Improving vitamin D content in pork meat by UVB biofortification.

Vitamin D deficiency is prevalent worldwide and identification of alternative food-based strategies are urgently warranted. In two studies, 12-week old crossbred pigs (Duroc x (Large White x Landrace)) were exposed daily to narrowband UVB radiation for ∼10 weeks or control (no UVB exposure) until slaughter. In Study 1 (n = 48), pigs were exposed to UVB for 2 min and in Study 2 (n = 20), this duration was tripled to 6 min. All pigs were fed the maximum permitted 2000 IU vitamin D3/kg feed. Loin meat was cooked prior to vitamin D LC-MS/MS analysis. In Study 1, pork loin vitamin D3 did not differ between groups. Study 2 provided longer UVB exposure time and resulted in significantly higher loin vitamin D3 (11.97 vs. 6.03 µg/kg), 25(OH)D3 (2.09 vs. 1.65 µg/kg) and total vitamin D activity (22.88 vs. 14.50 µg/kg) concentrations, compared to control (P < 0.05). Pigs remained healthy during both studies and developed no signs of erythema. Biofortification by UVB radiation provides an effective strategy to further safely increase the naturally occurring vitamin D content of pork loin, alongside feed supplementation.

Bioavailability of vitamin D biofortified pork meat: results of an acute human crossover study in healthy adults.

Vitamin D intakes are concerningly low. Food-based strategies are urgently warranted to increase vitamin D intakes and subsequently improve 25-hydroxyvitamin D (25(OH)D) concentrations. This acute randomised three-way crossover study investigated the efficacy of vitamin D biofortified pork derived from pigs exposed to UVB light to increase serum 25(OH)D3 concentrations, compared to a dose-matched vitamin D3 supplement and control pork in adults (n = 14). Blood samples were obtained at baseline and then 1.5, 3, 6, 9 and 24 h postprandially. There was a significant effect of time (p < 0.01) and a significant treatment*time interaction (p < 0.05). UV pork and supplement significantly increased within-group serum 25(OH)D3 concentrations over timepoints (p < 0.05) (max. change 0.9 nmol/L (2.2%) UV pork, 1.5 nmol/L (3.5%) supplement, 0.7 nmol/L (1.9%) control). Vitamin D biofortified pork modestly increased 25(OH)D3 concentrations and produced a similar response pattern as a dose-matched vitamin D supplement, but biofortification protocols should be further optimised to ensure differentiation from standard pork.

Antibacterial Activity of Four Plant Extracts Extracted from Traditional Chinese Medicinal Plants against Listeria monocytogenes, Escherichia coli, and Salmonella enterica subsp. enterica serovar Enteritidis.

The worldwide ethnobotanical use of four investigated plants indicates antibacterial properties. The aim of this study was to screen and determine significant antibacterial activity of four plant extracts in vitro and in a poultry digest model. Using broth microdilution, the concentrations at which four plant extracts inhibited Listeria monocytogenes, Salmonella enteritidis, and Escherichia coli over 24 hours was determined. Agrimonia pilosa Ledeb, Iris domestica (L.) Goldblatt and Mabb, Anemone chinensis Bunge, and Smilax glabra Roxb all exhibited a minimum inhibitory concentration (MIC) of 62.5mg/L and a minimum bactericidal concentration (MBC) of 500mg/L against one pathogen. A. pilosa Ledeb was the most effective against L. monocytogenes and E. coli with the exception of S. enteritidis, for which A. chinensis Bunge was the most effective. Time-kills of A. pilosa Ledeb and A. chinensis Bunge against L. monocytogenes, E. coli and S. enteritidis incubated in poultry cecum were used to determine bactericidal activity of these plant extracts. A. chinensis Bunge, significantly reduced S. enteritidis by ≥ 99.99% within 6 hours. A. pilosa Ledeb exhibited effective significant bactericidal activity within 4 hours against L. monocytogenes and E. coli. This paper highlights the potential of these plant extracts to control pathogens commonly found in the poultry gastrointestinal tract.

Adrenal Hormone and Metabolic Biomarker Responses to 30 min of Intermittent Cycling Exercise in Breast Cancer Survivors.

The aim of this study was to explore the effect of one bout of aerobic exercise on epinephrine, norepinephrine, cortisol, glucose, lactate, and free fatty acid (FFA) responses in breast cancer survivors and healthy controls. 9 female breast cancer survivors and 9 women without a history of cancer completed 30 min of cycle ergometry exercise at 60% of VO2peak. Blood samples were taken pre-exercise, immediately post-exercise, and 2 h post-exercise from which plasma concentrations of study variables were measured. Immediately and 2 h post-exercise, increases were observed in epinephrine (control group only) norepinephrine (both groups), lactate (both groups), and FFA (both groups immediately post-exercise; breast cancer survivor group only at 2 h post-exercise) (p<0.05). Cortisol decreased immediately and 2 h post-exercise in the control group while glucose decreased immediately post-exercise in the breast cancer survivor group (p<0.05). In conclusion, breast cancer survivors appeared to display attenuated epinephrine, cortisol, and lactate responses while displaying larger magnitude changes in glucose and FFA responses compared to controls. These preliminary findings may have implications for the regulation of metabolism during exercise in breast cancer survivors.

[Anticonvulsant add-on therapy with Eslicarbazepine acetate : Results of the EPOS-study in adults in Germany]. / Antikonvulsive Zusatztherapie mit Eslicarbazepinacetat : Ergebnisse der EPOS-Studie bei Erwachsenen in Deutschland.

BACKGROUND: Due to inadequate seizure control achieved with antiepileptic drug (AED) monotherapy and the considerable side effects at high required doses, patients with partial-onset seizures (POS) often require AED combination therapy. Eslicarbazepine acetate (ESL) is licensed as an add-on therapy for POS and has a favorable tolerability profile. OBJECTIVES: To investigate retention, utilization, reported efficacy, safety and tolerability as well as effects on health-related quality of life using ESL as an add-on treatment to an established monotherapy in a real-world adult population with POS in Germany. PATIENTS AND METHODS: A subgroup analysis was performed on the data derived from the German study sites that had participated in an international, non-interventional, open-label study conducted in eight European countries (eslicarbazepine acetate in partial-onset seizures, EPOS). Adult patients with POS whose physician had decided to prescribe add-on treatment with ESL to an established monotherapy were followed over a total period of approximately six months (three visits: baseline and after periods of approximately three and six months). Data collection included patient retention, reported efficacy, safety and tolerability as well as quality of life (QOLIE-10). RESULTS AND DISCUSSION: The subgroup analysis included 104 patients which had been enrolled at 38 German study sites. After 6 months, retention of ESL add-on therapy was 86.5 %, with 44.7 % of patients reporting seizure freedom over the 3 months prior to this visit. The overall tolerability of ESL add-on therapy was favorable: 32 adverse events (AE) were reported in 20 patients (19.2 %), while only two events in two patients were considered serious. No new safety signals were detected.

Real-world data on eslicarbazepine acetate as add-on to antiepileptic monotherapy.

OBJECTIVE: To assess retention, tolerability, and safety, efficacy and effects on quality of life (QoL) of eslicarbazepine acetate (ESL) add-on treatment over 6 months in a real-world adult population with partial-onset seizures. METHODS: This non-interventional, multicenter, prospective study was performed in eight European countries. Adult patients (n = 247) for whom the physician had decided to initiate ESL as add-on to an existing antiepileptic drug (AED) monotherapy were invited to participate. The study comprised three visits: baseline, and after 3 and 6 months. Data on ESL retention, efficacy, tolerability, safety, and QoL were collected. RESULTS: After 6 months, the retention rate of ESL was 82.2%, and 81.8% of patients reported a reduction of seizure frequency of at least 50%; 39.2% of patients reported seizure freedom at this time. The mean QOLIE-10 score improved from 2.9 (SD ± 0.8) at baseline to 2.1 (SD ± 0.8) after 6 months. 109 adverse events (AEs) were reported in 57 patients (26.0%); the majority were rated as related to ESL by the investigator and led to a discontinuation of ESL in 25 patients (11.4%). Eight patients (3.7%) suffered at least one serious AE. The most frequently reported AEs were dizziness, headache, convulsion, and fatigue. CONCLUSIONS: This study shows that ESL was well tolerated and efficacious as add-on therapy to one baseline AED. The use of ESL in patients less refractory than those included in previous clinical trials led to higher responder and seizure freedom rates. No new safety issues were observed.

Self-reported and accelerometer-measured physical activity by body mass index in US Hispanic/Latino adults: HCHS/SOL.

The association between obesity and physical activity has not been widely examined in an ethnically diverse sample of Hispanic/Latino adults in the US. A cross-sectional analysis of 16,094 Hispanic/Latino adults 18-74 years was conducted from the multi-site Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Body mass index (BMI) was measured and categorized into normal, overweight, and obese; underweight participants were excluded from analyses. Physical activity was measured using the 16-item Global Physical Activity Questionnaire and by an Actical accelerometer. Minutes/day of physical activity and prevalence of engaging in ≥ 150 moderate-vigorous physical activity (MVPA) minutes/week were estimated by BMI group and sex adjusting for covariates. No adjusted differences were observed in self-reported moderate (MPA), vigorous (VPA), or MVPA across BMI groups. Accelerometry-measured MPA, VPA, and MVPA were significantly higher for the normal weight (females: 18.9, 3.8, 22.6 min/day; males: 28.2, 6.1, 34.3 min/day, respectively) compared to the obese group (females: 15.3, 1.5, 16.8 min/day; males: 23.5, 3.6, 27.1 min/day, respectively). The prevalence of engaging in ≥ 150 MVPA minutes/week using accelerometers was lower compared to the self-reported measures. Efforts are needed to reach the Hispanic/Latino population to increase opportunities for an active lifestyle that could reduce obesity in this population at high risk for metabolic disorders.

The family partners for health study: a cluster randomized controlled trial for child and parent weight management.

OBJECTIVE: The purpose of this study was to test a two-phased nutrition and exercise education, coping skills training, and exercise intervention program for overweight or obese low-income ethnic minority 2nd to 4th grade children and their parents in rural North Carolina, USA. METHODS: A cluster randomized controlled trial was carried out with 358 children (7-10 years) and a parent for each child (n=358). General linear mixed models were used to determine the effects of the intervention on weight, adiposity, health behaviors, and eating and exercise self-efficacy by examining changes in children and parents from baseline to completion of the study (18 months). RESULTS: At 18 months, children in the experimental group did not have a significantly decreased body mass index (BMI) percentile (P=0.470); however, they showed a reduction in the growth rate of their triceps (P=0.001) and subscapular skinfolds (P<0.001) and an improvement in dietary knowledge (P=0.018) and drank less than one glass of soda per day (P=0.052) compared with the control group. Parents in the experimental group had decreased BMI (P=0.001), triceps (P<0.001) and subscapular skinfolds (P<0.001) and increased nutrition (P=0.003) and exercise (P<0.001) knowledge and more often drank water or unsweetened drinks (P=0.029). At 18 months, children in the experimental group did not show significant improvement in eating (P=0.956) or exercise self-efficacy (P=0.976). Experimental parents demonstrated improved socially acceptable eating self-efficacy (P=0.013); however, they did not show significant improvement in self-efficacy pertaining to emotional eating (P=0.155) and exercise (P=0.680). CONCLUSION: The results suggest that inclusion of children and parents in the same intervention program is an effective way to decrease adiposity and improve nutrition behaviors in both children and parents and improve weight and eating self-efficacy in parents.

Surface topography regulates wnt signaling through control of primary cilia structure in mesenchymal stem cells.

The primary cilium regulates cellular signalling including influencing wnt sensitivity by sequestering ß-catenin within the ciliary compartment. Topographic regulation of intracellular actin-myosin tension can control stem cell fate of which wnt is an important mediator. We hypothesized that topography influences mesenchymal stem cell (MSC) wnt signaling through the regulation of primary cilia structure and function. MSCs cultured on grooves expressed elongated primary cilia, through reduced actin organization. siRNA inhibition of anterograde intraflagellar transport (IFT88) reduced cilia length and increased active nuclear ß-catenin. Conversely, increased primary cilia assembly in MSCs cultured on the grooves was associated with decreased levels of nuclear active ß-catenin, axin-2 induction and proliferation, in response to wnt3a. This negative regulation, on grooved topography, was reversed by siRNA to IFT88. This indicates that subtle regulation of IFT and associated cilia structure, tunes the wnt response controlling stem cell differentiation.

Compensation or displacement of physical activity in middle-school girls: the Trial of Activity for Adolescent Girls.

OBJECTIVE: The 'activitystat' hypothesis suggests that increases in moderate-to-vigorous physical activity (MVPA) are accompanied by a compensatory reduction in light physical activity (LPA) and/or an increase in inactivity to maintain a consistent total physical activity level (TPA). The purpose of this study was to identify the evidence of compensation in middle-school girls. SUBJECTS: Participants were 6916, 8th grade girls from the Trial of Activity for Adolescent Girls (TAAG). DESIGN: Inactivity and physical activity were measured over 6- consecutive days using accelerometry (MTI Actigraph). A within-girl, repeated measures design was used to assess associations between physical activity and inactivity using general linear mixed models. RESULTS: Within a given day, for every one MET-minute more of inactivity, there was 3.18 MET-minutes (95% confidence interval (CI): -3.19, -3.17) less of TPA (activity >2 METS) on the same day. Daily inactivity was also negatively associated with TPA on the following day. Each additional minute of MVPA was associated with 1.85 min less of inactivity on the same day (95% CI: -1.89, -1.82). Daily MVPA was also negatively associated with inactivity the following day. CONCLUSION: Our results, based on 6 days of observational data, were not consistent with the 'activitystat' hypothesis, and instead indicated that physical activity displaced inactivity, at least in the short term. Longer intervention trials are needed, nevertheless our findings support the use of interventions to increase physical activity over discrete periods of time in middle-school girls.

Effects of chronic exposure to DDT and TCDD on disease activity in murine systemic lupus erythematosus.

Oestrogens contribute to the female preponderance of autoimmune diseases such as systemic lupus erythematosus (SLE). Environmental xenoestrogens superimposed upon endogenous pituitary-gonadal axis may affect the development of autoimmunity. This study examined the effects of chronic exposure to xenoestrogens -- o,p'-dichlorodiphenyltrichloroethane (DDT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on disease activity in the New Zealand Black/New Zealand White F1 hybrid (B/W) mouse model of SLE. Intact female mice had repeatedly received injections of DDT, TCDD or control vehicle since 6 weeks of age. Weight change, albuminuria, mortality, relevant immunological and histological parameters were assessed. DDT exposure markedly increased the incidence of albuminuria and reduced uterine weight but had no measured effects on immunity or mortality in this study. TCDD-exposed mice had significantly lower incidence of albuminuria, serum anti-DNA antibody and total IgG levels, and mortality compared to controls. Also, TCDD group had significantly lower thymic and splenic weights, decreased percentages of CD4(+)CD8(+) thymocytes and splenic CD4(+) T cells, increased percentage of splenic B220(+)sIgM(+) B cells and higher serum interferon gamma concentration. Taken together, DDT exposure appeared to accelerate the development of albuminuria in lupus-prone mice. TCDD was immunosuppressive to murine SLE. Xenoestrogens may have compound- and tissue-specific effects that require further elucidation in future work.

Rationale, design and methods of the HEALTHY study physical education intervention component.

The HEALTHY primary prevention trial was designed to reduce risk factors for type 2 diabetes in middle school students. Middle schools at seven centers across the United States participated in the 3-year study. Half of them were randomized to receive a multi-component intervention. The intervention integrated nutrition, physical education (PE) and behavior changes with a communications strategy of promotional and educational materials and activities. The PE intervention component was developed over a series of pilot studies to maximize student participation and the time (in minutes) spent in moderate-to-vigorous physical activity (MVPA), while meeting state-mandated PE guidelines. The goal of the PE intervention component was to achieve > or =150 min of MVPA in PE classes every 10 school days with the expectation that it would provide a direct effect on adiposity and insulin resistance, subsequently reducing the risk of type 2 diabetes in youth. The PE intervention component curriculum used standard lesson plans to provide a comprehensive approach to middle school PE. Equipment and PE teacher assistants were provided for each school. An expert in PE at each center trained the PE teachers and assistants, monitored delivery of the intervention and provided ongoing feedback and guidance.

Vigorous physical activity and cytokines in adolescents.

Habitual physical activity and chronic exercise may positively influence circulating cytokines in youth as in adults. The purpose of this study was to determine if adolescents reporting higher amounts of physical activity had a better cytokine profile independent of weight status. We compared the concentrations of cytokines in highly active (n = 60) and less active adolescents (n = 60) of different weight status [normal weight (BMI < 75th percentile), and overweight (BMI > 95th percentile)]. Vigorous physical activity (VPA) was obtained through a questionnaire and included activities with a MET level of > or =6. Adiponectin, resistin, TNF-alpha and IL-6 were measured in fasting plasma samples. Anovas indicated that girls with high VPA had higher adiponectin than girls with low VPA (P < 0.05), but similar resistin, TNF-alpha and IL-6 concentrations (P > 0.05). Boys with high VPA had only a trend to lower resistin than those with low VPA (P = 0.052). Differences between VPA groups were independent of weight status. In adolescents, higher amounts of accumulated habitual VPA may improve some cytokines, reducing the risk of inflammation associated with increased adiposity and insulin resistance. The effect of physical activity appears to be independent of weight status.

Body fat and circulating leukocytes in children.

OBJECTIVE: To determine the effects of obesity on baseline levels of circulating granulocytes, monocytes, and lymphocyte subtypes in otherwise healthy children. DESIGN: Two group comparison of leukocytes in normal weight control and overweight children. SUBJECTS: In total, 38 boys and girls, ages 6-18 years, divided in two groups: normal weight, (NW, BMI<85th %tile, n=15) and overweight (OW, body mass index (BMI)>85th %tile, n=23). MEASUREMENTS: BMI obtained from direct measures of height and body mass. Body fat was assessed by DEXA. Complete blood counts (CBC) were obtained by standard clinical hematology methods and surface antigen staining by flow cytometry. RESULTS: The OW group compared to the NW group had increased total leukocytes counts (P=0.011), neutrophils (P=0.006), monocytes (P=0.008), total T (CD3) lymphocytes (P=0.022), and Helper T (CD4(+)) cells (P=0.003). Significant correlations were evident between leukocytes, and BMI percentile, BMI, or percent body fat. Neither lean body mass nor VO(2peak) per unit lean body mass were significantly related to any of the leukocytes. Percent body fat and BMI percentile were positively correlated (P<0.05) to total T cells (CD3) and/or helper T cells (CD4(+)). CONCLUSION: A group of 23 overweight children displayed elevated counts in most types of circulating immune cells, suggesting the presence of low-grade systemic inflammation, a known pathogenetic mechanism underlying most long-term complications of obesity. Our data provide an additional rationale for the importance of avoiding or correcting pediatric obesity.

Raloxifene analog LY117018 enhances the regeneration of sciatic nerve in ovariectomized female mice.

The aim of this study was to examine the effects of LY117018, a selective estrogen receptor modulator, on peripheral nerve regeneration, using a model of sciatic nerve crush injury in mice. Sciatic functional index, an index of functional recovery, was significantly higher in LY117018 treated mice throughout regeneration. Analysis of semi-thin sections revealed a significant increase in both the total number of regenerating nerve fibers at day 7, and the mean axonal area of myelinated fibers at 7, 14, and 21 days after injury, in LY117018 treated mice. Analysis of axonal transport through retrograde labeling of motor neurons showed that LY117018 increased transport, and ICI 182,780 blocked the effects of LY117018, delineating estrogen receptors as its target. Our study suggests that LY117018 may markedly accelerate peripheral nerve regeneration and functional recovery through activation of estrogen receptors.

Estrogen and progesterone modulate monocyte cell cycle progression and apoptosis.

PROBLEM: Pregnancy is characterized by dramatic immunologic changes most commonly characterized as suppression of cell-mediated immunity. Mechanisms of this immunosuppression are obscure but may be caused by increases in pregnancy-associated sex steroids such as 17-beta-estradiol or progesterone. METHOD OF STUDY: Using five myelomonocytic cell lines in various stages of differentiation, the effects of 17-beta-estradiol and progesterone on cell cycling, apoptosis, and bcl-2 expression in randomly cycling cells before and after lipopolysaccharide (LPS) activation were examined. RESULTS: Lipopolysaccharide alone inhibited cell cycle progression in THP-1 monocyte-like cells and U-937 histiocyte-like cells. Estrogen alone produced cell cycle arrest in all myelomonocytic cells except HL-60 pro-myelocyte-like cells. Progesterone had effects predominantly on pro-myelocytic-like HL-60 cells, inducing apoptosis. Estrogen and progesterone both decreased levels of bcl-2 in KG-1alpha, HL-60, and THP-1 cells. LPS partially antagonized both estrogen-induced THP-1 apoptosis and its suppression of bcl-2 protein. CONCLUSIONS: Sex steroid-induced effects on cell cycle transition and apoptosis are potential mechanisms by which pregnancy-induced cell-mediated immune suppression may occur. Further investigation should provide a better understanding of pregnancy-induced immune changes and, perhaps, sex-based differences in monocyte function and immunologic responses.

Relationship between caloric intake, body composition, and physical activity to leptin, thyroid hormones, and cortisol in adolescents.

This study examined the interrelationships between (1) the hormones leptin, TSH, free T3, and cortisol, and (2) caloric intake, body composition, and physical activity to these select hormones in adolescent boys and girls (n = 125, age = 13.4 +/- 0.9 years). The data indicate that adolescent boys and girls have some common hormonal interrelationships. However, certain hormonal relationships are not in agreement with reports for adults, suggesting that researchers should not assume that all endocrine findings in adults are automatically applicable to adolescents.

Prolactin in murine systemic lupus erythematosus.

Murine systemic lupus erythematosus (SLE) manifests several autoimmune perturbations that resemble human SLE, including cytokine aberrations, lymphoproliferation, hypergammaglobulinemia, autoantibody formation, and immune complex glomerulonephritis. In multiple studies, elevated serum prolactin concentrations (hyperprolactinemia) stimulated appearance or progression of murine lupus. Autoimmune disease acceleration by prolactin appears to be accentuated by estrogen stimulation of prolactin secretion and independent of immunosuppressive effects of androgens such as testosterone. Conversely, suppression of serum prolactin concentrations by bromocriptine inhibits development of murine SLE. These data clearly support the concept that prolactin is immunostimulatory in autoimmune disease and that the therapeutic goal of lowering serum prolactin concentrations may be beneficial to patients. Further utilization of murine SLE models will facilitate dissection of the actions and interactions of prolactin with estrogen, progesterone and testosterone and lead to a better understanding of hormonal immunomodulation and therapy of autoimmune disease.

Sex hormones in the pathogenesis of systemic lupus erythematosus.

Sex hormones--estrogens, progestins, androgens, and prolactin--have well-documented effects on the development, progression, or severity of systemic lupus erythematosus (SLE). These effects are complex and are confounded by in vitro and in vivo considerations that obscure a simple explanation of the sexual dichotomies in SLE. An overview of available experimental and clinical data suggests that low androgens and abnormalities in the prolactin-gonadal axis are the most consistent hormonal aberrations found in human SLE. Additional studies focusing on interactions of gonadal steroids with prolactin and other pituitary hormones should expand our understanding of the role of sex hormones in the pathogenesis of SLE and strengthen the potential of hormonal immunotherapy.

Differential effects of sex steroids on T and B cells: modulation of cell cycle phase distribution, apoptosis and bcl-2 protein levels.

Sex steroids have dramatic and differential effects on classic endocrine organ proliferation and apoptosis. In this investigation we sought to delineate similar effects of sex steroids on proliferation, cell cycle phase and apoptosis in lymphocyte cell lines as models for T and B cells. Estrogen and testosterone inhibited T cell line proliferation, induced accumulation of cells in S/G(2)M phases of the cell cycle, and increased apoptosis in a concentration- and time-dependent manner. There was a more modest effect of estrogen and testosterone on cell cycling and apoptosis in B lymphocyte cell lines, suggesting that estrogen and testosterone are inhibitory to T but not B cell lines. In comparison, progesterone induced cytostasis and modestly increased apoptosis in both T and B cell lines. Estrogen and testosterone were not antagonistic or synergistic to each other in their effects on cell cycle phase distribution, and only minimally synergistic for apoptosis. In contrast, progesterone antagonized cell cycle and apoptotic effects of estrogen in T cells. Estrogen-induced cell cycle and apoptotic effects in T cell lines were associated with suppression of bcl-2 protein levels, which were unaffected in Raji B cells. Progesterone also antagonized the estrogen-induced changes in T cell bcl-2 protein levels. These results suggest that there may be significant and differential sex steroid effects on T and B lymphocytes that may be important to sexual dichotomies in immune and autoimmune responses.