Female Response Research Articles

Distribution of prostatic markers in glands of the female urethra and anterior vaginal wall-a rapid autopsy study.

There are varying reports of immunohistochemically detected prostatic marker protein distribution in glands associated with the female urethra that may be related to tissue integrity at the time of fixation. In this study we used tissue derived from rapid autopsies of female patients to determine the distribution of glandular structures expressing prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) along the female urethra and in surrounding tissues, including the anterior vaginal wall (AVW). Tissue blocks from 7 donors that contained the entire urethra and adjacent AVW were analyzed. These tissue samples were fixed within 4-12hours of death and divided into 5-mm transverse slices that were paraffin embedded. Sections cut from each slice were immunolabeled for PSA or PSAP and a neighboring section was stained with hematoxylin and eosin. The sections were reviewed by light microscopy and analyzed using QuPath software. In tissue from all donors, glandular structures expressing PSA and/or PSAP were located within the wall of the urethra and were present along its whole length. In the proximal half of the urethra from all donors, small glands expressing PSAP, but not PSA, were observed adjacent to the and emptying into the lumen. In the distal half of the urethra from 5 of the 7 donors, tubuloacinar structures lined by a glandular epithelium expressed both PSA and PSAP. In addition, columnar cells at the surface of structures with a multilayered transitional epithelium in the distal half of the urethra from all donors expressed PSAP. No glands expressing PSA or PSAP were found in tissues surrounding the urethra, including the AVW. Greater understanding of the distribution of urethral glands expressing prostatic proteins in female patients is important because these glands are reported to contribute to the female sexual response and to urethral pathology, including urethral cysts, diverticula, and adenocarcinoma. Strengths of the present study include the use of rapid autopsy to minimize protein degradation and autolysis, and the preparation of large tissue sections to demonstrate precise anatomical relations within all the tissues surrounding the urethral lumen. Limitations include the sample size and that all donors had advanced malignancy and had undergone previous therapy which may have had unknown tissue effects. Proximal and distal glands expressing prostate-specific proteins were observed in tissue from all donors, and these glands were located only within the wall of the urethra.

UCP1-dependent brown adipose activation accelerates cardiac metabolic remodeling and reduces initial hypertrophic and fibrotic responses to pathological stress.

Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p < .05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of β-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-β1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7- and 2.4-fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1-dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress.

Endocrine effect of phthalate metabolites and a butterfly effect of prenatal exposure to androgens on qualitative aspects of female sexual response- an initial survey.

There is growing evidence that endocrine disruptive chemicals have deleterious effects on sexual and reproductive function. To examine subjective sexual functions in human females and their relationship to postnatal phthalate exposure and perinatal androgenization, a Sexuality Score (SS) was established from a first-stage survey questionnaire of subjective sexual function filled out by female university students (n = 68; average age 25.23 ± 5.17 years; rural 25.51 ± 6.74 vs. urban 25.85 ± 1.43 years). Seventeen phthalate metabolites in urine samples were analyzed by high-performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS). Females were also assessed for the 2D:4D digit ratio as an index of perinatal androgenization. The mean age of menarche was 12.82 ± 1.35 years (rural 12.59 ± 1.39 vs. urban 13.18 ± 1.27; p = 0.01). The mean age at first sexual intercourse was 14.88 ± 6.89 years (rural 14.62 ± 7.20 vs. urban 15.24 ± 6.55), and as the age of first sexual intercourse increases, the SS score tends to increase as well, albeit moderately (r = 0.25, p = 0.037). Mono-iso-butyl phthalate, mono(2-ethyl-5-carboxypentyl) phthalate, mono(hydroxy-n-butyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate (p ≤ 0.05) and mono(2-carboxymethylhexyl) phthalate (p ≤ 0.01) were negatively associated with SS. A compounding butterfly effect of prenatal exposure to androgens was observed with disruptive effects of mono(2-ethyl-5-oxohexyl) phthalate and mono(2-ethyl-5-carboxypentyl) phthalate on sexual function. Exposure to phthalates in adult females may lead to disruption of subjective sexual function, especially concerning sexual desire and sexual satisfaction, and perinatal androgenization could augment these effects.

Mathematical Modeling Suggests That Monocyte Activity May Drive Sex Disparities during Influenza Infection.

In humans, females of reproductive age often experience a more severe disease during influenza A virus infection, which may be due to differences in their innate immune response. Sex-specific outcomes to influenza infection have been recapitulated in mice, enabling researchers to study viral and immune dynamics in vivo in order to identify immune mechanisms that are differently regulated between the sexes. This study is based on the hypothesis that sex-specific outcomes emerge due to differences in the rates/speeds that select immune components respond. Using publicly available sex-specific murine data, we utilized dynamic mathematical models of the innate immune response to identify candidate mechanisms that may lead to increased disease severity in female mice. We implemented a large computational screen using the Bayesian information criterion (BIC), wherein the goodness of fit of the competing model scenarios is balanced against complexity (i.e., the number of parameters). Our results suggest that having sex-specific rates for proinflammatory monocyte induction by interferon and monocyte inhibition of virus replication provides the simplest (lowest BIC) explanation for the difference observed in the male and female immune responses. Markov-chain Monte Carlo (MCMC) analysis and global sensitivity analysis of the top performing scenario were performed to provide rigorous estimates of the sex-specific parameter distributions and to provide insight into which parameters most affect innate immune responses. Simulations using the top-performing model suggest that monocyte activity could be a key target to reduce influenza disease severity in females. Overall, our Bayesian statistical and dynamic modeling approach suggests that monocyte activity and induction parameters are sex-specific and may explain sex-differences in influenza disease immune dynamics.

Quantitative evaluation of factors influencing the 3 Hz repetitive nerve stimulation test in patients with amyotrophic lateral sclerosis.

Previous studies have suggested that treatments targeting the neuromuscular junction (NMJ) may play a role in the treatment of amyotrophic lateral sclerosis (ALS). However, factors impacting repetitive nerve stimulation (RNS), a technique to evaluate NMJ function, have yet to be fully elucidated. We aimed to identify independent factors contributing to the decremental response of the accessory nerve and evaluated its value in ALS clinical practice. A total of 626 patients who were diagnosed with ALS and underwent 3 Hz RNS tests on the accessory nerve were enrolled. Data on their clinical and electrophysiological indicators were divided into a training set (collected from June 2016 to December 2022) and a test set (collected from January to August 2023). Stepwise regression was used in independent variable selection and model building. Forty-two percent of patients had a decrement larger than 10% and 24% had a decrement larger than 15%. Onset age, sex, onset site, forced vital capacity (FVC) and motor unit potential (MUP) duration were independent factors contributing to the results of the RNS test. MUP duration had the greatest impact on decremental response, followed by FVC and onset age. The decremental response in females was larger than in males. Upper limb onset was found to contribute more to the decrement than lower limb or bulbar onset. In patients with ALS, NMJ safety factor is reduced during re-innervation. Decremental response is affected by multiple factors, which needs to be considered in clinical trials targeting the NMJ in these patients.

Females Present Different Single-Leg Squat Kinematics and Muscle Activation Strategies than Males Even after Hip Abductor Fatigue

Background: Despite the potential connection between hip and knee muscle control, there is limited research on the effects of hip abductor fatigue on the hip and knee neuromuscular responses in both males and females. This study aimed to investigate the influence of sex on the hip and knee frontal plane kinematics and the EMG responses of the hip abductors and knee extensor muscles during the single-leg squat before and after hip abductor fatigue. Methods: A total of 30 participants (males, n = 15; females, n = 15) performed single-leg squats before and immediately after a hip abductor fatigue protocol (10° hip abduction position while bearing a 20% load of their estimated 1RM until exhaustion). The frontal plane kinematics (hip adduction and knee frontal plane projection angle) and EMG parameters (amplitude and median frequency) of the gluteus medius (GMed), tensor fascia latae (TFL), vastus lateralis (VL) and vastus medialis (VM) were measured during the single-leg squat. Results: We did not find any effects of hip abductor fatigue or interaction between fatigue and sex on the evaluated parameters (p &gt; 0.05). However, compared to males, females had greater values for the hip and knee frontal plane kinematics (p = 0.030), GMed EMG amplitude (+10.2%, p = 0.012) and median frequency (+10.3%; p = 0.042) and lower VL median frequency (−9.80%; p = 0.007). Conclusions: These findings establish sex-related differences in the kinematics and hip and knee EMG parameters during the single-leg squat, which were not influenced by the hip abductor fatigue protocol.

Autonomic responses in young females with typical vasovagal syncope

To determine whether young women who have experienced typical vasovagal syncope (tVVS) have altered autonomic response parameters, based on a battery of autonomic tests and maneuvers. Notably, previous studies including small cohorts and a partial list of tests yielded conflicting results. A total of 91 otherwise healthy women were included and divided according to those who had experienced tVVS (39 patients) or not (52 patients). Heart rate variability was evaluated at rest, under strict conditions, during 5 min of standing and during a deep breathing test. Response to Valsalva maneuver and Ewing maneuver were also quantified and compared. Both groups had similar clinical characteristics at baseline. No significant differences were found between the two groups in any of the autonomic parameters evaluated. Autonomic responses in young women who experienced typical vasovagal syncope at baseline were indistinguishable from those who did not. Thus, using non-tilt test autonomic screening tests does not seem to provide diagnostic benefits, and may not be useful in predicting recurrence in this patient population.

Does diphenhydramine exert a sex-dependent effect on sudomotor responses during exertional heat stress?

Introduction: The first-generation H1 antihistamine diphenhydramine hydrochloride (DPH) is a potent antimuscarinic agent which may compromise sweat output during heat stress. DPH consumption prior to exertional heat stress could further suppress the sweating response in females due to their lower postjunctional cholinergic sensitivity of the sweat glands relative to males. Objective and Hypothesis: The purpose of the present study was to test the hypothesis that DPH would reduce sweating to a greater extent in females relative to males due to differences in cholinergic sensitivity at the sweat gland. Methods: Equal groups (10 per group) of males (24±3 y; 82.6±10.1 kg; 182±5 cm) and females (22±3 y, 67.7±7.8 kg, 171±6 cm) completed two experimental trials presented in a randomized double-blind fashion. Upon arrival to lab, participants consumed either i) a placebo (PLA) pill or ii) 50 mg DPH and then rested in a room maintained at ~29.5°C &amp; 35% RH for 2 hours before conducting a 60-minute treadmill march at a fixed rate of heat production relative to body surface area (~245 W/m2). Rectal temperature (Trec), local sweat rate of the forearm (LSR), and whole body sweat loss (WBSL) were measured. Sex-segregated analysis was conducted for each outcome variable as the difference between PLA and DPH. Results: Baseline Trec did not differ within sex between PLA and DPH (males: -0.10±0.26°C; females: -0.05±0.33°C, P=0.70), however a higher absolute baseline Trec was observed in females compared to males (P=0.006). In comparison to PLA, DPH did not exert a sex-dependent effect on ΔTrec following 60-min of exercise (males: 0.04±0.11°C; females: 0.02±0.37°C, P=0.90). No sex-dependent effect on the onset of sweating was observed between DPH and PLA (males: -0.4±2.6 min; females: 0.6±2.4 min, P=0.34). DPH did not exert a sex-dependent effect on LSR at steady-state (males: 0.03±0.25 mg/cm2/min; females: -0.01±0.21 mg/cm2/min, P=0.71). Lastly, no sex-dependent effect on WBSL was observed between PLA and DPH (males: 14±34 g; females: 6±43 g, P=0.98). Conclusion: Current evidence suggests that sex does not independently modulate the sweating response during exertional heat stress following the consumption of 50 mg of DPH. This research is supported by Dr. Ravanelli’s Research Seed Grant from the Centre for Research in Occupational Safety &amp; Health, and Dr. Ravanelli’s Natural Sciences and Engineering Research Council of Canada Discovery Grant (PIN#2022-05096). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of Sex on the β-Adrenergic Receptor Contribution to Hypoxic Vasodilation

Introduction: Hypoxia elicits peripheral vasodilation to preserve oxygen delivery to tissues. Approximately 10% of hypoxic vasodilation has been attributed to β-adrenergic receptors on the vascular endothelium and smooth muscle. Based on data supporting greater vascular β-adrenergic receptor responsiveness in females compared to males, we examined the effect of sex on the relative contribution of the β-adrenergic receptors to hypoxic vasodilation. We hypothesized β-adrenergic receptor blockade (oral propranolol, 1 mg/kg) would attenuate hypoxic vasodilation and the effect would be greater in females compared to males. Methods: Five female (26±8 yrs, 22±2 kg/m2) and eight male (27±7 yrs, 26±2 kg/m2) participants completed two randomized, single-blinded, and placebo-controlled visits (NCT05256069). On each visit (placebo, propranolol), forearm blood flow (venous occlusion plethysmography) and blood pressure (BP, finger photoplethysmography) were measured during normoxia (SpO2 ~98%) and hypoxia (SpO2 ~80%). Blood flow was normalized for mean BP and expressed as forearm vascular conductance (FVC). The relative change in FVC with hypoxia (%FVC = Hypoxia − Normoxia / Normoxia x 100) was assessed as an index of hypoxic vasodilation. Differences in %FVC between study visits (propranolol − placebo) are reported. Results: %FVC was unaffected by β-adrenergic blockade in female (placebo 15±14%, propranolol -1±15%, p=0.066) and male (placebo 19±25%, propranolol 16±15%, p=0.755) participants. Any effect of β-adrenergic receptor blockade on hypoxic vasodilation did not differ by sex (females: -16±14%, males -3±29%; p=0.383). Conclusion: These preliminary data suggest any effect of β-adrenergic receptor blockade on hypoxic vasodilation does not differ between young healthy female and male participants, although studies are ongoing. Our results further understanding of the effect of sex on vascular control mechanisms during hypoxia. Funding: AHA 909014 (DWJ), APS-SURF (BJB), HL153523 (JKL). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

CYP450 Inhibition on Cerebral Hemodynamics in Healthy, Young Males and Females During Simulated Hypovolemia

Animal models have shown that cytochrome P450 2C9 (CYP450) is involved in vascular control within the cerebrovasculature. However, the role sex plays on CYP450 within human cerebral circulation has not been examined. PURPOSE: To determine the contribution of CYP450 to cerebrovascular hemodynamics between healthy young males and females at rest and during mild simulated hypovolemia. METHODS: 18 subjects (9 females, tested during days 1-5 of early follicular phase) participated in 1 familiarization and 2 experimental visits. During experimental visits, subjects ingested a CYP450 inhibitor (fluconazole, FLZ 150mg) or placebo (PLC, 250mg microcrystalline cellulose) in a randomized, single-blind, crossover design. Following ingestion and 120 minutes of supine rest, middle cerebral artery velocity (MCAv, cm/s, Transcranial Doppler) and mean arterial pressure (MAP, mmHg, finger photoplethysmography) were continuously measured during 5 minutes of supine rest and 5 minutes of lower-body negative pressure (LBNP, -20mmHg). Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. RESULTS: Means ± SD. Resting values for all variables were not different between treatments (p &gt; 0.05). Therefore, all data are presented as a change (Δ) from rest to LBNP. There was no treatment*time*sex effect for MCAv or CVCi (p = 0.52, pη2 = 0.08; p = 0.34, pη2 = 0.06, respectively). MCAv responded similarly to LBNP between sexes within PLC and FLZ with a low-to-moderate effect (M -4.2 ± 5.2 vs. F -2.4 ± 7.3, p = 0.63, r = 0.11; M -4.2 ± 6.2 vs. F -8.1 ± 6.3, p = 0.06, r = 0.45, respectively). Similarly, male and female CVCi responses to LBNP were similar within treatments with a low effect (PLC M -0.04 ± 0.05 vs. -0.02 ± 0.08, p = 0.69, r = 0.09; FLZ M -0.06 ± 0.06 vs. -0.08 ± 0.05, p = 0.31, r = 0.24). Two one-sided testing (TOST) analysis, used to assess equivalence between groups (1), revealed that the differences between PLC and FLZ ΔMCAv and ΔCVCi were non-equivalent between the sexes (Mean = 5.67, t(13.84) = 0.42, p = 0.55; Mean = 0.05, t(15.02) = 0.34, p = 0.63, respectively). CONCLUSION: Although no significant differences were seen between sexes, small-to-moderate effect sizes and TOST analysis suggest male and female hemodynamic responses to LBNP are not equal following CYP450 inhibition. These data argue that CYP450 may have differential contributions to cerebral vascular control between the sexes and further exploration is warranted. 1. O’Brien MW, Kimmerly DS. Is “not different” enough to conclude similar cardiovascular responses across sexes? American Journal of Physiology-Heart and Circulatory Physiology 322: H355–H358, 2022. doi: 10.1152/ajpheart.00687.2021. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of Sex on Sympatho-inhibitors and Non-inhibitor Phenotypes during Acute Hyperoxia

Acute hyperoxia (i.e., breathing air consisting of 100% oxygen, O2) reduces muscle sympathetic nerve activity (MSNA), positioning hyperoxia as a potential anti-hypertensive therapeutic. However, the link between hyperoxia and MSNA has not been established in females. We tested the hypothesis that males would exhibit greater reductions in MSNA during hyperoxia than females. We tested healthy females (n=18, 27±5yr, body mass index [BMI] 23±3kg/m2) and males (n=13, 27±5yr, 25±3kg/m2) of similar age (P=0.99) and BMI (P=0.08). Integrated MSNA, blood pressure, and end-tidal O2 (ETO2) and CO2 (ETCO2) were measured during normal room air breathing (BSL; 3-min) and hyperoxic breathing (100% O2; 3-min). Integrated MSNA was quantified as burst frequency (BF; bursts/min), amplitude (BA; a.u.), and total MSNA (a.u.); blood pressure was quantified as mean arterial pressure (MAP). Baseline MSNA BF was not different between females and males (24±7 vs 23±8 bursts/min, respectively, P=0.68); MAP was lower in females than males (85±7 vs 93±7 mmHg; p&lt;0.01). Hyperoxia increased ETO2 (effect of cond: p&lt;0.01) and reduced ETCO2 (effect of cond: p&lt;0.01) in a manner similar between sexes for ETO2 (sex*cond: P=0.56) whereas ETCO2 decreased more in females than males (sex*cond: P=0.01). Overall, hyperoxia evoked reductions in MSNA BF (effect of cond: P=0.02) but not BA (effect of cond: P=0.80) or total MSNA (effect of cond: P=0.26). Nadir MSNA responses during hyperoxia unveiled sex differences insofar as total MSNA was reduced consistently only in males (sex*cond: P=0.04); within the females we observed the presence of sympatho-inhibitors and non-inhibitors. Whereas female and male inhibitors reduced total MSNA via substantial reductions in BF and non-significant reductions in BA, female non-inhibitors demonstrated limited reductions in BF (P=0.11 vs inhibitors) coupled with increases in BA (p&lt;0.01 vs inhibitors), resulting in no net change in total MSNA (p&lt;0.01 vs inhibitors). Overall, these findings indicate sex differences exist in the sympathetic response to hyperoxia, in marked variability in the female sympathetic response to acute hyperoxia. The Women and Children's Health Research Institute. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sexual receptivity of females on Neotropical scorpion Tityus pusillus Pocock, 1893 in response to male reproductive advances

Due to the high reproductive investment, females are the decisive sex when making decisions about whether or not to reproduce. Generally, female scorpions display aggressive sexual behavior in response to male reproductive advances when they are not receptive. However, female receptivity can vary over time, depending on environmental factors favorable to reproduction Thus, the current study aimed to examine the correlation between the number of reproductive attempts by male Tityus pusillus scorpion and mating success over time, considering the female's behavioral response. Behavioral analyses were monthly conducted on 150 T. pusillus field-caught pairs over a five-month period. Our results indicate that despite females reacting aggressively to male advances, the persistence of the male has a positive effect in courtship probability. Furthermore, we observed variations in female behavior throughout the studied period, suggesting that female receptivity might be linked to the reproductive season. Therefore, environmental factors may play a significant role in regulating scorpion reproduction in Neotropical forests.

Down-regulating the stress axis: Living in the present while preparing for the future

The measurement of glucocorticoid (GC) hormones provides us with a window into the stress physiology of vertebrates and the adaptative responses they use to cope with predictable and unpredictable changes in the environment. Baseline GCs inform us about the metabolic demands they are subject to at that point in their yearly life-history stage, whereas GC changes (often increases) in response to acute challenges inform us on their capacity to cope with more immediate environmental challenges. However, baseline GC levels and the kinetics of GC responses to acute stressors can vary substantially among and within species, depending on individual characteristics (age, sex, condition, life-history stage). In addition, a thorough understanding of the stress status of an animal requires moving beyond the measurement of GCs alone by focusing on downstream measures of metabolic activation, such as oxidative stress. Here, we evaluated the changes in blood cortisol and oxidative stress markers in wild adult Columbian ground squirrels (Urocitellus columbianus), following a 30-min capture-handling stress performed in mid-late June. Measurements were taken when males were post-reproductive and preparing for hibernation and adult females were weaning litters. We found three key results. First, the time-course of GC increase was markedly slower (by an order of magnitude) than what is currently reported in the literature for most species of mammals, birds and reptiles. Second, there were marked differences in the male and female response, linked to differences in life-history stage: females close to weaning had abolished GC responses, whereas post-reproductive males did not. Third, there were mild to moderate increases in oxidative damage and decreases in oxidative defenses in response to our short-term challenge, consistent with the idea that short-term acute metabolic activation may carry physiological costs. However, these changes were not correlated to the changes in GCs, a novel result suggesting a disconnect between the hormonal stress response and oxidative damage.

Differential ovulation responses in nulliparous and multiparous rabbit females: A cannula-mediated study

In order to explore a less stressful and hormone-independent insemination method in rabbits, we aimed to evaluate the influence of a new insemination cannula on reproductive performance. Two assays were conducted. In the first, 136 nulliparous and multiparous females were treated with 12.5 IU of eCG to improve their receptivity and divided into four stimulation groups (aGnRHControl, Extender, Seminal and Sperm) to test ovulation frequency and rate. The control group received 1 µg of buserelin acetate intramuscularly to induce ovulation. The other groups used a 3D printed cannula to introduce 0.5 ml of extender, undiluted seminal plasma or resuspended sperm into the vagina. After six days, laparoscopy was performed to assess ovulation frequency and rate. Results showed that nulliparous does exhibited higher ovulation frequencies compared to multiparous does, regardless of the stimulation group.In the second assay, reproductive performance (delivery rate and litter size at birth) of 109 females treated with 12.5 IU of eCG to improve their receptivity was studied after insemination with a seminal dose using the 3D printed cannula. Forty-nine of them were induced to ovulate with buserelin acetate as a control. The results confirmed previous findings, as cannula stimulation allowed better delivery rates in receptive nulliparous than multiparous does. Differential response to multiparous does to the physical stimulus of the cannula could be supported by the histological changes and loss of contractile response that occur after multiple births. Litter sizes at birth were similar between experimental groups.In conclusion, the 3D designed cannula showed promising results in nulliparous does in ovulating frequency, and further refinement is needed to enhance its effectiveness, particularly in multiparous rabbits.

Sex-dependent effects of chronic intermittent hypoxia: implication for obstructive sleep apnea

BackgroundObstructive sleep apnea (OSA) affects 10–26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS).MethodsAdult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1β, IL-6, IL-10, TNF-α), circulating steroid hormones, circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). Rats were implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype.ResultsSex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex.ConclusionsOur results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments.

Comparison of Adult Female and Male PMHS Pelvis and Lumbar Response to Underbody Blast.

The goal of this study was to gather and compare kinematic response and injury data on both female and male whole-body Post-mortem Human Surrogates (PMHS) responses to Underbody Blast (UBB) loading. Midsized males (50th percentile, MM) have historically been most used in biomechanical testing and were the focus of the Warrior Injury Assessment Manikin (WIAMan) program, thus this population subgroup was selected to be the baseline for female comparison. Both small female (5th percentile, SF) and large female (75th percentile, LF) PMHS were included in the test series to attempt to discern whether differences between male and female responses were predominantly driven by sex or size. Eleven tests, using 20 whole-body PMHS, were conducted by the research team. Preparation of the rig and execution of the tests took place at the Aberdeen Proving Grounds (APG) in Aberdeen, MD. Two PMHS were used in each test. The Accelerative Loading Fixture (ALF) version 2, located at APG's Bear Point range was used for all male and female whole-body tests in this series. The ALF was an outdoor test rig that was driven by a buried explosive charge, to accelerate a platform holding two symmetrically mounted seats. The platform was designed as a large, rigid frame with a deformable center section that could be tuned to simulate the floor deformation of a vehicle during a UBB event. PMHS were restrained with a 5-point harness, common in military vehicle seats. Six-degree-of-freedom motion blocks were fixed to L3, the sacrum, and the left and right iliac wings. A three-degree-of freedom block was fixed to T12. Strain gages were placed on L4 and multiple locations on the pelvis. Accelerometers on the floor and seat of the ALF provided input data for each PMHS' feet and pelvis. Time histories and mean peak responses in z-axis acceleration were similar among the three PMHS groups in this body region. Injury outcomes were different and seemed to be influenced by both sex and size contributions. Small females incurred pelvis injuries in absence of lumbar injures. Midsized males had lumbar vertebral body fractures without pelvis injuries. And large females with injuries had both pelvis and lumbar VB fractures. This study provides evidence supporting the need for female biomechanical testing to generate female response and injury thresholds. Without the inclusion of female PMHS, the differences in the injury patterns between the small female and midsized male groups would not have been recognized. Standard scaling methods assume equivalent injury patterns between the experimental and scaled data. In this study, small female damage occurred in a different anatomical structure than for the midsized males. This is an important discovery for the development of anthropomorphic test devices, injury criteria, and injury mitigating technologies. The clear separation of small female damage results, in combination with seat speeds, suggest that the small female pelvis injury threshold in UBB events lies between 4 - 5 m/s seat speed. No inference can be made about the small female lumbar threshold, other than it is likely at higher speeds and/or over longer duration. Male lumbar spine damage occurred in both the higher- and lower lower-rate tests, indicating the injury threshold would be below the seat pulses tested in these experiments. Large females exhibited injury patterns that reflected both the small female and midsized male groups - with damaged PMHS having fractures in both pelvis and lumbar, and in both higher- and lower- rate tests. The difference in damage patterns between the sex and size groups should be considered in the development of injury mitigation strategies to protect across the full population.

Maternal dietary fatty acid composition and content prior to and during pregnancy and lactation influences serum profile, liver phenotype and hepatic miRNA expression in young male and female offspring

This study aimed to investigate whether modifying the pre-gestational lipid content could mitigate metabolic damage in offspring from dams exposed to a high-fat (HF) diet before conception and during pregnancy and lactation, with a focus on sex-specific outcomes. Specific effects of maternal normolipidic diets on offspring were also assessed. Female Wistar rats received control (C) or HF diets before conception. During pregnancy and lactation, females were distributed in five groups: C-C, HF-HF, HF-C, HF-saturated (HF-S) or HF-polyunsaturated n-3 group (HF-P). Saturated and PUFA n-3 diets were normolipidic. In 21-day-old offspring, corporal parameters, adiposity, serum metabolites, OGTT, liver phenotype, and miR-34a-5p hepatic expression were determined. Pre-gestational HF diet impaired glycemic response in females, independent of any change in body weight. Female and male offspring from dams continuously exposed to HF diet exhibited hyperglycemia, increased adiposity, and disrupted serum lipid profiles. Male offspring showed increased hepatic fat accumulation and miR-34a-5p expression. Shifting maternal dietary lipid content to normolipidic diets restored offspring's phenotype; however, decreased SIRT1, IRβ and IRS1 expression in offspring from dams exposed to HF diet before conception suggested early indicators of glucose metabolism damage. Our findings indicated a pronounced metabolic impact on males. In conclusion, glucose tolerance impairment in females before conception disturbed intrauterine environment, influencing in offspring's phenotype. Modifying maternal dietary lipid content mitigated effects of pre-gestational HF diet exposure on young offspring. Nevertheless, decreased hepatic levels of critical insulin signaling proteins indicated that independently of the maternal diet, pre-existing HF diet-induced glucose intolerance before conception may adversely program the offspring's phenotype.

Low-Dose Radiation Therapy Impacts Microglial Inflammatory Response without Modulating Amyloid Load in Female TgF344-AD Rats.

Low-dose radiation therapy (LD-RT) has demonstrated in preclinical and clinical studies interesting properties in the perspective of targeting Alzheimer's disease (AD), including anti-amyloid and anti-inflammatory effects. Nevertheless, studies were highly heterogenous with respect to total doses, fractionation protocols, sex, age at the time of treatment and delay post treatment. Recently, we demonstrated that LD-RT reduced amyloid peptides and inflammatory markers in 9-month-old TgF344-AD (TgAD) males. As multiple studies demonstrated a sex effect in AD, we wanted to validate that LD-RT benefits are also observed in TgAD females analyzed at the same age. Females were bilaterally treated with 2 Gy×5 daily fractions, 2 Gy×5 weekly fractions, or 10 fractions of 1 Gy delivered twice a week. The effect of each treatment on amyloid load and inflammation was evaluated using immunohistology and biochemistry. A daily treatment did not affect amyloid and reduced only microglial-mediated inflammation markers, the opposite of the results obtained in our previous male study. Moreover, altered fractionations (2 Gy×5 weekly fractions or 10 fractions of 1 Gy delivered twice a week) did not influence the amyloid load or neuroinflammatory response in females. A daily treatment consequently appears to be the most efficient for AD. This study also shows that the anti-amyloid and anti-inflammatory response to LD-RT are, at least partly, two distinct mechanisms. It also emphasizes the necessity to assess the sex impact when evaluating responses in ongoing pilot clinical trials testing LD-RT against AD.

TrkB-mediated neuroprotection in female hippocampal neurons is autonomous, estrogen receptor alpha-dependent, and eliminated by testosterone: a proposed model for sex differences in neonatal hippocampal neuronal injury

Highlights Following in vitro ischemia, the nerve growth factor receptor TrkB is activated in the presence of the TrkB agonist 7,8-DHF only in female and not in male cultured hippocampal neurons, leading to increased neuronal survival.Expression of ERα is increased following in vitro ischemia in female but not male hippocampal neurons.The female hippocampal neuronal specific responses to in vitro ischemia are blocked by pre-treatment with testosterone.The data support a model for a female-specific a neuroprotective pathway in hippocampal neurons. The pathway is activated by a TrkB agonist, dependent on ERα and blocked by testosterone.

1 Sex Differences in Middle Cerebral Artery Velocity in Patients with Persistent Post-Concussion Convergence Insufficiency (PPCS-CI)

OBJECTIVES/GOALS: The objective of this study is to investigate the neurophysiological mechanism of vision therapy in male and female adolescents with persistent post-concussion convergence insufficiency (PPCS-CI). This study may improve diagnostics and inform more effective personalized point of care treatment strategies to remediate symptoms. METHODS/STUDY POPULATION: Participants (ages 11-25) were diagnosed with PPCS by a physician, CI was diagnosed by an optometrist and OBVAT was performed by certified therapists. Patients with PPCS-CI were randomly assigned to a therapy type (immediate therapy or natural recovery). Hemodynamic measures were examined in patients with PPCS-CI at baseline (1-3 months post-concussion), and post OBVAT to evaluate recovery outcomes. Non-invasive techniques were used to measure middle cerebral artery velocity (MCAv), blood pressure, heart rate, and end-tidal CO2 at rest and during objective symmetrical convergence step eye movements. Functional magnetic resonance imaging (fMRI) was acquired during convergence step eye movement experiments contrasted to sustained fixation and resting state data collection. RESULTS/ANTICIPATED RESULTS: To investigate the neural mechanism of OBVAT, eye movements, fMRI and physiological measures were collected in 8 patients with PPCS-CI (4 men and 4 women). Results show an 10% decrease in the MCA during 4-degree symmetrical convergent eye movement responses in males post-OBVAT and a 19% increase in MCA during convergent eye movement responses in females. Furthermore, there was a group level activation of the frontal eye fields, which improves post-OBVAT. The beta weights in the left frontal eye fields show a trending decrease in male patients post-OBVAT and trending increase in females. Males had a decrease in MCAv post OBVAT (baseline 83.6 ± 7.5 cm/sec &amp; 75.7 ± 12.5 cm/sec post-OBVAT), while females show a significant increase post-OBVAT (baseline 53.77 ± 5.2 cm/sec &amp; post-OBVAT 65.13 cm/sec ± 12.5). DISCUSSION/SIGNIFICANCE: This initial pilot demonstrates there may be different underlying pathophysiological outcomes associated with a concussion dependent on sex. This work may have direct implications on treatment strategies for male and female adolescent patients with PPCS-CI.