Reduced platelet activation and thrombus formation in male transgenic model mice of Alzheimer's disease suggests early sex-specific differences in platelet pathophysiology.

Alzheimer's disease (AD) is the most common form of dementia and characterized by extracellular amyloid-ß (Aß) plaques, intracellular neurofibrillary tau tangles and neurodegeneration. Over 80 % of AD patients also exhibit cerebral amyloid angiopathy (CAA). CAA is a cerebrovascular disease caused by deposition of Aß in the walls of cerebral blood vessels leading to vessel damage and impairment of normal blood flow. To date, different studies suggest that platelet function, including activation, adhesion and aggregation, is altered in AD due to vascular Aß deposition. For example, the transgenic AD model mice APP23 mice that exhibit CAA and parenchymal Aß plaques, show pre-activated platelets in the blood circulation and increased platelet integrin activation leading to a pro-thrombotic phenotype in these mice late stages of AD. However, it is still an open question whether or not platelets exhibit changes in their activation profile before they are exposed to vascular Aß deposits. Therefore, the present study examined platelets from middle-aged transgenic APP23 mice at the age of 8-10 months. At this age, APP23 mice show amyloid plaques in the brain parenchyma but not in the vasculature. Our analyses show that these APP23 mice have unaltered platelet numbers and size, and unaltered surface expression of glycoproteins. However, the number of dense granules in transgenic platelets was increased while the release was unaltered. Male, but not female APP23 mice, exhibited reduced platelet activation after stimulation of the thrombin receptor PAR4 and decreased thrombus stability on collagen under flow conditions ex vivo compared to control mice. In an arterial thrombosis model in vivo, male APP23 mice showed attenuated occlusion of the injured artery compared to controls. These findings provide clear evidence for early changes in platelet activation and thrombus formation in male mice before development of overt CAA. Furthermore, reduced platelet activation and thrombus formation suggest sex-specific differences in platelet physiology in AD that has to be considered in future studies of platelets and their role in AD.

Gyral and sulcal connectivity in the human cerebral cortex.

The rapid evolution of image acquisition and data analytic methods has established in vivo whole-brain tractography as a routine technology over the last 20 years. Imaging-based methods provide an additional approach to classic neuroanatomical studies focusing on biomechanical principles of anatomical organization and can in turn overcome the complexity of inter-individual variability associated with histological and tractography studies. In this work we propose a novel, reliable framework for determining brain tracts resolving the anatomical variance of brain regions. We distinguished 4 region types based on anatomical considerations: (i) gyral regions at borders between cortical communities; (ii) gyral regions within communities; (iii) sulcal regions at invariant locations across subjects; and (iv) other sulcal regions. Region types showed strikingly different anatomical and connection properties. Results allowed complementing the current understanding of the brain's communication structure with a model of its anatomical underpinnings.

Sex and disease severity-based analysis of steroid hormones in ME/CFS.

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by persistent fatigue and decreased daily activity following physical and/or cognitive exertion. While ME/CFS affects both sexes, there is a higher prevalence in women. However, studies evaluating this sex-related bias are limited. METHODS: Circulating steroid hormones, including mineralocorticoids (aldosterone), glucocorticoids (cortisol, corticosterone, 11-deoxycortisol, cortisone), androgens (androstenedione, testosterone), and progestins (progesterone, 17α-hydroxyprogesterone), were measured in plasma samples using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Samples were obtained from mild/moderate (ME/CFSmm; females, n=20; males, n=8), severely affected patients (ME/CFSsa; females, n=24; males, n=6), and healthy controls (HC, females, n=12; males, n=17). RESULTS: After correction for multiple testing, we observed that circulating levels of 11-deoxycortisol, 17α-hydroxyprogesterone in females, and progesterone in males were significantly different between HC, ME/CFSmm, and ME/CFSsa. Comparing two independent groups, we found that female ME/CFSsa had higher levels of 11-deoxycortisol (vs. HC and ME/CFSmm) and 17α-hydroxyprogesterone (vs. HC). In addition, female ME/CFSmm showed a significant increase in progesterone levels compared to HC. In contrast, our study found that male ME/CFSmm had lower circulating levels of cortisol and corticosterone, while progesterone levels were elevated compared to HC. In addition to these univariate analyses, our correlational and multivariate approaches identified differential associations between our study groups. Also, using two-component partial least squares discriminant analysis (PLS-DA), we were able to discriminate ME/CFS from HC with an accuracy of 0.712 and 0.846 for females and males, respectively. CONCLUSION: Our findings suggest the potential value of including steroid hormones in future studies aimed at improving stratification in ME/CFS. Additionally, our results provide new perspectives to explore the clinical relevance of these differences within specific patient subgroups.

Regional disparities, age-related changes and sex-related differences in knee osteoarthritis.

BACKGROUND: The objective of the study is to analyse the regions, age and sex differences in the incidence of knee osteoarthritis (KOA). METHODS: Data were extracted from the global burden of diseases (GBD) 2019 study, including incidence, years lived with disability (YLD), disability-adjusted life-years (DALYs) and risk factors. Estimated annual percentage changes (EAPCs) were calculated to quantify the temporal trends in age standardized rate (ASR) of KOA. Paired t-test, paired Wilcoxon signed-rank test and spearman correlation were performed to analyze the association of sex disparity in KOA and socio-demographic index (SDI). RESULTS: There were significant regional differences in the incidence of knee osteoarthritis. In 2019, South Korea had the highest incidence of knee osteoarthritis (474.85,95%UI:413.34-539.64) and Thailand had the highest increase in incidence of knee osteoarthritis (EAPC = 0.56, 95%CI = 0.54-0.58). Notably, higher incidence, YLD and DALYs of knee osteoarthritis were associated with areas with a high socio-demographic index (r = 0.336, p < 0.001; r = 0.324, p < 0.001; r = 0.324, p < 0.001). In terms of age differences, the greatest increase in the incidence of knee osteoarthritis was between the 35-39 and 40-44 age groups. (EAPC = 0.52, 95%CI = 0.40-0.63; 0.47, 95%CI = 0.36-0.58). In addition, there were significant sex differences in the disease burden of knee osteoarthritis (P < 0.001). CONCLUSIONS: The incidence of knee osteoarthritis is significantly different with regions, age and sex.

Sex- and Gender-Related Differences in Obesity: From Pathophysiological Mechanisms to Clinical Implications.

Obesity, primarily characterized by excessive fat accumulation, is a multifactorial chronic disease with an increasing global prevalence. Despite the well-documented epidemiology and significant advances in understanding its pathophysiology and clinical implications, the impact of sex is typically overlooked in obesity research. Worldwide, women have a higher likelihood to become obese compared to men. Although women are offered weight loss interventions more often and at earlier stages than men, they are more vulnerable to psychopathology. Men, on the other hand, are less likely to pursue weight loss intervention and are more susceptible to the metabolic implications of obesity. In this narrative review, we comprehensively explored sex- and gender-specific differences in the development of obesity, focusing on a variety of biological variables, such as body composition, fat distribution and energy partitioning, the impact of sex steroid hormones and gut microbiota diversity, chromosomal and genetic variables, and behavioural and sociocultural variables influencing obesity development in men and women. Sex differences in obesity-related comorbidities and varying effectiveness of different weight loss interventions are also extensively discussed.

Investigation of murine host sex as a biological variable in epithelial barrier function and muscle contractility in human intestinal organoids.

Intestinal failure (IF) occurs when intestinal surface area or function is not sufficient to support digestion and nutrient absorption. Human intestinal organoid (HIO)-derived tissue-engineered intestine is a potential cure for IF. Research to date has demonstrated successful HIO transplantation (tHIO) into mice with significant in vivo maturation. An area lacking in the literature is exploration of murine host sex as a biological variable (SABV) in tHIO function. In this study, we investigate murine host SABV in tHIO epithelial barrier function and muscle contractility. HIOs were generated in vitro and transplanted into nonobese diabetic, severe combined immunodeficiency gamma chain deficient male and female mice. tHIOs were harvested after 8-12 weeks in vivo. Reverse transcriptase polymerase chain reaction and immunohistochemistry were conducted to compare tight junctions and contractility-related markers in tHIOs. An Ussing chamber and contractility apparatus were used to evaluate tHIO epithelial barrier and muscle contractile function, respectively. The expression and morphology of tight junction and contractility-related markers from tHIOs in male and female murine hosts is not significantly different. Epithelial barrier function as measured by transepithelial resistance, short circuit current, and fluorescein isothiocyanate-dextran permeability is no different in tHIOs from male and female hosts, although these results may be limited by HIO epithelial immaturity and a short flux time. Muscle contractility as measured by total contractile activity, amplitude, frequency, and tension is not significantly different in tHIOs from male and female hosts. The data suggest that murine host sex may not be a significant biological variable influencing tHIO function, specifically epithelial barrier maintenance and muscle contractility, though limitations exist in our model.

Editor's Choice - Sex Related Differences in Indication and Procedural Outcomes of Carotid interventions in VASCUNET.

OBJECTIVE: It has been suggested that peri-operative complications after carotid surgery may be higher in women than in men. This assumption may affect the treatment patterns, and it is thus possible that carotid endarterectomy (CEA) is provided to women less often. The aim of the current VASCUNET study was to determine sex related differences in operative risk in routine clinical practice among non-selected patients undergoing carotid revascularisation. METHODS: Data on CEA and carotid artery stenting (CAS) from 14 vascular registries were collected and amalgamated. Comprehensive data were available for 223 626 carotid artery procedures; these were analysed overall and by country. The primary outcome was any stroke and or death within 30 days of carotid revascularisation. Secondary outcomes were stroke, death, or any major cardiac event or haemorrhage leading to re-operation. RESULTS: Of the procedures, 34.8% were done in women. The proportion of CEA for asymptomatic stenosis compared with symptomatic stenosis was significantly higher among women than men (38.4% vs. 36.9%, p < .001). The proportion of octogenarians was higher among women than men who underwent CEA in both asymptomatic (21.2% vs. 19.9%) and symptomatic patients (24.3% vs. 21.4%). In the unadjusted analysis of symptomatic and asymptomatic patients, there were no significant differences between men and women in the rate of post-operative combined stroke and or death, any major cardiac event, or combined death, stroke, and any major cardiac event after CEA. Also, after stenting for asymptomatic or symptomatic carotid stenosis, there were no significant differences between men and women in the rate of post-operative complications. In adjusted analyses, sex was not significantly associated with any of the end points. Higher age and CAS vs. CEA were independently associated with all four end points. CONCLUSION: This study confirmed that, in a large registry among non-selected patients, no significant sex related differences were found in peri-operative complication rates after interventions for carotid stenosis.

Differences between sexes in patients who underwent total arch replacement and frozen elephant trunk procedures for acute dissection.

OBJECTIVE: To analyze the effect of sex on the short-time prognosis in two different age subgroups (≤55 years old and >55 years old). METHODS: From January 2009 to 2019, 1522 patients with DeBakey I acute aortic dissection (AAD) underwent frozen elephant trunk and total arch replacement at a Tertiary Center in China were divided into female group (n = 324) and male group (n = 1198). The demographic characteristics, clinical presentation, management, short-term outcomes were described in the different sex groups. The risk factors of 30-days mortality for females and males were identified by univariate and multivariable logistic regression analysis. Then, random Forest regression was used to analyze the association between age and 30-days mortality in the different sexes groups. The cut-off age for 30-days mortality in females was then identified as 55 years. The patients were divided into two subgroups: young patients (≤55 years old) and elderly patients (>55 years old). Clinical prognosis between different sex groups was further compared in the age subgroups. RESULTS: Approximately four-fifths of the patients were males. Males with DeBakey I AAD were younger than females (47 vs 52 years; p < 0.01). The proportion of males gradually declined with age. The cut-off age for 30-days mortality in females and males was identified as 55 years old and 63 years old, respectively. In young patients (≤55 years old), the 30-days mortality rate for females was lower than males (hazard ratio [HR, 2.02, p < 0.05). Following adjustment using the multivariable Cox regression analysis, females were identified as an independent protective factor for 30-days mortality (HR, 2.24, p = 0.03). CONCLUSIONS: Our study showed that females present with DeBakey I AAD less frequently than males and they tend to present with DeBakey AAD later in life. In young patients, females had better early outcomes despite similar time for symptom onset to diagnosis and surgical technique than males.

HLA-E and Its Soluble Form as Indicators of a Sex-Specific Immune Response in Patients with Oral Squamous Cell Carcinoma.

The human leukocyte antigene E (HLA-E) is associated with tumorigenesis in various cancers. Immunoncology along with sex-specific aspects in cancer therapy are now in scientific focus. Therefore, immunohistochemical HLA-E expression was retrospectively analysed in a cohort of oral squamous cell carcinomas (OSCC) after surgical therapy. Then, serum concentration of HLA-E (sHLA-E) was quantified in a prospective cohort by enzyme-linked immunosorbent assay. High HLA-E expression was associated with advanced UICC stage (Spearman's correlation: p = 0.002) and worse survival (Cox-regression: progression-free survival: hazard ratio (HR) 3.129, confidence range (CI) 1.443-6.787, p = 0.004; overall survival: HR 2.328, CI 1.071-5.060, p = 0.033). The sHLA-E concentration was significantly higher in the control group than in tumor group (Mann-Whitney U-test (MW-U): p = 0.021). Within the tumor group, women showed significantly higher sHLA-E levels than men (MW-U: p = 0.049). A closer look at the tumor group and the control group showed that gender-specific differences exist: while no differences in sHLA-E concentration were detectable between female subjects of tumor group and control group (MW-U: p = 0.916), male subjects of tumor group had a significantly lower sHLA-E concentration compared to those of control group (MW-U: p = 0.001). In summary, our results provide evidence for sex-specific differences in immune responses in OSCC. This fact should be considered regarding future immunotherapy regimens.

Evaluation of Murine Host Sex as a Biological Variable in Transplanted Human Intestinal Organoid Development.

BACKGROUND: Human intestinal organoids (HIOs), when transplanted into immunocompromised mice (tHIOs), demonstrate significant growth and maturation. While both male and female mice are reported to be viable hosts for these experiments, a direct comparison of sex-related differences in tHIO structure and development has not been performed. AIMS: We sought to identify host sex-related differences in tHIO engraftment, morphology, and epithelial and mesenchymal development. METHODS: HIOs were generated in vitro and transplanted beneath the kidney capsule of NSG male and female mice. tHIOs were harvested at 8-9 weeks. Anthropometric measurements were captured. tHIOs were divided in half and histology or RT-qPCR performed. Morphology was evaluated and epithelial architecture graded on a scale of 1 (absence of crypts/villi) to 4 (elongated crypt-villus axis). RT-qPCR and immunofluorescence microscopy were performed for epithelial and mesenchymal differentiation markers. RESULTS: Host survival and tHIO engraftment were equivalent in male and female hosts. tHIO weight and length were also equivalent between groups. The number of lumens per tHIOs from male and female hosts was similar, but the mean lumen circumference was larger for tHIOs from male hosts. tHIOs from male hosts were more likely to demonstrate higher grades of epithelial development. However, both groups showed similar differentiation into secretory and absorptive epithelial lineages. Markers for intestinal identity, mesenchymal development, and brush border enzymes were also expressed similarly between groups. CONCLUSIONS: While male host sex was associated with larger tHIO lumen size and mucosal maturation, tHIOs from both groups had similar engraftment, growth, and epithelial and mesenchymal cytodifferentiation.

Prevalence of chronic comorbidities in people with multiple sclerosis: descriptive study based on administrative data in Tuscany (Central Italy).

OBJECTIVE: Chronic comorbidities are common in people with multiple sclerosis (PwMS), thus worsening their prognosis and quality of life, and increasing disease burden. The aim of the present study was to evaluate the prevalence of common comorbidities in PwMS in Tuscany (Central Italy) and to compare it with the general population. METHODS: The prevalence of comorbidities, including diabetes, chronic obstructive pulmonary disease (COPD), hypertension, stroke, heart failure (HF), cardiac infarction and ischemic heart disease (IHD), was assessed in PwMS and in general population resident in Tuscany, aged > 20 years, using administrative data. RESULTS: In total, we identified 8,274 PwMS. Among them, 34% had at least one comorbidity, with hypertension being the most common (28.5%). Comparing PwMS with the general population, PwMS had a higher frequency of hypertension and stroke when considering the whole group, and of diabetes, COPD, and IHD when considering sex and age subgroups. This increased risk was especially evident in the young and intermediate age groups, where multiple sclerosis may play an important role as risk factor for some comorbidities. In PwMS, as well as in the general population, prevalence of chronic diseases was higher in males and increased with age. CONCLUSIONS: Comorbidities frequently coexist with multiple sclerosis and they may have an impact on this complex disease, from the health, clinical, and socioeconomic points of view. Therefore, a routine screening of chronic comorbidities should be a crucial step in clinical practice, as well as the promotion of healthy lifestyles to prevent the onset and to reduce their burden.

Sex and Gender-Related Differences in the Outcome of Total Hip Arthroplasty: A Current Concepts Review.

Background and Objectives: Sex and gender-related differences may influence the outcome of patients undergoing total hip arthroplasty (THA). The present paper aims to depict the importance of sex and gender-related issues in the perioperative management of patients undergoing THA to improve clinical outcomes and prevent postoperative complications. Materials and Methods: From January 2002 to August 2022, OVID-MEDLINE, EMBASE, SCOPU S, Web of Science, Google Scholar, and PubMed were searched to identify relevant studies for further analysis. The search strategy included the following terms: (("gender-related differences" [MeSH Terms] OR "sex-related differences" [All Fields]) OR ("gender indicators" [MeSH Terms] OR "sex" [All Fields])) AND ("total hip arthroplasty" [MeSH Terms] OR (total hip replacement [All Fields])). Results: Twenty-eight papers were included in this current concepts review. Sex and gender-related differences were analyzed with regard to the following points: (1) surgical approach, robotic surgery, scar cosmesis, and implant choice; (2) postoperative clinical outcome and complications; (3) sexual activity after THA; and (4) psychological status and daily functional requirements. The data analysis showed that female patients need more specific attention in the preoperative, intraoperative, and postoperative phases to improve clinical and functional outcomes, reduce complications risk, and manage patient satisfaction. Conclusions: THA outcomes may be influenced by sex and gender-related factors which should be carefully assessed and addressed in patients undergoing surgery to improve the postoperative outcomes of patients' satisfaction and reduce postoperative complications that can differ between the two sexes.

Sex Differences in the Evolution of Neutralizing Antibodies to Severe Acute Respiratory Syndrome Coronavirus 2.

We measured anti-spike (S), nucleoprotein (N), and neutralizing antibodies in sera from 308 healthcare workers with a positive reverse-transcription quantitative polymerase chain reaction result for severe acute respiratory syndrome coronavirus 2 and with mild disease, collected at 2 timepoints up to 6 months after symptom onset. At month 1, anti-S and -N antibody levels were higher in male participants aged >50 years and participants with a body mass index (BMI) >25 kg/m2. At months 3-6, anti-S and anti-N antibodies were detected in 99% and 59% of individuals, respectively. Anti-S antibodies and neutralizing antibodies declined faster in men than in women, independent of age and BMI, suggesting an association of sex with evolution of the humoral response.

Vitamin C Differentially Impacts the Serum Proteome Profile in Female and Male Mice.

A suboptimal blood vitamin C (ascorbate) level increases the risk of several chronic diseases. However, the detection of hypovitaminosis C is not a simple task, as ascorbate is unstable in blood samples. In this study, we examined the serum proteome of mice lacking the gulonolactone oxidase (Gulo) required for the ascorbate biosynthesis. Gulo-/- mice were supplemented with different concentrations of ascorbate in drinking water, and serum was collected to identify proteins correlating with serum ascorbate levels using an unbiased label-free liquid chromatography-tandem mass spectrometry global quantitative proteomic approach. Parallel reaction monitoring was performed to validate the correlations. We uncovered that the serum proteome profiles differ significantly between male and female mice. Also, unlike Gulo-/- males, a four-week ascorbate treatment did not entirely re-establish the serum proteome profile of ascorbate-deficient Gulo-/- females to the optimal profile exhibited by Gulo-/- females that never experienced an ascorbate deficiency. Finally, the serum proteins involved in retinoid metabolism, cholesterol, and lipid transport were similarly affected by ascorbate levels in males and females. In contrast, the proteins regulating serum peptidases and the protein of the acute phase response were different between males and females. These proteins are potential biomarkers correlating with blood ascorbate levels and require further study in standard clinical settings. The complete proteomics data set generated in this study has been deposited to the public repository ProteomeXchange with the data set identifier: PXD027019.

Sex-Related Differences in Chronic Myeloid Neoplasms: From the Clinical Observation to the Underlying Biology.

Chronic myeloid neoplasms are clonal diseases with variable clinical course and outcomes and despite the introduction of novel therapies, patients with high-risk disease continue to have overall poor outcomes. Different groups have highlighted that men have overall worse survival and higher incidence of transformation to acute leukemia compared to women across neoplasms such as myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap neoplasms, and CML. More recent studies evaluating the genomic profile of patients with these neoplasms demonstrated a male predominance for mutations in high-risk genes including ASXL1, U2AF1, SRSF2 and ZRSR2. The understanding of the underlying biology is limited but a number of hypotheses have been developed and are currently being investigated. This review summarizes the current knowledge about sex-related differences in the clinical outcomes and genomic profile of patients with chronic myeloid neoplasms and discusses the hypothesized biologic mechanisms as an attempt to explain these observations.

Sex-Related Differences in Outcomes for Patients With ST Elevation Myocardial Infarction (STEMI): A Tamil Nadu-STEMI Program Subgroup Analysis.

BACKGROUND: ST elevation myocardial infarction (STEMI) represents a large proportion of the clinical presentation of coronary artery disease in Indian people. Owing to multiple factors contributing to the sex difference, women with STEMI are thought to have a higher risk of adverse outcomes than men. The aim of this study was to evaluate sex-related differences in the clinical characteristics and prognosis of patients with STEMI within a system of care. METHOD: This study was a subgroup analysis of the Tamil Nadu-STEMI (TN-STEMI) program, a multicentre, prospective, observational study of a quality-improvement program studying patients with STEMI at four hub-and-spoke clusters in the southern state of Tamil Nadu, India. In total, 2,420 patients were enrolled between 2012 and 2014, and the data from all four clusters, pre- and postimplementation of integrated STEMI systems, were combined for this analysis, with a 1-year follow-up. RESULTS: The mean ± SD age of presentation of female patients (16%) was significantly later (60.1±10.9 years) compared with males (84%; 53.7±12 years). Diabetes was more prevalent in women (35.2% vs 23.8%; p<0.001), as was hypertension (35.2% vs 22.9%; p<0.001). Symptom to first medical contact in female patients was significantly delayed compared with males (193 mins vs 170 mins; p≤0.009). Women had higher mortality, both in hospital (10.4% vs 4.8%; p≤0.001) and at 1 year (26.7% vs 13%; p≤0.001). This pattern was persistent, even in the younger STEMI (<45 years) population (in-hospital: 9.1% vs 3% [p≤0.05]; at 1 year: 18.2% vs 3% [p≤ 0.05]). In the regression model, females had a 1.8 times increased likelihood (p<0.04) of mortality after adjusting for confounders. CONCLUSIONS: Among patients with STEMI, women have an unfavourable risk profile and adverse short- and long-term prognoses when compared to men.

Heritability of Structural Patterning in the Human Cerebral Cortex.

Genetic influences that govern the spatial patterning of the human cortex and its structural variability are still incompletely known. We analyzed structural MR images in twins, siblings, and pairs of unrelated subjects. A comprehensive set of methods was employed to quantify properties of cortical features at different spatial scales. Measures were used to assess the influence of genetic similarity on structural patterning. Results indicated that: (1) Genetic effects significantly influence all structural features assessed here at all spatial resolutions, albeit at different strengths. (2) While strong genetic effects were found at the whole-brain and hemisphere level, effects were weaker at the regional and vertex level, depending on the measure under study. (3) Besides cortical thickness, sulcal (geodesic) depth was found to be under strong genetic control. The local pattern indicated that two axes along (a) the anterior-posterior direction (insula to parieto-occipital sulcus), and (b) superior-inferior direction (central sulcus to callosal sulcus) presumably determine the segregation of four quadrants in each hemisphere early in development. (4) While strong structural asymmetries were found at the regional level, genetic influences on laterality were relatively minor.

The inclusion of interstimulus interval variability does not mitigate electrically-evoked fatigue of the knee extensors.

PURPOSE: Transcutaneous electrical stimulation (TES) is used to activate muscles when volitional capacity is impaired but potential benefits are limited by rapid force loss (fatigue). Most TES fatigue protocols employ constant-frequency trains, with stimuli at a fixed interstimulus interval (ISI); however, a brief ISI between the first two pulses (variable-frequency train, VFT) to maximize the catchlike property of muscle can attenuate fatigue development. The purpose of this study was to investigate if a VFT that simulates intrinsic variability of voluntary motor unit discharge rates would also mitigate fatigue, owing to the sensitivity of muscle to acute activation history. METHODS: On two visits, 24 healthy adults (25.3 ± 3.7 years; 12 females) received 3 min of intermittent TES to the quadriceps of the dominant leg. Trains of eight pulses at 10 Hz were delivered with a constant (100 ms) or variable ISI (80-120 ms). Contractile impulse, rate of force development (RFD), and rate of relaxation (RFR) were determined for each tetanus RESULTS: During fatigue and recovery, contractile impulse did not differ between protocols (p ≥ 0.796) and sexes (p ≥ 0.493), with values of 77 ± 17% control at task end and 125 ± 19% control 2 min later. RFD and RFR also showed no effect of the protocol (p ≥ 0.310) or participant sex (p ≥ 0.119). Both measures slowed (38 ± 23% and 33 ± 22%, respectively) but dissociated during recovery as RFD remained 16 ± 18% below control at 5 min, whereas RFR recovered to control by 30 s (101 ± 22%). CONCLUSION: Contrary to expectations, the VFT protocol did not attenuate fatigue development, which suggests no benefit to mimicking the inherent variability of motor unit discharge rates.

Cross-lateralisation in children with attention-deficit/hyperactivity disorder and motor skill performance.

Cross-lateralisation and increased motor difficulties have been reported in children with attention-deficit/hyperactivity disorder (ADHD). Nevertheless, the question of how crossed (i.e. mixed preference) or uncrossed (i.e. same side preference) lateralisation impacts motor performance in children with ADHD has yet to be examined. In this study, previously validated observational measures of hand and foot preference were used to identify right-handed children with ADHD who display cross- (n = 29) and uncross-lateralisation (n = 31). An uncross-lateralised typically developing (TD) group (n = 32) was also identified, and included as a control. Motor performance was assessed with seven valid and reliable fine and gross motor tasks performed with both preferred and non-preferred limbs. Group, task and sex-related effects were examined. Findings revealed that male (but not female) cross-lateralised children with ADHD performed significantly worse, respectively, in two of the fine motor tasks (spiral tracing [p < .01], and dot filling [p < .05]). Results suggest that cross-lateralised hand and foot preference may affect complex motor skills in male children with ADHD. Furthermore, characteristics of ADHD may manifest differently in male and female children. Findings highlight the importance of considering both hand and foot preference when targeting motor interventions for children with ADHD.

Sex-related differences in the intratubular renin-angiotensin system in two-kidney, one-clip hypertensive rats.

The intratubular renin-angiotensin system (RAS) is thought to play an essential role in hypertensive renal disease, but information regarding sex-related differences in this system is limited. The present study investigated sex differences in the intratubular RAS in two-kidney, one-clip (2K1C) rats. A 2.5-mm clip was placed on the left renal artery of Sprague-Dawley rats, and rats were euthanized 3 or 5 wk after the operation. Systolic blood pressure increased in 2K1C rats in both sexes but was significantly higher in male rats than in female rats, and an antihypertensive effect was not observed in 2K1C ovariectomized (OVX) female rats. Compared with male 2K1C rats, intratubular angiotensin-converting enzyme (ACE) and ANG II were repressed, and intratubular ACE2, angiotensin (1-7), and Mas receptor were increased in both kidneys in female 2K1C rats 5 wk after surgery. Comparison with male and female rats and intratubular mRNA levels of ACE and ANG II type 1 receptor were augmented in OVX female rats, regardless of the clipping surgery 3 wk postoperation. ANG II type 2 receptor was upregulated in female rats with or without OVX; thus, the ANG II type 1-to-type 2 receptor ratio was higher in male rats than in female rats. In conclusion, female rats were protected from hypertensive renal and cardiac injury after renal artery clipping. An increase in the intratubular nonclassic RAS [ACE2/angiotensin (1-7)/Mas receptor] and a decrease in the ANG II type 1-to-type 2 receptor ratio could limit the adverse effects of the classic RAS during renovascular hypertension in female rats, and estrogen is suggested to play a primary role in the regulation of intratubular RAS components.