Passively transferred human NMO-IgG exacerbates demyelination in mouse experimental autoimmune encephalomyelitis

BACKGROUND: Neuromyelitis optica (NMO) is a devastating inflammatory disorder of the optic nerves and spinal cord characterized by frequently recurring exacerbations of humoral inflammation. NMO is associated with the highly specific NMO-IgG biomarker, an antibody that binds the aquaporin-4 water channel. Aquaporin-4 is present on glial endfeet in the central nervous system (CNS). In humans, the NMO-IgG portends more frequent exacerbations and a worse long-term clinical outcome. METHODS: We tested the longer-term outcome of mice with EAE injected with NMO-IgG and followed them for 60 days. Clinical exams and pathology of the spinal cord and optic nerves were compared to mice that received control human IgG. RESULTS: Passively transferred human NMO-IgG leads to more severe neurology disability over two months after onset of disease. Clinical worsening is associated with an increased concentration of large demyelinating lesions primarily to subpial AQP4-rich regions of the spinal cord. CONCLUSIONS: NMO-IgG is pathogenic in the context of EAE in mice

Prevalence and Predictors of Exclusive Breastfeeding among Women in Kilimanjaro Region, Northern Tanzania: A Population Based Cross-Sectional Study.

Exclusive breastfeeding (EBF) is a simple and cost-effective intervention to improve child health and survival. Effective EBF has been estimated to avert 13% - 15% of under-five mortality and contribute to reduce mother to child transmission of HIV. The prevalence of EBF for infant less than six months is low in most developing countries, including Tanzania (50%). While the Tanzania Demographic Health Survey collects information on overall EBF prevalence, it does not evaluate factors influencing EBF. The aim of this paper was to determine the prevalence and predictors of exclusive breastfeeding in urban and rural areas in Kilimanjaro region. A population-based cross-sectional study was conducted between June 2010 to March 2011 among women with infants aged 6-12 months in Kilimanjaro. Multi-stage proportionate to size sampling was used to select participants from all the seven districts of the region. A standardized questionnaire was used to collect socio-demographic, reproductive, alcohol intake, breastfeeding patterns and nutritional data during the interviews. Estimation on EBF was based on recall since birth. Multivariable logistic regression was used to obtain independent predictors of EBF. A total of 624 women participated, 77% (483) from rural areas. The prevalence of EBF up to six months in Kilimanjaro region was 20.7%, without significant differences in the prevalence of EBF up to six months between urban (22.7%) and rural areas (20.1%); (OR = 0.7, 95% CI 0.5,1.4).In multivariable analysis, advice on breastfeeding after delivery (Adjusted odds ratio, AOR = 2.6, 95% CI 1.5, 4.6) was positively associated with EBF up to six months. Compared to married/cohabiting and those who do not take alcohol, single mothers (AOR = 0.4, 95% CI 0.2, 0.9) and mothers who drank alcohol (AOR = 0.4, 95% CI 0.3, 0.7) had less odds to practice EBF up to six months. Prevalence of EBF up to six months is still low in Kilimanjaro, lower than the national coverage of 50%. Strengthening of EBF counseling in all reproductive and child health clinics especially during antenatal and postnatal periods may help to improve EBF rates

Three-Dimensional Imaging of the Mouse Neurovasculature with Magnetic Resonance Microscopy

Knowledge of the three-dimensional (3D) architecture of blood vessels in the brain is crucial because the progression of various neuropathologies ranging from Alzheimer's disease to brain tumors involves anomalous blood vessels. The challenges in obtaining such data from patients, in conjunction with development of mouse models of neuropathology, have made the murine brain indispensable for investigating disease induced neurovascular changes. Here we describe a novel method for “whole brain” 3D mapping of murine neurovasculature using magnetic resonance microscopy (μMRI). This approach preserves the vascular and white matter tract architecture, and can be combined with complementary MRI contrast mechanisms such as diffusion tensor imaging (DTI) to examine the interplay between the vasculature and white matter reorganization that often characterizes neuropathologies. Following validation with micro computed tomography (μCT) and optical microscopy, we demonstrate the utility of this method by: (i) combined 3D imaging of angiogenesis and white matter reorganization in both, invasive and non-invasive brain tumor models; (ii) characterizing the morphological heterogeneity of the vascular phenotype in the murine brain; and (iii) conducting “multi-scale” imaging of brain tumor angiogenesis, wherein we directly compared in vivo MRI blood volume measurements with ex vivo vasculature data

Effectiveness of nail bed repair in children with or without replacing the fingernail : NINJA multicentre randomized clinical trial

Background Surgery for nail bed injuries in children is common. One of the key surgical decisions is whether to replace the nail plate following nail bed repair. The aim of this RCT was to assess the clinical effectiveness and cost-effectiveness of nail bed repair with fingernail replacement/substitution compared with repair without fingernail replacement. Methods A two-arm 1 : 1 parallel-group open multicentre superiority RCT was performed across 20 secondary-care hospitals in the UK. The co-primary outcomes were surgical-site infection at around 7 days after surgery and cosmetic appearance summary score at a minimum of 4 months. Results Some 451 children presenting with a suspected nail bed injury were recruited between July 2018 and July 2019; 224 were allocated to the nail-discarded arm, and 227 to the nail-replaced arm. There was no difference in the number of surgical-site infections at around 7 days between the two interventions or in cosmetic appearance. The mean total healthcare cost over the 4 months after surgery was €84 (95 per cent c.i. 34 to 140) lower for the nail-discarded arm than the nail-replaced arm (P < 0.001). Conclusion After nail bed repair, discarding the fingernail was associated with similar rates of infection and cosmesis ratings as replacement of the finger nail, but was cost saving

Effect of CXCR2 Inhibition on Behavioral Outcomes and Pathology in Rat Model of Neuromyelitis Optica

Objective. To reduce immune-mediated damage in a rat model of neuromyelitis optica (NMO) by blocking neutrophil migration using SCH527123, a drug that inhibits CXCR2. Background. Neuromyelitis optica is a relapsing autoimmune disease that preferentially targets the optic nerves and spinal cord leading to blindness and paralysis. Part of the immunopathogenesis of this disease is thought to involve neutrophils, which are present within NMO lesions. We tested the effect of blocking neutrophil migration in an NMO rat model. Methods. The Lewis rat model of NMO uses a myelin-reactive experimental autoimmune encephalomyelitis (EAE) background with passive transfer of pooled human antibody from patients with aquaporin-4 (AQP4) seropositive NMO at onset of EAE symptoms. We treated rats early in the course of EAE with CXCR2 inhibitor and assessed the extent of neutrophil infiltration into the spinal cord and the extent of AQP4 depletion. Results. CXCR2 inhibitor decreased neutrophil migration into the spinal cord of AQP4 IgG-treated EAE rats. However, there was no difference in the acute behavioral signs of EAE or the extent and distribution of AQP4 lesions. This suggests that neutrophils are not centrally involved in the immunopathogenesis of the Lewis rat NMO disease model. Conclusions. CXCR2 inhibitor blocks neutrophil migration into the spinal cord during EAE but does not significantly reduce inflammation or AQP4 lesions in the Lewis rat model of NMO

Ultra-high resolution 3D μMRI and “zonal” analyses of the neurovasculature.

<p>(a) 3D rendering of the neurovasculature in a non-invasive, 9L tumor bearing mouse brain acquired using ultra-high resolution (30 µm×30 µm×30 µm) μMRI. The vasculature has been color coded into three different “zones”: normal vessels (blue), tumor vessels (red) and vessels at the tumor-brain interface or transition zone (green). The transition-zone or tumor-brain tissue interface is crucial to understanding both, brain tumor angiogenesis and invasion. The radius and length of every individual vessel segment was measured in each zone. (b) Box plot of the average vessel length in each zone, wherein the width of each box includes 75% of the measured lengths and the median length is indicated by a horizontal line in each box. In addition, the radius of every vessel segment is plotted for each zone, with the color and size of each symbol proportional to the vessel radius. The normal zone exhibited significantly longer vessel segments compare to the transition (p = 0.002) and tumor zones (p<0.001), respectively. At this tumor stage, vessel radii were similar between the tumor and normal zones. These data demonstrate our ability to characterize the neurovasculature in physiologically relevant “zones”, and could provide new insight into the relationship between brain tumor angiogenesis and invasion. (c) T₂-weighted μMRI slice through a 9L brain tumor (gold rendering) bearing brain. (d) 3D overlay of the neurovasculature acquired using ultra-high resolution μMRI. (e) 3D DTI image showing reorganization of the fibers of the anterior commissure (<i>ac</i>) and internal capsule (<i>ic</i>) around the tumor. (f) Overlay of (d) and (e) illustrating simultaneous changes in vascular and white matter structures.</p

Multi-scale MRI of a 9L brain tumor model.

<p>(a) In vivo T₂-weighted MRI at the ‘systemic’ scale (∼150 µm); ex vivo μMRI at two ‘intermediate’ scales: (b) ∼60 µm, and (c) ∼30 µm. (d) Ultra-high resolution vascular μMRI image in which vessels have been segmented into tumor vessels (gold) and normal vessels (red). One can clearly visualize the abnormal tumor vessel architecture and changes in vessel morphology at the tumor-host tissue interface (arrows).</p

3D imaging of the murine neurovasculature with μMRI and validation with μCT and optical microscopy.

<p>(a) Photograph of a freshly excised mouse brain showing blue Microfil® perfused vessels (arrows). (b) X-ray radiograph of the same brain in which radio-opaque microfilled vessels are clearly visible. Arrows indicate major vessels that are also visible in (a). (c) Slice through the 3D R₂* map of the same brain. The Microfil-brain tissue interface is characterized by elevated R2* (hot colors) values. Note that background voxels are assigned R2* of zero. (d) ∼1.2 mm slab from another intact brain, in which μMRI-derived vasculature (gold) is overlaid on that acquired using μCT (purple). One can clearly visualize the vascular architecture and the agreement between μMRI and μCT. (e) Bright-field images (2×) of ROIs corresponding to colored squares in (d). Images are from a 1 mm thick, unstained brain section. Dark microfilled vessels provide corroboration of the μMRI data in (d). Arrows indicate major vessels that are also visible in (d). μCT data were resampled to match the μMRI spatial resolution, and the fractional vascular volume (FV) computed within 8×8×1 subvolumes for each dataset. The correlation between the μMRI and μCT-derived FVs for the 1 mm thick slice is plotted in (f). A similar analysis was conducted for the <i>whole</i> brain, wherein the FV was computed within 8×8×8 subvolumes for each dataset. The correlation between the μMRI and μCT-derived FVs for the <i>whole</i> brain is plotted in (g) and demonstrate good agreement between μMRI and μCT-derived vasculature. The red lines in (f) and (g) are the best linear fit to the data, and blue lines indicate the 95% confidence limits about the mean.</p