertensive rats (n = 17) and WKY rats (n = 10) were instrumented with artery and vein catheters and sodium intake was clamped at 2.1 mEq/day. By day 2 of fasting, MAP decreased -10+/-1 mm Hg (P < .001) in SHR, but did not change significantly in WKY rats. Heart rate decreased significantly in both groups by day 2 of fasting and there was a significant increase in urine volume and sodium excretion. Thus, fasting caused a rapid decrease in MAP in SHR that was not due to decreased sodium intake, but may be related, in part, to volume loss and improved renal excretory function.

Cardiovascular and renal responses to a high-fat diet in Osborne-Mendel rats.

This study examined the cardiovascular, renal, and hormonal responses of dietary-induced obesity in Osborne-Mendel (OM) rats. Male OM rats were fed either a low (LF; n = 10)- or high-fat (HF; n = 11) diet for 17 wk. During week 15 of the study, arterial pressure was measured directly, 24 h/day, from chronically indwelling catheters. Body and kidney weights were 46 +/- 5 and 33 +/- 5% greater, respectively, in rats fed HF vs. LF diet. Left and right ventricular weights were also greater in rats fed HF diet (21 +/- 7 and 36 +/- 6%, respectively). Direct measurement of arterial pressure revealed only a slight increase in mean arterial pressure (88 +/- 1 in rats fed HF diet vs. 85 +/- 1 mmHg in rats fed LF diet), whereas there was no difference in resting heart rate between the two groups. Consumption of HF diet was also associated with a 3.5-fold increase in plasma insulin, a 16 +/- 4% higher blood glucose, and a 40 +/- 6% reduction in plasma renin activity compared with LF-fed rats. Thus feeding OM rats HF diet led to obesity, cardiac and renal hypertrophy, and hyperinsulinemia but only a slight increase in mean arterial pressure.

Arterial pressure control at the onset of type I diabetes: the role of nitric oxide and the renin-angiotensin system.

Little is known about how hyperglycemia in diabetes directly affects renal and cardiovascular function. Therefore, we modified the streptozotocin-model of Type I diabetes in rats to enable chronic cardiovascular study at the earliest stages of diabetes, before there was time for development of vascular structural changes. We showed that the onset of diabetic hyperglycemia increased total peripheral resistance, decreased skeletal muscle blood flow, increased thromboxane production, and caused a transient increase in plasma renin activity (PRA). Mean arterial pressure (MAP) also increased, but the amplitude was modest. Moreover, we measured significant increases in glomerular filtration rate (GFR) and renal plasma flow, and also showed that endothelially mediated vasodilation in skeletal muscle was not impaired. We then tested the hypothesis that nitric oxide (NO) was playing an important role in counteracting a pressor response to the onset of diabetes. Our results showed that induction of diabetes in rats with chronic NO synthase inhibition caused a marked and progressive increase in MAP. In addition, PRA increased progressively under those conditions and the increase in GFR was prevented. This suggests that NO may work to keep arterial pressure in control at the onset of hyperglycemia very early in the development of diabetes, possibly by facilitating renal vasodilation and by suppressing activity of the renin-angiotensin system. However, the mechanisms for these interactions and the role of renal vascular resistance and other factors in mediating the hypertensive response remain unknown.

Preliminary evaluation of an abstinence-based program for 7th grade students from a small rural school district.

The purpose of this study was to investigate the effects of an abstinence-based program designed for 7th grade students (n = 59) from a rural school district. Analysis suggested that after the program more students intended to avoid having sex before marriage but no change was noted for knowledge, attitudes, and self-efficacy.

Long-term glucose infusion increases arterial pressure in dogs with cyclooxygenase-2 inhibition.

A series of studies has shown that long-term infusion of insulin and glucose does not increase mean arterial pressure (MAP) in dogs, but we have shown that the same infusion protocol or infusion of glucose alone increases arterial pressure in rats. This study tested the hypothesis that infusing glucose alone in dogs, with all insulin derived from endogenous secretion, would increase arterial pressure. Because fructose feeding in dogs also has been shown not to cause hypertension and because we have shown that prostaglandin production increases during insulin and glucose infusion, this study also tested whether prostaglandins prevent the pressor response in dogs. Dogs were instrumented and assigned in random crossover design to long-term cyclooxygenase-2 (COX-2) inhibition. After baseline measurements, glucose was infused in all dogs for 6 days ( approximately 500 g/d IV). Plasma insulin increased 3- to 4-fold and blood glucose increased significantly in both groups. The MAP (measured 24 h/d) response in control dogs was variable but on average tended to increase, although not significantly. In the dogs with COX-2 inhibition, however, MAP increased significantly to a peak of 9+/-2 mm Hg and an average of 6+/-1 mm Hg above control. There was significant sodium and volume retention during glucose infusion and a significant increase in glomerular filtration rate, but there were no between-group differences. Plasma renin activity increased only in the control group. This is the first study to report a long-term pressor response with glucose infusion and hyperinsulinemia in dogs, and it suggests that the inability to detect this relationship previously was due to prostaglandins.

Renovascular hypertension: structural changes in the renal vasculature.

Experimental narrowing of the main renal artery to produce hypertension increases the aorta-glomerular capillary pressure difference and vascular resistance. This article examines the hypothesis that hypertension also may be caused by structural changes that narrow intrarenal blood vessels, similarly increasing preglomerular vascular resistance and the aortic-glomerular capillary pressure gradient. There is evidence of both wall hypertrophy and lumen narrowing of the preglomerular arteries in spontaneously hypertensive rats, with increased preglomerular resistance and aortic-glomerular capillary pressure difference. We have also attempted to induce structural changes in renal-preglomerular vessels experimentally by infusing angiotensin II at low doses (0.5 to 4.5 ng/kg per minute) into the renal artery of Sprague-Dawley rats and greyhound dogs for up to 4 weeks. This angiotensin II infusion produced apparent dose-related effects on preglomerular vessel structure and hypertension. The possibility that hypertension may be induced by structural changes in preglomerular resistance vessel walls, by simulation of the hemodynamic effects of main renal artery stenosis, deserves further investigation.

Nitric oxide may be required to prevent hypertension at the onset of diabetes.

Nitric oxide (NO) plays an important role in the regulation of vascular tone, and evidence suggests that endothelial-dependent relaxation, possibly mediated via NO, is impaired in diabetes. However, the role of the endothelium in arterial pressure control early in diabetes, before dysfunction develops, is not known. This was evaluated in the present study by comparing the responses to induction of diabetes in vehicle-treated rats (D, n = 7) vs. rats chronically treated with N(G)-nitro-L-arginine methyl ester (L-NAME; D+L, n = 8). A nondiabetic group also was treated with L-NAME (L, n = 7) to control for L-NAME effects over time, independent of diabetes. After baseline measurements, rats were given either vehicle or L-NAME (10 microg. kg(-1). min(-1) iv) infusion throughout the experiment. Six days later, streptozotocin (60 mg/kg iv) was administered, followed by a 3-wk diabetic study period. Induction of diabetes in the D+L rats caused a marked and progressive increase in mean arterial pressure throughout the diabetic period, averaging approximately 70 mmHg greater than in the D rats and approximately 20 mmHg greater than in the L rats. Glomerular filtration rate and renal plasma flow tended to increase during diabetes, but this trend was reversed in the D+L rats. In addition, plasma renin activity increased in the D and D+L rats during week 1 of diabetes but then returned to control in the D rats, while continuing to increase in the D+L rats. These results suggest that, in the early stages of diabetes, NO synthesis is important to prevent hypertension from developing, possibly through actions to maintain glomerular filtration and suppress renin secretion.

Placebo-controlled trial of glycine added to clozapine in schizophrenia.

OBJECTIVE: The purpose of this study was to evaluate the effects of high-dose oral glycine on positive and negative symptoms and cognitive function when added to clozapine in adults with schizophrenia. METHOD: The authors conducted a double-blind, placebo-controlled, parallel-group trial of 60 g/day of glycine added to clozapine for 8 weeks in 30 adults with schizophrenia. Clinical ratings were performed every 2 weeks. RESULTS: Twenty-seven patients completed the trial. Glycine augmentation of clozapine produced no statistically significant change in positive or negative symptoms or cognitive functioning. No subjects showed clinically significant worsening of clinical ratings. CONCLUSIONS: These data, combined with data from previous trials with D-cycloserine and glycine, suggest that agonists at the glycine site may be less effective when combined with clozapine than they are when combined with conventional antipsychotics.

Decreased cardiac output at the onset of diabetes: renal mechanisms and peripheral vasoconstriction.

Recently we reported that hindquarter blood flow, measured 24 h/day, decreased progressively over the first 6 days of type 1 diabetes in rats. That response, coupled with the tendency of mean arterial pressure to increase, suggested a vasoconstrictor response. The purpose of this study was to measure the changes in cardiac output together with the renal hemodynamic and excretory responses to allow integrative determination of whether vasoconstriction likely accompanies the onset of type 1 diabetes. Rats were instrumented with a Transonic flow probe on the ascending aorta and with artery and vein catheters, and cardiac output and mean arterial pressure were measured continuously, 24 h/day, throughout the study. The induction of diabetes, by withdrawing intravenous insulin-replacement therapy in streptozotocin-treated rats, caused a progressive decrease in cardiac output that was 85 +/- 5% of control levels by day 7. This was associated with significant increases in glomerular filtration rate, renal blood flow, and microalbuminuria as well as urinary fluid and sodium losses, with a negative cumulative sodium balance averaging 15.7 +/- 1.6 meq by day 7. Restoring insulin-replacement therapy reversed the renal excretory responses but did not correct the negative sodium balance, yet cardiac output returned rapidly to control values. Increasing sodium intake during the diabetic and recovery periods also did not significantly affect the cardiac output response during any period. These results indicate that cardiac output decreases significantly at the onset of type 1 diabetes without glycemic control, and although volume loss may contribute to this response, there also is a component that is not volume or sodium dependent. We suggest this may be due to vasoconstriction, but to what extent local blood flow autoregulation or active vasoconstriction may have mediated that response is not known.

Chronic intravenous glucose infusion causes moderate hypertension in rats.

We have reported that chronic insulin infusion increases mean arterial pressure (MAP) in rats. In those studies, glucose was coinfused to prevent hypoglycemia, but it is possible that the glucose infusion rate may have exceeded the rate actually required to prevent hypoglycemia. If true, then the glucose infusion alone should have a similar effect, and this study tested that hypothesis. In six rats (insulin group) instrumented with artery and vein catheters, insulin was infused for 7 days intravenously (iv) at 1.5 mU/kg/min together with glucose iv at 18.6 mg/kg/min. Seven other rats (glucose group) received the same glucose infusion for 7 days but without iv insulin. MAP increased significantly in both groups, from 98 +/- 3 and 96 +/- 2 mm Hg to 107 +/- 5 and 104 +/- 3 mm Hg in the insulin and glucose groups, respectively, and the renal and hormonal changes were similar to those previously reported during insulin infusion. There were no significant differences between the two groups for any variable measured. These data indicate that the sugar intake provided by the glucose infusion essentially mimics the response to our insulin and glucose infusion protocol, and that similar mechanisms underlie the renal and cardiovascular responses to each protocol.

Inhibition of nitric oxide synthesis potentiates hypertension during chronic glucose infusion in rats.

Endothelial dysfunction has been proposed to contribute to impaired blood flow control or hypertension in many conditions characterized by hyperinsulinemia or hyperglycemia. However, most studies have focused on whether endothelial dysfunction is present in the established phases of these various hypertensive states, and there is little known concerning the role of the endothelium in the initial stages. This study tested whether nitric oxide production, before endothelial dysfunction develops, plays an important role in counteracting the hypertensive response to chronic glucose infusion. Glucose was infused (18.6 mg/kg per minute IV) for 7 days in 8 normal rats (G) and in 9 rats with a long-term background intravenous infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) at 10 microg/kg per minute (G+L). Mean arterial pressure (MAP), measured 24 hours per day, increased an average of approximately 11 mm Hg in the G rats. L-NAME treatment increased MAP an average of 28+/-2 mm Hg in the G+L rats, and glucose infusion raised MAP >30 mm Hg above that, averaging 155+/-8 mm Hg by day 6. In addition, heart rate increased from an average of 389+/-8 bpm to 441+/-16 bpm by day 6, whereas there was no significant change in the G rats. Glomerular filtration rate decreased significantly with L-NAME treatment and decreased in both groups by day 3 of glucose infusion, reaching lower levels in the G+L rats. These results show that NO is required to minimize the increase in MAP during glucose infusion and suggest that renal and neural mechanisms may be important in mediating that effect.

Renal hemodynamic responses to intrarenal infusion of ligands for the putative angiotensin IV receptor in anesthetized rats.

Angiotensin IV, a hexapeptide fragment (3-8) of angiotensin II metabolism, has been reported to produce vasodilatation within the renal vasculature by activation of the putative AT4 receptor. However, there are conflicting findings, with previous in vivo studies providing evidence for and against a renal vasodilator action of angiotensin IV. In this study, the renal hemodynamic responses to activation of the putative AT4 receptor were studied in anesthetized rats by left renal arterial infusion of two endogenous ligands, angiotensin IV and LVV-hemorphin-7. Angiotensin IV (10, 100, and 1,000 pmol/min) infusion caused dose-dependent reductions in blood flow to the infused kidney, which were abolished by pretreatment with losartan. In respect to this effect, angiotensin IV was approximately 300-fold less potent than angiotensin II. There were no significant effects of angiotensin IV on mean arterial pressure, heart rate, or blood flow to the noninfused kidney. Intrarenal infusion of LVV-hemorphin-7 (10, 100, and 1,000 pmol/min) had no significant effect on renal blood flow in the infused and noninfused kidneys, or on mean arterial pressure or heart rate. These results provide no evidence for a renal vasodilatory action of angiotensin IV or LVV-hemorphin-7. On the contrary, intrarenal angiotensin IV infusion produced vasoconstriction of the renal vasculature, mediated by activation of AT1 receptors. These observations provide evidence against a vasodilatory role of putative AT4 receptors in the rat kidney.

Munchausen by proxy syndrome: the forensic challenge of recognition, diagnosis, and reporting.

Munchausen by Proxy Syndrome (MBPS) is a rare form of abuse in which a caregiver fabricates or produces symptoms of an illness in a child, elder, or disabled person. The deception is usually repeated on numerous occasions, resulting in many hospitalizations, considerable morbidity, and sometimes death. MBPS is a factitious disorder in which caregivers injure their victims in order to gain sympathy or attention for themselves. It was named after Baron Karl von Munchausen, the 18th century cavalry officer who returned home from war and told embellished tales of his adventures. MBPS is a very horrifying circumstance of abuse. Unwillingness or the inability to recognize this abuse deprives the victim of the opportunity to be shielded from future harm. There is a need for strategic protocols and a multidisciplinary approach to this baffling problem. Discussing the clinical profile of the perpetrator, the victim, and the family may help nurses distinguish medical fact from fiction.

Acute endothelium-mediated vasodilation is not impaired at the onset of diabetes.

Vascular injury and impaired vascular function are central to the increased mortality associated with diabetes. Hyperglycemia in diabetes has been suggested to play a role in this process, in part by impairing the function of the vascular endothelium. It has been difficult, however, to isolate the direct effect of glucose in both humans and in animal models of diabetes. This was evaluated in the present study in 7 rats that were chronically instrumented with a Transonic flow probe at the iliac bifurcation of the abdominal aorta, a nonoccluding catheter inserted immediately anterior to the flow probe, and a femoral vein catheter. Acute infusions of acetylcholine and sodium nitroprusside (1 and 10 microg/min IA) increased hindquarter blood flow significantly by approximately 27 and 10 mL/min over baseline, respectively, at the high dose. Streptozotocin (70 mg/kg IV) was administered, but normoglycemia was maintained with continuous intravenous insulin infusion to control for potential streptozotocin side effects. Diabetes was induced 5 to 7 days later by stopping the insulin infusion. Hindlimb blood flow (measured 24 hours per day) decreased during the diabetic period and was accompanied by an increase in mean arterial pressure, suggesting a vasoconstrictor response. However, the responses to acetylcholine and sodium nitroprusside were not altered significantly on either day 2 or day 6 of the diabetic period. This suggests that neither endothelium-mediated vasorelaxation nor responsiveness to nitric oxide is impaired during the initial phase of diabetes and that diabetic hyperglycemia does not have a significant, direct effect to impair endothelium-mediated relaxation in insulin-dependent diabetes mellitus. The mechanism for the change in baseline blood flow and its potential influence on endothelial function, however, are not known.

Effects of long-term intrarenal angiotensin II infusion on renal vascular responsiveness to vasoactive agents.

1. We tested whether chronic intrarenal angiotensin II (AngII) infusion altered renal vascular responsiveness to vasoactive agents, which would provide evidence of vascular structural changes. 2. The renal blood flow (RBF) responses to renal arterial administration of bolus doses of acetylcholine, glyceryl trinitrate, AngII and noradrenaline were measured before commencement of and 1 day after cessation of 28 days intrarenal AngII infusion (0.5 ng/kg per min) in chronically instrumented conscious dogs. 3. The RBF responses to these vasoactive agents were unaltered by chronic intrarenal AngII infusion in conscious dogs. 4. These functional studies provide no evidence for renal vascular hypertrophy in response to chronic intrarenal AngII infusion in conscious dogs.