Angiopoietin-1 protects the adult vasculature against plasma leakage.

Pathological increases in vascular leakage lead to edema and swelling, causing serious problems in brain tumors, in diabetic retinopathy, after strokes, during sepsis and also in inflammatory conditions such as rheumatoid arthritis and asthma. Although many agents and disease processes increase vascular leakage, no known agent specifically makes vessels resistant to leaking. Vascular endothelial growth factor (VEGF) and the angiopoietins function together during vascular development, with VEGF acting early during vessel formation, and angiopoietin-1 acting later during vessel remodeling, maturation and stabilization. Although VEGF was initially called vascular permeability factor, there has been less focus on its permeability actions and more effort devoted to its involvement in vessel growth and applications in ischemia and cancer. Recent transgenic approaches have confirmed the profound permeability effects of VEGF (refs. 12-14), and have shown that transgenic angiopoietin-1 acts reciprocally as an anti-permeability factor when provided chronically during vessel formation, although it also profoundly affects vascular morphology when thus delivered. To be useful clinically, angiopoietin-1 would have to inhibit leakage when acutely administered to adult vessels, and this action would have to be uncoupled from its profound angiogenic capabilities. Here we show that acute administration of angiopoietin-1 does indeed protect adult vasculature from leaking, countering the potentially lethal actions of VEGF and inflammatory agents.

Blood pressure control and risk of incident atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia that affects more than 2 million people in the United States. We sought to determine whether the risk of incident AF among patients treated for hypertension differs by the degree of blood pressure control. METHODS: A population-based, case-control study of 433 patients with verified incident AF and 899 controls was conducted to investigate the relationship between average achieved systolic (SBP) and diastolic (DBP) blood pressure and risk of AF. All patients were members of an integrated health-care delivery system and were pharmacologically treated for hypertension. Medical records were reviewed to confirm the diagnosis of new onset AF and to collect information on medical conditions, health behaviors, and measured blood pressures. Average achieved SBP and DBP were calculated from the three most recent outpatient blood pressure measurements. RESULTS: Compared with the reference level of 120-129 mm Hg, for categories of average achieved SBP of <120, 130-139, 140-149, 150-159, 160-169, and > or =170 mm Hg, the odds ratios (ORs; 95% confidence interval (CI)) for incident AF were 1.99 (1.10, 3.62), 1.19 (0.78, 1.81), 1.40 (0.93, 2.09), 2.02 (1.30, 3.15), 2.27 (1.31, 3.93), and 1.84 (0.89, 3.80), respectively. Based on the population attributable fraction, we estimated that, among patients with treated hypertension, 17.2% (95% CI 4.3%, 28.3%) of incident AF was attributable to an average achieved SBP > or =140 mm Hg. CONCLUSION: Among patients treated for hypertension, uncontrolled elevated SBP and SBP <120 mm Hg were associated with an increased risk of incident AF.

Comparison of betaxolol, a new beta 1-adrenergic antagonist, to propranolol in the treatment of mild to moderate hypertension.

A double-blind, multicenter study compared the safety and efficacy of oral betaxolol 10 to 40 mg once daily (n = 68) with propranolol 40 to 160 mg twice daily (n = 73) in the treatment of mild to moderate essential hypertension. Both agents produced significant (P less than 0.01) and comparable reductions in mean supine systolic and diastolic blood pressures (7/11 mm Hg on betaxolol and 9/10 mm Hg on propranolol). Both betaxolol and propranolol significantly (P less than 0.01) reduced mean supine heart rate by 9 beats per minute. Patients achieved a more significant (P less than 0.01) reduction in blood pressure earlier (weeks 2 and 4 of the titration period) with betaxolol. By the end of treatment there was no significant difference in response between treatment groups. A higher incidence of central nervous system side effects (insomnia, bizarre dreams, depression, hallucinations, dizziness), however, was seen with propranolol than with betaxolol. Overall, the data show that in patients with mild to moderate essential hypertension, betaxolol 10 to 40 mg administered once daily is as effective as and better tolerated than propranolol 40 to 160 mg administered twice daily.

Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes.

BACKGROUND: Miyazaki et al. demonstrated using the hyperinsulinemic, euglycemic clamp that pioglitazone (PIO) enhanced insulin sensitivity in patients (n = 23) with type 2 diabetes (T2D). Although considered the reference method for measuring insulin sensitivity, the clamp is seldom used in large clinical trials because of its complexity. The Homeostasis Model Assessment Insulin Sensitivity (HOMA-S) and Quantitative Insulin Sensitivity Check Index (QUICKI) are two alternative insulin sensitivity surrogates that correlate with the clamp method and are suitable for use with large study populations. STUDY AIM: To evaluate the effect of PIO monotherapy and in combination therapy with sulfonylurea (SU) or metformin (MET) on insulin sensitivity as assessed by HOMA-S and QUICKI in a large group of patients (approximately 1000). RESEARCH DESIGN AND METHODS: Patient data from three randomized, double blind, multicenter, parallel group, placebo-controlled registration trials (Studies-001 PIO monotherapy and 010 and 027 combination therapy with SU or MET, respectively) were analyzed for this study. We evaluated insulin sensitivity for all three studies using HOMA-S and QUICKI. RESULTS: PIO 15, 30 and 45 mg enhanced HOMA-S compared with baseline (56.9-63.6%, p = 0.0298); (53.7-64.7%, p = 0.0008); (59.0-75.9%, p < 0.0001), respectively. Only the 45 mg dose showed a difference from placebo (p = 0.0025). Similarly, PIO enhanced QUICKI versus baseline (0.290-0.296, p = 0.0026); (0.287-0.299, p = 0.0001); (0.290-0.306, p = 0.0001), respectively. Both the 30 and 45 mg doses were different from placebo for QUICKI (p = 0.0005, p < 0.0001). PIO 15 and 30 mg plus SU enhanced HOMA-S compared with baseline (58.4-66.7%, p = 0.0007; 53.2-68.4%, p < 0.0001) and placebo plus SU (p = 0.0129, p < 0.0001, respectively). Likewise, PIO 15 and 30 mg plus SU enhanced QUICKI versus baseline (0.289-0.300, p = 0.0001; 0.287-0.305, p = 0.0001, respectively). Both doses had different effects from placebo plus SU (p = 0.0001) for QUICKI. PIO 30mg combined with MET enhanced HOMA-S versus baseline (66.2-82.2%, p < 0.0001) and placebo plus MET (p = 0.0002). Similarly, PIO 30 mg plus MET enhanced QUICKI compared with baseline (0.295-0.309, p = 0.0001) and placebo plus MET (p = 0.0001). CONCLUSION: PIO monotherapy and combination therapy with SU or MET enhanced insulin sensitivity as evaluated by HOMA-S and QUICKI. Both measures can detect changes in sensitivity for large numbers of subjects when the reference method hyperinsulinemic euglycemic clamp, or other complex methods are not feasible.

Twenty-four hour blood pressure effect of once-daily lisinopril, enalapril, and placebo in patients with mild to moderate hypertension.

This multicentre, double-blind, parallel-group, placebo-controlled study compared the antihypertensive effects of equal doses of two long-acting angiotensin converting enzyme (ACE) inhibitors. After a two-week, placebo run-in phase, 110 patients with mild to moderate hypertension were randomised to receive 10 mg lisinopril or enalapril, or placebo for 4 weeks. Office BPs were measured at regular intervals throughout the study. Twenty-four hour ambulatory blood pressure (ABP) was measured at baseline and after the first and final doses of study drug. Serum ACE activity and aldosterone were obtained concomitantly with each ABP monitoring. Office BP differences from placebo reached (P less than 0.05) or approached (P less than 0.10) statistical significance at all observations for the lisinopril group but were not significant for any observation in the enalapril group and approached significance on two occasions. After four weeks of treatment, ABP analysis revealed that the lisinopril and enalapril groups, when compared with placebo, had similar and significant systolic and diastolic AUC reductions (P less than 0.01) from baseline over the 24 h dosing interval. During the second half of the dosing interval, 13-24 h post drug administration, the lisinopril group was significantly different from placebo (systolic BP, P = 0.002; diastolic BP, P = 0.005) while the enalapril group was not. Both drugs were well tolerated. The results indicate that monotherapy with 10 mg of lisinopril is as effective as with 10 mg of enalapril, and that ABP monitoring is useful in more precisely depicting the clinical effect of the known pharmacokinetic properties of these two agents.

Combination therapy with pioglitazone plus metformin or sulfonylurea in patients with Type 2 diabetes: influence of prior antidiabetic drug regimen.

PURPOSE: To evaluate two trials of combination therapy, pioglitazone together with metformin or sulfonylurea, for Type 2 diabetes mellitus and to examine how pretrial antidiabetic therapies may have influenced the results. SUBJECTS AND METHODS: The results of two published trials that examine combination therapy, pioglitazone plus metformin or pioglitazone plus sulfonylurea were analyzed. A post hoc analysis was performed in which patients from both of these trials were subdivided on the basis of their oral antidiabetic therapy before enrollment into the trials. Those subsets receiving pretrial therapy with a sulfonylurea plus metformin - and discontinuing one of the agents before randomization - were compared to those receiving only one of the agents before enrollment. RESULTS: Patients in the combination pioglitazone (30 mg/day) plus metformin therapy arm of one trial, who entered with stable metformin monotherapy, experienced a significant decrease in glycosylated hemoglobin (HbA(1C)) levels during the 16-week course of the trial (-1.0+/-0.1 [mean+/-S.E.] percentage points; P<.05). In contrast, those in the same arm of the trial whose pretrial therapy included metformin plus a sulfonylurea - and who discontinued the sulfonylurea before enrollment - experienced no significant change in HbA(1C) levels (0.2+/-0.2 percentage points; P>.05). The difference between groups was significant (P<.001). Patients in the combination pioglitazone (15 or 30 mg/day) plus sulfonylurea therapy arm of the other trial, who entered the trial on stable sulfonylurea monotherapy, experienced significant decreases in HbA(1C) levels (-1.0+/-0.1 and -1.4+/-0.1 percentage points, respectively, for the 15- and 30-mg pioglitazone arms; P<.05). Those in the same arm whose pretrial therapy included sulfonylurea plus metformin - and who discontinued the metformin before enrollment - experienced no significant change in HbA(1C) levels. Differences between the groups separated on the basis of pretrial antidiabetic regimen were significant (P<.001). CONCLUSIONS: The efficacy of pioglitazone as an add-on in combination therapy (with metformin or a sulfonylurea) is likely to be greater than in previous reports, because those trial results were influenced by treatment regimens used by a portion of the patients before enrollment. Trials of oral hypoglycemic agents must be carefully constructed to consider the effects of agents given prior to the trial.

The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus.

BACKGROUND: To evaluate the glycemic control, lipid effects, and safety of pioglitazone in patients with type 2 diabetes mellitus. DESIGN AND METHODS: Patients (n = 197) with type 2 diabetes mellitus, a hemoglobin A1c (HbA1c) > or = 8.0%, fasting plasma glucose (FPG) > 7.7 mmol/l (140 mg/dl), and C-peptide > 0.331 nmol/l (1 ng/ml) were enrolled in this 23-week multi-center (27 sites), double-blind clinical trial and randomized to receive either a placebo or pioglitazone HCl 30 mg (pioglitazone), administered once daily, as monotherapy. Patients were required to discontinue all anti-diabetic medications 6 weeks before receiving study treatment. Efficacy parameters included HbA1c fasting plasma glucose (FPG), serum C-peptide, insulin, triglycerides (Tg), and cholesterol (total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C]). Adverse event rates, serum chemistry, and physical examinations were recorded. RESULTS: Compared with placebo, pioglitazone significantly (P= 0.0001) reduced HbA1c (-1.37% points), FPG (-3.19 mmol/l; -57.5 mg/dl), fasting C-peptide (-0.076+/-0.022 nmol/l), and fasting insulin (-11.88+/-4.70 pmol/l). Pioglitazone significantly (P < 0.001) decreased insulin resistance (HOMA-IR; -12.4+/-7.46%) and improved beta-cell function (Homeostasis Model Assessment (HOMA-BCF); +47.7+/-11.58%). Compared with placebo, fasting serum Tg concentrations decreased (-16.6%; P = 0.0178) and HDL-C concentrations increased (+12.6%; P= 0.0065) with pioglitazone as monotherapy. Total cholesterol and LDL-C changes were not different from placebo. The overall adverse event profile of pioglitazone was similar to that of placebo, with no evidence of drug-induced elevations of serum alanine transaminase (ALT) concentrations or hepatotoxicity. CONCLUSIONS: Pioglitazone improved insulin resistance and glycemic control, as well as Tg and HDL-C - which suggests that pioglitazone may reduce cardiovascular risk for patients with type 2 diabetes.

The latest developments in insulin injection devices.

The next several years promise dramatic changes in the treatment of diabetes, many of which will be driven by rapidly developing technology. Today's patient with diabetes has ready access to more information about the disease and its treatment options. As a result of this increased knowledge base, insulin-treated patients have become more autonomous in the management of their diabetes and may be better prepared to participate in making informed choices regarding insulin delivery devices. As with any insulin regimen, diabetes educators are encouraged to provide ongoing patient education and follow-up to assure optimal use of these new technologies.

Safety of insulin lispro: pooled data from clinical trials.

The safety of insulin lispro was compared with that of regular human insulin of recombinant DNA origin (Humulin R, Lilly), with special emphasis on the development and progression of the chronic complications of diabetes mellitus in relation to insulin therapy. Ten clinical trials of 3634 patients with type 1 and type 2 diabetes mellitus were analyzed. The primary focus was treatment-emergent adverse events, and the secondary focus was the development and progression of the chronic complications of diabetes. The evaluations were based on pertinent laboratory values, predetermined disease-specific COSTART (coding symbol and thesaurus for adverse event terminology) terms, physician evaluations of patients, and physical examinations. There were no clinically or statistically significant differences in the frequency of treatment-emergent adverse events or progression of retinopathy, neuropathy, or cardiovascular disease reported with each therapy. There was no difference between insulin lispro and Humulin R in the occurrence and progression of kidney disease as measured by changes in serum creatinine levels. Pooled data from clinical studies show that insulin lispro has a safety profile comparable to that of Humulin R.

A double-blind study of oxprenolol once and twice daily in hypertensive patients.

In a randomized double-blind study of 175 patients with mild-to-moderate hypertension, oxprenolol hydrochloride (160-480 mg) given once daily was compared with the same drug given twice daily for efficacy, safety, and tolerability. Of these patients, 123 (58 receiving the once daily regimen and 65 receiving the twice daily regimen) were included in the analysis of efficacy. Both groups showed similar significant (p less than 0.01) reductions in mean blood pressure during the 6-week titration period and for the remainder of the trial. A comparison of mean standing diastolic blood pressure and supine systolic and diastolic blood presses showed no significant difference between groups during the fixed dosage period. The number of patients reporting adverse experiences was not significantly different for the two regimens. Plasma triglycerides increased in both groups, but there were no other laboratory abnormalities related to treatment. This study shows that oxprenolol given once daily is effective, safe, and well tolerated in the treatment of mild-to-moderate hypertension.

Overlooked, overworked: women's unpaid and paid work in the health services' "cost crisis".

Dewaging shifts work from the marketplace to the household. The shift seems a short-term strategy used by capitalists, governmental policy-makers, and managers to reduce the wage bill for service workers in such areas as schooling, retailing, health services, and banking. In health services, the expansion of women's unpaid nursing in the household and a new labor process among paid nursing workers are necessary for new corporate and federal cost-containment strategies. Registered and licensed nurses, nurse's assistants and aides see their jobs eliminated, expanded, or moved from one work site to another. Increased use of outpatient clinics, in-and-out hospital stays of less than one day, and shortened hospital stays mean sick people in their homes, not hospitals. The work of caring for the sick does not disappear, however, though people may go without. Much nursing work is shifted to patients and to their families, and even to friends and neighbors. Within the family, women's unwaged work is central, supporting the new labor process among paid nurses. Wives, mothers, daughters, friends, etc., do the work once done for pay in clinics and hospitals.

Genome-wide association studies of cardiovascular risk factors: design, conduct and interpretation.

Relying on known biology, candidate-gene studies have been only modestly successful in identifying genetic variants associated with cardiovascular risk factors. Genome-wide association (GWA) studies, in contrast, allow broad scans across millions of loci in search of unsuspected genetic associations with phenotypes. The large numbers of statistical tests in GWA studies and the large sample sizes required to detect modest-sized associations have served as a powerful incentive for the development of large collaborative efforts such as the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. This article uses published data on three phenotypes, fibrinogen, uric acid, and electrocardiographic QT interval duration, from the CHARGE Consortium to describe several methodologic issues in the design, conduct, and interpretation of GWA studies, including the use of imputation and the need for additional genotyping. Even with large studies, novel genetic loci explain only a small proportion of the variance of cardiovascular phenotypes.

ABO genotype and risk of thrombotic events and hemorrhagic stroke.

BACKGROUND: The non-O alleles of the ABO genotype have been associated with an increased risk of thrombosis. Risk associated with the specific A(1), A(2) or B alleles is not well defined. OBJECTIVES: To examine the association of the ABO genotype with myocardial infarction (MI), ischemic stroke, hemorrhagic stroke, and venous thrombosis (VT). PATIENTS AND METHODS: We used data from two ongoing population-based case-control studies of MI, stroke, and VT. Cases included hypertensive adults and postmenopausal women with incident non-fatal MI (n = 1063), ischemic stroke (n = 469), and hemorrhagic stroke (n = 91), and postmenopausal women with incident non-fatal VT (n = 504). Controls were frequency matched to cases on age, sex, hypertension status, and year of identification. ABO genotypes were determined using single-nucleotide polymorphisms, and subjects were grouped by diplotype according to the presence of O(1), O(2), A(11), A(2) and B alleles. Logistic regression was used to test the association of diplotypes with risk of each outcome. RESULTS: As compared with the O(1)O(1) group, the A(11) allele was associated with an increased risk of VT [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.41-2.26] and MI (OR 1.23; 95% CI 1.05-1.44). The B allele was associated with an increased risk of VT (OR 1.82; 95% CI 1.29-2.57) and ischemic stroke (OR 1.59; 95% CI 1.17-2.17). The AB diplotype category was associated with a 2.7-fold risk of VT (OR 2.70; 95% CI 1.73-4.21). No other associations reached significance. CONCLUSIONS: The VT and MI findings are confirmatory, and the ischemic stroke finding with the B allele is a novel finding and needs replication.