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Maternal behaviours disrupted by Gprasp2 deletion modulate neurodevelopmental trajectory in progeny.Scientific Reports May 2024Autism spectrum disorders (ASDs) are known to present sex-specific differences. At the same time, understanding how maternal behaviours are affected by pathogenic...
Autism spectrum disorders (ASDs) are known to present sex-specific differences. At the same time, understanding how maternal behaviours are affected by pathogenic mutations is crucial to translate research efforts since rearing may recursively modulate neurodevelopment phenotype of the progeny. In this work, we focused on the effects of Gprasp2 deletion in females and its impact in progeny care and development. Female mice, wild-type (WT), Gprasp2 (HET) or Gprasp2 (KO) mutants and their progeny were used and behavioural paradigms targeting anxiety, memory, maternal care, and other social behaviours were performed. Analysis of communication was carried out through daily recordings of ultrasonic vocalizations in isolated pups and cross-fostering experiments were performed to understand the effect of maternal genotype in pup development. We found that Gprasp2 females presented striking impairments in social and working memory. Females also showed disruptions in maternal care, as well as physiological and molecular alterations in the reproductive system and hypothalamus, such as the structure of the mammary gland and the expression levels of oxytocin receptor (OxtR) in nulliparous versus primiparous females. We observed alterations in pup communication, particularly a reduced number of calls in Gprasp2 KO pups, which resulted from an interaction effect of the dam and pup genotype. Cross-fostering mutant pups with wild-type dams rescued some of the early defects shown in vocalizations, however, this effect was not bidirectional, as rearing WT pups with Gprasp2 dams was not sufficient to induce significant phenotypical alterations. Our results suggest Gprasp2 mutations perturb social and working memory in a sex-independent manner, but impact female-specific behaviours towards progeny care, female physiology, and gene expression. These changes in mutant dams contribute to a disruption in early stages of progeny development. More generally, our results highlight the need to better understand GxE interactions in the context of ASDs, when female behaviour may present a contributing factor in postnatal neurodevelopmental trajectory.
Topics: Animals; Maternal Behavior; Female; Mice; Mice, Knockout; Social Behavior; Male; Receptors, G-Protein-Coupled; Behavior, Animal; Receptors, Oxytocin; Autism Spectrum Disorder; Vocalization, Animal; Gene Deletion
PubMed: 38816497
DOI: 10.1038/s41598-024-62088-x -
Frontiers in Endocrinology 2024Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by... (Review)
Review
Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in , resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the ; copy number variants in , , , , , and , and sequence variants in , , , , , , and . Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.
Topics: Humans; Adrenal Hyperplasia, Congenital; 46, XX Disorders of Sex Development; Female; Male; Disorders of Sex Development
PubMed: 38812815
DOI: 10.3389/fendo.2024.1354759 -
The Journal of Nutrition, Health & Aging Jun 2024Liver cancer is the world's sixth most prevalent cancer and the third most frequent cause of cancer-related mortality. Glucose metabolic disorders, indicated by a high...
OBJECTIVE
Liver cancer is the world's sixth most prevalent cancer and the third most frequent cause of cancer-related mortality. Glucose metabolic disorders, indicated by a high fasting plasma glucose (HFPG) concentration, is a contributor to the etiology of liver cancer. With the rising prevalence of glucose metabolic disorders, an assessment of the global burden of liver cancer attributable to HFPG is warranted to inform global liver cancer prevention and control strategies.
METHODS AND ANALYSIS
We evaluated the global death and disability-adjusted life years (DALYs) of liver cancer and its subtypes attributable to HFPG at global, regional, and country level. The temporal trend and disparity across geographic regions, social development level, age groups and sex were assessed.
RESULTS
In 2019, HFPG-attributable liver cancer was estimated to have caused 4,729.49 deaths and to be responsible for 99,302.25 DALYs. The age-standardized mortality and DALY rate were 0.06 and 1.20 per 100,000 population, and displayed a significantly increasing temporal trend from 1990 to 2019. The age-standardized mortality rate of patients with liver cancer that was attributable to HFPG was higher in men than women. Sex-based disparity narrowed after the women reached menopause, but increased between 1990 and 2019.
CONCLUSION
The burden of liver cancer that are attributable to HFPG has been influenced by longitudinal changes in lifestyle, the etiology of liver disease, age demographics, and hormonal status in women. These findings suggest that comprehensive strategies could be implemented, especially for patients with NASH and hyperglycemia, to prevent liver cancer.
Topics: Humans; Liver Neoplasms; Male; Female; Global Burden of Disease; Blood Glucose; Middle Aged; Aged; Fasting; Global Health; Disability-Adjusted Life Years; Adult; Aged, 80 and over; Prevalence
PubMed: 38810511
DOI: 10.1016/j.jnha.2024.100261 -
JAMA Network Open May 2024Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years.
OBJECTIVES
To assess the feasibility and tolerability of maternal progesterone therapy as well as the magnitude of the effect on neurodevelopment for fetuses with CHD.
DESIGN, SETTING, AND PARTICIPANTS
This double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD was conducted between July 2014 and November 2021 at a quaternary care children's hospital. Participants included maternal-fetal dyads where the fetus had CHD identified before 28 weeks' gestational age and was likely to need surgery with cardiopulmonary bypass in the neonatal period. Exclusion criteria included a major genetic or extracardiac anomaly other than 22q11 deletion syndrome and known contraindication to progesterone. Statistical analysis was performed June 2022 to April 2024.
INTERVENTION
Participants were 1:1 block-randomized to vaginal progesterone or placebo by diagnosis: hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and other CHD diagnoses. Treatment was administered twice daily between 28 and up to 39 weeks' gestational age.
MAIN OUTCOMES AND MEASURES
The primary outcome was the motor score of the Bayley Scales of Infant and Toddler Development-III; secondary outcomes included language and cognitive scales. Exploratory prespecified subgroups included cardiac diagnosis, fetal sex, genetic profile, and maternal fetal environment.
RESULTS
The 102 enrolled fetuses primarily had HLHS (n = 52 [50.9%]) and TGA (n = 38 [37.3%]), were more frequently male (n = 67 [65.7%]), and without genetic anomalies (n = 61 [59.8%]). The mean motor score differed by 2.5 units (90% CI, -1.9 to 6.9 units; P = .34) for progesterone compared with placebo, a value not statistically different from 0. Exploratory subgroup analyses suggested treatment heterogeneity for the motor score for cardiac diagnosis (P for interaction = .03) and fetal sex (P for interaction = .04), but not genetic profile (P for interaction = .16) or maternal-fetal environment (P for interaction = .70).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of maternal progesterone therapy, the overall effect was not statistically different from 0. Subgroup analyses suggest heterogeneity of the response to progesterone among CHD diagnosis and fetal sex.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02133573.
Topics: Humans; Progesterone; Female; Heart Defects, Congenital; Male; Pregnancy; Double-Blind Method; Infant; Adult; Infant, Newborn; Child Development; Progestins; Neurodevelopmental Disorders
PubMed: 38805228
DOI: 10.1001/jamanetworkopen.2024.12291 -
Scientific Reports May 2024Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and...
Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and infertility. Early hormonal intervention is preventive, but excessive glucocorticoid poses risks. Developing reliable methods for early TART diagnosis and monitoring is crucial. The present study aims to formulate a scoring system to identify high-risk infertility through analysis of TART ultrasound features. Grayscale and power Doppler ultrasound were employed in this retrospective study to evaluate testicular lesions in male CAH patients. Lesion assessment encompassed parameters such as range, echogenicity, and blood flow, and these were subsequently correlated with semen parameters. Results of 49 semen analyzes from 35 patients demonstrated a notable inverse correlation between lesion scores and both sperm concentration (r = - 0.83, P < 0.001) and progressive motility (r = - 0.56, P < 0.001). The ROC curve areas for evaluating oligospermia and asthenozoospermia were calculated as 0.94 and 0.72, respectively. Establishing a lesion score threshold of 6 revealed a sensitivity of 75.00% and specificity of 93.94% for oligospermia and a sensitivity of 53.85% and specificity of 100.00% for asthenozoospermia. These findings underscore the potential utility of incorporating ultrasound into routine CAH patient management, facilitating timely interventions to preserve male fertility.
Topics: Humans; Male; Adrenal Hyperplasia, Congenital; Adult; Retrospective Studies; Infertility, Male; Ultrasonography; Risk Assessment; Semen Analysis; Testis; Young Adult; Adrenal Rest Tumor
PubMed: 38802468
DOI: 10.1038/s41598-024-62954-8 -
Andes Pediatrica : Revista Chilena de... Apr 2024Growth hormone (GH) is effective in improving height in several conditions.
UNLABELLED
Growth hormone (GH) is effective in improving height in several conditions.
OBJECTIVE
To describe the evolution of a group of children who received GH in a tertiary center between 2012-2022.
PATIENTS AND METHOD
Descriptive, retrospective study. We analyzed the impact on height after GH use with Z-score according to etiology, age at onset and bone age. Patients under 15 years old at baseline and receiving GH for at least 12 months, with diagnoses of GH deficiency (GHD), idiopathic short stature (ISS), small for gestational age (SGA), SHOX Haploinsufficiency (SHOX) and Turner syndrome (TS) were included. Height was expressed as Z-score for age and sex, according to NCHS curves.
RESULTS
145 children received GH. Sixty patients were excluded due to irregular administration, incomplete data, less than 12 months of GH, change of hospital, and associated comorbidities. Seventy-three patients were analyzed, 23 GHD, 15 ISS, 20 SGA, 9 SHOX and 6 TS patients. Significant improvement in height (Z-score for age and sex) was observed in SGA (1.4 ± 0.8 gain; p < 0.001), GHD (1.1 ± 1.0; p < 0.001), ISS (1.1 ± 0.8; p < 0.001) and SHOX (0.8 ± 0.7; p = 0.007) patients. In TS, a non-statistically significant improvement was observed (0.7 ± 0.8; p = 0.085). In GHD, onset before 3 years showed a gain of 1.9 ± 1.1, vs 0.7 ± 0.6 (p = 0.083) and in ISS onset with bone age less than 9 years increased it by 1.7 ± 0.5 vs 0.5 ± 0.5 (p < 0.001).
ADVERSE EVENTS
27/73 (37%) headache, 18/73 (24%) lower extremity pain, 1/73 (1.5%) dizziness, 1/73 (1.5%) scoliosis, 1/73 (1.5%) epiphysiolysis and 1/73 (1.5%) craniopharyngioma recurrence.
CONCLUSIONS
Children with GHD, ISS, SHOX mutation and SGA significantly improved their height, highlighting in GHD and ISS the importance of early treatment. Treatment was well tolerated in the 5 groups analyzed.
Topics: Humans; Short Stature Homeobox Protein; Turner Syndrome; Female; Retrospective Studies; Male; Child; Human Growth Hormone; Infant, Small for Gestational Age; Body Height; Growth Disorders; Child, Preschool; Adolescent; Mutation; Treatment Outcome; Infant; Haploinsufficiency
PubMed: 38801362
DOI: 10.32641/andespediatr.v95i2.4941 -
International Journal of Qualitative... Dec 2024This paper examines the subjective experience of medical interventions on intersex bodies to reduce cancer risk.
PURPOSE
This paper examines the subjective experience of medical interventions on intersex bodies to reduce cancer risk.
METHODS
Twenty-five individuals with intersex variations took part in semi-structured interviews, analysed through thematic discourse analysis.
RESULTS
Intersex bodies were positioned as inherently sick and in need of modification, with cancer risk legitimating surgical and hormonal intervention. This resulted in embodied shame, with negative impacts on fertility and sexual wellbeing. However, many participants resisted discourses of bio-pathologisation and embraced intersex status. Some medical interventions, such as HRT, were perceived to have increased the risk of cancer. Absence of informed consent, and lack of information about intersex status and the consequences of medical intervention, was positioned as a human rights violation. This was compounded by ongoing medical mismanagement, including health care professional lack of understanding of intersex variations, and the objectification or stigmatization of intersex people within healthcare. The consequence was non-disclosure of intersex status in health contexts and lack of trust in health care professionals.
CONCLUSIONS
The legitimacy of poorly-evidenced cancer risk discourses to justify medical intervention on intersex bodies needs to be challenged. Healthcare practitioners need to be provided with education and training about cultural safety practices for working with intersex people.
Topics: Humans; Male; Female; Neoplasms; Adult; Middle Aged; Disorders of Sex Development; Fear; Qualitative Research; Young Adult; Shame
PubMed: 38796859
DOI: 10.1080/17482631.2024.2356924 -
Journal of Neurodevelopmental Disorders May 2024Synthetic oxytocin (sOT) is frequently administered during parturition. Studies have raised concerns that fetal exposure to sOT may be associated with altered brain...
BACKGROUND
Synthetic oxytocin (sOT) is frequently administered during parturition. Studies have raised concerns that fetal exposure to sOT may be associated with altered brain development and risk of neurodevelopmental disorders. In a large and diverse sample of children with data about intrapartum sOT exposure and subsequent diagnoses of two prevalent neurodevelopmental disorders, i.e., attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), we tested the following hypotheses: (1) Intrapartum sOT exposure is associated with increased odds of child ADHD or ASD; (2) associations differ across sex; (3) associations between intrapartum sOT exposure and ADHD or ASD are accentuated in offspring of mothers with pre-pregnancy obesity.
METHODS
The study sample comprised 12,503 participants from 44 cohort sites included in the Environmental Influences on Child Health Outcomes (ECHO) consortium. Mixed-effects logistic regression analyses were used to estimate the association between intrapartum sOT exposure and offspring ADHD or ASD (in separate models). Maternal obesity (pre-pregnancy BMI ≥ 30 kg/m) and child sex were evaluated for effect modification.
RESULTS
Intrapartum sOT exposure was present in 48% of participants. sOT exposure was not associated with increased odds of ASD (adjusted odds ratio [aOR] 0.86; 95% confidence interval [CI], 0.71-1.03) or ADHD (aOR 0.89; 95% CI, 0.76-1.04). Associations did not differ by child sex. Among mothers with pre-pregnancy obesity, sOT exposure was associated with lower odds of offspring ADHD (aOR 0.72; 95% CI, 0.55-0.96). No association was found among mothers without obesity (aOR 0.97; 95% CI, 0.80-1.18).
CONCLUSIONS
In a large, diverse sample, we found no evidence of an association between intrapartum exposure to sOT and odds of ADHD or ASD in either male or female offspring. Contrary to our hypothesis, among mothers with pre-pregnancy obesity, sOT exposure was associated with lower odds of child ADHD diagnosis.
Topics: Humans; Female; Pregnancy; Oxytocin; Male; Attention Deficit Disorder with Hyperactivity; Child; Body Mass Index; Autism Spectrum Disorder; Prenatal Exposure Delayed Effects; Adult; Obesity, Maternal; Child, Preschool; Cohort Studies; Obesity
PubMed: 38796448
DOI: 10.1186/s11689-024-09540-1 -
Journal of Clinical Medicine May 2024In recent times, epigenetics alterations in Hidradenitis suppurativa (HS) have been explored and exploited translationally to guide investigation of new therapeutic...
In recent times, epigenetics alterations in Hidradenitis suppurativa (HS) have been explored and exploited translationally to guide investigation of new therapeutic approaches. On the other hand, long noncoding RNAs (LncRNAs), main regulators of the epigenetic status of the human genome, have been scarcely investigated, notwithstanding their potential relevance in broad pathogenesis comprehension. Here, we aim to explore the methylation pattern of lncRNAs in HS. : In this case-control study, 24 HS patients and age-, sex- and BMI-matched controls were analyzed to characterize the methylome of lncRNA genes in peripheral blood cells. Gene ontology analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network, and MCODE analysis were performed. : A set of fifteen lncRNA genes exhibited significantly differential methylation patterns, with ten of them showing hypomethylation and five displaying hypermethylation at specific CpG sites. The hypomethylated lncRNA genes were , , , , , , , , , and , while the hypermethylated ones were , , , , and These lncRNA genes have been linked to various important biological processes, including cell proliferation, apoptosis, inflammation, chronic inflammatory skin diseases, and wound healing. Their altered methylation status suggests potential roles in regulating these processes, and may contribute to HS pathogenesis and healing mechanisms. : This study revealed an interesting dysregulation pattern of definite lncRNAs in the methylome which is linked to both the development of HS and its comorbidities. Epigenetically altered lncRNAs genes could represent useful biomarkers, and could help in guiding innovative treatment strategies.
PubMed: 38792557
DOI: 10.3390/jcm13103016 -
Journal of Clinical Medicine May 2024Chronic pain is a common symptom in various types of neuromuscular disorders. However, for patients with spinal muscular atrophy (SMA), the literature regarding chronic...
Chronic pain is a common symptom in various types of neuromuscular disorders. However, for patients with spinal muscular atrophy (SMA), the literature regarding chronic pain is scarce. Thus, this study assessed the prevalence of chronic pain in children, adolescents, and adults with SMA and investigated the influence of clinical characteristics on chronic pain. This study used data from 141 patients, which were collected by the Swiss Registry for Neuromuscular Disorders. Extracted data included information on pain (present yes/no, pain location, and pain medication) and clinical characteristics, such as SMA type, motor function, wheelchair use, scoliosis, and contractures. The analyses revealed that the highest prevalence of chronic pain was observed in adolescents with 62%, followed by adults with 48%, children (6-12 years) with 39%, and children < 6 years with 10%. The legs, back, and hips were most frequently reported as pain locations. Sex (females), age (adolescents), and the presence of contractures and scoliosis (with surgery) were factors that were associated with chronic pain. These findings contribute to a better understanding of pain in SMA, shedding light on its prevalence and characteristics in different age groups, which underscores the importance of assessing and managing pain in patients with SMA.
PubMed: 38792340
DOI: 10.3390/jcm13102798