Neuroprotection by minocycline in murine traumatic spinal cord injury: analyses of matrix metalloproteinases

Aim: Minocycline has neuroprotective activities in several models of neurological disorders including spinal cord injury (SCI) where it prevents axonal loss and improves functional recovery. There are still gaps of knowledge on minocycline in SCI including whether it ameliorates neuronal loss at the focal site of trauma, and whether minocycline reduces the activity of matrix metalloproteinases (MMPs), a family of enzymes implicated in the pathophysiology of SCI. This study addressed these gaps. Methods: Mice were treated with either minocycline or vehicle control after a spinal cord contusion. MMPs were compared between the two groups using real time polymerase chain reaction and zymography. Immunohistochemistry was used to examine microglial activation and neuronal cell death. Results: While several MMP members were elevated in the spinal cord following injury, treatment with minocycline did not affect their expression. Importantly, minocycline reduced the loss of neurons in the epicenter of damage to the spinal cord and in segments caudal and rostral to the injury. Conclusion: Despite the inability of minocycline to alter MMPs, the results of neuroprotection at the lesion site support the continued testing of minocycline as a neuroprotective medication in experimental and clinical SCI

Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity

system. mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging.Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Acute Pharmacological DVT Prophylaxis after Spinal Cord Injury

A systematic review of the literature was performed to address pertinent clinical questions regarding deep vein thrombosis (DVT) prophylaxis in the setting of acute spinal cord injury (SCI). Deep vein thromboses are a common occurrence following SCI. Administration of low-molecular-weight heparin (LMWH) within 72 h of injury is recommended to minimize the occurrence of DVT. Furthermore, when surgical intervention is required, LMWH should be held the morning of surgery, and resumed within 24 h post-operatively

Acute Management of Nutritional Demands after Spinal Cord Injury

A systematic review of the literature was performed to address pertinent clinical questions regarding nutritional management in the setting of acute spinal cord injury (SCI). Specific metabolic challenges are present following spinal cord injury. The acute stage is characterized by a reduction in metabolic activity, as well as a negative nitrogen balance that cannot be corrected, even with aggressive nutritional support. Metabolic demands need to be accurately monitored to avoid overfeeding. Enteral feeding is the optimal route following SCI. When oral feeding is not possible, nasogastric, followed by nasojejunal, then by percutaneous endoscopic gastrostomy, if necessary, is suggested

Impact of preoperative insomnia on poor postoperative pain control after elective spine surgery and the modified Calgary postoperative pain after spine surgery (MCAPPS) score

Background: Approximately 30% to 64% of patients experience inadequate pain control following spine surgery. The Calgary postoperative pain after spine surgery (CAPPS) score was developed to identify this subset of patients. The impact of preoperative insomnia on postoperative pain control is unknown. This study aimed to investigate the relationship between preoperative insomnia and poor pain control after spine surgery, as well as improve the predictive accuracy of the CAPPS score. Methods: A prospective cohort study was conducted in patients undergoing elective spine surgery. Poor pain control was defined as a mean numeric rating scale pain score >4 at rest within the first 24-hours after surgery. Patients were evaluated using the CAPPS score, which included 7 prognostic factors. A multivariable logistic regression model was used to examine the association between preoperative insomnia severity index (ISI) and poor pain control, adjusting for the CAPPS score. The Modified CAPPS score was derived from this model. Results: Of 219 patients, 49.7% experienced poorly controlled pain. Prevalence of clinical insomnia (ISI≥15) was 26.9%. Preoperative ISI was independently associated with poor pain control (odds ratio [OR] 1.09, [95%CI=1.03–1.16], p=.004), after adjusting for the CAPPS score (OR 1.61, [95%CI=1.38–1.89], p<.001). The model exhibited good discrimination (c-statistics 0.80, [95%CI=0.74–0.86]) and calibration (Hosmer-Lemeshow chi-square=8.95, p=.35). The Modified CAPPS score also demonstrated good discrimination (c-statistic 0.78, [95%CI=0.72–0.84]) and calibration (Hosmer-Lemeshow chi-square=2.92, p=.57). Low-, high-, and extreme-risk groups stratified by the Modified CAPPS score had 17.3%, 49.1%, and 80.7% predicted probability of experiencing inadequate pain control compared to 32.0%, 64.0%, and 85.1% in the CAPPS score. Conclusions: Preoperative insomnia is prevalent and is a modifiable risk factor for poor pain control following spine surgery. Early identification and management of preoperative insomnia may lead to improved postoperative pain outcomes. Future external validation is needed to confirm the accuracy of the Modified CAPPS score

First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury

BACKGROUND Neutralization of central nervous system neurite growth inhibitory factors, for example, Nogo-A, is a promising approach to improving recovery following spinal cord injury (SCI). In animal SCI models, intrathecal delivery of anti-Nogo-A antibodies promoted regenerative neurite growth and functional recovery. OBJECTIVE This first-in-man study assessed the feasibility, safety, tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A antibody ATI355 following intrathecal administration in patients with acute, complete traumatic paraplegia and tetraplegia. METHODS Patients (N = 52) started treatment 4 to 60 days postinjury. Four consecutive dose-escalation cohorts received 5 to 30 mg/2.5 mL/day continuous intrathecal ATI355 infusion over 24 hours to 28 days. Following pharmacokinetic evaluation, 2 further cohorts received a bolus regimen (6 intrathecal injections of 22.5 and 45 mg/3 mL, respectively, over 4 weeks). RESULTS ATI355 was well tolerated up to 1-year follow-up. All patients experienced ≥1 adverse events (AEs). The 581 reported AEs were mostly mild and to be expected following acute SCI. Fifteen patients reported 16 serious AEs, none related to ATI355; one bacterial meningitis case was considered related to intrathecal administration. ATI355 serum levels showed dose-dependency, and intersubject cerebrospinal fluid levels were highly variable after infusion and bolus injection. In 1 paraplegic patient, motor scores improved by 8 points. In tetraplegic patients, mean total motor scores increased, with 3/19 gaining >10 points, and 1/19 27 points at Week 48. Conversion from complete to incomplete SCI occurred in 7/19 patients with tetraplegia. CONCLUSIONS ATI335 was well tolerated in humans; efficacy trials using intrathecal antibody administration may be considered in acute SCI

Emerging Safety of Intramedullary Transplantation of Human Neural Stem Cells in Chronic Cervical and Thoracic Spinal Cord Injury

Abstract BACKGROUND Human central nervous system stem cells (HuCNS-SC) are multipotent adult stem cells with successful engraftment, migration, and region-appropriate differentiation after spinal cord injury (SCI). OBJECTIVE To present data on the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after SCI. METHODS Intramedullary free-hand (manual) transplantation of HuCNS-SC cells was performed in subjects with thoracic (n = 12) and cervical (n = 17) complete and sensory incomplete chronic traumatic SCI. RESULTS Intramedullary stem cell transplantation needle times in the thoracic cohort (20 M HuCNS-SC) were 19:30 min and total injection time was 42:15 min. The cervical cohort I (n = 6), demonstrated that escalating doses of HuCNS-SC up to 40 M range were well tolerated. In cohort II (40 M, n = 11), the intramedullary stem cell transplantation needle times and total injection time was 26:05 ± 1:08 and 58:14 ± 4:06 min, respectively. In the first year after injection, there were 4 serious adverse events in 4 of the 12 thoracic subjects and 15 serious adverse events in 9 of the 17 cervical patients. No safety concerns were considered related to the cells or the manual intramedullary injection. Cervical magnetic resonance images demonstrated mild increased T2 signal change in 8 of 17 transplanted subjects without motor decrements or emerging neuropathic pain. All T2 signal change resolved by 6 to 12 mo post-transplant. CONCLUSION A total cell dose of 20 M cells via 4 and up to 40 M cells via 8 perilesional intramedullary injections after thoracic and cervical SCI respectively proved safe and feasible using a manual injection technique

sEMMPRIN in sera was not altered in different inflammatory conditions.

<p>sEMMPRIN in sera from HC (healthy controls) and patients with CD (Crohn’s disease), UC (ulcerative colitis), T1D (Type 1 diabetes) or RRMS were measured by ELISA. The number of subjects is shown in parentheses. The scatter plot shows that sEMMPRIN levels did not significantly differ between the groups (one-way ANOVA with Tukey’s post hoc test). Values are represented in pg/ml, with each entry representing a single subject performed in duplicate, and data is represented as mean ± SD.</p