Search

Objective: Little is known about the emotional health of parents caring for children with shunted hydrocephalus. The aim of this pilot study was to find out whether parents caring for shunt-treated hydrocephalic children experience serious psychological problems and psychosocial distress and whether these problems are related to the sociodemographic background of the caregivers, the clinical characteristics of their children, and parents' illness-related concerns and perceived burden of their children's illness., Methods: This pilot study was performed in an outpatient setting at two German hospitals. The following questionnaires were handed out to parents of children with shunted hydrocephalus (< 21 years of age): the Patient Health Questionnaire (PHQ-9) for depression, the Generalized Anxiety Disorder Scale (GAD-7) for anxiety, the Distress Thermometer (DT) for psychosocial distress, the Hydrocephalus Concerns Questionnaire (HCQ) for assessment of parents' illness-related concerns, and the Hydrocephalus Outcome Questionnaire (HOQ) for assessment of perceived children's disease burden. Clinical data of the respective children were collected from electronic charts. Parents' demographic data were evaluated via questionnaires. Parents' psychological variables were correlated with demographic and clinical data and HCQ and HOQ scores. Regression analyses of HCQ and HOQ scores with psychological items were performed., Results: Sixty-three parents were included in this study. Of these, 60% reported clinically relevant levels of either depression (11%), anxiety (10%), and/or psychosocial distress (57%). There were no associations between parental sociodemographic or children's clinical characteristics with parents' psychosocial well-being or psychosocial distress. Depression, anxiety, and DT scores were highly intercorrelated and significantly correlated with HCQ scores (r = 0.508, r = 0.516, r = 0.442; p < 0.01). Thereby, worries about shunt-related complications were the most reported concern in the HCQ. Depression and anxiety correlated with the scores of some HOQ subcategories. In preliminary regression analyses, higher illness-related concerns predicted occurrence of parents' anxiety., Conclusions: The authors' results support the notion that there is a need for psychosocial support for a proportion of parents who care for shunted hydrocephalic children. Perceived child symptom burden and parental illness concerns were identified as relevant correlates of parental psychological well-being. Thus, concerns specific to shunt-related problems could be a first starting point for the development of individual support measures.

Competing Interests: None

Arachnoid cysts (AC) occur in different intracranial locations. Management and prognosis depend on the clinical presentation and treatment guidelines do not exist. With this study, we want to demonstrate the clinical variety of arachnoid cysts in children and place a focus on outcome factors in operated cases. This retrospective study of a consecutive single unit series of children, who underwent AC surgery between January 2010 and September 2019, provides demographic, clinical, imaging data, and information about surgical treatment and outcome. Overall, 63 patients (71.4 male) underwent surgery. Mean age was 50 months (0-191). Mean follow-up was 40 months (0-121). Eighty-one percent of patients presented with symptoms/signs of raised ICP. Focal neurological deficits were present in 15.9%, headache in 11.1% of children. Galassi cysts represented the predominant type (30.2%), followed by suprasellar (14.3%), quadrigeminal (12.7%), retrocerebellar, CPA and midline (each 11.1%), and hemispheric cysts (7.9%). Endoscopic and microsurgical fenestrations were performed in 27% and 58.7%, stent or shunt insertion in 6.3%/57.9% of the cases. In 33.3% of the cases one and in 12.7%, a second reintervention became necessary. Reoperation rate was significantly higher in children < 1 year (p = 0.003). Cyst volume decreased in 85.7%. Seventy percent of the patients were symptom free, 5% suffered from headache, and 22% from developmental disorders. All focal neurological symptoms resolved. Complication rate and outcome are depending on age and cyst location. Recurrence and revision rates are significantly higher in young infants (p = 0.003). Midline cysts with CCA are associated with developmental disorders., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The cellular and molecular mechanisms that presumably underlie the progressive functional decline of the myelomeningocele (MMC) placode are not well understood. We previously identified key players in post-traumatic spinal cord injury cascades in human MMC tissues obtained during postnatal repair. In this study, we conducted experiments to further investigate these mediators in the prenatal time course under standardized conditions in a retinoic acid-induced MMC rat model. A retinoic acid MMC model was established using time-dated Sprague-Dawley rats, which were gavage-fed with all-trans retinoic acid (RA; 60 mg/kg) dissolved in olive oil at E10. Control animals received olive oil only. Fetuses from both groups were obtained at E16, E18, and E22. The spinal cords (SCs) of both groups were formalin-fixed or snap-frozen. Tissues were screened by real-time reverse transcription polymerase chain reaction for the expression of cytokines and chemokines known to play a role in the lesion cascades of the central nervous system after trauma. MMC placodes exhibited inflammatory cells and glial activation in the later gestational stages. At the messenger RNA (mRNA) level, interleukin-1 beta, tumor necrosis factor alpha, and tumor necrosis factor receptor type 1 exhibited significant induction at E22. interleukin-1 beta receptor type 1 mRNA was induced significantly at E16 and E22. Double labeling experiments confirmed the co-staining of these cytokines and their receptors with ionized calcium-binding adapter molecule 1 (i.e., inflammatory cells), vimentin, and nestin in different anatomical SC areas and neuronal nuclear protein in ventral horn neurons. C-X-C motif chemokine 12 mRNA was elevated in control and MMC animals at E16 compared with E18 and E22. C-X3-C motif ligand 1 mRNA was lower in MMC tissues than in control tissues on E16. The presented findings contribute to the concept that pathophysiological mechanisms, such as cytokine induction in the neuroplacode, in addition to the "first hit," promote secondary spinal cord injury with functional loss in the late fetal time course. Further, these mediators should be taken into consideration in the development of new therapeutic approaches for open spinal dysraphism.

Objective: Lumbosacral lipomas (LSLs), one form of closed spinal dysraphism, are congenital disorders of the terminal spinal cord (SC). Delayed neurologic deterioration often occurs in the subsequent developmental course of the patient. Identifying the cellular and molecular factors underlying the progressive damage to neural structures is a prerequisite for developing treatment strategies for LSLs., Methods: Nine LSL specimens obtained from the SC/lipoma interface during surgical resection were examined. Normal SC tissue served as a control. Clinical characteristics were obtained, and spinal magnetic resonance imaging was re-evaluated. Cellular marker profiles were established. Immunoreactivity (IR) of hypoxia-inducible factor 1α (HIF-1α/-2α), erythropoietin (Epo)/erythropoietin receptor (EpoR), interleukin-1β (IL-1β)/IL-1R1, and tumor necrosis factor α/tumor necrosis factor receptor type 1 were analyzed qualitatively and semiquantitatively by densitometry. Colabeling with cellular markers was determined by multifluorescence labeling. Cytokines were further analyzed by real-time reverse transcription polymerase chain reaction., Results: LSL specimens showed significant gliosis. HIF-1α/HIF-2α-IR and Epo/Epo-IR were found at significantly higher levels in the LSL specimens, as were IL-1β-/IL-1β receptor type 1 (IL1-R1) and tumor necrosis factor α/tumor necrosis factor receptor type 1 (P < 0.001), than were the controls. At the messenger RNA level, cytokines appeared partially induced. Double immunofluorescence labeling confirmed the costaining of these factors with inflammatory and glial markers., Conclusions: The expression of hypoxia-related and inflammatory mediators was shown for the first time in LSL specimens. These factors might play a role in multifactorial secondary lesion cascades underlying further damage to the neural placode in closed dysraphism., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: A preliminary survey of pediatric neurosurgeons working at different centers around the world suggested differences in clinical practice resulting in variation in the risk of pediatric cerebellar mutism (CM) and cerebellar mutism syndrome (CMS) after posterior fossa (PF) tumor resection. The purposes of this study were (1) to determine the incidence and severity of CM and CMS after midline PF tumor resection in children treated at these centers and (2) to identify potentially modifiable factors related to surgical management (rather than tumor biology) that correlate with the incidence of CM/CMS., Methods: Attending pediatric neurosurgeons at British Columbia's Children's Hospital (BCCH) and neurosurgeons who completed a pediatric neurosurgery fellowship at BCCH were invited to provide data from the center where they currently practiced. Children aged from birth to less than 18 years who underwent initial midline PF tumor resection within a contemporary, center-selected 2-year period were included. Data was obtained by retrospective chart and imaging review. Modifiable surgical factors that were assessed included pre-resection surgical hydrocephalus treatment, surgical positioning, ultrasonic aspirator use, intraoperative external ventricular drain (EVD) use, surgical access route to the tumor, and extent of resection. CM was defined as decreased or absent speech output postoperatively and CMS as CM plus new or worsened irritability., Results: There were 263 patients from 11 centers in 6 countries (Canada, Germany, the Netherlands, India, Indonesia, and the USA). Median age at surgery was 6 years (range < 1 to 17 years). The overall incidence of postoperative CM was 23.5% (range 14.7-47.6% for centers with data on ≥ 20 patients). The overall incidence of CMS was 6.5% (range 0-10.3% for centers contributing data on ≥ 20 patients). A multivariate logistic regression on the full data set showed no significant association between pre-resection surgical hydrocephalus treatment, prone position, ultrasonic aspirator use, EVD use, telovelar approach, complete or near total resection, or treating center and either postoperative CM or CMS., Conclusions: While there was variation in surgical management of midline PF tumors among centers participating in this study, the factors in management that were examined did not predict postoperative CM or CMS.

Objective: In this "how we do it" survey, we review our management regimen of symptomatic CM1 and provide an analysis of our institutional case series of "bony only" decompression of the craniocervical junction without dural opening., Methods: In regard to the latter clinical symptomatology, neurological status, electrophysiology data, and pre- and post-surgical MRI were analyzed. Surgery was performed in standard fashion under IOM, evaluated by intraoperative ultrasound., Results: We reviewed 22 patients (mean age at surgery 13 ± 7 years; 11 female, 11 male). Neck pain, occipital headaches, sensory symptoms, and dizziness were the predominating symptoms; 9% had central apnea, 5 patients had scoliosis, and 2 patients had a history of premature synostosis. On MRI, preoperative mean tonsillar herniation was 16.55 ± 6.19, compared to 14.25 ± 6.75 after surgery. About half of patients with syringomyelia (n = 11) experienced imagining improvement after surgery. Patients with neck pain, occipital headaches, dizziness, and sensory abnormalities benefited most from surgery. Of the 6 cases that presented with pathological SSEPs, 4 exhibited improved measurements after surgery. There were no postoperative complications., Conclusion: To conclude bony decompression for CM1 resulted in clinical and imaging wise improvement and can be viewed as a safe first-lane option for symptomatic CM1.

Purpose: The literature on histopathological and molecular changes that might underlie secondary tethered cord syndrome (TCS) after myelomeningocele (MMC) repair surgeries remains sparse. To address this problem, we analyzed specimens, which were obtained during untethering surgeries of patients who had a history of MMC repair surgery after birth., Methods: Specimens of 12 patients were analyzed in this study. Clinical characteristics were obtained retrospectively including pre-operative neurological and bowel/bladder-function, contractures and spasticity of lower extremities, leg and back pain, syringomyelia, and conus position on spinal MRI. Cellular marker expression profiles were established. Further, immunoreactivities (IR) of IL-1ß/IL-1R1, TNF-α/TNF-R1, and HIF-1α/-2α were analyzed qualitatively and semi-quantitatively by densitometry. Co-labeling with cellular markers was determined by multi-fluorescence-labeling. Cytokines were further analyzed on mRNA level. Immunostaining for cleaved PARP and TUNEL was performed to detect apoptotic cells., Results: Astrocytosis, appearance of monocytes, activated microglia, and apoptotic cells in TCS specimens were one substantial finding of these studies. Besides neurons, these cells co-stained with IL-1ß and TNF-α and their receptors, which were found on significantly elevated IR-level and partially mRNA-level in TCS specimens. Staining for HIF-1α/-2α confirmed induction of hypoxia-related factors in TCS specimens that were co-labeled with IL-1ß. Further, hints for apoptotic cell death became evident by TUNEL and PARP-positive cells in TCS neuroepithelia., Conclusions: Our studies identified pro-inflammatory and pro-apoptotic mediators that, besides mechanical damaging and along with hypoxia, might promote TCS development. Besides optimizing surgical techniques, these factors should also be taken into account when searching for further options to improve TCS treatment.

Purpose: Surgical antibiotic prophylaxis (SAP) in pediatric neurosurgery has poorly been characterized until now. This review gives an overview on the current literature extracting recommendations and guidelines., Methods: The current literature on SAP with special forcus on pediatric neurosurgerical procedures was reviewed. Further, available recommendations in online databases were checked. Clean neurosurgical, shunt, and implant surgeries are considered separately., Results: To date, evidence-based data on SAP in pediatric neurosurgery remain sparse and there are no standardized approaches to an adequate use of antimicrobial agents for SSI prevention for this age group., Conclusion: Due to statistical needs, multi-center surveillance studies are needed for implementing SAP recommendations in pediatric neurosurgery.

Purpose: Magnetic resonance imaging (MRI) is a sensitive imaging tool which lacks the burden of ionizing radiation. It is not established as primary diagnostic tool in traumatic brain injury (TBI). The purpose of this study was to evaluate the usefulness of MRI as initial imaging modality in the emergency management of mild pediatric TBI., Methods: Children (0-18 years, sub-divided in four age-groups) with mild TBI who received MRI in the emergency department were identified. Clinical characteristics and trauma mechanisms were evaluated retrospectively. Univariate and multivariate logistic regression analyses were used to identify clinical factors that might be indicative for trauma sequelae on MRI scans., Results: An institutional case series of 569 patients (322 male/247 female; age < 18years; (GCS ≥ 13), who received MRI for mild TBI, was analyzed. Multi-sequence imaging (including T2, T2*, FLAIR, and diffusion-weighted sequences) was feasible without sedation in 96.8% of cases (sedation, 1.8%; general anesthesia, 1.4%). MRI revealed trauma-associated findings in 13% of all cases; incidental findings were detected in 4.7%. In our cohort, GCS deterioration, scalp hematoma, clinical signs of skull base fractures, and horseback riding accidents were related to structural trauma sequelae on MRI., Conclusions: MRI is a practical primary imaging tool for evaluating children with mild TBI in the emergency department. The presented analyses demonstrated that in our institution, MRI imaging is performed frequently in the emergency department. It resulted mostly in normal findings. This may reflect uneasiness of when to perform imaging in mild TBI and appears retrospectively as an "overdo." There are clinical factors that are more likely associated with MRI-positive findings. Their reliability has to be evaluated in prospective studies in order to formulate further decision rules of when to perform MRI imaging or not.

Erythropoietin (Epo) exhibits promising neuroregenerative potential for spinal cord injury (SCI), and might be involved in other long-term sequelae, such as neuropathic pain development. The current studies investigated the time courses and spatial and cellular patterns of Epo and erythropoietin receptor (EpoR) expression along the spinal axis after graded SCI. Male Long Evans rats received 100 kdyn, 150 kdyn, and 200 kdyn thoracic (T9) contusions from an Infinite Horizon impactor. Sham controls received laminectomies. Anatomical and quantitative immunohistochemical analyses of the EpoR/Epo expression along the whole spinal axis were performed 7, 15, and 42 postoperative days (DPO) after the lesioning. Cellular expression was investigated by double- and triple-labeling for EpoR/Epo with cellular markers and proliferating cells in subgroups of 5-bromo-2-deoxyuridine pre-treated animals. Prolonged EpoR/Epo-expression was confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Quantified EpoR/Epo immunoreactivities in pain-related spinal cord regions and ventrolateral white matter (VLWM) were correlated with the mechanical sensitivity thresholds and locomotor function of the respective animals. EpoR and Epo were constitutively expressed in the ventral horn neurons and vascular and glial cells in the dorsal columns (DC) and the VLWM. After SCI, in addition to expression in the lesion core, EpoR/Epo immunoreactivities exhibited significant time- and lesion grade-dependent induction in the DC and VLWM along the spinal axis. EpoR and Epo immunoreactive cells were co-stained with markers for astroglial, neural precursor cell and vascular markers. In the VLWM, EpoR- and Epo-positive proliferating cells were co-stained with glial fibrillary acidic protein (GFAP) and nestin. The DC EpoR/Epo immunoreactivities exhibited linear relationships with the behavioral correlates of post-lesional chronic pain development at DPO 42. SCI leads to long-lasting multicellular EpoR/Epo induction beyond the lesion core in the spinal cord regions that are involved in central pain development and regenerative processes. Our studies provide a time frame to investigate the effects of Epo application on motor function or pain development, especially in the later time course after lesioning.

OBJECTIVE Focal cortical dysplasia (FCD) Type II is divided into 2 subgroups based on the absence (IIA) or presence (IIB) of balloon cells. In particular, extratemporal FCD Type IIA and IIB is not completely understood in terms of clinical, imaging, biological, and neuropathological differences. The aim of the authors was to analyze distinctions between these 2 formal entities and address clinical, MRI, and immunohistochemical features of extratemporal epilepsies in children. METHODS Cases formerly classified as Palmini FCD Type II nontemporal epilepsies were identified through the prospectively maintained epilepsy database at the British Columbia Children's Hospital in Vancouver, Canada. Clinical data, including age of seizure onset, age at surgery, seizure type(s) and frequency, affected brain region(s), intraoperative electrocorticographic findings, and outcome defined by Engel's classification were obtained for each patient. Preoperative and postoperative MRI results were reevaluated. H & E-stained tissue sections were reevaluated by using the 2011 International League Against Epilepsy classification system and additional immunostaining for standard cellular markers (neuronal nuclei, neurofilament, glial fibrillary acidic protein, CD68). Two additional established markers of pathology in epilepsy resection, namely, CD34 and α-B crystallin, were applied. RESULTS Seven nontemporal FCD Type IIA and 7 Type B cases were included. Patients with FCD Type IIA presented with an earlier age of epilepsy onset and slightly better Engel outcome. Radiology distinguished FCD Types IIA and IIB, in that Type IIB presented more frequently with characteristic cortical alterations. Nonphosphorylated neurofilament protein staining confirmed dysplastic cells in dyslaminated areas. The white-gray matter junction was focally blurred in patients with FCD Type IIB. α-B crystallin highlighted glial cells in the white matter and subpial layer with either of the 2 FCD Type II subtypes and balloon cells in patients with FCD Type IIB. α-B crystallin positivity proved to be a valuable tool for confirming the histological diagnosis of FCD Type IIB in specimens with rare balloon cells or difficult section orientation. Distinct nonendothelial cellular CD34 staining was found exclusively in tissue from patients with MRI-positive FCD Type IIB. CONCLUSIONS Extratemporal FCD Types IIA and IIB in the pediatric age group exhibited imaging and immunohistochemical characteristics; cellular immunoreactivity to CD34 emerged as an especially potential surrogate marker for lesional FCD Type IIB, providing additional evidence that FCD Types IIA and IIB might differ in their etiology and biology. Although the sample number in this study was small, the results further support the theory that postoperative outcome-defined by Engel's classification-is multifactorial and determined by not only histology but also the extent of the initial lesion, its location in eloquent areas, intraoperative electrocorticographic findings, and achieved resection grade.

Myelomeningoceles (mmc) are clinically challenging CNS malformations. Although improvement in their management has been achieved with respect to antenatal diagnosis, prevention, and fetal surgery, the cellular mechanisms of damage in the neural placode are poorly understood. We aimed to identify cellular and molecular factors in lesion amplifying cascades in mmc placodes. Seventeen mmc specimens obtained during reconstructive surgery that harbored sufficient neuroepithelial tissue were investigated. Normal adult and stillborn spinal cord tissue served as controls. Placodes exhibited similar cellular profiles with consistent neuronal marker expression, elevated GFAP-/vimentin immunoreactivity in all, and CD3/CD11b/CD68-immunolabeling in some cases. Increased expression of pro-inflammatory (tumor necrosis factor, interleukin-1β [Il-1β]/IL-1 receptor type 1 [IL-R1]) and neuroprotective erythropoietin/erythropoietin receptor (Epo/EpoR) cytokines was detected by immunohistochemistry, double-fluorescence labeling, and real-time RT-PCR. In all cases, there was a multi-cellular induction of IL-1β and IL1-R1. EpoR and Epo immunoreactivity was elevated in some cases with neuronal expression patterns. Epo was further co-expressed with HIF-1/-2α, which paralleled Epo induction in the corresponding placodes. These observations confirm the induction of cellular and molecular alterations in human mmc placodes that resemble the secondary lesion cascades induced by spinal cord injury. The pro-inflammatory and neuroprotective cytokine expression in mmc placodes may represent new targets for the treatment of open neural tube defects., (© 2016 American Association of Neuropathologists, Inc. All rights reserved.)

The cytokine hormone erythropoietin (EPO) and the chemokine CCL3 are known to be produced in the brain under various pathological conditions. In this study, we investigated whether EPO and CCL3 influence on each other during neuroinflammation. We showed that EPO could reduce lipopolysaccharide (LPS)-induced CCL3 mRNA expression in rat cerebellar neuron-enriched preparations (real-time RT-PCR). Whereas administration of EPO or CCL3 respectively mediated neuroprotective properties after LPS treatment, the combinations of both molecules resulted in increased caspase 3/7 activity. Thus, it seems that - probably depending on particular conditions - EPO and CCL3 may cancel each other's functional properties.

Object: Cerebellar cavernous malformations (CCMs) have not been specifically described in the pediatric age group. Authors of this study, after considering the published literature, describe the characteristic clinical, radiological, and surgical features of CCM in children. METHOSDS: Patients younger than 18 years of age who were known to have CCM and had undergone surgery between 1992 and 2014 at the authors' institution were reviewed. Pediatric CCM cases reported in the literature (case reports and cases included in series on CMs in the pediatric age group) were also analyzed for specific features of this entity., Results: Four male patients and 1 female patient (2.5-14 years of age) with CCM presented acutely with severe headache followed by cerebellar dysfunction. In all patients, neuroimaging (cranial CT and MRI) demonstrated hemorrhagic cerebellar lesions with heterogeneous T1 and T2 signal intensities and hyperintense blooming on susceptibility-weighted imaging. The lesions reached large sizes exhibiting spherical, cystic, and often "pseudotumoral" morphology. In 3 patients, developmental venous anomalies (DVAs) were found. In 4 of the 5 patients, the CCMs and hematomas were totally removed. All patients had a clinically excellent functional outcome without surgical complication and with complete resolution of their presenting symptoms., Conclusions: Cerebellar CMs occur in all pediatric age groups and display characteristic clinical and imaging features. In children, CCMs reach large sizes and can result in massive hemorrhage, often leading to a possible diagnosis of hemorrhage into a tumor. An associated DVA is quite common. Surgery is a safe and efficient treatment option with excellent outcomes in patients.

The existence of endogenous neural progenitor cells (NPCs) in the adult spinal cord (sc) provides the potential for tailored repair therapies after spinal cord injury (SCI). This study investigates the impact of inflammatory mediators on properties of NPC cultures derived from adult rats after SCI. The Infinite Horizon impactor was used to apply 200-kdyn thoracic sc lesions in adult rats. Control groups received laminectomies to equivalent sc regions. Thoracic sc segments were taken for neurosphere cell cultures. Cell proliferation was found to be significantly higher in lesion groups. Neurosphere-derived cells differentiated into neurons, oligodendroglia, and astroglia. Lesion cultures exhibited significantly higher amounts of glial fibrillary acidic protein (GFAP) mRNA (P < 0.0005) and β-III-tubulin mRNA (P < 0.05) compared with sham animals. Neurospheres from different treatment groups exhibited the same amounts of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 mRNA. C-C chemokine receptor (CCR) expression on neurospheres was examined by real-time RT-PCR. CCR1 was expressed most consistently in mRNA levels in neurospheres from both treatment groups. After cell differentiation, CCR1 mRNA amounts decreased. CCR1 was detectable by immunohistochemistry in neurospheres and differentiated cells of both groups. Application of CCL3 during differentiation cycles led to significantly higher GFAP mRNA amounts in sham animals compared with CCL3-free cultures; in contrast, CCL3 had no impact on cell differentiation in the lesion group. In conclusion, impact SCI alters differentiation tendencies and proliferation rates of adult-derived sc NPCs. Thereby, CCR1/CCL3 promotes specifically astroglial differentiation of NPCs, which provides a potential target for future neurorestorative approaches., (© 2014 Wiley Periodicals, Inc.)

Spinal cord injury (SCI) results in complex posttraumatic sequelae affecting the whole neuraxis. Due to its involvement in varied neuromodulatory processes, the chemokine-ligand/receptor-network is a key element of secondary lesion cascades induced by SCI. This review will provide a synopsis of chemokine-ligand/receptor-expression along the whole neuraxis after traumatic spinal cord (sc) insults on basis of recent in vivo and in vitro findings in a SCI paradigm of thoracic force-defined impact lesions (Infinite Horizon Impactor) in adult rats. Analyses of chemokine-ligand/receptor-expression at defined time points after sc lesion of different severity grades or sham operation revealed that these inflammatory mediators are induced in distinct anatomical sc regions and in thalamic nuclei, periaqueductal grey, and hippocampal structures in the brain. Cellular and anatomical expression profiles together with colocalization/expression of neural stem/progenitor cell markers in adult sc stem cells niches or with pain-related receptors and mediators in dorsal horns, dorsal columns, and pain-processing brain areas support the notion that chemokines are involved in distinct cascades underlying clinical posttraumatic impairments and syndromes. These aspects and their implication in concepts of tailored SCI treatment are reviewed in the context of the recent literature on chemokine-ligand/receptor involvement in complex secondary lesion cascades.

Background: 18:1/18:1-Dioleoyl-phosphatidylgycerol (DOPG) is a surfactant phospholipid that is nearly non-detectable in neonatal surfactant films. When alveolar macrophages are exposed to DOPG in vitro, secretory phospholipase A2 (sPLA2) production is blocked, resulting in suppressed macrophage activity and improved surfactant function. We investigated whether the addition of DOPG to a commercially available surfactant preparation would improve lung function in a neonatal piglet model of acute respiratory distress syndrome., Materials and Methods: Respiratory failure was achieved by triple-hit lung injury (repeated broncho-alveolar lavage, injurious ventilation, tracheal lipopolysaccharide instillation, each intervention 24 h apart) in twenty-four domestic piglets aged 2-6 days and subject to mechanical ventilation. Following each lung injury protocol the piglets were treated with surfactant alone or with surfactant + DOPG., Results: Within 72 h of mechanical ventilation, we observed significantly improved gas exchange (oxygenation and ventilation), lung mechanics (compliance and resistance of the respiratory system), and pulmonary oedema (extra-vascular lung water index) in the surfactant + DOPG group. This favourable clinical effect could be attributed to improved surfactant function, reduced sPLA2 secretion, inhibition of macrophage migration, reduced alveolar epithelial apoptosis, and suppression of amphiregulin and TGF-β1 expression in pulmonary tissues as a prerequisite for fibrous lung repair., Conclusions: We conclude that surfactant fortified by DOPG preserves lung function, and prevents alveolar epithelial injury and fibrous stimulus by reduction of sPLA2 in a neonatal model of acute respiratory distress syndrome without any relevant discernable side effects. Hence, DOPG supplementation in a neonatal lung exerts important function protecting effects and seems to be justified in cases of overwhelming pulmonary inflammation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF) family ligands (GFL) are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson's disease. However, little is known about direct influences of the GFL on microglia function, which are known to express part of the GDNF receptor system. Using RT-PCR and immunohistochemistrym we investigated the expression of the GDNF family receptor alpha 1 (GFR alpha) and the coreceptor transmembrane receptor tyrosine kinase (RET) in rat microglia in vitro as well as the effect of GFL on the expression of proinflammatory molecules in LPS activated microglia. We could show that GFL are able to regulate microglia functions and suggest that part of the well known neuroprotective action may be related to the suppression of microglial activation. We further elucidated the functional significance and pathophysiological implications of these findings and demonstrate that microglia are target cells of members of the GFL (GDNF and the structurally related neurotrophic factors neurturin (NRTN), artemin (ARTN), and persephin (PSPN)).

Hypoxemic respiratory failure of the neonatal organism involves increased acid sphingomyelinase (aSMase) activity and production of ceramide, a second messenger of a pro-inflammatory pathway that promotes increased vascular permeability, surfactant alterations and alveolar epithelial apoptosis. We comparatively assessed the benefits of topical aSMase inhibition by either imipramine (Imi) or phosphatidylinositol-3,5-bisphosphate (PIP2) when administered into the airways together with surfactant (S) for fortification. In this translational study, a triple-hit acute lung injury model was used that entails repeated airway lavage, injurious ventilation and tracheal lipopolysaccharide instillation in newborn piglets subject to mechanical ventilation for 72 hrs. After randomization, we administered an air bolus (control), S, S+Imi, or S+PIP2. Only in the latter two groups we observed significantly improved oxygenation and ventilation, dynamic compliance and pulmonary oedema. S+Imi caused systemic aSMase suppression and ceramide reduction, whereas the S+PIP2 effect remained compartmentalized in the airways because of the molecule's bulky structure. The surfactant surface tensions improved by S+Imi and S+PIP2 interventions, but only to a minor extent by S alone. S+PIP2 inhibited the migration of monocyte-derived macrophages and granulocytes into airways by the reduction of CD14/CD18 expression on cell membranes and the expression of epidermal growth factors (amphiregulin and TGF-β1) and interleukin-6 as pro-fibrotic factors. Finally we observed reduced alveolar epithelial apoptosis, which was most apparent in S+PIP2 lungs. Exogenous surfactant "fortified" by PIP2, a naturally occurring surfactant component, improves lung function by topical suppression of aSMase, providing a potential treatment concept for neonates with hypoxemic respiratory failure., (© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

D-myo-inositol-1,2,6-trisphosphate (IP3) is an isomer of the naturally occurring second messenger D-myo-inositol-1,4,5-trisphosphate, and exerts anti-inflammatory and antiedematous effects in the lung. Myo-inositol (Inos) is a component of IP3, and is thought to play an important role in the prevention of neonatal pulmonary diseases such as bronchopulmonary dysplasia and neonatal acute lung injury (nALI). Inflammatory lung diseases are characterized by augmented acid sphingomyelinase (aSMase) activity leading to ceramide production, a pathway that promotes increased vascular permeability, apoptosis, and surfactant alterations. A novel, clinically relevant triple-hit model of nALI was developed, consisting of repeated airway lavage, injurious ventilation, and lipopolysaccharide instillation into the airways, every 24 hours. Thirty-five piglets were randomized to one of four treatment protocols: control (no intervention), surfactant alone, surfactant + Inos, and surfactant + IP3. After 72 hours of mechanical ventilation, lungs were excised from the thorax for subsequent analyses. Clinically, oxygenation and ventilation improved, and extravascular lung water decreased significantly with the S + IP3 intervention. In pulmonary tissue, we observed decreased aSMase activity and ceramide concentrations, decreased caspase-8 concentrations, reduced alveolar epithelial apoptosis, the reduced expression of interleukin-6, transforming growth factor-β1, and amphiregulin (an epithelial growth factor), reduced migration of blood-borne cells and particularly of CD14(+)/18(+) cells (macrophages) into the airspaces, and lower surfactant surface tensions in S + IP3-treated but not in S + Inos-treated piglets. We conclude that the admixture of IP3 to surfactant, but not of Inos, improves gas exchange and edema in our nALI model by the suppression of the governing enzyme aSMase, and that this treatment deserves clinical evaluation.

Object: Central neuropathic pain is a frequent challenging complication after spinal cord injury (SCI), and specific therapeutic approaches remain elusive. The purpose of the present investigations was to identify potential key mediators of these pain syndromes by analyzing detailed expression profiles of important chemokines in an experimental SCI paradigm of posttraumatic neuropathic pain in rats., Methods: Expression of CCR1, CCL3(MIP-1α), CXCR4, and CXCL12(SDF-1α) was investigated in parallel with behavioral testing for mechanical and thermal nociceptive thresholds after standardized SCI; 100-kdyn (moderate injury) and 200-kdyn (severe injury) force-defined thoracic spinal cord contusion lesions were applied via an Infinite Horizon Impactor at the T-9 level. Sham controls received laminectomies. Hindlimb locomotor function as well as mechanical and thermal sensitivities were monitored weekly by standardized behavioral testing after SCI. Chemokine expression was analyzed by real-time reverse transcriptase polymerase chain reaction in the early (7 days postoperatively) and late (42 days postoperatively) time courses after SCI, and immunohistochemical analysis (anatomical and quantitative) was performed 2, 7, 14, and 42 days after lesioning. Double staining with cellular markers and pain-related peptides (substance P and CGRP) or receptors (TRPV-1, TRPV-2, VRL-1, and TLR-4) was performed. Based on data obtained from behavioral testing, quantified immunohistochemical chemokine expressions in individual animals were correlated with the respective mechanical and thermal sensitivity thresholds 6 weeks after SCI., Results: After 200-kdyn lesions, the animals exhibited prolonged reduction in their nociceptive thresholds, while 100-kdyn groups showed pain-related behaviors only in the early time course after SCI. Investigated chemokines were widely induced after SCI, involving cervical, thoracic, and lumbar spinal cord levels far beyond the lesion core. CCR1 and CCL3 were induced significantly in the dorsal horns 2 days after lesioning and remained at high levels after SCI with significantly higher intensities after 200-kdyn than 100-kdyn contusions. CXCR4 and CXCL12 levels continuously increased from 2 to 42 days after moderate and severe lesions. Additionally, chemokines were induced significantly in dorsal columns, with highest density levels 42 days after 200-kdyn lesions. In dorsal horns, CCR1 was coexpressed with TRPV-1 while CXCR4 and CXCL12 were partially coexpressed with substance P and CGRP. In dorsal columns, CCL3/CCR1 colabeled with GFAP, TRPV-2, TRPV-1, TLR-4; CXCR4/CXCL12 coexpressed with GFAP, CD68/ED1, and TLR4. Chemokine immunoreactivity density levels, especially CCL3 and its receptor, correlated in part significantly with nociceptive thresholds., Conclusions: The authors report lesion grade-dependent upregulation of different chemokines/chemokine receptors after spinal cord contusion lesions in pain-processing spinal cord regions in a clinically relevant model of traumatic SCI in rats. Prolonged chemokine induction further correlated with below-level pain development in the delayed time course after severe SCI and was coexpressed with pain-associated peptides and receptors, suggesting that chemokines play a crucial role in chronic central pain mechanisms after SCI.

Due to their involvement in neuro-modulatory processes, the endogenous cannabinoid system and chemokine network, which were shown to interact which each other, are potential key elements in the cascades underlying central neuropathic pain development after spinal cord injury (SCI). Expression profiles of cannabinoid receptor type-1 (CB(1)), and of the chemokines chemokine ligand 2 (C-C motif ) (CCL2), chemokine ligand 3 (C-C motif ) (CCL3), plus their main receptors CCR2 and CCR1, were investigated in brain regions related to pain, emotion, learning, and memory in a rat SCI paradigm of post-traumatic neuropathic pain. Immunoreactivity (IR) was investigated 7 days and 42 days after sham operation, and moderate (100-kdyn), and severe (200-kdyn) thoracic spinal cord contusion lesions. Hippocampal (HC) subregions, amygdaloid complex, anterior cingulate cortex (ACC), periaqueductal gray (PAG), and thalamic nuclei were analyzed. Seven days after lesioning, CB(1) IR was induced in thalamic nuclei and HC subregions (CA3 and dentate gyrus), and downregulated in amygdaloid nuclei, ACC, and PAG. On day 42, CB(1) IR remained elevated in the HC and thalamic areas, and was induced in ACC after 100-kdyn, but downregulated after 200-kdyn lesions. It remained reduced in the PAG of severely lesioned animals, paralleling their prolonged neuropathic pain-related behavior. Double-labeling revealed partial co-expression of CB(1) with the pain-related vanilloid receptor transient receptor potential vanilloid receptor 1 (TRPV1), and chemokines (CCL2 and CCL3). These chemokines were induced in the PAG, thalamus, and HC, especially in the chronic time course after severe SCI. Thus interactions of CB(1), C-C chemokines, and TRPV1 likely play a role in SCI-induced plastic changes in the brain, underlying emotional-affective pain responses and central pain development after spinal cord lesions.

The nuclear autoantigen SP100 (speckled protein 100) is reported to control cellular gene expression, cell growth and differentiation. To investigate its relevance in brain tumors, we investigated SP100 expression and function in human glioblastomas and meningiomas. SP100 was expressed in both tumors at the mRNA and protein levels in situ and in vitro, however, expression in meningioma samples and meningioma cells exceeded that in glioblastoma samples and cultivated cells significantly. Moreover, whereas nearly all meningioma cells were SP100-immunopositive, only part of the glioblastoma cells were SP100 stainable. In vitro, SP100 was upregulated by interferon-α and -γ in both malignant cell types. To study its functional role, SP100 was overexpressed in glioblastoma cells. This SP100 overexpression reduced considerably the glioblastoma cell proliferation and migration to fetal calf serum. We conclude that SP100 expression reduces malignancy of brain tumors. Since meningiomas show a generally higher SP100 expression, this may be one of the factors explaining their lower malignancy compared to glioblastomas.

Inflammatory cascades induced by spinal cord injuries (SCI) are localized in the white matter, a recognized neural stem- and progenitor-cell (NSPC) niche of the adult spinal cord. Chemokines, as integrators of these processes, might also be important determinants of this NSPC niche. CCL3/CCR1, CCL2/CCR2, and SDF-1alpha/CXCR4 were analyzed in the ventrolateral white matter after force defined thoracic SCI: Immunoreactivity (IR) density levels were measured 2 d, 7 d, 14 d, and 42 d on cervical (C 5), thoracic (T 5), and lumbar (L 5) levels. On day post operation (DPO) 42, chemokine inductions were further evaluated by real-time RT-PCR and Western blot analyses. Cellular phenotypes were confirmed by double labeling with markers for major cell types and NSPCs (nestin, Musashi-1, NG2, 3CB2, BLBP). Mitotic profiles were investigated in parallel by BrdU labeling. After lesion, chemokines were induced in the ventrolateral white matter on IR-, mRNA-, and protein-level. IR was generally more pronounced after severe lesions, with soaring increases of CCL2/CCR2 and continuous elevations of CCL3/CCR1. SDF-1alpha and CXCR4 IR induction was focused on thoracic levels. Chemokines/-receptors were co-expressed with astroglial, oligodendroglial markers, nestin, 3CB2 and BLBP by cells morphologically resembling radial glia on DPO 7 to DPO 42, and NG2 or Musashi-1 on DPO 2 and 7. In the white matter BrdU positive cells were significantly elevated after lesion compared with sham controls on all investigated time points peaking in the early time course on thoracic level: Here, chemokines were co-expressed by subsets of BrdU-labeled cells. These findings suggest an important role of chemokines/-receptors in the subpial white matter NSPC niche after SCI.

The transmembrane chemokine CX3CL1 and its receptor CX3CR1 are thought to be involved in the trafficking of immune cells during an immune response and in the pathology of various human diseases including cancer. However, little is known about the expression and function of CX3CR1 in human glioma-infiltrating microglia/macrophages (GIMs), representing the major cellular stroma component of highly malignant gliomas. Here, we show that CX3CR1 is overexpressed at both the mRNA and protein level in solid human astrocytomas of different malignancy grades and in glioblastomas. CX3CR1 was localized in ionized calcium-binding adapter molecule 1 (Iba1) and CD11b/c positive GIMs in situ as shown by fluorescence microscopy. In accordance with this, freshly isolated human GIM-enriched fractions separated by CD11b MACS technology displayed high Iba1 and CX3CR1 mRNA expression levels in vitro. Moreover, cultured human GIMs responded to CX3CL1-triggered activation of CX3CR1 with adhesion and migration in vitro. Besides an increase in motility, CX3CL1 also enhanced expression of matrix metalloproteases 2, 9, and 14 in GIM fractions in vitro. These data indicate that the CX3CL1/CX3CR1 system has a crucial tumor-promoting role in human glioblastomas via its impact on glioma-infiltrating immune subsets., (Copyright 2010. Published by Elsevier Inc.)

Spinal cord injury (SCI) often results in intractable chronic central pain syndromes. Recently chemokines such as CCL2 were identified as possible key integrators of neuropathic pain and inflammation after peripheral nerve lesion. The focus of the current study was the investigation of time-dependent CCL2 and CCR2 expression in relation to central neuropathic pain development after spinal cord impact lesions of 100, 150, or 200 kdyn force on spinal cord level T9 in adult rats. Below-level pain was monitored with weekly sensory testing for 42 days after SCI. In parallel expression of CCL2/CCR2 on cervical, thoracic, and lumbar levels was investigated by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry early (7 days [7d]), intermediate (15d), and late (42d) after lesion. Cellular source and anatomical pain related expression was determined by double-immunohistochemistry. Force-defined SCI led to acute mechanical hypersensitivity in all lesion groups, and to persistent below-level pain in severely injured animals. While in the early post-operative time course, CCL2 and CCR2 were expressed in astroglia and granulocytes only on level T9; there was additional astroglial CCL2 expression in dorsal columns and dorsal horns above and below T9 of severely injured animals 42d after lesion. In dorsal horns (level L3-L5) of animals exhibiting chronic below-level pain CCL2 was co-expressed with transmitters and receptors that are involved in nociceptive processing like calcitonin gene-related peptide (CGRP), Substance-P, vanilloid-receptor-1, and its activated phosphorylated form. These data demonstrate lesion grade dependence of below-level pain development and suggest chemokines as potential candidates for integrating inflammation and central neuropathic pain after SCI.