Study Protocol: Short Against Long Antibiotic Therapy for Infected Orthopaedic Sites - SALATIO Trials

Background: Few studies address the appropriate duration of post-surgical antibiotic therapy for orthopedic infections; with or without infected residual implants. We perform two similar randomized-clinical trials (RCT) to reduce the antibiotic use and associated adverse events. Methods: Two unblinded RCTs in adult patients (non-inferiority with a margin of 10%, a power of 80%) with the primary outcomes "remission" and "microbiologically-identical recurrences" after a combined surgical and antibiotic therapy. The main secondary outcome are antibiotic-related adverse events. The RCTs allocate the participants between 3 vs. 6 weeks of post-surgical systemic antibiotic therapy for implant-free infections; and between 6 vs. 12 weeks for residual implant-related infections. We need a total of 280 episodes (randomization schemes 1:1) with a minimal follow-up 12 months. We perform two interim analyses starting approximately after 1 and 2 years. The study approximatively lasts 3 years. Discussion: Both parellel RCT will enable to prescribe less antibiotics for future orthopedic infections in adult patients. Trial registration: ClinicalTrial.gov NCT05499481. Registered on 12 August 2022. Protocol version: 2 (19 May 2022

Sustained efficacy of natalizumab in the treatment of relapsing-remitting multiple sclerosis independent of disease activity and disability at baseline: real-life data from a Swiss cohort

OBJECTIVES: Therapy for relapsing-remitting multiple sclerosis with natalizumab (Tysabri; Biogen Idec) has been shown to be effective in the reduction of the clinical relapse rate and disability progression. However, real-life longitudinal data, including years before baseline, are rare. METHODS: An observational single-center study was carried out. We analyzed data from 64 consecutive patients with multiple sclerosis. RESULTS: After 1 year of treatment (n = 64), score on the Expanded Disability Status Scale (EDSS) decreased by 0.47 points (P = 0.047) and the annualized relapse rate (ARR) decreased by 82% (P 2) or EDSS score and was not biased by exceptional high disease activity or relapses around baseline. CONCLUSIONS: These real-life data reinforce that natalizumab is effective over years, reduces ARR, and stabilizes EDSS score independent of baseline ARR, baseline EDSS score, or baseline treatment

Effects of season and reproductive state on lipid intake and fatty acid composition of gastrointestinal tract contents in the European hare

We investigated lipid content and fatty acid (FA) composition of gastrointestinal tract contents in free-living, herbivorous European hares (Lepus europaeus). Mean crude fat content in hare stomachs and total gastrointestinal (GI) tracts was higher than expected for typical herbivore forages and peaked in late fall when hares massively deposited body fat reserves. Changes of FA proportions in different parts of the GI-tract indicated a highly preferential absorption of polyunsaturated fatty acids (PUFA). A further reduction of PUFA content in the caecum, along with the appearance of odd-chained FAs in caecum, caecotrophes, and colon content, pointed to a biohydrogenation of PUFA in the hare’s hindgut. GI-tract contents showed significant seasonal changes in their FA composition. Among PUFA, α-linolenic acid peaked in spring while linoleic acid was predominant in late summer and fall, which probably reflected changes in the plant composition of forage. However, independent of seasonal changes, GI-tracts of lactating females showed a significantly (+33%) higher content of linoleic acid, a FA that is known to increase reproductive performance in European hares. This finding suggests that lactating females actively selected dietary plants rich in linoleic acid, a PUFA that may represent a limited resource for European hares

Perineuronal Nets Play a Role in Regulating Striatal Function in the Mouse

The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs), aggregations of chondroitin-sulfate proteoglycans (CSPGs), form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41%) of these structures surrounds parvalbumin positive (PV+) interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse

Role of the lesion scar in the response to damage and repair of the central nervous system

Traumatic damage to the central nervous system (CNS) destroys the blood-brain barrier (BBB) and provokes the invasion of hematogenous cells into the neural tissue. Invading leukocytes, macrophages and lymphocytes secrete various cytokines that induce an inflammatory reaction in the injured CNS and result in local neural degeneration, formation of a cystic cavity and activation of glial cells around the lesion site. As a consequence of these processes, two types of scarring tissue are formed in the lesion site. One is a glial scar that consists in reactive astrocytes, reactive microglia and glial precursor cells. The other is a fibrotic scar formed by fibroblasts, which have invaded the lesion site from adjacent meningeal and perivascular cells. At the interface, the reactive astrocytes and the fibroblasts interact to form an organized tissue, the glia limitans. The astrocytic reaction has a protective role by reconstituting the BBB, preventing neuronal degeneration and limiting the spread of damage. While much attention has been paid to the inhibitory effects of the astrocytic component of the scars on axon regeneration, this review will cover a number of recent studies in which manipulations of the fibroblastic component of the scar by reagents, such as blockers of collagen synthesis have been found to be beneficial for axon regeneration. To what extent these changes in the fibroblasts act via subsequent downstream actions on the astrocytes remains for future investigation

Modulation of spinal reflex by assisted locomotion in humans with chronic complete spinal cord injury

OBJECTIVE: In healthy subjects, spinal reflexes (SR) evoked by non-noxious tibial nerve stimulation consist of an early (60-120ms latency) and an occasional late-appearing (120-450ms latency) component in the ipsilateral tibialis anterior. In chronic (>1year) complete spinal cord injured (cSCI) subjects early components are small or lacking while late components are dominant. Here we report on the modulation of SR by assisted locomotion in healthy and chronic motor cSCI subjects. METHODS: SR was evoked by tibial nerve stimulation at the terminal stance phase during assisted locomotion and was compared to SR recorded during upright stance. RESULTS: In chronic cSCI subjects only a late SR component was consistently present during upright stance. However during assisted locomotion, an early SR component appeared, while amplitude of the late SR component became small. In contrast, in healthy subjects the early SR component dominated in all conditions, but a small late component appeared during assisted locomotion. CONCLUSION: A more balanced activity of early and late SR components occurred in both subject groups if an appropriate proprioceptive input was provided. SIGNIFICANCE: Early and late SR components are assumed to reflect the activity of separate neuronal circuits, which are associated with the locomotor circuitry possibly by shaping the pattern

Fampridine-induced changes in walking kinetics are associated with clinical improvements in patients with multiple sclerosis

Gait dysfunction is common in patients with multiple sclerosis (PwMS). Treatment with prolonged-release fampridine (PR-fampridine) improves walking ability in some PwMS. Associated fampridine-induced changes in the walking pattern are still poorly understood but may provide a better understanding of the mechanisms underlying the beneficial drug effects. 61 PwMS were treated with PR-fampridine in a randomized, monocentric, double-blind and placebo-controlled clinical trial with crossover design (FAMPKIN). Drug-induced improvements in walking speed (Timed-25-Foot Walk; T25FW) and endurance (6-Minute Walk Test; 6MWT) were quantified. In this sub-study of the FAMPKIN trial, fampridine-induced changes in kinetic gait patterns were analyzed by pressure-based foot print analysis during treadmill walking. Vertical ground reaction forces were analyzed during different gait phases. Kinetic data of 44 PwMS was eligible for analysis. During double-blind treatment with PR-fampridine, patients performed significantly better in the T25FW and 6MWT than during placebo treatment (p < 0.0001 for both). At the group level (n = 44), there were no significant changes of gait kinetics under PR-fampridine vs. placebo. However, we found relevant changes of walking kinetics regarding forces during loading, single limb and pre-swing phase in a patient sub-group (n = 8). Interestingly, this sub-group demonstrated superior responsiveness to PR-fampridine in the clinical walking tests compared to those patients without any fampridine-induced changes in kinetics (n = 36). Our results demonstrate fampridine-induced changes in gait kinetics in a sub-group of PwMS. These gait pattern changes were accompanied by improved clinical walking performance under PR-fampridine. These results shed some light on the biomechanical changes in walking patterns underlying enhanced fampridine-induced gait performance

Functional and anatomical reorganization of the sensory-motor cortex after incomplete spinal cord injury in adult rats

A lateral hemisection injury of the cervical spinal cord results in Brown-Séquard syndrome in humans and rats. The hands/forelimbs on the injured side are rendered permanently impaired, but the legs/hindlimbs recover locomotor functions. This is accompanied by increased use of the forelimb on the uninjured side. Nothing is known about the cortical circuits that correspond to these behavioral adaptations. In this study, on adult rats with cervical spinal cord lateral hemisection lesions (at segment C3/4), we explored the sensory representation and corticospinal projection of the intact (ipsilesional) cortex. Using blood oxygenation level-dependent functional magnetic resonance imaging and voltage-sensitive dye (VSD) imaging, we found that the cortex develops an enhanced representation of the unimpaired forepaw by 12 weeks after injury. VSD imaging also revealed the cortical spatio-temporal dynamics in response to electrical stimulation of the ipsilateral forepaw or hindpaw. Interestingly, stimulation of the ipsilesional hindpaw at 12 weeks showed a distinct activation of the hindlimb area in the intact, ipsilateral cortex, probably via the injury-spared spinothalamic pathway. Anterograde tracing of corticospinal axons from the intact cortex showed sprouting to recross the midline, innervating the spinal segments below the injury in both cervical and lumbar segments. Retrograde tracing of these midline-crossing axons from the cervical spinal cord (at segment C6/7) revealed the formation of a new ipsilateral forelimb representation in the cortex. Our results demonstrate profound reorganizations of the intact sensory-motor cortex after unilateral spinal cord injury. These changes may contribute to the behavioral adaptations, notably for the recovery of the ipsilesional hindlimb