Pediatric mild head trauma: is outpatient follow-up imaging necessary or beneficial?

OBJECTIVE: Pediatric traumatic brain injury (TBI) is the leading cause of death among children and is a significant cause of morbidity. However, the majority of injuries are mild (Glasgow Coma Scale score 13-15) without any need for neurosurgical intervention, and clinically significant neurological decline rarely occurs. Although the question of repeat imaging within the first 24 hours has been discussed in the past, the yield of short-term follow-up imaging has never been thoroughly described. In this paper, the authors focus on the yield of routine repeat imaging for pediatric mild TBI (mTBI) at the first clinic visit following hospital discharge. METHODS: The authors conducted a retrospective review of patients with pediatric brain trauma who had been admitted to Johns Hopkins All Children's Hospital (JHACH). Patients with mTBI were identified, and their presentation, hospital course, and imaging results were reviewed. Those pediatric patients with mTBI who had undergone no procedure during their initial admission (only conservative treatment) were eligible for inclusion in the study. Two distinct groups were identified: patients who underwent repeated imaging at their follow-up clinic visit and those who underwent only clinical evaluation. Each case was assessed on whether the follow-up imaging had changed the follow-up course. RESULTS: Between 2010 and 2015, 725 patients with TBI were admitted to JHACH. Of those, 548 patients qualified for analysis (i.e., those with mTBI who received conservative treatment without any procedure and were seen in the clinic for follow-up evaluation within 8 weeks after the trauma). A total of 392 patients had only clinic follow-up, without any diagnostic imaging study conducted as part of their clinic visit, whereas the other 156 patients underwent repeat MRI. Only 1 patient had a symptomatic change and was admitted after undergoing imaging. For 30 patients (19.2%), it was decided after imaging to continue the neurosurgical follow-up, which is a change from the institutional paradigm after mTBI. None of these patients had a change in neurological status, and all had a good functional status. All of these patients had one more follow-up in the clinic with new MRI, and none of them required further follow-up. CONCLUSIONS: Children with mTBI are commonly followed up in the ambulatory clinic setting. The authors believe that for children with mTBI, normal clinical examination, and no new symptoms, there is no need for routine ambulatory imaging since the clinical yield of such is relatively low.

Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer.

Peripheral nerve injury can lead to great morbidity in those afflicted, ranging from sensory loss, motor loss, chronic pain, or a combination of deficits. Over time, research has investigated neuronal molecular mechanisms implicated in nerve damage, classified nerve injury, and developed surgical techniques for treatment. Despite these advancements, full functional recovery remains less than ideal. In this review, we discuss historical aspects of peripheral nerve injury and introduce nerve transfer as a therapeutic option, as well as an adjunct therapy to transplantation of Schwann cells and their stem cell derivatives for repair of the damaged nerve. This review furthermore, will provide an elaborated discussion on the sources of Schwann cells, including sites to harvest their progenitor and stem cell lines. This reflects the accessibility to an additional, concurrent treatment approach with nerve transfers that, predicated on related research, may increase the efficacy of the current approach. We then discuss the experimental and clinical investigations of both Schwann cells and nerve transfer that are underway. Lastly, we provide the necessary consideration that these two lines of therapeutic approaches should not be exclusive, but conversely, should be pursued as a combined modality given their mutual role in peripheral nerve regeneration.

Kainic Acid-Induced Golgi Complex Fragmentation/Dispersal Shifts the Proteolysis of Reelin in Primary Rat Neuronal Cells: An In Vitro Model of Early Stage Epilepsy.

The endoplasmic reticulum-lysosome-Golgi network plays an important role in Reelin glycosylation and its proteolytic processing. Golgi complex fragmentation is associated with the separation of Reelin from this network. Kainic acid (KA) is an excitotoxic agent commonly used to induce epilepsy in rodents. The relationship between KA-induced neuronal damage and Golgi complex fragmentation has not been investigated, leaving a major gap in our understanding of the molecular mechanism underlying the development of pathophysiology in epilepsy. We cultured primary rat cortical neurons eitherin ambient condition (control) or treated with a range of KA doses to reveal whether Golgi complex fragmentation impaired neuronal function. The half-life maximal inhibitory concentration (IC50) value of KA was detected to be approximately 5 µM, whereby at these concentrations, KA impaired neuronal viability, which was closely associated with initial Golgi complex fragmentation and subsequent reduction in both the expression and glycosylation patterns of Reelin. These findings implicate that Golgi complex fragmentation and Reelin dysfunction are key contributors to neuronal cell death in the early stage of epilepsy pathophysiology, thereby representing as novel disease biomarkers, as well as potent therapeutic targets for epilepsy.

A possible new focus for stroke treatment - migrating stem cells.

INTRODUCTION: Stroke is a leading cause of mortality in the US. More so, its infliction often leaves patients with lasting morbidity and deficits. Ischemic stroke comprises nearly 90% of incidents and the majority of medical treatment aims at reestablishing perfusion and preventing recurrence. AREAS COVERED: Long-term options for neurorestoration are limited by the infancy of their innovative approach. Accumulating evidence suggests the therapeutic potential of stem cells in neurorestoration, however, proper stem cell migration remains a challenge in translating stem cell therapy from the laboratory to the clinic. In this paper, we propose the role that exogenous stem cell transplantation may serve in facilitating the migration of endogenous stem cells to the site of injury, an idea termed 'biobridge'. EXPERT OPINION: Recent research in the field of traumatic brain injury has provided a foundational understanding that, through the use of exogenous stem cells, native tissue architecture may be manipulated by proteinases to allow better communication between the endogenous sites of neural stem cells and the regions of injury. There is still much to be learned about these mechanisms, though it is the devastating nature of stroke that necessitates continued research into the prospective therapeutic potential of this novel approach.

Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats.

Traumatic brain injury (TBI) survivors exhibit motor and cognitive symptoms from the primary injury that can become aggravated over time because of secondary cell death. In the present in vivo study, we examined the beneficial effects of human adipose-derived stem cells (hADSCs) in a controlled cortical impact model of mild TBI using young (6 months) and aged (20 months) F344 rats. Animals were transplanted intravenously with 4 × 10(6) hADSCs (Tx), conditioned media (CM), or vehicle (unconditioned media) at 3 h after TBI. Significant amelioration of motor and cognitive functions was revealed in young, but not aged, Tx and CM groups. Fluorescent imaging in vivo and ex vivo revealed 1,1' dioactadecyl-3-3-3',3'-tetramethylindotricarbocyanine iodide-labeled hADSCs in peripheral organs and brain after TBI. Spatiotemporal deposition of hADSCs differed between young and aged rats, most notably reduced migration to the aged spleen. Significant reduction in cortical damage and hippocampal cell loss was observed in both Tx and CM groups in young rats, whereas less neuroprotection was detected in the aged rats and mainly in the Tx group but not the CM group. CM harvested from hADSCs with silencing of either NEAT1 (nuclear enriched abundant transcript 1) or MALAT1 (metastasis associated lung adenocarcinoma transcript 1), long noncoding RNAs (lncRNAs) known to play a role in gene expression, lost the efficacy in our model. Altogether, hADSCs are promising therapeutic cells for TBI, and lncRNAs in the secretome is an important mechanism of cell therapy. Furthermore, hADSCs showed reduced efficacy in aged rats, which may in part result from decreased homing of the cells to the spleen.

Stem Cells for Neurovascular Repair in Stroke.

Stem cells exert therapeutic effects against ischemic stroke via transplantation of exogenous stem cells or stimulation of endogenous stem cells within the neurogenic niches of subventricular zone and subgranular zone, or recruited from the bone marrow through peripheral circulation. In this paper, we review the different sources of stem cells that have been tested in animal models of stroke. In addition, we discuss specific mechanisms of action, in particular neurovascular repair by endothelial progenitor cells, as key translational research for advancing the clinical applications of stem cells for ischemic stroke.

Advancing critical care medicine with stem cell therapy and hypothermia for cerebral palsy.

With limited clinical trials on stem cell therapy for adult stroke underway, the assessment of efficacy also needs to be considered for neonatal hypoxic-ischemic brain injury, considering its distinct symptoms. The critical nature of this condition leads to establishment of deficits that last a lifetime. Here, we will highlight the progress of current translational research, commenting on the critical nature of the disease, stem cell sources, the use of hypothermia, safety and efficacy of each treatment, modes of action, and the possibility of combination therapy. With this in mind, we reference translational guidelines established by a consortium of research partners called Stem cell Therapeutics as an Emerging Paradigm for Stroke (STEPS). The guidelines of STEPS are directed toward evaluating outcomes of cell therapy in adult stroke; however, we identify the overlapping pathology, as we believe that these guidelines will serve well in the investigation of neonatal hypoxic-ischemic therapy. Finally, we discuss emerging treatments and a case report, altogether suggesting that the potential for these treatments to be used in synergy has arrived and the time for advancing stem cell use in combination with hypothermia for cerebral palsy is now.

Stem cell transplantation for neuroprotection in stroke.

Stem cell-based therapies for stroke have expanded substantially over the last decade. The diversity of embryonic and adult tissue sources provides researchers with the ability to harvest an ample supply of stem cells. However, the optimal conditions of stem cell use are still being determined. Along this line of the need for optimization studies, we discuss studies that demonstrate effective dose, timing, and route of stem cells. We recognize that stem cell derivations also provide uniquely individual difficulties and limitations in their therapeutic applications. This review will outline the current knowledge, including benefits and challenges, of the many current sources of stem cells for stroke therapy.

Regeneration of neuronal cells following cerebral injury.

Stem cells possess a definitive role in neuronal rejuvenation following a cerebral injury. Whether endogenous, from the neurogenic niches of the subventricular zone and subgranular zone, or recruited from the bone marrow through peripheral circulation, accumulating evidence demonstrates that stem cells ameliorate the consequences of cerebrovascular events, particularly cerebral ischemia. In this chapter, we review milestone studies implicating the role of stem cells in response to disease. Furthermore, we outline specific mechanisms of action along with their clinical potential as therapeutic treatments for ischemic stroke.

In vivo animal stroke models: a rationale for rodent and non-human primate models.

On average, every four minutes an individual dies from a stroke, accounting for 1 out of every 18 deaths in the United States. Approximately 795,000 Americans have a new or recurrent stroke each year, with just over 600,000 of these being first attack [1]. There have been multiple animal models of stroke demonstrating that novel therapeutics can help improve the clinical outcome. However, these results have failed to show the same outcomes when tested in human clinical trials. This review will discuss the current in vivo animal models of stroke, advantages and limitations, and the rationale for employing these animal models to satisfy translational gating items for examination of neuroprotective, as well as neurorestorative strategies in stroke patients. An emphasis in the present discussion of therapeutics development is given to stem cell therapy for stroke.

The battle of the sexes for stroke therapy: female- versus male-derived stem cells.

Cell therapy is a major discipline of regenerative medicine that has been continually growing over the last two decades. The aging of the population necessitates discovery of therapeutic innovations to combat debilitating disorders, such as stroke. Menstrual blood and Sertoli cells are two gender-specific sources of viable transplantable cells for stroke therapy. The use of autologous cells for the subacute phase of stroke offers practical clinical application. Menstrual blood cells are readily available, display proliferative capacity, pluripotency and angiogenic features, and, following transplantation in stroke models, have the ability to migrate to the infarct site, regulate the inflammatory response, secrete neurotrophic factors, and have the possibility to differentiate into neural lineage. Similarly, the testis-derived Sertoli cells secrete many growth and trophic factors, are highly immunosuppressive, and exert neuroprotective effects in animal models of neurological disorders. We highlight the practicality of experimental and clinical application of menstrual blood cells and Sertoli cells to treat stroke, from cell isolation and cryopreservation to administration.

An Update on Translating Stem Cell Therapy for Stroke from Bench to Bedside.

With a constellation of stem cell sources available, researchers hope to utilize their potential for cellular repair as a therapeutic target for disease. However, many lab-to-clinic translational considerations must be given in determining their efficacy, variables such as the host response, effects on native tissue, and potential for generating tumors. This review will discuss the current knowledge of stem cell research in neurological disease, mainly stroke, with a focus on the benefits, limitations, and clinical potential.