Sex-Dependent Effects of 7,8-Dihydroxyflavone on Metabolic Health Are Associated with Alterations in the Host Gut Microbiome

7,8-Dihydroxyflavone (DHF) is a naturally occurring flavonoid that has been reported to protect against a variety of pathologies. Chronic administration of DHF prevents high-fat diet (HFD)-induced obesity in female, but not male, mice. However, the mechanisms underlying this sexual dimorphism have not been elucidated. We have discovered that oral DHF supplementation significantly attenuates fat mass, hepatic lipid accumulation, and adipose tissue inflammation in female mice. In contrast, male mice were not protected from adiposity, and had a paradoxical worsening of hepatic lipid accumulation and adipose tissue inflammation upon DHF supplementation. Consistent with these sexually dimorphic effects on body weight and metabolic health, 7,8-DHF induced early and stable remodeling of the female intestinal microbiome. DHF supplementation significantly increased gut microbial diversity, and suppressed potentially detrimental bacteria, particularly Desulfovibrionaceae, which are pro-inflammatory and positively associated with obesity and inflammation. Changes in the female gut microbiome preceded alterations in body weights, and in silico analyses indicated that these early microbial changes were highly predictive of subsequent weight gain in female mice. While some alterations in the intestinal microbiome were also observed in male DHF-supplemented mice, these changes were distinct from those in females and, importantly, were not predictive of subsequent body weight changes in male animals. The temporality of microbial changes preceding alterations in body weight in female mice suggests a role for the gut microbiome in mediating the sexually dimorphic effects of DHF on body weight. Given the significant clinical interest in this flavonoid across a wide range of pathologies, further elucidation of these sexually dimorphic effects will aid the development of effective clinical therapies.     

Reporting and Analyzing Demographics in the Journal of Arthroplasty: Are We Making Progress?

BackgroundDemographic factors, including age, sex, body mass index (BMI), race, and ethnicity have great effects on the outcomes of patients undergoing total joint arthroplasty. A portion of this data is included in nearly every study, but the completeness with which it is reported is variable. The purpose of this study is to investigate the frequency at which demographic information is reported and analyzed through formal statistical methods in randomized controlled trials (RCTs) published in the Journal of Arthroplasty (JOA).MethodsA systematic review was conducted of RCTs published in JOA between 2015 and 2019. For each study, we determined if age, sex, weight, height, BMI, race, and ethnicity were reported and/or analyzed. The overall frequency was assessed, along with the rates of reporting by individual year. Studies were evaluated using Cochrane risk-of-bias tool.ResultsAge (96.7%), sex (96.7%), and BMI (80.4%) were reported by the majority of studies. There was very little information provided regarding race (6.2%) and ethnicity (3.8%); although both were reported at the highest frequency in 2019, the final year of articles reviewed. Sex was the most frequently analyzed variable at 11.5%. Only 1 study (0.5%) analyzed ethnicity and no studies analyzed race.ConclusionAlthough age, sex, and BMI are reported at a high rate, RCTs published in JOA rarely reported information on patient race and ethnicity. Demographics were infrequently included as part of statistical analysis. The importance of this information should be recognized and included in the analysis and interpretation of future studies.     

Ten‐year attrition and antiretroviral therapy response among HIV‐positive adults: a sex‐based cohort analysis from eight West African countries

IntroductionSex differences have already been reported in sub‐Saharan Africa for attrition and immunological response after antiretroviral therapy (ART) initiation, but follow‐up was usually limited to the first two to three years after ART initiation. We evaluated sex differences on the same outcomes in the 10 years following ART initiation in West African adults.MethodsWe used cohort data of patients included in the IeDEA West Africa collaboration, who initiated ART between 2002 and 2014. We modelled no‐follow‐up and 10‐year attrition risks, and immunological response by sex using logistic regression analysis, survival analysis with random effect and linear mixed models respectively.ResultsA total of 71,283 patients (65.8% women) contributed to 310,007 person‐years of follow‐up in 16 clinics in eight West African countries. The cumulative attrition incidence at 10‐year after ART initiation reached 75% and 68% for men and women respectively. Being male was associated with an increased risk of no follow‐up after starting ART (5.1% vs. 4.0%, adjusted Odds Ratio: 1.25 [95% CI: 1.15 to 1.35]) and of 10‐year attrition throughout the 10‐year period following ART initiation: adjusted Hazard Ratios were 1.22 [95% CI: 1.17 to 1.27], 1.08 [95% CI: 1.04 to 1.12] and 1.04 [95% CI: 1.01 to 1.08] during year 1, years 2 to 4 and 5 to 10 respectively. A better immunological response was achieved by women than men: monthly CD4 gain was 30.2 and 28.3 cells/mL in the first four months and 2.6 and 1.9 cells/μL thereafter. Ultimately, women reached the average threshold of 500 CD4 cells/μL in their sixth year of follow‐up, whereas men failed to reach it even at the end of the 10‐year follow‐up period. The proportion of patients reaching the threshold was much higher in women than in men after 10 years since ART initiation (65% vs. 44%).ConclusionsIn West Africa, attrition is unacceptably high in both sexes. Men are more vulnerable than women on both attrition and immunological response to ART in the 10 years following ART initiation. Innovative tracing strategies that are sex‐adapted are needed for patients in care to monitor attrition, detect early high‐risk groups so that they can stay in care with a durably controlled infection.     

Endogenous estrogen status, but not genistein supplementation, modulates 7,12-dimethylbenz[a]anthracene-induced mutation in the liver cII gene of transgenic big blue rats

A growing number of studies suggest that isoflavones found in soybeans have estrogenic activity and may safely alleviate the symptoms of menopause. One of these isoflavones, genistein, is commonly used by postmenopausal women as an alternative to hormone replacement therapy. Although sex hormones have been implicated as an important risk factor for the development of hepatocellular carcinoma, there are limited data on the potential effects of the estrogens, including phytoestrogens, on chemical mutagenesis in liver. Because of the association between mutation induction and the carcinogenesis process, we investigated whether endogenous estrogen and supplemental genistein affect 7,12-dimethylbenz[a]anthracene (DMBA)-induced mutagenesis in rat liver. Intact and ovariectomized female Big Blue rats were treated with 80 mg DMBA/kg body weight. Some of the rats also received a supplement of 1,000 ppm genistein. Sixteen weeks after the carcinogen treatment, the rats were sacrificed, their livers were removed, and mutant frequencies (MFs) and types of mutations were determined in the liver cII gene. DMBA significantly increased the MFs in liver for both the intact and ovariectomized rats. While there was no significant difference in MF between the ovariectomized and intact control animals, the mutation induction by DMBA in the ovariectomized groups was significantly higher than that in the intact groups. Dietary genistein did not alter these responses. Molecular analysis of the mutants showed that DMBA induced chemical-specific types of mutations in the liver cII gene. These results suggest that endogenous ovarian hormones have an inhibitory effect on liver mutagenesis by DMBA, whereas dietary genistein does not modulate spontaneous or DMBA-induced mutagenesis in either intact or ovariectomized rats.     

Social/sexual awareness of persons with autism: A parental perspective

A parental survey that addressed the social sexual awareness, sex education, and sex behaviors of persons with autism, a developmental disability is provided. Questionnaires from 100 caregivers of persons with autism 9 years of age and older and with the DSM-III-R diagnosis were analyzed. Eighty-five percent of respondents were mothers, 8% both parents, 5% fathers, and 2% others; 32% of the persons with autism were female and 68% male with an age range of 9.1 to 38.9 years. The verbal level of the person with autism related to parents' beliefs about the relevance of sex relations (² = 6.99, p < 0.05) and sex education (² = 22.91, p < 0.001). No relationship between parents' report of the verbal level of the individual and the display of inappropriate sexual behaviors was found (² = 2.56, ns). Parents of males were more concerned about their son being taken advantage of by a same-sex person (² = 15.90, p < 0.001); parents of females were worried about an opposite-sex person (² = 4.06, p < 0.05). Parental concerns and beliefs regarding sexuality varied and could not be generalized. The nonsignificant finding regarding verbal level and display of inappropriate sexual behaviors suggests that the need for sex education is best determined by the behaviors of the person rather than the functioning or verbal levels.     

Etiology of individual differences in reading performance: A test of sex limitation

To test the hypothesis that the etiology of individual differences in reading performance differs in males and females, reading performance data from twin pairs tested in the Colorado Learning Disabilities Research Center were fitted to structural equation models of sex limitation. The sample included 513 pairs of twins in which at least one member of each pair has a positive school history of reading problems [228 monozygotic (MZ), 176 same-sex dizygotic (DZ), and 109 opposite-sex DZ pairs] and 302 matched control pairs [148 MZ, 98 same-sex DZ, and 56 opposite-sex DZ pairs]. Estimates of the genetic correlation between performance in males and females were obtained by analysis of data from both same-sex and opposite-sex twin pairs (Neale and Cardon, 1992). The full model fit the data well ²=17,74, df=16,p=0.340), and the resulting genetic parameter estimates were highly similar in males and females in both the proband and the control samples. The correlations between genetic influences in males and females do not differ among groups (change in ²=0.95, df=1,p0.25), and the resulting pooled estimate is about .5. Thus, results of this analysis suggest that the etiology of individual differences in reading performance may differ to some extent in males and females.     

Homosexuality,type 1: An Xq28 phenomenon

Despite the absence of phenotypic manifestations in alternating generations characteristic of X-linked disorders, a thesis is presented that a major type of Kinsey grades 5 and 6 male homosexuality is determined by a gene in the Xq28 region. A total of 133 families in 78 kinships of male and female homosexual probands, in addition to 116 families (including those of 40 famous homosexuals) from the literature, revealed an unbalanced secondary sex ratio in the maternal generation of male, but not of female, homosexuals. On the maternal side, in this study, the ratio of all uncles to all aunts of 90 males homosexuals was 132/209, ² = 8.52, p = 0.004. On the maternal side for the total of all sources, the ratio of uncles to aunts of male homosexuals was 241/367, ² = 13.20; p < 0.0001. The male/female ratio of the total number of maternal sibships bearing homosexuals (310/628: 0.491) was a measure of fetal wastage of the mothers' male sibs: 49%. This ratio was very close to that of the total number of children born to fathers affected with any one of nine Xq28-linked male semilethal conditions (255/508: ratio 0.556); for the difference between the two populations ² = 0.859, p = 0.354. The male/female ratio of the total number of children born to female carriers of any one of these same conditions (1,232/1,062: ratio 1.16), ² = 13.8 p 0.0001, is close to that of the total number of children in homosexual sibships: 511/413, ² = 10.4, p = 0.005. Between the number of children born to Xq28 mothers and to those born of mothers of homosexuals ² = 0.581, p = 0.446. One may readily surmise that the maternal influence so often related to homosexuality may lie in the mother being a genetic carrier, with traits thereto associated. In this study, 65% of the mothers of homosexuals had no or only one live-born brother. Additional support for a genetic hypothesis is found in the occurrence of multiple instances—almost exclusively among maternal relatives—of infertility, spontaneous abortions, miscarriages, stillbirths, remaining single past age 30, and suicide. Of 109 male and 43 female homosexual index cases in the present series there were 6 instances of brother/sister homosexual sibships. Instances of homosexual parent-to-homosexual child transmission occurred as follows: one father-to-son; one father-to-daughter; one bisexual father-son; one father/mother-to-2 sons; one of mother-to-son, and one of father-to-son and father-to-bisexual daughter. There were 16 instances of presumptive transmissions from heterosexual father-to-homosexual son and 5 of heterosexual father-to-homosexual daughter. A hypothesis is proposed: Homosexuality is due to a gene at Xq28 characterized by (i) elongated cytosine-containing trinucleotide repeats upstream to translation of a gene, (ii) elongated CpG islands upstream of the trinucleotides, and (iii) cytosine methylation of CpG islands and of the cytosine-containing trinucleotides.A limited number of long tables of data, and pedigree charts, which provide the details from which this paper was developed, may be obtained on paper or on disc from the author or, for a modest fee, from the Librarian, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York 11794.     

Dexamethasone effects on cerebral protein synthesis prior to and following hypoxia-ischemia in immature rat

We hypothesized that the neuroprotection against cerebral hypoxic-ischemic damage observed with dexamethasone treatment in immature rats is related to a change in cerebral protein synthesis. Six-day-old Wistar rats were injected with either vehicle (10 ml/kg) or dexamethasone (0.1 mg/kg) 24 h prior to cerebral hypoxia-ischemia. Local cerebral protein synthesis (incorporation of 14C-leucine into proteins) was measured in 7-day-old rats during normoxia, during hypoxia-ischemia, and after hypoxia-ischemia which was produced with right carotid artery ligation and 2-h exposure to 8% O2. In normoxic controls, cerebral protein synthesis was similar in dexamethasone and vehicle-treated animals. During hypoxia-ischemia, local cerebral protein synthesis decreased markedly (p < 0.0001) in ischemic regions ipsilateral to the occlusion, irrespective of treatment. After hypoxia-ischemia, protein synthesis declined even further in vehicle-treated animals. Reductions in protein synthesis were substantially more severe in vehicle- than dexamethasone-treated animals, particularly after hypoxia-ischemia (p < 0.0001). Thus, neuroprotection with dexamethasone is not related to a reduction in basal levels of cerebral protein synthesis, but is associated with an improved protein synthesis during and following hypoxia-ischemia.     

Sexually dimorphic expression of sst1 and sst2 somatostatin receptor subtypes in the arcuate nucleus and anterior pituitary of adult rats

The pattern of growth hormone (GH) secretion and rate of somatic growth are markedly sexually dimorphic, but the underlying neuroendocrine mechanisms are far from clear. In the present study, we tested the hypothesis that the sexual dimorphism of GH secretion may be due to gender-related differences in the transduction of somatostatin's actions in brain and/or pituitary. To accomplish this, we compared the distributional pattern and level of expression of two somatostatin receptor subtypes, sst1 and sst2, in the brain and pituitary of adult male and female rats by in-situ hybridization using 35S-labelled antisense riboprobes. In the brain, the hybridization pattern and labelling density of sst1 and sst2 mRNA-expressing cells, as revealed by computer-assisted image analysis, in areas including the cerebral cortex, medial habenula (MHb) and ventromedial hypothalamic nucleus (VMN), were similar in male and female rats. In contrast, there was a marked sex-related difference in sst1 expression in the arcuate nucleus of the hypothalamus; both the number and labelling density of sst1 mRNA-expressing cells were two- to threefold greater in males than in females and this significant increase was homogenous throughout the rostrocaudal extent of the nucleus. No gender-related differences in arcuate sst2 mRNA levels were found. At the level of the anterior pituitary, the labelling density of sst2 mRNA in males was significantly higher than that of females. No sex-related difference in pituitary sst1 mRNA was observed. These results demonstrate a sexual dimorphism in the expression of two somatostatin receptor subtypes, sst1 and sst2, at the level of the arcuate nucleus and anterior pituitary, respectively. Such dimorphism suggests a differential involvement of sst1 and sst2 in GH regulation with respect to gender, and may imply roles for sst2 and sst1 in transducing somatostatin's actions on pituitary somatotrophs and GH-releasing hormone-containing arcuate neurones, respectively, to generate the lower basal and higher GH pulse levels characteristic of the male rat.