Genomic NGFB variation and multiple sclerosis in a case control study

<p>Abstract</p> <p>Background</p> <p>Nerve growth factor β (NGFB) is involved in cell proliferation and survival, and it is a mediator of the immune response. ProNGF, the precursor protein of NGFB, has been shown to induce cell death via interaction with the p75 neurotrophin receptor. In addition, this neurotrophin is differentially expressed in males and females. Hence NGFB is a good candidate to influence the course of multiple sclerosis (MS), much like in the murine model of experimental autoimmune encephalomyelitis (EAE).</p> <p>Methods</p> <p>Ten single nucleotide polymorphisms (SNPs) were genotyped in the <it>NGFB </it>gene in up to 1120 unrelated MS patients and 869 controls. Expression analyses were performed for selected MS patients in order to elucidate the possible functional relevance of the SNPs.</p> <p>Results</p> <p>Significant association of NGFB variations with MS is evident for two SNPs. <it>NGFB </it>mRNA seems to be expressed in sex- and disease progression-related manner in peripheral blood mononuclear cells.</p> <p>Conclusion</p> <p>NGFB variation and expression levels appear as modulating factors in the development of MS.</p

Lesion site and therapy time predict responses to a therapy for anomia after stroke: a prognostic model development study

Stroke is a leading cause of disability, and language impairments (aphasia) after stroke are both common and particularly feared. Most stroke survivors with aphasia exhibit anomia (difficulties with naming common objects), but while many therapeutic interventions for anomia have been proposed, treatment effects are typically much larger in some patients than others. Here, we asked whether that variation might be more systematic, and even predictable, than previously thought. 18 patients, each at least 6 months after left hemisphere stroke, engaged in a computerised treatment for their anomia over a 6-week period. Using only: (a) the patients' initial accuracy when naming (to-be) trained items; (b) the hours of therapy that they devoted to the therapy; and (c) whole-brain lesion location data, derived from structural MRI; we developed Partial Least Squares regression models to predict the patients' improvements on treated items, and tested them in cross-validation. Somewhat surprisingly, the best model included only lesion location data and the hours of therapy undertaken. In cross-validation, this model significantly out-performed the null model, in which the prediction for each patient was simply the mean treatment effect of the group. This model also made promisingly accurate predictions in absolute terms: the correlation between empirical and predicted treatment response was 0.62 (95% CI 0.27, 0.95). Our results indicate that individuals' variation in response to anomia treatment are, at least somewhat, systematic and predictable, from the interaction between where and how much lesion damage they have suffered, and the time they devoted to the therapy

Assessment of Sleep Pattern in Egyptian Elderly Subjects with Vascular Dementia: An Egyptian Study on Elderly Population

Background: Sleep is considered to be very important for cognitive function and also cognitive deficits and sleep disorders are influenced by one another. Currently, growing evidence suggests that sleep disturbances is common in vascular dementia (VaD). Study Objectives: The goal of the current study was to assess the disturbance in sleep pattern in patients with vascular dementia(VaD) and compare it to healthy normally cognitive elderly individuals. The study further investigated whether meaningful differences in the Subjective sleep assessment (ESS and PSQI) and sleep measurements (PSG) in VaD patients. Study Design/Method: Overnight PSG recordings and self-reported sleep measures were obtained from 20 healthy elderly subjects and 20 VaD patients at the sleep laboratory. Results: This study showed abnormal subjective sleep quality in all patients and revealed that the most common sleep complaintsamong VaD patients were excessive daytime sleepiness (EDS), sleep disordered breathing (SDB), insomnia and RLS and PLMS and REM behavioral disordered, respectively. Moreover, patients spent more time in stage I sleep, but less time in SWS and REM sleep compared to control populations, with delayed REML and less 1st REML. In addition, increased sleep fragmentation (WASO and SFI) and increased AI and PLMS index were detected in VaD patients. Finally, VaD patients had significantly (p < 0.05) high apnea, hypopnea and RDI score with high average SpO2 desaturation. Conclusions: It is conclude that sleep is significantly (p < 0.05) impaired in patients with VaD at both the objective and subjective levels which may be used as a diagnostic marker of VaD. SBD is a common feature of VaD leading to fragmented sleep, increased nocturnal confusion and excessive daytime sleepiness. Subjective sleep assessment questionnaire by (ESS and PSQI) can be used in VaD patients when objective sleep assessment by PSG recordings is difficult to be done. The PSG study of sleep continuity, sleep architecture and REM sleep may help in the prevention of progression of VaD

Transcriptional and Cellular Diversity of the Human Heart

Background: The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low-input RNA sequencing have allowed definitions of cellular transcriptomes at single-cell resolution at scale, we have applied these approaches to assess the cellular and transcriptional diversity of the nonfailing human heart. Methods: Microfluidic encapsulation and barcoding was used to perform single nuclear RNA sequencing with samples from 7 human donors, selected for their absence of overt cardiac disease. Individual nuclear transcriptomes were then clustered based on transcriptional profiles of highly variable genes. These clusters were used as the basis for between-chamber and between-sex differential gene expression analyses and intersection with genetic and pharmacologic data. Results: We sequenced the transcriptomes of 287 269 single cardiac nuclei, revealing 9 major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses include 2 distinct groups of resident macrophages, 4 endothelial subtypes, and 2 fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs but also in subtypes involved in extracellular matrix remodeling and vascularization. Using genetic association data, we identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Intersection of our data set with genes on cardiac clinical testing panels and the druggable genome reveals striking patterns of cellular specificity. Conclusions: Using large-scale single nuclei RNA sequencing, we defined the transcriptional and cellular diversity in the normal human heart. Our identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases

Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS

Background Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. Methods MOG35-55 induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. Results EAE disease course was slightly attenuated in male apoE-deficient (apoE −/− ) mice compared to wildtype mice (cumulative median score: apoE −/−  = 2 [IQR 0.0–4.5]; wildtype = 4 [IQR 1.0–5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE −/− mice compared to wildtype mice (cumulative median score: apoE −/−  = 3 [IQR 2.0–4.5]; wildtype = 3 [IQR 0.0–4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. Conclusions apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease

Leukocyte Telomere Dynamics: Longitudinal Findings Among Young Adults in the Bogalusa Heart Study

Leukocyte telomere length (LTL) is ostensibly a biomarker of human aging. Cross-sectional analyses have found that LTL is relatively short in a host of aging-related diseases. These studies have also provided indirect estimates of age-dependent LTL shortening. In this paper, the authors report findings of the first comprehensive longitudinal study of 450 whites and 185 African Americans in Louisiana (aged 31.4 and 37.4 years at baseline (1995–1996) and follow-up (2001–2006) examinations, respectively) participating in the Bogalusa Heart Study. Rate of change in LTL was highly variable among individuals, with some displaying a paradoxical gain in LTL during the follow-up period. The most striking observation was that age-dependent LTL shortening was proportional to LTL at baseline examination. At both baseline and follow-up examinations, African Americans had longer LTLs than whites, and smokers had shorter LTLs than nonsmokers. The longer LTL in African Americans than in whites explained in part the faster rate of LTL shortening observed among African Americans. These findings underscore the complexity of leukocyte telomere dynamics in vivo and suggest that determinants in addition to the “end-replication problem” contribute to telomere shortening in vivo

Deep learning enables genetic analysis of the human thoracic aorta

Genome-wide association analyses identify variants associated with thoracic aortic diameter. A polygenic score for ascending aortic diameter was associated with a diagnosis of thoracic aortic aneurysm in independent samples. Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals, identifying 82 loci associated with ascending and 47 with descending thoracic aortic diameter, of which 14 loci overlapped. Transcriptome-wide analyses, rare-variant burden tests and human aortic single nucleus RNA sequencing prioritized genes including SVIL, which was strongly associated with descending aortic diameter. A polygenic score for ascending aortic diameter was associated with thoracic aortic aneurysm in 385,621 UK Biobank participants (hazard ratio = 1.43 per s.d., confidence interval 1.32-1.54, P = 3.3 x 10(-20)). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images

Postepidemic Analysis of Rift Valley Fever Virus Transmission in Northeastern Kenya: A Village Cohort Study

RVFV infection causes significant disease in both human and animal populations, resulting in significant agricultural, economic and public health consequences. We conducted a cohort study on residents of a high-risk area to measure human anti-RVFV seroprevalence, to identify risk factors, and to estimate the durability of prior RVFV immunity. One hundred two individuals tested for RVFV exposure before the 2006–2007 RVF outbreak were restudied to determine interval anti-RVFV seroconversion and persistence of humoral immunity since 2006. Ninety-two additional subjects were enrolled from randomly selected households to help identify risk factors for current seropositivity. Seroprevalence in the region was high (23%). 1/85 at-risk individuals restudied in the follow-up cohort had seroconverted since early 2006. 29% of newly tested individuals were seropositive. After adjustment in multivariable logistic models, age, village, and drinking raw milk were significantly associated with RVFV seropositivity. Visual impairment (defined as ≤20/80) was much more likely in the RVFV-seropositive group. Among those with previous exposure, RVFV titers remained at protective levels (>1∶40) for more than 3 years. This study highlights the high seroprevalence among Northeastern Kenyans and the ongoing surge in seroprevalence with each RVF outbreak

Supramolecular behaviour and fluorescence of rhodamine-functionalised ROMP polymers

Inherently fluorescent polymers are of interest in materials and medicine. We report a ring-opening metathesis polymerisation (ROMP) platform for creation of amphiphilic block copolymers in which one block is formed from rhodamine B-containing monomers. The polymers self-assemble into well-defined micelles which are able to sequester molecular dyes and further interact with them by energy transfer. Despite incorporating a cationic dye known to bind DNA, the polymer micelles do not interact with DNA, indicating that they are potentially safe for use in bioanalytical applications

Methylation of class II transactivator gene promoter IV is not associated with susceptibility to Multiple Sclerosis

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci <it>HLA-DRB1 </it>and <it>HLA-DQB1 </it>contribute significantly to genetic risk. The MHC class II transactivator (<it>MHC2TA</it>) is the master controller of expression of class II genes, and methylation of the promoter of this gene has been previously been shown to alter its function. In this study we sought to assess whether or not methylation of the <it>MHC2TA </it>promoter pIV could contribute to MS disease aetiology.</p> <p>Methods</p> <p>In DNA from peripheral blood mononuclear cells from a sample of 50 monozygotic disease discordant MS twins the <it>MHC2TA </it>promoter IV was sequenced and analysed by methylation specific PCR.</p> <p>Results</p> <p>No methylation or sequence variation of the <it>MHC2TA </it>promoter pIV was found.</p> <p>Conclusion</p> <p>The results of this study cannot support the notion that methylation of the pIV promoter of <it>MHC2TA </it>contributes to MS disease risk, although tissue and timing specific epigenetic modifications cannot be ruled out.</p