Influence of the X-chromosome on neuroanatomy: evidence from Turner and Klinefelter syndromes.

Studies of sex effects on neurodevelopment have traditionally focused on animal models investigating hormonal influences on brain anatomy. However, more recent evidence suggests that sex chromosomes may also have direct upstream effects that act independently of hormones. Sex chromosome aneuploidies provide ideal models to examine this framework in humans, including Turner syndrome (TS), where females are missing one X-chromosome (45X), and Klinefelter syndrome (KS), where males have an additional X-chromosome (47XXY). As these disorders essentially represent copy number variants of the sex chromosomes, investigation of brain structure across these disorders allows us to determine whether sex chromosome gene dosage effects exist. We used voxel-based morphometry to investigate this hypothesis in a large sample of children in early puberty, to compare regional gray matter volumes among individuals with one (45X), two (typically developing 46XX females and 46XY males), and three (47XXY) sex chromosomes. Between-group contrasts of TS and KS groups relative to respective sex-matched controls demonstrated highly convergent patterns of volumetric differences with the presence of an additional sex chromosome being associated with relatively decreased parieto-occipital gray matter volume and relatively increased temporo-insular gray matter volumes. Furthermore, z-score map comparisons between TS and KS cohorts also suggested that this effect occurs in a linear dose-dependent fashion. We infer that sex chromosome gene expression directly influences brain structure in children during early stages of puberty, extending our understanding of genotype-phenotype mechanisms underlying sex differences in the brain

Systems identification and application systems development for monitoring the physiological and health status of crewmen in space

The use of automated, analytical techniques to aid medical support teams is suggested. Recommendations are presented for characterizing crew health in terms of: (1) wholebody function including physiological, psychological and performance factors; (2) a combination of critical performance indexes which consist of multiple factors of measurable parameters; (3) specific responses to low noise level stress tests; and (4) probabilities of future performance based on present and periodic examination of past performance. A concept is proposed for a computerized real time biomedical monitoring and health care system that would have the capability to integrate monitored data, detect off-nominal conditions based on current knowledge of spaceflight responses, predict future health status, and assist in diagnosis and alternative therapies. Mathematical models could play an important role in this approach, especially when operating in a real time mode. Recommendations are presented to update the present health monitoring systems in terms of recent advances in computer technology and biomedical monitoring systems

Classic cardiovascular risk factors improve in very elderly hypopituitary patients treated on standard hormone replacement in long term follow-up

Background - Hypopituitarism in the elderly population is an underdiagnosed condition and may increase comorbidities related to glucose metabolism, dyslipidemia, and cardiovascular risk factors. Optimization of hormone replacement that considers alterations in clearance rates of hormones, interaction with other medications, and evaluation of the risk-benefit ratio of treatment is a big challenge for clinical practice. Objectives - This study aimed to evaluate classic cardiovascular risk factors in hypopituitary septuagenarians and octagenarians by diagnosis and after long-term hormone replacement. Methods - This is a retrospective observational study, with patients recruited and selected from a registry in a tertiary medical center. We included patients aged 70–99 years with hypopituitarism, evaluated hormonal and biochemical parameters, and cardiovascular risk scores were calculated by diagnosis and compared after long-term follow-up. All patients gave informed consent. Patient data were compared to a sex and age-matched control group, with long-term geriatric follow-up, without endocrine diseases. Results - Thirty-five patients were included, 16 patients aged 70–75 years (72.61), 12 patients 76–80 years (72.28), 7 patients 81–99 years (89.28). Pituitary macroadenomas were the main cause of hypopituitarism, mean maximal diameter 3.4 cm (2.9–4.3), and invasive craniopharyngiomas. At the moment of diagnosis, most patients were overweight, and abdominal adiposity was observed in 76.9% of women and 36.4% of men, primarily in octagenarians and nonagenarians. Comorbidities were frequent; 85.7% presented hypertension, 37.1% diabetes, 53.1% low HDL, 51.5% hypertriglyceridemia. Most patients presented more than two combined pituitary deficiencies; hypogonadism in 88.6%, central hypothyroidism in 82.9%, GH deficiency in 65.7%, and adrenal insufficiency in 25.7%. Analysis of cardiovascular risk prediction in the total cohort showed that 57.1% of patients presented a reduction in the General Cardiovascular Disease (CVD) Risk Prediction Score and 45.7% in atherosclerotic CVD risk estimated by ACC/AHA 2013 Pooled Cohort Equation, despite being submitted to conventional hormone replacement, during the mean follow-up of 14.5 years. This reduction was not observed in the control group. Discussion and conclusion - In this study, aged hypopituitary patients presented a reduction in estimated general CVD risk during long-term follow-up, despite replacement with corticosteroids, levothyroxine, or gonadal steroids. Early diagnosis and treatment of hypopituitarism in the elderly remain challenging. Larger studies should be performed to assess the risk-benefit ratio of hormone replacement on the metabolic profile in septuagenarian and octogenarian patients

Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function

The recent unraveling of structures of genes for the gonadotropin subunits and gonadotropin receptors has provided reproductive endocrinologists with new tools to study normal and pathological functions of the hypothalamic-pituitary-gonadal axis. Rare inactivating mutations that produce distinctive phenotypes of isolated LH or FSH deficiency have been discovered in gonadotropin subunit genes. In addition, there is a common polymorphism in the LHbeta subunit gene with possible clinical significance as a contributing factor to pathologies of LH-dependent gonadal functions. Both activating and inactivating mutations have been detected in the gonadotropin receptor genes, a larger number in the LH receptor gene, but so far only a few in the gene for the FSH receptor. These mutations corroborate and extend our knowledge of clinical consequences of gonadotropin resistance and inappropriate gonadotropin action. The information obtained from human mutations has been complemented by animal models with disrupted or inappropriately activated gonadotropin ligand or receptor genes. These clinical and experimental genetic disease models form a powerful tool for exploring the physiology and pathophysiology of gonadotropin function and provide an excellent example of the power of molecular biological approaches in the study of pathogenesis of diseases

Adenokartsinoomi mikrokeskkonna muutuste kvantifitseerimine ja diagnostilise tähenduse hindamine eesnäärmes, rakendades uuemaid digipatoloogilisi programmiarendusi

Väitekirja elektrooniline versioon ei sisalda publikatsiooneEesnäärme adenokartsinoom on meestel diagnoositud pahaloomulistest kasvajatest maailmas sageduselt teisel kohal ning viiendal kohal vähkidest põhjustatud meeste surmadest. Tervise Arengu Instituudi andmetel diagnoositi 2017. aastal Eestis prostata adenokartsinoomi 1113 juhul, mis moodustas 25,2% kõikidest pahaloomulistest kasvajatest. Haiguse diagnoos püstitatakse enne radikaalset prostatektoomiat kasutades biopsiate uuringut. Kuigi eesnäärme bioptaatide käsitluses toimub pidev areng, on jätkuvalt suur tõenäosus, et radikaalse prostatektoomia järgselt muutub kasvaja histoloogiline aste – Gleason’i skoor hinnatakse prostatektioomia materjali alusel raskemaks 23,3% kuni 42,7% juhtudest. Kõikidel bioptaatidel on epiteliaalset komponenti ümbritsev mikrokeskkond, mis potentsiaalselt võib anda täiendavat diagnostilist ja prognostilist informatsiooni. Selle hüpoteesi testimiseks kasutati kahte stromaalset markerit: Masson’i trikroomi ja antud paikme vaates uut markerit anti-FANCM antikeha. Kvantitatiivne stromaalsete muutuste hindamine mikroskoobis on sageli aeganõudev, väljakutseid pakkuv ning hindajast lähtuvalt subjektiivne. Tänapäevaste digitaalse patoloogia lahendustega saaks hinnangu anda kiirelt ja usaldusväärselt. Uurimistöö käigus töötati välja avatud lähtekoodiga programm Pathadin, mis imiteerib patoloogi üldiseid töövõtteid. Arsti poolt treenitud mudel õppis eristama eesnäärme erinevaid struktuure – näärmeid, närve, stroomat, rasva ja optilisi tühimikke, analüüsima neid, kasutama erinevaid filtreid, näiteks värvifiltrit strooma analüüsiks (FANCM, Masson’i trikroom) ning loendama näärmelises komponendis DAB positiivsete rakkude hulka. Mudel sai hakkama oluliste diagnostiliste parameetrite skriinimisega, näiteks tuvastas eesnäärmes edukalt perineuraalse invasiooni ja ekstraprostaatilise leviku. Uurimistöö tulemuste alusel saab välja tuua mitmed olulised järeldused. Esiteks kirjeldab töö süsteemselt ära uue immunohistokeemilise markeri FACNM kasutamise eesnäärmes. Teiseks tõestab, et stromaalset päritolu muutused on Gleason’i skoorist sõltuvad, kuid on piiratud väärtusega madala tundlikkuse tõttu. Kolmandaks näitab, et masinõpe kui mitte veel täielikult usaldusväärne inimesest sõltumatute lõplike diagnooside püstitamisel, võib juba praegu olla abiks histoloogilistes ja teaduslikes uuringutes. Töö kirjelduses esitatud juhendid on universaalsed: neid saab kasutada erinevatel kudedel, nad võiksid julgustada patolooge kasutama arvuti poolt abistatavat diagnostikat ning looma ja arendama oma mudeleid.Prostate adenocarcinoma is the second most frequently diagnosed cancer in males worldwide. According to 2017 data of the Estonian National Institute for Health Development, it was diagnosed in 1113 cases, making 25.2% of all diagnosed malignancies. The standard for the definitive diagnosis prior to the radical prostatectomy is a systematic biopsy sampling. Nevertheless, despite the progress in biopsy sampling, the final Gleason score is upgraded in 23.3% to 42.7% of all radical prostatectomy samples. To increase the concordance between biopsy and prostatectomy, an idea of evaluating the diagnostic significance of microenvironmental changes surrounding the epithelial component has emerged. Two markers were tested to study stromogenic changes — Masson’s trichrome and, a novel in the prostate, anti-FANCM antibody. The precise quantification of histological stains using a microscope is frequently time-consuming, challenging, and depends on human reliability. However, modern digital pathology solutions could perform the analysis quickly and accurately. During the studies, an open-source set of tools under the name of Pathadin and a model for prostate segmentation were developed. The program imitates pathologists' work in its basics: trained by a doctor, it learned to distinguish glands, nerves, stroma, fat, and empty compartments in the prostate to analyze these independently and apply specific filters such as color analysis for FANCM and Masson’s trichrome in the stroma, or DAB positive cell counting in the glandular component. The model was also able to assist in the screening of significant diagnostic features, as the perineural invasion or extraprostatic extension. The work had several essential outcomes. Firstly, a novel in the prostate immunohistochemical marker, FACNM, was systematically described. Secondly, it was shown that stromogenic changes are indeed Gleason dependant yet are of a limited clinical value due to low sensitivity. Thirdly, if not yet fully reliable for independent definitive diagnoses, machine learning can already be beneficial in histological routines and scientific research. The workflow and manuals provided in the manuscript are somewhat universal and can be used for different tissues, encouraging pathologists to test computer-assisted diagnostics and train their own, more advanced, models.https://www.ester.ee/record=b546203

Knowledge-based trend detection and diagnosis

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1994.Includes bibliographical references (p. 167-181) and index.by Ira Joseph Haimowitz.Ph.D

Early Life Determinants of Metabolic and Reproductive Health

Events in early life have consistently been associated with health outcomes in later life. The ‘developmental origins’ theory first hypothesised that adverse conditions in-utero can lead to physiological adaptations in the developing foetus which have long lasting influences on health. This concept has been extended to early childhood and adolescence, whereby exposures during critical periods of development can impact health throughout the life course of an individual. In particular, a secular trend for a decreasing age of puberty onset has been linked to the global increases in prevalence of cardio-metabolic diseases and cancer. It has been suggested that childhood obesity and lifetime sex hormone exposure may act as key mediating factors in this relationship. As the prevalence of obesity continues to rise globally and consequent comorbidities place an increasing burden on healthcare systems, understanding the mechanisms that link early life events to later life health have become of increasing importance. While environmental exposures are often cited as being highly influential on growth and development, the role of genetics has become gradually more apparent in recent years. This has been aided by the availability of increasingly large data resources. Genetic studies have shown that many developmental traits are highly heritable and share genetic determinants with metabolic and reproductive health outcomes. In this thesis I use data from large-scale, population-based resources to further elucidate the role of genetic and epigenetic factors in explaining observed associations between developmental traits and later life metabolic and reproductive health. I begin by examining the genetic aetiology of puberty timing in men, a key stage of sexual development which is understudied compared to women. I identify 29 novel genes involved in the control of puberty timing, implicating new biological pathways and demonstrate genetic correlations between earlier age of puberty and adverse health in adulthood. I then expand on the theme of genetic discovery by conducting genome-wide association studies (GWAS) for reproductive traits in the UK Biobank study. These outcomes have important societal and public health impacts but many have not previously been investigated from a genetic perspective. I identify over 800 variant-trait associations, highlighting genomic regions with highly pleiotropic influences on a diverse range of reproductive traits. This data is then leveraged to construct a framework for conducting phenome-wide association studies (PheWAS), which is used to explore the extent to which both BMI and sex hormone exposure act as mediating factors to explain the link between earlier puberty and heightened reproductive health risks. I go on to examine mechanisms linking early life markers of development to adult health. I investigate the association between weight at birth and body composition in adulthood, determining that foetal and maternal-specific genetic determinants of birth weight have differential influences on fat and lean mass distribution. Downstream analyses suggest that these operate through distinct biological pathways, adding to our understanding of the association between low birth weight and poor health. Finally, I conduct an epigenome-wide association study (EWAS) as a complementary approach to GWAS for both BMI and puberty timing to identify additional genomic loci associated with both traits. Using EWAS data I present evidence for a casual epigenetic effect on puberty timing, functioning through both BMI-mediated and independent pathways. The findings from this thesis contribute to the understanding of the genetic determinants of early life developmental processes and their relationship with later health, which have important implications for the improvement of individualised disease prevention and management

Science, Physiology, and Nutrition For the Nonscientist

A wonderful blend of physiology, nutrition, biochemistry, genetics, biology, evolution, chemistry--what we all need to know as informed citizens. A basic knowledge of the life sciences and how our bodies work--to promote our own good health, especially as we\u27re bombarded with misleading advertisements, soundbites, and the like. DNA fingerprinting, calorie requirements, dietary advice, genetic engineering (including gene editing with CRISPR cas9)--all in an easy-to understand book.https://scholarworks.sjsu.edu/oer/1002/thumbnail.jp