Citations

We tested the hypothesis that reduced nitric oxide (NO) bioavailability contributes to the attenuated peak and total vasodilation following single-muscle contractions in older adults. Young ( n = 10; 24 ± 2 yr) and older ( n = 10; 67 ± 2 yr) adults performed single forearm contractions at 10, 20, and 40% of maximum during saline infusion (control) and NO synthase (NOS) inhibition via NG-monomethyl-l-arginine. Brachial artery diameters and velocities were measured using Doppler ultrasound and forearm vascular conductance (FVC; in ml·min−1·100 mmHg−1) was calculated from blood flow (ml/min) and blood pressure (mmHg). Peak and total vasodilator responses [change (Δ) in FVC from baseline] were attenuated in older adults at all intensities ( P < 0.05). NOS inhibition reduced the peak ΔFVC at 10% (88 ± 12 vs. 52 ± 9 ml·min−1·100 mmHg−1), 20% (125 ± 13 vs. 83 ± 13 ml·min−1·100 mmHg−1), and 40% (207 ± 26 vs. 133 ± 20 ml·min−1·100 mmHg−1) in young subjects, ( P < 0.05 for all) and in older adults at 10% (59 ± 5 vs. 47 ± 7 ml·min−1·100 mmHg−1, P < 0.05) and 20% (88 ± 9 vs. 68 ± 9 ml·min−1·100 mmHg−1, P < 0.05), but not 40% (128 ± 12 vs. 105 ± 11 ml·min−1·100 mmHg−1, P = 0.11). The relative (%) reduction in peak ΔFVC due to NOS inhibition was greater in young vs. older adults at 20% (−36 ± 5 vs. −23 ± 5%, P < 0.05) and 40% (−35 ± 6 vs. −16 ± 7%, P < 0.05). The reduction in the total vasodilator response (area under the curve) with NOS inhibition was also greater in young vs. older adults at all intensities. Our data suggest that contraction-induced rapid vasodilation is mediated in part by NO, and that the contribution of NO is greater in young adults.

Prehypertensives exhibit marked endothelial dysfunction, a risk factor for future cardiovascular morbidity and mortality. However, the ability of exercise to ameliorate endothelial dysfunction in prehypertensives is grossly underinvestigated. This prospective randomized and controlled study examined the separate effects of resistance and endurance training on conduit artery endothelial function in young prehypertensives. Forty-three unmedicated prehypertensive (systolic blood pressure [SBP]=120–139 mmHg; diastolic blood pressure [DBP]=80–89 mmHg) but otherwise healthy men and women and 15 normotensive matched time-controls (NMTC); n = 15) between 18 and 35 y of age met screening requirements and participated in the study. Prehypertensive subjects were randomly assigned to either a resistance exercise training (PHRT; n = 15), endurance exercise training (PHET; n = 13) or time-control group (PHTC; n = 15). The treatment groups performed exercise training three days per week for eight weeks. The control groups did not initiate exercise programs throughout the study. Flow mediated dilation (FMD) of the brachial artery, biomarkers of enodothelial function and peripheral blood pressure were evaluated before and after exercise intervention or time-matched control. PHRT and PHET reduced resting SBP (9.6 ± 3.6 and 11.9 ± 3.4 mmHg, respectively; P < 0.05) and DBP (8.0 ± 5.1 and 7.2 ± 3.4 mmHg, respectively; P < 0.05). Exercise training improved brachial artery FMD absolute diameter, percent dilation and normalized percent dilation by 30%, 34% and 19% for PHRT, P < 0.05; and by 54%, 63% and 75% for PHET, P < 0.05; respectively. PHRT and PHET increased plasma concentrations of 6-keto prostaglandin F1 α (19% and 22%, respectively; P < 0.05), NO x (19% and 23%, respectively; P < 0.05), and reduced endothelin-1 by (16% and 24%, respectively; P < 0.01). This study provides novel evidence that resistance and endurance exercise separately have beneficial effects on resting peripheral blood pressure, brachial artery FMD and endothelial-derived vasoactive agents in young prehypertensives.

AbstractFrontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD‐TDP). Recently, a genome‐wide association study identified the first FTLD‐TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD‐TDP risk. Intriguingly, the most significant association was in FTLD‐TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD‐TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B‐specific antibody for investigation of this protein. Enzyme‐linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over‐expression. However, over‐expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N‐glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD‐TDP risk. image We studied the p.T185S TMEM106B genetic variant previously implicated in frontotemporal dementia with TAR DNA binding protein 43 pathology caused by progranulin mutations. Our cell culture studies provide evidence that the protective S185 isoform is degraded more rapidly than T185 TMEM106B, potentially due to differences in glycosylation. These findings suggest that low TMEM106B levels might protect against FTLD‐TDP in these patients.

Abstract Background: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. Methods: We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign. Results: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. Conclusions: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk. Cancer Epidemiol Biomarkers Prev; 22(7); 1239–51. ©2013 AACR.

We hypothesized that demographic/anthropometric parameters can be used to estimate effective reflecting distance (EfRD), required to derive aortic pulse wave velocity (APWV), a prognostic marker of cardiovascular risk, from peripheral waveforms and that such estimates can discriminate differences in APWV and EfRD with aging and habitual endurance exercise in healthy adults. Ascending aortic pressure waveforms were derived from peripheral waveforms (brachial artery pressure, n = 25; and finger volume pulse, n = 15) via a transfer function and then used to determine the time delay between forward- and backward-traveling waves (Δ tf-b). True EfRDs were computed as directly measured carotid-femoral pulse wave velocity (CFPWV) × ½Δ tf-b and then used in regression analysis to establish an equation for EfRD based on demographic/anthropometric data (EfRD = 0.173·age + 0.661·BMI + 34.548 cm, where BMI is body mass index). We found good agreement between true and estimated APWV (Pearson's R2 = 0.43; intraclass correlation = 0.64; both P < 0.05) and EfRD ( R2 = 0.24; intraclass correlation = 0.40; both P < 0.05). In young sedentary (22 ± 2 years, n = 6), older sedentary (62 ± 1 years, n = 24), and older endurance-trained (61 ± 2 years, n = 14) subjects, EfRD (from demographic/anthropometric parameters), APWV, and ½Δ tf-b (from brachial artery pressure waveforms) were 52.0 ± 0.5, 61.8 ± 0.4, and 60.6 ± 0.5 cm; 6.4 ± 0.3, 9.6 ± 0.2, and 8.1 ± 0.2 m/s; and 82 ± 3, 65 ± 1 and 76 ± 2 ms (all P < 0.05), respectively. Our results demonstrate that APWV derived from peripheral waveforms using age and BMI to estimate EfRD correlates with CFPWV in healthy adults. This method can reliably detect the distal shift of the reflecting site with age and the increase in APWV with sedentary aging that is attenuated with habitual endurance exercise.

ABSTRACT Purpose We conducted a pilot randomized clinical trial of office‐based active vision therapy for the treatment of childhood amblyopia to determine the feasibility of conducting a full‐scale randomized clinical trial. Methods A training and certification program and manual of procedures were developed to certify therapists to administer a standardized vision therapy program in ophthalmology and optometry offices consisting of weekly visits for 16 weeks. Nineteen children, aged 7 to less than 13 years, with amblyopia (20/40–20/100) were randomly assigned to receive either 2 hours of daily patching with active vision therapy or 2 hours of daily patching with placebo vision therapy. Results Therapists in diverse practice settings were successfully trained and certified to perform standardized vision therapy in strict adherence with protocol. Subjects completed 85% of required weekly in‐office vision therapy visits. Eligibility criteria based on age, visual acuity, and stereoacuity, designed to identify children able to complete a standardized vision therapy program and judged likely to benefit from this treatment, led to a high proportion of screened subjects being judged ineligible, resulting in insufficient recruitment. There were difficulties in retrieving adherence data for the computerized home therapy procedures. Conclusions This study demonstrated that a 16‐week treatment trial of vision therapy was feasible with respect to maintaining protocol adherence; however, recruitment under the proposed eligibility criteria, necessitated by the standardized approach to vision therapy, was not successful. A randomized clinical trial of in‐office vision therapy for the treatment of amblyopia would require broadening of the eligibility criteria and improved methods to gather objective data regarding the home therapy. A more flexible approach that customizes vision therapy based on subject age, visual acuity, and stereopsis might be required to allow enrollment of a broader group of subjects.

PurposeIn 2D SENSE‐accelerated 3D Cartesian acquisition, the net acceleration factor R is the product of the two individual accelerations, R = RY × RZ. Acceleration Apportionment tailors acceleration parameters (RY, RZ) to improve parallel imaging performance on a patient‐ and coil‐specific basis and is demonstrated in contrast‐enhanced MR angiography.MethodsA performance metric is defined based on coil sensitivity information which identifies the (RY, RZ) pair that optimally trades off image quality with scan time reduction on a patient‐specific basis. Acceleration Apportionment is evaluated using retrospective analysis of contrast‐enhanced MR angiography studies, and prospective studies in which optimally apportioned parameters are compared with standard acceleration parameters.ResultsThe retrospective studies show strong variability in optimal acceleration parameters between anatomic regions and between patients. Prospective application of apportionment to foot contrast‐enhanced MR angiography with an 8‐channel receiver array provides a 20% increase in net acceleration with improved contrast‐to‐noise ratio. Application to 16‐channel contrast‐enhanced MR angiography of the feet and calves suggests 10% acceleration increase to R > 13 and no contrast‐to‐noise ratio loss. The specific implementation allows the optimum (RY, RZ) pair to be determined within one minute.ConclusionOptimum 2D SENSE acceleration parameters can be automatically chosen on a per‐exam basis to allow improved performance without disrupting the clinical workflow. Magn Reson Med 71:672–680, 2014. © 2013 Wiley Periodicals, Inc.