Swimming is ideal for older adults because it includes minimum weight-bearing stress and decreased heat load. However, there is very little information available concerning the effects of regular swimming exercise on vascular risks. We determined if regular swimming exercise would decrease arterial blood pressure (BP) and improve vascular function. Forty-three otherwise healthy adults >50 years old (60 ؎ 2) with prehypertension or stage 1 hypertension and not on any medication were randomly assigned to 12 weeks of swimming exercise or attention time controls. Before the intervention period there were no significant differences in any of the variables between groups. Body mass, adiposity, and plasma concentrations of glucose and cholesterol did not change in either group throughout the intervention period. Casual systolic BP decreased significantly from 131 ؎ 3 to 122 ؎ 4 mm Hg in the swimming training group. Significant decreases in systolic BP were also observed in ambulatory (daytime) and central (carotid) BP measurements. Swimming exercise produced a 21% increase in carotid artery compliance (p <0.05). Flow-mediated dilation and cardiovagal baroreflex sensitivity improved after the swim training program (p <0.05). There were no significant changes in any measurements in the control group that performed gentle relaxation exercises. Regular exercise is universally the first-line approach to prevent and treat age-related increases in blood pressure (BP).1 Most studies to date, however, have employed walking, jogging, or cycling as activity modes.2 Currently, there is very little information available concerning the BP-lowering effects of regular swimming exercise. Thus far swimming exercise has been widely promoted and prescribed without the underpinning of firm scientific support from clinical studies.3 This is unfortunate because swimming is an ideal form of physical activity for older adults, particularly those with orthopedic problems, bronchospasm, heat disorders, and/or obesity, because it includes minimum weight-bearing stress, a humid environment, and decreased heat load.3 In addition, no information is available on whether regular swimming exercise modulates key measurements of vascular function (arterial stiffness and endothelium-dependent vasodilation) and whether they are related to the hypotensive effects of swimming exercise. The primary aim of the present study was to determine the effect of swimming exercise intervention on arterial BP and key measurements of vascular functions in adults Ͼ50 years of age with increased BP. To evaluate the effects on BP as comprehensively as possible, measurements of ambulatory, central, and casual BP were performed. MethodsMen and women 50 to 80 years of age were recruited from Austin, Texas and the surrounding communities. Every subject had a systolic BP at rest from 140 to 159 mm Hg (stage 1 systolic hypertension) or 120 to 139 mm Hg (prehypertension) with a diastolic BP of Ͻ99 mm Hg.1 No subjects had been smoking or taking antihypertensive medications. Subject...

Flow-mediated dilation (FMD) is a surrogate marker for endothelial function. In the FMD procedure, arterial response during cuff inflation is not taken into consideration yet studies have demonstrated vasoconstriction, vasodilation, and no change in the brachial artery during cuff inflation. The term low flow-mediated constriction (L-FMC) has been introduced to describe the vasoconstriction that occurs in some individuals during inflation of the cuff. PURPOSE: To determine 1) if brachial artery response during cuff inflation differed in a population with varied coronary artery disease (CAD) risk factor profiles, 2) the impact of this response on the subsequent calculation of FMD, and 3) the role of arterial stiffness in this variable response. METHODS: Low flow-mediated constriction (L-FMC), "traditional" FMD, and "modified" FMD that accounts for L-FMC by using inflation diameter in place of baseline diameter in calculating FMD, were studied in a total of 46 subjects. Subjects varied in age (38-62 years) and risk factor profiles for coronary artery disease. RESULTS: During cuff inflation, brachial artery responses varied widely from -5.6% (vasoconstriction) to 5.0% (vasodilation). When subjects were divided into healthy versus multiple risk factors (n=34), L-FMC and FMD were not different between the groups but modified FMD was significantly different (p=0.02). L-FMC was modestly but significantly associated with FMD (r=0.41) and positively correlated with brachial artery pulse wave velocity (r=0.30). CONCLUSION: Our results indicate that brachial artery responses to inflation of the cuff are very variable and are associated with arterial stiffness and that accounting for so-called L-FMC may provide a more comprehensive assessment of endothelial vasodilatory function.

PurposeWe hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination.Experimental DesignPatients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression.ResultsNinety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m2. Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥6 months (Total SD≥6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in Ktrans although analysis was limited by small sample size (N=12).ConclusionCombination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved.

Purpose The combination of DNA methylation inhibitors and histone deacetylase inhibitors is synergistic in gene expression activation and may overcome platinum resistance. Sequential treatment with azacitidine and valproic acid (VPA) in combination with carboplatin may overcome resistance to platinum-based therapy, and we conducted a phase I trial to assess safety, maximum tolerated dose (MTD), and clinical correlates. Experimental Design Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received azacitidine for 5 days from days 1 to 5, VPA for 7 days from days 5 to 11, and carboplatin starting in the second cycle on days 3 and 10. Clinical correlates included evaluation of epigenetic changes, methylation patterns, and histone acetylation levels in peripheral blood mononuclear cells. Results Thirty-two patients were treated. The MTD was 75 mg/m2 azacitidine, 20 mg/kg VPA, and AUC 3.0 carboplatin. Minor responses or stable disease lasting ≥4 months were achieved by six patients (18.8%), including three with platinum-resistant or platinum-refractory ovarian cancer. The most common adverse events grade ≥3 were fatigue (81%) and neutropenia (69%). Dose-limiting toxicity occurred in six patients (18.8%), including four patients with grade 3 altered mental status. Death receptor 4 (DR4) methylation was shown to decrease in a subset of patients, but there was no relationship with tumor response or number of cycles received. Conclusions Combination of azacitidine, VPA, and carboplatin demonstrates decreased DR4 methylation and modest evidence of antitumor activity in patients with heavily treated advanced malignancies.

Flow-mediated dilation (FMD) is a non-invasive index of endothelial function. In an attempt to standardize FMD for shear stimulus, shear rate (velocity/diameter), rather than shear stress (viscosity*velocity/diameter), is commonly used as a surrogate measure, although it is limited by individual differences in blood viscosity. The purpose of this study was to determine the contribution of whole blood viscosity to FMD and other key measures of vascular function. Blood viscosity, FMD, carotid artery compliance, and carotid-femoral pulse wave velocity (cfPWV) were measured in 98 apparently healthy adults varying widely in age (18-63 years). Whole blood viscosity was not significantly correlated with FMD, cfPWV, or carotid artery compliance. Shear rate was a stronger correlate with FMD than shear stress that takes blood viscosity into account (r = 0.43 vs 0.28). No significant differences were observed between whole blood viscosity and traditional risk factors for cardiovascular disease. Age was positively correlated with cfPWV (r = 0.65, p < 0.001) and negatively correlated with FMD (r = -0.24, p < 0.05) and carotid artery compliance (r = -0.45, p < 0.01). Controlling for viscosity did not reduce the strength of these relations. These results indicate that whole blood viscosity does not significantly impact measures of vascular function and suggests that the common practice to use shear rate, rather than shear stress, in the adjustment of FMD is valid.