Healthy Twins Research Articles

Heritability of amygdala reactivity to angry faces and its replicable association with the schizophrenia risk locus of miR-137.

Among healthy participants, the interindividual variability of brain response to facial emotions is associated with genetic variation, including common risk variants for schizophrenia, a heritable brain disorder characterized by anomalies in emotion processing. We aimed to identify genetic variants associated with heritable brain activity during processing of facial emotions among healthy participants and to explore the impact of these identified variants among patients with schizophrenia. We conducted a data-driven stepwise study including samples of healthy twins, unrelated healthy participants and patients with schizophrenia. Participants approached or avoided pictures of faces with negative emotional valence during functional magnetic resonance imaging (fMRI). We investigated 3 samples of healthy participants - including 28 healthy twin pairs, 289 unrelated healthy participants (genome-wide association study [GWAS] discovery sample) and 90 unrelated healthy participants (replication sample) - and 1 sample of 48 patients with schizophrenia. Among healthy twins, we identified the amygdala as the brain region with the highest heritability during processing of angry faces (heritability estimate 0.54, p < 0.001). Subsequent GWAS in both discovery and replication samples of healthy non-twins indicated that amygdala activity was associated with a polymorphism in the miR-137 locus (rs1198575), a micro-RNA strongly involved in risk for schizophrenia. A significant effect in the same direction was found among patients with schizophrenia (p = 0.03). The limited sample size available for GWAS analyses may require further replication of results. Our data-driven approach shows preliminary evidence that amygdala activity, as evaluated with our task, is heritable. Our genetic associations preliminarily suggest a role for miR-137 in brain activity during explicit processing of facial emotions among healthy participants and patients with schizophrenia, pointing to the amygdala as a brain region whose activity is related to miR-137.

Epigenetic Findings in Twins with Esophageal Atresia.

Esophageal atresia (EA) is the most common malformation of the upper gastrointestinal tract. The estimated incidence of EA is 1 in 3500 births. EA is more frequently observed in boys and in twins. The exact cause of isolated EA remains unknown; a multifactorial etiology, including epigenetic gene expression modifications, is considered. The study included six pairs of twins (three pairs of monozygotic twins and three pairs of dizygotic twins) in which one child was born with EA as an isolated defect, while the other twin was healthy. DNA samples were obtained from the blood and esophageal tissue of the child with EA as well as from the blood of the healthy twin. The reduced representation bisulfite sequencing (RRBS) technique was employed for a whole-genome methylation analysis. The analyses focused on comparing the CpG island methylation profiles between patients with EA and their healthy siblings. Hypermethylation in the promoters of 219 genes and hypomethylation in the promoters of 78 genes were observed. A pathway enrichment analysis revealed the statistically significant differences in methylation profile of 10 hypermethylated genes in the Rho GTPase pathway, previously undescribed in the field of EA (ARHGAP36, ARHGAP4, ARHGAP6, ARHGEF6, ARHGEF9, FGD1, GDI1, MCF2, OCRL, and STARD8).

66 The PROMOTe study: prebiotic supplementation improves cognition versus placebo in healthy older twins

Abstract Background There is a growing body of evidence linking the microbiota in the human gut, to the brain and to physical function. Animal and human studies have shown that inducing changes in the microbiota can alter muscle physiology and cognitive behaviour, indicating causative pathways. The PROMOTe trial aimed to test whether the gut microbiome mediates anabolic resistance to protein in older adults. A secondary objective was to test whether modulation of the gut microbiome using a pre-biotic food supplement, improved cognition versus placebo. Methods This placebo-controlled double-blinded randomised controlled trial used twin pairs, recruited from the TwinsUK cohort. Those aged &amp;gt; = 60, with low baseline protein intake, and access to a computer (due to remote trial delivery) were included. One twin received protein supplementation plus placebo and the other received protein supplementation plus a gut microbiome modulator (prebiotic). Intervention period was 12 weeks. Participants were advised to take 1 supplement sachet daily, and to undertake resistance exercises. The primary outcome was muscle strength as measured using chair-rise time. Cognition (CANTAB battery) was a secondary outcome. Linear mixed effects regression models were used to compare intervention groups (arm 1 vs arm 2; blinded). Twin clustering was considered as random effects, both family identifier and zygosity, and treatment group as fixed effect. Results Target sample size was 70 individuals. We screened 626 and randomised 72 participants (36 pairs). More adverse events occurred in the prebiotic group (n = 8 versus n = 2 in placebo group; p = 0.041), but compliance remained high in both groups (% adherence &amp;gt;78% in each group; p = 0.37). There was no significant difference between arms for the primary outcome of chair rise time (coefficient 0.184; 95% CI -0.569-0.938; p = 0.631). The prebiotic intervention arm had an improved cognition factor score versus the placebo group (coefficient 0.482; 95% CI 0.823–0.141; p = 0.014). Conclusion Prebiotic food supplementation improves cognition versus placebo in a cohort of healthy older twins.

Prenatal Diagnosis of Chromosomal Mosaicism in 18,369 Cases of Amniocentesis.

The prenatal diagnosis of chromosomal mosaicism is fraught with uncertainty. Karyotyping, chromosomal microarray analysis (CMA), and fluorescence in situ hybridization (FISH) are three commonly used techniques. In this study, we evaluated these techniques for the prenatal diagnosis of chromosomal mosaicism and its clinical outcome. A retrospective review of mosaicism was conducted in 18,369 pregnant women from January 2016 to November 2021. The subjects underwent amniocentesis to obtain amniotic fluid for G-band karyotyping with or without CMA/FISH. Cases diagnosed with chromosomal mosaicism were selected for further analysis. In total, 101 cases of chromosomal mosaicism were detected in 100 pregnant women (0.54%, 100/18,369). Four were lost during follow-up, 61 opted to terminate their pregnancy, and 35 gave birth to a healthy singleton or twins. Among these 35 cases, postnatal cytogenetic testing was performed on eight and two exhibited mosaicism; however, nothing abnormal was observed in the postnatal phenotype follow-up. Karyotyping identified 96 incidents of chromosomal mosaicism including 13 with level II mosaicism and 83 with level III mosaicism, FISH identified 37 cases of mosaicism, and CMA identified 17. The most common form of chromosomal mosaicism involved monosomy X, of which the mosaic fraction in cultured karyotyping appeared higher or comparable to uncultured FISH/CMA (p < 0.05). Discordant mosaic results were observed in 34 of 101 cases (33.7%), most of which resulted from the detection limit of different techniques and/or the dominant growth of a certain cell line. Based on the postnatal follow-up results from the babies born, we obtained a more hopeful result for the prognosis of chromosomal mosaicism. Although karyotyping was the most sensitive method for detecting chromosomal mosaicism, artifacts and bias resulting from culture should be considered, particularly for sex chromosomal abnormalities involving X monosomy, in which the combination with uncultured FISH was necessary. · Karyotyping combined with uncultured FISH or CMA is beneficial for prenatal diagnosis of chromosomal mosaicism.. · Fetuses without ultrasound structural anomalies with chromosomal mosaicism often have optimistic prognosis..

An Isocaloric High-Fat Diet Regulates Partially Genetically Determined Fatty Acid and Carbohydrate Uptake and Metabolism in Subcutaneous Adipose Tissue of Lean Adult Twins.

The dysfunction of energy metabolism in white adipose tissue (WAT) induces adiposity. Obesogenic diets that are high in saturated fat disturb nutrient metabolism in adipocytes. This study investigated the effect of an isocaloric high-fat diet without the confounding effects of weight gain on the gene expression of fatty acid and carbohydrate transport and metabolism and its genetic inheritance in subcutaneous (s.c.) WAT of healthy human twins. Forty-six healthy pairs of twins (34 monozygotic, 12 dizygotic) received an isocaloric carbohydrate-rich diet (55% carbohydrates, 30% fat, 15% protein; LF) for 6 weeks followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein; HF) for another 6 weeks. Gene expression analysis of s.c. WAT revealed that fatty acid transport was reduced after one week of the HF diet, which persisted throughout the study and was not inherited, whereas intracellular metabolism was decreased after six weeks and inherited. An increased inherited gene expression of fructose transport was observed after one and six weeks, potentially leading to increased de novo lipogenesis. An isocaloric dietary increase of fat induced a tightly orchestrated, partially inherited network of genes responsible for fatty acid and carbohydrate transport and metabolism in human s.c. WAT.

Successful pregnancy and delivery after ovulation induction therapy in a woman with congenital hypogonadotropic hypogonadism: a case report

BackgroundCongenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting from a deficient secretion of the episodic gonadotropin-releasing hormone, leading to delayed or absent puberty and infertility. In female patients with CHH, the most commonly used treatment is gonadotropin (Gn) therapy. Due to the rarity of the disease in females, there are limited case reports available. This article offers a management approach for this unusual disease that can be helpful for clinicians.Case presentationWe report the case of a 29-year-old woman who successfully achieved pregnancy and delivered healthy twin girls after ovulation induction therapy. The patient was diagnosed with CHH at 18 years of age due to primary amenorrhea and the absence of secondary sexual characteristics. After experiencing infertility for three years, the patient sought medical assistance for conceiving. The patient was treated with gonadotropin therapy due to anovulation. In her first treatment cycle, the initial dose of HMG used for treatment was 75IU, which was increased to 150IU after six days. However, the cycle was canceled due to follicular dysplasia. In the second cycle, the treatment began with an initial dose of 150IU, and the follicles grew normally, but the estrogen level was low. Consequently, the treatment was interrupted. In a third ovulation stimulation cycle, HMG was adjusted to 150IU, and recombinant LH was added. After 12 days of ovulation, three mature follicles grew, the estrogen level was normal,and the treatment resulted in successful ovulation and subsequent pregnancy. At 35 weeks of gestation, the patient underwent a cesarean section and delivered two healthy female infants weighing 2,405 g and 2,755 g with an Apgar score of 10/10.ConclusionsEarly diagnosis and timely and appropriate hormone replacement therapy are important for future pregnancy. Ovulation induction therapy is necessary to stimulate fertility. Gn therapy is a feasible and effective treatment for reproduction in CHH females, but the selection of Gn type and dosage must be personalized to maximize fertility outcomes. Effective treatment is available not only for inducing estrogenization and promoting fertility, but also for addressing concerns about psychological and emotional well-being.

A Case of a Pregnant Woman with IgA Nephropathy Showing Histological Preeclampsia Findings without Hypertension Treated with Steroids: A Case Report and Literature Review.

A 35-year-old woman pregnant with twins developed nephrotic syndrome (NS) at 33 weeks' gestation, but her blood pressure remained within the normal range throughout gestation and puerperium. At 34 weeks' gestation, she delivered healthy twins via Caesarean section. After delivery, she developed massive proteinuria (21.1 g/day) and severe hypoalbuminemia (1.0 g/dL). A renal biopsy performed 19 days after delivery revealed IgA nephropathy (IgAN) and preeclampsia. She was treated with steroids, and the NS gradually resolved. This is a rare case of massive gestational proteinuria with IgAN and preeclampsia pathologically that did not meet the clinical criteria for preeclampsia.

Natural killer cell memory precedes HLH in monozygotic twins discordant for chronic active Epstein-Barr virus disease

Severe mosquito bite allergy (SMBA) is a manifestation of chronic active Epstein-Barr virus (CAEBV) infection defined by necrotic ulceration of the stings. CAEBV with SMBA has a high mortality rate as most patients eventually develop fulminant and refractory hemophagocytic lymphohistiocytosis (HLH). However, how self-resolving SMBA escalates to systemic lethal HLH remains unclear. Through comprehensive immune profiling of a SMBA patient with CAEBV and her healthy monozygotic twin, we found that both twins were seropositive for EBV but showed high discordance in their circulating natural killer (NK) cells. The patient's EBV-infected NK cells displayed memory-like properties, including low CD16, high CD226 and induction of enhanced IFNγ production by IL-2 or IL-12. Her leukocytes also produced high levels of IL-2 and IL-12 when stimulated with salivary gland extract (SGE) specifically from A. albopictus mosquitoes, connected again with hyperproduction of IFNγ by her NK cells. Strikingly, pharmacological inhibition of STAT3 suppressed the NK memory-associated cytokine axis of IFNγ, IL-2 and IL-12 that is generated by A. albopictus SGE stimulation. Altogether, this study shows that NK memory is promoted during CAEBV with SMBA by repeated cytokine restimulation leading up to lethal HLH, and proposes STAT3 as a therapeutic target to halt its progression.

Higher dietary protein intake is associated with sarcopenia in older British twins.

Sarcopenia, characterised by an accelerated loss of skeletal muscle mass and function, is associated with negative outcomes. This study aimed to evaluate factors associated with skeletal muscle strength, mass and sarcopenia, particularly protein intake, and to assess whether shared twin characteristics are important. This study utilised cross-sectional data from a study of community-dwelling twins aged ≥60years. Multivariable logistic regression and between- and within-twin pair regression modelling were used. Participants (n = 3,302) were 89% female (n = 2,923), aged a mean of 72.1 (±7.3) years and composed of 858 (55%) monozygotic, 709 (45%) dizygotic twin pairs and 168 individual lone twins. Using optimal protein intake as the reference group (1.0-1.3g/kg/day), there was no significant association between protein intake (neither high nor low) and low muscle strength, or between low protein intake and sarcopenia (odds ratio (OR) 0.7; 95% confidence interval (CI) 0.39-1.25; P = 0.229) in unadjusted models. High protein intake (>1.3g/kg/day) was associated with low muscle mass (OR 1.76; 95% CI 1.39-2.24; P < 0.0001), while low protein intake was protective (OR 0.52; 95% CI 0.40-0.67; P < 0.0001). High protein intake was associated with sarcopenia (OR 2.04; 95% CI 1.21-3.44; P = 0.008), and this was robust to adjustment for demographic, anthropometric and dietary factors. The association between muscle strength and weight, body mass index, healthy eating index, protein intake and alpha diversity was not significantly influenced by shared twin factors, indicating greater amenability to interventions. High protein intake is associated with sarcopenia in a cohort of healthy older twins.

Calcium, Potassium, Sodium, and Magnesium Concentrations in the Placenta, Umbilical Cord, and Fetal Membrane from Women with Multiple Pregnancies.

Calcium (Ca), potassium (K), sodium (Na), and magnesium (Mg) are the elements responsible for the fundamental metabolic and biochemical processes in the cells of the body. The demand for these elements increases significantly during pregnancy, where an adequate supply protects women from the hypertension common in pre-eclampsia and preterm labor. This study aimed to evaluate the association between macro-elements (Ca, Mg, Na, and K) in the placenta, fetal membrane, and umbilical cord and the morphometric parameters of newborns from multiple pregnancies. The study involved 57 pregnant European women with healthy uncomplicated twin pregnancies (n = 52) and triple pregnancies (n = 5); 40 pairs of dichorionic diamniotic twins, 11 pairs of monochorionic diamniotic twins, 1 pair of monochorionic monoamniotic twins, 3 trichorionic triamniotic triplets, and 2 dichorionic triamniotic triplets. Placentas (n = 107), umbilical cords (n = 114), and fetal membranes (n = 112) were collected immediately following delivery, and then weighed and measured. The levels of Ca, K, Na, and Mg were determined using inductively coupled plasma atomic emission spectroscopy (ICP-OES) in a Thermo Scientific ICAP 7400 Duo (Waltham, MA, USA). The respective mean concentrations of Ca, K, Na, and Mg (mg/kg-1 dry mass) were: 2466, 8873, 9323, and 436 in the placenta; 957, 6173, 26,757, and 326 in the umbilical cord, and 1252, 7460, 13,562, and 370 in the fetal membrane. In the studied materials from northwestern Poland, we found strong positive correlations between Ca and Mg concentrations in both the umbilical cord (r = 0.81, p = 0.00) and the fetal membrane (r = 0.73, p = 0.00); between K and Mg concentrations in the umbilical cord (r = 0.73, p = 0.00); between Ca and K concentrations in the fetal membrane (r = 0.73, p = 0.00), and we found moderately positive correlations between placental Ca concentration and placental weight (ρ = 0.42, p = 0.00) and between umbilical cord Mg concentrations and the length of the pregnancy (ρ = 0.42, p = 0.00). Negative correlations were found between Na and Ca concentrations in the fetal membrane (r = -0.40, p = 0.00) and Na concentrations in the fetal membrane and Mg concentrations in the placenta (r = -0.16, p = 0.02). Negative correlations were confirmed between the length of pregnancy and head circumference (ρ = -0.42; p = 0.00), infant weight (ρ = -0.42; p = 0.00), infant length (ρ = -0.49; p = 0.00), shoulder width (ρ = -0.49; p = 0.00); and between the infant weight and head circumference (ρ = -0.62; p = 0.00), weight before delivery (ρ = -0.36; p = 0.00), infant length (ρ = -0.45; p = 0.00), shoulder width (ρ = -0.63; p = 0.00), and weight gain during pregnancy (ρ = -0.31; p = 0.01). We found statistically significant correlations between cigarette smoking before pregnancy and the women's weight before delivery (ρ = 0.32, p = 0.00), and a negative correlation between the women's ages and infant head circumference (ρ = -0.20, p = 0.02). This is probably the first study to evaluate Ca, Na, K, and Mg concentrations in the afterbirth tissues of multiple pregnancies. It adds to the knowledge of elemental concentrations in multiple pregnancies and their possible effects on fetal morphometric parameters.

The Potential Role of Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis (ALS); A Longitudinal Case Study Comparing Patients with Genetically Identical Healthy Twin.

Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neurons. The causes of ALS are heterogeneous, and are only partially understood to date. We studied percentage and function of immune cell subsets in particular natural killer (NK) and CD8+ T cells in an ALS patient and compared the results to those obtained from his genetically identical healthy twin in a longitudinal study. We found several basic mechanisms which were potentially involved in the disease induction and progression. Our findings demonstrate that ALS patient's peripheral blood contained higher NK and B cells and, lower T cell percentages compared with the healthy twin brother's peripheral blood. Significantly increased interferon-gamma secretion by anti-CD3/28 monoclonal antibody-treated peripheral blood mononuclear cells, and sorted CD8+ T cells were observed in the ALS patient, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism of ALS progression. Significant increase in NK cell function due to genetic mutations in ALS associated genes may partly be responsible for the increase expansion and function of CD8+ T cells with effector/memory phenotype, in addition to direct activation and expansion of antigen specific T cells by such mutations. Weekly N-acetyl cysteine infusion to block cell death in patient in addition to a number of other therapies listed in this paper were not effective, and even though the treatments might have extended the patient's life, it was not curative. Therefore, activated CD8+ T and NK cells are likely cells targeting motor neurons in the patient, and strategies should be designed to decrease the aggressive nature of these cells to achieve longer lasting therapeutic benefits.

Pregnancy length and health in giant pandas: What can metabolic and urinary endocrine markers unveil?

Mature female giant pandas usually ovulate once a year. This is followed by an obligatory luteal phase, consisting of a long-lasting corpus luteum dormancy phase (CLD; primary increase in progestogens) and a much shorter active luteal phase (AL; secondary increase in progestogens). Varying duration of both the dormant (embryonic diapause) and AL (post-embryo reactivation) phases has hampered unambiguous pregnancy length determination in giant pandas until today. Additionally, progestogen profiles have been considered not to differ between pregnant and pseudopregnant cycles. Only ceruloplasmin, 13,14-dihydro-15-keto-PGF2α (PGFM) and – more recently – estrogens have been assigned diagnostic power so far. Our study investigated the competence of metabolic (fecal output) and Urinary Specific Gravity (USpG)-normalized urinary endocrine (progestogens, PGFM, glucocorticoids (GCM) and ceruloplasmin) markers for pregnancy monitoring including defining the duration of the AL phase length. Research on 24 (6 pregnant, 8 pseudopregnant and 10 non-birth) cycles of 6 giant pandas revealed a fixed AL phase length of 42 days in giant pandas, e.g. representing 6 weeks of post- diapause development in case of pregnancy. Progestogen concentrations were significantly higher in pregnant cycles throughout the majority of the AL phase, with significant higher values during the AL phase in healthy twin compared to singleton pregnancies. GCM concentrations were also markedly higher in giant pandas expecting offspring, with a clear increase towards birth in the final 2 weeks of pregnancy. This increase in GCM was running in parallel with elevating estrogen and PGFM concentrations, and decreasing progestogens. In addition, during the AL phase, a more pronounced decrease in fecal output was obvious for pregnant females. The combined profiles of non-invasive metabolic and endocrine markers, the latter normalized based on USpG, showed a true pregnancy signature during the AL phase. The findings of this study are applicable to retrospective evaluations of non-birth cycles facilitating categorizing those into pseudopregnant or lost pregnancies, with USpG-normalization of the urinary endocrine markers as a prerequisite.

Genetic and environmental influence on resting state networks in young male and female adults: a cartographer mapping study.

We propose a unique, minimal assumption, approach based on variance analyses (compared with standard approaches) to investigate genetic influence on individual differences on the functional connectivity of the brain using 65 monozygotic and 65 dizygotic healthy young adult twin pairs' low-frequency oscillation resting state functional Magnetic Resonance Imaging (fMRI) data from the Human Connectome Project. Overall, we found high number of genetically-influenced functional (GIF) connections involving posterior to posterior brain regions (occipital/temporal/parietal) implicated in low-level processes such as vision, perception, motion, categorization, dorsal/ventral stream visuospatial, and long-term memory processes, as well as high number across midline brain regions (cingulate) implicated in attentional processes, and emotional responses to pain. We found low number of GIF connections involving anterior to anterior/posterior brain regions (frontofrontal > frontoparietal, frontotemporal, frontooccipital) implicated in high-level processes such as working memory, reasoning, emotional judgment, language, and action planning. We found very low number of GIF connections involving subcortical/noncortical networks such as basal ganglia, thalamus, brainstem, and cerebellum. In terms of sex-specific individual differences, individual differences in males were more genetically influenced while individual differences in females were more environmentally influenced in terms of the interplay of interactions of Task positive networks (brain regions involved in various task-oriented processes and attending to and interacting with environment), extended Default Mode Network (a central brain hub for various processes such as internal monitoring, rumination, and evaluation of self and others), primary sensorimotor systems (vision, audition, somatosensory, and motor systems), and subcortical/noncortical networks. There were >8.5-19.1 times more GIF connections in males than females. These preliminary (young adult cohort-specific) findings suggest that individual differences in the resting state brain may be more genetically influenced in males and more environmentally influenced in females; furthermore, standard approaches may suggest that it is more substantially nonadditive genetics, rather than additive genetics, which contribute to the differences in sex-specific individual differences based on this young adult (male and female) specific cohort. Finally, considering the preliminary cohort-specific results, based on standard approaches, environmental influences on individual differences may be substantially greater than that of genetics, for either sex, frontally and brain-wide. [Correction added on 10 May 2023, after first online publication: added: functional Magnetic Resonance Imaging. Added: individual differences in, twice. Added statement between furthermore … based on standard approaches.].

Heritability of Subcortical Grey Matter Structures.

Background and Objectives: Subcortical grey matter structures play essential roles in cognitive, affective, social, and motoric functions in humans. Their volume changes with age, and decreased volumes have been linked with many neuropsychiatric disorders. The aim of our study was to examine the heritability of six subcortical brain volumes (the amygdala, caudate nucleus, pallidum, putamen, thalamus, and nucleus accumbens) and four general brain volumes (the total intra-cranial volume and the grey matter, white matter, and cerebrospinal fluid (CSF) volume) in twins. Materials and Methods: A total of 118 healthy adult twins from the Hungarian Twin Registry (86 monozygotic and 32 dizygotic; median age 50 ± 27 years) underwent brain magnetic resonance imaging. Two automated volumetry pipelines, Computational Anatomy Toolbox 12 (CAT12) and volBrain, were used to calculate the subcortical and general brain volumes from three-dimensional T1-weighted images. Age- and sex-adjusted monozygotic and dizygotic intra-pair correlations were calculated, and the univariate ACE model was applied. Pearson's correlation test was used to compare the results obtained by the two pipelines. Results: The age- and sex-adjusted heritability estimates, using CAT12 for the amygdala, caudate nucleus, pallidum, putamen, and nucleus accumbens, were between 0.75 and 0.95. The thalamus volume was more strongly influenced by common environmental factors (C = 0.45-0.73). The heritability estimates, using volBrain, were between 0.69 and 0.92 for the nucleus accumbens, pallidum, putamen, right amygdala, and caudate nucleus. The left amygdala and thalamus were more strongly influenced by common environmental factors (C = 0.72-0.85). A strong correlation between CAT12 and volBrain (r = 0.74-0.94) was obtained for all volumes. Conclusions: The majority of examined subcortical volumes appeared to be strongly heritable. The thalamus was more strongly influenced by common environmental factors when investigated with both segmentation methods. Our results underline the importance of identifying the relevant genes responsible for variations in the subcortical structure volume and associated diseases.

Relationship between Serum Testosterone Level and Carotid Intima-Media Thickness among Korean Men and Postmenopausal Women.

Given that the role of serum testosterone on incident cardiovascular disease has been uncertain, it is necessary to find out the relationship between serum testosterone and carotid atherosclerosis. The study participants included 1,302 Korean adults (873 men and 429 postmenopausal women) who participated in the Healthy Twin Study and were not receiving androgen deprivation therapy. The participants were classified into three groups: men aged <40 and ≥40 years and postmenopausal women. Total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations were measured using electrochemiluminescence immunoassays, and free testosterone (cFT) levels were calculated using Vermeulen's method. Carotid intima-media thickness (IMT) was measured at three levels using a high-resolution B-mode ultrasound equipped with a 7-MHz linear transducer. The associations between sex hormone concentrations and carotid IMT were evaluated using a mixed linear regression analysis. After adjusting for cardiovascular risk factors, TT was found to be inversely associated with common carotid IMT in men aged ≥40 years, with a 4.5% decrease in common carotid IMT for every one-standard deviation increase in TT concentration (P=0.0063). In contrast, TT was not significantly associated with carotid IMT in all segments in men aged <40 years and postmenopausal women. Additionally, SHBG and cFT were not associated with carotid IMT in any segment. The significant association between TT level and common carotid IMT in men aged ≥40 years suggests that decreased testosterone levels are involved in the development of atherosclerosis in men.

Wear patterns in knee OA correlate with native limb geometry.

Background: To date, the amount of cartilage loss is graded by means of discrete scoring systems on artificially divided regions of interest (ROI). However, optimal statistical comparison between and within populations requires anatomically standardized cartilage thickness assessment. Providing anatomical standardization relying on non-rigid registration, we aim to compare morphotypes of a healthy control cohort and virtual reconstructed twins of end-stage knee OA subjects to assess the shape-related knee OA risk and to evaluate possible correlations between phenotype and location of cartilage loss. Methods: Out of an anonymized dataset provided by the Medacta company (Medacta International SA, Castel S. Pietro, CH), 798 end-stage knee OA cases were extracted. Cartilage wear patterns were observed by computing joint space width. The three-dimensional joint space width data was translated into a two-dimensional pixel image, which served as the input for a principal polynomial autoencoder developed for non-linear encoding of wear patterns. Virtual healthy twin reconstruction enabled the investigation of the morphology-related risk for OA requiring joint arthroplasty. Results: The polynomial autoencoder revealed 4 dominant, orthogonal components, accounting for 94% of variance in the latent feature space. This could be interpreted as medial (54.8%), bicompartmental (25.2%) and lateral (9.1%) wear. Medial wear was subdivided into anteromedial (11.3%) and posteromedial (10.4%) wear. Pre-diseased limb geometry had a positive predictive value of 0.80 in the prediction of OA incidence (r 0.58, p < 0.001). Conclusion: An innovative methodological workflow is presented to correlate cartilage wear patterns with knee joint phenotype and to assess the distinct knee OA risk based on pre-diseased lower limb morphology. Confirming previous research, both alignment and joint geometry are of importance in knee OA disease onset and progression.

PSAT005 The Third Twin: A Rare Presentation of Adrenocortical Carcinoma

Abstract Introduction Adrenocortical carcinoma (ACC) is rare, even more so during pregnancy. It is frequently aggressive and carries an extremely poor prognosis. Although it is limited to &amp;lt; 2% of adrenal incidentaloma (AI), it remains a significant concern. Here we present a case of ACC that was diagnosed postpartum 4 years after discovering an AI. Case presentation A 30-year-old female G3P4 presented to the emergency department 4-weeks postpartum with intermittent fever and decreased appetite following an uncomplicated vaginal delivery of healthy twin boys. On physical examination, she had a palpable left-sided abdominal mass. She had a known left 2.2×2.2×2 cm adrenal mass that was discovered on Magnetic resonance imaging 4 years prior. At that the time, she had a comprehensive biochemical evaluation with 1 mg overnight dexamethasone suppression test, PM salivary cortisol, 24-hour urine free cortisol, DHEAS, total testosterone, 24-hour urine dopamine, 24-hour urine epinephrine, 24-hour urine norepinephrine, plasma metanephrine, normetanephrine, renin, and aldosterone. This testing was all unrevealing and she was diagnosed with non-functional AI. She did not undergo follow-up repeat imaging. Computed tomography of the abdomen and pelvis obtained on presentation revealed 19.3×15.6×12.7 cm left retroperitoneal heterogeneous soft tissue mass with a Hounsfield Unit (HU) of &amp;gt; 10. Metastatic workup was negative and repeat biochemical testing remained inconsistent with a functional lesion. She underwent radical left nephrectomy and adrenalectomy. Surgical pathology confirmed the diagnosis of ACC confined within the capsule. The surgery was complicated by a pancreatic leak and short-term total parental nutrition. Fortunately, she was doing well at her 4-month postoperative follow-up. Discussion ACC has an extremely poor prognosis, especially in pregnancy and in the postpartum period. A previous study has shown a 50% and 0% survival rate at 1 and 8-year follow-up for pregnant patients, respectively [1]. AI is a common finding radiologically and on autopsy with a prevalence of 1-9%. It is mostly benign nonetheless; ACC can occur in 1.9% of cases. Although a published review article about AI in New England Journal of Medicine recommends no further testing for adrenal masses &amp;lt; 4 cm and HU &amp;lt;10, the Italian Association of Clinical Endocrinologists (AME) recommends repeat imaging 12 months after initial diagnosis to reconfirm diagnosis of a benign adrenal mass [2]. Unfortunately, this patient did not undergo repeat imaging and was subsequently diagnosed with an impressive ACC. Hence, this case highlights the importance of radiologic monitoring of AI.

Bacteroides vulgatus SNUG 40005 Restores Akkermansia Depletion by Metabolite Modulation

Weight loss and exercise intervention have been reported to increase the interaction between Bacteroides spp and Akkermansiamuciniphila (Am), although the underlying mechanisms and consequences of the interaction remain unknown. Using a healthy Korean twin cohort (n= 582), we analyzed taxonomic associations with host body mass index. B vulgatus strains were isolated from mice and human subjects to investigate the strain-specific effect of B vulgatus SNUG 40005 (Bvul) on obesity. The mechanisms underlying Am enrichment by Bvul administration were investigated by multiple experiments: (1) invitro cross-feeding experiments, (2) construction of Bvul mutants with the N-acetylglucosaminidase gene knocked out, and (3) invivovalidation cohorts with different metabolites. Finally, metabolite profiling in mouse and human fecal samples was performed. An interaction between Bvul and Am was observed in lean subjects but was disrupted in obese subjects. The administration of Bvul to mice fed a high-fat diet decreased body weight, insulin resistance, and gut permeability. In particular, Bvul restored the abundance of Am, which decreased significantly after a long-term high-fat diet. A cross-feeding analysis of Am with cecal contents or Bvul revealed that Am enrichment was attributed to metabolites produced during mucus degradation by Bvul. The metabolome profile of mouse fecal samples identified N-acetylglucosamine ascontributing to Am enrichment, which was confirmed by invitro and invivo experiments. Metabolite network analysis of the twin cohort found that lysine serves as a bridge between N-acetylglucosamine, Bvul, and Am. Strain-specific microbe-microbe interactions modulate the mucosal environment via metabolites produced during mucin degradation in the gut.

Comparison of Concordance of Peptic Ulcer Disease, Non-Adenomatous Intestinal Polyp, and Gallstone Disease in Korean Monozygotic and Dizygotic Twins: A Cross-Sectional Study.

Epidemiological studies have suggested the role of multiple genetic and environmental factors in the development of non-neoplastic gastrointestinal (GI) diseases; however, little information is available on these factors in the Korean population. Therefore, this cross-sectional study explored the effect of these factors by analyzing the concordance of several benign GI disorders in 525 monozygotic twins compared to that in 122 dizygotic twins aged >20 years from the Healthy Twin Study data of the Korean Genome and Epidemiology Study (2005–2014). Chi-square test, Wilcoxon rank-sum, and binomial and multinomial logistic regression models were used for statistical analysis. There was lack of concordance of gastric/duodenal ulcers and cholelithiasis/cholangitis between monozygotic twins compared to that in dizygotic twins, suggesting that environmental factors may mediate those concordant disease expressions in monozygotic twins. The concordance of intestinal polyps in monozygotic twins was 32% lower than that in dizygotic twins (p = 0.028), indicating that the effect of genetic factors on the risk for intestinal polyp development may be low. In conclusion, the lack or low concordance of several benign GI diseases between monozygotic and dizygotic twin groups suggests the relative importance of environmental factors, indicating that these are preventable diseases.

COPHYD (Corona Owed Physical Deficiency): The Impact of Lockdown on Cardiopulmonary Function in Paediatric Cardiology Patients.

Due to the Corona-lockdowns the closure of sports facilities and schools has led to a decline in physical activity (PA) for months. PA is essential for maintaining cardiopulmonary function assessed by peak oxygen uptake. Since peak oxygen uptake represents the best predictor for mortality and morbidity in children with congenital heart disease the impact of lockdowns on this parameter is vital. We evaluated retrospectively cardiopulmonary exercise data from our patient collective from before lockdown with twin-paired data from during lockdown. The twin-pairing was achieved by matching patients with similar heart disease, age, sex, and test method. Cardiopulmonary exercise testing was achieved on either the treadmill or the bicycle. We were able to twin-pair 90 cases (26 twins with heart disease and 19 healthy twins). There was a significant decrease of cardiopulmonary function (V̇O2peak: 35.7±9.8 vs.30.4±10.6) in the heart disease cohort along with a significant decrease in peak oxygen pulse (13.3±4.1 vs. 11.4±4.5), and peak minute ventilation (V ̇E: 83.05±29.08 vs.71,49±24.96). The healthy children improved over the timeframe, but this only reached significance for peak minute ventilation (81.72±25.79 vs.97.94±31.4). We observed a significant decline of peak oxygen uptake during lockdown in the group of congenital heart disease (CHD) patients. This involved a loss of cardiac function as well as pulmonary function. This could be explained by limited access to sports facilities and restriction of regular daily movement due to school closure and overprotection. Healthy children improved their pulmonary function. This might be an indication of an improvement of exercise during confinement.Aufgrund des Corona-Lockdowns hat die Schließung von Sportanlagen und Schulen über Monate zu einem Rückgang der körperlichen Aktivität geführt. Körperliche Aktivität ist für die Aufrechterhaltung der kardiopulmonalen Funktion, bewertet durch die maximale Sauerstoffaufnahme, unerlässlich. Da die maximale Sauerstoffaufnahme der beste Prädiktor für Mortalität und Morbidität bei Kindern mit angeborenen Herzerkrankungen ist, sind die Auswirkungen des Lockdowns auf diesen Parameter von entscheidender Bedeutung. Spiroergometriedaten unseres Patientenkollektivs aus der Zeit vor dem Lockdown wurde mit Daten von statistischen Zwillingen aus dem gleichen Kollektiv während des Lockdowns verglichen. Die Zwillingspaarung wurde erreicht, indem Patienten mit ähnlichen Herzerkrankungen, Alter, Geschlecht und Testmodalitäten verglichen wurden. Die Spiroergometrie wurde entweder auf dem Laufband oder auf dem Fahrrad durchgeführt. Insgesamt wurden 90 Datensätze verbunden (26 Zwillinge mit Herzkrankheit und 19 gesunde Zwillinge). In der Kohorte der Herzerkrankten konnte eine signifikante Verschlechterung der kardiopulmonalen Funktion (V̇O2peak: 35,7±9,8 vs. 30,4±10,6), des Spitzensauerstoffpulses (O2puls: 13,3±4,1 vs. 11,4±4,5) und der Spitzenminutenventilation (VE: 83,05 ± 29,08 vs. 71,49 ± 24,96) beobachtet werden. Die gesunden Kinder verbesserten sich im Laufe der Zeit, wobei der Anstieg nur bei der Spitzenminutenventilation (81,72±25,79 vs. 97,94 ± 31,4) signifikant war. in der Kohorte der Patienten mit angeborenen Herzerkrankungen (CHD) beobachteten wir einen deutlichen Rückgang der maximalen Sauerstoffaufnahme während des Lockdowns. Dies liegt begründet in einer Verschlechterung der Herz-, sowie der Lungenfunktion. Erklärung dafür könnte der begrenzte Zugang zu Sporteinrichtungen, sowie Einschränkungen der täglichen Bewegungsfreiheit durch Schulschließungen und Überbehütung sein. Gesunde Kinder konnten ihr Atemminutenvolumen während dem Lockdown steigern und zeigten einen Trend zu besserer Belastbarkeit. Dies könnte auf eine Zunahme der körperlichen Bewegung während des Lockdowns hindeuten.