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Find video protocols related to scientific articles indexed in Pubmed.
The SIRT1 Activator SRT1720 Reverses Vascular Endothelial Dysfunction, Excessive Superoxide Production and Inflammation with Aging in Mice.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 10-19-2014
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Reductions in arterial SIRT1 expression and activity with aging are linked to vascular endothelial dysfunction. We tested the hypothesis that the specific SIRT1 activator, SRT1720, improves endothelial function (endothelium-dependent dilation, EDD) in old mice. Young (4-9 months) and old (29-32 months) male B6D2F1 mice treated with SRT1720 (100 mg/kg BW) or vehicle for four weeks were studied with a group of young controls. Compared with the young controls, aortic SIRT1 expression and activity were reduced (p < 0.05) and EDD was impaired (83 ± 2% vs. 96 ± 1%, p < 0.01) in old vehicle-treated animals. SRT1720 normalized SIRT1 expression/activity in old mice, and restored EDD (95 ± 1%) by enhancing cyclooxygenase (COX)-2 mediated dilation and protein expression in the absence of changes in nitric oxide bioavailability. Aortic superoxide production and expression of NOX4 were increased in old vehicle mice (p < 0.05), and ex vivo administration of the superoxide scavenger TEMPOL restored EDD in that group. SRT1720 normalized aortic superoxide production in old mice, without altering NOX4, and abolished the improvement in EDD with TEMPOL, while selectively increasing aortic antioxidant enzymes. Aortic nuclear factor ?B (NF-?B) activity and tumor necrosis factor-? (TNF-?) were increased in old vehicle mice (p < 0.05), whereas SRT1720 normalized NF-?B activation and reduced TNF-? in old animals. SIRT1 activation with SRT1720 ameliorates vascular endothelial dysfunction with aging in mice by enhancing COX-2 signaling and reducing oxidative stress and inflammation. Specific activation of SIRT1 is a promising therapeutic strategy for age-related endothelial dysfunction in humans.
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The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction.
J. Physiol. (Lond.)
PUBLISHED: 07-18-2014
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The critical influence of the white adipose tissue (WAT) on metabolism is well-appreciated in obesity, but adipose tissue dysfunction as a mechanism underlying age-associated metabolic dysfunction requires elucidation. To explore this possibility, we assessed metabolism and measures of epididymal (e)WAT mitochondria and artery function in young (6.1 ± 0.4 months) and old (29.6 ± 0.2 months) B6D2F1 mice. There were no group differences in average daily oxygen consumption, fasted blood glucose or plasma free fatty acids, but fasted plasma insulin and the homeostatic model assessment of insulin resistance (HOMA-IR%) were higher in the old (?50-85%, P < 0.05). Tissue mass (P < 0.05) and adipocyte area were lower (?60%) (P < 0.01) and fibrosis was greater (sevenfold, P < 0.01) in eWAT with older age. The old also exhibited greater liver triglycerides (?60%, P < 0.05). The mitochondrial respiratory oxygen flux after the addition of glutamate and malate (GM), adenosine diphosphate (d), succinate (S) and octanoyl carnitine (O) were one- to twofold higher in eWAT of old mice (P < 0.05). Despite no change in the respiratory control ratio, substrate control ratios of GMOd/GMd and GMOSd/GMd were ?30-40% lower in old mice (P < 0.05) and were concomitant with increased nitrotyrosine (P < 0.05) and reduced expression of brown adipose markers (P < 0.05). Ageing reduced vascularity (?50%, P < 0.01), angiogenic capacity (twofold, P < 0.05) and expression of vascular endothelial growth factor (?50%, P < 0.05) in eWAT. Finally, endothelium-dependent dilation was lower (P < 0.01) in isolated arteries from eWAT arteries of the old mice. Thus, metabolic dysfunction with advancing age occurs in concert with dysfunction in the adipose tissue characterized by both mitochondrial and arterial dysfunction.
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Evaluation of Trends of Inpatient Hospitalisation for Significant Haemorrhage in Patients Anticoagulated for Atrial Fibrillation before and after the Release of Novel Anticoagulants.
Heart Lung Circ
PUBLISHED: 07-03-2014
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Compared to Vitamin K antagonists (VKA), novel oral anticoagulants (NOACs) appear to be safer in terms of major bleeding risks with added advantage of having fixed dosing schedules when used in patients with non-valvular atrial fibrillation (AF). We sought to study the differences as sources and severity of anticoagulant-associated haemorrhage in patients with AF in the year preceding introduction of NOACs (first cohort) as compared to post approval of the NOACs (second cohort) by retrospectively reviewing the hospital admissions, as well as the pharmacodynamic and pharmacokinetic interactions between time periods. There were 359 patients for the first cohort and 405 patients for the second cohort, including 57 patients prescribed NOACs. There was no significant difference in age, deaths, source of bleeding, or rate of pharmacokinetic or pharmacodynamic interaction between the two time periods. Comparing all VKA patients to patients prescribed NOAC's, there were non-significant but higher rates of intracerebral bleed, significantly higher rates of pharmacokinetic (194 (25.4%) versus 0 (0%), p<.001) and similar rates of pharmacodynamic interactions (505 (66.1%) versus 39 (68.4%), p=.70). Drug-renal interactions were seen in 7 of the 57 (12.3%) NOAC-treated patients, in which all seven had acute renal failure that may have prolonged the effects of the anticoagulants. NOACs hold promise in that drug interactions are far less common than those seen in VKAs, and intracerebral bleeds appear to be less common in randomised trials as well as our review. For patients on dabigatran or rivaroxaban, consideration should be given to serial monitoring of renal function.
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Self-directed study using MP3 players to improve auscultation proficiency of physicians: a randomized, controlled trial.
J Contin Educ Health Prof
PUBLISHED: 06-19-2014
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Studies of physicians at all levels of training demonstrate significant deficiencies in cardiac auscultation skills. The best instructional methods to augment these skills are not known.
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Meta-analysis on efficacy of statins for prevention of contrast-induced acute kidney injury in patients undergoing coronary angiography.
Am. J. Cardiol.
PUBLISHED: 06-11-2014
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Contrast-induced acute kidney injury (CIAKI) is a leading cause of hospital-acquired acute kidney injury, and pretreatment with hydroxymethylglutaryl CoA reductase inhibitors (statins) have shown promise in prevention. A systematic review and meta-analysis was performed including randomized controlled trials of short-term high-dose statins (compared with either low-dose statin or placebo) for CIAKI prevention in patients undergoing coronary angiography. Study-specific odds ratios (ORs) were calculated, and between-study heterogeneity was assessed using the I(2) statistic. We used a random-effects model meta-analysis to pool the OR. Twelve RCTs, including 5,564 patients, were included. CIAKI occurred in 94 of 2,769 patients (3.4%) pretreated with high-dose statins and 213 of 2,795 patients (7.6%) in the low-dose or no-statin group (OR 0.43, 95% confidence interval [CI] 0.33 to 0.55, I(2) = 19%, p <0.001). Subgroup analysis showed that the occurrence of CIAKI did not differ in patients with diabetes (OR 0.60, 95% CI 0.43 to 0.85, I(2) = 0%, p = 0.004) or in patients with documented renal insufficiency (creatinine clearance <60 ml/min/m(2); OR 0.66, 95% CI 0.45 to 0.96, I(2) = 0%, p = 0.03). In conclusion, pretreatment with high-dose statins, compared with low-dose statins or placebo, in patients undergoing coronary angiography reduces the incidence of CIAKI. This benefit was seen irrespective of the presence of diabetes and chronic kidney disease. Future studies should identify optimum dosing protocols for each statin.
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Endothelin-A-Mediated Vasoconstriction During Exercise With Advancing Age.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 05-14-2014
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The endothelin-1 vasoconstrictor pathway contributes to age-related elevations in resting peripheral vascular tone primarily through activation of the endothelin subtype A (ETA) receptor. However, the regulatory influence of ETA-mediated vasoconstriction during exercise in the elderly is unknown. Thus, in 17 healthy volunteers (n = 8 young, 24±2 years; n = 9 old, 70±2 years), we examined leg blood flow, mean arterial pressure, leg arterial-venous oxygen (O2) difference, and leg O2 consumption (VO2) at rest and during knee-extensor exercise before and after intra-arterial administration of the ETA antagonist BQ-123. During exercise, BQ-123 administration increased leg blood flow to a greater degree in the old (+29±5 mL/min/W) compared with the young (+16±3 mL/min/W). The increase in leg blood flow with BQ-123 was accompanied by an increase in leg VO2 in both groups, suggesting a reduced efficiency following ETA receptor blockade. Together, these findings have identified an age-related increase in ETA-mediated vasoconstrictor activity that persists during exercise, suggesting an important role of this pathway in the regulation of exercising skeletal muscle blood flow and maintenance of arterial blood pressure in the elderly.
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Cellular aging of skeletal muscle: telomeric and free radical evidence that physical inactivity is responsible and not age.
Clin. Sci.
PUBLISHED: 04-09-2014
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Telomeres play an essential role in maintaining chromosomal integrity in the face of physiological stressors. Although the age-related shortening of TL (telomere length) in highly proliferative tissue is predominantly due to the replication process, the mechanism for telomere shortening in skeletal muscle, which is minimally proliferative, is unclear. By studying TL in both the upper and lower limbs of the young, old-mobile and old-immobile subjects and by virtue of the bipedal nature of human locomotion, which declines with age, it may be possible to elucidate the mechanism(s) responsible for cellular aging of skeletal muscle. With this approach, we revealed that TL (~15 kb) in arm skeletal muscle is unaffected by age. In contrast TL fell progressively in the legs across the young (~15 kb), the old mobile (~13 kb) and old immobile (~11 kb) subjects. Interestingly, there was a reciprocal increase in leg muscle free radicals across these groups that was correlated with TL (r=0.7), with no such relationship in the arm (r=0.09). Our results document that chronological age does not affect the cellular aging of skeletal muscle, but reveals that physical inactivity, probably mediated by free radicals, has a profound effect upon this process.
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Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping.
J. Hypertens.
PUBLISHED: 04-02-2014
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Telomere shortening in arteries could lead to telomere uncapping and cellular senescence, which in turn could promote the development of hypertension.
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Meta-analysis of efficacy and safety of rivaroxaban compared with warfarin or dabigatran in patients undergoing catheter ablation for atrial fibrillation.
Am. J. Cardiol.
PUBLISHED: 03-28-2014
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Several studies have been conducted to study the efficacy and safety of rivaroxaban in the atrial fibrillation periprocedural ablation period with similar rates of thromboembolism and major bleeding risks compared with warfarin or dabigatran. We sought to systematically review this evidence using pooled data from multiple studies. Studies comparing rivaroxaban with warfarin or dabigatran in patients undergoing catheter ablation for atrial fibrillation were identified through electronic literature searches of MEDLINE, EMBASE, clinicaltrials.gov, and the Cochrane library up to March 2014. Study-specific risk ratios (RRs) were calculated and combined using a random-effects model meta-analysis. In an analysis involving 3,575 patients, thromboembolism (composite of stroke, transient ischemic attack, and systemic and pulmonary emboli) occurred in 3 of 789 patients (0.4%) in the rivaroxaban group and 10 of 2,786 patients (0.4%) in the warfarin group (RR 0.71, 95% CI 0.26 to 1.96, I(2) = 0%, p = 0.51). Major hemorrhage occurred in 9 of 749 patients (1.2%) in the rivaroxaban group and 22 of 975 patients (2.3%) in the warfarin group (RR 0.49, 95% CI 0.24 to 1.02, I(2) = 0%, p = 0.06). Furthermore, direct efficacy and safety comparisons between rivaroxaban and dabigatran showed nonsignificant differences in rates of thromboembolism (0.5% vs 0.4%, respectively, RR 1.12, 95% CI 0.25 to 4.99, I(2) = 0%, p = 0.88) and major bleeding (1.0% vs 1.6%, respectively, RR = 0.71, 95% CI 0.16 to 3.15, I(2) = 22%, p = 0.66). In conclusion, our study suggests that patients treated with rivaroxaban during periprocedural catheter ablation have similar rates of thromboembolic events and major hemorrhage. Similar results were seen in direct comparisons between dabigatran and rivaroxaban.
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A Gut Gone to Pot: A Case of Cannabinoid Hyperemesis Syndrome due to K2, a Synthetic Cannabinoid.
Case Rep Emerg Med
PUBLISHED: 02-23-2014
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Cannabinoid Hyperemesis Syndrome (CHS) was first described in 2004. Due to its novelty, CHS is often unrecognized by clinicians leading to expensive workup of these patients with cyclical symptoms. It may take up to 9 years to diagnose CHS. CHS is characterized by cyclical nausea and vomiting, abdominal pain, and an unusual compulsion to take hot showers in the presence of chronic use of cannabinoids. Cannabicyclohexanol is a synthetic cannabinoid, popularly known as K2 spice. It is a popular marijuana alternative among teenagers and young adults since it is readily available as herbal incense. Unlike marijuana, many users know that K2 is not detected in conventional urine drug screens, allowing those users to conceal their intake from typical detection methods. Serum or urine gas chromatography mass spectrophotometry is diagnostic, though not widely available. Thus, it is imperative for clinicians to recognize CHS, even with negative UDS, to provide cost-effective care. We present a 38-year-old man with a 10-year history of cannabis, and 1-year history of K2 abuse admitted with 1-week history of episodes of nausea, vomiting of clear fluids, and epigastric discomfort. Symptoms are relieved only by hot showers. Extensive laboratory, radiologic, and endoscopic evaluation was unrevealing. CHS was diagnosed, based on proposed criteria by Simonetti et al.
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Smooth muscle specific disruption of the endothelin-A receptor in mice reduces arterial pressure, and vascular reactivity and affects vascular development.
Life Sci.
PUBLISHED: 01-14-2014
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The role of vascular smooth muscle endothelin A receptors (ETA) in development and normal physiology remains incompletely understood. To address this, mice were generated with smooth muscle-specific knockout (KO) of ETA.
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Dichotomous mechanisms of aortic stiffening in high-fat diet fed young and old B6D2F1 mice.
Physiol Rep
PUBLISHED: 01-01-2014
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Abstract Advancing age is associated with increased stiffness of large elastic arteries as assessed by aortic pulse wave velocity (PWV). Greater PWV, associated with increased risk of cardiovascular diseases, may result from altered expression of the extracellular matrix proteins, collagen and elastin, as well as cross-linking of proteins by advanced glycation end products (AGEs). Indeed, aortic PWV is greater in old (28-31 months) normal chow (NC, 16% fat by kcal)-fed male B6D2F1 mice compared with young (Y: 5-7 months) NC-fed mice (397 ± 8 vs. 324 ± 14 cm/s, P < 0.05). Aging also induces a ~120% increase in total aortic collagen content assessed by picosirius red stain, a ~40% reduction in medial elastin assessed by Verhoeff's Van Geison stain, as well as a 90% greater abundance of AGEs in the aorta (P < 0.05). The typical American diet contains high dietary fat and may contribute to the etiology of arterial stiffening. To that end, we hypothesized that the age-associated detriments in arterial stiffening are exacerbated in the face of high dietary fat. In young animals, high-fat (40% fat by kcal) diet increases aortic stiffness by 120 ± 18 cm/s relative to age-matched NC-fed mice (P < 0.001). High-fat was without effect on aortic collagen or AGEs content in young animals; however, elastin was greatly reduced (~30%) after high-fat in young mice. In old animals, high-fat increased aortic stiffness by 108 ± 47 cm/s but was without effect on total collagen content, medial elastin, or AGEs. These data demonstrate that both aging and high-fat diet increase aortic stiffness, and although a reduction in medial elastin may underlie increased stiffness in young mice, stiffening of the aorta in old mice after high-fat diet does not appear to result from a similar structural modification.
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Mesenteric vein thrombosis in a patient heterozygous for factor V Leiden and G20210A prothrombin genotypes.
World J. Gastroenterol.
PUBLISHED: 07-26-2013
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Mesenteric venous thrombosis (MVT) is a rare but life threatening form of bowel ischemia. It is implicated in 6%-9% of all cases of acute mesenteric ischemia. The proportion of patients with primary (or idiopathic) MVT varies from 0% to 49%, with a decrease in frequency secondary to more recent availability of newer investigations for hypercoagulability. The presence of factor V Leiden (FVL) and prothrombin G20210A mutations (PGM) have been well documented in these cases. However, there have been scarce case reports describing MVT in heterozygotes of both these mutations occurring simultaneously and its implications on long term management. Our case describes acute MVT in a previously asymptomatic young patient with no prior history of venous thromboembolism. The patient was found to be heterozygous for FVL and PGM and treated with lifelong anticoagulation with warfarin (goal international normalized ratio: 2-3) and avoidance of hormonal contraceptives.
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Sun, iron, alcohol and intrinsic liver disease: a recipe for failure.
BMJ Case Rep
PUBLISHED: 07-04-2013
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A 62-year-old Caucasian woman, with remote history of painful skin blistering and hypertrichosis, recent history of travel to Mexico and increased alcohol consumption, presented with progressively worsening jaundice and fatigue. Physical examination was remarkable for severe generalised jaundice, scleral icterus and erythematous facial blistering and scarring. Laboratory workup revealed markedly elevated total and direct bilirubin, mildly elevated transaminases, severe iron overload and increased urine coproporphyrin. Porphyria cutanea tarda was diagnosed, and she was treated with supportive measures including hydration and alcohol cessation. Pathology of her liver demonstrated mild iron overload and severe fatty infiltration. Hospital follow-up revealed complete resolution of jaundice and fatigue and near-normalisation of liver function tests.
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Never too early for the opportunists!
BMJ Case Rep
PUBLISHED: 06-19-2013
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Primary HIV infection can occur in 40-90% of individuals recently infected with HIV. Variable symptoms usually suggestive of a flu-like illness as well as high-level HIV viraemia and steep decline in CD4 cell count are often noted. We report a case of a previously healthy homosexual man who presented with symptoms suspicious of primary HIV infection as well as non-productive cough associated with chest CT finding of diffuse ground glass appearance in lungs. Recent HIV seroconversion was confirmed. Diagnosis of Pneumocystis jirovecii pneumonia was made on transbronchial lung biopsy. The symptoms improved rapidly after initiation of treatment with trimethoprim-sulfamethoxazole. It is important to recognise that although Pneumocystis pneumonia is generally seen in the setting of AIDS, it can occasionally also occur during primary HIV infection.
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Beneficial effects of lifelong caloric restriction on endothelial function are greater in conduit arteries compared to cerebral resistance arteries.
Age (Dordr)
PUBLISHED: 05-31-2013
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Endothelial dysfunction occurs in conduit and cerebral resistance arteries with advancing age. Lifelong caloric restriction (CR) can prevent the onset of age-related dysfunction in many tissues, but its effects on cerebral resistance artery function, as compared with conduit artery function, have not been determined. We measured endothelium-dependent dilation (EDD) in the carotid artery and middle cerebral artery (MCA) from young (5-7 months), old ad libitum fed (AL, 29-32 months), and old lifelong CR (CR, 40 % CR, 29-32 months) B6D2F1 mice. Compared with young, EDD for old AL was 24 % lower in the carotid and 47 % lower in the MCA (p??0.05), but was 25 % lower than young in the MCA (p??0.05), with no effect in young or old CR (p?>?0.05). In the MCA, incubation with TEMPOL or the NADPH oxidase inhibitor apocynin augmented EDD in old AL (p?
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Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice.
Aging Cell
PUBLISHED: 05-13-2013
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Aging impairs arterial function through oxidative stress and diminished nitric oxide (NO) bioavailability. Life-long caloric restriction (CR) reduces oxidative stress, but its impact on arterial aging is incompletely understood. We tested the hypothesis that life-long CR attenuates key features of arterial aging. Blood pressure, pulse wave velocity (PWV, arterial stiffness), carotid artery wall thickness and endothelium-dependent dilation (EDD; endothelial function) were assessed in young (Y: 5-7 month), old ad libitum (Old AL: 30-31 month) and life-long 40% CR old (30-31 month) B6D2F1 mice. Blood pressure was elevated with aging (P < 0.05) and was blunted by CR (P < 0.05 vs. Old AL). PWV was 27% greater in old vs. young AL-fed mice (P < 0.05), and CR prevented this increase (P < 0.05 vs. Old AL). Carotid wall thickness was greater with age (P < 0.05), and CR reduced this by 30%. CR effects were associated with amelioration of age-related changes in aortic collagen and elastin. Nitrotyrosine, a marker of cellular oxidative stress, and superoxide production were greater in old AL vs. young (P < 0.05) and CR attenuated these increase. Carotid artery EDD was impaired with age (P < 0.05); CR prevented this by enhancing NO and reducing superoxide-dependent suppression of EDD (Both P < 0.05 vs. Old AL). This was associated with a blunted age-related increase in NADPH oxidase activity and p67 expression, with increases in superoxide dismutase (SOD), total SOD, and catalase activities (All P < 0.05 Old CR vs. Old AL). Lastly, CR normalized age-related changes in the critical nutrient-sensing pathways SIRT-1 and mTOR (P < 0.05 vs. Old AL). Our findings demonstrate that CR is an effective strategy for attenuation of arterial aging.
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Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 05-10-2013
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Arterial telomere dysfunction may contribute to chronic arterial inflammation by inducing cellular senescence and subsequent senescence-associated inflammation. Although telomere shortening has been associated with arterial aging in humans, age-related telomere uncapping has not been described in non-cultured human tissues and may have substantial prognostic value. In skeletal muscle feed arteries from 104 younger, middle-aged, and older adults, we assessed the potential role of age-related telomere uncapping in arterial inflammation. Telomere uncapping, measured by p-histone ?-H2A.X (ser139) localized to telomeres (chromatin immunoprecipitation; ChIP), and telomeric repeat binding factor 2 bound to telomeres (ChIP) was greater in arteries from older adults compared with those from younger adults. There was greater tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence, measured by P53 bound to P21 gene promoter (ChIP), and greater expression of P21, interleukin 8, and monocyte chemotactic protein 1 mRNA (RT-PCR) in arteries from older adults compared with younger adults. Telomere uncapping was a highly influential covariate for the age-group difference in P53/P21-induced senescence. Despite progressive age-related telomere shortening in human arteries, mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence. Collectively, these findings demonstrate that advancing age is associated with greater telomere uncapping in arteries, which is linked to P53/P21-induced senescence independent of telomere shortening.
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Aging compounds western diet-associated large artery endothelial dysfunction in mice: prevention by voluntary aerobic exercise.
Exp. Gerontol.
PUBLISHED: 05-09-2013
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We tested the hypothesis that aging will exacerbate the negative vascular consequences of exposure to a common physiological stressor, i.e., consumption of a "western" (high fat/high sucrose) diet (WD), by inducing superoxide-associated reductions in nitric oxide (NO) bioavailability, and that this would be prevented by voluntary aerobic exercise. Incremental stiffness and endothelium-dependent dilation (EDD) were measured in the carotid arteries of young (5.4±0.3 mo, N=20) and old (30.4±0.2 mo, N=19) male B6D2F1 mice fed normal chow (NC: 17% fat, 0% sucrose) or a western diet (40% fat, 19% sucrose) and housed in either standard cages or cages equipped with running wheels for 10-14 weeks. Incremental stiffness was higher in old NC (P<0.05) and both young (P<0.01) and old (P<0.01) WD fed mice compared with young NC mice, but WD did not further increase stiffness in the old mice. In cage control mice, maximal EDD was 17% lower in both NC fed old mice and young WD fed mice (P<0.05). Consumption of WD by old mice led to a further 20% reduction in maximal EDD (P<0.05). Incremental stiffness was 28% lower and maximal EDD was 38% greater in old WD fed mice with access to running wheels vs. old WD fed control mice (P<0.05) and not different from young NC fed controls. Wheel running also tended to improve maximal EDD (+9%, P=0.11), but not incremental stiffness in young WD fed mice. Ex vivo treatment with the superoxide scavenger TEMPOL and NO inhibitor l-NAME abolished these respective effects of age, WD and voluntary running on EDD. Ingestion of a WD induces similar degrees of endothelial dysfunction in old and young adult B6D2F1 mice, and these effects are mediated by a superoxide-dependent impairment of NO bioavailability. However, the combination of old age and WD, a common occurrence in our aging society, results in a marked, additive reduction in endothelial function. Importantly, regular voluntary aerobic exercise reduces arterial stiffness and protects against the adverse influence of WD on endothelial function in old animals by preventing superoxide suppression of NO. These findings may have important implications for arterial aging and the prevention of age-associated cardiovascular diseases.
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Habitually exercising older men do not demonstrate age-associated vascular endothelial oxidative stress.
Aging Cell
PUBLISHED: 10-17-2011
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We tested the hypothesis that older men who perform habitual aerobic exercise do not demonstrate age-associated vascular endothelial oxidative stress compared with their sedentary peers. Older exercising men (n=13, 62±2 years) had higher (P<0.05) physical activity (79±7 vs. 30±6 MET hours per week) and maximal exercise oxygen consumption (42±1 vs. 29±1 mL kg(-1) per minute) vs. sedentary men (n=28, 63±1 years). Brachial artery flow-mediated dilation (FMD), a measure of vascular endothelial function, was greater (P<0.05) in the exercising vs. sedentary older men (6.3±0.5 vs. 4.9±0.4%?) and not different than young controls (n=20, 25±1 years, 7.1±0.5%?). In vascular endothelial cells sampled from the brachial artery, nitrotyrosine, a marker of oxidative stress, was 51% lower in the exercising vs. sedentary older men (0.38±0.06 vs. 0.77±0.10 AU). This was associated with lower endothelial expression of the oxidant enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47(phox) subunit, 0.33±0.05 vs. 0.61±0.09 AU) and the redox-sensitive transcription factor nuclear factor kappa B (NF?B) (p65 subunit, 0.36±0.05 vs. 0.72±0.09 AU). Expression of the antioxidant enzyme manganese superoxide dismutase (SOD) (0.57±0.13 vs. 0.30±0.04 AU) and activity of endothelium-bound extracellular SOD were greater (6.4±0.5 vs. 5.0±0.6 U mL(-1) per minute) in the exercising men (both P<0.05), but differences no longer were significant after correcting for adiposity and circulating metabolic factors. Overall, values for the young controls differed with those for the sedentary, but not the exercising older men. Older men who exercise regularly do not demonstrate vascular endothelial oxidative stress, and this may be a key molecular mechanism underlying their reduced risk of cardiovascular diseases.
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MicroRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation.
Exp. Gerontol.
PUBLISHED: 09-09-2011
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A senescent phenotype in endothelial cells is associated with increased apoptosis, reduced endothelial nitric oxide synthase (eNOS) and inflammation, which are implicated in arterial dysfunction and disease in humans. We tested the hypothesis that changes in microRNAs are associated with a senescent phenotype in human aortic endothelial cells (HAEC). Compared with early-passage HAEC, late-passage HAEC had a reduced proliferation rate and increased staining for senescence-associated beta-galactosidase and the tumor suppressor p16(INK4a). Late-passage senescent HAEC had reduced expression of proliferation-stimulating/apoptosis-suppressing miR-21, miR-214 and miR-92 and increased expression of tumor suppressors and apoptotic markers. eNOS-suppressing miR-221 and miR-222 were increased and eNOS protein and eNOS activation (phosphorylation at serine1177) were lower in senescent HAEC. Caveolin-1 inhibiting miR-133a was reduced and caveolin-1, a negative regulator of eNOS activity, was elevated in senescent HAEC. Inflammation-repressing miR-126 was reduced and inflammation-stimulating miR-125b was increased, whereas inflammatory proteins were greater in senescent HAEC. Development of a senescent arterial endothelial cell phenotype featuring reduced cell proliferation, enhanced apoptosis and inflammation and reduced eNOS is associated with changes in miRNAs linked to the regulation of these processes. Our results support the hypothesis that miRNAs could play a critical role in arterial endothelial cell senescence.
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Stridor and dysphagia associated with subthalamic nucleus stimulation in Parkinson disease.
J. Neurosurg.
PUBLISHED: 08-05-2011
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Refractory symptoms in Parkinson disease show good response to deep brain stimulation (DBS). This procedure improves United Parkinsons Disease Rating Scale scores and reduces dyskinesias, whereas speech and swallowing dysfunction typically do not improve and may even worsen. Rarely, DBS can cause idiosyncratic dystonias of muscle groups, including those of the neck and throat. The authors describe a patient experiencing stridor and dysphagia with confirmed pulmonary restriction and aspiration following subthalamic nucleus deep brain stimulator adjustment, with a resolution of symptoms and signs when the stimulator was switched off.
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SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans.
J. Physiol. (Lond.)
PUBLISHED: 07-11-2011
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We tested the hypothesis that reductions in the cellular deacetylase, sirtuin-1 (SIRT-1), contribute to vascular endothelial dysfunction with ageing via modulation of endothelial nitric oxide synthase (eNOS) acetylation/activation-associated nitric oxide (NO) production. In older (30 months, n = 14) vs. young (5-7 months, n = 16) B6D2F1 mice, aortic protein expression of SIRT-1 and eNOS phosphorylated at serine 1177 were lower (both P < 0.05), and acetylated eNOS was 6-fold higher (P < 0.05), whereas total eNOS did not differ (P = 0.65). Acetylcholine (ACh)-induced peak endothelium-dependent dilatation (EDD) was lower in isolated femoral arteries with ageing (P < 0.001). Incubation with sirtinol, a SIRT-1 inhibitor, reduced EDD in both young and older mice, abolishing age-related differences, whereas co-administration with l-NAME, an eNOS inhibitor, further reduced EDD similarly in both groups. Endothelium-independent dilatation to sodium nitroprusside (EID), was not altered by age or sirtinol treatment. In older (64 ± 1 years, n = 22) vs. young (25 ± 1 years, n = 16) healthy humans, ACh-induced forearm EDD was impaired (P = 0.01) and SIRT-1 protein expression was 37% lower in endothelial cells obtained from the brachial artery (P < 0.05), whereas EID did not differ. In the overall group, EDD was positively related to endothelial cell SIRT-1 protein expression (r = 0.44, P < 0.01). Reductions in SIRT-1 may play an important role in vascular endothelial dysfunction with ageing. SIRT-1 may be a key therapeutic target to treat arterial ageing.
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Aerobic exercise reverses arterial inflammation with aging in mice.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 05-27-2011
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We tested the hypothesis that regular aerobic exercise reverses arterial inflammation with aging. When compared with young controls (6.2 ± 0.4 mo; n = 7), old (31.3 ± 0.5 mo; n = 11) male B6D2F1 cage-restricted mice demonstrated increased arterial activation of the proinflammatory transcription factor NF-?B, as indicated by greater aortic phosphorylation of both the inhibitor of NF-?B kinase (IKK) and the p65 subunit of NF-?B (both P < 0.05). Similarly, aortic expression of the proinflammatory cytokines IL-1 and IL-6, IFN-?, and TNF-? were greater in the old mice (all P < 0.05). Macrophage and T lymphocyte abundance was unchanged with age in the aortic intima and media but was markedly increased in the adventitia and perivascular fat tissue of old mice (all P < 0.05). This proinflammatory arterial phenotype with aging was associated with vascular dysfunction, as reflected by impaired nitric oxide-mediated endothelium-dependent dilation. Voluntary wheel running (10-14 wk) normalized aortic IKK-NF-?B activation, cytokine expression, adventitial and perivascular macrophage infiltration, and vascular function in old mice (32.4 ± 0.3 mo; n = 8) while having no consistent effects in young mice. Short-term voluntary wheel running started late in life reverses arterial inflammation with aging in mice possibly via outside-in actions. These anti-inflammatory effects may play an important role in the amelioration of age-associated vascular dysfunction by regular aerobic exercise.
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Increased proinflammatory and oxidant gene expression in circulating mononuclear cells in older adults: amelioration by habitual exercise.
Physiol. Genomics
PUBLISHED: 05-24-2011
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We tested the hypothesis that peripheral blood mononuclear cells (PBMC) of older adults demonstrate a proinflammatory/-oxidative gene expression profile that can be improved by regular aerobic exercise. PBMC were isolated from young (n = 25, 18-33 yr) and middle-aged/older (n = 40, 50-76 yr) healthy adults. The older adults had greater mRNA expression (real-time RT-PCR) of the proinflammatory/-oxidant transcription factor nuclear factor-?B (1.58-fold, P < 0.05) and receptor for advanced glycation end products (1.12-fold, P < 0.05), the proinflammatory cytokines tumor necrosis factor-? (1.90-fold, P < 0.05) and monocyte chemoattractant protein-1 (1.47-fold, P < 0.05), and the oxidant-producing enzymes nicotinamide adenine dinucleotide phosphate-oxidase (0.91-fold, P < 0.05) and inducible nitric oxide synthase (2.60-fold, P < 0.05). In 11 subjects (58-70 yr), maximal oxygen consumption (+11%) and exercise time (+19%) were increased (both P < 0.001), and expression of the above proinflammatory/-oxidative genes was or tended to be decreased in PBMC after vs. before 2 mo of aerobic exercise (brisk walking ?6 days/wk, 50 min/day, 70% of maximal heart rate). Expression of interleukin-6 was not different with age or exercise intervention. Age group- and exercise intervention-related differences in gene expression were independent of other factors. PBMC of healthy older adults demonstrate increased expression of several genes associated with inflammation and oxidative stress, which is largely ameliorated by habitual aerobic exercise. This proinflammatory/-oxidative gene signature may represent a therapeutic target for lifestyle and pharmacological prevention and treatment strategies.
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Predictive accuracy of ST depression during rapid atrial fibrillation on the presence of obstructive coronary artery disease.
Am J Emerg Med
PUBLISHED: 05-15-2011
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Rapid atrial fibrillation (AF) is commonly associated with ST-segment depressions. ST-segment depression during a chest pain episode or exercise stress testing in sinus rhythm is predictive of obstructive coronary artery disease (CAD), but it is unclear if the presence or magnitude of ST-segment depression during rapid AF has similar predictive accuracy.
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Salicylate treatment improves age-associated vascular endothelial dysfunction: potential role of nuclear factor kappaB and forkhead Box O phosphorylation.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 02-08-2011
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We hypothesized that I kappa B kinase (IKK)-mediated nuclear factor kappa B and forkhead BoxO3a phosphorylation will be associated with age-related endothelial dysfunction. Endothelium-dependent dilation and aortic protein expression/phosphorylation were determined in young and old male B6D2F1 mice and old mice treated with the IKK inhibitor, salicylate. IKK activation was greater in old mice and was associated with greater nitrotyrosine and cytokines. Endothelium-dependent dilation, nitric oxide (NO), and endothelial NO synthase phosphorylation were lower in old mice. Endothelium-dependent dilation and NO bioavailability were restored by a superoxide dismutase mimetic. Nuclear factor kappa B and forkhead BoxO3a phosphorylation were greater in old and were associated with increased expression/activity of nicotinamide adenine dinucleotide phosphate oxidase and lower manganese superoxide dismutase expression. Salicylate lowered IKK phosphorylation and reversed age-associated changes in nitrotyrosine, endothelium-dependent dilation, NO bioavailability, endothelial NO synthase, nuclear factor kappa B and forkhead BoxO3a phosphorylation, nicotinamide adenine dinucleotide phosphate oxidase, and manganese superoxide dismutase. Increased activation of IKK with advancing age stimulates nuclear factor kappa B and inactivates forkhead BoxO3a. This altered transcription factor activation contributes to a pro-inflammatory/pro-oxidative arterial phenotype that is characterized by increased cytokines and nicotinamide adenine dinucleotide phosphate oxidase and decreased manganese superoxide dismutase leading to oxidative stress-mediated endothelial dysfunction.
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Aging and vascular endothelial function in humans.
Clin. Sci.
PUBLISHED: 01-20-2011
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Advancing age is the major risk factor for the development of CVD (cardiovascular diseases). This is attributable, in part, to the development of vascular endothelial dysfunction, as indicated by reduced peripheral artery EDD (endothelium-dependent dilation) in response to chemical [typically ACh (acetylcholine)] or mechanical (intravascular shear) stimuli. Reduced bioavailability of the endothelium-synthesized dilating molecule NO (nitric oxide) as a result of oxidative stress is the key mechanism mediating reduced EDD with aging. Vascular oxidative stress increases with age as a consequence of greater production of reactive oxygen species (e.g. superoxide) without a compensatory increase in antioxidant defences. Sources of increased superoxide production include up-regulation of the oxidant enzyme NADPH oxidase, uncoupling of the normally NO-producing enzyme, eNOS (endothelial NO synthase) (due to reduced availability of the cofactor tetrahydrobiopterin) and increased mitochondrial synthesis during oxidative phosphorylation. Increased bioactivity of the potent endothelial-derived constricting factor ET-1 (endothelin-1), reduced endothelial production of/responsiveness to dilatory prostaglandins, the development of vascular inflammation, formation of AGEs (advanced glycation end-products), an increased rate of endothelial apoptosis and reduced expression of oestrogen receptor ? (in postmenopausal females) also probably contribute to impaired EDD with aging. Several lifestyle and biological factors modulate vascular endothelial function with aging, including regular aerobic exercise, dietary factors (e.g. processed compared with non-processed foods), body weight/fatness, vitamin D status, menopause/oestrogen deficiency and a number of conventional and non-conventional risk factors for CVD. Given the number of older adults now and in the future, more information is needed on effective strategies for the prevention and treatment of vascular endothelial aging.
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The paradox of oxidative stress and exercise with advancing age.
Exerc Sport Sci Rev
PUBLISHED: 01-06-2011
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Aging, vascular function, and exercise are thought to have a common link in oxidative stress. Both antioxidant supplementation and exercise training have been identified as interventions that may reduce oxidative stress, but their interaction in older humans is not well understood.
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Human vascular aging: limb-specific lessons.
Exerc Sport Sci Rev
PUBLISHED: 09-28-2010
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Unlike quadrupeds, human limbs are exposed to differing homeostatic challenges and uses across the life span. This raises the question of whether vascular function and skeletal muscle blood flow regulation differs between human limbs and whether these limb-specific parameters may be altered during exercise as a consequence of aging and disease.
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Life-long caloric restriction elicits pronounced protection of the aged myocardium: a role for AMPK.
Mech. Ageing Dev.
PUBLISHED: 05-19-2010
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Short-term caloric restriction (CR) protects the young myocardium against ischemia/reperfusion (I/R) injury through a mechanism involving AMP-activated protein kinase (AMPK). Here we ask whether a life-long CR intervention can extend this protection to the aged myocardium, and whether AMP-activated protein kinase (AMPK) plays a role in that protection. Hearts from ad libitum fed (AL) and life-long calorically restricted (LCR) mice were examined at 30 months of age by 25/90min global I/R, with and without AMPK inhibition (AraA). LCR hearts were protected from infarction (AL, 28±4% vs. LCR, 10±1%, p<0.01) and post-ischemic functional deficit (LVDP recovery: AL, 65±8% vs. LCR, 93±7%, p<0.01). Pre-ischemic AraA impaired both of these protective effects (Infarct size: LCR+AraA, 22±4%; LVDP recovery: LCR+AraA, 82±9%, both p vs. AL >0.1). AMPK? phosphorylation was dramatically increased in LCR hearts prior to I/R (AL, 1.18±0.01 vs. LCR, 1.68±0.04, ratio, p<0.0001), and accompanied by a more modest increase in total AMPK? (AL, 2.18±0.03 vs. LCR, 2.39±0.08 ratio, p<0.05). These results indicate that life-long caloric restriction profoundly protects the aged heart against I/R injury, and suggest that AMPK may play a role in that protection.
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Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography.
Thromb. Res.
PUBLISHED: 04-05-2010
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CT Pulmonary Angiography has been shown to be equivalent to Ventilation/ Perfusion scanning in 3-month outcome studies, but it detects more pulmonary emboli. Isolated subsegmental pulmonary emboli are thought to account for some of the increase in diagnosis, but it is not known whether these emboli represent a harbinger for future thromboembolic events. The objective of this study was to determine the 3-month clinical outcomes of a cohort of patients diagnosed with isolated subsegmental pulmonary emboli.
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Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress.
Aging Cell
PUBLISHED: 03-13-2010
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To determine if short-term calorie restriction reverses vascular endothelial dysfunction in old mice, old (O, n = 30) and young (Y, n = 10) male B6D2F1 mice were fed ad libitum (AL) or calorie restricted (CR, approximately 30%) for 8 weeks. Ex vivo carotid artery endothelium-dependent dilation (EDD) was impaired in old ad libitum (OAL) vs. young ad libitum (YAL) (74 +/- 5 vs. 95 +/- 2% of maximum dilation, P < 0.05), whereas old calorie-restricted (OCR) and YCR did not differ (96 +/- 1 vs. 94 +/- 3%). Impaired EDD in OAL was mediated by reduced nitric oxide (NO) bioavailability associated with decreased endothelial NO synthase expression (aorta) (P < 0.05), both of which were restored in OCR. Nitrotyrosine, a cellular marker of oxidant modification, was markedly elevated in OAL (P < 0.05), whereas OCR was similar to Y. Aortic superoxide production was 150% greater in OAL vs. YAL (P < 0.05), but normalized in OCR, and TEMPOL, a superoxide dismutase (SOD) mimetic that restored EDD in OAL (to 97 +/- 2%), had no effect in Y or OCR. OAL had increased expression and activity of the oxidant enzyme, NADPH oxidase, and its inhibition (apocynin) improved EDD, whereas NADPH oxidase in OCR was similar to Y. Manganese SOD activity and sirtuin1 expression were reduced in OAL (P < 0.05), but restored to Y in OCR. Inflammatory cytokines were greater in OAL vs. YAL (P < 0.05), but unaffected by CR. Carotid artery endothelium-independent dilation did not differ among groups. Short-term CR initiated in old age reverses age-associated vascular endothelial dysfunction by restoring NO bioavailability, reducing oxidative stress (via reduced NADPH oxidase-mediated superoxide production and stimulation of anti-oxidant enzyme activity), and upregulation of sirtuin-1.
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Vascular endothelial function is related to white blood cell count and myeloperoxidase among healthy middle-aged and older adults.
Hypertension
PUBLISHED: 01-04-2010
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Endothelium-dependent dilation (EDD) is impaired with aging, but there is significant variability among healthy middle-aged and older adults. We tested the hypothesis that EDD is related to white blood cell (WBC) count in healthy men and women aged 55 to 75 years (n=48) who have a WBC count within the clinically normal range. The peak forearm blood flow response to intrabrachial artery infusion of acetylcholine was inversely related to WBC count (r=-0.38; P=0.004) and was 34% smaller in subjects with higher versus lower WBC count (more versus less than the median of 5.0x10(9) cells per liter; P=0.001). Vascular smooth muscle responsiveness to NO (peak forearm blood flow response to sodium nitroprusside) was inversely related to WBC count (r=-0.30; P=0.02) but did not fully explain the associations with EDD. Inhibition of NO with N(G)-monomethyl-L-arginine reduced EDD in subjects with lower (-56%; P=0.01) but not higher WBC count. Tetrahydrobiopterin selectively improved EDD in subjects with higher WBC count (+35%; P=0.01) by increasing NO bioavailability. EDD was related (P<0.05) to neutrophil, eosinophil, and monocyte but not lymphocyte or basophil counts. Myeloperoxidase, which is secreted by neutrophils and monocytes, consumes NO and produces molecules that oxidize tetrahydrobiopterin, was inversely related to EDD (r=-0.35; P=0.02), and was 42% higher in subjects with a higher WBC count (P=0.02). No other factors contributed to the relation between EDD and WBC count. Among healthy middle-aged and older adults, impaired EDD is related to higher neutrophil, eosinophil, and monocyte-based WBC count mediated by reduced responsiveness to NO and increased myeloperoxidase-associated reductions in tetrahydrobiopterin and NO bioavailability.
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Exercise-induced brachial artery vasodilation: effects of antioxidants and exercise training in elderly men.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 12-04-2009
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Aging, vascular function, and exercise are thought to have a common link in oxidative stress. Of the 28 subjects studied (young, 26 +/- 2 yr; old, 71 +/- 6 yr), 12 took part in a study to validate an antioxidant cocktail (AOC: vitamins C, E, and alpha-lipoic acid), while the remaining 8 young and 8 old subjects performed submaximal forearm handgrip exercise with placebo or AOC. Old subjects repeated forearm exercise with placebo or AOC following knee-extensor (KE) exercise training. Brachial arterial diameter and blood velocity (Doppler ultrasound) were measured at rest and during exercise. During handgrip exercise, brachial artery vasodilation in the old subjects was attenuated compared with that in young subjects following placebo (maximum = approximately 3.0 and approximately 6.0%, respectively). In contrast to the previously documented attenuation in exercise-induced brachial artery vasodilation in the young group with AOC, in the old subjects the AOC restored vasodilation (maximum = approximately 7.0%) to match the young. KE training also improved exercise-induced brachial artery vasodilation. However, in the trained state, AOC administration no longer augmented brachial artery vasodilation in the elderly, but rather attenuated it. These data reveal an age-related pro-/antioxidant imbalance that impacts vascular function and show that exercise training is capable of restoring equilibrium such that vascular function is improved and the AOC-mediated reduction in free radicals now negatively impacts brachial artery vasodilation, as seen in the young.
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Protein expression in vascular endothelial cells obtained from human peripheral arteries and veins.
J. Vasc. Res.
PUBLISHED: 08-06-2009
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Studying molecular mechanisms of vascular endothelial function in humans is difficult in part because of limited access to arteries. Access to peripheral veins is more practical. We determined if differences in protein expression of endothelial cells (EC) collected from a peripheral artery are reflected in measurements made on EC obtained from peripheral veins. EC were collected from the brachial artery and an antecubital vein of 106 healthy adults (60 men and 46 women, age 18-77 years). Quantitative immunofluorescence was used to measure protein expression of endothelial nitric oxide synthase (eNOS), Ser-1177 phosphorylated eNOS, manganese superoxide dismutase, nitrotyrosine, xanthine oxidase and nuclear factor-kappaB p65. Protein expression in EC obtained from brachial artery and antecubital vein sampling was moderately to strongly related (r = 0.59-0.81, all p < 0.0001, mean r = 0.70). Moreover, differences between subgroups in the lowest and highest tertiles of protein expression in EC obtained from arterial samples were consistently reflected in EC obtained from venous collections. These findings indicate that interindividual and group differences in expression of several proteins involved in nitric oxide production, oxidant production, antioxidant defense and inflammatory signaling in EC obtained from brachial artery sampling are consistently reflected in EC obtained from venous samples. Thus, EC collected from peripheral veins may provide a useful surrogate for EC obtained from arteries for measurements of EC protein expression in humans.
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Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 05-22-2009
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To determine whether impaired endothelium-dependent dilation (EDD) in older adults is associated with changes in the expression of major vasoconstrictor or vasodilator proteins in the vascular endothelium, endothelial cells (EC) were obtained from the brachial artery and peripheral veins of 56 healthy men, aged 18-78 yr. Brachial artery EC endothelin-1 (ET-1) [0.99 +/- 0.10 vs. 0.57 +/- 0.10 ET-1/human umbilical vein EC (HUVEC) intensity, P = 0.01] and serine 1177 phosphorylated endothelial nitric oxide synthase (PeNOS) (0.77 +/- 0.09 vs. 0.44 +/- 0.07 PeNOS/HUVEC intensity, P < 0.05) (quantitative immunofluorescence) were greater, and EDD (peak forearm blood flow to intrabrachial acetylcholine) was lower (10.2 +/- 0.9 vs. 14.7 +/- 1.7 ml.100 ml(-1).min(-1), P < 0.05) in older (n = 18, 62 +/- 1 yr) vs. young (n = 15, 21 +/- 1 yr) healthy men. EDD was inversely related to expression of ET-1 (r = -0.39, P < 0.05). Brachial artery EC eNOS expression did not differ significantly with age, but tended to be greater in the older men (young: 0.23 +/- 0.03 vs. older: 0.33 +/- 0.07 eNOS/HUVEC intensity, P = 0.08). In the sample with venous EC collections, EDD (brachial artery flow-mediated dilation) was lower (3.50 +/- 0.44 vs. 7.68 +/- 0.43%, P < 0.001), EC ET-1 and PeNOS were greater (P < 0.05), and EC eNOS was not different in older (n = 23, 62 +/- 1 yr) vs. young (n = 27, 22 +/- 1 yr) men. EDD was inversely related to venous EC ET-1 (r = -0.37, P < 0.05). ET-1 receptor A inhibition with BQ-123 restored 60% of the age-related impairment in carotid artery dilation to acetylcholine in B6D2F1 mice (5-7 mo, n = 8; 30 mo, n = 11; P < 0.05). ET-1 expression is increased in vascular EC of healthy older men and is related to reduced EDD, whereas ET-1 receptor A signaling tonically suppresses EDD in old mice. Neither eNOS nor PeNOS is reduced with aging. Changes in ET-1 expression and bioactivity, but not eNOS, contribute to vascular endothelial dysfunction with aging.
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Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase.
J. Physiol. (Lond.)
PUBLISHED: 05-05-2009
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Habitual aerobic exercise is associated with enhanced endothelium-dependent dilatation (EDD) in older humans, possibly by increasing nitric oxide bioavailability and reducing oxidative stress. However, the mechanisms involved are incompletely understood. EDD was measured in young (6-8 months) and old (29-32 months) cage control and voluntary wheel running (VR) B6D2F1 mice. Age-related reductions in maximal carotid artery EDD to acetylcholine (74 vs. 96%, P < 0.01) and the nitric oxide (NO) component of EDD (maximum dilatation with ACh and l-NAME minus that with ACh alone was -28% vs. -55%, P < 0.01) were restored in old VR (EDD: 96%, NO: -46%). Nitrotyrosine, a marker of oxidative stress, was increased in aorta with age, but was markedly lower in old VR (P < 0.05). Aortic superoxide dismutase (SOD) activity was greater (P < 0.01), whereas NADPH oxidase protein expression (P < 0.01) and activity (P = 0.05) were lower in old VR vs. old cage control. Increasing SOD (with 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl) and inhibition of NADPH oxidase (with apocynin) improved EDD and its NO component in old cage control, but not old VR mice. VR increased endothelial NO synthase (eNOS) protein expression (P < 0.05) and activation (Ser1177 phosphorylation) (P < 0.05) in old mice. VR did not affect EDD in young mice. Our results show that voluntary aerobic exercise restores the age-associated loss of EDD by suppression of oxidative stress via stimulation of SOD antioxidant activity and inhibition of NADPH oxidase superoxide production. Increased eNOS protein and activation also may contribute to exercise-mediated preservation of NO bioavailability and EDD with ageing.
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B6D2F1 Mice are a suitable model of oxidative stress-mediated impaired endothelium-dependent dilation with aging.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 02-10-2009
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To determine if B6D2F1 mice represent a suitable model of oxidative stress-mediated impaired endothelium-dependent dilation (EDD) with aging, mice were studied at 6.9 +/- 0.3 and 31.9 +/- 0.6 months. EDD to acetylcholine (ACh) was 26% (p < .001) and 12% (p < .001) lower, respectively, in isolated carotid (n = 10-11) and femoral (n = 10) arteries from older mice, and reductions in arterial pressure to systemic ACh infusion were smaller in older mice (n = 6-10; p < .01). Nitrotyrosine was marked in aorta of older mice (p < .05, n = 4). Superoxide production in carotid arteries was greater (p < .05), and TEMPOL restored dilation in carotid arteries and systemically in older mice. N(G)-nitro-l-arginine methyl ester (l-NAME) reduced carotid artery dilation in young more than older mice, whereas TEMPOL restored the effects of l-NAME in older mice. Carotid artery stiffness was increased in older compared with young mice (p = .04). Our results provide the first comprehensive evidence that B6D2F1 mice are a useful model for investigating mechanisms of reduced nitric oxide-dependent, oxidative stress-associated EDD and increased arterial stiffness with aging.
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Taming the "sleeping giant": the role of endothelin-1 in the regulation of skeletal muscle blood flow and arterial blood pressure during exercise.
Am. J. Physiol. Heart Circ. Physiol.
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The cardiovascular response to exercise is governed by a combination of vasodilating and vasoconstricting influences that optimize exercising muscle perfusion while protecting mean arterial pressure (MAP). The degree to which endogenous endothelin (ET)-1, the bodys most potent vasoconstrictor, participates in this response is unknown. Thus, in eight young (24 ± 2 yr), healthy volunteers, we examined leg blood flow, MAP, tissue oxygenation, heart rate, leg arterial-venous O(2) difference, leg O(2) consumption, pH, and net ET-1 and lactate release at rest and during knee extensor exercise (0, 5, 10, 15, 20, and 30 W) before and after an intra-arterial infusion of BQ-123 [ET subtype A (ET(A)) receptor antagonist]. At rest, BQ-123 did not evoke a change in leg blood flow or MAP. During exercise, net ET-1 release across the exercising leg increased approximately threefold. BQ-123 increased leg blood flow by ~20% across all work rates (changes of 113 ± 76, 176 ± 83, 304 ± 108, 364 ± 130, 502 ± 117, and 570 ± 178 ml/min at 0, 5, 10, 15, 20, and 30 W, respectively) and attenuated the exercise-induced increase in MAP by ~6%. The increase in leg blood flow was accompanied by a ~9% increase in leg O(2) consumption with an unchanged arterial-venous O(2) difference and deoxyhemoglobin, suggesting a decline in intramuscular efficiency after ET(A) receptor blockade. Together, these findings identify a significant role of the ET-1 pathway in the cardiovascular response to exercise, implicating vasoconstriction via the ET(A) receptor as an important mechanism for both the restraint of blood flow in the exercising limb and maintenance of MAP in healthy, young adults.
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Thrombolysis in acute pulmonary thromboembolism.
South. Med. J.
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Acute pulmonary embolism (PE) is a common clinical condition with presentations that may vary from asymptomatic subsegmental emboli to massive vascular obstruction and shock with high risk of death. Identifying patients at highest risk for death is critical to select those who would benefit most from thrombolytic therapy. New and evolving clinical prediction models, serum tests, and imaging modalities are being used to improve our ability to identify potential thrombolytic candidates. We review the evolution of the present guidelines on the management of PE, specifically regarding the evolving role of thrombolytics; outcomes following thrombolytic therapy, including mortality, hemorrhage, hemodynamic improvement, and prevention of chronic thromboembolic pulmonary hypertension; and our strategy for risk stratification of pulmonary embolism.
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Effects of aging, TNF-?, and exercise training on angiotensin II-induced vasoconstriction of rat skeletal muscle arterioles.
J. Appl. Physiol.
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Skeletal muscle vascular resistance during physical exertion is higher with old age. The purpose of this study was to determine whether 1) aging enhances angiotensin II (ANG II)-induced vasoconstriction; 2) the proinflammatory cytokine tumor necrosis factor (TNF)-? contributes to alterations in ANG II-mediated vasoconstriction with aging; 3) exercise training attenuates putative age-associated increases in ANG II-mediated vasoconstriction; and 4) the mechanism(s) through which aging and exercise training alters ANG II-induced vasoconstriction in skeletal muscle arterioles. Male Fischer 344 rats were assigned to four groups: young sedentary (4 mo), old sedentary (24 mo), young trained, and old trained. In a separate group of young sedentary and old sedentary animals, a TNF type 1 receptor inhibitor was administered subcutaneously for 10 wk. First-order arterioles were isolated from soleus and gastrocnemius muscles for in vitro experimentation. Old age augmented ANG II-induced vasoconstriction in both soleus (young: 27 ± 3%; old: 38 ± 4%) and gastrocnemius (young: 42 ± 6%; old: 64 ± 9%) muscle arterioles; this augmented vasoconstriction was abolished with the removal of the endothelium, N(G)-nitro-l-arginine methyl ester, and chronic inhibition of TNF-?. In addition, exercise training ameliorated the age-induced increase in ANG II vasoconstriction. These findings demonstrate that old age enhances and exercise training diminishes ANG II-induced vasoconstrictor responses in skeletal muscle arterioles through an endothelium-dependent nitric oxide synthase signaling pathway. In addition, the enhancement of ANG II vasoconstriction with old age appears to be related to a proinflammatory state.
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TNF-? impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity.
Am. J. Physiol. Heart Circ. Physiol.
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We tested the hypothesis that high fat (HF) feeding results in endothelial dysfunction in resistance arteries of epididymal white adipose tissue (eWAT) and is mediated by adipose tissue inflammation. When compared with normal chow (NC)-fed mice (n = 17), HF-fed male B6D2F1 mice were glucose intolerant and insulin resistant as assessed by glucose tolerance test (area under the curve; HF, 18,174 ± 1,889 vs. NC, 15,814 ± 666 mg·dl(-1)·min(-1); P < 0.05) and the homeostatic model assessment (HF, 64.1 ± 4.3 vs. NC, 85.7 ± 6.4; P = 0.05). HF diet-induced metabolic dysfunction was concomitant with a proinflammatory eWAT phenotype characterized by greater macrophage infiltration (HF, 3.9 ± 0.8 vs. NC, 0.8 ± 0.4%; P = 0.01) and TNF-? (HF, 22.6 ± 4.3 vs. NC, 11.4 ± 2.5 pg/dl; P < 0.05) and was associated with resistance artery dysfunction, evidenced by impaired endothelium-dependent dilation (EDD) (maximal dilation; HF, 49.2 ± 10.7 vs. NC, 92.4 ± 1.4%; P < 0.01). Inhibition of nitric oxide (NO) synthase by N(?)-nitro-L-arginine methyl ester (L-NAME) reduced dilation in NC (28.9 ± 6.3%; P < 0.01)- and tended to reduce dilation in HF (29.8 ± 9.9%; P = 0.07)-fed mice, eliminating the differences in eWAT artery EDD between NC- and HF-fed mice, indicative of reduced NO bioavailability in eWAT resistance arteries after HF feeding. In vitro treatment of excised eWAT arteries with recombinant TNF-? (rTNF) impaired EDD (P < 0.01) in NC (59.7 ± 10.9%)- but not HF (59.0 ± 9.3%)-fed mice. L-NAME reduced EDD in rTNF-treated arteries from both NC (21.9 ± 6.4%)- and HF (29.1 ± 9.2%)-fed mice (both P < 0.01). In vitro treatment of arteries with a neutralizing antibody against TNF-? (abTNF) improved EDD in HF (88.2 ± 4.6%; P = 0.05)-fed mice but was without effect on maximal dilation in NC (89.0 ± 5.1%)-fed mice. L-NAME reduced EDD in abTNF-treated arteries from both NC (25.4 ± 7.5%)- and HF (27.1 ± 16.8%)-fed mice (both P < 0.01). These results demonstrate that inflammation in the visceral adipose tissue resulting from diet-induced obesity impairs endothelial function and NO bioavailability in the associated resistance arteries. This dysfunction may have important implications for adipose tissue blood flow and appropriate tissue function.
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Sustained activation of AMPK ameliorates age-associated vascular endothelial dysfunction via a nitric oxide-independent mechanism.
Mech. Ageing Dev.
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Exercise restores endothelium-dependent dilation (EDD) in old mice by reducing oxidative stress and increasing nitric oxide (NO) bioavailability. Adenosine monophosphate protein kinase (AMPK) activation mimics some effects of exercise. Old (28-30 months) B6D2F1 mice had reduced arterial AMPK expression and superoxide-mediated suppression of EDD vs. young (3-6 months) controls. Pharmacological activation of AMPK by aminoimidazole carboxamide ribonucleotide (AICAR) for 2 weeks increased arterial AMPK and reversed this superoxide-induced impairment of EDD. The improvement in EDD was independent of NO or prostaglandin signaling, suggesting enhanced endothelium-dependent hyperpolarizing factor-related dilation. AMPK activation may represent a novel therapy for treating age-associated vascular dysfunction.
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Lupus anticoagulant and ANCA associated thrombotic vasculopathy due to cocaine contaminated with levamisole: a case report and review of the literature.
J. Thromb. Thrombolysis
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A 2010 US report recently detected the presence of levamisole in greater than 77 % of seized cocaine samples. A syndrome of retiform purpura, often involving ears and flanks, with vasculopathy or vasculitis on biopsy, associated with anti-nuclear cytoplasmic antibodies as well as antiphospholipid antibodies, previously associated with therapeutic use of levamisole has now re-emerged, and is associated with cocaine adulterated with levamisole. Patients with this unusual constellation of signs and laboratory findings should be questioned about exposure to cocaine.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.