Cystic Cavitation Research Articles

Cutaneous, Cranial, and Skeletal Defects in Children and Adults with Focal Dermal Hypoplasia.

The diagnostic process for children and adults manifesting a constellation of ectodermal abnormalities requires a conscientious and highly structured process. Six girls (aged 6-month-8 years) and two older girls (aged 13 and 16 years) were born with variable skin lesions of varying intensities associated with noticeable cranial and skeletal malformation complexes. Cleft palate, abnormal dentition, and multiple papillomas were evident around the mouth, mostly bilateral but asymmetrical in the upper and lower limbs. Exaggerated frontal bossing (macrocephaly) and in some patients' microcephaly with variable skeletal defects of the craniocervical junction and diverse forms of lower limb deformities of syndactyly, polydactyly, and split-hand/foot (ectrodactyly). All patients manifested the constellation of abnormalities with variable intensities ranging between alopecia, papillomas, striated skin pigmentations split-hand/foot (ectrodactyly), and major bone defects. A 3D reconstruction CT scan was directed mainly to further scrutinize children with pseudo cleft lip, submucus cleft, and cleft palate. Interstingly, they manifested massive demineralization of the cranium associated with severely defective dentition. A spine 3D reconstruction CT scan in two girls showed marked cystic cavitation of the upper jaw associated with excessive cavitation of the mastoid, causing tremendous frailty of the mastoid bone. A 3D sagittal CT scan showed odontoid hypoplasia and C1-2 instability associated with the rudimentary atlas and the persistence of extensive synchondrosis of the cervico-thoracic spine. The overall clinical and radiological phenotypic characterizations were consistent with the diagnosis of focal dermal hypoplasia (Goltz syndrome). Two children manifested heterozygous mutations in the PORCN gene, chromosome Xp11. In this study, we believe it's a good opportunity to share our novel scientific findings, which are intriguing and can be inspiring to readers, and to further aid the current scientific literature with exceptionally new unveiling results. This is the first comprehensive study of the cranio-skeletal malformation complex in children with GS.

Subcortical implantation of a passive microchip in rodents – an observational proof-of-concept study

ABSTRACT The use of brain-computer interface (BCI) technologies is a rapidly developing area of interest in neurosurgery. Studies investigating the use of BCIs have primarily focused on surface electrodes; however, subcortically implanted microchips may provide novel, non-pharmacological approaches for managing nervous system disorders. Accessing subcortical regions without disrupting surrounding tissues remains a significant challenge. Accordingly, we conducted an observational, proof-of-concept study to evaluate the use of a modified BrainPath® device to implant subcortical microchips in a rodent model. All animals survived the procedure and lived with a microchip in situ for one or three months with no apparent neurological effects. Histological examination revealed that implantation of a small chip was associated with some tissue damage, tract formation, and surrounding reactive changes. Gliosis and hemosiderin-laden macrophages were evident surrounding tract marks after one month and focal cystic cavitation consistent with infarcted tissue was evident after three months. While a more extensive cellular proliferation response was apparent one month after implantation of a large microchip, there was no significant collagen deposition suggestive of fibrosis. This study is the first demonstration of subcortical microchip implantation using a novel neurosurgical technique that may facilitate the development of BCI technologies for treatment of neurological disorders.

Reassessing Patterns of Response to Immunotherapy with PET: From Morphology to Metabolism.

Cancer demands precise evaluation and accurate and timely assessment of response to treatment. Imaging must be performed early during therapy to allow adjustments to the course of treatment. For decades, cross-sectional imaging provided these answers, showing responses to the treatment through changes in tumor size. However, with the emergence of immune checkpoint inhibitors, complex immune response patterns were revealed that have quickly highlighted the limitations of this approach. Patterns of response beyond tumor size have been recognized and include cystic degeneration, necrosis, hemorrhage, and cavitation. Furthermore, new unique patterns of response have surfaced, like pseudoprogression and hyperprogression, while other patterns were shown to be deceptive, such as unconfirmed progressive disease. This evolution led to new therapeutic evaluation criteria adapted specifically for immunotherapy. Moreover, inflammatory adverse effects of the immune checkpoint blockade were identified, many of which were life threatening and requiring prompt intervention. Given complex concepts like tumor microenvironment and novel therapeutic modalities in the era of personalized medicine, increasingly sophisticated imaging techniques are required to address the intricate patterns of behavior of different neoplasms. Fluorine 18-fluorodeoxyglucose PET/CT has rapidly emerged as one such technique that spans both molecular biology and immunology. This imaging technique is potentially capable of identifying and tracking prognostic biomarkers owing to its combined use of anatomic and metabolic imaging, which enables it to characterize biologic processes in vivo. This tailored approach may provide whole-body quantification of the metabolic burden of disease, providing enhanced prediction of treatment response and improved detection of adverse events. ©RSNA, 2020.

The therapeutic potential of targeting exchange protein directly activated by cyclic adenosine 3',5'-monophosphate (Epac) for central nervous system trauma.

Millions of people worldwide are affected by traumatic spinal cord injury, which usually results in permanent sensorimotor disability. Damage to the spinal cord leads to a series of detrimental events including ischaemia, haemorrhage and neuroinflammation, which over time result in further neural tissue loss. Eventually, at chronic stages of traumatic spinal cord injury, the formation of a glial scar, cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth. This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system. The intracellular signalling molecule, cyclic adenosine 3′,5′-monophosphate (cAMP), is known to play many important roles in the central nervous system, and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models. However, therapies directly targeting cAMP have not found their way into the clinic, as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects. A downstream effector of cAMP, exchange protein directly activated by cAMP 2 (Epac2), is mainly expressed in the adult central nervous system, and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration. Recently, using ex vivo modelling of traumatic spinal cord injury, Epac2 activation was found to profoundly modulate the post-lesion environment, such as decreasing the activation of astrocytes and microglia. Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury. Therefore, targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair, and future work is needed to fully establish its therapeutic potential.

Case report of hyperacute edema and cavitation following deep brain stimulation lead implantation

Background: Postoperative cerebral edema around a deep brain stimulation (DBS) electrode is an uncommonly reported complication of DBS surgery. The etiology of this remains unknown, and the presentation is highly variable; however, the patients generally report a good outcome.Case Description: Here, we report an unusual presentation of postoperative edema in a 66-year-old female who has bilateral dentatorubrothalamic tract (specifically, the ventral intermediate nucleus) DBS for a mixed type tremor disorder. Initial postoperative computed tomography (CT) was unremarkable and the patient was admitted for observation. She declined later on postoperative day (POD) 1 and became lethargic. Stat head CT scan performed revealed marked left-sided peri-lead edema extending into the centrum semiovale with cystic cavitation, and trace right-sided edema. On POD 2, the patient was alert, but with global aphasia, right-sided neglect, and a plegic right upper extremity. Corticosteroids were started and a complete infectious workup was unremarkable. She was intubated and ultimately required a tracheostomy and percutaneous gastrostomy tube. She returned to the clinic 3 months postoperatively completely recovered and ready for battery implantation.Conclusion: While this is an unusual presentation of cerebral edema following DBS placement, ultimately, the outcome was good similar to other reported cases. Supportive care and corticosteroids remain the treatment of choice for this phenomenon.

Advanced Pneumonic-type Lung Carcinoma: A Retrospective Study of Clinical-radiological-pathological Characteristics with Survival Analysis in A Single Chinese Hospital

背景与目的肺炎型肺癌是一种临床和影像表现特殊的肺癌。本研究旨在总结此类肺癌的临床、影像及病理学特征，诊断手段，治疗方案及预后情况。方法肺炎型肺癌定义为：肺部计算机断层扫描（computed tomography, CT）以磨玻璃或实变影为主要表现，经组织学或细胞学明确诊断的肺癌。收集2013年1月1日-2018年8月30日期间，就诊于北京协和医院呼吸与危重症医学科的晚期肺炎型肺癌病例，回顾性分析这些患者临床资料并进行生存随访。结果共纳入46例患者，均为肺腺癌。咳嗽（41/46, 89.1%）、咳痰（35/46, 76.1%）是最常见的临床表现。胸部CT常见表现为磨玻璃影（87.0%）、实变影（84.8%）、以及多发磨玻璃结节（84.8%），多发囊样变和空洞分别为40.0%和13.0%。同侧及对侧肺转移分别见于95.3%和84.8%的病例。从出现症状到明确诊断的中位时间为214天（95%CI: 129-298）。CT引导肺穿刺活检及外科肺活检的确诊率为100%，支气管镜下的支气管肺泡灌洗（BAL）联合经支气管肺活检（TBLB）的确诊率为80.9%（17/21），痰液病理学检查的确诊率为45.0%（9/20）。病理亚型，26例（26/46, 56.5%）为浸润性粘液腺癌，20例患者因缺乏足够的病理标本量而无法进一步区分亚型。38例进行了EGFR基因检测，6例（6/38, 15.8%）有突变。33例进行ALK基因检测，仅1例（1/33, 3.0%）有ALK重排。中位总生存期（overall survival, OS）为522天（95%CI: 424-619）。EGFR野生型或ALK融合基因阴性的患者，化疗明显延长中位OS（HR=0.155, P=0.002, 2），接受化疗者中位OS 547天（95%CI: 492-602），不接受化疗者中位OS 331天（95%CI: 22-919）。结论肺炎型肺癌由于其临床和影像特征与肺部感染相似而经常导致延误诊断。支气管镜下的BAL联合TBLB有相当高的确诊率。浸润性粘液腺癌为肺炎型肺癌的主要病理亚型。肺炎型肺癌EGFR突变及ALK重排发生率很低。对于无明确驱动基因的患者，应积极行化疗，延长患者生存期。

Fibroadhesive scarring of grafted collagen scaffolds interferes with implant-host neural tissue integration and bridging in experimental spinal cord injury.

Severe traumatic spinal cord injury (SCI) results in a devastating and permanent loss of function, and is currently an incurable condition. It is generally accepted that future intervention strategies will require combinational approaches, including bioengineered scaffolds, to support axon growth across tissue scarring and cystic cavitation. Previously, we demonstrated that implantation of a microporous type-I collagen scaffold into an experimental model of SCI was capable of supporting functional recovery in the absence of extensive implant–host neural tissue integration. Here, we demonstrate the reactive host cellular responses that may be detrimental to neural tissue integration after implantation of collagen scaffolds into unilateral resection injuries of the adult rat spinal cord. Immunohistochemistry demonstrated scattered fibroblast-like cell infiltration throughout the scaffolds as well as the presence of variable layers of densely packed cells, the fine processes of which extended along the graft–host interface. Few reactive astroglial or regenerating axonal profiles could be seen traversing this layer. Such encapsulation-type behaviour around bioengineered scaffolds impedes the integration of host neural tissues and reduces the intended bridging role of the implant. Characterization of the cellular and molecular mechanisms underpinning this behaviour will be pivotal in the future design of collagen-based bridging scaffolds intended for regenerative medicine.

Pattern analysis of 532- and 1064-nm microlens array-type, picosecond-domain laser-induced tissue reactions in ex vivo human skin.

Optical pulses from picosecond lasers can be delivered to the skin using microlens array (MLA) optics or a diffractive beam splitter to generate multiple, focused, high-intensity, micro-injury zones in the epidermis and dermis. The aim of our study was to histopathologically and immunohistochemically evaluate the patterns of 532- and 1064-nm MLA-type, picosecond laser-induced tissue reactions in human skin immediately after treatment. Picosecond neodymium:yttrium-aluminum-garnet (Nd:YAG) laser treatment using an MLA-type beam at the wavelengths of 532nm and 1064nm was delivered ex vivo to human skin. Irradiated skin specimens were then microscopically analyzed after hematoxylin and eosin staining and CD31 and Melan-A immunostaining. A single pulse of 532-nm MLA-type, picosecond laser treatment elicited cystic cavitation lesions at sizes of 83.4 ± 16.5μm × 70.2 ± 17.3μm (31-mm distance step) and 91.0 ± 44.7μm × 81.2 ± 36.3μm (48-mm distance step) in the epidermis and papillary dermis. Meanwhile, a single pulse of 1064-nm laser treatment generated cystic cavitation lesions at sizes of 107.0 ± 18.1μm × 83.3 ± 37.4μm (single-pulse mode) and 100.8 ± 40.4μm × 83.1 ± 29.4μm (dual-pulse mode) throughout the lower epidermis and upper papillary dermis. Lining epithelial cells in cystic cavitation lesions in the epidermis showed Melan-A-positive immunoreactivity, while cystic cavitation lesions in the dermis exhibited CD31-positive or CD31-negative/Melan-A-negative immunoreactivity. The present data can be used to predict 532- and 1064-nm MLA-type, picosecond-domain laser-induced tissue reactions in human skin.

An anti-inflammatory peptide and brain-derived neurotrophic factor-modified hyaluronan-methylcellulose hydrogel promotes nerve regeneration in rats with spinal cord injury.

BackgroundTraumatic spinal cord injury (SCI) causes neuronal death, demyelination, axonal degeneration, inflammation, glial scar formation, and cystic cavitation resulting in interruption of neural signaling and loss of nerve function. Multifactorial targeted therapy is a promising strategy for SCI.MethodsThe anti-inflammatory peptide KAFAKLAARLYRKALARQLGVAA (KAFAK) and brain-derived neurotrophic factor (BDNF)-modified hyaluronan-methylcellulose (HAMC) hydrogel was designed for minimally invasive, localized, and sustained intrathecal protein delivery. The physical and biological characteristics of HAMC-KAFAK/BDNF hydrogel were measured in vitro. SCI model was performed in rats and HAMC-KAFAK/BDNF hydrogel was injected into the injured site of spinal cord. The neuronal regeneration effect was evaluated by inflammatory cytokine levels, behavioral test and histological analysis at 8 weeks post operation.ResultsHAMC-KAFAK/BDNF hydrogel showed minimally swelling property and sustained release of the KAFAK and BDNF. HAMC-KAFAK/BDNF hydrogel significantly improved the proliferation of PC12 cells in vitro without cytotoxicity. Significant recovery in both neurological function and nerve tissue morphology in SCI rats were observed in HAMC-KAFAK/BDNF group. HAMC-KAFAK/BDNF group showed significant reduction in proinflammatory cytokines expression and cystic cavitation, decreased glial scar formation, and improved neuronal survival in the rat SCI model compared to HAMC group and SCI group.ConclusionThe HAMC-KAFAK/BDNF hydrogel promotes functional recovery of rats with spinal cord injury by regulating inflammatory cytokine levels and improving axonal regeneration.

Translational Advances in the Management of Acute Spinal Cord Injury

Translational Advances in the Management of Acute Spinal Cord Injury

Generating level-dependent models of cervical and thoracic spinal cord injury: Exploring the interplay of neuroanatomy, physiology, and function

The majority of spinal cord injuries (SCI) occur at the cervical level, which results in significant impairment. Neurologic level and severity of injury are primary endpoints in clinical trials; however, how level-specific damages relate to behavioural performance in cervical injury is incompletely understood. We hypothesized that ascending level of injury leads to worsening forelimb performance, and correlates with loss of neural tissue and muscle-specific neuron pools. A direct comparison of multiple models was made with injury realized at the C5, C6, C7 and T7 vertebral levels using clip compression with sham-operated controls. Animals were assessed for 10weeks post-injury with numerous (40) outcome measures, including: classic behavioural tests, CatWalk, non-invasive MRI, electrophysiology, histologic lesion morphometry, neuron counts, and motor compartment quantification, and multivariate statistics on the total dataset. Histologic staining and T1-weighted MR imaging revealed similar structural changes and distinct tissue loss with cystic cavitation across all injuries. Forelimb tests, including grip strength, F-WARP motor scale, Inclined Plane, and forelimb ladder walk, exhibited stratification between all groups and marked impairment with C5 and C6 injuries. Classic hindlimb tests including BBB, hindlimb ladder walk, bladder recovery, and mortality were not different between cervical and thoracic injuries. CatWalk multivariate gait analysis showed reciprocal and progressive changes forelimb and hindlimb function with ascending level of injury. Electrophysiology revealed poor forelimb axonal conduction in cervical C5 and C6 groups alone. The cervical enlargement (C5-T2) showed progressive ventral horn atrophy and loss of specific motor neuron populations with ascending injury. Multivariate statistics revealed a robust dataset, rank-order contribution of outcomes, and allowed prediction of injury level with single-level discrimination using forelimb performance and neuron counts. Level-dependent models were generated using clip-compression SCI, with marked and reliable differences in forelimb performance and specific neuron pool loss.

Concise Review: Bridging the Gap: Novel Neuroregenerative and Neuroprotective Strategies in Spinal Cord Injury

Spinal cord injuries (SCIs) result in devastating lifelong disability for patients and their families. The initial mechanical trauma is followed by a damaging secondary injury cascade involving proapoptotic signaling, ischemia, and inflammatory cell infiltration. Ongoing cellular necrosis releases ATP, DNA, glutamate, and free radicals to create a cytotoxic postinjury milieu. Long-term regeneration of lost or injured networks is further impeded by cystic cavitation and the formation of an inhibitory glial-chondroitin sulfate proteoglycan scar. In this article, we discuss important neuroprotective interventions currently applied in clinical practice, including surgical decompression, blood pressure augmentation, and i.v. methylprednisolone. We then explore exciting translational therapies on the horizon, such as riluzole, minocycline, fibroblast growth factor, magnesium, and hypothermia. Finally, we summarize the key neuroregenerative strategies of the next decade, including glial scar degradation, Rho-ROCK inhibition, cell-based therapies, and novel bioengineered adjuncts. Throughout, we emphasize the need for combinatorial approaches to this multifactorial problem and discuss relevant studies at the forefront of translation. We conclude by providing our perspectives on the future direction of SCI research. Spinal cord injuries (SCIs) result in devastating, lifelong disability for patients and their families. This article discusses important neuroprotective interventions currently applied in clinical practice, including surgical decompression, blood pressure augmentation, and i.v. methylprednisolone. Translational therapies on the horizon are discussed, such as riluzole, minocycline, fibroblast growth factor, magnesium, and hypothermia. The key neuroregenerative strategies of the next decade are summarized, including glial scar degradation, Rho-ROCK inhibition, cell-based therapies, and novel bioengineered adjuncts. The need for combinatorial approaches to this multifactorial problem is emphasized, relevant studies at the forefront of translation are discussed, and perspectives on the future direction of SCI research are presented.

A preclinical model of hyperalgesia following spinal stenosis/compression.

Identification of mechanisms for pain/hyperalgesia following spinal cord injury requires long-term evaluation of individual subjects because of the variability in effect over time for humans. Rats were trained on an operant escape task that determined their preference for occupancy of a brightly lit compartment versus a dark compartment with a floor preheated to 10, 32 or 44.5 °C. Following determination of baseline preferences, the animals received extradural implantation of a small piece of polymer in the thoracic spinal canal. The polymer narrowed the spinal canal and compressed the spinal cord. Post-operative tests of escape preference were conducted over 23 weeks (experiments 1 and 2) and 62 weeks (experiment 3), permitting statistical evaluation of individual effects. Spinal stenosis/compression produced hyperalgesia for cold and/or heat stimulation (17 animals; 77%), no post-operative change in sensitivity (4 animals) or hypoalgesia for cold or heat (2 animals). When hyperalgesia occurred, it developed gradually over 4 months. Following removal of the polymer in experiment 3, heat sensitivity returned to baseline levels for four of four animals that had been hyperalgesic when the polymer was in place, but cold hyperalgesia was retained for four of five animals. Overall, post-operative changes in cold and heat sensitivity were not strongly related, indicating that different mechanisms were responsible for enhanced sensitivity to 10 and 44.5 °C. Histology revealed that hyperalgesia occurred when there was: (1) damage to spinal white matter; or (2) cystic cavitation; or (3) compression and distortion of the spinal cord without an obvious loss of grey or white matter.

Functional improvement following implantation of a microstructured, type-I collagen scaffold into experimental injuries of the adult rat spinal cord

The formation of cystic cavitation following severe spinal cord injury (SCI) constitutes one of the major barriers to successful axonal regeneration and tissue repair. The development of bioengineered scaffolds that assist in the bridging of such lesion-induced gaps may contribute to the formulation of combination strategies aimed at promoting functional tissue repair. Our previous in vitro investigations have demonstrated the directed axon regeneration and glial migration supporting properties of microstructured collagen scaffold that had been engineered to possess mechanical properties similar to those of spinal cord tissues. Here, the effect of implanting the longitudinally orientated scaffold into unilateral resection injuries (2mm long) of the mid-cervical lateral funiculus of adult rats has been investigated using behavioural and correlative morphological techniques. The resection injuries caused an immediate and long lasting (up to 12 weeks post injury) deficit of food pellet retrieval by the ipsilateral forepaw. Implantation of the orientated collagen scaffold promoted a significant improvement in pellet retrieval by the ipsilateral forepaw at 6 weeks which continued to improve up to 12 weeks post injury. In contrast, implantation of a non-orientated gelatine scaffold did not result in significant functional improvement. Surprisingly, the improved motor performance was not correlated with the regeneration of lesioned axons through the implanted scaffold. This observation supports the notion that biomaterials may support functional recovery by mechanisms other than simple bridging of the lesion site, such as the local sprouting of injured, or even non-injured fibres.

Effects of an immunomodulatory therapy and chondroitinase after spinal cord hemisection injury.

Individually, immunomodulatory therapy and chondroitinases have demonstrated neuroprotective and potential neuroregenerative effects following spinal cord injury. To investigate the therapeutic potential of combined immunomodulatory and chondroitin sulfate-glycosaminoglycan degradation therapy in spinal cord injury. A combined immunomodulatory treatment using (1) liposome-encapsulated clodronate (selectively depletes peripheral macrophages), and (2) rolipram (a selective type 4 phosphodiesterase inhibitor), along with the chondroitin sulfate proteoglycan-glycosaminoglycan-degrading enzyme, chondroitinase ABC (ChABC), was assessed for its potential to promote axonal regrowth and improve locomotor recovery following midthoracic spinal cord hemisection injury in adult rats. We demonstrate that combined treatment with liposomal clodronate, rolipram, and ChABC attenuates macrophage accumulation at the site of injury, reduces axonal die-back of injured dorsal column axons, and produces the greatest improvement in locomotor recovery at 6 weeks postinjury compared with controls and noncombined therapy. Anterograde and retrograde tracing revealed that delivery of clodronate, rolipram, and ChABC did not promote substantial axonal regeneration through the site of injury, although the treatment did limit the extent of axonal die-back. Histological assessments revealed that combined treatment with clodronate/rolipram and/or ChABC resulted in a significant reduction in lesion size and cystic cavitation in comparison with injured controls. Combined clodronate, rolipram, and ChABC treatment reduced the accumulation of macrophages within the injured spinal cord 7 weeks after injury. The present data suggest that delivery of an immunomodulatory therapy consisting of clodronate and rolipram, in combination with ChABC, reduces axonal injury and enhances neuroprotection, plasticity, and hindlimb functional recovery after hemisection spinal cord injury in adult rats.

Synergistic effects of self-assembling peptide and neural stem/progenitor cells to promote tissue repair and forelimb functional recovery in cervical spinal cord injury

While neural stem/progenitor cells (NPCs) show promise for traumatic spinal cord injury (SCI), their efficacy in cervical SCI remains to be established. Moreover, their application to SCI is limited by the challenges posed by the lesion including the glial scar and the post-traumatic cavitation. Given this background, we sought to examine the synergistic effect of self-assembling peptide (SAP) molecules, designed to optimize the post-traumatic CNS microenvironment, and NSCs in a clinically-relevant model of contusive/compressive cervical SCI. We injected K2(QL)6K2 (QL6) SAPs into the lesion epicenter 14 days after bilateral clip compression-induced cervical SCI in rats, combined with simultaneous transplantation of neural stem/progenitor cells (NPCs) intraspinally adjacent to the lesion epicenter. The QL6 SAPs reduced the volume of cystic cavitation in the spinal cord lesion. Simultaneously engrafted NPCs preserved motor neurons and attenuated perilesional inflammation. The combination of QL6 and NPCs promoted forelimb neurobehavioral recovery and was associated with significant improvement in forelimb print area and stride length. In summary, we report for the first time histologic and functional benefits in a clinically-relevant model of cervical SCI through the synergistic effects of combined SAP and NPCs.

Decorin blocks scarring and cystic cavitation in acute and induces scar dissolution in chronic spinal cord wounds

In the injured central nervous system (CNS), transforming growth factor (TGF)-β1/2-induced scarring and wound cavitation impede axon regeneration implying that a combination of both scar suppression and axogenic treatments is required to achieve functional recovery. After treating acute and chronic dorsal funicular spinal cord lesions (DFL) in adult rats with the pan-TGF-β1/2 antagonist Decorin, we report that in: (1), acute DFL, the development of all injury parameters was significantly retarded e.g., wound cavity area by 68%, encapsulation of the wound by a glia limitans accessoria (GLA) by 65%, GLA basal lamina thickness by 94%, fibronectin, NG2 and Sema-3A deposition by 87%, 48% and 48%, respectively, and both macrophage and reactive microglia accumulations by 60%; and (2), chronic DFL, all the above parameters were attenuated to a lesser extent e.g., wound cavity area by 11%, GLA encapsulation by 25%, GLA basal lamina thickness by 31%, extracellular fibronectin, NG2 and Sema-3A deposition by 58%, 22% and 29%, respectively, and macrophage and reactive microglia accumulations by 44%. Moreover, in acute and chronic DFL, levels of tissue plasminogen activator (tPA) were raised (by 236% and 482%, respectively), as were active-MMP-2 (by 64% and 91%, respectively) and active-MMP-9 (by 122% and 18%, respectively), while plasminogen activator inhibitor-1 (PAI-1) was suppressed (by 56% and 23%, respectively) and active-TIMP-1 and active TIMP-2 were both lower but only significantly suppressed in acute DFL (by 56 and 21%, respectively). These findings demonstrate that both scar tissue mass and cavitation are attenuated in acute and chronic spinal cord wounds by Decorin treatment and suggest that the dominant effect of Decorin during acute scarring is anti-fibrogenic through suppression of inflammatory fibrosis by neutralisation of TGF-β1/2 whereas, in chronic lesions, Decorin-induction of tPA and MMP (concomitant with reduced complimentary levels of TIMP and PAI-1) leads to dissolution of the mature established scar by fibrolysis. Decorin also promoted the regeneration of similar numbers of axons through acute and chronic wounds. Accordingly, intrathecal delivery of Decorin offers a potential translatable treatment for scar tissue attenuation in patients with spinal cord injury.

Knockout of vascular early response gene worsens chronic stroke outcomes in neonatal mice

Vascular early response gene (Verge) is a novel immediate early gene that is highly expressed during developmental angiogenesis and after ischemic insults in adult brain. However, the role of Verge after neonatal injury is not known. In the present study, we investigated the hypothesis that Verge contributes to vascular remodeling and tissue repair after neonatal ischemic injury. The Rice-Vanucci model (RVM) was employed to induce neonatal stroke in both Verge knockout (KO) and wild-type (WT) postnatal day 10 (P10) mice. Histological and behavioral outcomes at acute (24h), subacute (7 days) and chronic (30 days) phases were evaluated. Angiogenesis, neurogenesis, and glial scar formation were also examined in the ischemic brain. No significant differences in outcomes were found between WT and Verge mice at 24h or 7 days after stroke. However genetic deletion of Verge led to pronounced cystic cavitation, decreased angiogenensis and glial scar formation in the ischemic hemisphere compared to WT mice at 30 days. Verge KO mice also had significantly worse functional outcomes at 30 days which was accompanied by decreased neurogenesis and angiogenesis in the ischemic hemisphere. Our study suggests that Verge plays an important role in the induction of neurogenesis and angiogenesis after ischemia, contributes to improved tissue repair, and enhances chronic functional recovery.

Abnormal iron homeostasis and neurodegeneration

Abnormal iron metabolism is observed in many neurodegenerative diseases, however, only two have shown dysregulation of brain iron homeostasis as the primary cause of neurodegeneration. Herein, we review one of these - hereditary ferritinopathy (HF) or neuroferritinopathy, which is an autosomal dominant, adult onset degenerative disease caused by mutations in the ferritin light chain (FTL) gene. HF has a clinical phenotype characterized by a progressive movement disorder, behavioral disturbances, and cognitive impairment. The main pathologic findings are cystic cavitation of the basal ganglia, the presence of ferritin inclusion bodies (IBs), and substantial iron deposition. Mutant FTL subunits have altered sequence and length but assemble into soluble 24-mers that are ultrastructurally indistinguishable from those of the wild type. Crystallography shows substantial localized disruption of the normally tiny 4-fold pores between the ferritin subunits because of unraveling of the C-termini into multiple polypeptide conformations. This structural alteration causes attenuated net iron incorporation leading to cellular iron mishandling, ferritin aggregation, and oxidative damage at physiological concentrations of iron and ascorbate. A transgenic murine model parallels several features of HF, including a progressive neurological phenotype, ferritin IB formation, and misregulation of iron metabolism. These studies provide a working hypothesis for the pathogenesis of HF by implicating (1) a loss of normal ferritin function that triggers iron accumulation and overproduction of ferritin polypeptides, and (2) a gain of toxic function through radical production, ferritin aggregation, and oxidative stress. Importantly, the finding that ferritin aggregation can be reversed by iron chelators and oxidative damage can be inhibited by radical trapping may be used for clinical investigation. This work provides new insights into the role of abnormal iron metabolism in neurodegeneration.

A CASE OF TOXIC CYSTIC LEUKOENCEPHALOPATHY AFTER ANTI-PSYCHOTIC OVERDOSE

We present the case of a 41-year-old lady who was admitted following an overdose of olanzapine, venlafaxine, quetiapine and propranolol. She was intubated in ITU and treated for aspiration pneumonia,...