Cord Inflammation Research Articles

Atractylenolide-I Ameliorates Motor Deficits and Reduces Inflammation of the Spinal Cord by SIRT1/PGC-1α Pathway in MPTP Subacute Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder that impacts various systems, including the substantia nigra (SN) par compacta (SNpc) and extranigral regions like the spinal cord. The presence of persistent inflammation in the SN and spinal cord is associated with movement difficulties in PD. Atractylenolide-I (ATR-I) is a natural sesquiterpene recognized for its anti-inflammatory and neuroprotective effects. This research aimed to assess the impact of ATR-I treatment on motor function and inflammation in MPTP-induced subacute PD mice, particularly focusing on the role of ATR-I in spinal cord inflammation. The motor functions of the mice were assessed using suspension and gait tests. Dopaminergic neuronal loss in the SNpc and microglial activation in both the SNpc and spinal cord were evaluated through immunofluorescence staining. The levels of inflammatory mediators in the spinal cord were measured using RT-qPCR analysis. The expressions of SIRT1 and PGC-1α in the spinal cord were analyzed through Western blotting and RT-qPCR. ATR-I treatment improved motor deficits in MPTP-induced mice. Moreover, ATR-I reduced the loss of dopamine neurons and microglial activation in the SNpc of MPTP-induced mice. Additionally, ATR-I suppressed spinal cord inflammation by decreasing microglial activation and the mRNA expression of TNF-α, IL-1β, and iNOS in MPTP-induced mice. Interestingly, ATR-I also upregulated SIRT1 and PGC-1α levels in the spinal cord of MPTP-induced mice. These findings suggest that ATR-I exhibits anti-inflammatory and neuroprotective properties in PD. The attenuation of spinal cord inflammation via the SIRT1/PGC-1α pathway may contribute to enhancing motor function, highlighting ATR-I as a potential therapeutic avenue for PD.

The Impact of Caffeic Acid Phenethyl Ester on Spinal Cord Inflammation in Mice Model of Multiple Sclerosis

Since the majority of the current therapies lack effectiveness and efficiency in treating Multiple Sclerosis, in addition to their high cost, monitoring during usage, and the serious side effects associated with using this therapy, which in some cases may be fatal, for these reasons, there is a necessary need for effective therapy in the clinical setting and searching for an alternative therapy that is effective and safe. For this purpose, this study evaluated the impact and efficiency of Caffeic acid phenethyl ester(CAPE) in the amelioration of inflammation and demyelination in the spinal cord of experimental autoimmune encephalomyelitis(EAE) mouse model multiple sclerosis, which could be a candidate therapy for MS. Multiple sclerosis is an autoimmune T-cell mediated disease, that T- cells become active, and differentiate into Th sub-set.α4β1integrin increased on the surface of T-cells during inflammation, which regulates immune cell cross through the blood-brain barrier into the central nervous system, and causes inflammation in the brain and spinal cord, myelin sheath damage, and neuron demyelination. The in-vivo experiment used mice. The twenty-five mice were divided into control negative, control positive, and three treatment groups. After this, EAE was induced in mice by injecting myelin oligodendrocyte glycoprotein peptide. The mice were monitored and scored daily for clinical signs. CAPE was orally administered to mice at 5 mg/kg for T1, 10 mg/kg for T2, and 20 mg/kg for T3 for 14 days. Immunofluorescence was used to assess α4integrin, Immunohistochemistry (IHC) was used to evaluate infiltration of CD3-T cell marker, and Luxol Fast Blue stain was used to evaluate demyelination. We found that CAPE treated mice model had a reduced infiltration of immune cells, demyelination in the spinal cord mice model, and decreasing α4integrin expression. These findings strongly demonstrated that CAPE could be a potential therapy for Multiple sclerosis, as it ameliorated the inflammation and demyelination in mice models.

Evaluating Therapeutic Plasma Exchange in Pediatric Acute Disseminated Encephalomyelitis: A Comprehensive Review.

Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune disorder characterized by brain and spinal cord inflammation. In pediatric patients, ADEM presents unique challenges due to its potential for rapid progression and long-term neurological sequelae. Therapeutic plasma exchange (TPE) has emerged as a potential treatment option by targeting the underlying autoimmune process and modulating the inflammatory response. This comprehensive review evaluates the role of TPE in pediatric ADEM, synthesizing evidence from clinical studies and providing insights into its efficacy, safety, and potential benefits. The review highlights the variability in TPE efficacy based on disease severity and patient-specific factors. Implications for clinical practice include considering TPE as a therapeutic option, particularly in severe or refractory cases, and emphasizing the importance of early intervention. Recommendations for future research include long-term prospective studies, comparative effectiveness trials, and efforts to standardize TPE protocols. Overall, continued investigation and innovation in managing pediatric ADEM are essential for improving outcomes and quality of life for affected children and their families.

Histological Chorioamnionitis - Experience from a Tertiary Care Center.

Chorioamnionitis (CA) mostly represents the presence of intra-amniotic infection. The features of the disease can be detected during histopathological examination of the delivered fetal membranes. The current study aims to explore the features of all histological chorioamnionitis cases received in the Pathology Department of a university hospital over a period of five years. This retrospective cross-sectional study was conducted between January 2015 and December 2019 and used data from 78 women with histologically confirmed chorioamnionitis. All data were gathered from the hospital information system. The SPSS software's statistical methods were used to show and analyze descriptive and categorical data. The selected patients had an average age of 36.18 ± 6.153 years (age range 21-50 years) and different stages of the disease: 29 (37.2%) in the first stage, 25 (32%) in the second stage and the remaining 24 (30.7%) subjects in the third stage. Nearly half of cases showed concomitant umbilical cord inflammation, whereas placental inflammation occurred much less frequently. The most common cause of chorioamnionitis was bacterial infection, where Streptococcus agalactiae was the most prevalent. This study showed that the majority of histological chorioamnionitis were of mild intensity (stage 1). Many cases were associated with umbilical cord and, to a lesser extent, with placental inflammation. Bacteria were the most typical cause of chorioamnionitis. The most common strain was Streptococcus agalactiae.

Dabrafenib mitigates the neuroinflammation caused by ferroptosis in experimental autoimmune encephalomyelitis by up regulating Axl receptor

Multiple sclerosis is an autoimmune disease that causes inflammatory damage to the central nervous system. At present, the pathogenesis of the disease is unknown. There is a lack of few effective therapy medications available. Therefore, it is necessary to further explore the pathogenesis of this illness and develop potential therapeutic drugs. Dabrafenib is potential therapeutic medicine for nervous system disease. In this study, we preliminarily studied the possible mechanism of dabrafenib in the treatment of multiple sclerosis from the perspective of ferroptosis. First, we observed that dabrafenib significantly improved symptoms of gait abnormalities, limb weakness or paralysis, and down-regulated levels of spinal cord inflammation in an experimental autoimmune encephalitis (EAE) model. Meanwhile, we also observed that dabrafenib could inhibit the proteins of ferroptosis in spinal cord tissue of EAE mice by Western blot. The results of immunohistochemical analysis showed that the effect of dabrafenib on ferroptosis mainly occurred in microglia. Second, dabrafenib was demonstrated to be able to inhibit the S phase of the cell cycle, reduce ROS levels, and reinstate mitochondrial activity in the LPS-induced BV2 inflammatory cell model. Futhermore, we found that dabrafenib inhibits P-JAK2 and P-STAT3 activation by acting Axl receptor, which in turn prevents neurogenic inflammation in microglia. The co-stimulated BV2 cell model with LPS and Erastin also verified these findings. Ultimately, the Axl knockout mice used to construct the EAE model allowed for the confirmation that dabrafenib prevented ferroptosis in microglia by up-regulating Axl receptor, which reduced the inflammatory demyelination associated with EAE. In summary, our research demonstrates the advantages of dabrafenib in multiple sclerosis treatment, which can prevent ferroptosis in microglia in multiple sclerosis through up-regulating Axl receptor, thus halting the progression of multiple sclerosis.

Long non-coding RNA DANCR increases spinal cord neuron apoptosis and inflammation of spinal cord injury by mediating the microRNA-146a-5p/MAPK6 axis.

This research was to unravel the impact of the lncRNA differentiation antagonizing non-protein coding RNA (DANCR)/microRNA (miR)-146a-5p/mitogen-activated protein kinase 6 (MAPK6) axis on spinal cord injury (SCI). SCI mouse models were established and injected with si-DANCR or miR-146a-5p agomir. The recovery of motor function was assessed by Basso Mouse Scale. SCI was pathologically evaluated, and serum inflammatory factors were measured in SCI mice. Mouse spinal cord neurons were injured by H2O2 and transfected, followed by assessment of proliferation and apoptosis. DANCR, miR-146a-5p, and MAPK6 in tissues and cells were detected, as well as their relationship. DANCR increased and miR-146a-5p decreased in SCI. Silencing DANCR or enhancing miR-146a-5p stimulated the proliferation of mouse spinal cord neurons and reduced apoptosis. DANCR was bound to miR-146a-5p to target MAPK6. DANCR affected the proliferation and apoptosis of spinal cord neurons by mediating the miR-146a-5p/MAPK6 axis. Downregulating DANCR or upregulating miR-146a-5p improved inflammation, the destruction of spinal cord tissue structure, and apoptosis in SCI mice. DANCR affects spinal cord neuron apoptosis and inflammation of SCI by mediating the miR-146a-5p/MAPK6 axis.

Combining imaging mass spectrometry and immunohistochemistry to analyse the lipidome of spinal cord inflammation

Inflammation is a complex process that accompanies many pathologies. Actually, dysregulation of the inflammatory process is behind many autoimmune diseases. Thus, treatment of such pathologies may benefit from in-depth knowledge of the metabolic changes associated with inflammation. Here, we developed a strategy to characterize the lipid fingerprint of inflammation in a mouse model of spinal cord injury. Using lipid imaging mass spectrometry (LIMS), we scanned spinal cord sections from nine animals injected with lysophosphatidylcholine, a chemical model of demyelination. The lesions were demonstrated to be highly heterogeneous, and therefore, comparison with immunofluorescence experiments carried out in the same section scanned by LIMS was required to accurately identify the morphology of the lesion. Following this protocol, three main areas were defined: the lesion core, the peri-lesion, which is the front of the lesion and is rich in infiltrating cells, and the uninvolved tissue. Segmentation of the LIMS experiments allowed us to isolate the lipid fingerprint of each area in a precise way, as demonstrated by the analysis using classification models. A clear difference in lipid signature was observed between the lesion front and the epicentre, where the damage was maximized. This study is a first step to unravel the changes in the lipidome associated with inflammation in the context of diverse pathologies, such as multiple sclerosis.Graphical abstract

Unravelling the impact of COVID-19 on pregnancy: In aspect of placental histopathology and umbilical cord macrophage immunoactivity with neonatal outcomes

COVID-19 has turned into a global pandemic since it was first detected in 2019, causing serious public health problems. Our objective was to investigate the impact of COVID-19 on pregnant women and newborns, who belong to the vulnerable segments of society. Our study involved the histopathological examination of placentas and umbilical cords from two groups of pregnant women. Group I consisted of pregnant women who had never tested positive for COVID-19 during their pregnancy (n: 20). Group II consisted of pregnant women who had contracted COVID-19, exhibited moderate and mild symptoms, and recovered from the disease before giving birth (n: 23). Furthermore, we employed immunofluorescence techniques to detect macrophage activity in the umbilical cord. Prenatal assessments were based on maternal complete blood counts and coagulation assays (n:40 in both groups). Newborn conditions were evaluated using birth weight, height, head circumference, and APGAR (n:40 in both groups). Our analyses reveal that COVID-19 causes placental and umbilical cord inflammation and maternal and foetal vascular malperfussion. Our immunofluorescence investigations demonstrate a notable increase in macrophage numbers and the macrophage-to-total cell ratio within the COVID-19 group. In this aspect, this study provides the initial report incorporating macrophage activity results from Warton's jelly in pregnants who have recovered from COVID-19. We have also ascertained that COVID-19 abbreviates gestation periods and concurrently diminishes maternal haemoglobin concentrations. Consequently, COVID-19 with mild and moderate symptoms during pregnancy, causes significant changes to the placenta and umbilical cord, but propitiously does not cause a significant difference in the neonatal outcomes.

Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization.

JOURNAL/nrgr/04.03/01300535-202410000-00027/figure1/v/2024-02-06T055622Z/r/image-tiff Spinal cord injury is a disabling condition with limited treatment options. Multiple studies have provided evidence suggesting that small extracellular vesicles (SEVs) secreted by bone marrow mesenchymal stem cells (MSCs) help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury. Strikingly, hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs (HSEVs) exhibit increased therapeutic potency. We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair. SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation. HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation. HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro. MicroRNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that miR-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1. Reducing miR-146a-5p expression in HSEVs partially attenuated macrophage polarization. Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting miR-146a-5p, which alters macrophage polarization. This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.

Effects of oral and intranasal resveratrol nanoparticle administration on neurodegeneration and neuronal dysfunction in a model of multiple sclerosis

Aims/Purpose: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. Immunomodulatory treatments seek to reduce inflammation in MS but have limited effect on neurodegeneration. Resveratrol is a natural polyphenol with antioxidant and anti‐inflammatory properties which could be neuroprotective in MS. The purpose of this study is to compare the oral and intranasal administration of resveratrol nanoparticles (RN) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS with ocular and neurological endpoints.Methods: RN were formulated using a thin rehydration technique. In the 1st experiment, 16.9 mg/kg RN (n = 6) or equivalent vehicle (n = 5) were given orally to EAE mice daily for 30 days. In the 2nd experiment, 8.44 mg/kg RN (n = 6) or vehicle (n = 6) were given intranasally to EAE mice daily for 30 days. EAE mice were assessed daily for clinical signs of ascending paralysis and weekly for visual function. After sacrifice at day 30, retinas were immunostained for brn3a to count retinal ganglion cells (RGC), and spinal cords and optic nerves were stained by H&E and luxol fast blue to assess inflammation and demyelination.Results: 16.9 mg/kg oral RN treatment reduced RGC loss compared to vehicle (4164 ± 406 vs 2422 ± 401 RGC/1.56 mm2, p < 0.05). Similarly, 8.44 mg/kg RN given intranasally reduced RGC loss compared to vehicle (3569 ± 241 vs 2280 ± 329 RGC/1.56 mm2, p < 0.05). Oral and intranasal RN showed similar neuroprotective effects (4164 ± 406 vs 3569 ± 241 RGC/1.56 mm2, p > 0.05). Although neither route of administration showed a reduction of ascending paralysis, 16.9 mg/kg oral RN reduced the severity of paralysis compared to vehicle and 8.44 mg/kg intranasal RN (survival analysis with median survival 29.5 vs 19.0 and 19.0 days, p < 0.05). Likewise, the severity of visual function loss was reduced by the administration of 16.9 mg/kg oral RN compared to vehicle and 8.44 mg/kg intranasal RN (median survival > 28.0 vs 28.0 and 21.0 days, p < 0.05). Neither oral nor intranasal administration showed a significant reduction of spinal cord or optic nerve inflammation or demyelination.Conclusions: RN were able to reduce RGC loss independent of their administration route, but oral administration demonstrated additional neuroprotective effects by reducing paralysis severity.

Maresin-1 prevents blood-spinal cord barrier disruption associated with TRPV4 elevation in the experimental model of spinal cord injury

Recently, we reported the TRPV4 ion channel activation and its association with secondary damage after spinal cord injury (SCI). TRPV4 activation is linked with blood-spinal cord barrier (BSCB) disruption, endothelial damage, and inflammation after SCI. Specialized pro-resolving mediators (SPM) are endogenous lipid mediators released for inflammation resolution. Studies suggest that SPM could act as an endogenous antagonist of ion channels directly or indirectly at the plasma membrane. Herein, we studied the effect of maresin-1, a docosahexaenoic acid (DHA)-derived SPM, in SCI-induced TRPV4 expression and subsequent associated damage. First, employing a particular agonist (4αPDD) in endothelial and neuronal cell lines, we examined the potential of maresin-1 to block TRPV4 activation. Then we quantify the DHA levels in plasma and epicenter of the spinal cord in sham and at 1, 3, 7, 14, 21, and 28-days post-injury (DPI) using LC-MS. Then, we exogenously administered maresin-1 using two dosing regimens i.e., single-dose (1 μg) and multiple-dose (1 μg/day for seven days), to confirm its role in the TRPV4 inhibition and its linked damage. After SCI, DHA levels decrease in the spinal cord epicenter area as well as in the plasma. Treatment with maresin-1 attenuates TRPV4 expression, inflammatory cytokines, and chemokines and impedes neutrophil infiltration. Furthermore, treatment with maresin-1 prevents BSCB disruption, alleviates glial scar formation, and improves functional recovery. Thus, our results suggest that maresin-1 could modulate TRPV4 expression and could be a safe and promising approach to target inflammation and BSCB damage after SCI.

Duroplasty for injured cervical spinal cord with uncontrolled swelling: protocol of the DISCUS randomized controlled trial

BackgroundCervical traumatic spinal cord injury is a devastating condition. Current management (bony decompression) may be inadequate as after acute severe TSCI, the swollen spinal cord may become compressed against the surrounding tough membrane, the dura. DISCUS will test the hypothesis that, after acute, severe traumatic cervical spinal cord injury, the addition of dural decompression to bony decompression improves muscle strength in the limbs at 6 months, compared with bony decompression alone.MethodsThis is a prospective, phase III, multicenter, randomized controlled superiority trial. We aim to recruit 222 adults with acute, severe, traumatic cervical spinal cord injury with an American Spinal Injury Association Impairment Scale grade A, B, or C who will be randomized 1:1 to undergo bony decompression alone or bony decompression with duroplasty. Patients and outcome assessors are blinded to study arm. The primary outcome is change in the motor score at 6 months vs. admission; secondary outcomes assess function (grasp, walking, urinary + anal sphincters), quality of life, complications, need for further surgery, and mortality, at 6 months and 12 months from randomization. A subgroup of at least 50 patients (25/arm) also has observational monitoring from the injury site using a pressure probe (intraspinal pressure, spinal cord perfusion pressure) and/or microdialysis catheter (cord metabolism: tissue glucose, lactate, pyruvate, lactate to pyruvate ratio, glutamate, glycerol; cord inflammation: tissue chemokines/cytokines). Patients are recruited from the UK and internationally, with UK recruitment supported by an integrated QuinteT recruitment intervention to optimize recruitment and informed consent processes. Estimated study duration is 72 months (6 months set-up, 48 months recruitment, 12 months to complete follow-up, 6 months data analysis and reporting results).DiscussionWe anticipate that the addition of duroplasty to standard of care will improve muscle strength; this has benefits for patients and carers, as well as substantial gains for health services and society including economic implications. If the addition of duroplasty to standard treatment is beneficial, it is anticipated that duroplasty will become standard of care.Trial registrationIRAS: 292031 (England, Wales, Northern Ireland) - Registration date: 24 May 2021, 296518 (Scotland), ISRCTN: 25573423 (Registration date: 2 June 2021); ClinicalTrials.gov number : NCT04936620 (Registration date: 21 June 2021); NIHR CRN 48627 (Registration date: 24 May 2021).

Carboplatin ameliorates the pathogenesis of experimental autoimmune encephalomyelitis by inducing T cell apoptosis.

Apoptosis is a natural physiological process that can maintain the homeostasis of the body and immune system. This process plays an important role in the system's resistance to autoimmune development. Because of the dysfunction of cell apoptosis mechanism, the number of autoreactive cells in the peripheral tissue increases along with their accumulation. This will lead to the development of autoimmune diseases, such as multiple sclerosis (MS). MS is an immune-mediated disease of the central nervous system characterized by severe white matter demyelination. Because of the complexity of its pathogenesis, there is no drug to cure it completely. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Carboplatin (CA) is a second-generation platinum anti-tumor drug. In this study, we attempted to assess whether CA could be used to ameliorate EAE. CA reduced spinal cord inflammation, demyelination, and disease scores in mice with EAE. Moreover, the number and proportion of pathogenic T cells especially Th1 and Th17 in the spleen and draining lymph nodes were reduced in CA-treated EAE mice. Proteomic differential enrichment analysis showed that the proteins related to apoptosis signal changed significantly after CA treatment. CFSE experiment showed that CA significantly inhibited the T cell proliferation. Finally, CA also induced apoptosis in activated T cells and MOG-specific T cells in vitro. Overall, our findings indicated that CA plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS.

Divergent functional outcomes of NLRP3 blockade downstream of multi-inflammasome activation: therapeutic implications for ALS.

NOD-Like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome modulation has emerged as a potential therapeutic approach targeting inflammation amplified by pyroptotic innate immune cell death. In diseases characterized by non-cell autonomous neurodegeneration including amyotrophic lateral sclerosis (ALS), the activation of several inflammasomes has been reported. Since functional redundancy can exist among inflammasome pathways, here we investigate the effects of NLRP3 inhibition on NLRP3, NLR family CARD Domain Containing 4 (NLRC4) and non-canonical pathways to understand whether NLRP3 blockade alone can mitigate pro-inflammatory cytokine release and pyroptotic cell death in contexts where single or multiple inflammasome pathways independent of NLRP3 are activated. In this study we do not limit our insights into inflammasome biology by solely relying on the THP-1 monocytic line under the LPS/nigericin-mediated NLRP3 pathway activation paradigm. We assess therapeutic potential and limitations of NLRP3 inhibition in multi-inflammasome activation contexts utilizing various human cellular systems including cell lines expressing gain of function (GoF) mutations for several inflammasomes, primary human monocytes, macrophages, healthy and Amyotrophic Lateral Sclerosis (ALS) patient induced pluripotent stem cells (iPSC)-derived microglia (iMGL) stimulated for canonical and non-canonical inflammasome pathways. We demonstrate that NLRP3 inhibition can modulate the NLRC4 and non-canonical inflammasome pathways; however, these effects differ between immortalized, human primary innate immune cells, and iMGL. We extend our investigation in more complex systems characterized by activation of multiple inflammasomes such as the SOD1G93A mouse model. Through deep immune phenotyping by single-cell mass cytometry we demonstrate that acute NLRP3 inhibition does not ameliorate spinal cord inflammation in this model. Taken together, our data suggests that NLRP3 inhibition alone may not be sufficient to address dynamic and complex neuroinflammatory pathobiological mechanisms including dysregulation of multiple inflammasome pathways in neurodegenerative disease such as ALS.

Minimally Invasive Microglial and Neuronal Imaging in Mouse Spinal Cord Dorsal Horn

The spinal cord dorsal horn is a relay hub that receives sensory information from the peripheral nervous system and transmits bioelectrical signals to the brain. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">In vivo</i> imaging of neuronal and glial activity in the dorsal horn can provide insights into both functions and dysfunctions of the neuronal network in the spinal cord. With multimodal NLO microscopy, we identified a thin-myelin sheath region allowing to image over 200 μm deep below pia with subcellular resolution. By using an optically cleared intervertebral window, dorsal horn neuron and microglia activities can be observed without activating spinal cord inflammation. Two-photon imaging of neurons and microglia as well as the optical clearing improvement at different tissue depths were further characterized over time. Using this inflammation-free imaging method, we conducted a longitudinal study of dorsal horn microglia dynamics following sciatic nerve transection. Furthermore, stable <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in vivo</i> calcium imaging of neurons in the dorsal horn was performed with electrical stimulation on the mouse's hind paw. The subcellular-resolution imaging enabled characterization of the distinct calcium transients of neuronal somas and dendrites. This minimally invasive imaging approach to spinal dorsal horn through an optically cleared intervertebral window provides a reliable platform for studying and understanding cellular activities in the spinal dorsal horn.

A Prospective Analysis of the Retinopathy of Prematurity Correlated with the Inflammatory Status of the Extremely Premature and Very Premature Neonates.

Retinopathy of Prematurity (ROP) is a major cause of blindness in premature infants. This study aimed to evaluate the association between inflammatory markers and ROP development in extremely premature and very premature neonates and identify potential inflammatory biomarkers for ROP risk prediction. This prospective study was conducted from January 2021 to January 2023 in two clinical hospitals associated with the "Victor Babes" University of Medicine and Pharmacy Timisoara. The study population comprised neonates with a gestational age of less than 32 weeks. Various inflammatory markers, including total white blood cell count, polymorphonuclear leukocytes, C-reactive protein, interleukin-6, and lactate dehydrogenase, were analyzed from blood samples collected at birth and three days postnatally. ROP was diagnosed and classified following the International Classification of Retinopathy of Prematurity. The study included 48 neonates, 12 Extremely Premature Infants (EPI), and 36 Very Premature Infants (VPI). The EPI group had significantly higher mean interleukin-6 and lactate dehydrogenase levels at birth and three days postnatally than the VPI group. C-reactive protein levels at three days were significantly higher in the VPI group. Umbilical cord inflammation and ROP severity were found to have a statistically significant positive correlation. Half of the EPIs had moderate to severe ROP, significantly more than in the VPI group. The duration of oxygen supplementation, mechanical ventilation, Continuous Positive Airway Pressure (CPAP), gestational age less than 28 weeks, and umbilical cord inflammation at or above stage 3 were significant risk factors for developing ROP stage 2 or above. Elevated CRP and IL-6 were also significantly associated with an increased risk of developing ROP stage 2 or above, highlighting their potential as biomarkers for ROP risk prediction. This study suggests a significant association between inflammatory markers and ROP development in extremely premature and very premature neonates. These findings could contribute to the identification of potential inflammatory biomarkers for ROP risk prediction, improving early diagnosis and intervention strategies for this condition.

Osmotic blood-brain barrier disruption with mannitol followed by methotrexate, rituximab, and carboplatin in treating patients with newly diagnosed primary central nervous system lymphoma.

2077 Background: Osmotic blood-brain barrier disruption (BBBD) uses intra-arterial (IA) mannitol to open the neuro-vascular unit to enhance delivery of therapeutic agents to the brain. We report the results of a multi-institutional, single arm, phase 2 study evaluating the efficacy and safety of BBBD-enhanced chemotherapy in combination with immunotherapy in patients with newly diagnosed primary central nervous system lymphoma (PCNSL). PCNSL is a rare non-Hodgkin’s lymphoma that is limited to the brain, cerebrospinal fluid, spinal cord and/or the vitreoretinal compartment. Methods: Non-immunocompromised subjects with newly diagnosed PCNSL received rituximab IV over 5 hours on day 1. On days 2 and 3, under general anesthesia in the angiography suite, subjects received IA mannitol immediately followed by IA methotrexate over 10 minutes, and then IA carboplatin over 10 minutes. Subjects received sodium thiosulfate IV for hearing protection at 4 and 8 hours after each carboplatin dose. Treatment was repeated every month for up to 12 courses in the absence of disease progression or unacceptable toxicity. Per institutional recommendations, further accrual was terminated during the COVID-19 pandemic. Contrast MRI was used for response assessment based on IPCG criteria. Results: Twenty subjects (10 F, 10 M, Median KPS = 80; range 40-100) received a median of 8 cycles at 3 US institutions. Sixteen radiographic complete responses (80%) and 1 partial response were documented, 3 subjects were not evaluable (2 withdrew consent and 1 unrelated death). Median PFS was 55.2 months (95% CI :10.3 – not reached) and Median Overall survival was 82.8 months (95% CI :19.8-145.8). Fourteen patients (82% of evaluable patients) had grade 3 or 4 adverse events (AE). Grade 4 AEs (n = 14 in n = 7 patients) included neurologic toxicities (ischemia, cervical cord inflammation, neuropathy) and blood/bone marrow toxicities (lymphopenia, neutropenia, granulocytopenia). There were no treatment-related deaths. Conclusions: We demonstrate the feasibility of performing BBBD in a multi-institutional setting with excellent PFS and OS in patients without whole brain radiation or autologous transplant. Our CR rates, PFS and OS are comparable to other IV high-dose MTX regimens, with acceptable toxicity profile and no documented treatment-related deaths. Clinical trial information: NCT00293475 .

Sciatic Nerve Block Combined with Flurbiprofen Inhibits Spinal Cord Inflammation and Improves Postoperative Pain in Rats with Plantar Incision.

Peripheral nerve block is often used to relieve postoperative pain. But the effect of nerve block on inflammatory response is not fully understood. Spinal cord is the primary center of pain processing. This study is to investigate the effect of single sciatic nerve block on the inflammatory response of the spinal cord in rats with plantar incision and the combined effect with flurbiprofen. The plantar incision was used to establish a postoperative pain model. Single sciatic nerve block, intravenous flurbiprofen or the combination of both were used for intervention. The sensory and motor functions after nerve block and incision were evaluated. The changes of IL-1β, IL-6, TNF-α, microglia and astrocytes in the spinal cord were examined by qPCR and immunofluorescence respectively. Sciatic nerve block with 0.5% ropivacaine in rats induced sensory block for 2h and motor block for 1.5h. In the rats with plantar incision, the single sciatic nerve block did not alleviate postoperative pain or inhibit the activation of spinal microglia and astrocytes, but the levels of IL-1β and IL-6 in spinal cord were decreased when the nerve block wore off. The combined effect of a single sciatic nerve block and intravenous flurbiprofen not only decreased the levels of IL-1β, IL-6, and TNF-α, but also relieved the pain and alleviated the activation of microglia and astrocytes. The single sciatic nerve block cannot improve postoperative pain or inhibit the activation of spinal cord glial cells, but can reduce the expression of spinal inflammatory factors. Nerve block combined with flurbiprofen can inhibit spinal cord inflammation and improve postoperative pain. This study provides a reference for rational clinical application of nerve block.

The absence of antibodies in longitudinally extensive transverse myelitis and the impact on prognosis (P9-5.029)

<h3>Objective:</h3> Evaluation of clinical outcomes in LETM. <h3>Background:</h3> Longitudinally extensive transverse myelitis (LETM) is typically defined as spinal cord inflammation that spans 3 or more vertebral segments on MRI. It is a prototypical manifestation of neuromyelitis optica spectrum disorder (NMOSD) but is also seen in myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and much less commonly multiple sclerosis. In some cases, despite extensive investigation, a definitive diagnosis cannot be reached, a condition referred to as double seronegative LETM (dsLETM). <h3>Design/Methods:</h3> Cohort study of LETM cases reviewed in NMO UK Highly Specialised Service at the Walton Centre NHS Foundation Trust between Jan 2008-March 2022. Clinical presentation, radiological characteristics, aquaporin-4 antibodies (AQP4-IgG) and MOG antibodies, relapses, treatment, and EDSS at follow-up were extracted from case records. <h3>Results:</h3> LETM=93 cases were identified; NMOSD=41 (AQP4-IgG positive; 88%), dsLETM=29, MOGAD=17, others=6. The median onset age was 46 (15–85) yrs with a median follow-up of 46 (1–144) months. EDSS at nadir was similar between subgroups (NMOSD; 7, MOGAD; 7.5, dsLETM; 6.7, p&gt;0.05) but patients with dsLETM were less likely to relapse (dsLETM; 21% vs. NMOSD; 56% vs. MOGAD; 29%, p=0.008). Long term immunosuppression was used in NMOSD (100%), MOGAD (76%) and dsLETM (34%) and was associated with a reduction in median annualised relapse rate (NMOSD; 1.65 to 0.09, MOGAD; 0.75 to 0.07, and dsLETM; 1 to 0.11). Although EDSS scores at last review were higher in NMOSD than MOGAD (6 vs. 4; p=0.018) and dsLETM (6 vs 4.5; p=0.04), dsLETM patients still reached a significant disability (EDSS&gt;6) in 35% of cases. <h3>Conclusions:</h3> Patients with dsLETM relapsed less as compared to NMOSD and MOGAD and immunosuppression reduced the risk further. Although last EDSS was lower in dsLETM as compared to NMOSD, a third of patients still suffered from significant disability. <b>Disclosure:</b> Dr. Rocchi has nothing to disclose. Dr. Forcadela has nothing to disclose. Dr. Jacob has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ALEXION. Dr. Hamid has nothing to disclose. Dr. Huda has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Guidepoint.

Chapter 16: Spinal Cord Lesions

Spinal cord lesions produce dramatic neurologic deficits including paraparesis, quadriparesis, sensory loss, and dysautonomia. MRI of the spinal cord is an important adjunct to the history and physical examination in determining the etiology of myelopathy. Myelopathy is a term which encompasses a broad range of spinal cord pathologies, whereas myelitis specifically alludes to spinal cord inflammation (commonly occurring with immune-mediated myelopathies).