STRUCTURED ABSTRACT Importance The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQoL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the <15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry. Objectives Determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); describe military service metrics of men with SCAs; compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis to matched controls. Design Cross-sectional, case-control Setting United States Veterans Administration Healthcare System Participants Biologic males enrolled in the MVP biobank with genomic identification of an additional X or Y chromosome (cases); controls matched 1:5 on sex, age, and genetic ancestry Main Outcome(s) and Measure(s) Prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index (CCI); rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; standardized mortality ratio (SMR) Results An additional X or Y chromosome was present in 145 and 125 per 100,000 males in the MVP, respectively, with the highest prevalence among men with European and East Asian ancestry. At a mean age of 61±12 years, 74% of male veterans with 47,XXY and >99% with 47,XYY remained undiagnosed. Individuals with 47,XXY (n=862) and 47,XYY (n=747) had similar military service history, all-cause SMR, and age of death compared to matched controls. CCI and healthcare utilization were higher among individuals with SCA, while several measures of HRQoL were lower. Men with a clinical diagnosis of 47,XXY had higher healthcare utilization but lower comorbidity score compared to those undiagnosed. Conclusion and Relevance One in 370 males in the MVP cohort have SCA, a prevalence comparable to estimates in the general population. While these men have successfully served in the military, they have higher morbidity and report poorer HRQoL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics. KEY POINTS Comparable to the general population, approximately 1 in 370 male veterans have a sex chromosome aneuploidy, but most are undiagnosed. Men with X or Y chromosome aneuploidy successfully complete US miliary duty with similar service history compared to their 46,XY peers. Medical comorbidities and healthcare utilization metrics are higher in male veterans with 47,XXY and 47,XYY during aging, however life expectancy is similar to matched controls.
Abstract Utilizing data from the Million Veteran Program (MVP), we investigated the genetic determinants underlying total testosterone levels via a multi-ancestral analysis of 124,593 individuals of European (n=88,385), African (n=25,235) and Hispanic (n=10,973) ancestry. We identified 46 trans-ancestry variants and 17 ancestry-specific variants, of which 14 trans-ancestry variants and 15 ancestry-specific variants are novel associations with testosterone. Results implicate genes regulating testosterone shared across ancestral groups, which include SHBG, JMJD1C, FXR2, SENP3, TNFSF12-TNFSF13 while implicating genes such as MSN, DMD, VSIG4, CHEK2, TKTL1 that may underlie ancestry-group differences in testosterone regulation. We also linked testosterone variants on the X chromosome with differential risk of chronic kidney disease and hereditary hemolytic anemias in African and Hispanic ancestry groups, respectively. Lastly, we constructed a polygenic score from our 46 trans-ancestry variants and associated it with testicular dysfunction, hyperlipidemia, gout and prostate cancer with stronger prostate cancer associations in Hispanic and African ancestry groups compared to the European ancestry group. These findings provide insight into ancestry-specific androgen regulation and identify novel variants for disease risk stratification in patients.
Animal studies suggest that central vasopressin plays a facilitatory role in aggressive behavior. To examine this possibility in humans, the relationship between cerebrospinal fluid (CSF) arginine vasopressin (AVP) and indices of aggression and central serotonin system function was examined in personality-disordered subjects.
Methods
We used CSF (AVP), CSF 5-hydroxyindoleacetic acid, and the prolactin response tod-fenfluramine challenge (PRL[d-FEN]) as central indices of vasopressin and serotonergic system function, respectively, in 26 subjects who met theDSM-IVcriteria for personality disorder. Measures of aggression and impulsivity included the Life History of Aggression assessment and the Barratt Impulsiveness Scales.
Results
The CSF AVP level was correlated directly with life history of general aggression and aggression against persons and inversely with PRL[d-FEN] responses (but not with CSF 5-hydroxyindoleacetic acid), which in turn was correlated inversely with these 2 measures of life history of aggression. The positive relationship between CSF AVP and life history of aggression remained even when the variance associated with PRL[d-FEN] responses in these subjects was accounted for.
Conclusion
Central AVP may play a role in enhancing, while serotonin plays a role in inhibiting, aggressive behavior in personality-disordered individuals. In addition to the possibility of central AVP and serotonin interacting to influence human aggression, central AVP may also influence human aggressive behavior through a mechanism independent of central serotonin in personality-disordered subjects.
Electroconvulsive therapy (ECT) under anesthesia is associated with hypertension and tachycardia. The cardiovascular effects of ECT were studied after pretreatment of 10 patients with esmolol (1.0 mg/kg), fentanyl (1.5 μg/kg), labetalol (0.3 mg/kg), lidocaine (1.0 mg/kg), and saline solution (control), using a double-blind, randomized block-design. Each patient received all five pretreatment regimens over the course of five ECT sessions. During control studies, arterial blood pressure and heart rate increased significantly in all patients after ECT (P < 0.05 and P < 0.01, respectively). The rate-pressure product increased by an average of 336% ± 14% (P < 0.01). There were appreciable individual differences in the cardiovascular response to ECT, independent of pretreatment (P < 0.01). Pretreatment with esmolol and labetalol significantly reduced the hemodynamic response to ECT, compared with fentanyl, lidocaine, or saline solution (P < 0.05). Esmolol attenuated arterial blood pressure to a larger extent than did labetalol (P < 0.05). Compared with saline solution (control), pretreatment with labetalol, fentanyl, or lidocaine significantly reduced seizure duration (P < 0.05) and increased the frequency with which a second electrical stimulus was required. In contrast, esmolol pretreatment did not significantly affect seizure duration. Esmolol (1 mg/kg), administered 1 min before induction of anesthesia, produced significant amelioration of the cardiovascular response to ECT with minimal effect on seizure duration.
Virgin, ovariectomized rats exposed to 2 wk of sequential estradiol (E 2 ) and progesterone (P) followed by P withdrawal have increased hypothalamic oxytocin (OT) mRNA and peptide levels relative to sham-treated animals. This increase is prevented if P is sustained. In the central nervous system, P is metabolized to the neurosteroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one), which exerts effects by acting as a positive allosteric modulator of GABA A receptor/Cl − -channel complexes. In the present study, ovariectomized rats that received sequential E 2 and P for 2 wk followed by P withdrawal were administered allopregnanolone at the time of P withdrawal. Hypothalamic and plasma allopregnanolone concentrations, serum E 2 and P concentrations, and hypothalamic OT mRNA levels were measured at death. Steroid-induced increases in OT mRNA were attenuated in animals treated with allopregnanolone at the time of P withdrawal. The results suggest that allopregnanolone plays an important modulatory role in steroid-mediated increases in hypothalamic OT.
