A systematic review investigating fatigue, psychological and cognitive impairment following TIA and minor stroke:protocol paper

Approximately 20,000 people have a transient ischemic attack (TIA) and 23,375 have a minor stroke in England each year. Fatigue, psychological and cognitive impairments are well documented post-stroke. Evidence suggests that TIA and minor stroke patients also experience these impairments; however, they are not routinely offered relevant treatment. This systematic review aims to: (1) establish the prevalence of fatigue, anxiety, depression, post-traumatic stress disorder (PTSD) and cognitive impairment following TIA and minor stroke and to investigate the temporal course of these impairments; (2) explore impact on quality of life (QoL), change in emotions and return to work; (3) identify where further research is required and to potentially inform an intervention study

IGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort

The insulin-like growth factor 1 gene (IGF1) is a strong candidate gene for a breast cancer susceptibility model. We investigated a dinucleotide repeat 969 bp upstream from the transcription start site of the IGF1 gene for possible associations with plasma IGF1 levels and breast cancer risk in a multiethnic group of postmenopausal women. Furthermore, we investigated the relation between race/ethnicity, mean plasma IGF1 levels and breast cancer rates in the Hawaii/Los Angeles Multiethnic Cohort. The mean age-adjusted IGF1 level among Latino-American women, 116 ng ml(-1), was statistically significantly lower than the mean age-adjusted IGF1 levels for each of the three other racial/ethnic groups, African-American, Japanese-American and Non-Latino White women (146, 144 and 145 ng ml(-1), respectively) (P<0.0001). Latino-American women have the lowest breast cancer rates of any racial/ethnic group in the cohort. These results support the investigation of an expansion of the hypothesis for an important role of IGF1 in breast cancer tumorigenesis to different racial/ethnic groups and to postmenopausal women. It is unlikely that any involvement of IGF1 in breast cancer aetiology is mediated by the IGF1 dinucleotide repeat polymorphism, which was not significantly associated with circulating IGF1 levels nor breast cancer risk in this study. Research into relevant determinants of IGF1 levels in the blood must continue

Serum cytokine and glucose levels as predictors of poststroke fatigue in acute ischemic stroke patients

Fatigue is a common but often overlooked symptom after stroke. This study investigated whether stroke type, infarct volume, and laterality, as well as the levels of various cytokines and other blood components in the acute phase of acute ischemic stroke (AIS), can predict the level of fatigue at 6, 12, and 18 months after its onset. In 45 patients with acute stroke, serum levels of C-reactive protein, hemoglobin, glucose, and 13 cytokines were measured within 72 h of stroke onset. The cytokine measurements were performed using BioPlex XMap technology (Luminex). The acute serum levels of interleukin (IL)-1β and glucose were positively correlated with the score on the Fatigue Severity Scale (FSS) at 6 months after the stroke (r = 0.37, p = 0.015, and r = 0.37, p = 0.017, respectively). The acute serum levels of IL-ra and IL-9 were negatively correlated with FSS score at 12 months after the stroke (r = −0.38, p = 0.013, and r = −0.36, p = 0.019, respectively). The FSS score at 12 months after stroke was significantly lower in patients with radiologically confirmed infarction than in those without such confirmation (p = 0.048). The FSS score at 18 months was not correlated with any of the measured variables. High acute serum levels of glucose and IL-1β, and low IL1-ra and IL-9 may predict fatigue after AIS, indicating that the development of poststroke fatigue can be accounted for by the proinflammatory response associated with AIS. These novel findings support a new cytokine theory of fatigue after stroke. However, more research is needed to validate the results of this study

Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia.

Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology

The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor

Simple SummaryIt is well-recognised the strong contribution of genetic factors to prostate cancer (PrCa) susceptibility, thus genetic screening is critical for presymptomatic diagnosis and identification of individuals at high-risk. In this context, recurrent founder variants in cancer predisposing genes, by providing specific targets for early identification of carriers at risk of developing the disease, may be leveraged to implement cost-efficient targeted genetic screening strategies. The goal of this study was to investigate whether CHEK2 c.349A>G, the only recurrent "likely pathogenic" variant in CHEK2 gene reported in the Portuguese population, plays an important role in PrCa development, and the possibility of a founder effect behind its origin. Our results clearly demonstrate that c.349A>G in the CHEK2 tumour-suppressor gene is a founder variant significantly associated with an increased risk of PrCa, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM

Primary progressive aphasia: a clinical approach

This work was supported by the Alzheimer’s Society (AS-PG-16-007), the National Institute for Health Research University College London Hospitals Biomedical Research Centre and the UCL Leonard Wolfson Experimental Neurology Centre (PR/ylr/18575). Individual authors were supported by the Leonard Wolfson Foundation (Clinical Research Fellowship to CRM), the National Institute for Health Research (NIHR Doctoral Training Fellowship to AV), the National Brain Appeal–Frontotemporal Dementia Research Fund (CNC) and the Medical Research Council (PhD Studentships to CJDH and RLB, MRC Research Training Fellowship to PDF, MRC Clinician Scientist to JDR). MNR and NCF are NIHR Senior Investigators. SJC is supported by Grants from ESRC-NIHR (ES/L001810/1), EPSRC (EP/M006093/1) and Wellcome Trust (200783). JDW was supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (091673/Z/10/Z)

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling