👤 Jean Pierre Salles

Nicotine pouches are rapidly increasing in popularity, yet their long-term neurological consequences remain poorly understood. Emerging evidence suggests nicotine may influence seizure susceptibility and neuroimmune signaling, while cannabidiol (CBD) has demonstrated neuroprotective and anti-inflammatory effects. This study investigated the time-dependent impact of acute versus chronic oral nicotine exposure on seizure vulnerability, neuroinflammation, and glymphatic function, and evaluated whether inhaled CBD can reverse these pathological changes. Mice were exposed to acute or 7-day chronic nicotine pouch prior to kainic acid-induced seizures. Seizure severity was scored using the Racine scale. Neuroinflammatory markers (IL-6, HMGB1), neuronal activation markers (BDNF, c-FOS), and Aquaporin-4 (AQP4) expression were quantified via flow cytometry, immunofluorescence, and western blotting. Glymphatic function was assessed using cisterna magna injection of rhodamine dextran tracers. An ex vivo IL-6 modulation assay evaluated nicotine-induced cytokine production and CBD-mediated suppression, with or without IL-6 receptor blockade. Acute nicotine transiently reduced seizure severity, whereas chronic exposure significantly exacerbated seizures, elevated IL-6, HMGB1, BDNF, and c-FOS, and markedly downregulated AQP4. CSF tracer studies confirmed impaired glymphatic influx following chronic nicotine exposure. CBD inhalation effectively reversed seizure severity restored AQP4 expression, normalized IL-6 and HMGB1 levels, and reduced c-FOS protein expression. The IL-6R blockade assay showed that nicotine induces IL-6 production in brain-derived immune cells, while CBD suppresses this response upstream of IL-6 signaling. Chronic nicotine pouch exposure promotes seizure susceptibility through converging neuroimmune and glymphatic disruptions. Inhaled CBD counteracts these effects, supporting its potential as a targeted therapeutic strategy for nicotine-associated neurological risk. This study provides the first evidence that chronic nicotine pouch exposure disrupts glymphatic function, amplifies neuroinflammation, and increases seizure susceptibility through an IL-6-centered neuroimmune network. These findings challenge the perception of nicotine pouches as low-risk products and highlight previously unrecognized neurological vulnerabilities associated with long-term use. The ability of inhaled CBD to reverse these pathological effects identifies a promising therapeutic strategy and underscores the need for further investigation into neuroimmune-glymphatic interactions in nicotine-related brain health. Show less

Achondroplasia is a genetic skeletal condition that results in disproportionately short stature and medical complications throughout life. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia. In this phase 2 dose-finding study, we evaluated the safety and efficacy of oral infigratinib in children with achondroplasia between the ages of 3 and 11 years. A total of 72 children were enrolled in five sequential cohorts to receive daily infigratinib at doses of 0.016 mg per kilogram of body weight (cohort 1), 0.032 mg per kilogram (cohort 2), 0.064 mg per kilogram (cohort 3), 0.128 mg per kilogram (cohort 4), and 0.25 mg per kilogram (cohort 5) for 6 months, followed by 12 months of extended treatment in which the dose in cohorts 1 and 2 could be escalated to the next ascending level at months 6 and 12. The primary safety outcome was the incidence of adverse events that led to a decrease in the dose or discontinuation of infigratinib. The primary efficacy outcome was the change from baseline in the annualized height velocity. During treatment, all the children had at least one adverse event, most of which were mild or moderate in severity; none resulted in treatment discontinuation. In cohort 5, an increased annualized height velocity was observed, which persisted throughout the duration of the study, with a mean change from baseline at 18 months of 2.50 cm per year (95% confidence interval [CI], 1.22 to 3.79; P = 0.001). The mean change from baseline in height z score was 0.54 (95% CI, 0.35 to 0.72) relative to an untreated achondroplasia reference population at 18 months; the mean change from baseline in the upper-to-lower body segment ratio was -0.12 (95% CI, -0.18 to -0.06). The administration of oral infigratinib did not result in any apparent major safety signal and increased the annualized height velocity and z score and decreased the upper-to-lower body segment ratio at 18 months of treatment in cohort 5. (Funded by BridgeBio Pharma; PROPEL2 ClinicalTrials.gov number, NCT04265651.). Show less

Knowledge of the genetic factors in normal pressure hydrocephalus (NPH) is rapidly evolving, with significant advances in recent years. We conducted a systematic review examining genetic contributions to NPH risk. Ovid Embase, Ovid Medline, Web of Science, and Cochrane Central were searched from inception through October 14, 2024, for human studies in English reporting familial NPH cases, genetic variants associated with NPH, and associations with other neurogenetic disorders and exploring transcriptomics. Studies on secondary, obstructive, and congenital hydrocephalus were excluded, and findings were reported narratively. Of 2562 titles and abstracts screened, 56 met inclusion criteria, predominantly involving European populations. More than 30 familial cases were identified, and two cohorts found that 10%-16% of patients with NPH had relatives with NPH symptoms. Whole-genome/exome sequencing, copy-number variant analyses, and genome-wide association studies showed risk variants enriched in NPH cohorts in or near CFAP43, SFMBT1, CWH43, AK9, RXFP2, PRKD1, HAVCR1, OTOG, MYO7A, NOTCH1, SPG11, MYH13, FOXJ1, AMZ1/GNA12, and C16orf95, alongside protective variants near SLCO1A2 and MLLT10. These genes are associated with blood-brain and blood-cerebrospinal fluid barriers, cilia, and ependymal function. In addition, higher rates of pathological C9orf72 repeat expansions were observed in an NPH cohort compared with controls. NPH was also more prevalent in frontotemporal dementia cohorts without this expansion and co-occurred with myotonic dystrophy type 1 in several cases. Despite heterogeneity in outcome measures, this review highlights the genetic contribution to NPH risk. Future research should encourage collaborations for big data generation, identify genetic variants addressing diversity, and integrate clinical, environmental, and shunt-response data. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Show less

The study was conducted to understand better the mechanisms involved in liver changes when there is a combination of diet-induced obesity (DIO) and vitamin D deficiency (VDD). After 8 wk of feeding a control diet (C group) or a high-fat diet (HF), both with vitamin D, and counterpart groups without vitamin D (VitD- groups), we found in plasma: higher alanine aminotransferase, and aspartate aminotransferase in the VitD- groups, and more elevated total cholesterol in the HF group. Compared to their counterparts, HF and HF/VitD- showed hyperinsulinemia and higher hepatic triglycerides and steatosis. The protein expressions of markers linked with the vitamin D action were altered by VDD (vitamin D receptor VDR, 25-hydroxyvitamin D-24-hydroxylase CYP24A1, CYP27B1, and CYP2R1). The hepatic lipogenesis and fatty acid synthesis were enhanced by VDD (peroxisome proliferator-activated receptor PPARγ, sterol regulatory element-binding proteins SREBP1c, carbohydrate-responsive element-binding protein ChREBP, and fatty acid synthase FAS), but markers of beta-oxidation were reduced (PPARα and phosphoenolpyruvate carboxykinase PEPCK). In conclusion, the study provides convincing new evidence that there is an additive and adverse effect on the liver caused by the combination of VDD and DIO. The essence of these changes in the liver is in an increased lipogenesis and a reduced beta-oxidation, which predisposes to the accumulation of fat in the liver, accompanied by IR. The worsening of the pathogenesis of NAFLD may tilt to more severe stages of liver disease. Show less