Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H.

Mucopolysaccharidosis (MPS) type-IH is a lysosomal storage disease that results from mutations in the IDUA gene causing the accumulation of glycosaminoglycans (GAGs). Historically, children with the severe phenotype, MPS-IH (Hurler syndrome) develop progressive neurodegeneration with death in the first decade due to cardio-pulmonary complications. New data suggest that inflammation may play a role in MPS pathophysiology. To date there is almost no information on the pathophysiologic changes within the cerebral spinal fluid (CSF) of these patients. We evaluated the CSF of 25 consecutive patients with MPS-IH. While CSF glucose and total protein were within the normal range, we found a significantly mean elevated CSF opening pressure at 24 cm H2O (range 14-37 cm H2O). We observed a 3-fold elevation in CSF heparan sulfate and a 3-8 fold increase in MPS-IH specific non-reducing ends, I0S0 and I0S6. Cytokine analyses in CSF of children with MPS-IH showed significantly elevated inflammatory markers including: MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF in comparison to unaffected children. This is the largest report of CSF characteristics in children with MPS-IH. Identification of key biomarkers may provide further insight into the inflammatory-mediated mechanisms related to MPS diseases and perhaps lead to improved targeted therapies

Anti-motility and reductions in the concentrations of gut electrolytes: Mechanisms for the anti-spasmodic use of the seeds of avocado (Persea americana Mill) in folk medicine

The seeds of avocado (Persea americana Mill) are used in traditional medicine to treat, allay or prevent some spasm-related disorders, for instance, diarrhoea. The chloroform and methanol fractions of the chloroform-methanol extract of the seeds of P. americana were investigated for their qualitative and quantitative phytochemical constituents as well as effects on gastro-intestinal motility (transit) and castor oil-induced intestinal fluid sodium ion (Na+) and potassium ion (K+) concentrations in Wistar rats. The qualitative and quantitative phytochemical studies of the chloroform and methanol fractions showed the presence and amounts of alkaloids (2.92 ± 0.14 g/100 g and 2.81 ± 0.08 g/100 g respectively), flavonoids (3.43 ± 0.19 g/100 g and 3.11 ± 0.16 g/100 g, respectively), tannins (2.64 ± 0.13 g/100 g and 2.85 ± 0.14 g/100 g, respectively), steroids (1.51 ± 0.07 g/100 g and 1.27 ± 0.04 g/100 g, respectively), saponins (2.35 ± 0.08 % and 2.47 ± 0.09%, respectively), terpenoids, proteins and carbohydrates in both fractions. Fats and oil were present only in the chloroform fraction. At the two doses (100 and 200 mg/kg body weight), the chloroform and methanol fractions produced significant (p<0.05) and dose-related decreases in the gastro-intestinal motility and concentration of the intestinal fluid potassium ions but only the chloroform fraction at the dose of 200 mg/kg body weight significantly (p<0.05) decreased the concentration of the intestinal fluid sodium ions. Results of the fractions were comparable with those of the standard anti-diarrhoeal drug, hyoscine butylbromide (3 mg/kg body weight). The results indicate that the chloroform-methanol extract of the seeds of P. americana contains compounds with anti-spasmodic effect.Keywords: Persea americana, spasm-related, castor oil, gastro-intestinal motility and electrolytesAfrican Journal of Biotechnology Vol. 12(37), pp. 5610-561

Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes.

PurposeAbnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change.MethodsIn addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association.ResultsOver treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant.ConclusionIntrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome

The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen's kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen's kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II-III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies

Beef Cattle Preference and Usage of Environmental Enrichments Provided Simultaneously in a Pasture-Based Environment

Environmental enrichment can improve livestock welfare through increasing environmental complexity to promote a greater range of natural behaviours. However, there is limited understanding of the need for and impacts of enrichments for extensively managed beef cattle that can sometimes be kept in grassed paddocks devoid of additional natural and artificial features, i.e., 'barren pastures'. This trial assessed which enrichments beef cattle preferred and utilised in a barren paddock environment. Eight groups of seven Angus steers housed on pastured paddocks devoid of natural or artificial features were observed during daylight hours for two days a week over a period of three weeks, after being presented with four enrichments simultaneously: a cattle brush, a piece of hanging rope, a tree stump, and a woodchip pile. Although enrichment use generally decreased over time, the brush, stump, and woodchip maintained a higher level of use than the rope, based on the frequency of interactions and number of displacements around the enrichments (both

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1

Contemporary Tendencies in Mediation

Editors: Humberto dalla Bernardina de Pinho, Juliana Loss de AndradePresentation / Humberto Dalla Bernardina de Pinho, Juliana Loss de Andrade. -- Mediation in England / Neil Andrews. -- Un Reto para la Mediación: el Diseño de su Código Deontológico / Nuria Belloso Martín. -- Alternative Dispute Resolution and Aboriginal-Crown Reconciliation in Canada / Roshan Danesh, Jessica Dickson. -- A False ‘Prince Charming’ Keeps ‘Sleeping Beauty’ in a Coma: On Voluntary Mediation Being the True Oxymoron of Dispute Resolution Policy / Giuseppe De Palo. -- Programa de Derivación Judicial en Puerto Rico Desde la Perspectiva de la Mediación / Jacqueline N. Font-Guzmán. -- Mediation in Switzerland / Isabelle Hering. -- Reconocimiento y eficacia de los acuerdos de mediación mercantil internacional / Juliana Loss de Andrade. -- The Uses of Mediation / Lela P. Love, Joseph B. Stulberg. -- Multi-Dimensional Mediation / Paul E. Mason. -- “Italy Is Doing It – Should We Be?” Civil and Commercial Mediation in Italy / Giovanni Matteucci. -- Limites dos Meios Alternativos de Conflito / José Marinho Paulo Junior. -- New Perspectives of Civil and Commercial Mediation in Brazil / Humberto Dalla Bernardina de Pinho. -- Practical Impacts of Theoretical Lenses / Elton Simoes, Andrea Maia. -- Development and Resistance in South Europe Justice Systems to Restorative Justice / Helena Soleto Muño

Introductory programming: a systematic literature review

As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming. This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research