Fingolimod induces neuroprotective factors in human astrocytes.

BACKGROUND: Fingolimod (FTY720) is the first sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of multiple sclerosis. The phosphorylated active metabolite FTY720-phosphate (FTY-P) interferes with lymphocyte trafficking. In addition, it accumulates in the CNS and reduces brain atrophy in multiple sclerosis (MS), and neuroprotective effects are hypothesized. METHODS: Human primary astrocytes as well as human astrocytoma cells were stimulated with FTY-P or S1P. We analyzed gene expression by a genome-wide microarray and validated induced candidate genes by quantitative PCR (qPCR) and ELISA. To identify the S1P-receptor subtypes involved, we applied a membrane-impermeable S1P analog (dihydro-S1P), receptor subtype specific agonists and antagonists, as well as RNAi silencing. RESULTS: FTY-P induced leukemia inhibitory factor (LIF), interleukin 11 (IL11), and heparin-binding EGF-like growth factor (HBEGF) mRNA, as well as secretion of LIF and IL11 protein. In order to mimic an inflammatory milieu as observed in active MS lesions, we combined FTY-P application with tumor necrosis factor (TNF). In the presence of this key inflammatory cytokine, FTY-P synergistically induced LIF, HBEGF, and IL11 mRNA, as well as secretion of LIF and IL11 protein. TNF itself induced inflammatory, B-cell promoting, and antiviral factors (CXCL10, BAFF, MX1, and OAS2). Their induction was blocked by FTY-P. After continuous exposure of cells to FTY-P or S1P for up to 7 days, the extent of induction of neurotrophic factors and the suppression of TNF-induced inflammatory genes declined but was still detectable. The induction of neurotrophic factors was mediated via surface S1P receptors 1 (S1PR1) and 3 (S1PR3). CONCLUSIONS: We identified effects of FTY-P on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes.

Earlier Tracheostomy Reduces Complications in Complete Cervical Spinal Cord Injury in Real-World Practice: Analysis of a Multicenter Cohort of 2001 Patients.

BACKGROUND AND OBJECTIVES: It is believed that early tracheostomy in patients with traumatic cervical spinal cord injury (SCI) may lessen the risk of developing complications and reduce the duration of mechanical ventilation and critical care stay. This study aims to assess whether early tracheostomy is beneficial in patients with traumatic cervical SCI. METHODS: We conducted a retrospective cohort study using data from the American College of Surgeons Trauma Quality Improvement Program database from 2010 to 2018. Adult patients with a diagnosis of acute complete (ASIA A) traumatic cervical SCI who underwent surgery and tracheostomy were included. Patients were stratified into those receiving early (at or before 7 days) and delayed tracheostomy. Propensity score matching was used to assess the association between delayed tracheostomy and the risk of in-hospital adverse events. Risk-adjusted variability in tracheostomy timing across trauma centers was investigated using mixed-effects regression. RESULTS: The study included 2001 patients from 374 North American trauma centers. The median time to tracheostomy was 9.2 days (IQR: 6.1-13.1 days), with 654 patients (32.7%) undergoing early tracheostomy. After matching, the odds of a major complication were significantly lower for early tracheostomy patients (OR: .90; 95% CI: .88-.98). Patients were also significantly less likely to experience an immobility-related complication (OR: .90; 95% CI: .88-.98). Patients in the early group spent 8.2 fewer days in the critical care unit (95% CI: -10.2 to -6.61) and 6.7 fewer days ventilated (95% CI: -9.44 to -5.23). There was significant variability in tracheostomy timeliness between trauma centers with a median odds ratio of 12.2 (95% CI: 9.7-13.7), which was not explained by case-mix and hospital-level characteristics. CONCLUSION: A 7-day threshold to implement tracheostomy seems to be associated with reduced in-hospital complications, time in the critical care unit, and time on mechanical ventilation.

Vertebral Body Replacement With an Anchored Expandable Titanium Cage in the Cervical Spine: A Clinical and Radiological Evaluation.

BACKGROUND: Expandable cervical cages have been used successfully to reconstruct the anterior spinal column. OBJECTIVE: To perform clinical and radiological evaluation of vertebral body replacement with an anchored expandable titanium cage in the cervical spine after single-level and 2-level corpectomies. METHODS: Between 2011 and 2017, 40 patients underwent a single-level (N = 32) or 2-level (N = 8) anterior corpectomy and fusion using an anchored expandable vertebral body replacement cage. Clinical and radiological data at admission, postoperatively, and at 3- and 12-mo follow-up were retrospectively analyzed. Clinical assessment was performed via standardized neurological evaluation, Odom score, and McCormick classification. Radiological assessment was performed via evaluation of sagittal profile, postoperative position, fusion, and subsidence rates. RESULTS: Mean last follow-up was 14.8 ± 7 mo. Overall clinical and myelopathy-related improvements were shown directly after operation and at last follow-up. A stable centralized positioning of cages was achieved in 37 patients (93%). A mild ventral (>1.5 mm) malplacement was noted in 3 patients (7%) without clinical consequences. Sagittal alignment and preoperative cervical kyphosis improved significantly (7.8° gain of lordosis) and remained stable. Mean preoperative height of operated segments increased by 10 mm postoperatively and remained stable. Fusion rate in non-neoplastic patients and subsidence rate at last follow-up comprised 87.5% and 17.8%. With exception of 1 patient suffering from severe osteoporosis and cage subsidence, no patient needed additional secondary stabilization. CONCLUSION: Anterior corpectomy and fusion by an expandable anchored titanium cage with anchor screws without additional instrumentation resulted in overall clinical improvement and radiological anterior column support, achieving significant and reliable restoration of the physiological sagittal cervical profile.

Dual-room CT with a sliding gantry for intraoperative imaging: feasibility and workflow analysis of an interdisciplinary concept.

PURPOSE: Currently, intraoperative computed tomography (iCT) is a scarcely used technique in neurosurgery. It remains unclear whether this phenomenon is explained by unfavorable iCT-related workflows and/or a limited number of indications. We here analyzed workflows of an installed dual-room iCT (DR-iCT) as compared to surgical procedures lacking iCT. We compared infection rates, utilizations rates, and the spectrum of indications of DR-iCT with that of a previously used single-room iCT. METHODS: The study refers to a consecutive series of patients undergoing either single-room iCT (January 2014-August 2014) or DR-iCT (September 2014-July 2016). A further group undergoing surgery without iCT in the interconnected operating rooms represents the reference group. Workflow measurements and infection rates were calculated. Indications for iCT and utilization rates were compared for each of the devices. CT image quality was rated. RESULTS: Application of DR-iCT led to a broader use of this technique as compared to the single-room device, which concerned in particular stereotactic neurosurgery. Accordingly, iCT utilization rates significantly increased (up to 50.8 ± 4.6 surgeries per month, p < 0.001). Workflow was slightly prolonged in case of DR-iCT imaging; the difference, however, was not statistically significant. Infections rates were low (range 0.0-0.17 infections per month) and not influenced by the utilization rate. Image quality of the DR-iCT was classified as very good in 34/43 evaluated microsurgical patients. CONCLUSIONS: The use of DR-iCT enhances utilization rates with a broader field of indications for intraoperative imaging. Workflow measurements are not significantly prolonged. The technology is safe, and the imaging quality of modern devices can be expected to be good.

Nocturia in Patients With Parkinson's Disease.

BACKGROUND: Waking up from sleep more than once to pass urine, known as nocturia, is an important nonmotor symptom in Parkinson's disease (PD). Very little is known about the cause for nocturia. The aim of this work was to evaluate lower urinary tract (LUT) symptoms in patients with PD reporting nocturia using standardized validated questionnaires and bladder diaries and to assess the impact of nocturia on quality of life and sleep. METHODS: Twenty-three consecutive patients with PD (17 males, 6 females; mean age: 68.5 years; range, 50-85) referred to a specialist uro-neurology clinic reporting nocturia according to the International Continence Society definition were included. Patients measured their daily fluid intake, urinary output per void, and recorded these with the timing of voids on a 3-day bladder diary. Standardized questionnaires were used to assess LUT symptoms (Urinary Symptom Profile, International Prostate Symptom Score, and Qualiveen Short Form) and sleep quality (Parkinson's Disease Sleep Scale). RESULTS: Mean duration of PD was 10.1 years, and mean severity on H & Y scale was 3.0 (range, 1.0-5.0). Median duration of LUT symptoms was 6.0 years. Mean night-time urinary frequency was 3.5 (range, 1.0-7.3), and mean nocturnal maximum voided volume was 242 mL. Mean Nocturnal Polyuria Index (NPi) was 0.4 (range, 0.13-0.75), and 13 patients (56.5%) had nocturnal polyuria (NPi > 0.33). Patients with nocturnal polyuria reported more-severe LUT symptoms that impacted quality of life and sleep. CONCLUSIONS: In this preliminary study, nocturnal polyuria seems to be common in patients with PD reporting nocturia and appears to affect quality of life and sleep, though this was not statistically significant. The bladder diary is an essential tool in the assessment of nocturia in patients with PD.

Bladder and Bowel Dysfunction Is Common in Both Men and Women with Mutation of the ABCD1 Gene for X-Linked Adrenoleukodystrophy.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a disorder caused by mutations in the ABCD1 gene. The commonest phenotype of X-ALD is adrenomyeloneuropathy (AMN), which is characterised by involvement of the spinal cord and peripheral nerves. The aim of this study was to evaluate bladder and bowel symptoms in men with AMN and female X-ALD carriers. METHODS: In this cross-sectional study, patients with confirmed mutation of the ABCD1 gene attending a tertiary care service were approached about bladder and bowel complaints and completed the Urinary Symptom Profile (USP), Qualiveen Short Form (SF-Qualiveen), International Prostate Symptom Score (IPSS) and Neurogenic Bowel Dysfunction (NBD) questionnaires. Neurological disability was assessed using the Expanded Disability Status Scale (EDSS). RESULTS: Forty-eight patients participated, 19 males (mean EDSS score (n = 16) 5.0 (95% CI ± 1.03)) and 29 females (mean EDSS score (n = 25) 3.2 (95% CI ± 0.98)). Overactive bladder (OAB) symptoms were reported in both males (100%, n = 19) and females (86.2%, n = 25). There was no significant gender difference in severity of OAB symptoms (P = 0.35) and impact on quality of life (P = 0.13). Furthermore, there was no significant difference in OAB severity when symptoms were compared between female carriers and a cohort of women (n = 17) with spinal cord damage due to multiple sclerosis (P = 0.27). Twenty-one percent (n = 4) of males and 10% (n = 3) of females had moderate to severe bowel dysfunction. CONCLUSIONS: Bladder and bowel complaints are common in both men with AMN and female carriers. They have a significant impact on the quality of life yet are under-reported and under-treated. Though having an X-linked pattern of inheritance, female carriers may experience overactive bladder symptoms which are as severe as in male patients and are likely to be neurological in origin.