The frequency and validity of self-reported diagnosis of Parkinson's Disease in the UK elderly: MRC CFAS cohort

BACKGROUND: Estimates of the incidence and prevalence of chronic diseases can be made using established cohort studies but these estimates may have lower reliability if based purely on self-reported diagnosis. METHODS: The MRC Cognitive Function & Ageing Study (MRC CFAS) has collected longitudinal data from a population-based random sample of 13004 individuals over the age of 65 years from 5 centres within the UK. Participants were asked at baseline and after a two-year follow-up whether they had received a diagnosis of Parkinson's disease. Our aim was to make estimates of the incidence and prevalence of PD using self-reporting, and then investigate the validity of self-reported diagnosis using other data sources where available, namely death certification and neuropathological examination. RESULTS: The self-reported prevalence of Parkinson's disease (PD) amongst these individuals increases with age from 0.7% (95%CI 0.5–0.9) for 65–75, 1.4% (95%CI 1.0–1.7) for 75–85, and 1.6% (95%CI 1.0–2.3) for 85+ age groups respectively. The overall incidence of self reported PD in this cohort was 200/100,000 per year (95%CI 144–278). Only 40% of the deceased individuals reporting prevalent PD and 35% of those reporting incident PD had diagnoses of PD recorded on their death certificates. Neuropathological examination of individuals reporting PD also showed typical PD changes in only 40%, with the remainder showing basal ganglia pathologies causing parkinsonism rather than true PD pathology. CONCLUSION: Self-reporting of PD status may be used as a screening tool to identify patients for epidemiological study, but inevitably identifies a heterogeneous group of movement disorders patients. Within this group, age, male sex, a family history of PD and reduced cigarette smoking appear to act as independent risk factors for self-reported PD

PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance

Multi-Omics and Pathway analyses of Genome-Wide associations Implicate Regulation and Immunity in Verbal Declarative Memory Performance

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. to identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals

The Cardiac Response to Reovirus Infection

LI, LIANNA. The Cardiac Response to Reovirus Infection. (Under the direction of Dr. Barbara Sherry). Viral myocarditis is a common disease in humans. Interferon-β (IFN-β) has been identified as critical for protection against viral myocarditis in mouse models, and IFN-α or -β treatment is beneficial in the treatment of human viral myocarditis. IFN-β expression and its antiviral effects are cell-type specific in murine cardiac myocytes and fibroblasts. However, expression and function of individual IFN-α subtypes in cardiac cells has not previously been investigated. Therefore, IFN-α subtype expression and antiviral effects were studied in reovirus-infected murine primary cardiac myocyte and cardiac fibroblast cultures. In order to quantify the thirteen highly conserved IFN-α subtype, a quantitative Real-Time PCR assay was developed. Results demonstrated that IFN-α induction by reovirus T3D in cardiac cells is both subtype- and cell type-specific, and that some individual IFN-α subtypes are likely important in the antiviral cardiac response. In brief, reovirus T3D induced five IFN-α subtypes in primary cultures of cardiac myocytes and fibroblasts: IFN-α1, -α2, -α4, -α5, and -α8/6. The levels of IFN-α expression were both higher and spanned a greater range in cardiac myocytes than in fibroblasts. Viral induction of IFN-α1, -α2, -α5, and -α8/6 required IFN-α/β signaling in both cell types, while induction of IFN-β and -α4 was more dependent on IFN signaling in myocytes than fibroblasts. Murine IFN-α1, -α2, -α4, or -α5 treatment induced IRF7 and ISG56 in both cardiac cell types, however induction was always greater in cardiac fibroblasts than in cardiac myocytes. Finally, each IFN-α subtype inhibited reovirus T3D replication in both cell types, but protection was subtype-specific. To discover novel proteins or protein post-translational modifications involved in the IFN pathway or displaying antiviral effects against viral myocarditis, a proteomics tool, two-dimensional difference gel electrophoresis (2D-DIGE) coupled with MALDI-TOF-TOF, was used to investigate the reovirus-induced proteome changes in murine primary cardiac myocyte cultures. Results demonstrated that the 2D-DIGE technique is quantitative and reproducible. Whole proteome changes based on differentially expressed proteins were clustered according to viral pathogenic phenotypes and induction of IFN. One hundred and twenty-four differentially expressed proteins were identified, including those involved in calcium signaling, ERK/ MAPK signaling, protein ubiquitination, mitochondrial dysfunction, oxidative stress, amino acid metabolism, and other pathways. Interestingly, 2D-DIGE results and additional studies demonstrated that heat shock protein Hsp25 is modulated differentially by myocarditic and non-myocarditic reoviruses, and suggested that it may play a role in the cardiac antiviral response. This is the eighth virus family found to modulate Hsp25 or its human homolog, Hsp27, suggesting that Hsp25/27 participation in the antiviral response may be widespread. However, results here provide the first evidence for a virus-induced decrease in Hsp25/27, and suggest that viruses may have evolved a mechanism to subvert this protective response, as they have for IFN

Efficacy, Safety, and Tumor Marker Inhibition of Apatinib Combined with Conventional Chemotherapy Regimens for Patients with Advanced Triple-Negative Breast Cancer

Objective. Triple-negative breast cancer (TNBC) is an aggressive disease with highly invasive nature and poor outcomes. Due to the absence of specific treatment strategies for this tumor subgroup, patients with TNBC are treated with conventional therapeutics, frequently leading to systemic relapse. In this study, we sought to investigate apatinib combined with conventional chemotherapy regimens in treating patients with advanced TNBC concerning the efficacy, safety, expressions of tumor markers, and patient survival. Methods. This is a prospective study including 150 cases of advanced TNBC who were randomly arranged into a conventional group and combined group, with 75 cases per group. The patients in the conventional group were treated with conventional chemotherapy, and those in the combined group were treated with apatinib combined with conventional chemotherapy. The peripheral blood was collected from each patient, and carcinoembryonic antigen (CEA), carbohydrate antigen 153 (CA153), and carbohydrate antigen 125 (CA125) were determined. The expressions of nuclear proliferation antigen marker (Ki67), β-catenin, and E-cadherin were determined in the biopsy collected from each patient. Results. The objective remission rate (ORR) and disease control rate (DCR) (41.33% and 81.33%) in the combined group were notably higher than those in the conventional group (29.33% and 68.00%) ( P &lt; 0.05 ). After treatment, the serum levels of CEA, CA153, and CA125 and the expressions of Ki67 and β-catenin were declined, but the expression of E-cadherin was increased in both groups; the combined group exhibited lower serum levels of CEA, CA153, and CA125, and the expressions of Ki67 and β-catenin were concurrent with a higher expression of E-cadherin than the conventional group ( P &lt; 0.05 ). No significant difference was noted between the two groups regarding the occurrence of adverse reactions ( P &gt; 0.05 ). Improved progression-free survival (PFS) was observed in the combined group compared to the conventional group ( P &lt; 0.05 . Conclusion. These findings suggest that apatinib combined with conventional chemotherapy regimens confers a prolonged PFS for treating patients with advanced TNBC.</jats:p