Clinical translation of a regeneration strategy for spinal cord injury

The complex and vulnerable tissue of the spinal cord does not heal after injury, leaving patients with lifelong disability after spinal cord injury (SCI). Many milestones have been reached during the last century through specialized centers for SCI, greatly increasing life expectancy and quality of life by battling common medical problems such as urinary tract infections, pressure ulcers, spasticity, neurogenic pain, and sexual function as well as providing means of rehabilitation to a meaningful and productive life after SCI. Despite the advances in preclinical knowledge of mechanisms in SCI and several clinical trials completed, to date no pivotal treatment exists for acute spinal cord injury or for the regeneration of lost function in the chronic state. The first reports of experimental regeneration of central axons through peripheral nerve grafts are more than a century old. In the last decades, regeneration of function after SCI has been reported by several research groups in different species using peripheral nerve grafts and FGF1. The regeneration strategy was furthered refined in our group by the use of a biodegradable scaffold for exact positioning of the nerve grafts. This thesis describes the translational process to reach a clinical trial of glial scar resection and implantation of peripheral nerve grafts and FGF1 using a biodegradable guiding scaffold. In paper I, we show that both the cranial and caudal demarcation of a thoracic spinal cord injury can be defined with electromyography of intercostal muscles in chronic SCI patients. We also present an MRI protocol with acceptable image contrast despite the presence of spinal instrumentation and showed that the injury length found with electromyography correlates well with length of injury on MRI. In paper II, we use a novel conversion table between spinal cord neuronal segments and vertebral segments and combine data on human spinal cord cross-sectional diameters from different published sources to yield continuous estimates on human spinal cord size and variability. In paper III, we describe the design of a set of spinal cord injury guiding devices based on the data from paper II, covering the normal variability found in human thoracic spinal cord segments T2–T12 with an acceptable error-of-fit for the elliptical shape as well as guiding channels proposed. In paper IV, we detail the adverse events reported during the first 60 days postoperatively in the ongoing clinical trial “Safety and Efficacy of SC0806 (Fibroblast Growth Factor 1 and a Device) in Traumatic Spinal Cord Injury Subjects.” Early results from the first six complete (AIS-A) thoracic spinal cord injury subjects operated on in the ongoing trial show that with precise preoperative and intraoperative neurophysiology, surgery and implantation can be performed without negative effects on neurological level, and safety and tolerability are acceptable to merit the continuation of the trial. In paper V, we describe the construction of a cost-effective light-sheet microscope by modification of an outdated microarray-scanner. The microscope was applied to an experimental model of hypoglossal nerve avulsion injury, and proliferation of Iba1+ cells could be quantified automatically demonstrating a possible application of the microscope. In conclusion, reaching clinical trial in a translational process is a significant and collaborative undertaking requiring co-operation of multiple institutions and professions as well as rigorous external control of data quality and adverse events to ensure safety of study subjects. The papers in this thesis detail some relevant steps necessary for the clinical translation of regeneration strategies in chronic SCI

The Challenge of Cooperative Regulatory Relations After Enlargement

This paper conceptualises European governance as a continuous series of collective action games among national regulators. European administration is theorized as a set of mutually beneficial relations among independent regulators, rather than as a hierarchy of supranational institutions, courts, and national administrators. The collective action approach highlights the importance of certain factors in fostering regulatory cooperation and enabling the common market to become an administrative reality: repeated interactions, monitoring and sanctioning by the Commission and the courts, reciprocity norms, and trust. It also suggests that one of the most significant challenges of enlargement will be to establish cooperative regulatory exchanges among old and new regulators. Regulators in the existing member states do not always trust the capacity of Central and Eastern European regulators to administer the acquis communautaire. Cooperation and trust among old and new regulators will also prove difficult because, after enlargement, their relations will gradually shift from ones of power to ones of mutually beneficial exchanges among equals. The solution lies in self-awareness of the structure of the collective action game, a more active role for the Commission and the Court in monitoring compliance, and strict adherence to a strategy of reciprocity in retaliating for non-compliance

Measuring the Environmental Footprint of Leather Processing Technologies

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OBJECTIVE: It has previously been shown that a combination of inhaled nitric oxide (iNO) and intravenous (IV) steroid attenuates endotoxin-induced organ damage in a 6-hour porcine endotoxemia model. We aimed to further explore these effects in a 30-hour model with attention to clinically important variables. DESIGN: Randomized controlled trial. SETTING: University animal laboratory. SUBJECTS: Domestic piglets (n = 30). INTERVENTIONS: Animals were randomized into 5 groups (n = 6 each): 1) Controls, 2) LPS-only (endotoxin/lipopolysaccharide (LPS) infusion), 3) LPS + iNO, 4) LPS + IV steroid, 5) LPS + iNO + IV steroid. MEASUREMENTS AND MAIN RESULTS: Exposure to LPS temporarily increased pulmonary artery mean pressure and impeded renal function with elevated serum creatinine and acidosis compared to a control group over the 30-hour study period. Double treatment with both iNO and IV steroid tended to blunt the deterioration in renal function, although the only significant effect was on Base Excess (p = 0.045). None of the LPS + iNO + IV steroid treated animals died during the study period, whereas one animal died in each of the other LPS-infused groups. CONCLUSIONS: This study suggests that combined early therapy with iNO and IV steroid is associated with partial protection of kidney function after 30 hours of experimental LPS infusion

Effect of skin-to-skin contact on parents\u27 sleep quality, mood, parent-infant interaction and cortisol concentrations in neonatal care units: Study protocol of a randomised controlled trial

INTRODUCTION: Separation after preterm birth is a major stressor for infants and parents. Skin-to-skin contact (SSC) is a method of care suitable to use in the neonatal intensive care unit (NICU) to minimise separation between parents and infants. Less separation leads to increased possibilities for parent-infant interaction, provided that the parents\u27 sleep quality is satisfactory. We aimed to evaluate the effect of continuous SSC on sleep quality and mood in parents of preterm infants borndischarge. METHODS AND ANALYSIS: A randomised intervention study with two arms-intervention versus standard care. Data will be collected from 50 families. Eligible families will be randomly allocated to intervention or standard care when transferred from the intensive care room to the family-room in the NICU. The intervention consists of continuous SSC for four consecutive days and nights in the family-room. Data will be collected every day during the intervention and again at the time of discharge from the hospital. Outcome measures comprise activity tracker (Actigraph); validated self-rated questionnaires concerning sleep, mood and bonding; observed scorings of parental sensitivity and emotional availability and salivary cortisol. Data will be analysed with pairwise, repeated measures, Mann Whitney U-test will be used to compare groups and analysis of variance will be used to adjust for different hospitals and parents\u27 gender. ETHICS AND DISSEMINATION: The study is approved by the Regional Research Ethics Board at an appropriate university (2016/89-31). The results will be published in scientific journals. We will also use conferences and social media to disseminate our findings. TRIAL REGISTRATION NUMBER: NCT03004677

Assessment of Platelet Function in Traumatic Brain Injury-A Retrospective Observational Study in the Neuro-Critical Care Setting.

BACKGROUND: Despite seemingly functional coagulation, hemorrhagic lesion progression is a common and devastating condition following traumatic brain injury (TBI), stressing the need for new diagnostic techniques. Multiple electrode aggregometry (MEA) measures platelet function and could aid in coagulopathy assessment following TBI. The aims of this study were to evaluate MEA temporal dynamics, influence of concomitant therapy, and its capabilities to predict lesion progression and clinical outcome in a TBI cohort. MATERIAL AND METHODS: Adult TBI patients in a neurointensive care unit that underwent MEA sampling were retrospectively included. MEA was sampled if the patient was treated with antiplatelet therapy, bled heavily during surgery, or had abnormal baseline coagulation values. We assessed platelet activation pathways involving the arachidonic acid receptor (ASPI), P2Y12 receptor, and thrombin receptor (TRAP). ASPI was the primary focus of analysis. If several samples were obtained, they were included. Retrospective data were extracted from hospital charts. Outcome variables were radiologic hemorrhagic progression and Glasgow Outcome Scale assessed prospectively at 12 months posttrauma. MEA levels were compared between patients on antiplatelet therapy. Linear mixed effect models and uni-/multivariable regression models were used to study longitudinal dynamics, hemorrhagic progression and outcome, respectively. RESULTS: In total, 178 patients were included (48% unfavorable outcome). ASPI levels increased from initially low values in a time-dependent fashion (p < 0.001). Patients on cyclooxygenase inhibitors demonstrated low ASPI levels (p < 0.001), while platelet transfusion increased them (p < 0.001). The first ASPI (p = 0.039) and TRAP (p = 0.009) were significant predictors of outcome, but not lesion progression, in univariate analyses. In multivariable analysis, MEA values were not independently correlated with outcome. CONCLUSION: A general longitudinal trend of MEA is identified in this TBI cohort, even in patients without known antiplatelet therapies. Values appear also affected by platelet inhibitory treatment and by platelet transfusions. While significant in univariate models to predict outcome, MEA values did not independently correlate to outcome or lesion progression in multivariable analyses. Further prospective studies to monitor coagulation in TBI patients are warranted, in particular the interpretation of pathological MEA values in patients without antiplatelet therapies

Systemic inflammation alters the neuroinflammatory response: a prospective clinical trial in traumatic brain injury.

BACKGROUND: Neuroinflammation following traumatic brain injury (TBI) has been shown to be associated with secondary injury development; however, how systemic inflammatory mediators affect this is not fully understood. The aim of this study was to see how systemic inflammation affects markers of neuroinflammation, if this inflammatory response had a temporal correlation between compartments and how different compartments differ in cytokine composition. METHODS: TBI patients recruited to a previous randomised controlled trial studying the effects of the drug anakinra (Kineret®), a human recombinant interleukin-1 receptor antagonist (rhIL1ra), were used (n = 10 treatment arm, n = 10 control arm). Cytokine concentrations were measured in arterial and jugular venous samples twice a day, as well as in microdialysis-extracted brain extracellular fluid (ECF) following pooling every 6 h. C-reactive protein level (CRP), white blood cell count (WBC), temperature and confirmed systemic clinical infection were used as systemic markers of inflammation. Principal component analyses, linear mixed-effect models, cross-correlations and multiple factor analyses were used. RESULTS: Jugular and arterial blood held similar cytokine information content, but brain-ECF was markedly different. No clear arterial to jugular gradient could be seen. No substantial delayed temporal associations between blood and brain compartments were detected. The development of a systemic clinical infection resulted in a significant decrease of IL1-ra, G-CSF, PDGF-ABBB, MIP-1b and RANTES (p < 0.05, respectively) in brain-ECF, even if adjusting for injury severity and demographic factors, while an increase in several cytokines could be seen in arterial blood. CONCLUSIONS: Systemic inflammation, and infection in particular, alters cytokine levels with different patterns seen in brain and in blood. Cerebral inflammatory monitoring provides independent information from arterial and jugular samples, which both demonstrate similar information content. These findings could present potential new treatment options in severe TBI patients, but novel prospective trials are warranted to confirm these associations

Energía y gases de efecto invernadero en la producción de distintos grupos de alimentos

El objetivo de este trabajo es estudiar la energía usada y los gases de efecto invernadero emitidos en la producción y transporte de distintos alimentos. Se realizaron inventarios de ciclo de vida para carnes, huevos y lácteos, legumbres, cereales, frutas, hortalizas, tubérculos, y semillas oleaginosas. Junto con la revisión de datos previos se analizaron 40 alimentos, que discriminados por región y sistema productivo constituyen 92 ítems alimentarios. La unidad funcional elegida es de 1 kg de alimento puesto en puerto de acceso al sistema de comercialización mayorista en Suecia. Se encontró que los productos de origen animal presentan requerimientos de energía mayor, y están asociados a mayores emisiones que los productos de origen vegetal, con la excepción de hortalizas producidas en invernaderos calefaccionados. El análisis de la cantidad de proteína producida por unidad de energía usada y por unidad de emisiones muestra eficiencias mayores en productos de origen vegetal.The aim of this work is to study the energy used and the greenhouse gas emissions associated with the production and transport of common food items. We have performed life cycle inventories for meats, eggs and dairy, legumes, cereals, fruits, vegetables, tubers and roots, and oily seeds. Along with previous published data, we have analysed 40 foods. When country of origin and means of production are sorted, we have studied a total of 92 food items. The functional unit was 1 kg of food at the input of the wholesale chain in Sweden. We have found that foods derived from animal production are associated with larger energy use and emissions than plant-origin foods, with the exception of vegetables produced in heated greenhouses. It was also found that the efficiency to produce protein is much higher for plant foods than for the animal origin ones.Asociación Argentina de Energías Renovables y Medio Ambiente (ASADES

Energía y gases de efecto invernadero en la producción de distintos grupos de alimentos

El objetivo de este trabajo es estudiar la energía usada y los gases de efecto invernadero emitidos en la producción y transporte de distintos alimentos. Se realizaron inventarios de ciclo de vida para carnes, huevos y lácteos, legumbres, cereales, frutas, hortalizas, tubérculos, y semillas oleaginosas. Junto con la revisión de datos previos se analizaron 40 alimentos, que discriminados por región y sistema productivo constituyen 92 ítems alimentarios. La unidad funcional elegida es de 1 kg de alimento puesto en puerto de acceso al sistema de comercialización mayorista en Suecia. Se encontró que los productos de origen animal presentan requerimientos de energía mayor, y están asociados a mayores emisiones que los productos de origen vegetal, con la excepción de hortalizas producidas en invernaderos calefaccionados. El análisis de la cantidad de proteína producida por unidad de energía usada y por unidad de emisiones muestra eficiencias mayores en productos de origen vegetal.The aim of this work is to study the energy used and the greenhouse gas emissions associated with the production and transport of common food items. We have performed life cycle inventories for meats, eggs and dairy, legumes, cereals, fruits, vegetables, tubers and roots, and oily seeds. Along with previous published data, we have analysed 40 foods. When country of origin and means of production are sorted, we have studied a total of 92 food items. The functional unit was 1 kg of food at the input of the wholesale chain in Sweden. We have found that foods derived from animal production are associated with larger energy use and emissions than plant-origin foods, with the exception of vegetables produced in heated greenhouses. It was also found that the efficiency to produce protein is much higher for plant foods than for the animal origin ones.Asociación Argentina de Energías Renovables y Medio Ambiente (ASADES