The developmental basis of fingerprint pattern formation and variation.

Fingerprints are complex and individually unique patterns in the skin. Established prenatally, the molecular and cellular mechanisms that guide fingerprint ridge formation and their intricate arrangements are unknown. Here we show that fingerprint ridges are epithelial structures that undergo a truncated hair follicle developmental program and fail to recruit a mesenchymal condensate. Their spatial pattern is established by a Turing reaction-diffusion system, based on signaling between EDAR, WNT, and antagonistic BMP pathways. These signals resolve epithelial growth into bands of focalized proliferation under a precociously differentiated suprabasal layer. Ridge formation occurs as a set of waves spreading from variable initiation sites defined by the local signaling environments and anatomical intricacies of the digit, with the propagation and meeting of these waves determining the type of pattern that forms. Relying on a dynamic patterning system triggered at spatially distinct sites generates the characteristic types and unending variation of human fingerprint patterns.

Limb development genes underlie variation in human fingerprint patterns.

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.

Rapid mechanosensitive migration and dispersal of newly divided mesenchymal cells aid their recruitment into dermal condensates.

Embryonic mesenchymal cells are dispersed within an extracellular matrix but can coalesce to form condensates with key developmental roles. Cells within condensates undergo fate and morphological changes and induce cell fate changes in nearby epithelia to produce structures including hair follicles, feathers, or intestinal villi. Here, by imaging mouse and chicken embryonic skin, we find that mesenchymal cells undergo much of their dispersal in early interphase, in a stereotyped process of displacement driven by 3 hours of rapid and persistent migration followed by a long period of low motility. The cell division plane and the elevated migration speed and persistence of newly born mesenchymal cells are mechanosensitive, aligning with tissue tension, and are reliant on active WNT secretion. This behaviour disperses mesenchymal cells and allows daughters of recent divisions to travel long distances to enter dermal condensates, demonstrating an unanticipated effect of cell cycle subphase on core mesenchymal behaviour.

Challenging the Hemodynamic Hypothesis in Heart Failure With Preserved Ejection Fraction: Is Exercise Capacity Limited by Elevated Pulmonary Capillary Wedge Pressure?

BACKGROUND: Exercise intolerance is a defining characteristic of heart failure with preserved ejection fraction (HFpEF). A marked rise in pulmonary capillary wedge pressure (PCWP) during exertion is pathognomonic for HFpEF and is thought to be a key cause of exercise intolerance. If true, acutely lowering PCWP should improve exercise capacity. To test this hypothesis, we evaluated peak exercise capacity with and without nitroglycerin to acutely lower PCWP during exercise in patients with HFpEF. METHODS: Thirty patients with HFpEF (70±6 years of age; 63% female) underwent 2 bouts of upright, seated cycle exercise dosed with sublingual nitroglycerin or placebo control every 15 minutes in a single-blind, randomized, crossover design. PCWP (right heart catheterization), oxygen uptake (breath × breath gas exchange), and cardiac output (direct Fick) were assessed at rest, 20 Watts (W), and peak exercise during both placebo and nitroglycerin conditions. RESULTS: PCWP increased from 8±4 to 35±9 mm Hg from rest to peak exercise with placebo. With nitroglycerin, there was a graded decrease in PCWP compared with placebo at rest (-1±2 mm Hg), 20W (-5±5 mm Hg), and peak exercise (-7±6 mm Hg; drug × exercise stage P=0.004). Nitroglycerin did not affect oxygen uptake at rest, 20W, or peak (placebo, 1.34±0.48 versus nitroglycerin, 1.32±0.46 L/min; drug × exercise P=0.984). Compared with placebo, nitroglycerin lowered stroke volume at rest (-8±13 mL) and 20W (-7±11 mL), but not peak exercise (0±10 mL). CONCLUSIONS: Sublingual nitroglycerin lowered PCWP during submaximal and maximal exercise. Despite reduction in PCWP, peak oxygen uptake was not changed. These results suggest that acute reductions in PCWP are insufficient to improve exercise capacity, and further argue that high PCWP during exercise is not by itself a limiting factor for exercise performance in patients with HFpEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04068844.

Effects of Synchronizing Foot Strike and Cardiac Phase on Exercise Hemodynamics in Patients With Cardiac Resynchronization Therapy: A Within-Subjects Pilot Study to Fine-Tune Cardio-Locomotor Coupling for Heart Failure.

BACKGROUND: Despite advances in medical and cardiac resynchronization therapy (CRT), individuals with chronic congestive heart failure (CHF) have persistent symptoms, including exercise intolerance. Optimizing cardio-locomotor coupling may increase stroke volume and skeletal muscle perfusion as previously shown in healthy runners. Therefore, we tested the hypothesis that exercise stroke volume and cardiac output would be higher during fixed-paced walking when steps were synchronized with the diastolic compared with systolic portion of the cardiac cycle in patients with CHF and CRT. METHODS: Ten participants (58±17 years of age; 40% female) with CHF and previously implanted CRT pacemakers completed 5-minute bouts of walking on a treadmill (range, 1.5-3 mph). Participants were randomly assigned to first walking to an auditory tone to synchronize their foot strike to either the systolic (0% or 100±15% of the R-R interval) or diastolic phase (45±15% of the R-R interval) of their cardiac cycle and underwent assessments of oxygen uptake (V̇o2; indirect calorimetry) and cardiac output (acetylene rebreathing). Data were compared through paired-samples t tests. RESULTS: V̇o2 was similar between conditions (diastolic 1.02±0.44 versus systolic 1.05±0.42 L/min; P=0.299). Compared with systolic walking, stroke volume (diastolic 80±28 versus systolic 74±26 mL; P=0.003) and cardiac output (8.3±3.5 versus 7.9±3.4 L/min; P=0.004) were higher during diastolic walking; heart rate (paced) was not different between conditions. Mean arterial pressure was significantly lower during diastolic walking (85±12 versus 98±20 mm Hg; P=0.007). CONCLUSIONS: In patients with CHF who have received CRT, diastolic stepping increases stroke volume and oxygen delivery and decreases afterload. We speculate that, if added to pacemakers, this cardio-locomotor coupling technology may maximize CRT efficiency and increase exercise participation and quality of life in patients with CHF.

Metabolomic profiles of 38 acylcarnitines in major depressive episodes before and after treatment.

BACKGROUND: Major depression is associated with changes in plasma L-carnitine and acetyl-L-carnitine. But its association with acylcarnitines remains unclear. The aim of this study was to assess metabolomic profiles of 38 acylcarnitines in patients with major depression before and after treatment compared to healthy controls (HCs). METHODS: Metabolomic profiles of 38 plasma short-, medium-, and long-chain acylcarnitines were performed by liquid chromatography-mass spectrometry in 893 HCs from the VARIETE cohort and 460 depressed patients from the METADAP cohort before and after 6 months of antidepressant treatment. RESULTS: As compared to HCs, depressed patients had lower levels of medium- and long-chain acylcarnitines. After 6 months of treatment, increased levels of medium- and long-chain acyl-carnitines were observed that no longer differed from those of controls. Accordingly, several medium- and long-chain acylcarnitines were negatively correlated with depression severity. CONCLUSIONS: These medium- and long-chain acylcarnitine dysregulations argue for mitochondrial dysfunction through fatty acid ß-oxidation impairment during major depression.

Impaired longitudinal systolic-diastolic coupling and cardiac response to exercise in patients with hypertrophic cardiomyopathy.

BACKGROUND: In patients with hypertrophic cardiomyopathy (HCM), impaired augmentation of stroke volume and diastolic dysfunction contribute to exercise intolerance. Systolic-diastolic (S-D) coupling characterizes how systolic contraction of the left ventricle (LV) primes efficient elastic recoil during early diastole. Impaired S-D coupling may contribute to the impaired cardiac response to exercise in patients with HCM. METHODS: Patients with HCM (n = 25, age = 47 ± 9 years) and healthy adults (n = 115, age = 49 ± 10 years) underwent a cardiopulmonary exercise testing (CPET) and echocardiogram. S-D coupling was defined as the ratio of LV longitudinal excursion of the mitral annulus during early diastole (EDexc) and systole (Sexc) and compared between groups. Peak oxygen uptake (peak V̇O2) (Douglas bags), cardiac index (C2H2 rebreathe), and stroke volume index (SVi) were assessed during CPET. Linear regression was performed between S-D coupling and peak V̇O2, peak cardiac index, and peak SVi. RESULTS: S-D coupling was lower in HCM (Controls: 0.63 ± 0.08, HCM: 0.56 ± 0.10, p < 0.001). Peak V̇O2 and stroke volume reserve were lower in patients with HCM (Peak VO2 Controls: 28.5 ± 5.5, HCM: 23.7 ± 7.2 mL/kg/min, p < 0.001, SV reserve: Controls 39 ± 16, HCM 30 ± 18 mL, p = 0.008). In patients with HCM, S-D coupling was associated with peak V̇O2 (r = 0.47, p = 0.018), peak cardiac index (r = 0.60, p = 0.002), and peak SVi (r = 0.63, p < 0.001). CONCLUSION: Systolic-diastolic coupling was impaired in patients with HCM and was associated with fitness and the cardiac response to exercise. Inefficient S-D coupling may link insufficient stroke volume generation, diastolic dysfunction, and exercise intolerance in HCM.

Habenular volume changes after venlafaxine treatment in patients with major depression.

BACKGROUND: Habenula, a hub brain region controlling monoaminergic brain center, has been implicated in major depressive disorder (MDD) and as a possible target of antidepressant response. Nevertheless, the effect of antidepressant drug treatment on habenular volumes remains unknown. The objective of the present research was to study habenular volume change after antidepressant treatment in patients with MDD, and assess whether it is associated with clinical improvement. METHODS: Fifty patients with a current major depressive episode (MDE) in the context of MDD, and antidepressant-free for at least 1 month, were assessed for habenula volume (3T MRI with manual segmentation) before and after a 3 months sequence of venlafaxine antidepressant treatment. RESULTS: A 2.3% significant increase in total habenular volume (absolute volume: P = 0.0013; relative volume: P = 0.0055) and a 3.3% significant increase in left habenular volume (absolute volume: P = 0.00080; relative volume: P = 0.0028) were observed. A significant greater variation was observed in male patients (4.8%) compared to female patients. No association was observed between habenular volume changes and response and remission. Some habenula volume changes were associated with improvement of olfactory pleasantness. CONCLUSION: Habenular volumes increased after 3 months of venlafaxine treatment in depressed patients. Further studies should assess whether cell proliferation and density or dendritic structure variations are implied in these volume changes.

Disparities in resource utilisation by families of children with cardiac conditions.

OBJECTIVES: There are limited data documenting sources of medical information that families use to learn about paediatric cardiac conditions. Our study aims to characterise these resources and to identify any disparities in resource utilisation. We hypothesise there are significant variations in the resources utilised by families from different educational and socio-economic backgrounds. METHODS: A survey evaluating what resources families use (websites, healthcare professionals, social media, etc.) to better understand paediatric cardiac conditions was administered to caretakers and paediatric patients at Morgan Stanley Children's Hospital. Patients with a prior diagnosis of CHD, cardiac arrhythmia, and/or heart failure were included. Caretakers' levels of education (fewer than 16 years vs. 16 years or more) and patients' medical insurance types (public vs. private) were compared with regard to the utilisation of resources. RESULTS: Surveys completed by 137 (91%) caretakers and 27 (90%) patients were analysed. Websites were utilised by 72% of caretakers and 56% of patients. Both private insurance and higher education were associated with greater reported utilisation of websites, healthcare professionals, and personal networks (by insurance p = 0.009, p = 0.001, p = 0.006; by education p = 0.022, p < 0.001, p = 0.018). They were also more likely to report use of electronic devices (such as a computer) compared to those with public medical insurance and fewer than 16 years of education (p < 0.001, p < 0.001, respectively). CONCLUSION: Both levels of education and insurance status are associated with the utilisation of informative resources and digital devices by families seeking to learn more about cardiac conditions in children.

The impact of surgery resident training on the duration of tibial plateau leveling osteotomy surgery.

OBJECTIVE: To investigate the impact of surgery resident training on surgery duration in tibial plateau leveling osteotomy (TPLO) and evaluate whether surgery duration differs with each year of residency training. STUDY DESIGN: Retrospective medical record review. ANIMALS: A total of 256 client-owned dogs underwent TPLO. METHODS: Records of dogs that underwent TPLO between August 2019 and August 2022 were reviewed. The effects of the surgeon (faculty/resident) and the procedure (arthrotomy/arthroscopy) on TPLO surgery duration were examined with an analysis of variance, and geometric least squares means (GLSM) were compared. A linear mixed effects model (LMM) was fitted to quantify fixed and random effects. RESULTS: Four faculty surgeons performed 74 (29%) TPLOs, while 10 residents performed 182 (71%) TPLOs under the direct supervision of a faculty surgeon. All TPLOs were conducted with arthrotomy (109; 43%) or arthroscopy (147; 57%). Overall, residents (GLSM, 153 min) required 54% more surgery duration than faculty surgeons (GLSM, 99 min). Surgery duration among first-year residents (GLSM, 170 min) was 15% longer than second- (GLSM, 148 min) and third-year (GLSM, 147 min) residents, whereas the duration did not differ statistically between second- and third-year residents. Arthroscopy, meniscal tear treatment, surgery on the right stifle, and increasing patient weight were also associated with longer surgery duration. CONCLUSION: The duration of TPLO surgery significantly decreased after the first year of residency, but did not decrease afterward. CLINICAL SIGNIFICANCE: The results will aid with resource allocation, curricula planning, and cost management associated with resident training.

Realistic numerical simulations of diffusion tensor cardiovascular magnetic resonance: The effects of perfusion and membrane permeability.

PURPOSE: To study the sensitivity of diffusion tensor cardiovascular magnetic resonance (DT-CMR) to microvascular perfusion and changes in cell permeability. METHODS: Monte Carlo (MC) random walk simulations in the myocardium have been performed to simulate self-diffusion of water molecules in histology-based media with varying extracellular volume fraction (ECV) and permeable membranes. The effect of microvascular perfusion on simulations of the DT-CMR signal has been incorporated by adding the contribution of particles traveling through an anisotropic capillary network to the diffusion signal. The simulations have been performed considering three pulse sequences with clinical gradient strengths: monopolar stimulated echo acquisition mode (STEAM), monopolar pulsed-gradient spin echo (PGSE), and second-order motion-compensated spin echo (MCSE). RESULTS: Reducing ECV intensifies the diffusion restriction and incorporating membrane permeability reduces the anisotropy of the diffusion tensor. Widening the intercapillary velocity distribution results in increased measured diffusion along the cardiomyocytes long axis when the capillary networks are anisotropic. Perfusion amplifies the mean diffusivity for STEAM while the opposite is observed for short diffusion encoding time sequences (PGSE and MCSE). CONCLUSION: The effect of perfusion on the measured diffusion tensor is reduced using an increased reference b-value. Our results pave the way for characterization of the response of DT-CMR to microstructural changes underlying cardiac pathology and highlight the higher sensitivity of STEAM to permeability and microvascular circulation due to its longer diffusion encoding time.

Plasma acetyl-l-carnitine and l-carnitine in major depressive episodes: a case-control study before and after treatment.

BACKGROUND: Major depressive disorder (MDD) is the main cause of disability worldwide, its outcome is poor, and its underlying mechanisms deserve a better understanding. Recently, peripheral acetyl-l-carnitine (ALC) has been shown to be lower in patients with major depressive episodes (MDEs) than in controls. l-Carnitine is involved in mitochondrial function and ALC is its short-chain acetyl-ester. Our first aim was to compare the plasma levels of l-carnitine and ALC, and the l-carnitine/ALC ratio in patients with a current MDE and healthy controls (HCs). Our second aim was to assess their changes after antidepressant treatment. METHODS: l-Carnitine and ALC levels and the carnitine/ALC ratio were measured in 460 patients with an MDE in a context of MDD and in 893 HCs. Depressed patients were re-assessed after 3 and 6 months of antidepressant treatment for biology and clinical outcome. RESULTS: As compared to HC, depressed patients had lower ALC levels (p < 0.00001), higher l-carnitine levels (p < 0.00001) and higher l-carnitine/ALC ratios (p < 0.00001). ALC levels increased [coefficient: 0.18; 95% confidence interval (CI) 0.12-0.24; p < 0.00001], and l-carnitine levels (coefficient: -0.58; 95% CI -0.75 to -0.41; p < 0.00001) and l-carnitine/ALC ratios (coefficient: -0.41; 95% CI -0.47 to -0.34; p < 0.00001), decreased after treatment. These parameters were completely restored after 6 months of antidepressant. Moreover, the baseline l-carnitine/ALC ratio predicted remission after 3 months of treatment (odds ratio = 1.14; 95% CI 1.03-1.27; p = 0.015). CONCLUSIONS: Our data suggest a decreased mitochondrial metabolism of l-carnitine into ALC during MDE. This decreased mitochondrial metabolism is restored after a 6-month antidepressant treatment. Moreover, the magnitude of mitochondrial dysfunction may predict remission after 3 months of antidepressant treatment. New strategies targeting mitochondria should be explored to improve treatments of MDD.

Caleosin/peroxygenases: multifunctional proteins in plants.

BACKGROUND: Caleosin/peroxygenases (CLO/PXGs) are a family of multifunctional proteins that are ubiquitous in land plants and are also found in some fungi and green algae. CLO/PXGs were initially described as a class of plant lipid-associated proteins with some similarities to the oleosins that stabilize lipid droplets (LDs) in storage tissues, such as seeds. However, we now know that CLO/PXGs have more complex structures, distributions and functions than oleosins. Structurally, CLO/PXGs share conserved domains that confer specific biochemical features, and they have diverse localizations and functions. SCOPE: This review surveys the structural properties of CLO/PXGs and their biochemical roles. In addition to their highly conserved structures, CLO/PXGs have peroxygenase activities and are involved in several aspects of oxylipin metabolism in plants. The enzymatic activities and the spatiotemporal expression of CLO/PXGs are described and linked with their wider involvement in plant physiology. Plant CLO/PXGs have many roles in both biotic and abiotic stress responses in plants and in their responses to environmental toxins. Finally, some intriguing developments in the biotechnological uses of CLO/PXGs are addressed. CONCLUSIONS: It is now two decades since CLO/PXGs were first recognized as a new class of lipid-associated proteins and only 15 years since their additional enzymatic functions as a new class of peroxygenases were discovered. There are many interesting research questions that remain to be addressed in future physiological studies of plant CLO/PXGs and in their recently discovered roles in the sequestration and, possibly, detoxification of a wide variety of lipidic xenobiotics that can challenge plant welfare.

The cardiac preparticipation sports evaluation.

PURPOSE OF REVIEW: Sudden cardiac death (SCD) is the leading cause of death in young athletes during sports participation. Preparticipation cardiovascular screening aims to identify those at an increased risk of SCD. This review aims to provide a background of SCD in young athletes, to discuss the various screening recommendations of major medical societies, and to review recent evidence and current practice. RECENT FINDINGS: Numerous studies have evaluated various preparticipation screening practices, particularly regarding the inclusion of ECG as part of an initial evaluation to identify conditions with an increased risk of SCD. Some analyses have shown ECG inclusion to provide increased screening sensitivity and specificity, though others have shown no benefit when compared with evaluation with history and physical examination alone. Furthermore, in countries for which more extensive screening protocols have been employed, postimplementation statistics have not shown a significant decrease in SCD. SUMMARY: SCD in young athletes primarily results from underlying cardiac disease. Various preparticipation screening recommendations exist globally, with the common goal of decreasing the rates of SCD by identifying youth at risk during sports participation. Current guidelines in the United States support universal preparticipation evaluation using history and physical examination, with cardiology referral if abnormalities are identified.

Female-to-male differential transcription patterns of miRNA-mRNA networks in the livers of dioxin-exposed mice.

Non-coding microRNAs (miRNAs) have important roles in regulating the expression of liver mRNAs in response to xenobiotic-exposure, but their roles concerning dioxins such as TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin) are less clear. This report concerns the potential implication of liver (class I) and circulating (class II) miRNAs in hepatotoxicity of female and male mice after acute exposure to TCDD. The data show that, of a total of 38 types of miRNAs, the expression of eight miRNAs were upregulated in both female and male mice exposed to TCDD. Inversely, the expression of nine miRNAs were significantly downregulated in both animal genders. Moreover, certain miRNAs were preferentially induced in either females or males. The potential downstream regulatory effects of miRNAs on their target genes was evaluated by determining the expression of three group of genes that are potentially involved in cancer biogenesis, other diseases and in hepatotoxicity. It was found that certain cancer-related genes were more highly expressed females rather than males after exposure to TCDD. Furthermore, a paradoxical female-to-male transcriptional pattern was found for several disease-related and hepatotoxicity-related genes. These results suggest the possibility of developing of new miRNA-specific interfering molecules to address their dysfunctions as caused by TCDD.

Chylous pericardial effusion with cardiac tamponade in a child treated with imatinib.

Chylous pericardial effusions are extremely rare outside of thoracic and cardiac surgery patients. We report the case of an 8-year-old girl with history of recurrent benign giant cell granulomas who developed a large chylous pericardial effusion with cardiac tamponade soon after beginning therapy with imatinib. In this article, we discuss the presentation, diagnosis, and management and review the published literature of this rarely reported side effect of this medication.

A Rare Complication of Anomalous Left Coronary Artery From the Pulmonary Artery Identified by Point-of-Care Ultrasound.

ABSTRACT: Point-of-care ultrasound is a valuable tool in the evaluation of undifferentiated respiratory distress in children. This case report describes a 9-month-old male infant who presented with 4 months of progressively worsening cough and was found to be tachypneic in the emergency department. Chest radiography revealed complete opacification of the left hemithorax with cardiomegaly. Point-of-care ultrasound demonstrated atelectasis of the entire left lung and severe dilation of the left ventricle with poor function. Electrocardiogram and echocardiogram findings were consistent with a diagnosis of anomalous left coronary artery from the pulmonary artery. The patient underwent successful cardiac surgery to improve myocardial perfusion. Bronchoscopy visualized the etiology of his atelectasis, pulsatile compression of the left mainstem bronchus by the dilated heart. Focused cardiac and lung ultrasound techniques, as well as pertinent sonographic findings, are reviewed.

Stifle joint osteoarthritis in small-breed and medium-breed dogs is more severe after cranial cruciate ligament injury than medial patellar luxation.

This retrospective observational study aimed to characterize the severity and distribution of OA in the stifle joints of small and medium dogs with CCL injury and/or MPL. Radiographs of the stifle joints from 218 dogs from 10 small and medium breeds were included; 127 joints had CCL injury, 76 joints had MPL, and 73 joints had CCL injury and MPL. OA was graded at 33 sites within the joint. The mean ± SD OA score was 20.3 ± 9.9. For all joints, OA was more severe in heavier than lighter dogs (P = 0.003). Joints with MPL (14.9 ± 8.2) had lower OA scores than joints with CCL injury (22.2 ± 10.0, P = 0.003) or CCL injury and MPL (22.6 ± 9.4, P < 0.001). OA scores were higher in joints with MPL for older dogs (r = 0.408, P < 0.001) but did not change with age in joints with CCL injury. The pattern of OA did not differ among joints with CCL injury or MPL. The retrospective nature of the study limited findings to associations but did not allow conclusions regarding factors causing OA or enhancing its progression. We concluded that, in small- and medium-breed dogs, the patterns of stifle OA joint after CCL injury and MPL are similar. Radiographic OA after CCL injury is more severe than MPL. An increase in age leads to an increase in OA at the time of presentation at a referral hospital in stifle joints with MPL and without CCL injury.

Vitamin C Supplementation and Athletic Performance: A Review.

ABSTRACT: Many athletes utilize high-dose vitamin C supplementation to optimize athletic performance. A review of research over the past 10 years on the use of vitamin C and athletic performance show mixed results. Fourteen randomized control trials were reviewed. In most studies, vitamin C was used with at least one additional supplement, usually vitamin E. Three studies showed positive outcomes associated with decreased markers of muscle damage after intense exercise with some form of vitamin C supplementation. The remaining 11 articles showed either neutral or negative effects of high dose vitamin C supplementation on muscle damage, physical performance, perceived muscle soreness, and/or adaptations to training. Based on a lack of consistent data and potential for blunted physiologic adaptations to training, long-term high-dosage supplementation with vitamin C is not recommended. Athletes should obtain antioxidants through a nutrient-rich diet instead of through supplement use.

Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear-mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)-dependency of CVR and cSMD. Eleven volunteers underwent a steady-state CVR test and transient CO2 test of cSMD during intravenous infusion of the NO synthase inhibitor NG -monomethyl-l-arginine (l-NMMA) or volume-matched saline (placebo; single-blinded and counter-balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra-arterial blood pressure and PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ . Paired arterial and jugular venous blood sampling allowed for the determination of trans-cerebral NO2- exchange (ozone-based chemiluminescence). l-NMMA reduced arterial NO2- by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady-state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ ; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. -1.8 ± 8.2 nM/min at 120 s post-CO2 ; P = 0.044) shifted trans-cerebral NO2- exchange towards a greater net release (a negative value indicates release). Although this trans-cerebral NO2- release was abolished by l-NMMA, CVR did not differ between the saline and l-NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l-NMMA impact peak internal carotid artery dilatation during the steady-state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l-NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady-state CVR. Further, our novel transient CO2 test of cSMD is largely NO-dependent and provides an in vivo bioassay of NO-mediated cerebrovascular function in humans. KEY POINTS: Emerging evidence indicates that a transient CO2 stimulus elicits shear-mediated dilatation of the internal carotid artery, termed cerebral shear-mediated dilatation. Whether or not cerebrovascular reactivity to a steady-state CO2 stimulus is NO-dependent remains unclear in humans. During both a steady-state cerebrovascular reactivity test and a transient CO2 test of cerebral shear-mediated dilatation, trans-cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non-selective NO synthase inhibitor NG -monomethyl-l-arginine. NO synthase blockade did not alter cerebrovascular reactivity in the steady-state CO2 test; however, cerebral shear-mediated dilatation following a transient CO2 stimulus was reduced by ∼37% following intravenous infusion of NG -monomethyl-l-arginine. NO is not obligatory for cerebrovascular reactivity to CO2 , but is a key contributor to cerebral shear-mediated dilatation.