Effects of pre- and post- natal exposure to flutamide on connexin 43 expression in testes and ovaries of prepubertal pigs

The aim of this study was to show whether connexin43 (C×43) expression in gonads is affected by an anti-androgen action. To perform this test, pigs were prenatally (on gestational days 20–28 and 80–88; GD20, GD80) and postnatally (on days 2–10 after birth; PD2) exposed to flutamide, which was given in five doses every second day and its effect was observed in prepubertal gilts and boars. Morphology and expression of C×43 was investigated in testes and ovaries by means of routine histology, immunohistochemistry, Western blotting, and RT-PCR. In boars exposed to flutamide varying degrees of seminiferous tubule abnormality, including reduced number of Sertoli cells, tubules with severely dilated lumina and multinucleated germ cells were observed, whereas in gilts, the administration of flutamide at GD20 resulted in delayed folliculogenesis. Only follicles at the preantral stage were observed. Qualitative analysis of immunohistochemical staining for C×43 was confirmed by quantitative image analysis, where the staining intensity was expressed as relative optical density of diaminobenzidine deposits. After flutamide exposure, statistically significant increase in C×43 signal intensity was observed between interstitial tissue of GD20 and control pigs (**P<0.01), between seminiferous tubules of PD2 and control boars (**P<0.01) and between theca cells of GD80, of PD2 and control gilts (**P<0.01). In contrast, statistically significant decrease in C×43 signal intensity was found between granulosa cells of GD20, of PD2 and control gilts (**P<0.01 and *P<0.05, respectively) and between theca cells of GD20 and control gilts (**P<0.01). Since we demonstrated changes in gonad morphology and in the expression of C×43 at the level of protein of prepubertal boars and gilts, it seems possible that flutamide, through blocking androgen action, causes delayed gonadal maturation in later postnatal life and, among other factors, may be involved in the regulation of C×43 gene expression in pig gonads

Чутливість рецепторів клітин ендометрію до естрогенів та прогестерону у корів хворих на субклінічний ендометрит

Pathological processes that strongly affect the uterine endometrium lead to infertility and abortion. The most common of these pathologies are clinical and subclinical endometritis. Subclinical endometritis is characterized by endometrial inflammation in the absence of clinical signs of endometritis. In this study, we used uterine samples obtained from Ukrainian black-and-white dairy cows aged 4 to 7 years to compare the histology of the uterine endometrium and changes in estrogen-α (ER-α), estrogen-β (ER-β) and progesterone (PgR) nuclear receptor sensitivity in cows with subclinical endometritis. Cows were separated based on cytological examination of the endometrium into a healthy group, or those presenting with subclinical endometritis. From these groups endometrial and epithelial tissue samples were obtained using biopsy forceps and an endoscope then analyzed using immunohistochemistry. Our results demonstrate that the sensitivity of ER-α and ER-β is lower while PgR sensitivity is elevated in cows with subclinical endometritis compared to the healthy control group. Additionally, we observed markedly altered histological changes characterized by enlargement of uterine glands, epithelial desquamation, and infiltration of leukocytes. These results suggest that there are significant changes in the endometrium linked to the sensitivity of nuclear steroid hormone receptors that may also play an immunoregulatory role in cows with subclinical endometriosis. While the interaction of steroid hormones and immunoregulation in the uterus remains to be elucidated, it may provide key insights into the uterine immune response.В основі патологічних процесів, що проходять у матці приводять до неплідності та абортів, важливу роль відіграє ендометрій. Найбільш поширеними патологіями, що проходять у матці є клінічний та субклінічний ендометрит. Субклінічний ендометрит характеризується запальним процесом у ендометрії без клінічних ознак. Метою нашої роботи було проаналізувати гістологічні зміни та зміни чутливості ендометрію матки до естроген-α (ER-α), естроген-β (ER-β) та прогестерону (PgR), що відбуваються у матці здорових корів та у корів за субклінічного ендометриту. Дослідження проводилось на двох групах корів української чорно-рябої молочної породи віком від 4 до 7 років. На основі цитологічного дослідження ендометрію, корови були поділені на дві групи. Контрольну групу (К), що включала клінічно здорових корів, та дослідну (Д), що включала корів хворих на субклінічний ендометрит. Надалі проводили забір зразків за допомогою біопсійних щипців та ендоскопу. Наші результати дають змогу більш глибоко зрозуміти процеси, що відбуваються у ендометрії корів хворих на субклінічний ендометрит. Активність рецепторів ядер ER-α, ER-β та PgR спостерігали у епітелії ендометрію, епітелії маткових залоз та стромі ендометрію. Активність рецепторів ядер ER-α та ER-β була нижчою у корів з субклінічним ендометритом, ніж у корів контрольної групи. Активність рецепторів ядер PgR була вищою у корів хворих на субклінічний ендометрит, ніж у корів контрольної групи. На основі отриманих даних встановлено, що ендометрій хворих на субклінінчий ендометрит зазнає значних змін, що характеризується появою лейкоцитів, розширенням маткових залоз та ділянками десквамації епітелію. Зміни відбуваються на основі чутливості ядер ендометрію до рецепторів ER-α, ER-β та PgR. Чутливість ендометрію до гормонів є важливою у локальному захисті матки. В перспективі подальших досліджень слід вивчити експресію стероїдних гормонів та цитокінів у корів хворих на субклінічний ендометрит

Опыт применения золадекса у больных эндометриозом и рецидивирующими гиперпластическими процессами эндометрия

ЭНДОМЕТРИОЗ /ЛЕК ТЕРЭНДОМЕТРИЯ ГИПЕРПЛАЗИЯ /ЛЕК ТЕРЗОЛАДЕК

Quantitative Modeling of Cerenkov Light Production Efficiency from Medical Radionuclides

There has been recent and growing interest in applying Cerenkov radiation (CR) for biological applications. Knowledge of the production efficiency and other characteristics of the CR produced by various radionuclides would help in accessing the feasibility of proposed applications and guide the choice of radionuclides. To generate this information we developed models of CR production efficiency based on the Frank-Tamm equation and models of CR distribution based on Monte-Carlo simulations of photon and β particle transport. All models were validated against direct measurements using multiple radionuclides and then applied to a number of radionuclides commonly used in biomedical applications. We show that two radionuclides, Ac-225 and In-111, which have been reported to produce CR in water, do not in fact produce CR directly. We also propose a simple means of using this information to calibrate high sensitivity luminescence imaging systems and show evidence suggesting that this calibration may be more accurate than methods in routine current use

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations:Experience from the MJFF Global Genetic Parkinson's Disease Project

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.</p

Using global team science to identify genetic parkinson's disease worldwide.

No abstract available

Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Michael J. Fox Foundation for Parkinson's Research. Grant Number: ID 15015.02. NIHR Cambridge Biomedical Research Centre. Grant Number: BRC-1215-20014info:eu-repo/semantics/publishedVersio

Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array

We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration