Positive experiences with the use of an eHealth smartphone application during the treatment of an abdominal aortic aneurysm.

OBJECTIVE: To evaluate the patient perceived satisfaction and feasibility of a personalized eHealth application (app) for abdominal aortic aneurysm (AAA) patients undergoing surgery. METHODS: Patients were offered to download the app prior to undergoing AAA surgery, in a prospective single centre cohort study, using a mixed methods sequential explanatory design. It offers information via the timely delivery of push notifications with text, images, and videos. The information includes chapters regarding the AAA, surgical techniques (endovascular aneurysm repair and open surgical repair), and perioperative lifestyle advice such as; physical exercise programmes, healthy and protein rich diet, geriatric care, and to stop smoking or drinking alcohol. RESULTS: The app was installed by 59/65 patients (91%). After installation, six patients deactivated the app (10%). The mean age was 74 years (SD = 7) and 85% of patients were male. The app was opened a median of 67 times (interquartile range [IQR] 33-127) and with a median time interval of 50 hours (IQR 28-74). Overall, 90% (53/59) completed a satisfaction questionnaire. On a numeric rating scale from 0 to 10, the median scored satisfaction for guidance was 8 (IQR 6-8), provided information was 8 (IQR 6-8), usefulness was 7 (IQR 6-8.5), and for recommending it to others 8 (IQR 6-9). Using purposeful sampling, seven patients underwent a semi-structured interview on user-experience of the app. They described experiencing positive changes to lifestyle habits, and appreciating the ability to share it with loved ones or informal caregivers. Several areas of improvement were reported. CONCLUSION: The personalized eHealth app is feasible in older AAA patients and valued as a useful supplement to the standard of care. We argue that the app aids in managing a prehabilitation programme, aids in the digital transformation of healthcare, and thereby decreases the workload of hospital staff.

Reliability of the passive leg movement assessment of vascular function in men.

NEW FINDINGS: What is the central question of this study? Use of the passive leg movement (PLM) test, a non-invasive assessment of microvascular function, is on the rise. However, PLM reliability in men has not been adequately investigated, nor has such reliability data, in men, been compared to the most commonly employed vascular function assessment, flow-mediated vasodilation (FMD). What is the main finding and its importance? PLM is a reliable method to assess vascular function in men, and is comparable to values previously reported for PLM in women, and for FMD. Given the importance of vascular function as a predictor of cardiovascular disease risk, these data support the utility of PLM as a clinically relevant measurement. ABSTRACT: Although vascular function is an independent predictor of cardiovascular disease risk, and therefore has significant prognostic value, there is currently not a single clinically accepted method of assessment. The passive leg movement (PLM) assessment predominantly reflects microvascular endothelium-dependent vasodilation and can identify decrements in vascular function with advancing age and pathology. Reliability of the PLM model was only recently determined in women, and has not been adequately investigated in men. Twenty healthy men (age: 27 ± 2 year) were studied on three separate experimental days, resulting in three within-day and three between-day trials. The hyperemic response to PLM was assessed with Doppler ultrasound, and expressed as the absolute peak in leg blood flow (LBFpeak ), change from baseline to peak (ΔLBFpeak ), absolute area under the curve (LBFAUC ), and change in AUC from baseline (ΔLBFAUC ). PLM-induced hyperemia yielded within-day coefficients of variation (CV) from 10.9 to 22.9%, intraclass correlation coefficients (ICC) from 0.82 to 0.90, standard error of the measurement (SEM) from 8.3 to 17.2%, and Pearson's correlation coefficients (r) from 0.56 to 0.81. Between-day assessments of PLM hyperemia resulted in CV from 14.4 to 25%, ICC from 0.75 to 0.87, SEM from 9.8 to 19.8%, and r from 0.46 to 0.75. Similar to previous reports in women, the hyperemic responses to PLM in men display moderate-to-high reliability, and are comparable to reliability data for brachial artery flow mediated vasodilation. These positive reliability findings further support the utility of PLM as a clinical measurement of vascular function and cardiovascular disease risk.

Peanut components measured by ISAC: comparison with ImmunoCap and clinical relevance in peanut allergic children.

BACKGROUND: Specific IgE (sIgE) against the peanut component Arachis hypogaea (Ara h) 2 has been shown to be the most important allergen to discriminate between peanut allergy and peanut tolerance. Several studies determined sIgE cut off values for Ara h 2, determined by singleplex measurements. However, cut off values for Ara h 2 from multiplex arrays are less well defined. The aim of this study was to evaluate the correlation between Ara h 2 sIgE determined by singleplex versus multiplex measurements and to assess the diagnostic value of the different peanut components included in Immuno Solid-phase Allergen Chip (ISAC) multiplex analysis in children with a suspected peanut allergy. METHODS: In this retrospective study we analyzed Ara h 2 sIgE values with singleplex Fluorescence Enzyme Immunoassay (FEIA, ImmunoCap) and multiplex microarray (ISAC) measurements in 117 children with a suspected peanut allergy. Also, other peanut components measured by ISAC were analyzed. Double blinded placebo controlled oral food challenges were used as golden standard. RESULTS: Among all studied peanut components FEIA Ara h 2 sIgE showed the highest area under the curve (AUC, 0.922), followed by ISAC Ara h 6 and Ara h 2 sIgE with AUCs of respectively 0.906 and 0.902. Best cut off values to diagnose peanut allergy were 4.40 kU/l for FEIA Ara h 2 sIgE and, 7.43 ISU and 8.13 ISU for respectively Ara h 2 and Ara h 6 sIgE in ISAC microarray. Ara h 2 sIgE determined in FEIA and ISAC showed a good correlation (r = 0.88; p < 0.01). CONCLUSION: Ara h 6 and Ara h 2 sIgE in multiplex ISAC are both good predictors of clinical peanut allergy in Dutch children, and their performance is comparable to the use of Ara h 2 in singleplex FEIA. The simultaneous measurement of different peanut components using ISAC is an advantage and clinically useful to detect peanut allergic children that are Ara h 2 negative but sensitized to other peanut proteins such as Ara h 6.

Effect of conservative treatment in aortoiliac occlusive disease.

Objective: To determine the effect of primary conservative treatment without revascularization in patients with proven aortoiliac occlusive disease (AIOD) presenting with intermittent claudication (IC).Background: The initial treatment of IC should focus on supervised exercise therapy (SET) and pharmacotherapy. Nowadays, primary endovascular revascularization (EVR) has become increasingly popular in patients with all types of AIOD. But in daily practice, EVR is often performed without initially extensive exercise.Method: This is a single centre retrospective study from December 2012 to September 2017. Primary outcomes were maximum walking distance (MWD) and patient satisfaction. Secondary outcomes were revascularization rate and mortality.Results: Twenty-four patients were included. Mean age was 64 years (SD: 9). Mean follow-up was 28 months (SD: 17). Nineteen patients (80%) had SET. In 18 (75%) patients, the MWD was improved compared to the initial situation. In five (21%) patients, the MWD stayed the same. The MWD of one (4%) patient decreased. Overall satisfaction rate was 87%. Three patients (13%) were not satisfied with the conservative treatment and eventually got an EVR. There was no disease related death.Conclusions: Conservative treatment, especially with SET, has acceptable subjective symptom outcomes in selected patients with AIOD. It could be a good alternative treatment for certain patients with AIOD and IC.

α-Adrenergic receptor regulation of skeletal muscle blood flow during exercise in heart failure patients with reduced ejection fraction.

Patients suffering from heart failure with reduced ejection fraction (HFrEF) experience impaired limb blood flow during exercise, which may be due to a disease-related increase in α-adrenergic receptor vasoconstriction. Thus, in eight patients with HFrEF (63 ± 4 yr) and eight well-matched controls (63 ± 2 yr), we examined changes in leg blood flow (Doppler ultrasound) during intra-arterial infusion of phenylephrine (PE; an α1-adrenergic receptor agonist) and phentolamine (Phen; a nonspecific α-adrenergic receptor antagonist) at rest and during dynamic single-leg knee-extensor exercise (0, 5, and 10 W). At rest, the PE-induced reduction in blood flow was significantly attenuated in patients with HFrEF (-15 ± 7%) compared with controls (-36 ± 5%). During exercise, the controls exhibited a blunted reduction in blood flow induced by PE (-12 ± 4, -10 ± 4, and -9 ± 2% at 0, 5, and 10 W, respectively) compared with rest, while the PE-induced change in blood flow was unchanged compared with rest in the HFrEF group (-8 ± 5, -10 ± 3, and -14 ± 3%, respectively). Phen administration increased leg blood flow to a greater extent in the HFrEF group at rest (+178 ± 34% vs. +114 ± 28%, HFrEF vs. control) and during exercise (36 ± 6, 37 ± 7, and 39 ± 6% vs. 13 ± 3, 14 ± 1, and 8 ± 3% at 0, 5, and 10 W, respectively, in HFrEF vs. control). Together, these findings imply that a HFrEF-related increase in α-adrenergic vasoconstriction restrains exercising skeletal muscle blood flow, potentially contributing to diminished exercise capacity in this population.

The Role of Delirium and Other Risk Factors on Mortality in Elderly Patients with Critical Limb Ischemia Undergoing Major Lower Limb Amputation.

BACKGROUND: Delirium in patients with critical limb ischemia (CLI) is associated with increased mortality. The main goal of this study was to investigate the association between delirium and mortality in patients undergoing major lower limb amputation for CLI. In addition, other risk factors associated with mortality were analyzed. METHODS: An observational cohort study was conducted including all patients aged ≥70 years with CLI undergoing a major lower limb amputation between January 2014 and July 2017. Delirium was scored using the Delirium Observation Screening Score in combination with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Risk factors for mortality were analyzed by calculating hazard ratios using a Cox proportional hazards model. RESULTS: In total, 95 patients were included; of which, 29 (31%) patients developed a delirium during admission. Delirium was not associated with an increased risk of mortality (hazard ratio [HR] = 0.84; 95 % confidence interval [CI]: 0.51-1.73; P = 0.84). Variables independently associated with an increased risk of mortality were age (HR 1.1; 95% CI 1.0-1.1), cardiac history (HR 3.3; 95% CI 1.8-6.1), current smoking (HR 2.9; 95% CI 1.6-5.5), preoperative anemia (HR 2.8; 95% CI 1.1-7.2), and living in a nursing home (HR 2.2; 95% CI 1.1-4.4). CONCLUSION: Delirium was not associated with an increased mortality risk in elderly patients with CLI undergoing a major lower limb amputation. Factors related to an increased mortality risk were age, cardiac history, current smoking, preoperative anemia, and living in a nursing home.

Attenuated nitric oxide bioavailability in systemic sclerosis: Evidence from the novel assessment of passive leg movement.

NEW FINDINGS: What is the central question of this study? Do systemic sclerosis patients exhibit impaired nitric oxide-mediated vascular function of the lower limb and are these decrements correlated with plasma biomarkers for inflammation and oxidative stress? What is the main finding and its importance? Findings indicate impaired nitric oxide-mediated vascular function, linked to the incidence of digital ulcers and a milieu of inflammation and oxidative stress. However, the absence of significant correlations between individual biomarkers and blood flow responses suggests that the vasculopathy observed in systemic sclerosis may not be solely the result of derangements in the redox balance or inflammatory signalling. ABSTRACT: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, which may be the consequence of inflammation and oxidative stress that ultimately leads to a reduced nitric oxide (NO) bioavailability. Passive leg movement (PLM) is a novel methodology for assessing lower limb vascular function that is predominantly NO dependent. We combined this vascular assessment with a comprehensive panel of plasma biomarkers to assess the axis of inflammation, oxidative stress and NO in SSc patients (n = 12; 62 ± 11 years of age) compared with healthy control subjects (n = 17; 60 ± 16 years of age). The PLM-induced changes in leg blood flow (LBF; 191 ± 104 versus 327 ± 217 ml min-1 ) and LBF area under the curve (39 ± 104 versus 125 ± 131 ml) were reduced in SSc compared with control subjects. Stratification of patients according to history of digital ulcer (DU) formation revealed a further reduction in LBF area under the curve in DU (-13 ± 83 ml) versus non-DU (91 ± 102 ml) patients. Biomarkers of inflammation (C-reactive protein) and oxidative stress (malondialdehyde and protein carbonyl) were all elevated in SSc (C-reactive protein, 3299 ± 2372 versus 984 ± 565 ng ml-1 ; malondialdehyde, 3.2 ± 1.1 versus 1.1 ± 0.7 µm; and protein carbonyl, 0.15 ± 0.05 versus 0.12 ± 0.03 nmol mg-1 ), and C-reactive protein was further elevated in patients with a history of DU (4551 ± 2752 versus 2047 ± 1019 ng ml-1 ) compared with non-DU, although these were not individually correlated with changes in LBF. These findings of impaired NO-mediated vascular function, linked to DU and a milieu of inflammation and oxidative stress, suggest that redox balance plays an important, but not necessarily deterministic, role in the vascular pathophysiology of SSc.

sIgE Ana o 1, 2 and 3 accurately distinguish tolerant from allergic children sensitized to cashew nuts.

BACKGROUND: The double-blind, placebo-controlled food challenge test (DBPCFC) is the gold standard in cashew nut allergy. This test is costly, time consuming and not without side effects. Analysis of IgE reactivity to cashew nut components may reduce the need for food challenge tests. METHODS: In a prospective and multicentre study, children with suspected cashew nut allergy underwent a DBPCFC with cashew nut. Specific IgE to cashew nut and to the components Ana o 1, 2 and 3 were determined. A skin prick test (SPT) with cashew nut extract was performed. The association between the outcome of the food challenge test and specific IgE to Ana o 1, 2 and 3 was assessed with logistic regression analyses, unadjusted and adjusted for other diagnostic variables. Discriminative ability was quantified with a concordance index (c). RESULTS: A total of 173 children (103 boys, 60%) with a median age of 9 years were included. About 79% had a positive challenge test outcome. A steep rise in the risk of a positive challenge was observed for specific IgE to each individual component Ana o 1, 2 and 3 with estimated risks up to approximately 100%. Median values of Ana o 1, 2, 3 were 1.29 kU/l (range 0-100 kU/l), 4.77 kU/l (range 0-100 kU/l) and 8.33 kU/l (range 0-100 kU/l) respectively and varied significantly (p < 0.001). Specific IgE to Ana o 1, 2 and 3 was better distinguished between cashew-allergic and tolerant children (c = 0.87, 0.85 and 0.89, respectively) than specific IgE to cashew nut or SPT (c = 0.76 and 0.83, respectively). CONCLUSION: The major cashew nut allergens Ana o 1, 2 and 3 are each individually predictive for the outcome of food challenge tests in cashew-allergic children.

A nurse-led sexual rehabilitation intervention after radiotherapy for gynecological cancer.

PURPOSE: Although vaginal dilator use after combined pelvic radiation therapy and brachytherapy (RT/BT) is recommended to prevent vaginal shortening and stenosis, women fail to use them and experience sexual problems. A nurse-led sexual rehabilitation intervention targeting sexual recovery and vaginal dilatation was developed. Its feasibility was investigated during a prospective, longitudinal, observational pilot study. METHODS: Four oncology nurses were specifically trained to conduct the intervention. Gynecologic cancer patients treated with RT/BT were assessed using (i) questionnaires on frequency of dilator use (monthly), sexual functioning, and sexual distress (at baseline and 1, 6, and 12 months) and psychological and relational distress (at 1, 6, and 12 months); (ii) semi-structured interviews (between 6 and 12 months); and (iii) consultation recordings (a random selection of 21 % of all consults). RESULTS: Twenty participants were 26-71 years old (mean = 40). Eight participants discontinued participation after 3 to 9 months. At 6 months after RT, 14 out of 16 (88 %), and at 12 months 9 out of 12 (75 %), participants dilated regularly, either by having sexual intercourse or by using dilators. Sexual functioning improved between 1 and 6 months after RT, with further improvement at 12 months. Most participants reported that the intervention was helpful and the nurses reported having sufficient expertise and counseling skills. CONCLUSIONS: According to the pilot results, the intervention was feasible and promising for sexual rehabilitation and regular dilator use after RT. Its (cost-)effectiveness will be investigated in a randomized controlled trial.

Vascular function assessed by passive leg movement and flow-mediated dilation: initial evidence of construct validity.

The vasodilatory response to passive leg movement (PLM) appears to provide a novel, noninvasive assessment of vascular function. However, PLM has yet to be compared with the established noninvasive assessment of vascular health, flow-mediated dilation (FMD). Therefore, as an initial evaluation of the construct validity of PLM and upright seated and supine PLM as well as brachial (BA) and superficial femoral (SFA) artery FMDs were performed in 10 young (22 ± 1) and 30 old (73 ± 2) subjects. During upright seated PLM, the peak change in leg blood flow (ΔLBF) and leg vascular conductance (ΔLVC) was significantly correlated with BA (r = 0.57 and r = 0.66) and SFA (r = 0.44 and r = 0.41, ΔLBF and ΔLVC, respectively) FMD. Furthermore, although the relationships were not as strong, the supine PLM response was also significantly correlated with BA (r = 0.38 and r = 0.35) and SFA (r = 0.39 and r = 0.35, ΔLBF and ΔLVC, respectively) FMD. Examination of the young and old separately, however, revealed that significant relationships persisted in both groups only for the upright seated PLM response and BA FMD (young: r = 0.73 and r = 0.77; old: r = 0.35 and r = 0.45, ΔLBF and ΔLVC, respectively). Normalizing FMD for shear rate during PLM abrogated all significant relationships between the PLM and FMD response, suggesting a role for nitric oxide (NO) in these associations. Collectively, these data indicate that PLM, particularly upright seated PLM, likely provides an index of vascular health analogous to the traditional FMD test. Given the relative ease of PLM implementation, these data have important positive implications for PLM as a clinical vascular health assessment.

No difference in health-related quality of life, after a food challenge with cashew nut in children participating in a clinical trial.

BACKGROUND: Previous studies showed that health-related quality of life (HRQL) significantly improved after the food challenge, with greater improvements in HRQL after a negative outcome than after a positive outcome. It is currently unknown whether this also occurs in patients undergoing DBPCFCs with cashew nut in the context of a clinical trial. METHODS: Quality of life was studied in children enrolled in a cashew nut study using Food Allergy Quality of Life Questionnaires (FAQLQs). Children, teenagers and parents of the children completed the questionnaires before the challenge test and 6 months after the DBPCFC with cashew nut. The difference in the change in HRQL between the children with a positive and negative DBPCFC outcome was studied by Mann-Whitney U-test. RESULTS: In total, 112 children (67 boys, median age of 9 years) were included. The children, teenagers and parents of the children completed 143 sets of questionnaires in total. There were no significant differences in baseline total and domain scores compared to the follow-up scores in the FAQLQ-CF, FAQLQ-TF and FAQLQ-PF. In children, the delta FAIM score in the negative DBPCFC tested group was significantly better than the delta FAIM score in the positive challenged group (p = 0.026). There were no significant differences in the changes in the scores of the FAQLQ-CF and FAQLQ-PF in the children with a positive challenge outcome, compared to the children with a negative challenge result. However, there was a significant difference in the change in score between the latter groups in the domain 'accidental exposure' of the FAQLQ-TF (p = 0.049). CONCLUSION: This study showed no difference in the change in HRQL scores after a DBPCFC with cashew nut in children participating in a clinical trial. The utility of HRQL as an outcome for clinical trials in food allergy may be limited if participant baseline HRQL is relatively unimpaired.

The role of nitric oxide in passive leg movement-induced vasodilatation with age: insight from alterations in femoral perfusion pressure.

The passive leg movement (PLM) model is a novel approach to assess vascular function. Increasing femoral perfusion pressure (FPP) by moving from the supine to the upright-seated posture augments the vasodilatory response to PLM in the young, with no effect in the old, but whether this augmented vasodilatation is nitric oxide (NO) dependent is unknown. Using an intra-arterial infusion of N(G) -monomethyl-L -arginine (L -NMMA) to inhibit nitric oxide synthase (NOS), the posture-induced increases in the PLM responses in the young were nearly ablated, with no effect of NOS inhibition in the old. Therefore, PLM in combination with alterations in posture can be used to determine changes in NO-mediated vasodilatation with age, and thus, may be a clinically useful tool for assessing NO bioavailability across the human lifespan. We sought to better understand the contribution of nitric oxide (NO) to passive leg movement (PLM)-induced vasodilatation with age, with and without a posture-induced increase in femoral perfusion pressure (FPP). PLM was performed in eight young (24 ± 1 years) and eight old (74 ± 3 years) healthy males, with and without NO synthase inhibition via intra-arterial infusion of N(G) -monomethyl-L -arginine (L -NMMA) into the common femoral artery in both the supine and upright-seated posture. Central and peripheral haemodynamic responses were determined second-by-second with finger photoplethysmography and Doppler ultrasound, respectively. PLM-induced increases in heart rate, stroke volume, cardiac output and reductions in mean arterial pressure were similar between age groups and conditions. In the young, L -NMMA attenuated the peak change in leg vascular conductance (ΔLVCpeak ) in both the supine (control: 7.4 ± 0.9; L -NMMA: 5.2 ± 1.1 ml min(-1) mmHg(-1) , P < 0.05) and upright-seated (control: 12.3 ± 2.0; L -NMMA: 6.4 ± 1.0 ml min(-1) mmHg(-1) , P < 0.05) posture, with no significant change in the old (supine control: 4.2 ± 1.3; supine L -NMMA: 3.4 ± 0.8; upright-seated control: 4.5 ± 0.8; upright-seated L -NMMA: 3.4 ± 0.8 ml min(-1) mmHg(-1) , P > 0.05). Increased FPP augmented the ΔLVCpeak in the young control condition only (P < 0.05). In the upright-seated posture, NOS inhibition attenuated the FPP-induced augmentation of rapid vasodilatation in the young (control: 1.25 ± 0.23; L -NMMA: 0.74 ± 0.11 ml min(-1) mmHg(-1) s(-1) ; P < 0.05), but not the old (control: 0.37 ± 0.07; L -NMMA: 0.25 ± 0.07 ml ml min(-1) mmHg(-1) s(-1) ; P > 0.05). These data reveal that greater FPP increases the role of NO in PLM-induced vasodilatation in the young, but not the old, due to reduced NO bioavailability with age. Therefore, PLM involving alterations in posture may be useful to determine changes in NO bioavailability with age.

TNF-alpha and melphalan-based isolated limb perfusion: no evidence supporting the early destruction of tumour vasculature.

BACKGROUND: Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) is a highly effective treatment for locally advanced tumours of the extremities. Previous research suggests an almost immediate disintegration of the blood supply of the tumour. The aim of the present study was to verify this hypothesis using non-invasive measurements of microvascular perfusion and tissue oxygenation. METHODS: A total of 11 patients were included in the study. TM-ILP was performed under mildly hyperthermic conditions (39 °C) in the extremities via proximal vascular access. Capillary-venous microvascular blood flow, haemoglobin level (Hb) and oxygen saturation (SO2) were determined using laser Doppler and white-light spectroscopy, respectively, before TM-ILP and at 30 min, 4 h, 1 day, 4 days, 1 week, 2 weeks and 6 weeks after TM-ILP from tumour and healthy muscle tissues. RESULTS: Blood flow and Hb were mostly higher, whereas SO2 was lower, in tumour tissue compared with muscle tissue. In both tumour and muscle tissues, blood flow significantly increased immediately after TM-ILP and remained elevated for at least 2 weeks, followed by a return to the initial values 6 weeks after the procedure. CONCLUSION: No signs were found of early destruction of the tumour vasculature. The observations suggest that an inflammatory reaction is one of the key elements of TM-ILP.

Passive leg movement-induced vasodilation in women: the impact of age.

Passive leg movement (PLM), an assessment of predominantly nitric oxide-dependent vasodilation, is decreased with age and cannot be augmented by posture-induced increases in femoral perfusion pressure in older men. However, this novel method of assessing vascular function has yet to be used to evaluate alterations in nitric oxide-dependent vasodilation with age in females. PLM was performed in 10 young (20 ± 1 yr) and 10 old (73 ± 2 yr) women in both the supine and upright-seated postures, whereas central and peripheral hemodynamic measurements were acquired second by second using noninvasive techniques (finger photoplethysmography and Doppler ultrasound, respectively). The heart rate response to PLM was attenuated in the old compared with the young in both the supine (young, 10 ± 1; and old, 5 ± 1 beats/min; P < 0.05) and upright-seated posture (young, 10 ± 2; and old, 5 ± 1 beats/min; P < 0.05), leading to a blunted cardiac output response in the old in the upright-seated posture (young, 1.0 ± 0.2; and old, 0.3 ± 0.1 l/min; P < 0.05). The PLM-induced peak change in leg vascular conductance was lower in the old compared with the young in both postures (young supine, 5.7 ± 0.5; old supine, 2.6 ± 0.3; young upright, 9.2 ± 0.7; and old upright, 2.2 ± 0.4 ml·min(-1)·mmHg(-1); P < 0.05) and was significantly augmented by the upright-seated posture in the young only, revealing a vasodilatory reserve capacity in the young (3.5 ± 0.6 ml·min(-1)·mmHg(-1), P < 0.05) that was absent in the old (-0.5 ± 0.3 ml·min(-1)·mmHg(-1), P = 0.18). These data support previous literature demonstrating attenuated PLM-induced vasodilation with age and extend these findings to include the female population, thus bolstering the utility of PLM as a novel assessment of vascular function across the life span in humans.

Passive leg movement and nitric oxide-mediated vascular function: the impact of age.

In young healthy men, passive leg movement (PLM) elicits a robust nitric oxide (NO)-dependent increase in leg blood flow (LBF), thus providing a novel approach to assess NO-mediated vascular function. While the magnitude of the LBF response to PLM is markedly reduced with age, the role of NO in this attenuated response in the elderly is unknown. Therefore, this study sought to determine the contribution of NO in the PLM-induced LBF with age. Fourteen male subjects (7 young, 24 ± 1 yr; and 7 old, 75 ± 3 yr) underwent PLM with and without NO synthase (NOS) inhibition achieved by intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA). LBF was determined second-by-second by Doppler ultrasound, and central hemodynamics were measured by finger photoplethysmography. NOS inhibition blunted the PLM-induced peak increase in LBF in the young (control: 668 ± 106; L-NMMA: 431 ± 95 Δml/min; P = 0.03) but had no effect in the old (control: 266 ± 98; L-NMMA: 251 ± 92 Δml/min; P = 0.59). Likewise, the magnitude of the reduction in the overall (i.e., area under the curve) PLM-induced LBF response to NOS inhibition was less in the old (LBF: -31 ± 18 ml) than the young (LBF: -129 ± 21 ml; P < 0.01). These findings suggest that the age-associated reduction in PLM-induced LBF in the elderly is primarily due to a reduced contribution to vasodilation from NO and therefore support the use of PLM as a novel approach to assess NO-mediated vascular function across the lifespan.

Impact of age on exercise-induced ATP supply during supramaximal plantar flexion in humans.

Currently, the physiological factors responsible for exercise intolerance and bioenergetic alterations with age are poorly understood due, at least in art, to the confounding effect of reduced physical activity in the elderly. Thus, in 40 healthy young (22 ± 2 yr) and old (74 ± 8 yr) activity-matched subjects, we assessed the impact of age on: 1) the relative contribution of the three major pathways of ATP synthesis (oxidative ATP synthesis, glycolysis, and the creatine kinase reaction) and 2) the ATP cost of contraction during high-intensity exercise. Specifically, during supramaximal plantar flexion (120% of maximal aerobic power), to stress the functional limits of the skeletal muscle energy systems, we used (31)P-labeled magnetic resonance spectroscopy to assess metabolism. Although glycolytic activation was delayed in the old, ATP synthesis from the main energy pathways was not significantly different between groups. Similarly, the inferred peak rate of mitochondrial ATP synthesis was not significantly different between the young (25 ± 8 mM/min) and old (24 ± 6 mM/min). In contrast, the ATP cost of contraction was significantly elevated in the old compared with the young (5.1 ± 2.0 and 3.7 ± 1.7 mM·min(-1)·W(-1), respectively; P < 0.05). Overall, these findings suggest that, when young and old subjects are activity matched, there is no evidence of age-related mitochondrial and glycolytic dysfunction. However, this study does confirm an abnormal elevation in exercise-induced skeletal muscle metabolic demand in the old that may contribute to the decline in exercise capacity with advancing age.

Perfluorodecalin-soluble fluorescent dyes for the monitoring of circulating nanocapsules with intravital fluorescence microscopy.

Perfluorodecalin (PFD) is an established artificial oxygen carrier due to its physical capability to solve the respiratory gases oxygen and carbon dioxide. PFD-filled poly(n-butyl-cyanoacrylate) (PACA) nanocapsules are already discussed as effective artificial oxygen carriers, and their principal suitability for intravenous administration had been shown. To further elucidate their action in vivo, it is imperative to characterise their preclinical safety and particularly their biodistribution. For these purposes, intravital fluorescence microscopy would display an attractive technique in order to monitor the PACA nanocapsules in vivo, but unfortunately, it is impossible to stain the PACA nanocapsules with a fluorescent dye fulfilling special criteria required for in vivo microscopy. In order to develop such a dye, a long-chained fluorinated thiol was used to modify a BODIPY derivative that is a highly fluorescent organic compound belonging to the difluoro-boraindacene family, as well as to functionalise mesoscopic systems, such as CdSe/ZnS-quantum dots and gold nanoparticles. Furthermore, a functionalisation of porphyrin derivatives was investigated by placing divalent ions in the centre of these systems. Due to the high solubility of all synthesised dyes in PFD, it should be possible to stain PFD-filled particles in general. However, only the functionalised BODIPY derivative was suitable for in vivo monitoring of the PFD-filled PACA nanocapsules.

Perfusion pressure and movement-induced hyperemia: evidence of limited vascular function and vasodilatory reserve with age.

To better understand the mechanisms contributing to reduced blood flow with age, this study sought to elucidate the impact of altered femoral perfusion pressure (FPP) on movement-induced hyperemia. Passive leg movement was performed in 10 young (22 ± 1 yr) and 12 old (72 ± 2 yr) healthy men for 2 min, with and without a posture-induced change in FPP (~7 ± 1 ΔmmHg). Second-by-second measurements of central and peripheral hemodynamic responses were acquired noninvasively (finger photoplethysmography and Doppler ultrasound, respectively), with FPP confirmed in a subset of four young and four old subjects with arterial and venous catheters. Central hemodynamic responses (heart rate, stroke volume, cardiac output, mean arterial pressure) were not affected by age or position. The young exhibited a ~70% greater movement-induced peak change in leg blood flow (ΔLBF(peak)) in the upright-seated posture (supine: 596±68 ml/min; upright: 1,026 ± 85 ml/min). However, in the old the posture change did not alter ΔLBF(peak) (supine: 417±42 ml/min; upright: 412±56 ml/min), despite the similar increases in FPP. Similarly, movement-induced peak change in leg vascular conductance was ~80% greater for the young in the upright-seated posture (supine: 7.1 ± 0.8 ml·min(-1)·mmHg(-1); upright: 12.8 ± 1.3 ml·min(-1)·mmHg(-1)), while the old again exhibited no difference between postures (supine: 4.7 ± 0.4 ml·min(-1)·mmHg(-1); upright: 4.8 ± 0.5 ml·min(-1)·mmHg(-1)). Thus this study reveals that, unlike the young, increased FPP does not elicit an increase in movement-induced hyperemia or vasodilation in the old. In light of recent evidence that the majority of the first minute of passive movement-induced hyperemia is predominantly nitric oxide (NO) dependent in the young, these findings in the elderly may be largely due to decreased NO bioavailability, but this remains to be definitively determined.

Ascorbate infusion increases skeletal muscle fatigue resistance in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is associated with systemic oxidative stress and skeletal muscle dysfunction. The purpose of this study was to examine the impact of intravenous ascorbate administration (AO) on biological markers of antioxidant capacity and oxidative stress, and subsequently skeletal muscle function during dynamic, small muscle mass exercise in patients with COPD. Ten patients with spirometric evidence of COPD performed single-leg knee extensor (KE) trials matched for intensity and time (isotime) following intravenous ascorbate (2 g) or saline infusion (PL). Quadriceps fatigue was quantified by changes in force elicited by maximal voluntary contraction (MVC) and magnetic femoral nerve stimulation (Qtw,pot). AO administration significantly increased antioxidant capacity, as measured by the ferric-reducing ability of plasma (PL: 1 ± 0.1 vs. AO: 5 ± 0.2 mM), and significantly reduced malondialdehyde levels (PL: 1.16 ± 0.1 vs. AO: 0.97 ± 0.1 mmol). Additionally, resting blood pressure was significantly reduced (PL: 104 ± 4 vs. AO: 93 ± 6 mmHg) and resting femoral vascular conductance was significantly elevated after AO (PL: 2.4 ± 0.2 vs. AO: 3.6 ± 0.4 ml·min(-1)·mmHg(-1)). During isotime exercise, the AO significantly attenuated both the ventilatory and metabolic responses, and patients accumulated significantly less peripheral quadriceps fatigue, as illustrated by less of a fall in MVC (PL: -11 ± 2% vs. AO: -5 ± 1%) and Qtw,pot (PL: -37 ± 1% vs. AO: -30 ± 2%). These data demonstrate a beneficial role of AO administration on skeletal muscle fatigue in patients with COPD and further implicate systemic oxidative stress as a causative factor in the skeletal muscle dysfunction observed in this population.

Nitric oxide and passive limb movement: a new approach to assess vascular function.

Passive limb movement elicits a robust increase in limb blood flow (LBF) and limb vascular conductance (LVC), but the peripheral vascular mechanisms associated with this increase in LBF and LVC are unknown. This study sought to determine the contribution of nitric oxide (NO) to movement-induced LBF and LVC and document the potential for passive-limb movement to assess NO-mediated vasodilatation and therefore NO bioavailability. Six subjects underwent passive knee extension with and without nitric oxide synthase (NOS) inhibition via intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA). LBF was determined second-by-second by Doppler ultrasound, and central haemodynamics were measured by finger photoplethysmography. Although L-NMMA did not alter the immediate increase (initial ∼9 s) in LBF and LVC, NOS blockade attenuated the peak increase in LBF (control: 653 ± 81; L-NMMA: 399 ± 112 ml(−1) min(−1), P = 0.03) and LVC (control: 7.5 ± 0.8; L-NMMA: 4.1 ± 1.1 ml min(−1) mmHg(−1), P = 0.02) and dramatically reduced the overall vasodilatory and hyperaemic response (area under the curve) by nearly 80% (LBF: control: 270 ± 51; L-NMMA: 75 ± 32 ml, P = 0.001; LVC: control: 2.9 ± 0.5; L-NMMA: 0.8 ± 0.3 ml mmHg(−1), P < 0.001). Passive movement in control and L-NMMA trials evoked similar increases in heart rate, stroke volume, cardiac output and a reduction in mean arterial pressure. As movement-induced increases in LBF and LVC are predominantly NO dependent, passive limb movement appears to have significant promise as a new approach to assess NO-mediated vascular function, an important predictor of cardiovascular disease risk.