Anger, Quality of Life and Mood in Multiple Sclerosis

This research was funded by The Multiple Sclerosis Society (UK).Peer reviewedPublisher PD

Phenotypic impacts of CSF1R deficiencies in humans and model organisms

Mϕ proliferation, differentiation, and survival are controlled by signals from the Mϕ CSF receptor (CSF1R). Mono‐allelic gain‐of‐function mutations in CSF1R in humans are associated with an autosomal‐dominant leukodystrophy and bi‐allelic loss‐of‐function mutations with recessive skeletal dysplasia, brain disorders, and developmental anomalies. Most of the phenotypes observed in these human disease states are also observed in mice and rats with loss‐of‐function mutations in Csf1r or in Csf1 encoding one of its two ligands. Studies in rodent models also highlight the importance of genetic background and likely epistatic interactions between Csf1r and other loci. The impacts of Csf1r mutations on the brain are usually attributed solely to direct impacts on microglial number and function. However, analysis of hypomorphic Csf1r mutants in mice and several other lines of evidence suggest that primary hydrocephalus and loss of the physiological functions of Mϕs in the periphery contribute to the development of brain pathology. In this review, we outline the evidence that CSF1R is expressed exclusively in mononuclear phagocytes and explore the mechanisms linking CSF1R mutations to pleiotropic impacts on postnatal growth and development

The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology

Amino acid substitutions in the kinase domain of the human CSF1R protein are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r locus. Previous analysis demonstrated that heterozygous mutation (Csf1rE631K/+) had a dominant inhibitory effect on CSF1R signaling in vitro and in vivo but did not recapitulate the pathology of the human disease. We speculated that leukoencephalopathy in humans requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles. Here we examine the impact of heterozygous Csf1r mutation on microglial phenotype, normal postnatal brain development, age-related changes in gene expression and on two distinct pathologies in which microgliosis is a prominent feature, prion disease and experimental autoimmune encephalitis (EAE). The heterozygous Csf1rE631K/+ mutation reduced microglial abundance and the expression of microglial-associated transcripts relative to wild-type controls at 12 weeks and 43 weeks of age but had no selective effect on homeostatic markers such as P2ry12. An epistatic interaction was demonstrated between Csf1rE631K/+ and Cxc3r1EGFP/+ genotypes leading to dysregulated microglial and neuronal gene expression in both hippocampus and striatum. Heterozygous Csf1rE631K mutation reduced the microgliosis associated with both diseases. There was no significant impact on disease severity or progression in prion disease. In EAE, induced expression of inflammation-associated transcripts in the hippocampus and striatum was suppressed in parallel with microglia-specific transcripts, but spinal cord demyelination was exacerbated. The results support a dominant-negative model of CSF1R-associated leukoencephalopathy and likely contributions of an environmental trigger and/or genetic background to neuropathology

Goal attainment scaling as a measure of meaningful outcomes for children with sensory integration disorders.

Goal attainment scaling (GAS) is a methodology that shows promise for application to intervention effectiveness research and program evaluation in occupational therapy (Dreiling & Bundy, 2003; King et al., 1999; Lannin, 2003; Mitchell & Cusick, 1998). This article identifies the recent and current applications of GAS to occupational therapy for children with sensory integration dysfunction, as well as the process, usefulness, and problems of application of the GAS methodology to this population. The advantages and disadvantages of using GAS in single-site and multisite research with this population is explored, as well as the potential solutions and future programs that will strengthen the use of GAS as a measure of treatment effectiveness, both in current clinical practice and in much-needed larger, multisite research studies

Fidelity in sensory integration intervention research.

OBJECTIVE: We sought to assess validity of sensory integration outcomes research in relation to fidelity (faithfulness of intervention to underlying therapeutic principles). METHOD: We identified core sensory integration intervention elements through expert review and nominal group process. Elements were classified into structural (e.g., equipment used, therapist training) and therapeutic process categories. We analyzed 34 sensory integration intervention studies for consistency of intervention descriptions with these elements. RESULTS: Most studies described structural elements related to therapeutic equipment and interveners\u27 profession. Of the 10 process elements, only 1 (presentation of sensory opportunities) was addressed in all studies. Most studies described fewer than half of the process elements. Intervention descriptions in 35% of the studies were inconsistent with one process element, therapist-child collaboration. CONCLUSION: Validity of sensory integration outcomes studies is threatened by weak fidelity in regard to therapeutic process. Inferences regarding sensory integration effectiveness cannot be drawn with confidence until fidelity is adequately addressed in outcomes research

Elevated ferritin, mediated by IL-18 is associated with systemic inflammation and mortality in acute respiratory distress syndrome (ARDS)

BACKGROUND: Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. METHODS: Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality. RESULTS: Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality. CONCLUSIONS: Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS

CSF1R-dependent macrophages control postnatal somatic growth and organ maturation

Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r-mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43hi non-classical monocytes, absent in the Csf1rko, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE