Screening for rare variants in the coding region of ALS-associated genes at 9p21.2 and 19p13.3

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes progressive muscle weakness, eventually resulting in death because of respiratory failure. Genetic variants are thought to predispose to the disease. A recent, large, genome-wide association study identified 2 loci that increase susceptibility to ALS. These 2 loci on chromosomes 9 and 19 consist of 4 genes: UNC13a, IFNK, MOBKL2b, and C9ORF72. A hexanucleotide repeat expansion in the noncoding region of C9ORF72 was recently identified as the cause of chromosome 9-linked ALS-FTD (frontotemporal dementia). In this study, our aim was to determine whether the coding regions of these genes harbor rare, nonsynonymous variants that play a role in ALS pathogenesis. In DNA from 1019 sporadic ALS patients and 1103 control subjects of Dutch descent, we performed a mutation screening analysis in the coding region of these 4 genes by resequencing the exons. A total of 16 amino acid-changing rare variations were identified, 11 in UNC13a and 5 on chromosome 9. Some of these were unique to ALS, but were detected in a single patient. None of the genes showed significant enrichment of rare variants in the coding sequence. Rare variants in the coding region of UNC13a, IFNK, MOBKL2b, and C9ORF72 are unlikely to be a genetic cause of ALS.     

The choice of adjuvant determines the cytokine profile of T cells in proteoglycan‐induced arthritis but does not influence disease severity

Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic inflammation of the synovial joints. Collagen‐induced arthritis (CIA) and proteoglycan‐induced arthritis (PGIA) are mouse models of inflammatory arthritis; CIA is a T helper type 17 (Th17) ‐dependent disease that is induced with antigen in complete Freund's adjuvant, whereas PGIA is Th1‐mediated and is induced using antigen in dimethyldioctadecyl‐ammonium bromide (DDA) as an adjuvant. To investigate whether the type of adjuvant determines the cytokine profile of the pathogenic T cells, we have compared the effect of CFA and DDA on T‐cell responses in a single arthritis model. No differences in incidence or disease severity between aggrecan‐T‐cell receptor transgenic mice immunized with aggrecan in either CFA or DDA were observed. Immunization with CFA resulted in a higher proportion of Th17 cells, whereas DDA induced more Th1 cells. However, the levels of interleukin‐17 (IL‐17) produced by T cells isolated from CFA‐immunized mice after antigen‐specific stimulation were not significantly different from those found in DDA‐immunized mice, indicating that the increased proportion of Th17 cells did not result in significantly higher ex vivo IL‐17 levels. Hence, the choice of adjuvant can affect the overall proportions of Th1 and Th17 cells, without necessarily affecting the level of cytokine production or disease incidence and severity.     

Unravelling the blood supply to the zebrafish pharyngeal jaws and teeth

We describe the vascular supply to the pharyngeal jaws and teeth in zebrafish, from larval stages to juveniles, using serial high quality semithin sections and 3D reconstructions. We have identified that the arterial blood supply to the last pair of branchial arches, which carries the teeth, issues from the hypobranchial artery. Surprisingly, the arteries supplying the pharyngeal jaws show an asymmetric branching pattern that is modified over ontogeny. Moreover, the blood vessel pattern that serves each jaw can best be described as a sinusoidal cavity encircling the bases of both the functional and replacement teeth. Capillaries branching from this sinusoidal cavity enter the pulp and constitute the intrinsic blood supply to the attached teeth. The role of these blood vessels during tooth development (whether instructive or nutritive) remains to be determined and requires further study. However, we have provided a firm morphological basis that will aid in the interpretation of experiments addressing this question.     

Risk factors for calcification of the vertebrobasilar arteries in cardiovascular patients referred for a head CT,the SMART study

Background and purposeVertebrobasilar artery calcification (VBAC) has been associated with increased stroke occurrence. Little is known on VBAC risk factors, especially for patients with cardiovascular disease. We aimed to assess risk factors associated with VBAC in a cohort of cardiovascular patients referred for a head computed tomography (CT) scan.Materials and methodsAll patients who underwent a clinically indicated, unenhanced, thin slice head CT 6 months before or after inclusion in the SMART study were included. CTs were assessed for presence of VBAC (dichotomously). Relative risks of the associations of age, sex, diabetes mellitus (DM), obesity, body mass index, estimated glomerular filtration rate, hypertension, hyperlipidemia, use of lipid lowering medication, smoking status, high sensitivity C-reactive protein, ankle-brachial index (ABI; ≤ 0.90, ≥ 1.30, continuous), internal carotid artery stenosis ≥ 70%, and carotid intima-media thickness (IMT) with VBAC were estimated using Poisson regression analysis with robust standard errors, adjusted for age and sex.ResultsOf the 471 patients included (57% male, median age 58 [interquartile range 47–63]), 117 (24.8%) showed VBAC. Presence of VBAC was associated with older age (RR per 10 years = 1.70 [95%CI 1.46–1.99]), DM (RR = 1.45 [95%CI 1.03–2.06]), obesity (RR = 1.53 [95%CI 1.10–2.12]), ABI ≤ 0.90 (RR = 1.57 [95%CI 1.02–2.41]), and an increased carotid IMT (RR = 2.60 per mm [95%CI 1.20–5.62]). Other measurements were not associated with VBAC.ConclusionsWe identified several markers associated with VBAC in patients with cardiovascular disease referred for a head CT. Future investigation into the relationship between VBAC and stroke is warranted to determine the potential of VBAC in stroke prevention.     

Task-related motivation and academic achievement in children and adolescents with ADHD

European Child & Adolescent Psychiatry - Academic impairment in individuals with attention-deficit/hyperactivity disorder (ADHD) is in part due to reduced motivation for academic tasks, which...     

Brain dysconnectivity relates to disability and cognitive impairment in multiple sclerosis

The pathophysiology of cognitive dysfunction in multiple sclerosis (MS) is still unclear. This magnetoencephalography (MEG) study investigates the impact of MS on brain resting‐state functional connectivity (rsFC) and its relationship to disability and cognitive impairment. We investigated rsFC based on power envelope correlation within and between different frequency bands, in a large cohort of participants consisting of 99 MS patients and 47 healthy subjects. Correlations were investigated between rsFC and outcomes on disability, disease duration and 7 neuropsychological scores within each group, while stringently correcting for multiple comparisons and possible confounding factors. Specific dysconnections correlating with MS‐induced physical disability and disease duration were found within the sensorimotor and language networks, respectively. Global network‐level reductions in within‐ and cross‐network rsFC were observed in the default‐mode network. Healthy subjects and patients significantly differed in their scores on cognitive fatigue and verbal fluency. Healthy subjects and patients showed different correlation patterns between rsFC and cognitive fatigue or verbal fluency, both of which involved a shift in patients from the posterior default‐mode network to the language network. Introducing electrophysiological rsFC in a regression model of verbal fluency and cognitive fatigue in MS patients significantly increased the explained variance compared to a regression limited to structural MRI markers (relative thalamic volume and lesion load). This MEG study demonstrates that MS induces distinct changes in the resting‐state functional brain architecture that relate to disability, disease duration and specific cognitive functioning alterations. It highlights the potential value of electrophysiological intrinsic rsFC for monitoring the cognitive impairment in patients with MS.     

The role of hippocampal theta oscillations in working memory impairment in multiple sclerosis

Working memory (WM) problems are frequently present in people with multiple sclerosis (MS). Even though hippocampal damage has been repeatedly shown to play an important role, the underlying neurophysiological mechanisms remain unclear. This study aimed to investigate the neurophysiological underpinnings of WM impairment in MS using magnetoencephalography (MEG) data from a visual‐verbal 2‐back task. We analysed MEG recordings of 79 MS patients and 38 healthy subjects through event‐related fields and theta (4–8 Hz) and alpha (8–13 Hz) oscillatory processes. Data was source reconstructed and parcellated based on previous findings in the healthy subject sample. MS patients showed a smaller maximum theta power increase in the right hippocampus between 0 and 400 ms than healthy subjects (p = .014). This theta power increase value correlated negatively with reaction time on the task in MS (r = −.32, p = .029). Evidence was provided that this relationship could not be explained by a ‘common cause’ confounding relationship with MS‐related neuronal damage. This study provides the first neurophysiological evidence of the influence of hippocampal dysfunction on WM performance in MS.     

Reduced parenchymal cerebral blood flow is associated with greater progression of brain atrophy: The SMART-MR study

Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: –0.23 to –0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: –0.29 to –0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time (p = 0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF (p = 0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration.     

Correction to: Dry mouth: saliva substitutes which adsorb and modify existing salivary condition films improve oral lubrication

Clinical Oral Investigations - After publication of this paper, the authors observed that that figure 6 appears before figure 5.