A short story of the long telomere : evidence in aging epidemiology

Telomeres are the sequences of nucleotides at the end of chromosomes. Each time a cell divides, telomeres become shorter. The length of telomeres can be replenished by an enzyme, telomerase. Telomere shortening is hypothesized as the biological origin of aging. Indeed, telomeres are shorter in people with various diseases than others. Whether these observed associations are causal or due to other factors that could be the common causes of both telomere shortening and diseases are largely unknown. In this thesis, we aimed to disentangle the relationship between telomere length and several aging-associated diseases and traits to enhance our understanding of the biology underpinning disease pathogenesis. In Study I, we performed a Mendelian randomization (MR) study examining the association between telomere length and Alzheimer’s disease, using genome-wide association study (GWAS) summary statistics data released by the International Genomics of Alzheimer’s Project Consortium. We used seven single-nucleotide polymorphisms (SNPs) identified to be of genome-wide significance for telomere length as instrumental variables. The MR analysis showed that shorter telomere length was associated with higher odds of Alzheimer’s disease. In Study II, we explored the potential pathways from telomere length to coronary heart disease using network MR method. The same seven SNPs were used as instrumental variables as in Study I. Various GWAS summary statistics data of metabolic biomarkers and coronary heart disease were used. The MR analyses found that shorter telomeres were associated with higher levels of insulin, which also had an eff ect on coronary heart disease. Overall, this study indicates that insulin lies in the pathway from shorter telomeres to coronary heart disease. In Study III, we investigated the association of telomere length with trajectories of general cognitive abilities in two Swedish cohorts (SATSA and GENDER) and two US cohorts (MCSA and HRS). Telomere length was measured once, while general cognitive abilities were assessed repeatedly at up to seven occasions. Latent growth curve models were applied to examine the associations. We found that shorter telomere length was associated with lower mean levels of general cognitive ability in the age-adjusted models, but not in models when other covariates were further considered. We did not find evidence to support that telomere length was associated with the decline of general cognitive ability. In Study IV, we revisited the association of telomere length with all-cause mortality, allowing for time-varying eff ects in a Swedish twin sample where shared familial confounding could be controlled for. Telomere length was measured using Southern blot method, and data of all-cause mortality was obtained from the Swedish Population Registry. We applied between-within analyses in a shared-frailty generalized survival model framework. We found that shorter telomere length was associated with higher mortality rate when controlling for shared familial confounding. Further, we found significant time-varying effects of telomere length on mortality. In summary, we presented novel evidence about the role of shorter telomere length in aging related diseases and traits in this thesis. We took advantage of publicly available GWAS summary statistics data as well as individual-level cohort data and used various innovative designs and statistical methods to achieve this. This compiled thesis could contribute substantially to the literature of the short and long story of telomeres

Birthweight, BMI in adulthood and latent autoimmune diabetes in adults : a Mendelian randomisation study

Aims/hypothesis Observational studies have found an increased risk of latent autoimmune diabetes in adults (LADA) associated with low birthweight and adult overweight/obese status. We aimed to investigate whether these associations are causal, using a two-sample Mendelian randomisation (MR) design. In addition, we compared results for LADA and type 2 diabetes. Methods We identified 43 SNPs acting through the fetal genome as instrumental variables (IVs) for own birthweight from a gcnomc-wide association study (GWAS) of the Early Growth Genetics Consortium (EGG) and the UK Biobank. We identified 820 SNPs as IVs for adult BMI from a GWAS of the UK Biobank and the Genetic Investigation of ANthropometric Traits consortium (GIANT). Summary statistics for the associations between IVs and LADA were extracted from the only GWAS involving 2634 cases and 5947 population controls. We used the inverse-variance weighted (IVW) estimator as our primary analysis, supplemented by a series of sensitivity analyses. Results Genetically determined own birthweight was inversely associated with LADA (OR per SD [similar to 500 g] decrease in birthweight 1.68 [95% CI 1.01, 2.82]). In contrast, genetically predicted BMI in adulthood was positively associated with LADA (OR per SD [similar to 4.8 kg/m(2)] increase in BMI 1.40 [95% CI 1.14, 1.71]). Robust results were obtained in a range of sensitivity analyses using other MR estimators or excluding some IVs. With respect to type 2 diabetes, the association with birthweight was not stronger than in LADA while the association with adult BMI was stronger than in LADA. Conclusions/ interpretation This study provides genetic support for a causal link between low birthweight, adult overweight/obese status and LADA.Peer reviewe

Lipids, apolipoproteins, and prognosis of amyotrophic lateral sclerosis

Objective: To determine whether lipids and apolipoproteins predict prognosis of patients with amyo- trophic lateral sclerosis in a cohort study of 99 patients with amyotrophic lateral sclerosis who were diagnosed during 2015 to 2018 and followed up until October 31, 2018, at the Neurology Clinic in Karolinska University Hospital in Stockholm, Sweden. Methods: Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein AI, apolipoprotein B, and lipid ratios were measured at the time of amyotrophic lateral sclerosis diagnosis or shortly thereafter. Death after amyotrophic lateral sclerosis diagnosis was used as the main outcome. The Cox model was used to estimate hazard ratios with 95% confidence intervals of death after amyotrophic lateral sclerosis diagnosis, after controlling for sex, age at diagnosis, site of symptom onset, diagnostic delay, body mass index, Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised score, and progression rate. Results: A 1-SD increase of total cholesterol (hazard ratio 0.60, 95% confidence interval 0.41–0.89, p = 0.01), low-density lipoprotein cholesterol (hazard ratio 0.64, 95% confidence interval 0.44–0.92, p = 0.02), low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (hazard ratio 0.65, 95% confidence interval 0.46–0.92, p = 0.02), apolipoprotein B (hazard ratio 0.62, 95% confidence interval 0.44–0.88, p = 0.01), or apolipoprotein B/apolipoprotein AI ratio (hazard ratio 0.61, 95% confidence interval 0.43–0.86, p < 0.01) was associated with a lower risk of death after amyotrophic lateral sclerosis diagnosis. A dose-response relationship was also noted when these biomarkers were analyzed as categorical variables. Conclusions: Lipids and apolipoproteins are important prognostic indicators for amyotrophic lateral sclerosis and should be monitored at the diagnosis of amyotrophic lateral sclerosis.Swedish Research CouncilEuropean Research CouncilPublishe

Registering Histological and MR Images of Prostate for Image-based Cancer Detection

Rationale and Objectives Needle biopsy is currently the only way to confirm prostate cancer. To increase prostate cancer diagnostic rate, needles are expected to be deployed at suspicious cancer locations. High contrast MR imaging provides a powerful tool for detecting suspicious cancerous tissues. To do this, MR appearances of cancerous tissue should be characterized and learned from a sufficient number of prostate MR images with known cancer information. However, ground-truth cancer information is only available in histological images. Therefore, it is necessary to warp ground-truth cancerous regions in histological images to MR images by a registration procedure. The objective of this paper is to develop a registration technique for aligning histological and MR images of the same prostate. Material and Methods Five pairs of histological and T2-weighted MR images of radical prostatectomy specimens are collected. For each pair, registration is guided by two sets of correspondences that can be reliably established on prostate boundaries and internal salient blob-like structures of histological and MR images. Results Our developed registration method can accurately register histological and MR images. It yields results comparable to manual registration, in terms of landmark distance and volume overlap. It also outperforms both affine registration and boundary-guided registration methods. Conclusions We have developed a novel method for deformable registration of histological and MR images of the same prostate. Besides the collection of ground-truth cancer information in MR images, the method has other potential applications. An automatic, accurate registration of histological and MR images actually builds a bridge between in vivo anatomical information and ex vivo pathological information, which is valuable for various clinical studies

Особенности сбора анамнеза при рецидивирующих бронхолегочных заболеваниях у детей, ассоциированных с ГЭРБ

ЖЕЛУДОЧНО-КИШЕЧНЫЙ ТРАКТ /патолгастроэзофагеальный рефлюксЛЕГКИХ БОЛЕЗНИАНАМНЕЗА СБОРДЕТ

A glassy carbon electrode modified with tailored nanostructures of cobalt oxide for oxygen reduction reaction

Herein we report on various surface morphological characteristics of the synthesized cobalt oxide (Co3O4) nanostructures obtained by means of facile one-step hydrothermal method for oxygen reduction reaction (ORR). The synthesized nanostructures of Co3O4 were adequately characterized by field emission scanning electron microscopy (FESEM) fitted with Energy-dispersive X-ray spectroscopy (EDX) elemental mapping, X-ray diffraction (XRD) and Raman techniques. The electrochemical studies were carried out to analyse the performance of as-synthesized catalysts for ORR by cyclic voltammetry (CV), and chronoamperometric (CA) techniques. A higher electrocatalytic response was observed for Co3O4 nanocubes compared with all the other controlled electrodes by CV with a current density of 0.69 mA/cm2 at a potential value of −0.46 V. The as-synthesized material showed adequate tolerance against methanol observed by CV in the presence of 0.5 M methanol, and good stability when compared with commercial Pt/C catalyst using the CA technique