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Background and purpose: Cannabidiol is a Cannabis‐derived non‐psychotropic compound that exerts a plethora of pharmacological actions, including anti‐inflammatory, neuroprotective and antitumour effects, with potential therapeutic interest. However, the actions of cannabidiol in the digestive tract are largely unexplored. In the present study, we investigated the effect of cannabidiol on intestinal motility in normal (control) mice and in mice with intestinal inflammation. Experimental approach: Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; contractility in vitro was evaluated by stimulating the isolated ileum, in an organ bath, with ACh. Key results: In vivo, cannabidiol did not affect motility in control mice, but normalized croton oil‐induced hypermotility. The inhibitory effect of cannabidiol was counteracted by the cannabinoid CB1 receptor antagonist rimonabant, but not by the cannabinoid CB2 receptor antagonist SR144528 (N‐[‐1S‐endo‐1,3,3‐trimethyl bicyclo [2.2.1] heptan‐2‐yl]‐5‐(4‐chloro‐3‐methylphenyl)‐1‐(4‐methylbenzyl)‐pyrazole‐3‐carboxamide), by the opioid receptor antagonist naloxone or by the α2‐adrenergic antagonist yohimbine. Cannabidiol did not reduce motility in animals treated with the fatty acid amide hydrolase (FAAH) inhibitor N‐arachidonoyl‐5‐hydroxytryptamine, whereas loperamide was still effective. In vitro, cannabidiol inhibited ACh‐induced contractions in the isolated ileum from both control and croton oil‐treated mice. Conclusions and implications: Cannabidiol selectively reduces croton oil‐induced hypermotility in mice in vivo and this effect involves cannabinoid CB1 receptors and FAAH. In view of its low toxicity in humans, cannabidiol may represent a good candidate to normalize motility in patients with inflammatory bowel disease. British Journal of Pharmacology (2008) 154, 1001–1008; doi:10.1038/bjp.2008.177; published online 12 May 2008

Use of the ketogenic diet for seizure control in children with epilepsy has seen a recent resurgence. Little cost-benefit analysis of this therapy has been published. Lack of diet standardization and method for evaluation of diet efficacy makes the decision to implement this diet therapy problematic for dietetics practitioners. In 1995, a 3-year trial ketogenic diet program was implemented; the decision on whether to continue the program depended on patient outcomes and financial implications to the institution. The program initiation process involved development of a protocol encompassing inpatient and outpatient care, patient/caregiver education materials, and a parent/caregiver satisfaction survey for evaluation of subjective responses to therapy. The program was researched and developed by registered dietitians and required approximately 55 hours of labor over a period of 5 months. Nutrition management averaged 16 hours per patient. Available cost data revealed 83% reimbursement of hospital charges and 99% reimbursement of inpatient costs. Seizure reduction and/or improved behavior occurred in 6 of 11 (55%) patients. Although program development and patient-care management was labor intensive, results have been encouraging based on reduction in seizures and behavioral improvements in patients and parent/caregiver satisfaction. J Am Diet Assoc. 1999;99:1554–1558.

Multiple sclerosis is a chronic inflammatory disease of the CNS 1 . Astrocytes contribute to the pathogenesis of multiple sclerosis 2 , but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC–seq), chromatin immunoprecipitation with sequencing (ChIP–seq), genome-wide analysis of DNA methylation and in vivo CRISPR–Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2α to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2α and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis. Single-cell RNA sequencing of cells from humans with multiple sclerosis and mice with a model of the disease identifies a population of disease-promoting astrocytes in which anti-oxidant and anti-inflammatory proteins are suppressed.

Objectives To evaluate the effect at 3 months of an intensive cervical traction protocol on disability in people with cervical radiculopathy and compare with placebo traction. Design The trial is national, multi-centre, randomised, placebo-controlled and single-blinded. It began in March 2024 and will end in September 2027. Participants are allocated to receive mechanical cervical traction or placebo mechanical cervical traction. Setting Seven hospitals in France. Participants We will include 206 individuals with cervical radiculopathy diagnosed 3 to 12 months previously, hospitalised to undergo mechanical traction. Main inclusion criteria: age ≥ 18 years, Neck Disability Index ≥ 15/50 points and presence of ≥ 3 of 4 diagnostic signs of cervical radiculopathy. Interventions All participants undergo 2 × 30 min of traction per day for 5 consecutive days. For mechanical cervical traction, the maximum weight is ≤ 12 kg and for placebo traction ≤ 600g. Main outcome measures The primary outcome is disability (Neck Disability Index), secondary outcomes include pain related outcomes, medication consumption, surgery and days off work. Results This study will provide a robust evaluation of the mid-term effectiveness of mechanical traction on disability in chronic cervical radiculopathy. The results will demonstrate whether a simple technique involving a short, intensive protocol reduces the duration of disability and pain. Conclusions The availability of robust evidence supporting or refuting the use of cervical traction as part of the management of cervical radiculopathy will enable optimisation of treatment. The results could lead to the drafting of evidence-based recommendations regarding the use of mechanical traction to treat cervical radiculopathy. Clinial trial registration number ClinicalTrials.gov (NCT05952167).

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first step in the kynurenine pathway of tryptophan (Trp) degradation that produces several biologically active Trp metabolites. L-kynurenine (Kyn), the first byproduct by IDO1, promotes immunoregulatory effects via activation of the Aryl hydrocarbon Receptor (AhR) in dendritic cells (DCs) and T lymphocytes. We here identified the nuclear coactivator 7 (NCOA7) as a molecular target of 3-hydroxyanthranilic acid (3-HAA), a Trp metabolite produced downstream of Kyn along the kynurenine pathway. In cells overexpressing NCOA7 and AhR, the presence of 3-HAA increased the association of the two molecules and enhanced Kyn-driven, AhR-dependent gene transcription. Physiologically, conventional (cDCs) but not plasmacytoid DCs or other immune cells expressed high levels of NCOA7. In cocultures of CD4 T cells with cDCs, the co-addition of Kyn and 3-HAA significantly increased the induction of Foxp3 regulatory T cells and the production of immunosuppressive transforming growth factor β in an NCOA7-dependent fashion. Thus, the co-presence of NCOA7 and the Trp metabolite 3-HAA can selectively enhance the activation of ubiquitary AhR in cDCs and consequent immunoregulatory effects. Because NCOA7 is often overexpressed and/or mutated in tumor microenvironments, our current data may provide evidence for a new immune check-point mechanism based on Trp metabolism and AhR.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system 1 . Astrocytes are heterogeneous glial cells that are resident in the central nervous system and participate in the pathogenesis of multiple sclerosis and its model experimental autoimmune encephalomyelitis 2 , 3 . However, few unique surface markers are available for the isolation of astrocyte subsets, preventing their analysis and the identification of candidate therapeutic targets; these limitations are further amplified by the rarity of pathogenic astrocytes. Here, to address these challenges, we developed focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), a high-throughput microfluidic cytometry method that combines encapsulation of cells in droplets, PCR-based detection of target nucleic acids and droplet sorting to enable in-depth transcriptomic analyses of cells of interest at single-cell resolution. We applied FIND-seq to study the regulation of astrocytes characterized by the splicing-driven activation of the transcription factor XBP1, which promotes disease pathology in multiple sclerosis and experimental autoimmune encephalomyelitis 4 . Using FIND-seq in combination with conditional-knockout mice, in vivo CRISPR–Cas9-driven genetic perturbation studies and bulk and single-cell RNA sequencing analyses of samples from mouse experimental autoimmune encephalomyelitis and humans with multiple sclerosis, we identified a new role for the nuclear receptor NR3C2 and its corepressor NCOR2 in limiting XBP1-driven pathogenic astrocyte responses. In summary, we used FIND-seq to identify a therapeutically targetable mechanism that limits XBP1-driven pathogenic astrocyte responses. FIND-seq enables the investigation of previously inaccessible cells, including rare cell subsets defined by unique gene expression signatures or other nucleic acid markers. The pathogenic function of XBP1-expressing astrocytes in experimental autoimmune encephalomyelitis and multiple sclerosis have been studied using FIND-seq, a new method combining microfluidics cytometry, PCR-based detection of nucleic acids and cell sorting for in-depth single-cell transcriptomics analyses of rare cells.

Purpose Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusion Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

The Baveno VI consensus guidelines and an expanded algorithm suggest that transient elastography (TE) and platelet (PLT) count can be used to identify patients with cirrhosis who can avoid esophagogastroduodenoscopy (EGD). The primary aims of this study were to assess the ability of a simple algorithm, which uses only laboratory parameters, to predict medium/large esophageal varices (EV) in patients with hepatitis C virus (HCV) and cirrhosis from the Rete Sicilia Selezione Terapia-HCV (RESIST-HCV) cohort and to compare the performance of the algorithm with Baveno VI and Expanded Baveno VI criteria. The secondary aim was to assess the role of TE in ruling out large EV. In total, 1,381 patients with HCV-associated cirrhosis who had EGD and TE within 1 year of starting treatment with direct-acting antivirals were evaluated. Using multivariate logistic analysis, laboratory variables were selected to determine which were independently associated with medium/large EV to create the RESIST-HCV criteria. These criteria were tested in a training cohort with patients from a single center (Palermo) and validated with patients from the 21 other centers of the RESIST-HCV program (validation cohort). In the entire cohort, medium/large EV were identified in 5 of 216 patients (2.3%) using the Baveno VI criteria and 13 of 497 patients (2.6%) using the Expanded Baveno VI criteria. PLT count and albumin level were independently associated with medium/large EV. The best cut-off values were a PLT count greater than 120 × 10 cells/μL and serum albumin level greater than 3.6 g/dL; negative predictive values (NPVs) were 97.2% and 94.7%, respectively. In the training cohort of 326 patients, 119 (36.5%) met the RESIST-HCV criteria and the NPV was 99.2%. Among 1,055 patients in the validation cohort, 315 (30%) met the RESIST-HCV criteria and the NPV was 98.1%. Adding TE to the RESIST-HCV criteria reduced the avoided EGDs for approximately 25% of patients and the NPV was 98.2%. The \"easy-to-use\" RESIST-HCV algorithm avoids EGD for high-risk EV screening for more than 30% of patients and has the same performance criteria as TE. Using these criteria simplifies the diagnosis of portal hypertension.

Villarrica (Chile) is a basaltic stratovolcano, currently in an open-conduit condition. It now has relatively frequent Strombolian and effusive eruptions, but it had large explosive eruptions in prehistoric times. Among them, the most recent eruption was Chaimilla, which occurred about 3100 years ago and produced deposits that indicate complex, multiphase eruptive dynamics. Significant differences in mineralogy and glass compositions of the erupted scoria suggest the eruption was fed by two distinct magma batches with similar bulk compositions but distinct crystallization and degassing histories. The lower sequence scoria has a complex crystal assemblage with several crystal populations produced by mixing between a relatively degassed magma containing Fo 75-79 olivine, normally or reversely zoned plagioclase (An 70-94 ) and augite (type 1 magma), and a subordinate volume of more-primitive and more volatile-rich magma rising from depth (type 2 magma) and carrying normally zoned plagioclase and higher-Mg (Fo 81-85 ) olivine crystals. Type 2 magma was the main component emitted during the larger and more explosive eruptive phase that deposited the upper sequence. The Chaimilla eruption occurred under closed-vent conditions and was fed by water-rich magmas. When compared with the petrological features of the magma currently erupted at Villarrica, which has slightly more-evolved bulk compositions, lower crystal content and lower water content, these results suggest that the evolution in eruptive style of the volcano from highly explosive to a lava lake/Strombolian activity corresponds to significant changes in the shallow plumbing system (which is now at much shallower depths); these plumbing-system changes were not associated with significant changes in the parental magma compositions.