Law Enforcement Officers Have an Increased Prevalence of Subclinical Cardiovascular Disease That Is Not Explained by Traditional Risk Factors.

OBJECTIVES: The aim of the study is to determine if law enforcement officers develop subclinical atherosclerotic cardiovascular disease (ASCVD) earlier than nonofficers and, if so, the extent to which conventional risk factors explain this difference. Methods: Estimated pulse wave velocity (ePWV) was the marker of subclinical ASCVD. EPWV, ASCVD risk factors, metabolic syndrome (MetS), and 10-year risk for ASCVD were compared among 408 law enforcement officers and a civilian cohort. Results: EPWV, 10-year ASCVD risk, and MetS prevalence increased significantly with age. All but the officers age 55 and older had higher ePWV cohort than the civilian cohort ( P < 0.001). Ten-year ASCVD risk explained the most variability of ePWV ( R2 = 0.49, P < 0.001). Conclusions: Officers develop subclinical ASCVD earlier than nonofficers. Conventional ASCVD risk factors only explain about half of this increase. Occupational factors may play a role in contributing to this increased ASCVD risk.

Angiotensin II type 2 receptor-mediated dilation is greater in the cutaneous microvasculature of premenopausal women compared with men.

Differential activation of the renin-angiotensin system (RAS) likely contributes to sex differences in cardiovascular outcomes in premenopausal women compared with age-matched men. Women demonstrate reduced activation of the vasoconstrictor angiotensin II type 1 receptors (AT1R) compared with men, and evidence suggests that women also likely have increased sensitivity of the vasodilatory angiotensin II type 2 receptors (AT2R). However, few in vivo studies have directly examined sex differences in AT2R-mediated dilation, or the balance between AT1R- and AT2R-mediated vascular responses in humans. Using the cutaneous microcirculation as a model, we hypothesized that AT2R-mediated dilation would be greater in premenopausal women compared with men, and that AT1R-blockade would augment AT2R-mediated dilation to a greater extent in men than in women. Twelve healthy women (22 ± 3 yr) and 12 men (23 ± 5 yr) had two intradermal microdialysis fibers placed in the ventral forearm for graded infusions of compound 21 (AT2R agonist; 10-12 to 10-8 M) in a control fiber site and a site treated with 43 µM losartan (AT1R antagonist). Red blood cell flux was measured continuously by laser-Doppler flowmetry, and cutaneous vascular conductance [CVC = flux/mean arterial pressure (MAP)] was normalized to maximum [%max; 28 mM sodium nitroprusside (SNP) + 43 °C]. Women had greater AT2R-mediated dilation compared with men (women: 25 ± 4 vs. men: 15 ± 2%max, P = 0.03). Local AT1R inhibition increased AT2R-mediated dilation in men (losartan: 26 ± 4 vs. control: 15 ± 2%max, P < 0.001) but had no effect in women (losartan: 27 ± 6 vs. control: 25 ± 4%max, P > 0.05). These data suggest that premenopausal women have a greater AT2R-mediated vasodilation response than men, and that AT1R activation inhibits AT2R-mediated dilation in men, but not in women.NEW & NOTEWORTHY Premenopausal women have greater protection against cardiovascular disease than age-matched men. However, the role of vasoconstrictor angiotensin II type 1 receptors (AT1R) and vasodilatory angiotensin II type 2 receptors (AT2R) in mediating these sex differences is unclear. Here, we demonstrate that women have greater AT2R-mediated vasodilation than men and that AT1R negates AT2R-mediated dilation in men, but not in women.

Chronic intermittent hypoxia promotes glomerular hyperfiltration and potentiates hypoxia-evoked decreases in renal perfusion and PO2.

Introduction: Sleep apnea (SA) is highly prevalent in patients with chronic kidney disease and may contribute to the development and/or progression of this condition. Previous studies suggest that dysregulation of renal hemodynamics and oxygen flux may play a key role in this process. The present study sought to determine how chronic intermittent hypoxia (CIH) associated with SA affects regulation of renal artery blood flow (RBF), renal microcirculatory perfusion (RP), glomerular filtration rate (GFR), and cortical and medullary tissue PO2 as well as expression of genes that could contribute to renal injury. We hypothesized that normoxic RBF and tissue PO2 would be reduced after CIH, but that GFR would be increased relative to baseline, and that RBF, RP, and tissue PO2 would be decreased to a greater extent in CIH vs. sham during exposure to intermittent asphyxia (IA, FiO2 0.10/FiCO2 0.03). Additionally, we hypothesized that gene programs promoting oxidative stress and fibrosis would be activated by CIH in renal tissue. Methods: All physiological variables were measured at baseline (FiO2 0.21) and during exposure to 10 episodes of IA (excluding GFR). Results: GFR was higher in CIH-conditioned vs. sham (p < 0.05), whereas normoxic RBF and renal tissue PO2 were significantly lower in CIH vs. sham (p < 0.05). Reductions in RBF, RP, and renal tissue PO2 during IA occurred in both groups but to a greater extent in CIH (p < 0.05). Pro-oxidative and pro-fibrotic gene programs were activated in renal tissue from CIH but not sham. Conclusion: CIH adversely affects renal hemodynamic regulation and oxygen flux during both normoxia and IA and results in changes in renal tissue gene expression.

Remote ischaemic preconditioning - translating cardiovascular benefits to humans.

Remote ischaemic preconditioning (RIPC), induced by intermittent periods of limb ischaemia and reperfusion, confers cardiac and vascular protection from subsequent ischaemia-reperfusion (IR) injury. Early animal studies reliably demonstrate that RIPC attenuated infarct size and preserved cardiac tissue. However, translating these adaptations to clinical practice in humans has been challenging. Large clinical studies have found inconsistent results with respect to RIPC eliciting IR injury protection or improving clinical outcomes. Follow-up studies have implicated several factors that potentially affect the efficacy of RIPC in humans such as age, fitness, frequency, disease state and interactions with medications. Thus, realizing the clinical potential for RIPC may require a human experimental model where confounding factors are more effectively controlled and underlying mechanisms can be further elucidated. In this review, we highlight recent experimental findings in the peripheral circulation that have added valuable insight on the mechanisms and clinical benefit of RIPC in humans. Central to this discussion is the critical role of timing (i.e. immediate vs. delayed effects following a single bout of RIPC) and the frequency of RIPC. Limited evidence in humans has demonstrated that repeated bouts of RIPC over several days uniquely improves vascular function beyond that observed with a single bout alone. Since changes in resistance vessel and microvascular function often precede symptoms and diagnosis of cardiovascular disease, repeated bouts of RIPC may be promising as a preclinical intervention to prevent or delay cardiovascular disease progression.

Delayed Cutaneous Microvascular Responses With Non-consecutive 3 Days of Remote Ischemic Preconditioning.

The optimal frequency and duration of remote ischemic preconditioning (RIPC) that augments microvascular function is unknown. A single bout of RIPC increases cutaneous endothelial function for ∼48 h, whereas 1 week of daily RIPC bouts improves more sustained endothelium-independent function. We hypothesized that 3 days of RIPC separated by rest days (3QOD RIPC) would result in sustained increases in both endothelium-dependent and endothelium-independent functions. Cutaneous microvascular function was assessed in 13 healthy young participants (aged 20.5 ± 3.9 years; 5 males, 8 females) before 3QOD and then 24, 48, and 72 h and a week after 3QOD. RIPC consisted of four repetitions of 5 min of blood flow occlusion separated by 5 min of reperfusion. Skin blood flow responses to local heating (T loc = 42°C), acetylcholine (Ach), and sodium nitroprusside (SNP) were measured using laser speckle contrast imaging and expressed as cutaneous vascular conductance (CVC = PU⋅mmHg-1). Local heating-mediated vasodilation was increased 72 h after 3QOD and the increased responsivity persisted a week later (1.08 ± 0.24 vs. 1.34 ± 0.46, 1.21 ± 0.36 PU⋅mmHg-1; ΔCVC, pre-RIPC vs. 72 h, a week after 3QOD; P = 0.054). Ach-induced cutaneous vasodilation increased a week after 3QOD (0.73 ± 0.41 vs. 0.95 ± 0.49 PU⋅mmHg-1; ΔCVC, pre-RIPC vs. a week after 3QOD; P < 0.05). SNP-induced cutaneous vasodilation increased 24 h after 3QOD (0.47 ± 0.28 vs. 0.63 ± 0.35 PU⋅mmHg-1; ΔCVC, pre-RIPC vs. 24 h; P < 0.05), but this change did not persist thereafter. Thus, 3QOD induced sustained improvement in endothelium-dependent vasodilation but was not sufficient to sustain increases in endothelium-independent vasodilation.

Laser speckle contrast imaging and laser Doppler flowmetry reproducibly assess reflex cutaneous vasoconstriction.

OBJECTIVE: Reproducibility of the reflex cutaneous vasoconstriction response is currently unknown. Our aim was to determine the test-retest reproducibility of laser speckle contrast imaging (LSCI) and varying sampling depths of laser Doppler flowmetry (LDF) in response to whole-body cooling. METHODS: Over two studies, nine and fourteen healthy, young adults underwent a 40-min cooling bout over two separate experiments. Participants were cooled from 34.0 °C to 30.5 °C and held at a 30.5 °C plateau for 10-min prior to rewarming. Throughout the cooling bout, changes in blood flow were measured as LSCI flux and LDF flux for Study 1 and LDF flux by three different LDF sampling depths in Study 2. Test-retest reproducibility and reliability were evaluated by the coefficient of variation (CV) and intraclass correlation coefficients (ICC), respectively. Vasoconstriction was presented as cutaneous vascular conductance (CVC = flux / mean arterial pressure) and expressed as a percent change from baseline (%ΔCVCBASELINE). RESULTS: For Study 1, test-retest reproducibility displayed good reproducibility for LSCI (CV: <9.0%) and good-to-moderate for LDF (CV: <17.0%) throughout the cooling bout and at plateau (LSCI CV: 1.0%; LDF CV: 1.9%). For Study 2, all Doppler depths displayed good reproducibility during the cooling bout (CV: <9.0%) and at plateau (CV: 0.9-2.0%). Only LSCI demonstrated reliability across both studies (ICC: 0.58-0.88). A reduced vasoconstriction response was measured with the shallowest penetration in the skin (LSCI: 26 ± 0.9%ΔCVCBASELINE) compared to the Doppler with the deepest penetration (35 ± 0.6%ΔCVCBASELINE, p < 0.001). CONCLUSIONS: Although Dopplers better discriminate the reflex cutaneous vasoconstriction response, LSCI exhibits greater test-retest reproducibility and reliability, and thus may be more suitable for longitudinal assessments.

What We Are Learning from COVID-19 for Respiratory Protection: Contemporary and Emerging Issues.

Infectious respiratory diseases such as the current COVID-19 have caused public health crises and interfered with social activity. Given the complexity of these novel infectious diseases, their dynamic nature, along with rapid changes in social and occupational environments, technology, and means of interpersonal interaction, respiratory protective devices (RPDs) play a crucial role in controlling infection, particularly for viruses like SARS-CoV-2 that have a high transmission rate, strong viability, multiple infection routes and mechanisms, and emerging new variants that could reduce the efficacy of existing vaccines. Evidence of asymptomatic and pre-symptomatic transmissions further highlights the importance of a universal adoption of RPDs. RPDs have substantially improved over the past 100 years due to advances in technology, materials, and medical knowledge. However, several issues still need to be addressed such as engineering performance, comfort, testing standards, compliance monitoring, and regulations, especially considering the recent emergence of pathogens with novel transmission characteristics. In this review, we summarize existing knowledge and understanding on respiratory infectious diseases and their protection, discuss the emerging issues that influence the resulting protective and comfort performance of the RPDs, and provide insights in the identified knowledge gaps and future directions with diverse perspectives.

Delayed window of improvements in skin microvascular function following a single bout of remote ischaemic preconditioning.

NEW FINDINGS: What is the central question of this study? Animal infarct studies indicate a delayed window of cardiac protection after remote ischaemic preconditioning (RIPC); however, the presence and duration of this delayed effect have not been examined in human microvasculature in vivo. What is the main finding and its importance? Cutaneous vasodilatation induced by local heating or ACh was increased significantly 24 and 48 h after a single bout of RIPC, respectively. Neither response persisted beyond ∼48 h. Sodium nitroprusside-induced cutaneous vasodilatation was not altered. These findings reveal a delayed increase in microvascular endothelial function after a single bout of RIPC. ABSTRACT: Remote ischaemic preconditioning (RIPC) induces protective effects from ischaemia-reperfusion injury. In the myocardium and conduit vasculature, a single bout of RIPC confers delayed protection that begins 24 h afterwards and lasts for 2-3 days. However, the extent and the time line in which a single bout of RIPC affects the human microvasculature are unclear. We hypothesized that a single bout of RIPC results in a delayed increase in skin microvascular function. Sixteen healthy participants (age, 23 ± 4 years; seven males, nine females; MAP, 82 ± 7 mmHg) were recruited to measure cutaneous microvascular function immediately before a single bout of RIPC and 24, 48 and 72 h and 1 week after the bout. The RIPC consisted of four repetitions of 5 min of arm blood flow occlusion interspersed by 5 min reperfusion. Skin blood flow responses to local heating (local temperature of 42°C), ACh and sodium nitroprusside were measured by laser speckle contrast imaging and expressed as the cutaneous vascular conductance (CVC; in perfusion units per millimetre of mercury). Vasodilatation in response to local heating was increased 24 and 48 h after RIPC (ΔCVC, 1.05 ± 0.07 vs. 1.18 ± 0.07 and 1.24 ± 0.08 PU mmHg-1 , pre- vs. 24 and 48 h post-RIPC; P < 0.05). Acetylcholine-induced cutaneous vasodilatation increased significantly 48 h after RIPC (ΔCVC, 0.71 ± 0.07 vs. 0.93 ± 0.12 PU mmHg-1 , pre- vs. 48 h post-RIPC; P < 0.05) and returned to baseline thereafter. Sodium nitroprusside-mediated vasodilatation did not change. Thus, a single bout of RIPC elicited a delayed response in the microvasculature, resulting in an improvement in the endothelium-dependent cutaneous vasodilatory response that peaked ∼48 h post-RIPC.

Reproducibility and normalization of reactive hyperemia using laser speckle contrast imaging.

BACKGROUND: Impaired perfusion indices signal potential microvascular dysfunction preceding atherosclerosis and other cardiometabolic pathologies. Post-occlusive reactive hyperemia (PORH), a vasodilatory response following a mechanically induced ischemia, is a transient increase in perfusion and can assess microvascular function. The greatest blood flow change corresponding to the first minute of hyperemia (represented by time-to-peak, hyperemic velocity, AUC within 1st min) has been shown to indicate microvascular dysfunction. However, the reproducibility of these temporal kinetic indices of the PORH response is unknown. Our aim was to examine the inter- and intra-day reproducibility and standardization of reactive hyperemia, with emphasis on the kinetic indices of PORH, using laser speckle contrast imaging (LSCI) technique. METHODS AND RESULTS: Seventeen healthy adults (age = 24 ± 3 years) completed three PORH bouts over two lab visits. LSCI region of interest was a standardized 10 cm region on the dominant ventral forearm. A 5-min brachial artery occlusion period induced by inflating an arm cuff to 200 mmHg, preceded a 4-min hyperemic period. Inter- and intra-day reliability and reproducibility of cutaneous vascular conductance (LSCI flux / mean arterial pressure) were determined using intraclass correlation (ICC) and coefficient of variation (CV%). Maximal flow and area under the curve standardized to zero perfusion showed intra- and inter-day reliability (ICC > 0.70). Time to maximal flow (TMF) was not reproducible (inter-day CV = 18%). However, alternative kinetic indices such as 1-min AUC and overshoot rate-of-change (ORC), represented as a piecewise function (at 5s, 10s, 15s, and 20s into hyperemia), were reproducible (CV< 11%). Biological zero was a reliable normalization point. CONCLUSION: PORH measured with LSCI is a reliable assessment of microvascular function. However, TMF or its derived hyperemic velocity are not recommended for longitudinal assessment. Piecewise ORC and 1-min AUC are reliable alternatives to assess the kinetic response of PORH.

Baroreflex function in Parkinson's disease: insights from the modified-Oxford technique.

Nonmotor symptoms are common in Parkinson's disease (PD) and they include dysregulation of cardiovascular system, which adversely affects quality of life. Recent studies provide indirect evidence that baroreflex dysfunction may be one of the mechanisms of cardiovascular dysregulation in PD. Herein, we tested the hypothesis that the baroreflex gain, assessed across an extensive range of the reflex arc by eliciting rapid changes in blood pressure (BP) induced by sequential boluses of vasoactive drugs (modified-Oxford technique) would be attenuated in middle-aged patients with PD. Beat-to-beat heart rate (electrocardiography) and BP (finger photoplethysmography) were obtained during 10 min of supine rest preceding the modified-Oxford (bolus of nitroprusside followed by phenylephrine 1 min afterward) in 11 patients with PD (51 ± 6 yr) and 7 age-matched controls (47 ± 6 yr). The resulting systolic BP and R-R interval responses were plotted and fitted with segmental linear regression and symmetric sigmoid model. Spontaneous indices obtained via sequence technique were also used to estimate baroreflex gain. Compared with controls, the estimated gains measured by segmental linear regression (patients: 3.83 ± 2.6 ms/mmHg versus controls: 7.78 ± 1.7 ms/mmHg; P = 0.003) and symmetric sigmoid model (patients: 12.36 ± 6.9 ms/mmHg versus controls: 32.02 ± 19.0 ms/mmHg; P = 0.009) were lower in patients with PD. The operating range of BP was larger in patients with PD compared with controls (13 ± 7 mmHg versus controls: 7 ± 3 mmHg; P = 0.032). Of note, the gain obtained from spontaneous indices was similar between groups. These data indicate that baroreflex gain was reduced by >50% in PD, thereby providing clear and direct evidence that cardiovagal baroreflex dysfunction occurs in PD.NEW & NOTEWORTHY Attenuated baroreflex gain may contribute to adverse cardiovascular outcomes, including orthostatic intolerance symptoms typically observed in patients with Parkinson's disease. We found that the baroreflex gain (assessed by the modified-Oxford technique) is attenuated and accompanied by an increased operating range in patients with Parkinson's disease. These findings highlight that cardiovascular perturbations are required to detect baroreflex impairments and that spontaneous indices do not reveal cardiovagal-baroreflex dysfunction in a middle-aged group of patients with Parkinson's disease.

Long-term Effects of Calcium ß-Hydroxy-ß-Methylbutyrate and Vitamin D3 Supplementation on Muscular Function in Older Adults With and Without Resistance Training: A Randomized, Double-blind, Controlled Study.

The primary aim of this study was to determine whether supplementation with calcium ß-hydroxy-ß-methylbutyrate (HMB) and vitamin D3 (D) would enhance muscle function and strength in older adults. Older adults over 60 years of age with insufficient circulating 25-hydroxy-vitamin D (25OH-D) levels were enrolled in a double-blinded controlled 12-month study. Study participants were randomly assigned to treatments consisting of: (a) Control + no exercise, (b) HMB+D + no exercise, (c) Control + exercise, and (d) HMB+D + exercise. The study evaluated 117 participants via multiple measurements over the 12 months that included body composition, strength, functionality, and questionnaires. HMB+D had a significant benefit on lean body mass within the nonexercise group at 6 months (0.44 ± 0.27 kg, HMB+D vs -0.33 ± 0.28 kg, control, p < .05). In nonexercisers, improvement in knee extension peak torque (60°/s) was significantly greater in HMB+D-supplemented participants than in the nonsupplemented group (p = .04) at 3 months, 10.9 ± 5.7 Nm and -5.2 ± 5.9 Nm, respectively. A composite functional index, integrating changes in handgrip, Get Up, and Get Up and Go measurements, was developed. HMB+D + no exercise resulted in significant increases in the functional index compared with those observed in the control + no exercise group at 3 (p = .03), 6 (p = .04), and 12 months (p = .04). Supplementation with HMB+D did not further improve the functional index within the exercising group. This study demonstrated the potential of HMB and vitamin D3 supplementation to enhance muscle strength and physical functionality in older adults, even in individuals not engaged in an exercise training program.

Two weeks of remote ischaemic preconditioning alters sympathovagal balance in healthy humans.

NEW FINDINGS: What is the central question of this study? Delayed cardiovascular responses occur following a single bout of remote ischaemic preconditioning (RIPC). Is heart rate variability (HRV), a surrogate marker of cardiac vagal control, able to detect a delayed effect after a single bout of RIPC? Do repeated bouts of RIPC further alter HRV? What is the main finding and its importance? Indices of HRV indicated a shift in sympathovagal balance toward greater parasympathetic activity following 2 weeks of RIPC but not after a single bout of RIPC. Thus, repeated bouts of RIPC were necessary to elicit changes in autonomic function. ABSTRACT: Remote ischaemic preconditioning (RIPC), induced by brief periods of ischaemia followed by reperfusion, protects against ischaemia-reperfusion injury and improves microvascular function. However, the effect of RIPC on autonomic function remains unclear. We hypothesized that RIPC, administered as a single bout or repeated over a 2-week period, will increase markers of cardiac vagal control measured by heart rate variability (HRV). Thirty-two young adults performed a single bout (n = 13), repeated bouts (n = 11), or served as a time control (n = 8). RIPC sessions consisted of four repetitions of 5 min unilateral brachial artery occlusion interspersed by 5 min of reperfusion. For the single bout protocol, resting lead II electrocardiogram (ECG) was collected before and 24, 48, 72 and 168 h post-RIPC. The repeated bout protocol consisted of three 4-day periods of RIPC training, each interspersed by a 1-day break. Similar to time controls, ECG was collected before and 24 h after the last RIPC bout. HRV was analysed by power spectral density and symbolic dynamics using 350-beat ECG segments. After a single bout of RIPC, no changes in HRV were observed at any time point (P > 0.05). After 2 weeks of repeated RIPC, the percentage of zero-variation fragments (baseline = 13.1 ± 1.9%, post-RIPC = 6.9 ± 1.5%, P < 0.05) and the LF/HF ratio decreased (baseline = 1.1 ± 0.2, post-RIPC = 0.7 ± 0.1, P < 0.01), whereas the percentage of two-variation fragments increased (baseline = 42.9 ± 3.6%, post-RIPC = 52.5 ± 3.0%, P < 0.01). These data indicate that repeated RIPC is necessary to elicit changes in sympathovagal balance, specifically resulting in increased vagal and decreased sympathetic activity.

Cardiorespiratory Fitness and Muscular Strength on Arterial Stiffness in Older Adults.

PURPOSE: To evaluate the independent and combined associations of cardiorespiratory fitness (CRF) and muscular strength (MS) with arterial stiffness (AS), a strong predictor of cardiovascular disease, in older adults. METHODS: This cross-sectional study included 405 older adults (mean age, 72 yr). Cardiorespiratory fitness was assessed by time (s) to complete a 400-m walking test and MS by maximal handgrip strength (kg). Carotid-femoral pulse wave velocity was used to assess AS. High AS was defined as a pulse wave velocity of ≥10 m·s, a previously established threshold for increased cardiovascular risk. Poisson regression was used to calculate prevalence ratios (PR) and 95% confidence intervals (CI) of having high AS across sex-specific tertiles of CRF and MS. Muscular strength and CRF were further dichotomized into either "weak" or "unfit" (lower one third for each), or "strong" or "fit" (upper two thirds for each) to investigate the combined associations of CRF and MS with high AS. All analyses were adjusted for potential confounders, including MS for CRF and CRF for MS. RESULTS: Sixty-nine (17%) participants had high AS. Compared with lower CRF, PR (95% CI) of having high AS were 0.53 (0.30-0.95) and 0.69 (0.38-1.23) for middle and upper CRF, respectively. Compared with lower MS, PR (95% CI) of having high AS were 0.81 (0.49-1.34) and 0.52 (0.29-0.92) for middle and upper MS, respectively. In the joint analysis, compared with the "unfit and weak" group, PR (95% CI) of having high AS were 0.72 (0.38-1.35), 0.58 (0.29-1.16), and 0.46 (0.25-0.85) for "unfit and strong," "fit and weak," and "fit and strong" groups, respectively. CONCLUSIONS: Higher levels of CRF and MS were independently associated with lower (healthier) levels of AS in older adults.

Oral L-Tyrosine Supplementation Improves Core Temperature Maintenance in Older Adults.

INTRODUCTION: During cold exposure, an increase in sympathetic nerve activity evokes vasoconstriction (VC) of cutaneous vessels to minimize heat loss. In older adults, this reflex VC response is impaired thereby increasing their susceptibility to excess heat loss and hypothermia. Because L-tyrosine, the amino acid substrate necessary for catecholamine production, has been shown to augment reflex VC in age skin, we hypothesize that oral ingestion of L-tyrosine will attenuate the decline in core temperature (Tc) during whole-body cooling in older adults. METHODS: In a randomized, double-blind design, nine young (25 ± 3 yr) and nine older (72 ± 8 yr) participants ingested either 150 mg·kg of L-tyrosine or placebo before commencing 90 min of whole-body cooling to decrease skin temperature to approximately 29.5°C. Esophageal temperature and forearm laser Doppler flux (LDF) were measured continuously throughout the protocol to provide an index of Tc and skin blood flow, respectively. The change in esophageal temperature (ΔTES) was the difference in temperature at the end of cooling subtracted from baseline. Cutaneous vascular conductance (CVC) was calculated as CVC = LDF/mean arterial pressure and expressed as a percent change from baseline (%ΔCVCBASELINE). RESULTS: Oral tyrosine ingestion augmented the cutaneous VC response to cooling in older adults (placebo, 14.4 ± 2.0; tyrosine, 32.7% ± 1.7% ΔCVCBASELINE; P < 0.05). Additionally, tyrosine improved Tc maintenance throughout cooling in older adults (placebo, -0.29 ± 0.07; tyrosine, -0.07 ± 0.07 ΔTES; P < 0.05). Both the cutaneous VC and Tc during cooling were similar between young and older adults supplemented with tyrosine (P > 0.05). CONCLUSIONS: These results indicate that L-tyrosine supplementation improves Tc maintenance in response to acute cold exposure in an older population.

Improved endothelial-dependent and endothelial-independent skin vasodilator responses following remote ischemic preconditioning.

One week of daily remote ischemic preconditioning (RIPC) improves cutaneous vasodilatory (VD) function. However, the underlying mechanisms and the number of sessions needed to optimize this adaptive response remain unclear. We hypothesized that the responses to localized heating of the skin will be greater after 2 wk as opposed to 1 wk of RIPC. Furthermore, 2 wk of repeated RIPC will augment cutaneous VD responses to thermal and pharmacological stimuli. In methods, twenty-four participants (24 ± 2 yr; 13 men, 11 women) performed repeated RIPC (7 daily sessions over 1 wk, n = 11; 12 sessions over 2 wk, n = 13), consisting of four repetitions of 5 min of arm blood flow occlusion separated by 5 min reperfusion. Laser speckle contrast imaging was used to measure skin blood flow responses, in perfusion units (PU), to local heating (Tloc = 42°C), acetylcholine (ACh), and sodium nitroprusside (SNP) before and after repeated RIPC. Data were expressed as cutaneous vascular conductance (CVC, in PU/mmHg). In results, the VD response to local heating increased after RIPC (∆CVC from baseline; 1 wk: 0.94 ± 0.11 to 1.19 ± 0.15, 2 wk: 1.18 ± 0.07 to 1.33 ± 0.10 PU/mmHg; P < 0.05) but the ∆CVC did not differ between weeks. SNP-induced VD increased after 2 wk of RIPC (∆CVC; 0.34 ± 0.07 to 0.63 ± 0.11 PU/mmHg; P < 0.05), but ACh-induced VD did not. In conclusion, repeated RIPC improves local heating- and SNP-mediated cutaneous VD. When compared with 1 wk of RIPC, 2 wk of RIPC does not induce further improvements in cutaneous VD function.NEW & NOTEWORTHY Repeated RIPC increases the cutaneous vasodilatory response to local heating and to sodium nitroprusside but not to acetylcholine. Thus, endothelial-independent and local heating-mediated cutaneous vasodilation are improved following RIPC. However, 2 wk of RIPC sessions are not more effective than 1 wk of RIPC sessions in enhancing local heating-mediated cutaneous vasodilation.

Fenretinide, Tocilizumab, and Reparixin Provide Multifaceted Disruption of Oral Squamous Cell Carcinoma Stem Cell Properties: Implications for Tertiary Chemoprevention.

Locoregional recurrence of oral squamous cell carcinoma (OSCC) dramatically reduces patient survival. Further, as many OSCC recurrences are inoperable, radiotherapy and chemotherapy with or without biological adjuncts are the remaining treatment options. Although the tumors may initially respond, radiotherapy- and chemotherapy-resistant cancer stem cells (CSC) can readily repopulate OSCC tumors. Currently, following the initial OSCC treatment, patients are closely monitored until a recurrence or a second primary is detected. Identification of agents with complementary mechanisms to suppress CSC tumorigenic functions could change this passive approach. The goals of this study were twofold: (1) develop and validate CSC-enriched (CSCE) OSCC cell lines and (2) identify chemopreventive agents that obstruct multiple CSCE protumorigenic pathways. CSCE cultures, which were created by paclitaxel treatment followed by three tumorsphere passes, demonstrated CSC characteristics, including increased expression of stem cell and inflammatory genes, increased aldehyde dehydrogenase (ALDH) activity, and enhanced in vitro/in vivo proliferation and invasion. Three chemopreventives, fenretinide, tocilizumab, and reparixin, were selected due to their distinct and complementary CSC-disruptive mechanisms. The CSCE selection process modulated the cells' intermediate filaments resulting in an epithelial-predominant (enhanced cytokeratin, proliferation, IL6 release) line and a mesenchymal-predominant (upregulated vimentin, invasive, IL8 release) line. Our results confirm that 4HPR binds with appreciably higher affinity than Wnt at the Frizzled binding site and significantly inhibits CSC-enabling Wnt-ß-catenin downstream signaling. Notably, combination fenretinide-tocilizumab-reparixin treatment significantly suppressed IL6 and IL8 release, stem cell gene expression, and invasion in these diverse CSCE populations. These promising multiagent in vitro data provide the basis for our upcoming in vivo CSCE tertiary chemoprevention studies.

Age-related differences in the cutaneous vascular response to exogenous angiotensin II.

Angiotensin II (ANG II) is locally produced in human skin and contributes to the reflex vasoconstriction (VC) response in aged but not young skin. We hypothesized that the exogenous ANG II-mediated VC response would be greater in older adults and would be affected by inhibition of adrenoreceptor or ANG II type II receptor (AT2R) pathways. Three microdialysis (MD) fibers were placed in the forearm skin of 11 young (26 ± 3 yr) and 11 older (68 ± 4 yr) individuals for perfusion of 1) Ringer solution (control), 2) adrenoreceptor blockade with yohimbine + propranolol, and 3) AT2R inhibition with PD-123319. ANG II was then added to the perfusates at eight graded dose concentrations ranging from 10-10 to 10-3 M. Laser Doppler flux was measured at each MD site, and cutaneous vascular conductance (CVC) was calculated as CVC = laser Doppler flux/mean arterial pressure and normalized to baseline CVC values collected before ANG II perfusion (%ΔCVCbaseline). At the control site, older adults (-34 ± 4%ΔCVCbaseline) exhibited a greater peak VC compared with young adults (-22 ± 2%ΔCVCbaseline, P < 0.05), which was attenuated with adrenoreceptor blockade. Young skin exhibited a vasodilation in response to lower ANG II doses that was inhibited with AT2R inhibition. AT2R inhibition also increased the VC response to higher ANG II doses such that young skin responded similarly to older skin. These results indicate that ANG II has a greater VC influence in older than young individuals. Furthermore, ANG II may be affecting multiple targets, including adrenergic and AT2R pathways. NEW & NOTEWORTHY Intradermal perfusion of successive doses of angiotensin II (ANG II) revealed a role for ANG II type II receptors and dose-dependent, ANG II-mediated vasodilation in young but not older adults. In contrast, older adults exhibited greater vasoconstriction for a given dose of ANG II. The increased vasoconstriction in older adults was subsequently blunted with adrenoreceptor blockade, which indicates an interaction between ANG II and adrenergic signaling pathways in the cutaneous microcirculation.