Transgender people: health at the margins of society.

In this paper we examine the social and legal conditions in which many transgender people (often called trans people) live, and the medical perspectives that frame the provision of health care for transgender people across much of the world. Modern research shows much higher numbers of transgender people than were apparent in earlier clinic-based studies, as well as biological factors associated with gender incongruence. We examine research showing that many transgender people live on the margins of society, facing stigma, discrimination, exclusion, violence, and poor health. They often experience difficulties accessing appropriate health care, whether specific to their gender needs or more general in nature. Some governments are taking steps to address human rights issues and provide better legal protection for transgender people, but this action is by no means universal. The mental illness perspective that currently frames health-care provision for transgender people across much of the world is under scrutiny. The WHO diagnostic manual may soon abandon its current classification of transgender people as mentally disordered. Debate exists as to whether there should be a diagnosis of any sort for transgender children below the age of puberty.

A New Look at Genetic and Environmental Architecture on Lipids Using Non-Normal Structural Equation Modeling in Male Twins: The NHLBI Twin Study.

This study examined genetic and environmental influences on the lipid concentrations of 1028 male twins using the novel univariate non-normal structural equation modeling (nnSEM) ADCE and ACE models. In the best fitting nnSEM ADCE model that was also better than the nnSEM ACE model, additive genetic factors (A) explained 4%, dominant genetic factors (D) explained 17%, and common (C) and unique (E) environmental factors explained 47% and 33% of the total variance of high-density lipoprotein cholesterol (HDL-C). The percentage of variation explained for other lipids was 0% (A), 30% (D), 34% (C) and 37% (E) for low-density lipoprotein cholesterol (LDL-C); 30, 0, 31 and 39% for total cholesterol; and 0, 31, 12 and 57% for triglycerides. It was concluded that additive and dominant genetic factors simultaneously affected HDL-C concentrations but not other lipids. Common and unique environmental factors influenced concentrations of all lipids.

Circulating MicroRNAs and Life Expectancy Among Identical Twins.

Human life expectancy is influenced not only by longevity assurance mechanisms and disease susceptibility loci but also by the environment, gene-environment interactions, and chance. MicroRNAs (miRNAs) are a class of small noncoding RNAs closely related to genes. Circulating miRNAs have been shown as promising noninvasive biomarkers in the development of many pathophysiological conditions. However, the concentration of miRNA in the circulation may also be affected by environmental factors. We used a next-generation sequencing platform to assess the association of circulating miRNA with life expectancy, for which deaths are due to all causes independent of genes. In addition, we showed that miRNAs are present in 41-year archived plasma samples, which may be useful for both life expectancy and all-cause mortality risk assessment. Plasma miRNAs from nine identical male twins were profiled using next-generation sequencing. The average absolute difference in the minimum life expectancy was 9.68 years. Intraclass correlation coefficients were above 0.4 for 50% of miRNAs. Comparing deceased twins with their alive co-twin brothers, the concentrations were increased for 34 but decreased for 30 miRNAs. Identical twins discordant in life expectancy were dissimilar in the majority of miRNAs, suggesting that environmental factors are pivotal in miRNAs related to life expectancy.

Midlife moderation-quantified healthy diet and 40-year mortality risk from CHD: the prospective National Heart, Lung, and Blood Institute Twin Study.

It is unknown whether influences of midlife whole diet on the long-term CHD mortality risk are independent of genetic and common environmental factors or familial predisposition. We addressed this question prospectively using data from the National Heart, Lung, and Blood Institute Twin Study. We included 910 male twins who were middle-aged and had usual diet assessed with nutritionist-administered, cross-checked dietary history interview at baseline (1969-1973). Moderation-quantified healthy diet (MQHD), a dietary pattern, was created to evaluate a whole diet. Primary outcome was time-to-CHD death. Hazard ratios (HR) were estimated using frailty survival model. Known CHD risk factors were controlled. During the follow-up of 40 years through 31 December 2009, 113 CHD deaths, 198 total cardiovascular deaths and 610 all-cause deaths occurred. In the entire cohort, the multivariable-adjusted HR for the overall association (equivalent to a general population association) was 0·76 (95 % CI 0·66, 0·88) per 10-unit increment in the MQHD score for CHD, and the multivariable-adjusted HR for a twin with a MQHD score ten units higher than his co-twin brother was 0·79 (95 % CI 0·64, 0·96, P=0·02) for CHD independent of familial predisposition. Similar results were found for a slightly more food-specified alternative moderation-quantified healthy diet (aMQHD). The between-pair association (reflecting familial influence) was significant for CHD for both MQHD and aMQHD. It is concluded that associations of MQHD and aMQHD with a lower long-term CHD mortality risk are both nutritionally and familially affected, supporting their use for dietary planning to prevent CHD mortality.

Genetic and environmental influences on the prospective correlation between systemic inflammation and coronary heart disease death in male twins.

OBJECTIVE: Because of lack of evidence, we aimed to examine to what degree low-grade systemic inflammation and coronary heart disease (CHD) death shared common genetic and environmental substrates. APPROACH AND RESULTS: From the 41-year prospective National Heart, Lung, and Blood Institute Twin Study, we included 950 middle-aged male twins at baseline (1969-1973). Low-grade systemic inflammation was measured with plasma levels of interleukin-6 (IL-6) and C-reactive protein. Univariate and bivariate structural equation models were used, adjusted for a risk score for CHD death. The score-adjusted heritability was 19% for IL-6, 27% for C-reactive protein, and 22% for CHD death. The positive phenotypic correlation of IL-6 with CHD death (radjusted=0.27; 95% confidence interval [CI], 0.08-0.43) was driven by additive genetic factors (contribution [relative contribution], 0.30 [111%]) but attenuated by unique environment (-0.03 [-11%]). The genetic correlation between IL-6 and CHD death was 0.74 (95% CI, 0.21-1.00), whereas the unique environmental correlation was -0.05 (95% CI, -0.35 to 0.25). The proportion of genetic variance for CHD death shared with that for IL-6 was 74%. The phenotypic correlation of C-reactive protein with CHD death (radjusted=0.10; 95% CI, -0.02 to 0.22) was explained by additive genetic factors (0.20 [149%]) but was attenuated by the unique environment (-0.09 [-49%]). The genetic correlation of C-reactive protein with CHD death was 0.63 (95% CI, -0.07 to 1.00), whereas the unique environmental correlation was -0.07 (95% CI, -0.29 to 0.17). CONCLUSIONS: Low-grade systemic inflammation, measured by IL-6, and long-term CHD death share moderate genetic substrates that augment both traits.

Heritability of usual alcohol intoxication and hangover in male twins: the NAS-NRC Twin Registry.

BACKGROUND: Alcohol consumption is influenced by heritable factors. The genetic influence on usual high-density drinking, including alcohol intoxication and hangover, is unknown. We aim to estimate the heritability of usual high-density drinking. METHODS: A total of 13,511 male twins in this cross-sectional study were included from the National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry. Data on the frequency of alcohol intoxication and alcohol hangover over the past year, that is, usual high-density drinking (phenotypes), were collected through a self-administered questionnaire when twins were middle-aged in 1972. Structural equation modeling was used to estimate the variance components of phenotypes. RESULTS: The mean of the frequency of usual high-density drinking in the entire twin population was 0.16 times per month for intoxication and 0.18 times per month for hangover. The heritability of usual alcohol intoxication was 50.7% (95% confidence interval [CI] 46.2 to 55.0) before and 49.9% (95% CI 45.3 to 54.2) after the body mass index (BMI) adjustment. The heritability of usual hangover was 55.4% (95% CI 51.2 to 58.6) before and 54.8% (95% CI 50.6 to 58.8) after adjustment for BMI. Unshared environmental factors between co-twins explained the remaining variance in alcohol intoxication and in hangover. CONCLUSIONS: Both genetic and unshared environmental factors have important influences on usual alcohol intoxication and hangover. These findings are important in understanding the occurrence of and developing interventions for usual high-density drinking.

Whole-Genome Differentially Hydroxymethylated DNA Regions among Twins Discordant for Cardiovascular Death.

Epigenetics is a mechanism underlying cardiovascular disease. It is unknown whether DNA hydroxymethylation is prospectively associated with the risk for cardiovascular death independent of germline and common environment. Male twin pairs middle-aged in 1969-1973 and discordant for cardiovascular death through December 31, 2014, were included. Hydroxymethylation was quantified in buffy coat DNA collected in 1986-1987. The 1893 differentially hydroxymethylated regions (DhMRs) were identified after controlling for blood leukocyte subtypes and age among 12 monozygotic (MZ) pairs (Benjamini-Hochberg False Discovery Rate < 0.01), of which the 102 DhMRs were confirmed with directionally consistent log2-fold changes and p < 0.01 among additional 7 MZ pairs. These signature 102 DhMRs, independent of the germline, were located on all chromosomes except for chromosome 21 and the Y chromosome, mainly within/overlapped with intergenic regions and introns, and predominantly hyper-hydroxymethylated. A binary linear classifier predicting cardiovascular death among 19 dizygotic pairs was identified and equivalent to that generated from MZ via the 2D transformation. Computational bioinformatics discovered pathways, phenotypes, and DNA motifs for these DhMRs or their subtypes, suggesting that hydroxymethylation was a pathophysiological mechanism underlying cardiovascular death that might be influenced by genetic factors and warranted further investigations of mechanisms of these signature regions in vivo and in vitro.

Factors impacting human telomere homeostasis and age-related disease.

Loss of telomere length homeostasis has been linked to age-related disease especially cancer. In this review, we discuss two major causes of telomere dysfunction that potentially lead to tumorigenesis: replicative aging and environmental assaults. Aging has long been recognized as a source for telomere dysfunction through increasing numbers of cell divisions in the absence of sufficient telomerase activity. However, environmental assaults that cause telomere dysfunction are only beginning to be identified and recognized. Environmental stressors that influence telomere length may be physical or induced by psychological situations like stress. Knowledge of all factors, including genetic and environmental forces, that moderate telomere length will be critical for understanding basic mechanisms of human telomere maintenance during development and aging as well as for disease prevention and treatment strategies.

Genetic association of daytime sleepiness and depressive symptoms in elderly men.

STUDY OBJECTIVES: Clinical rating scales, self-reports, and diagnostic instruments measuring depression often inquire about daytime fatigue and tiredness. Excessive daytime sleepiness refers specifically to the tendency to feel drowsy or fall asleep during waking hours and is considered conceptually and operationally independent from the fatigue, tiredness, and sleeping difficulties that characterize depression. The objective of this study was to examine whether daytime sleepiness assessed using the Epworth Sleepiness Scale and depressive symptoms assessed using the Geriatric Depression Scale are genetically related. DESIGN/SETTING: Cross-sectional data were collected via questionnaire in 1998-2000. PARTICIPANTS: Population-based sample of more than 5,000 male elderly twins aged 69-82 years old at the time of survey. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: There was evidence for moderate heritability for daytime sleepiness (36.9%) and depressive symptoms (30.7%). There was evidence for a significant genetic correlation (0.40) between the 2 measures, suggesting that both daytime sleepiness and depressive symptoms have some genes in common. The genetic correlation was reduced to 0.21 after adjustment for several covariates. CONCLUSIONS: The results showed that the often reported phenotypic correlation between daytime sleepiness and depressive symptoms is due, in part, to modest overlap in genetic factors, at least in elderly men. However, the majority of individual variation in daytime sleepiness and depressive symptoms, in particular after covariate adjustment, was attributable to individual-specific environmental factors.

Shared environmental factors associated with telomere length maintenance in elderly male twins.

During aging, chromosome ends, or telomeres, gradually erode or shorten with each somatic cell division. Loss of telomere length homeostasis has been linked to age-related disease. Remarkably, specific environmental assaults, both physical and psychological, have been shown to correlate with shortened telomeres. However, the extent that genetic and/or environmental factors may influence telomere length during later stages of lifespan is not known. Telomere length was measured in 686 male US World War II and Korean War veteran monozygotic (MZ) and dizygotic (DZ) twins (including 181 MZ and 125 DZ complete pairs) with a mean age of 77.5 years (range 73-85 years). During the entire process of telomere length measurement, participant age and twin status were completely blinded. White blood cell mean telomere length shortened in this elderly population by 71 base pairs per year (P < 0.0001). We observed no evidence of heritable effects in this elderly population on telomere length maintenance, but rather find that telomere length was largely associated with shared environmental factors (P < 0.0001). Additionally, we found that individuals with hypertension and cardiovascular disease had significantly shorter telomeres (P = 0.0025 and 0.002, respectively). Our results emphasize that shared environmental factors can have a primary impact on telomere length maintenance in elderly humans.

Imagery in the clinical setting: a tool for healing.

This article addresses the why and how of imagery and its relation with holistic theories. The description of clinical applications, program development, and research demonstrates successful interventions in virtually every area of nursing. Case examples show the profound healing that is experienced by the patient and the nurse simultaneously through this work. Imagery is harmless, is time- and cost-effective, and creates a healing partnership between the nurse and patient.

Instrumentation for electrochemical performance characterization of neural electrodes.

In an effort to determine the chronic stability, sensitivity, and thus the potential viability of various neurochemical recording electrode designs and compositions, we have developed a custom device called the Voltammetry Instrument for Neurochemical Applications (VINA). Here, we describe the design of the VINA and initial testing of its functionality for prototype neurochemical sensing electrodes. The VINA consists of multiple electrode fixtures, a flowing electrolyte bath, associated reservoirs, peristaltic pump, voltage waveform generator, data acquisition hardware, and system software written in National Instrument's LabVIEW. The operation of VINA was demonstrated on a set of boron-doped diamond neurochemical recording electrodes, which were subjected to an applied waveform for a period of eighteen days. Each electrode's cyclic voltammograms (CVs) were recorded, and sensitivity calibration to dopamine (DA) was performed. Results showed an initial decline with subsequent stabilization in the CV current measured during the voltammetric sweep, corresponding closely with changes in electrode sensitivity to DA. The VINA has demonstrated itself as a useful tool for the characterization of electrode stability and chronic electrochemical performance.

Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause some forms of autosomal dominant Parkinson's disease. We measured the frequency of a novel mutation (Gly2019 ser) in familial Parkinson's disease by screening genomic DNA of patients and controls. Of 767 affected individuals from 358 multiplex families, 35 (5%) individuals were either heterozygous (34) or homozygous (one) for the mutation, and had typical clinical findings of idiopathic Parkinson's disease. Thus, our results suggest that a single LRRK2 mutation causes Parkinson's disease in 5% of individuals with familial disease. Screening for this mutation should be a component of genetic testing for Parkinson's disease.

Multifocal choroiditis with panuveitis incidence of ocular complications and of loss of visual acuity.

PURPOSE: To estimate the incidences of ocular complications and vision loss in patients with multifocal choroiditis with panuveitis (MFCPU) and to describe the association between therapy and the incidences thereof. DESIGN: Retrospective cohort study. PARTICIPANTS: Sixty-six patients (122 eyes) with MFCPU evaluated from January 1984 through June 2005 at a single-center academic practice. METHODS: Demographic and clinical information on patients diagnosed with MFCPU was collected and entered into a computerized database for statistical analyses. MAIN OUTCOME MEASURES: Development of ocular complications, including choroidal neovascularization, epiretinal membrane, and cystoid macular edema (CME), and loss of visual acuity (VA) to 20/50 or worse and to 20/200 or worse. RESULTS: Among affected eyes of patients with MFCPU, frequencies of VAs of 20/50 or worse and of 20/200 or worse at presentation were 55% and 38%, respectively. Choroidal neovascularization was observed in 22% of affected eyes at presentation and was the leading cause of poor VA at presentation. The incidence rates of vision loss to 20/50 or worse and to 20/200 or worse were 0.19/eye-year (EY) and 0.12/EY in affected eyes and 0.07/person-year (PY) and 0.04/PY in better-seeing eyes. Choroidal neovascularization was the most common cause of incident vision loss, with approximately 45% of incident vision loss attributed to new-onset or recurrent choroidal neovascularization. Presence of epiretinal membrane and CME also was associated with the development of vision loss during follow-up. When taken in combination, the incidence of any posterior pole complication was 0.13/EY in affected eyes. Use of immunosuppressive drug therapy (but not low-dose corticosteroid therapy) was associated with an 83% reduction in the risk of posterior pole complications (P = 0.004) and with a 92% reduction in the risk of 20/200 or worse VA in affected eyes (P = 0.05). Of the 6 eyes with recurrent choroidal neovascularization, only one recurrence was observed, in a patient receiving immunosuppressive drug therapy. CONCLUSIONS: Treatment with immunosuppressive drugs may improve VA outcomes among patients with MFCPU by reducing the risk of sight-threatening posterior pole complications, including new-onset choroidal neovascularization and recurrent choroidal neovascularization among eyes with existing choroidal neovascularization.

Hearing impairment susceptibility in elderly men and the DFNA18 locus.

OBJECTIVE: To identify any chromosomal region that shows evidence for linkage to age-related hearing loss in humans. DESIGN: Evaluation of genetic linkage using sibling-pair methods for hearing loss collected via self-report questionnaire and markers from a genome screening collected from a population-based representative sample of male fraternal twins born from 1917 to 1927. SUBJECTS: Members of a group of 6108 World War II and Korean War veteran twins (2059 complete pairs) who completed a health history questionnaire at a mean age of 74.3 years (range, 69-82 years). A subset of 711 twins (343 complete pairs) later provided a blood sample for DNA extraction in a study of genetic factors in healthy aging. Among the complete pairs were approximately 160 fraternal twins; 50 of these pairs were concordant for age-related hearing loss with at least 1 co-twin reporting bilateral hearing loss and with marker data available for analysis. RESULTS: A region suggestive of linkage was found on chromosome 3q, with a logarithm of the odds score of 2.5 in the same region of this chromosome where the DFNA18 locus resides, which has been reported to cause a form of progressive hereditary hearing loss. CONCLUSIONS: To our knowledge, this is the first sample from the general population that has been used in a genome screening for qualitative hearing loss. The results, if confirmed, suggest that genetic variation in the region of DFNA18 may be responsible for hearing loss with age in the general population.

Heritability of plasma sex hormones and hormone binding globulin in adult male twins.

Plasma sex hormone concentrations have been used as biomarkers in epidemiological studies of many conditions including cancer, obesity, bone density, and coronary heart disease. The objective of this analysis was to estimate genetic and nongenetic influences on endogenous sex hormones (testosterone, estradiol, estrone, and SHBG) in a large sample of 532 adult white male twins (134 monozygotic and 132 dizygotic twin pairs) from the National Heart, Lung, and Blood Institute Twin Study. Participants were aged 59-70 yr at the time of plasma collection, and hormone concentrations were determined with RIA. Genetic models were fitted by the method of maximum likelihood. Testosterone and SHBG concentrations have substantial genetic variation, with additive genetic factors accounting for 57 and 68% of the total phenotypic variation, respectively. In contrast, variation in estrone (37% shared environmental and 63% individual specific environmental effects) and estradiol concentrations (25% genetic effect, 44% shared environmental effects, and 31% individual specific environmental effects) were largely influenced by nongenetic factors. Assessment of the relative contribution of genetic and nongenetic influences on hormone concentrations may help in the search for genes underlying variation and covariation in complex traits affected by plasma sex hormone concentrations.

Verification of self-report of zygosity determined via DNA testing in a subset of the NAS-NRC twin registry 40 years later.

The National Academy of Sciences -- National Research Council (NAS-NRC) twin panel, created nearly 50 years ago, had twin zygosity determined primarily via a similarity questionnaire that has been estimated to correctly classify at least 95% of twins. In the course of a study on the genetics of healthy ageing in the NAS-NRC twins, DNA was collected for genome-wide scanning and zygosity confirmation was examined in 343 participating pairs. The sample was supplemented from two other studies using NAS-NRC twins where one or both co-twins were suspected to have Alzheimer disease or another dementia, or Parkinson's disease. Overall 578 twin pairs with DNA were analyzed. Zygosity assignment for 96.8% (519/536) was confirmed via questionnaire. Among 42 pairs whose questionnaire responses were inconclusive for assigning zygosity, 50% were found to be monozygous (MZ) and 50% were dizygous (DZ). There was some evidence for greater misclassification of presumed DZ pairs in the healthy ageing study where participation favored pairs who were similar in having a favorable health history and willingness to volunteer without any element of perceived risk for a specific disease influencing participation.

A cost-effective and versatile xenon gas dispenser.

OBJECTIVE: To modify a commercial xenon gas dispenser so that two xenon unit-dose vials could be combined with a modified dispenser to deliver a recommended dose. METHOD: To maintain the same operating mechanism, changes were made only to the vial shield and the needle port of the original gas dispenser. The modified gas dispenser consisted of two puncture needles and two vial holders shielded with the same thickness of lead as the commercial dispenser. RESULTS: Our evaluation showed that the modified gas dispenser operated the same way as the commercial unit, and the average 133Xe residual activity in either one or two xenon unit-dose vials of the modified gas dispenser was not significantly different from that in one vial of the commercial xenon gas dispenser. CONCLUSION: The modified xenon gas dispenser allows the stock of xenon gas vials to be managed cost-effectively. The modified unit can be used to dispense two low-activity xenon gas vials to deliver a standard dose to a patient. Also, the modified gas dispenser can be used to combine different amounts of xenon activity in two unit-dose vials in order to customize the dose delivered to patients with special needs (e.g., obese patients). Our modified device can also function as a single-dose dispenser by placing an empty vial alongside the unit-dose vial of radioactive xenon gas.

Higher usual alcohol consumption was associated with a lower 41-y mortality risk from coronary artery disease in men independent of genetic and common environmental factors: the prospective NHLBI Twin Study.

BACKGROUND: Evidence that alcohol consumption is inversely associated with long-term coronary artery disease (CAD) mortality independent of genetic and early life environmental factors is lacking. OBJECTIVE: We evaluated whether alcohol consumption was prospectively associated with CAD mortality risk independent of familial factors. DESIGN: In total, 843 male twins (396 pairs and 51 unpaired twins) aged 42-55 y (mean: 48 y) without baseline CAD reported beer, wine, and spirits consumption at baseline (1969-1973) and were followed up to 2010 in the prospective National Heart, Lung, and Blood Institute Twin Study. Data on usual alcohol consumption over the past year were collected. Outcome was time to event, where the primary event was death from CAD and secondary events were death from cardiovascular disease and all causes. HRs were estimated by using frailty survival models, both overall and within-pair. RESULTS: There were 129 CAD deaths and 219 cardiovascular deaths during 41 y of follow-up. In the whole cohort, after adjustment for caloric intake and cardiovascular disease risk factors, overall HRs per 10-g increment in alcohol intake were 0.94 (95% CI: 0.89, 0.98) for CAD and 0.97 (95% CI: 0.93, 1.00) for cardiovascular mortality. The within-pair adjusted HRs for a twin with 10-g higher daily alcohol consumption than his co-twin were 0.90 (95% CI: 0.84, 0.97) for CAD and 0.95 (95% CI: 0.90, 1.00) for cardiovascular disease mortality in the cohort pooled by zygosity, which remained similar among monozygotic twins. All 3 beverage types tended to be associated with lower CAD mortality risk within-pair to a similar degree. Alcohol consumption was not associated with total mortality risk overall or within-pair. CONCLUSION: Higher usual alcohol consumption is associated with lower CAD mortality risk, independent of germline and early life environment and adulthood experience shared among twins, supporting a possible causal role of alcohol consumption in lowering CAD death risk. This trial was registered at clinicaltrials.gov as NCT00005124.