Amyotrophic lateral sclerosis incidence following exposure to inorganic selenium in drinking water

Background and aim. Some laboratory and epidemiologic studies have documented an association between high intake of the trace element selenium and risk of amyotrophic lateral sclerosis (ALS), a degenerative disease of the motor neurons. There have been few epidemiologic studies of the association. Methods. From 1986 through 2015, we followed a community cohort in northern Italy that had been inadvertently exposed in the 1974-86 period to drinking water with unusually high levels of selenium, around 8 µg/ml, in its inorganic hexavalent form (selenate). In this cohort, we previously identified a high incidence of ALS during 1986-94. Here we report extended follow-up of this exposed cohort, as well as of an unexposed cohort including over 95,000 municipal residents, for an additional 21 years. We identified incident cases through administrative sources and a specialized registry. Results. During follow-up, 7 and 112 ALS cases were newly diagnosed in the exposed and unexposed cohorts, respectively, yielding incidence rates of 14 and 5 per 100,000 person-years. A Poisson regression analysis adjusting for age, sex, and calendar year produced an overall rate ratio (RR) for ALS of 2.8 (95% confidence interval (CI) 1.3 - 6) in the entire period of follow-up. The association was stronger earlier than later in follow-up (1986-1994 vs. 1994-2015), and among women than men. All exposed cases were of the sporadic, non-familial form for the disease. Conclusion. Overall, results from this ‘natural experiment’ indicate a positive association between chronic exposure to inorganic selenium and ALS incidence, with rates in the exposed cohort declining over time after cessation of exposure. Also taking into account the recognized neurotoxicity of selenium, particularly its selective toxicity on motor neurons observed in animal studies, the present study provides additional support for the hypothesis that selenium in its inorganic form increases ALS risk

Homeostatic competition drives tumor growth and metastasis nucleation

We propose a mechanism for tumor growth emphasizing the role of homeostatic regulation and tissue stability. We show that competition between surface and bulk effects leads to the existence of a critical size that must be overcome by metastases to reach macroscopic sizes. This property can qualitatively explain the observed size distributions of metastases, while size-independent growth rates cannot account for clinical and experimental data. In addition, it potentially explains the observed preferential growth of metastases on tissue surfaces and membranes such as the pleural and peritoneal layers, suggests a mechanism underlying the seed and soil hypothesis introduced by Stephen Paget in 1889 and yields realistic values for metastatic inefficiency. We propose a number of key experiments to test these concepts. The homeostatic pressure as introduced in this work could constitute a quantitative, experimentally accessible measure for the metastatic potential of early malignant growths.Comment: 13 pages, 11 figures, to be published in the HFSP Journa

Family in the spotlight: a systematic review of family factors associated with participation of children with disabilities

QMU Research Centre: FireflyStella Arakelyan - orcid: 0000-0003-0326-707X https://orcid.org/0000-0003-0326-707XUpdate history: 2019-01-09 (Gold OA version deposited, article title updated, deposit exception, publication & AM embargo dates updated); 2018-12-12 (Corrected version of AM deposited)Donald Maciver - orcid: 0000-0002-6173-429X https://orcid.org/0000-0002-6173-429XAIM: The aim of this review was to synthesise empirical evidence of family factors associated with participation of children with disabilities aged 5-12 years to inform the development of family-centred participation-fostering interventions. METHOD: A systematic search was performed for articles published in English between 2001 and 2017 in MEDLINE, PsycINFO, CINAHL, Scopus and ASSIA following the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines (registration no: CRD42017078202). Quality of evidence was appraised using the Research Triangle Institute Item Bank. Family factors associated with participation were identified and assessed using a multistage “semi-quantitative” approach. RESULTS: Thirty studies were included in the review. Four non-modifiable “status” factors consistently associated with participation were parental ethnicity, parental education, family type and family socio-economic status. Six modifiable “process” factors with consistent associations with participation were parental mental and physical health functioning, parental self-efficacy beliefs, parental support, parental time, family preferences and activity orientation. INTERPRETATION: Rehabilitation professionals should direct their focus towards modifiable family factors as primary targets for family-centred interventions. Strategies that can improve families’ access to information, counselling, and community support services are likely to support children’s participation by empowering families and optimizing their health and well-being.Funding: This research was completed as part of a PhD funded by Lothian National Health Service and Queen Margaret University, Edinburgh, Scotland.https://onlinelibrary.wiley.com/journal/1469874961pubpub

Weight management during teenage pregnancy: Issues to consider when developing appropriate support

Teenage pregnancy is more prevalent in areas of high obesity, compared to areas where obesity levels are low. Risks associated with maternal obesity in pregnant teenagers include pre-eclampsia and caesarean delivery. To reduce these risks, pregnant teenagers need to be supported to gain a healthy weight in pregnancy. This includes encouraging these women to eat healthily through providing appropriate information including online or smartphone apps in conjunction with face-to-face support. These young women also need encouragement to be physically active. This support must be tailored to the teenage population considering their specific barriers and facilitators to behaviour change. Midwives with the aid of a multidisciplinary team play a key role in encouraging these healthy behaviours

Genetic aspects of adolescent idiopathic scoliosis in a family with multiple affected members: a research article

<p>Abstract</p> <p>Background</p> <p>The etiology of idiopathic scoliosis remains unknown and different factors have been suggested as causal. Hereditary factors can also determine the etiology of the disease; however, the pattern of inheritance remains unknown. Autosomal dominant, X-linked and multifactorial patterns of inheritances have been reported. Other studies have suggested possible chromosome regions related to the etiology of idiopathic scoliosis. We report the genetic aspects of and investigate chromosome regions for adolescent idiopathic scoliosis in a Brazilian family.</p> <p>Methods</p> <p>Evaluation of 57 family members, distributed over 4 generations of a Brazilian family, with 9 carriers of adolescent idiopathic scoliosis. The proband presented a scoliotic curve of 75 degrees, as determined by the Cobb method. Genomic DNA from family members was genotyped.</p> <p>Results</p> <p>Locating a chromosome region linked to adolescent idiopathic scoliosis was not possible in the family studied.</p> <p>Conclusion</p> <p>While it was not possible to determine a chromosome region responsible for adolescent idiopathic scoliosis by investigation of genetic linkage using microsatellites markers during analysis of four generations of a Brazilian family with multiple affected members, analysis including other types of genomic variations, like single nucleotide polymorphisms (SNPs) could contribute to the continuity of this study.</p

Two spatiotemporally distinct value systems shape reward-based learning in the human brain

Avoiding repeated mistakes and learning to reinforce rewarding decisions is critical for human survival and adaptive actions. Yet, the neural underpinnings of the value systems that encode different decision-outcomes remain elusive. Here coupling single-trial electroencephalography with simultaneously acquired functional magnetic resonance imaging, we uncover the spatiotemporal dynamics of two separate but interacting value systems encoding decision-outcomes. Consistent with a role in regulating alertness and switching behaviours, an early system is activated only by negative outcomes and engages arousal-related and motor-preparatory brain structures. Consistent with a role in reward-based learning, a later system differentially suppresses or activates regions of the human reward network in response to negative and positive outcomes, respectively. Following negative outcomes, the early system interacts and downregulates the late system, through a thalamic interaction with the ventral striatum. Critically, the strength of this coupling predicts participants’ switching behaviour and avoidance learning, directly implicating the thalamostriatal pathway in reward-based learning

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis

Correction to Martin et al. available at: Genes & Development 30 (19): 2158 (http://genesdev.cshlp.org/content/31/9/953.full.pdf+html).Compaction of chromosomes is essential for accurate segregation of the genome duringmitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here,we report that biallelic mutations inNCAPD2,NCAPH, orNCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish “condensinopathies” as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size.This work was supported by funding from the Medical Research Council, the Lister Institute for Preventative Medicine, and the European Research Council (ERC; 281847 to A.P.J.); a Biotechnology and Biological Sciences Research Council grant (BB/ K017632/1 to P.V); a Sir Henry Dale Fellowship (grant 102560/ Z/13/Z to A.J.W.); Medical Research Scotland (to L.S.B.); the Potentials Foundation (to C.A.W.); and the Indian Council of Medical Research (BMS 54/2/2013 to S.R.P). The Deciphering Developmental Disorders Study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant no. WT098051). The views expressed here are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83) granted by the Cambridge South Research Ethics Committee, and GEN/ 284/12 granted by the Republic of Ireland. We acknowledge the support of the National Institute for Health Research through the Comprehensive Clinical Research Network

Robust penetrating microelectrodes for neural interfaces realized by titanium micromachining

Neural prosthetic interfaces based upon penetrating microelectrode devices have broadened our understanding of the brain and have shown promise for restoring neurological functions lost to disease, stroke, or injury. However, the eventual viability of such devices for use in the treatment of neurological dysfunction may be ultimately constrained by the intrinsic brittleness of silicon, the material most commonly used for manufacture of penetrating microelectrodes. This brittleness creates predisposition for catastrophic fracture, which may adversely affect the reliability and safety of such devices, due to potential for fragmentation within the brain. Herein, we report the development of titanium-based penetrating microelectrodes that seek to address this potential future limitation. Titanium provides advantage relative to silicon due to its superior fracture toughness, which affords potential for creation of robust devices that are resistant to catastrophic failure. Realization of these devices is enabled by recently developed techniques which provide opportunity for fabrication of high-aspect-ratio micromechanical structures in bulk titanium substrates. Details are presented regarding the design, fabrication, mechanical testing, in vitro functional characterization, and preliminary in vivo testing of devices intended for acute recording in rat auditory cortex and thalamus, both independently and simultaneously