CSF-space volumetric change following posterior fossa decompression in paediatric Chiari type-I malformation: a correlation with outcome.

OBJECTIVE: We have previously reported inferior post-operative clinical outcomes in younger children with Chiari type-I malformation (CIM). We sought to quantify the CSF volumetric changes pre- and post-decompression, in a paediatric cohort, to determine whether cisternal volume change is associated with clinical outcomes. METHODS: In this retrospective clinical study, the CSF spaces of the posterior fossa (supracerebellar/quadrigeminal, prepontine, fourth ventricle, cisterna magna) were measured on magnetic resonance images pre- and post-operatively using a semi-automated method. Additionally, we describe a novel CSF space of the upper cervical canal incorporating the subarachnoid space from the foramen magnum to the inferior cortex of the C2 body, FM-C2 cistern. Morphometric measurements included the pB-C2 distance, clivoaxial angle, clival length, clival angle and Boogard's angle. Volumetric and morphometric data were correlated with clinical outcomes at 4-12 months post-operatively as measured by the Chicago Chiari Outcome Scale (CCOS). RESULTS: Of 59 adequate clinical cases, 57 and 36 patients had acceptable imaging for morphometric and volumetric analysis respectively. All CSF spaces measured had a significant increase in volume post-operatively (p < 0.05). There was no correlation between the change in volume or post-operative CSF volumes and CCOS. The pre-operative volume of the FM-C2 was positively correlated with total CCOS (Wald [Formula: see text], [Formula: see text]) and was significantly smaller in the 0-6-year age group (2.38 ± 1.27 ml vs. 3.67 ± 1.56 ml, p = 0.014). No morphometric measurement changed significantly after surgery or demonstrated a relationship with CCOS. CONCLUSIONS: Volumetric changes in the CSF cisterns of the posterior cranial fossa and upper cervical canal do not correlate with the age-related differences in clinical outcomes in paediatric CIM. The pre-operative volume of the FM-C2 cistern may have a role in predicting the likelihood of a beneficial post-operative outcome in paediatric CIM.

Growth of Intramedullary Spinal Cord Dermoid Cyst from a Congenital Thoracic Dermal Sinus Tract after Negative Screening Ultrasound Imaging.

INTRODUCTION: Intramedullary thoracic dermoid cysts are rare lesions that are associated with dermal sinus tracts (DSTs). Current recommendations advocate for imaging-based screening of suspected DSTs shortly after birth to exclude associated inclusion lesions. CASE PRESENTATION: A 6-year-old male child presented with a 2-week history of progressive ataxia, lower limb weakness, and hyperreflexia. He was suspected to have a thoracic DST at birth, though initial screening ultrasound was negative for an inclusion lesion or intradural tract. On representation, MRI demonstrated a 3.9-cm intramedullary thoracic dermoid cyst causing significant spinal cord compression. Intraoperatively, a DST extending intradurally was found. The associated dermoid cyst was removed via intracapsular resection. CONCLUSIONS: Whilst dermoid cysts are presumed to progressively develop from DSTs, to our knowledge, this is the first case in English literature documenting a thoracic spinal cord intramedullary dermoid cyst following a negative screening ultrasound for a suspected DST. We use this case to highlight the false-negative rates associated with postnatal screening and advocate for early neurosurgical referral of suspected DSTs, regardless of imaging findings.

Co-ordinated expression of innate immune molecules during mouse neurulation.

The innate immune system is the first line of defence against pathogens and infection. Recently, it has become apparent that many innate immune factors have roles outside of immunity and there is growing evidence that these factors play important functional roles during the development of a range of model organisms. Several studies have documented developmental expression of individual factors of the toll-like receptor and complement systems, and we recently demonstrated a key role for complement C5a receptor (C5aR1) signalling in neural tube closure in mice. Despite these emerging studies, a comprehensive expression analysis of these molecules in embryonic development is lacking. In the current study, we therefore, examined the expression of key innate immune factors in the early development period of neurulation (7.5-10.5dpc) in mice. We found that complement factor genes were differentially expressed during this period of murine development. Interestingly, the expression patterns we identified preclude activation of the classical and alternative pathways and formation of the membrane attack complex. Additionally, several other classes of innate immune molecules were expressed during the period of neurulation, including toll-like receptors (TLR-2, -3, -4 and -9), receptor for advanced glycation end-products (RAGE), and their signalling adapters (TRAF-4, TRAF-6, TAK-1 and MyD88). Taken together, this study highlights a number of innate immune factors as potential novel players in early embryonic development.

Brief report: complement C5a promotes human embryonic stem cell pluripotency in the absence of FGF2.

The complement activation product, C5a, is a pivotal member of the innate immune response; however, a diverse number of nonimmune functions are now being ascribed to C5a signaling, including roles during embryonic development. Here, we identify the expression of the C5a precursor protein, C5, as well as the C5a receptors, C5aR and C5L2, in both human embryonic stem cells and human-induced pluripotent stem cells. We show that administration of a physiologically relevant dose of purified human C5a (1 nM) stimulates activation of ERK1/2 and AKT signaling pathways, and is able to promote maintenance of the pluripotent state in the absence of FGF2. C5a also reduced cell loss following dissociation of human pluripotent stem cells. Our results reveal that complement C5a signaling supports human stem cell pluripotency and survival, and thus may play a key role in shaping early human embryonic development.

C5a receptor signaling prevents folate deficiency-induced neural tube defects in mice.

The complement system is involved in a range of diverse developmental processes, including cell survival, growth, differentiation, and regeneration. However, little is known about the role of complement in embryogenesis. In this study, we demonstrate a novel role for the canonical complement 5a receptor (C5aR) in the development of the mammalian neural tube under conditions of maternal dietary folic acid deficiency. Specifically, we found C5aR and C5 to be expressed throughout the period of neurulation in wild-type mice and localized the expression to the cephalic regions of the developing neural tube. C5aR was also found to be expressed in the neuroepithelium of early human embryos. Ablation of the C5ar1 gene or the administration of a specific C5aR peptide antagonist to folic acid-deficient pregnant mice resulted in a high prevalence of severe anterior neural tube defect-associated congenital malformations. These findings provide a new and compelling insight into the role of the complement system during mammalian embryonic development.

Comparative efficacy of a secretory phospholipase A2 inhibitor with conventional anti-inflammatory agents in a rat model of antigen-induced arthritis.

INTRODUCTION: Previously, secretory phospholipase A2 (sPLA2) inhibition has been used as an adjunct to conventional rheumatoid arthritis therapy in human clinical trials without significant improvement of arthritic pathology. In this study, we compared the efficacy of a potent and orally active group IIa secretory phospholipase A2 inhibitor (sPLA2I) to conventional anti-arthritic agents; infliximab, leflunomide and prednisolone, in a rat model of antigen-induced arthritis. METHODS: Initially, to establish efficacy and dose-response, rats were orally dosed with the sPLA2I (1 and 5 mg/kg) two days prior to arthritis induction, and then daily throughout the 14-day study period. In the second trial, rats were orally dosed with the sPLA2I (5 and 10 mg/kg/day) beginning two days after the induction of arthritis, at the peak of joint swelling. Separate groups of rats were also dosed with the tumour necrosis factor-alpha (TNF-α) inhibitor infliximab (single 3 mg/kg i.v. injection), leflunomide (10 mg/kg/day, oral) or prednisolone (1 mg/kg/day, oral) at this same time point and used as comparative treatments. RESULTS: In the pathology prevention trial, both 1 and 5 mg/kg dose groups of sPLA2I demonstrated a significant reduction in joint swelling and gait disturbances; however, only the higher 5 mg/kg dose resulted in significantly reduced histopathology scores. In the post-induction trial, rats dosed with sPLA2I showed a significant improvement in joint swelling and gait scoring, whereas none of the conventional therapeutics achieved a significant decrease in both of these two disease markers. Histopathological scoring at the end-point of the study demonstrated significantly reduced median scores in rats treated with 10 mg/kg sPLA2I and leflunomide. CONCLUSIONS: The results from this study suggest a pathogenic role for sPLA2 enzymes in this model of arthritis in rats, and the potential clinical utility of sPLA2 inhibition as a safer, and more effective, alternative to conventional anti-arthritic therapeutics.