Nociceptive neuropeptide increases and periorbital allodynia in a model of traumatic brain injury.

OBJECTIVE: This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury. METHODS: Male C57BL/6 mice received either CCI or craniotomy-only followed by weekly periorbital von Frey (mechanical) sensory testing for up to 28 days post-injury. Mice receiving an incision only and naïve mice were included as control groups. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) within the brainstem were determined using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Activation of ionized calcium-binding adaptor molecule-1-labeled macrophages/microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were evaluated using immunohistochemistry because of their potential involvement in nociceptor sensitization. RESULTS: Incision-only control mice showed no changes from baseline periorbital von Frey mechanical thresholds. CCI significantly reduced mean periorbital von Frey thresholds (periorbital allodynia) compared with baseline and craniotomy-only at each endpoint, analysis of variance P \u3c .0001. Craniotomy significantly reduced periorbital threshold at 14 days but not 7, 21, or 28 days compared with baseline threshold, P \u3c .01. CCI significantly increased SP immunoreactivity in the brainstem at 7 and 14 days but not 28 days compared with craniotomy-only and controls, P \u3c .001. CGRP levels in brainstem tissues were significantly increased in CCI groups compared with controls (incision-only and naïve mice) or craniotomy-only mice at each endpoint examined, P \u3c .0001. There was a significant correlation between CGRP and periorbital allodynia (P \u3c .0001, r = -0.65) but not for SP (r = 0.20). CCI significantly increased the number of macrophage/microglia in the injured cortex at each endpoint up to 28 days, although cell numbers declined over weeks post-injury, P \u3c .001. GFAP(+) immunoreactivity was significantly increased at 7 but not 14 or 28 days after CCI, P \u3c .001. Craniotomy resulted in transient periorbital allodynia accompanied by transient increases in SP, CGRP, and GFAP immunoreactivity compared with control mice. There was no increase in the number of macrophage/microglia cells compared with controls after craniotomy. CONCLUSION: Injury to the somatosensory cortex results in persistent periorbital allodynia and increases in brainstem nociceptive neuropeptides. Findings suggest that persistent allodynia and increased neuropeptides are maintained by mechanisms other than activation of macrophage/microglia or astrocyte in the injured somatosensory cortex

Refractive Status and Vision Profile: evaluation of psychometric properties and comparison of Rasch and summated Likert-scaling. [Post-print]

The psychometric properties of the Refractive Status and Vision Profile (RSVP) questionnaire were evaluated using Rasch analysis. Ninety-one myopic patients from a refractive surgery clinic and general optometric practice completed the RSVP. Rasch analysis of the RSVP ordinal data was performed to examine for unidimensionality and item reduction. The traditional Likert-scoring system was compared with a Rasch-scored RSVP and a reduced item Rasch-scored RSVP. Rasch analysis of the original RSVP showed poor targeting of item difficulty to patient quality of life, items with a ceiling effect and underutilized response categories. Combining the underutilized response scales and removal of redundant and misfitting items improved the internal consistency and targeting of the RSVP, and the reduced 20-item Rasch scored RSVP showed greater relative precision over standard Likert scoring in discriminating between the two subject groups. A Rasch scaled quality of life questionnaire is recommended for use in refractive outcomes research

ELMO1 has an essential role in the internalization of Salmonella Typhimurium into enteric macrophages that impacts disease outcome.

Backgrounds and aims4-6 million people die of enteric infections each year. After invading intestinal epithelial cells, enteric bacteria encounter phagocytes. However, little is known about how phagocytes internalize the bacteria to generate host responses. Previously, we have shown that BAI1 (Brain Angiogenesis Inhibitor 1) binds and internalizes Gram-negative bacteria through an ELMO1 (Engulfment and cell Motility protein 1)/Rac1-dependent mechanism. Here we delineate the role of ELMO1 in host inflammatory responses following enteric infection.MethodsELMO1-depleted murine macrophage cell lines, intestinal macrophages and ELMO1 deficient mice (total or myeloid-cell specific) was infected with Salmonella enterica serovar Typhimurium. The bacterial load, inflammatory cytokines and histopathology was evaluated in the ileum, cecum and spleen. The ELMO1 dependent host cytokines were detected by a cytokine array. ELMO1 mediated Rac1 activity was measured by pulldown assay.ResultsThe cytokine array showed reduced release of pro-inflammatory cytokines, including TNF-α and MCP-1, by ELMO1-depleted macrophages. Inhibition of ELMO1 expression in macrophages decreased Rac1 activation (~6 fold) and reduced internalization of Salmonella. ELMO1-dependent internalization was indispensable for TNF-α and MCP-1. Simultaneous inhibition of ELMO1 and Rac function virtually abrogated TNF-α responses to infection. Further, activation of NF-κB, ERK1/2 and p38 MAP kinases were impaired in ELMO1-depleted cells. Strikingly, bacterial internalization by intestinal macrophages was completely dependent on ELMO1. Salmonella infection of ELMO1-deficient mice resulted in a 90% reduction in bacterial burden and attenuated inflammatory responses in the ileum, spleen and cecum.ConclusionThese findings suggest a novel role for ELMO1 in facilitating intracellular bacterial sensing and the induction of inflammatory responses following infection with Salmonella

Public health program capacity for sustainability: A new framework

Abstract Background Public health programs can only deliver benefits if they are able to sustain activities over time. There is a broad literature on program sustainability in public health, but it is fragmented and there is a lack of consensus on core constructs. The purpose of this paper is to present a new conceptual framework for program sustainability in public health. Methods This developmental study uses a comprehensive literature review, input from an expert panel, and the results of concept-mapping to identify the core domains of a conceptual framework for public health program capacity for sustainability. The concept-mapping process included three types of participants (scientists, funders, and practitioners) from several public health areas (e.g., tobacco control, heart disease and stroke, physical activity and nutrition, and injury prevention). Results The literature review identified 85 relevant studies focusing on program sustainability in public health. Most of the papers described empirical studies of prevention-oriented programs aimed at the community level. The concept-mapping process identified nine core domains that affect a program’s capacity for sustainability: Political Support, Funding Stability, Partnerships, Organizational Capacity, Program Evaluation, Program Adaptation, Communications, Public Health Impacts, and Strategic Planning. Concept-mapping participants further identified 93 items across these domains that have strong face validity—89% of the individual items composing the framework had specific support in the sustainability literature. Conclusions The sustainability framework presented here suggests that a number of selected factors may be related to a program’s ability to sustain its activities and benefits over time. These factors have been discussed in the literature, but this framework synthesizes and combines the factors and suggests how they may be interrelated with one another. The framework presents domains for public health decision makers to consider when developing and implementing prevention and intervention programs. The sustainability framework will be useful for public health decision makers, program managers, program evaluators, and dissemination and implementation researchers

Response to Professor Olsen's Commentary on ‘Random Sampling – Is It Worth It?’

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94518/1/ppe12019.pd

Lattice formulation of (2,2) supersymmetric gauge theories with matter fields

We construct lattice actions for a variety of (2,2) supersymmetric gauge theories in two dimensions with matter fields interacting via a superpotential.Comment: 13 pages, 2 figures. Appendix added, references updated, typos fixe

Exploring the wavelength range of InP/AlGaInP QDs and application to dual-state lasing

We explore the accessible wavelength range offered by InP/AlGaInP quantum dots (QD)s grown by metal–organic vapour phase epitaxy and explain how changes in growth temperature and wafer design can be used to influence the transition energy of the dot states and improve the performance of edge-emitting lasers. The self assembly growth method of these structures creates a multi-modal distribution of inhomogeneously broadened dot sizes, and via the effects of state-filling, allows access to a large range of lasing wavelengths. By characterising the optical properties of these dots, we have designed and demonstrated dual-wavelength lasers which operate at various difference-wavelengths between 8 and 63 nm. We show that the nature of QDs allows the difference-wavelength to be tuned by altering the operating temperature at a rate of up to 0.12 nm K−1 and we investigate the factors affecting intensity stability of the competing modes

Reducing thermal carrier spreading in InP quantum dot lasers

Record low values in this material system of threshold current density, particularly at elevated temperature, are presented for InP quantum dot lasers. Lasers with Ga0.58In0.42P in the dot upper confining layer have the lowest threshold current densities, 138 A·cm-2 at 300 K, and 235 A·cm-2 at 350 K (77 °C) (2-mm lasers, uncoated facets). Gain-current density data suggests laser performance with an upper confining layer of GaxIn1-xP with x = 0.54, 0.56 or 0.58 would be similar if not for the very low internal optical mode loss, αi of samples with x = 0.56 and 0.58. Gain measurements at fixed inversion level suggest that increasing x content in GaxIn1-xP increases gain at fixed inversion level but samples with x = 0.54 also exhibit reduced recombination current density. The increasing recombination current density at elevated temperature due to thermal carrier spreading is significantly reduced in samples with x = 0.56 and x = 0.58 but measurements at common operating points attribute this largely to the reduced αi for these samples and given the same αI, samples with x = 0.54, 0.56 and 0.58 would all benefit from reduced effects due to thermal carrier spreading compared to x = 0.52

ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation.

ObjectiveWe aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations.MethodsPatients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features.ResultsA total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy.ConclusionsARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy