Induction of antiviral interferon-stimulated genes by neuronal STING promotes the resolution of pain in mice.

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein stimulator of IFN genes (STING) in dorsal root ganglion nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an IFN-ß response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes and KChIP1 downstream of STING in the resolution of inflammatory pain.

Advances in spinal cord injury: insights from non-human primates.

Spinal cord injury results in significant sensorimotor deficits, currently, there is no curative treatment for the symptoms induced by spinal cord injury. Basic and pre-clinical research on spinal cord injury relies on the development and characterization of appropriate animal models. These models should replicate the symptoms observed in human, allowing for the exploration of functional deficits and investigation into various aspects of physiopathology of spinal cord injury. Non-human primates, due to their close phylogenetic association with humans, share more neuroanatomical, genetic, and physiological similarities with humans than rodents. Therefore, the responses to spinal cord injury in nonhuman primates most likely resemble the responses to traumatism in humans. In this review, we will discuss nonhuman primate models of spinal cord injury, focusing on in vivo assessments, including behavioral tests, magnetic resonance imaging, and electrical activity recordings, as well as ex vivo histological analyses. Additionally, we will present therapeutic strategies developed in non-human primates and discuss the unique specificities of non-human primate models of spinal cord injury.

CSF1R inhibition at chronic stage after spinal cord injury modulates microglia proliferation.

Traumatic spinal cord injury (SCI) induces irreversible autonomic and sensory-motor impairments. A large number of patients exhibit chronic SCI and no curative treatment is currently available. Microglia are predominant immune players after SCI, they undergo highly dynamic processes, including proliferation and morphological modification. In a translational aim, we investigated whether microglia proliferation persists at chronic stage after spinal cord hemisection and whether a brief pharmacological treatment could modulate microglial responses. We first carried out a time course analysis of SCI-induced microglia proliferation associated with morphological analysis up to 84 days post-injury (dpi). Second, we analyzed outcomes on microglia of an oral administration of GW2580, a colony stimulating factor-1 receptor tyrosine kinase inhibitor reducing selectively microglia proliferation. After SCI, microglia proliferation remains elevated at 84 dpi. The percentage of proliferative microglia relative to proliferative cells increases over time reaching almost 50% at 84 dpi. Morphological modifications of microglia processes are observed up to 84 dpi and microglia cell body area is transiently increased up to 42 dpi. A transient post-injury GW2580-delivery at two chronic stages after SCI (42 and 84 dpi) reduces microglia proliferation and modifies microglial morphology evoking an overall limitation of secondary inflammation. Finally, transient GW2580-delivery at chronic stage after SCI modulates myelination processes. Together our study shows that there is a persistent microglia proliferation induced by SCI and that a pharmacological treatment at chronic stage after SCI modulates microglial responses. Thus, a transient oral GW2580-delivery at chronic stage after injury may provide a promising therapeutic strategy for chronic SCI patients.

Persistence of FoxJ1+ Pax6+ Sox2+ ependymal cells throughout life in the human spinal cord.

Ependymal cells lining the central canal of the spinal cord play a crucial role in providing a physical barrier and in the circulation of cerebrospinal fluid. These cells express the FOXJ1 and SOX2 transcription factors in mice and are derived from various neural tube populations, including embryonic roof and floor plate cells. They exhibit a dorsal-ventral expression pattern of spinal cord developmental transcription factors (such as MSX1, PAX6, ARX, and FOXA2), resembling an embryonic-like organization. Although this ependymal region is present in young humans, it appears to be lost with age. To re-examine this issue, we collected 17 fresh spinal cords from organ donors aged 37-83 years and performed immunohistochemistry on lightly fixed tissues. We observed cells expressing FOXJ1 in the central region in all cases, which co-expressed SOX2 and PAX6 as well as RFX2 and ARL13B, two proteins involved in ciliogenesis and cilia-mediated sonic hedgehog signaling, respectively. Half of the cases exhibited a lumen and some presented portions of the spinal cord with closed and open central canals. Co-staining of FOXJ1 with other neurodevelopmental transcription factors (ARX, FOXA2, MSX1) and NESTIN revealed heterogeneity of the ependymal cells. Interestingly, three donors aged > 75 years exhibited a fetal-like regionalization of neurodevelopmental transcription factors, with dorsal and ventral ependymal cells expressing MSX1, ARX, and FOXA2. These results provide new evidence for the persistence of ependymal cells expressing neurodevelopmental genes throughout human life and highlight the importance of further investigation of these cells.

In vivo emergence of a still uncommon resistance to fidaxomicin in the urgent antimicrobial resistance threat Clostridioides difficile.

BACKGROUND: Fidaxomicin is a first-line treatment for Clostridioides difficile infections (CDIs). Fidaxomicin resistance has rarely been reported in this urgent antimicrobial resistance threat as defined by the CDC. OBJECTIVES: To report a case of fidaxomicin-resistant C. difficile isolation in a patient treated by fidaxomicin, characterize the genetic determinant for resistance and the consequences on pathophysiological traits, and review the literature. PATIENT AND METHODS: A 38-year-old male patient with several risk factors for CDI experienced three episodes of hospital-acquired CDI and received fidaxomicin for the first episode. The successive isolates were subjected to phenotypic characterization (antimicrobial susceptibility, growth, sporulation ability and toxin production) and WGS analysis to evaluate clonality and modifications associated with resistance. RESULTS: Resistance to fidaxomicin arose in isolates from the recurrences of CDI (MIC: 16 mg/L). WGS analysis showed a close genetic link between strains suggestive of relapses in this patient. A T3428G mutation in the rpoB gene might be associated with fidaxomicin resistance. The resistance was associated with defects in growth, sporulation and production of toxins. A review of the literature found only three previous fidaxomicin-resistant C. difficile clinical strains. CONCLUSIONS: Although rarely reported, resistance to fidaxomicin may quickly emerge in vivo after a single course of treatment. This observation supports the need for prospective surveillance of the susceptibility of C. difficile to treatment antibiotics. However, the clinical relevance of fidaxomicin resistance still needs to be elucidated, particularly due to its apparent rareness and associated fitness cost.

Intraputaminal Gene Delivery in Two Patients with Aromatic L-Amino Acid Decarboxylase Deficiency.

Background: Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, early-onset, dyskinetic encephalopathy mostly reflecting a defective synthesis of brain dopamine and serotonin. Intracerebral gene delivery (GD) provided a significant improvement among AADCD patients (mean age, ≤6 years). Objective: We describe the clinical, biological, and imaging evolution of two AADCD patients ages >10 years after GD. Methods: Eladocagene exuparvovec, a recombinant adeno-associated virus containing the human complimentary DNA encoding the AADC enzyme, was administered into bilateral putamen by stereotactic surgery. Results: Eighteen months after GD, patients showed improvement in motor, cognitive and behavioral function, and in quality of life. Cerebral l-6-[18F] fluoro-3, 4-dihydroxyphenylalanine uptake was increased at 1 month, persisting at 1 year compared to baseline. Conclusion: Two patients with a severe form of AADCD had an objective motor and non-motor benefit from eladocagene exuparvovec injection even when treated after the age of 10 years, as in the seminal study.

A cellular taxonomy of the adult human spinal cord.

The mammalian spinal cord functions as a community of cell types for sensory processing, autonomic control, and movement. While animal models have advanced our understanding of spinal cellular diversity, characterizing human biology directly is important to uncover specialized features of basic function and human pathology. Here, we present a cellular taxonomy of the adult human spinal cord using single-nucleus RNA sequencing with spatial transcriptomics and antibody validation. We identified 29 glial clusters and 35 neuronal clusters, organized principally by anatomical location. To demonstrate the relevance of this resource to human disease, we analyzed spinal motoneurons, which degenerate in amyotrophic lateral sclerosis (ALS) and other diseases. We found that compared with other spinal neurons, human motoneurons are defined by genes related to cell size, cytoskeletal structure, and ALS, suggesting a specialized molecular repertoire underlying their selective vulnerability. We include a web resource to facilitate further investigations into human spinal cord biology.

Deep brain stimulation effect in genetic dyskinetic cerebral palsy: The case of ADCY5- related disease.

BACKGROUND: Cerebral Palsy (CP) represents a frequent cause of disability in childhood. Early in life, genetic disorders may present with motor dysfunction and diagnosed as CP. Establishing the primary, genetic etiology allows more accurate prognosis, genetic counselling, and planning for symptomatic interventions in homogeneous etiological groups. Deep brain stimulation (DBS) is recommended in refractory movement disorders, including isolated pediatric dystonias. For dystonia evolving in more complex associations in genetic CP, the effect of DBS is still understudied and currently only sporadically described. OBJECTIVES: To report the effect of DBS applied to the globus pallidus pars interna (GPi) in children with complex movement disorders caused by pathogenic ADCY5 variants, diagnosed as dyskinetic CP previous to genetic diagnostic. METHODS: We conducted a retrospective study on evolution of treatment with DBS in ADCY5-related disease. A standardized proforma including the different type of movement disorders and associated neurological signs was completed at each follow-up time, based on video recordings, as well as functional assessments used in children with CP. RESULTS: Four children (mean of age, 13 ± 2.9 years) received GPi-DBS. The same de novo pathogenic missense variant (c.1252C > T, p.R418W) was identified in three out of four and a splice site variant (c.2088 + 2G > T) in one subject. Developmental delay and overlapping features including axial hypotonia, chorea, dystonic attacks, myoclonus, and cranial dyskinesia were present. The median age at DBS was 9 years and follow-up with DBS, 2.6 years. We identified a pattern of clinical response with early suppression of dystonic attacks, followed by improvement of myoclonus and facial dyskinesia. Effect on chorea was delayed and more limited. Two patients gained notable functional benefit related to sitting, standing, gait, use of upper limbs and speech. CONCLUSION: ADCY5-related disease may benefit from GPi-DBS. The most significant clinical response relates to the early and sustained benefit on dystonic attacks and a variable but still positive response on the other hyperkinetic features. Genetic etiology of CP will contribute to further elucidate genotype-phenotype correlations and to refine DBS indication as network-related symptomatic interventions.

Submammary Implantation of Internal Pulse Generators for Deep Brain Stimulation: Long-Term Follow-up of Device Acceptance and Quality of Life in Women.

BACKGROUND: A submammary approach to implanting pulse generators is innovative and has yielded good aesthetic results in the current literature. It was our aim to make a comparison of patient device acceptance, tolerance, and complications between submammary and abdominal device locations in deep brain stimulation. METHODS: Twenty-five and 28 patients were included in the submammary and abdominal groups, respectively. Our primary criterion was patient acceptance that was calculated using total Florida Patient Acceptance Survey (FPAS) scores in each group. Secondarily, tolerance was assessed in the submammary group by means of a specific questionnaire. RESULTS: Total FPAS scores from the submammary group [total FPAS: 77.1 versus 74.7, P = 0.29] revealed no significant difference when compared with the abdominal group. The same similarities were observed regarding the 4 subscales: return to function [16.3 versus 15.8, P = 0.53], device-related distress [22.0 versus 21.3, P = 0.31], body image concerns [9.2 versus 8.6, P = 0.14], and positive appraisal [17.8 versus 17.4, P = 0.58]. Tolerance was reported as good by the majority of the women from the submammary group. There was no evidence of higher infection rates in the submammary implantation (SMI) group. CONCLUSIONS: SMI is a satisfactory alternative to other deep brain stimulation locations. SMI is a feasible option for any young woman who is eligible for deep brain stimulation.

Highlighting the Dystonic Phenotype Related to GNAO1.

BACKGROUND: Most reported patients carrying GNAO1 mutations showed a severe phenotype characterized by early-onset epileptic encephalopathy and/or chorea. OBJECTIVE: The aim was to characterize the clinical and genetic features of patients with mild GNAO1-related phenotype with prominent movement disorders. METHODS: We included patients diagnosed with GNAO1-related movement disorders of delayed onset (>2 years). Patients experiencing either severe or profound intellectual disability or early-onset epileptic encephalopathy were excluded. RESULTS: Twenty-four patients and 1 asymptomatic subject were included. All patients showed dystonia as prominent movement disorder. Dystonia was focal in 1, segmental in 6, multifocal in 4, and generalized in 13. Six patients showed adolescence or adulthood-onset dystonia. Seven patients presented with parkinsonism and 3 with myoclonus. Dysarthria was observed in 19 patients. Mild and moderate ID were present in 10 and 2 patients, respectively. CONCLUSION: We highlighted a mild GNAO1-related phenotype, including adolescent-onset dystonia, broadening the clinical spectrum of this condition. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain.

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1+ sensory neurons. Notably, ALKAL2 was particularly enriched in both mouse and human peptidergic nociceptors, yet weakly expressed in nonpeptidergic, large-diameter myelinated neurons or in the brain. Using a coculture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar CFA or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds crizotinib or lorlatinib reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2/ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for non-small cell lung cancer and neuroblastomas could be repurposed to treat persistent pain conditions.

Transcutaneous ventriculo-peritoneal shunt catheter extrusion with silent bowel perforation following digestive surgery: a case report.

This case report provides an account of transcutaneous ventriculo-peritoneal (VP) shunt extrusion with silent bowel perforation occurring 2 years post digestive surgery. A 22-year-old man treated since childhood for post-infectious hydrocephalus was referred to our neurosurgery department for an inflammatory wound to the right hypochondrium caused by an abandoned calcified VP shunt. This VP shunt was surgically removed without complications. The perforated bowel required no direct repair. Progress is favorable at 1 year follow-up.

Isolation and Culture of Precursor Cells from the Adult Human Spinal Cord.

We demonstrated the presence of neural stem cells and/or progenitor cells in the adult human spinal cord. This chapter provides materials and methods to harvest high-quality samples of thoracolumbar, lumbar, and sacral adult human spinal cord and human dorsal root ganglia isolated from brain-dead patients who had agreed before passing to donate their bodies to science for therapeutic and scientific advances. The methods to culture precursor cells from the adult human spinal cord are also described.

Unlike Brief Inhibition of Microglia Proliferation after Spinal Cord Injury, Long-Term Treatment Does Not Improve Motor Recovery.

Microglia are major players in scar formation after an injury to the spinal cord. Microglia proliferation, differentiation, and survival are regulated by the colony-stimulating factor 1 (CSF1). Complete microglia elimination using CSF1 receptor (CSF1R) inhibitors worsens motor function recovery after spinal injury (SCI). Conversely, a 1-week oral treatment with GW2580, a CSF1R inhibitor that only inhibits microglia proliferation, promotes motor recovery. Here, we investigate whether prolonged GW2580 treatment further increases beneficial effects on locomotion after SCI. We thus assessed the effect of a 6-week GW2580 oral treatment after lateral hemisection of the spinal cord on functional recovery and its outcome on tissue and cellular responses in adult mice. Long-term depletion of microglia proliferation after SCI failed to improve motor recovery and had no effect on tissue reorganization, as revealed by ex vivo diffusion-weighted magnetic resonance imaging. Six weeks after SCI, GW2580 treatment decreased microglial reactivity and increased astrocytic reactivity. We thus demonstrate that increasing the duration of GW2580 treatment is not beneficial for motor recovery after SCI.