Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in mdx mice.

Current therapies for Duchenne muscular dystrophy (DMD) use phosphorodiamidate morpholino oligomers (PMO) to induce exon skipping in the dystrophin pre-mRNA, enabling the translation of a shortened but functional dystrophin protein. This strategy has been hampered by insufficient delivery of PMO to cardiac and skeletal muscle. To overcome these limitations, we developed the FORCETM platform consisting of an antigen-binding fragment, which binds the transferrin receptor 1, conjugated to an oligonucleotide. We demonstrate that a single dose of the mouse-specific FORCE-M23D conjugate enhances muscle delivery of exon skipping PMO (M23D) in mdx mice, achieving dose-dependent and robust exon skipping and durable dystrophin restoration. FORCE-M23D-induced dystrophin expression reached peaks of 51%, 72%, 62%, 90% and 77%, of wild-type levels in quadriceps, tibialis anterior, gastrocnemius, diaphragm, and heart, respectively, with a single 30 mg/kg PMO-equivalent dose. The shortened dystrophin localized to the sarcolemma, indicating expression of a functional protein. Conversely, a single 30 mg/kg dose of unconjugated M23D displayed poor muscle delivery resulting in marginal levels of exon skipping and dystrophin expression. Importantly, FORCE-M23D treatment resulted in improved functional outcomes compared with administration of unconjugated M23D. Our results suggest that FORCE conjugates are a potentially effective approach for the treatment of DMD.

The biggest problem confronting oligonucleotide therapeutics is a lack of compounds capable of targeting compounds to diseased tissues. This paper reports a major advance targeting the transferrin receptor to increase the delivery of morpholine oligomers to muscle cells in vivo. This work suggests the possibility for improved treatments of muscular dystrophy and other diseases.

Energy availability modulates regional blood flow via estrogen-independent pathways in regularly menstruating young women.

PURPOSE: This study aimed to investigate the impact of short-term low energy availability (LEA) on vascular function in young, regularly menstruating women. METHODS: Participants were 19 women, aged 22.9 ± 4.2 years, with body mass index 18-30 kg·m2. They were divided into two groups and completed two conditions in a crossover design: a 3-day control condition (CON) with an energy availability of 45 kcals·kgFFM-1·day-1 and a 3-day LEA condition of 15 kcals·kgFFM-1 day-1. Assessments were conducted during the early follicular phase of the menstrual cycle. Outcome measures included forearm blood flow (FBF), heart rate, blood pressure, arterial stiffness, resting energy expenditure (REE), metabolic blood markers and body composition. RESULTS: Significant time-by-condition interactions were found for resting FBF (p = .004), REE (p = .042), triiodothyronine (p = .006), ß-hydroxybutyrate (p = .002) and body mass (p < .001). Resting FBF was 1.43 ± 1.01 and 1.31 ± 0.61 (arbitrary units) at pre and post, respectively, in LEA and 1.52 ± 0.7 and 1.76 ± 0.57 at pre and post in CON. The LEA condition led to a decrease in triiodothyronine (pre: 1.54 ± 0.28, post: 1.29 ± 0.27 ng ml-1), REE (pre: 1588 ± 165, post: 1487 ± 160 kcals day-1) and body mass (pre: 61.4 ± 7.5, post: 59.6 ± 7.3 kg). Changes in resting FBF were significantly correlated with changes in REE in the LEA condition (r = 0.53; p = 0.02). CONCLUSION: Short-term LEA modifies regional blood flow and this might contribute to the observed decreased in REE. Findings emphasize the need for careful management of energy availability in populations at risk of LEA.

Calf blood flow is augmented in habitually aerobically trained versus untrained postmenopausal women in association with favorable modulation of vasculo-metabolic interactions.

INTRODUCTION: Menopause is associated with vascular dysfunction and increased risk of developing metabolic syndrome. Associations between vascular and metabolic health, and interactions with aerobic exercise training, are unknown in postmenopausal women (PMW). METHODS: In habitually aerobically trained PMW (PMWtr; n = 10; 57 ± 1 years; 40 ± 1 mL/kg/min), strain-gauge plethysmography was used to compare resting and peak calf blood flow (CBFr and CBFpk, respectively) and vascular resistance (CVRr; CVRpk) versus untrained PMW (PMWun; n = 13; 56 ± 1 years; 29 ± 1 mL/kg/min) and premenopausal women (PreM; n = 14; 26 ± 1 years; 40 ± 1 mL/kg/min). Vascular measures were taken before and 1 hour after 45 minutes of aerobic exercise (60% V̇ O2peak ), a known nitric oxide stimulus. Blood analyses included low- (LDLc) and high-density lipoprotein cholesterol (HDLc), insulin, and glucose. RESULTS: Pre-exercise, CBFr and CVRr did not differ (p > 0.05) between PMW groups, nor between PreM and PMWtr. CBFpk was highest (p < 0.05) and CVRpk was lowest (p < 0.05) in PMWtr. Blood markers were similar (p > 0.05) in PMW groups. However, in PMWtr, CBFpk was associated inversely (p < 0.05) with insulin (r = -0.725). Conversely, in PMWun, CBFpk correlated (p < 0.05) inversely with glucose (r = -0.717), positively with HDLc (r = 0.633), and CVRpk positively (p < 0.05) with LDLc (r = 0.568). Post-exercise, CBF increased and CVR decreased (p < 0.05) in all groups, yet CBFpk remained higher and CVRpk lower (p < 0.05) in PMWtr. CONCLUSION: In untrained PMW, peak CBF is associated inversely with circulating pro-atherogenic lipids and glucose. In contrast, peak CBF is associated inversely with insulin levels only in trained PMW. Habitual aerobic exercise may favorably modulate vasculo-metabolic interactions in PMW.

High-impact jumping mitigates the short-term effects of low energy availability on bone resorption but not formation in regularly menstruating females: A randomized control trial.

Low energy availability (LEA) is prevalent in active individuals and negatively impacts bone turnover in young females. High-impact exercise can promote bone health in an energy efficient manner and may benefit bone during periods of LEA. Nineteen regularly menstruating females (aged 18-31 years) participated in two three-day conditions providing 15 (LEA) and 45 kcals kg fat-free mass-1 day-1 (BAL) of energy availability, each beginning 3 ± 1 days following the self-reported onset of menses. Participants either did (LEA+J, n = 10) or did not (LEA, n = 9) perform 20 high-impact jumps twice per day during LEA, with P1NP, ß-CTx (circulating biomarkers of bone formation and resorption, respectively) and other markers of LEA measured pre and post in a resting and fasted state. Data are presented as estimated marginal mean ± 95% CI. P1NP was significantly reduced in LEA (71.8 ± 6.1-60.4 ± 6.2 ng mL-1 , p < 0.001, d = 2.36) and LEA+J (93.9 ± 13.4-85.2 ± 12.3 ng mL-1 , p < 0.001, d = 1.66), and these effects were not significantly different (time by condition interaction: p = 0.269). ß-CTx was significantly increased in LEA (0.39 ± 0.09-0.46 ± 0.10 ng mL-1 , p = 0.002, d = 1.11) but not in LEA+J (0.65 ± 0.08-0.65 ± 0.08 ng mL-1 , p > 0.999, d = 0.19), and these effects were significantly different (time by condition interaction: p = 0.007). Morning basal bone formation rate is reduced following 3 days LEA, induced via dietary restriction, with or without high-impact jumping in regularly menstruating young females. However, high-impact jumping can prevent an increase in morning basal bone resorption rate and may benefit long-term bone health in individuals repeatedly exposed to such bouts.

Influence of acute dietary nitrate supplementation timing on nitrate metabolism, central and peripheral blood pressure and exercise tolerance in young men.

PURPOSE: Dietary nitrate (NO3-) supplementation can lower systolic blood pressure (SBP) and improve exercise performance. Salivary flow rate (SFR) and pH are key determinants of oral NO3- reduction and purported to peak in the afternoon. We tested the hypotheses that NO3--rich beetroot juice (BR) would increase plasma [nitrite] ([NO2-]), lower SBP and improve exercise performance to a greater extent in the afternoon (AFT) compared to the morning (MORN) and evening (EVE). METHOD: Twelve males completed six experimental visits in a repeated-measures, crossover design. NO3--depleted beetroot juice (PL) or BR (~ 13 mmol NO3-) were ingested in the MORN, AFT and EVE. SFR and pH, salivary and plasma [NO3-] and [NO2-], brachial SBP and central SBP were measured pre and post supplementation. A severe-intensity exercise tolerance test was completed to determine cycling time to exhaustion (TTE). RESULTS: There were no between-condition differences in mean SFR or salivary pH. The elevation in plasma [NO2-] after BR ingestion was not different between BR-MORN, BR-AFT and BR-EVE. Brachial SBP was unchanged following BR supplementation in all conditions. Central SBP was reduced in BR-MORN (- 3 ± 4 mmHg), BR-AFT (- 4 ± 3 mmHg), and BR-EVE (- 2 ± 3 mmHg), with no differences between timepoints. TTE was not different between BR and PL at any timepoint. CONCLUSION: Acute BR supplementation was ineffective at improving TTE and brachial SBP and similarly effective at increasing plasma [NO2-] and lowering central SBP across the day, which may have implications for informing NO3- supplementation strategies.

Influence of sex and age on the relationship between aerobic fitness and muscle sympathetic nerve activity in healthy adults.

We examined the influence of sex and age on the relationship between aerobic fitness and muscle sympathetic nerve activity (MSNA) in healthy adults. Data were assessed from 224 volunteers (88 females), aged 18-76 yr, in whom resting MSNA (microneurography) and peak oxygen uptake (V̇o2peak; incremental exercise test) were evaluated. When separated into younger (<50 yr) and older (≥50 yr) subgroups, there were inverse relationships between relative V̇o2peak (mL·kg-1·min-1) and MSNA burst frequency in younger males (R2 = 0.21, P < 0.0001) and older females (R2 = 0.36, P < 0.01), but not older males (R2 = 0.05, P = 0.08) or younger females (R2 = 0.03, P = 0.14). Similar patterns were observed with absolute V̇o2peak (L·min-1) and percent-predicted (based on age, sex, weight, height, and modality), and with burst incidence. Sex and age influence the relationship between aerobic fitness and resting MSNA, and, thus, must be considered as key variables when studying these potential associations; inverse relationships are strongest in younger males and older females.NEW & NOTEWORTHY Our data reveal for the first time that associations between aerobic fitness and resting muscle sympathetic nerve activity are sex and age specific; inverse relationships are evident in younger males (<50 yr) and older females (≥50 yr), but absent in younger females (<50 yr) and older males (≥50 yr).

Distinct Body Mass Index Trajectories to Young-Adulthood Obesity and Their Different Cardiometabolic Consequences.

[Figure: see text].

How does hormone transition in transgender women change body composition, muscle strength and haemoglobin? Systematic review with a focus on the implications for sport participation.

OBJECTIVES: We systemically reviewed the literature to assess how long-term testosterone suppressing gender-affirming hormone therapy influenced lean body mass (LBM), muscular area, muscular strength and haemoglobin (Hgb)/haematocrit (HCT). DESIGN: Systematic review. DATA SOURCES: Four databases (BioMed Central, PubMed, Scopus and Web of Science) were searched in April 2020 for papers from 1999 to 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible studies were those that measured at least one of the variables of interest, included transwomen and were written in English. RESULTS: Twenty-four studies were identified and reviewed. Transwomen experienced significant decreases in all parameters measured, with different time courses noted. After 4 months of hormone therapy, transwomen have Hgb/HCT levels equivalent to those of cisgender women. After 12 months of hormone therapy, significant decreases in measures of strength, LBM and muscle area are observed. The effects of longer duration therapy (36 months) in eliciting further decrements in these measures are unclear due to paucity of data. Notwithstanding, values for strength, LBM and muscle area in transwomen remain above those of cisgender women, even after 36 months of hormone therapy. CONCLUSION: In transwomen, hormone therapy rapidly reduces Hgb to levels seen in cisgender women. In contrast, hormone therapy decreases strength, LBM and muscle area, yet values remain above that observed in cisgender women, even after 36 months. These findings suggest that strength may be well preserved in transwomen during the first 3 years of hormone therapy.

Incidence of bone stress injury is greater in competitive female distance runners with menstrual disturbances independent of participation in plyometric training.

Bone stress injury (BSI) is prevalent in female distance runners. Menstrual disturbances are associated with impaired bone health in endurance athletes. This study aimed to investigate the association between menstrual function and BSI and explore whether plyometric training may protect against BSI in individuals with menstrual disturbances. Competitive female distance runners (n = 183) aged 18-40 years were surveyed for training habits, menstrual function, and BSI, during the previous 12 months. Oligo/amenorrhoea during the previous 12 months (<9 menses) was deemed to indicate menstrual disturbance; hormonal contraceptive users and those previously diagnosed with a pathology that impacted menstrual function were excluded. BSI incidence rate was 2.25 (p = 0.02, 95% CI: 1.14-4.41) times greater in oligo/amenorrhoeic than eumenorrhoeic runners. BSI incidence rate was similar in oligo/amenorrhoeic and eumenorrhoeic runners that did plyometric training, but 3.78 (p = 0.001, 95% CI: 1.68-8.5) times greater in oligo/amenorrhoeic versus eumenorrhoeic runners that did not. However, the effect of plyometrics was non-significant (menstrual function × plyometric training interaction, p = 0.06; main effect, p = 0.89). Conventional plyometric training may not reduce BSI incidence in female distance runners, but menstrual disturbances and prolonged periods of low energy availability should be avoided.

Indexes of aortic wave reflection are not augmented in estrogen-deficient physically active premenopausal women.

BACKGROUND: Hypoestrogenemia due to menopause is associated with increased cardiovascular disease risk, in part due to elevated indexes of aortic wave reflection (AWRI) and central (aortic) blood pressure. We sought to investigate whether AWRI and central blood pressure are also augmented in hypoestrogenic exercise-trained premenopausal women with functional hypothalamic amenorrhea (ExFHA). METHODS: In age- (pooled mean ± SEM, 24 ± 1 years), BMI- (21 ± 1 kg/m2 ), and cardiorespiratory fitness-matched (45 ± 2 ml/kg/min) eumenorrheic ovulatory (ExOv; n = 11) and ExFHA women (n = 10), we assessed aortic blood pressure and waveform characteristics (augmentation index and wave reflection amplitude) obtained from radial pressure waves (applanation tonometry). Doppler ultrasound determined cardiac output (CO) and total peripheral resistance (TPR). Measures were recorded before and 1 hour after 45 minutes of moderate intensity exercise to determine the influence of exercise-induced increases in nitric oxide. RESULTS: Pre-exercise, AIx75, central systolic BP (SBPc), and CO were lower (P < .05) and TPR higher (P < .05) in ExFHA. Post-exercise, AIx75 was unchanged (P > .05) in ExFHA but was lowered (P < .05) in ExOv. Both groups demonstrated increased CO, and lowered SBPc and TPR, yet TPR remained higher (P < .05), and CO and SBPc lower (P < .05) in ExFHA. CONCLUSIONS: Despite hypoestrogenemia, functional compliance of the central arteries and central BP is not augmented, yet TPR is higher, in ExFHA versus ExOv. An acute bout of dynamic exercise did not alter AIx75 in ExFHA, suggesting blunted vascular responsiveness to exercise-induced increases in nitric oxide, possibly due to augmented vascular tone. These findings have relevance in understanding the vascular consequences of hypoestrogenemia during the premenopausal years.

Training heart failure patients with reduced ejection fraction attenuates muscle sympathetic nerve activation during mild dynamic exercise.

Muscle sympathetic nerve activity (MSNA) decreases during low-intensity dynamic one-leg exercise in healthy subjects but increases in patients with heart failure with reduced ejection fraction (HFrEF). We hypothesized that increased peak oxygen uptake (V̇o2peak) after aerobic training would be accompanied by less sympathoexcitation during both mild and moderate one-leg dynamic cycling, an attenuated muscle metaboreflex, and greater skin vasodilation. We studied 27 stable, treated HFrEF patients (6 women; mean age: 65 ± 2 SE yr; mean left ventricular ejection fraction: 30 ± 1%) and 18 healthy age-matched volunteers (6 women; mean age: 57 ± 2 yr). We assessed V̇o2peak (open-circuit spirometry) and the skin microcirculatory response to reactive hyperemia (laser flowmetry). Fibular MSNA (microneurography) was recorded before and during one-leg cycling (2 min unloaded and 2 min at 50% of V̇o2peak) and, to assess the muscle metaboreflex, during posthandgrip ischemia (PHGI). HFrEF patients were evaluated before and after 6 mo of exercise-based cardiac rehabilitation. Pretraining V̇o2peak and skin vasodilatation were lower (P < 0.001) and resting MSNA higher (P = 0.01) in HFrEF than control subjects. Training improved V̇o2peak (+3.0 ± 1.0 mL·kg-1·min-1; P < 0.001) and cutaneous vasodilation and diminished resting MSNA (-6.0 ± 2.0, P = 0.01) plus exercise MSNA during unloaded (-4.0 ± 2.5, P = 0.04) but not loaded cycling (-1.0 ± 4.0 bursts/min, P = 0.34) and MSNA during PHGI (P < 0.05). In HFrEF patients, exercise training lowers MSNA at rest, desensitizes the sympathoexcitatory metaboreflex, and diminishes MSNA elicited by mild but not moderate cycling. Training-induced downregulation of resting MSNA and attenuated reflex sympathetic excitation may improve exercise capacity and survival.

Impaired vascular function in exercising anovulatory premenopausal women is associated with low bone mineral density.

In estrogen-deficient post-menopausal women, osteoporosis shares a common link with cardiovascular disease risk, including endothelial dysfunction. The current study sought to examine associations between bone mineral density (BMD) and endothelial function in estrogen-deficient premenopausal women with exercise-associated menstrual disturbances. Recreationally trained women (24.3 ± 0.8 years; overall mean ± SEM) who were estrogen deficient (amenorrheic or eumenorrheic anovulatory cycles; E2Def; n = 13) or estrogen replete (eumenorrheic ovulatory cycles; E2Rep; n = 14) were studied. Total body and lumbar BMD (L1-L4) were determined using dual-energy X-ray absorptiometry. Serum markers of oxidative stress (oxidized low-density lipoprotein; OxLDL), energy deficiency (triiodothyronine), and bone turnover (osteocalcin, c-telopeptide X, P1NP) were assessed. Estrogen exposure was determined by assessing daily urinary estrone-3-glucuronide (E1G) across a monitoring period. Calf blood flow (CBF), an index of endothelial function, was measured using strain-gauge plethysmography. CBF, total body and L1-L4 BMD, triiodothyronine and E1G were lower (P < 0.05), and c-telopeptide crosslinks higher (P < 0.05) in E2Def. Osteocalcin and OxLDL did not differ (P > 0.05) between groups. L1-L4 BMD, osteocalcin, and E1G were the strongest predictors of CBF (R2 =0.615, P < 0.001). CBF was the strongest predictor of L1-L4 BMD (R2 =0.478, P < 0.001). L1-L4 (r = 0.558, P = 0.008) and CBF (r = 0.534, P = 0.004) were independently correlated with E1G. In young recreationally trained premenopausal women with anovulatory menstrual disturbances, low CBF predicts decreased lumbar BMD, suggesting impaired peripheral endothelial function may predict early unfavorable changes in bone metabolism. This finding may be of relevance in the early detection of cardiovascular and bone health decrements in otherwise healthy estrogen-deficient premenopausal women.

Augmented vagal heart rate modulation in active hypoestrogenic pre-menopausal women with functional hypothalamic amenorrhoea.

Compared with eumenorrhoeic women, exercise-trained women with functional hypothalamic amenorrhoea (ExFHA) exhibit low heart rates (HRs) and absent reflex renin-angiotensin-system activation and augmentation of their muscle sympathetic nerve response to orthostatic stress. To test the hypothesis that their autonomic HR modulation is altered concurrently, three age-matched (pooled mean, 24 ± 1 years; mean ± S.E.M.) groups of women were studied: active with either FHA (ExFHA; n=11) or eumenorrhoeic cycles (ExOv; n=17) and sedentary with eumenorrhoeic cycles (SedOv; n=17). Blood pressure (BP), HR and HR variability (HRV) in the frequency domain were determined during both supine rest and graded lower body negative pressure (LBNP; -10, -20 and -40 mmHg). Very low (VLF), low (LF) and high (HF) frequency power spectra (ms(2)) were determined and, owing to skewness, log10-transformed. LF/HF ratio and total power (VLF + LF + HF) were calculated. At baseline, HR and systolic BP (SBP) were lower (P<0.05) and HF and total power were higher (P<0.05) in ExFHA than in eumenorrhoeic women. In all groups, LBNP decreased (P<0.05) SBP, HF and total power and increased (P<0.05) HR and LF/HF ratio. However, HF and total power remained higher (P<0.05) and HR, SBP and LF/HF ratio remained lower (P<0.05) in ExFHA than in eumenorrhoeic women, in whom measures did not differ (P>0.05). At each stage, HR correlated inversely (P<0.05) with HF. In conclusion, ExFHA women demonstrate augmented vagal yet unchanged sympathetic HR modulation, both at rest and during orthostatic stress. Although the role of oestrogen deficiency is unclear, these findings are in contrast with studies reporting decreased HRV in hypoestrogenic post-menopausal women.

Estrogen status and the renin angiotensin aldosterone system.

The renin-angiotensin-aldosterone system (RAAS) is integrally involved in multiple cardiovascular physiological processes including arterial blood pressure (BP) regulation. Over activity of the RAAS has been implicated in the pathogenesis of a number of cardiovascular disease entities, including hypertension. Several lines of evidence suggest estrogen favorably modulates the RAAS. Conversely, estrogen deficiency due to menopause may contribute to over activity of the RAAS. Of importance, estrogen deficiency in women is not exclusive to the postmenopausal period. Functional hypothalamic amenorrhea is a reversible cause of premenopausal hypoestrogenemia. In contrast to postmenopausal women (PMW), premenopausal women with exercise-associated functional hypothalamic amenorrhea demonstrate decreased, not increased, resting BP compared with their estrogen-replete eumenorrheic counterpart. In this review we briefly examine the effects of estrogen status on the RAAS and present the hypothesis that the RAAS is altered in physically active women with functional hypothalamic amenorrhea.

Dental care for cardiac transplant patients in the UK.

Cardiac transplantation replaces a severely damaged non-functioning heart with a healthy heart from a donor. Within the UK, the number of cardiac transplants being performed each year is increasing, with significant improvements in longer-term survival. Dental professionals are therefore more likely to see and manage these patients in the pre- and post-transplant periods. This paper proposes a protocol for the dental management of these patients, reinforced by a case series from Scotland and London.

Impact of Secondary Amenorrhea on Cardiovascular Disease Risk in Physically Active Women: A Systematic Review and Meta-Analysis.

BACKGROUND: Exercise-associated secondary amenorrhea results in estrogen deficiency, which may lead to dysfunction in estrogen's normal cardioprotective pathways. Estrogen may be essential in a woman's endothelial adaptations to exercise. The objective of this review was to assess the association between secondary amenorrhea in physically active women and cardiovascular disease (CVD) risk. METHODS AND RESULTS: A literature search was performed in January 2023 and updated in August 2023 of the Cumulative Index to Nursing and Allied Health Literature (EBSCOhost), Cochrane Library, Embase (Ovid), MEDLINE (Ovid), SPORTDiscus (EBSCOhost), and Scopus from inception to present with no date or language limitations. Citation chaining was done to screen for additional studies. Eight sources were searched for gray literature. Studies that compared physically active women with amenorrhea to physically active women with eumenorrhea aged 18 to 35 years with evidence of CVD, alterations to cardiovascular physiology, or CVD risks were included. Eighteen observational studies from 3 countries were included. Overall, the quality of evidence was good. A meta-analysis was performed. Physically active women with secondary amenorrhea had significantly lower estradiol, flow-mediated dilation, resting heart rate, systolic blood pressure, and diastolic blood pressure and higher total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein cholesterol. CONCLUSIONS: Estrogen deficiency resulting from exercise-associated secondary amenorrhea in physically active women may impact cardiovascular physiology and certain CVD risk factors. The research in this area is observational; therefore, findings should be interpreted cautiously. However, as exercise-associated secondary amenorrhea is reversible and the primary prevention of CVD is important for public health, it may be important to treat secondary amenorrhea and restore estrogen levels.

Nitrate ingestion blunts the increase in blood pressure during cool air exposure: a double-blind, placebo-controlled, randomized, crossover trial.

Cold exposure increases blood pressure (BP) and salivary flow rate (SFR). Increased cold-induced SFR would be hypothesized to enhance oral nitrate delivery for reduction to nitrite by oral anaerobes and to subsequently elevate plasma [nitrite] and nitric oxide bioavailability. We tested the hypothesis that dietary nitrate supplementation would increase plasma [nitrite] and lower BP to a greater extent in cool compared with normothermic conditions. Twelve males attended the laboratory on four occasions. Baseline measurements were completed at 28°C. Subsequently, participants ingested 140 mL of concentrated nitrate-rich (BR; ∼13 mmol nitrate) or nitrate-depleted (PL) beetroot juice. Measurements were repeated over 3 h at either 28°C (Norm) or 20°C (Cool). Mean skin temperature was lowered compared with baseline in PL-Cool and BR-Cool. SFR was greater in BR-Norm, PL-Cool, and BR-Cool than PL-Norm. Plasma [nitrite] at 3 h was higher in BR-Cool (592 ± 239 nM) versus BR-Norm (410 ± 195 nM). Systolic BP (SBP) at 3 h was not different between PL-Norm (117 ± 6 mmHg) and BR-Norm (113 ± 9 mmHg). SBP increased above baseline at 1, 2, and 3 h in PL-Cool but not BR-Cool. These results suggest that BR consumption is more effective at increasing plasma [nitrite] in cool compared with normothermic conditions and blunts the rise in BP following acute cool air exposure, which might have implications for attenuating the increased cardiovascular strain in the cold.NEW & NOTEWORTHY Compared with normothermic conditions, acute nitrate ingestion increased plasma [nitrite], a substrate for oxygen-independent nitric oxide generation, to a greater extent during cool air exposure. Systolic blood pressure was increased during cool air exposure in the placebo condition with this cool-induced blood pressure increase attenuated after acute nitrate ingestion. These findings improve our understanding of environmental factors that influence nitrate metabolism and the efficacy of nitrate supplementation to lower blood pressure.

Sex Differences in Dementia.

BackgroundWomen in many cohorts have a higher risk for Alzheimer's disease (AD), the most common form of dementia. Sex is a biological construct whereby differences in disease manifestation and prevalence are rooted in genetic differences between XX and XY combinations of chromosomes. This chapter focuses specifically on sex-driven differences in dementia, as opposed to differences driven by gender - a social construct referring to the societal norms that influence people's roles, relationships, and positional power throughout their lifetime.MethodsUsing a narrative review, this chapter explored the characteristics and risk factors for the dementias, alongside a discussion of sex differences including loss of sex steroid hormones in middle-aged women, differences in the prevalence of cardiovascular diseases and engagement in lifestyle protective factors for dementia.ResultsThe sex difference in AD prevalence may exist because of systematic and historic differences in risk and protective factors for dementia, including level of education obtained and socioeconomic status differences, which can impact on health and dementia risk.Levels of sex steroids decline significantly after menopause in women, whereas this is more gradual in men with age. Animal and cell culture studies show strong biological plausibility for sex steroids to protect the ageing brain against dementia. Sex steroid hormone replacement therapy has in some observational studies shown to protect against AD, but treatment studies in humans have mainly shown disappointing results. Cardiovascular disease (CVD) shares midlife medical risk (e.g. hypertension, hyperlipidaemia, obesity etc.) factors with AD and other forms of dementia, but also with related lifestyle risk - and protective factors (e.g. exercise, not smoking etc.). Men tend to die earlier of CVD, so fewer survive to develop AD at an older age. Those who do survive may have healthier lifestyles and fewer risk factors for both CVD and AD. An earlier age at menopause also confers great risk for both without hormone treatment.DiscussionIt could be the case that the decline in sex steroids around the menopause make women more susceptible to lifestyle-related risk factors associated with dementia and CVD, but this remains to be further investigated. Combining hormone treatment with lifestyle changes in midlife (e.g. exercise) could be an important preventative treatment for dementia and CVD in later life, but this also requires further research.

Examining the Role of Physical Activity Interventions in Modulating Androgens and Cardiovascular Health in Postmenopausal Women: A Narrative Review.

A growing body of literature has examined the role of physical activity (PA) in modifying the effects of estrogen withdrawal on cardiovascular health in postmenopausal women, but the impact of PA on androgens is less clear. Changes in androgen concentrations following regular PA may improve cardiovascular health. This narrative review summarizes the literature assessing the impact of PA interventions on androgens in postmenopausal women. The association between changes in androgen concentrations and cardiovascular health following PA programs is also examined. Randomized controlled trials were included if they (i) implemented a PA program of any type and duration in postmenopausal women and (ii) measured changes in androgen concentrations. Following PA interventions, no changes in androstenedione, conflicting changes in dehydroepiandrosterone/dehydroepiandrosterone-sulfate, and increases in sex hormone-binding globulin concentrations were found. Total testosterone decreased following aerobic PA but increased after resistance training. Most aerobic PA interventions led to reductions in free testosterone. A combination of caloric restriction and/or fat loss enhanced the influence of PA on most androgens. Evidence exploring the relationship between changes in androgens and cardiovascular health indicators was scarce and inconsistent. PA has shown promise in modifying the concentrations of some androgens (free and total testosterone, sex hormone-binding globulin), and remains a well-known beneficial adjuvant option for postmenopausal women to manage their cardiovascular health. Fat loss influences the effect of PA on androgens, but the synergistic role of PA and androgens on cardiovascular health merits further examination. Many research gaps remain regarding the relationship between PA, androgens, and cardiovascular disease in postmenopausal women.

Un nombre croissant de publications ont examiné le rôle de l'activité physique (AP) pour contrer les effets de la privation en œstrogènes sur la santé cardiovasculaire des femmes ménopausées, mais les effets de l'AP sur les androgènes sont moins évidents. Les variations des taux d'androgènes associées à l'AP régulière pourraient améliorer la santé cardiovasculaire. Cette revue narrative résume des articles ayant évalué les répercussions des interventions fondées sur l'AP sur les taux d'androgènes chez les femmes ménopausées. Le lien entre la santé cardiovasculaire et les variations des taux d'androgènes consécutives à des programmes d'AP a également été examiné. Des essais contrôlés randomisés étaient inclus s'ils comprenaient (i) la mise en œuvre d'un programme d'AP quel qu'en soit le type ou la durée chez des femmes ménopausées et (ii) la mesure des variations des taux d'androgènes. Aucune variation des taux d'androstènedione n'a été observée après des interventions fondées sur l'AP. Toutefois, des variations conflictuelles des taux de déhydroépiandrostérone et de sulfate de déhydroépiandrostérone et des hausses des taux de la globuline liant les hormones sexuelles ont été observés. Le taux de testostérone totale a diminué après l'AP en aérobie, mais a augmenté après l'entraînement contre résistance. La plupart des interventions fondées sur l'AP en aérobie ont entraîné des réductions du taux de testostérone libre. En association avec la restriction calorique et/ou une perte de graisse corporelle, l'AP exerce une influence accrue sur la plupart des androgènes. Les données probantes explorant le lien entre les variations des taux d'androgènes et les indicateurs de santé cardiovasculaire étaient rares et contradictoires. L'AP s'est révélée prometteuse pour ce qui est de modifier les taux de certains androgènes (testostérone libre et testostérone totale, globuline liant les hormones sexuelles); elle demeure une option adjuvante bénéfique bien connue pour aider les femmes ménopausées à prendre en charge leur santé cardiovasculaire. La perte de graisse corporelle influe sur les effets de l'AP sur les androgènes, mais le rôle synergique de l'AP et des androgènes sur la santé cardiovasculaire mérite un examen plus approfondi. De nombreuses lacunes subsistent quant à la recherche d'un lien entre l'AP, les androgènes et les maladies cardiovasculaires chez les femmes ménopausées.

12-months of increased dietary intake does not exacerbate disordered eating-related attitudes, stress, or depressive symptoms in women with exercise-associated menstrual disturbances: The REFUEL randomized controlled trial.

Disordered eating-related attitudes are a leading cause of energy deficiency and menstrual disturbances in exercising women. Although treatment recommendations include psychological counseling with increases in dietary intake, a key concern is whether increased dietary intake may exacerbate negative eating behaviors. OBJECTIVE: To determine the effects of a 12-month nutritional intervention on eating-related attitudes and psychological characteristics in exercising women with oligomenorrhea/amenorrhea (Oligo/Amen). METHODS: Intent-to-treat analysis of the REFUEL randomized controlled trial (#NCT00392873) in 113 exercising women (age [mean±SEM]:] 21.9 ± 0.4 yrs; BMI: 20.9 ± 0.2 kg/m2). Women were randomized to increase energy intake 20-40% above baseline energy needs (Oligo/Amen+Cal, n = 40) or maintain energy intake (Oligo/Amen Control, n = 36) while maintaining their exercise behaviors. A reference group of ovulatory women (OVref, n = 37) maintained diet and exercise behaviors. Body composition, eating attitudes, stress, and depressive symptoms were assessed at baseline and every 3 months. RESULTS: At baseline, the Oligo/Amen groups had higher drive for thinness, cognitive restraint, and eating disorder risk than OVref group (p < 0.001). Increased energy intake led to increases in percent body fat and fat mass (p < 0.010), but not psychobehavioral outcomes, in the Oligo/Amen+Cal compared to Oligo/Amen Control group. Independent of group, cognitive restraint decreased (p < 0.001) and resilient coping increased (p < 0.007) over 12-months, while perceived stress (p = 0.143) and depressive symptoms (p = 0.344) were unchanged. DISCUSSION: Long-term nutritional intervention consisting of modest increases in dietary intake with guidance from a registered dietician and a psychologist increases body and fat mass without increasing disordered eating-related attitudes, stress, or depressive symptoms in exercising women with Oligo/Amen.