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Background: Cerebral Palsy (CP) is the most common physical pediatric neurodevelopmental disorder and spastic diplegic injury is its most frequent subtype. CP results in substantial neuromotor and cognitive impairments that have significant socioeconomic impact. Despite this, its underlying pathophysiological mechanisms and etiology remain incompletely understood. Furthermore, there is a need for clinically relevant injury models, which a) reflect the heterogeneity of the condition and b) can be used to evaluate new translational therapies. To address these key knowledge gaps, we characterized a chronic placental insufficiency (PI) model, using bilateral uterine artery ligation (BUAL) of dams. This injury model results in intrauterine growth restriction (IUGR) in pups, and animals recapitulate the human phenotype both in terms of neurobehavioural and anatomical deficits., Methods: Effects of BUAL were studied using luxol fast blue (LFB)/hematoxylin & eosin (H&E) staining, immunohistochemistry, quantitative Magnetic Resonance Imaging (MRI), and Catwalk neurobehavioural tests., Results: Neuroanatomical analysis revealed regional ventricular enlargement and corpus callosum thinning in IUGR animals, which was correlated with the extent of growth restriction. Olig2 staining revealed reductions in oligodendrocyte density in white and grey matter structures, including the corpus callosum, optic chiasm, and nucleus accumbens. The caudate nucleus, along with other brain structures such as the optic chiasm, internal capsule, septofimbrial and lateral septal nuclei, exhibited reduced size in animals with IUGR. The size of the pretectal nucleus was reduced only in moderately injured animals. MAG/NF200 staining demonstrated reduced myelination and axonal counts in the corpus callosum of IUGR animals. NeuN staining revealed changes in neuronal density in the hippocampus and in the thickness of hippocampal CA2 and CA3 regions. Diffusion weighted imaging (DWI) revealed regional white and grey matter changes at 3 weeks of age. Furthermore, neurobehavioural testing demonstrated neuromotor impairments in animals with IUGR in paw intensities, swing speed, relative print positions, and phase dispersions., Conclusions: We have characterized a rodent model of IUGR and have demonstrated that the neuroanatomical and neurobehavioural deficits mirror the severity of the IUGR injury. This model has the potential to be applied to examine the pathobiology of and potential therapeutic strategies for IUGR-related brain injury. Thus, this work has potential translational relevance for the study of CP.

Using cardiac magnetic resonance, we tested whether a single-breath-hold approach to cardiac functional evaluation was equivalent to the established multiple-breath-hold method. We examined 39 healthy volunteers (mean age, 31.9 ± 11.4 yr; 22 men) by using 1.5 T with multiple breath-holds and our proposed single breath-hold. Left ventricular and right ventricular ejection fractions (LVEF and RVEF), LV and RV end-diastolic volumes (LVEDV and RVEDV), and LV myocardial mass (LVMM) were compared by using Bland-Altman plots; LVEF and RVEF were tested for equivalence by inclusion of 95% confidence intervals (CIs). Equivalence of the methods was assumed within the range of -5% to 5%. In the multiple- versus the single-breath-hold method, LVEF was 0.62 ± 0.05 versus 0.62 ± 0.04, and RVEF was 0.59 ± 0.06 versus 0.59 ± 0.07. The mean difference in both methods was -0.2% (95% CI, -1 to 0.6) for LVEF and 0.3% (95% CI, -0.8 to 1.5) for RVEF. The mean differences between methods fit within the predetermined range of equivalence, including the 95% CI. The mean relative differences between the methods were 3.8% for LVEDV, 4.5% for RVEDV, and 1.6% for LVMM. Results of our single-breath-hold method to evaluate LVEF and RVEF were equivalent to those of the multiple-breath-hold technique. In addition, LVEDV, RVEDV, and LVMM showed low bias between methods.

Purpose: To introduce a dual-contrast fast spin-echo (dcFSE) sequence for signal decay mapping of myocardial edema., Materials and Methods: After consultation with the Institutional Review Board, 22 acute myocardial infarction (MI) patients were examined with magnetic resonance imaging (MRI) at 1.5T 2 days after revascularization. Edema was evaluated in 16 myocardial segments with an exponential fit for signal decay time (SDT) in dcFSE mapping and T2 signal intensity ratio for single-contrast FSE. Myocardial viability was evaluated in late gadolinium enhancement (LGE). A control group of 10 volunteers was examined for edema imaging. SDT was compared in segment groups: 1) with LGE in MI, 2) penumbra, 3) remote from LGE, 4) controls. Groups 1/3 and 3/4 were tested on difference. Three phantoms providing similar T2 but different T1 relaxation times (low, intermediate, high) were examined with dcFSE and multicontrast spin echo sequence as a reference., Results: The SDT/T2 ratio for segment groups was 1) 82msec/1.7 in segments with LGE; 2) 65msec/1.6 for penumbra, 3) 62msec/1.7 for remote segments, and 4) 50msec/1.6 in controls. In dcFSE group 1/3 (P < 0.0001) and in group 3/4 (P = 0.0002) SDT was significantly different. In single-contrast FSE the T2 ratio was not significantly different for both tests: 1/3 P = 0.1889; 3/4 P = 0.8879. T2 -overestimation of dcFSE was 23% in low, 29% in intermediate, and 35% in highly T1 contaminated phantoms., Conclusion: dcFSE signal decay edema mapping is feasible in volunteers and patients. DcFSE SDT is superior to T2 ratio for detection of high-grade and diffuse myocardial edema. J. Magn. Reson. Imaging 2016;44:186-193., (© 2015 Wiley Periodicals, Inc.)

The last decade has seen significant growth in scientific understanding and public awareness of autism. There is still a long road ahead before this awareness can be matched with parallel improvements in evidence-based practice. The process of translating evidence into community care has been hampered by the seeming disconnect between the mainstream scientific research agenda and the immediate priorities of many communities. The need for community engagement in the process of translating knowledge into impact has been recognized. However, there remains little consensus or empirical data regarding the process of such engagement and how to measure its impact. We shed light on a number of engagement models and tools, previously advocated in health research, as they apply to autism research. Furthermore, we illustrate the utility of such tools in supporting identification of knowledge gaps and priorities, using two community-based case studies. The case studies illustrate that information generated from research is indeed relevant and critical for knowledge users in the community. Simple and systematic methods can support the translation and uptake of knowledge in diverse communities, therefore enhancing engagement with research and bridging research findings with immediate community needs., (© The Author(s) 2014.)

Cerebral palsy (CP) is a chronic childhood disorder described by a group of motor and cognitive impairments and results in a substantial socio-economic burden to the individual, family, and healthcare system. With no effective biological interventions, therapies for CP are currently restricted to supportive and management strategies. Cellular transplantation has been suggested as a putative intervention for neural pathology, as mesenchymal and neural stem cells, as well as olfactory ensheathing glia and Schwann cells, have shown some regenerative and functional efficacy in experimental central nervous system disorders. This review describes the most common cell types investigated and delineates their purported mechanisms in vivo. Furthermore, it provides a cogent summary of both current early-phase clinical trials using neural precursor cells (NPCs) and the state of stem cell therapies for neurodegenerative conditions. Although NPCs are perhaps the most promising candidates for cell replacement therapy in the context of CP, much still remains to be understood regarding safety, efficacy, timing, dose, and route of transplantation, as well as the capacity for combinatorial strategies., (© 2013 Mac Keith Press.)

Stem cell repair shows substantial translational potential for neurological injury, but the mechanisms of action remain unclear. This study aimed to investigate whether transplanted stem cells could induce comprehensive functional remyelination. Subventricular zone (SVZ)-derived adult neural precursor cells (aNPCs) were injected bilaterally into major cerebral white matter tracts of myelin-deficient shiverer mice on postnatal day (P) 0, P7, and P21. Tripotential NPCs, when transplanted in vivo, integrated anatomically and functionally into local white matter and preferentially became Olig2+, Myelin Associated Glycoprotein-positive, Myelin Basic Protein-positive oligodendrocytes, rather than Glial Fibrillary Acidic Protein-positive astrocytes or Neurofiliment 200-positive neurons. Processes interacted with axons and transmission electron microscopy showed multilamellar axonal ensheathment. Nodal architecture was restored and by quantifying these anatomical parameters a computer model was generated that accurately predicted action potential velocity, determined by ex vivo slice recordings. Although there was no obvious phenotypic improvement in transplanted shi/shis, myelinated axons exhibited faster conduction, lower activation threshold, less refractoriness, and improved response to high-frequency stimulation than dysmyelinated counterparts. Furthermore, they showed improved resilience to ischemic insult, a promising finding in the context of perinatal brain injury. This study describes, for the first time mechanistically, the functional characteristics and anatomical integration of nonimmortalized donor SVZ-derived murine aNPCs in the dysmyelinated brain at key developmental time points.

The substantial socioeconomic burden of a diagnosis of cerebral palsy, coupled with a positive anecdotal and media spin on stem cell treatments, drives many affected families to seek information and treatment outside of the current clinical and scientific realm. Preclinical studies using several types of stem and adult cells--including mesenchymal stem cells, neural precursor cells, olfactory ensheathing glia and Schwann cells--have demonstrated some regenerative and functional efficacy in neurologic paradigms. This paper describes the most common cell types investigated for transplant in vivo and summarizes the current state of early-phase clinical trials. It investigates the most relevant and promising coadministered therapies, including rehabilitation, drug targeting, magnetic stimulation, and bioengineering approaches. We highlight the need for adjunctive combinatorial strategies to successfully transfer stem cell treatments from bench to bedside., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Although neural c-Jun is essential for successful peripheral nerve regeneration, the cellular basis of this effect and the impact of c-Jun activation are incompletely understood. In the current study, we explored the effects of neuron-selective c-Jun deletion, substitution of serine 63 and 73 phosphoacceptor sites with non-phosphorylatable alanine, and deletion of Jun N-terminal kinases 1, 2 and 3 in mouse facial nerve regeneration. Removal of the floxed c-jun gene in facial motoneurons using cre recombinase under control of a neuron-specific synapsin promoter (junΔS) abolished basal and injury-induced neuronal c-Jun immunoreactivity, as well as most of the molecular responses following facial axotomy. Absence of neuronal Jun reduced the speed of axonal regeneration following crush, and prevented most cut axons from reconnecting to their target, significantly reducing functional recovery. Despite blocking cell death, this was associated with a large number of shrunken neurons. Finally, junΔS mutants also had diminished astrocyte and microglial activation and T-cell influx, suggesting that these non-neuronal responses depend on the release of Jun-dependent signals from neighboring injured motoneurons. The effects of substituting serine 63 and 73 phosphoacceptor sites (junAA), or of global deletion of individual kinases responsible for N-terminal c-Jun phosphorylation were mild. junAA mutants showed decrease in neuronal cell size, a moderate reduction in post-axotomy CD44 levels and slightly increased astrogliosis. Deletion of Jun N-terminal kinase (JNK)1 or JNK3 showed delayed functional recovery; deletion of JNK3 also interfered with T-cell influx, and reduced CD44 levels. Deletion of JNK2 had no effect. Thus, neuronal c-Jun is needed in regeneration, but JNK phosphorylation of the N-terminus mostly appears to not be required for its function., (© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

Cell transplantation therapy holds potential for repair and functional plasticity following spinal cord injury (SCI). Stem and progenitor cells are capable of modifying the lesion environment, providing structural support and myelination and increasing neurotrophic factors for neuroprotection and endogenous activation. Through these effects, transplanted cells induce plasticity in the injured spinal cord by promoting axonal elongation and collateral sprouting, remyelination, synapse formation and reduced retrograde axonal degeneration. In light of these beneficial effects, cell transplantation could be combined with other treatment modalities, such as rehabilitation and immune modulation, to provide a synergistic functional benefit. This review will delineate 1) stem/progenitor cell types proposed for cell transplantation in SCI, 2) in vitro evidence of cell-induced mechanisms of plasticity, 3) promotion of functional recovery in animal models of SCI, 4) successful combinatorial strategies using cell transplantation. Current treatment modalities for SCI provide modest efficacy, especially in chronic stages of SCI. Hence, combinatorial stem cell transplantation strategies which could potentially directly address tissue sparing and neuroplasticity in chronic SCI show promise. Rigorous evaluation of combinatorial approaches using stem cell transplantation with appropriate preclinical animal models of SCI is needed to advance therapeutic strategies to the point where clinical trials are appropriate. Given the high patient demand for and clinical trial precedent of cell transplantation therapy, combination stem cell therapies have the promise to provide improved quality of life for individuals, with corresponding socioeconomic benefit., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The human central nervous system (CNS) may be the most complex structure in the universe. Its development and appropriate specification into phenotypically and spatially distinct neural subpopulations involves a precisely orchestrated response, with thousands of transcriptional regulators combining with epigenetic controls and specific temporal cues in perfect synchrony. Understandably, our insight into the sophisticated molecular mechanisms which underlie spinal cord development are as yet limited. Even less is known about abnormalities of this process - putative genetic and molecular causes of well-described defects have only begun to emerge in recent years. Nonetheless, modern scientific techniques are beginning to demonstrate common patterns and principles amid the tremendous complexity of spinal cord development and maldevelopment. These advances are important, given that developmental anomalies of the spinal cord are an important cause of mortality and morbidity (Sadler, 2000); it is hoped that research advances will lead to better methods to detect, treat, and prevent these lesions., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Postischemic seizures are associated with worsened outcome following stroke, but the underlying pathophysiology is poorly understood. Here we examined acute seizures in adult mice following hypoxia-ischemia (HI) via combined behavioral, electrophysiological, and histological assessments. C57BL/6 mice aged 4-9 months received a permanent occlusion of the right common carotid artery and then underwent a systemic hypoxic episode. Generalized motor seizures were observed within 72 h following HI. These seizures occurred nearly exclusively in animals with extensive brain injury in the hemisphere ipsilateral to the carotid occlusion, but their generation was not associated with electroencephalographic discharges in bilateral hippocampal and neocortical recordings. Animals exhibiting these seizures had a high rate of mortality, and post-HI treatments with diazepam and phenytoin greatly suppressed these behavioral seizures and improved post-HI animal survival. Based on these data, we conclude that these seizures are a consequence of HI brain injury, contribute to worsened outcome following HI, and that they originate from deep subcortical structures.

Repair of the chronically injured spinal presents with multiple challenges, including neuronal/axonal loss and demyelination as a result of primary injury (usually a physical insult), as well as secondary damage, which includes ischemia, inflammation, oxidative injury and glutamatergic toxicity. These processes cause neuronal loss, axonal disruption and lead to a cystic degeneration and an inhibitory astroglial scar. A promising therapeutic intervention for SCI is the use of neural stem cells. Cell replacement strategies using neural precursor cells (NPCs) and oligodendroglial precursor cells (OPCs) have been shown to replace lost/damaged cells, secrete trophic factors, regulate gliosis and scar formation, reduce cystic cavity size and axonal dieback, as well as to enhance plasticity, axonal elongation and neuroprotection. These progenitor cells can be obtained through a variety of sources, including adult neural tissue, embryonic blastocysts and adult somatic cells via induced pluripotent stem cell (iPSC) technology. The use of stem cell technology - especially autologous cell transplantation strategies - in regenerative therapy for SCI holds much promise; these therapies show high potential for clinical translation and for future disease treatment.

An exact vertical approximation of epidermal edges during wound suturing allows rapid reepithelialization of the sutured wound and may reduce scar formation. Over 20 patients have been treated with a unique suturing technique for wound-edge approximation using a sterile polyurethane adhesive dressing as an epidermal scaffolding, Some of these procedures and results were documented using intraoperative and postoperative photos to help evaluate potential benefits to wound healing. The polyurethane dressing acts as a barrier to microbes, water, and irritants. Postoperative wound care was found to be cost-effective and virtually maintenance-free, as the wound does not require daily dressing changes. The patients treated with this technique demonstrated well-approximated wound edges and excellent cosmesis. The authors have not found cases of contact dermatitis or wound infection as a result of treatment using this suturing technique.

Background: Positive patch-test results to nickel, cobalt, and chromate alone and in combinations with one another are well known to occur. Patient factors that may play a role in isolated and concurrent sensitization to these allergens have not been studied in the US population., Objective: We sought to determine the prevalence of isolated and concurrent nickel, cobalt, and chromate sensitizations and to investigate the impact of various patient factors on their development., Methods: A retrospective analysis was carried out on patch-test data of 1187 patients evaluated at one US center from January 1, 1995, to December 31, 2004, 208 of whom had a positive reaction to at least one metal. Statistical analyses to evaluate associations of metal contact allergy with patient factors were performed using the chi(2) test and conditional odds ratio., Results: All patients who reacted to metal had increased odds of cosensitization to another metal. Patients who reacted to nickel were more likely to be female. Those who reacted to chromate were more likely to be male and to have an occupational cause for their dermatitis. There was a strong trend for patients who reacted to cobalt to be non-Caucasian. All those who reacted to metal had increased odds of a history of atopic eczema. Chromate reactions and isolated cobalt reactions were less likely to have known relevance than other (nonmetal) allergens. Several metal allergy combinations showed a predilection toward specific dermatitis sites, especially the scalp, eyelids, ears, and lips., Limitations: The study was a retrospective analysis, exploratory in nature, and had relatively small numbers of patients with particular multiple metal allergy combinations., Conclusion: This research confirms the sex predilections toward nickel and chromate allergy and suggests enhanced sensitivity to metals among those with atopic eczema. The results also serve to raise questions regarding occupationally related chromate allergy in men, the relevance of cobalt allergy, exposure patterns resulting in enhanced sensitivity to cobalt in non-Caucasians, and associations between metal allergens and dermatitis site. The answers to these questions require more detailed studies.