Fondazione Santa Lucia

Abstract Background Spinal cord injury (SCI) triggers persistent neuroinflammation, gliosis, neuronal loss, and demyelination, leading to motor deficits and neuropathic pain. Botulinum neurotoxin type A (BoNT/A) has shown anti-inflammatory and neuroprotective effects in acute SCI, but its potential in the chronic phase remains unclear. This study investigates whether combining BoNT/A with electrical muscle stimulation (EMS) enhances recovery in chronic SCI. Methods Adult mice with severe thoracic SCI (paraplegic) underwent EMS (30 min/day for 10 non-consecutive days starting 3 days post-injury) or no stimulation. Fifteen days after SCI, animals received a single intrathecal injection of BoNT/A (15 pg/5 μL) or saline. Functional recovery was assessed up to 60 days as well as in moderate and mild SCI mice, neuropathic pain onset and maintenance were evaluated. Spinal cord tissue was analysed for astrocytic and microglial morphology, neuronal and oligodendroglia survival, myelin protein expression, and in vitro effects on oligodendrocyte precursor cells (OPCs). The phenotype of hindlimb muscles was evaluated through morphological and gene expression analyses. Results EMS was able to counteract muscle atrophy and fibrosis, and when combined with BoNT/A, also denervation. Moreover, the combination restored hindlimb motor function in chronic SCI, whereas BoNT/A or EMS alone were ineffective. Neuropathic pain, a common comorbidity associated with SCI, was mitigated by BoNT/A treatment even when administered in the chronic phase. BoNT/A reduced astrocytic hypertrophy and excitatory synapse association and was associated with a morphology-based redistribution of microglial profiles toward a resting-like classification, decreased apoptosis, and increased neuronal and oligodendroglia survival. Myelin basic protein expression was significantly elevated in vivo. In vitro, BoNT/A promoted OPC differentiation into myelinating oligodendrocytes, increased process complexity, and upregulated Myelin basic protein, galactocerebroside C, proteolipid protein, and myelin oligodendrocyte glycoprotein under both proliferative and differentiating conditions. Cleaved SNAP25 colocalization with OPC confirmed direct BoNT/A internalization and activity. Conclusions BoNT/A exerts multi-cellular neuroprotective actions in chronic SCI, supporting neuronal and oligodendroglia survival, reducing neuroinflammation, enhancing remyelination and the combination with EMS promotes substantial recovery of muscle homeostasis within a permissive microenvironment shaped by early stimulation. Its efficacy depends on a permissive microenvironment achieved through EMS. These results provide strong rationale for the clinical evaluation of BoNT/A as a therapeutic strategy for chronic SCI.

A descriptive quantitative study. To determine how much and what type of exercises and training were provided as part of usual physiotherapy and occupational therapy to participants of the SCI-MT Trial (the Early and Intensive Motor Training for People with Spinal Cord Injuries Trial). This information is important because the SCI-MT Trial concluded that additional motor training is redundant if people with SCI receive equivalent usual care as what was provided to participants of the SCI-MT Trial. Fifteen spinal injury units across Europe and Australia. Data were collected on the time participants of both groups of the SCI-MT Trial (n = 220) attended physiotherapy and occupational therapy provided as part of usual care over the 10-week intervention period. The International Spinal Cord Injury Physical Therapy and Occupational Therapy Basic Data Set was used to capture time spent on activity and impairment directed categories of exercises and training. Participants attended a median (interquartile range) of 8.3 (6.2 to 11.4) hours of physiotherapy and occupational therapy per week. Approximately 70% of therapy time was spent actively exercising or training with a median of 3.8 h per week spent on activity-directedand 1.9 h per week spent on impairment-directedexercises and training. The results of this study detail the amount and type of physiotherapy and occupational therapy that needs to be provided as part of usual rehabilitation care to render additional motor training redundant.

This exploratory study aimed to investigate grey matter (GM) volume changes in patients with hip osteoarthritis undergoing hip joint arthroplasty using voxel-based morphometry (VBM), assessing pre- and postoperative differences and comparing findings with healthy controls (HC). Twenty-one patients with unilateral hip osteoarthritis before and after hip prosthesis insertion (PT group) and 16 HC were studied. All participants were right-handed and free from neurological or psychiatric conditions. Structural T1-weighted MRI scans were acquired at 3T before and after surgery in the PT group, with an average interval of 112days, and in the HC group. VBM analyses were conducted using the Computational Anatomy Toolbox (CAT12). Preoperative GM volume differences between PT and HC groups, as well as changes in PT before and after surgery, were analysed using statistical parametric mapping with family-wise error (FWE) correction. Preoperative comparisons revealed a significant reduction in grey matter volume in the ipsilateral cerebellar Crus II in the PT group compared with HC (pFWE = 0.004). No significant GM volume differences were found between pre- and postoperative assessments in the PT group. Although all patients demonstrated marked clinical improvement at 1-month follow-up, MRI-clinical correlations could not be performed because clinical assessments and postoperative MRI were not acquired at the same time. The findings provide preliminary evidence of cerebellar GM changes in patients requiring hip prostheses, suggesting central nervous system involvement in chronic hip pathology. Interpretation is constrained by the modest sample size and by variability in postoperative imaging intervals. The absence of significant postoperative changes highlights the need for further research to explore the timeline and extent of neuroplastic recovery. These results underscore the importance of considering central adaptations in the management of peripheral joint disorders.

Background/Objectives: Dementia is a major global health challenge, with prevention strategies increasingly focusing on the preclinical stage of Subjective Cognitive Decline (SCD). This study aimed to evaluate the feasibility, usability, and acceptability of a 5-week immersive virtual reality and telemedicine-based multicomponent intervention, combining cognitive training with a health and lifestyle education program, in individuals with SCD. Methods: Thirty-nine individuals with SCD were randomly allocated to either the multi-component intervention (MC-I; n = 19) or the cognitive-only intervention (CO-I; n = 20). Both programs were delivered remotely via head-mounted displays and monitored through a telemedicine platform. Feasibility was assessed through retention, adherence, and safety measures. Post-intervention, participants completed the System Usability Scale (SUS), User Satisfaction Evaluation Questionnaire (USEQ), NASA Task Load Index (NASA-TLX), and Simulator Sickness Questionnaire (SSQ). Results: High feasibility was demonstrated by a 100% retention rate and 92% adherence. Both groups reported "excellent" usability (SUS mean: 84.04) and high satisfaction (USEQ mean: 26.7), with no significant differences between groups. The NASA-TLX reflected a moderate workload (mean: 56.1), characterized by high mental demand but low frustration. Safety was confirmed by remarkably low SSQ scores, indicating negligible cybersickness. Conclusions: The results provide strong preliminary evidence that a home-based, multi-component IVR intervention is safe, usable, and highly accepted by individuals with SCD. Integrating lifestyle education does not increase the perceived burden, supporting the scalability of this remote digital approach for dementia secondary prevention.

Since its 1987 approval, rifaximin has emerged as a gut-targeted, minimally absorbed antibiotic achieving high intestinal levels. Rifaximin works by blocking bacterial RNA polymerase to stop bacterial growth, which helps treat both traveler’s diarrhea and irritable bowel syndrome with diarrhea. It effectively modulates gut microbiota and alleviates dysbiosis-related symptoms. Beyond antimicrobial activity, rifaximin modulates dysbiosis, strengthens the epithelial barrier, and exerts pregnane X receptor (PXR)-mediated anti-inflammatory and anti-angiogenic effects, with implications along the gut–liver and gut–brain axes. These pleiotropic properties support expanding uses in small intestinal bacterial overgrowth (SIBO), inflammatory bowel diseases (IBD), functional dyspepsia, bloating, and lactose intolerance. However, high cost and potential resistance with prolonged exposure highlight the need for antimicrobial stewardship. The aims of this review are to summarize licensed and emerging indications and delineate non-conventional mechanisms. Patient stratification and further controlled clinical studies are required to optimize rifaximin’s precision-medicine potential.

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen for which new antimicrobial strategies are urgently needed. To facilitate the establishment of the infection, P. aeruginosa produces a remarkable assortment of both cell-associated and extracellular virulence factors. The expression of numerous virulence traits is regulated by the pqs quorum sensing (QS) system, which relies on multiple enzymes for the biosynthesis of 2-alkyl-4-quinolone (AQ) signal molecules and on the transcriptional regulator PqsR, whose activity is triggered by AQ binding. Herein, we report on the design and synthesis of novel quinazolinone-based PqsR modulators, which led to the identification of two novel compounds endowed with anti-PqsR activity in the submicromolar range. Additionally, these derivatives inhibited the production of PqsR-controlled virulence factors in laboratory strains and clinical isolates of P. aeruginosa.

Reproductive aging is a widespread process in wild populations, affecting both females and males across many species. It also plays a key role in shaping parental effects as older parents are expected to be unable to invest optimally in reproduction late in life, or such investments may be compromised by the detrimental consequences of aging. In most species, reproductive performance increases over the first breeding attempts, reaches a plateau, and then declines at older ages. Many long-lived species, however, deviate from this pattern, with older individuals maintaining high breeding performance or even improving it, often resulting in offspring of higher quality. Studies examining sex-specific patterns of reproductive aging in long-lived species from natural populations and their consequences for offspring fitness remain scarce compared to the extensive human literature. We used a long-term longitudinal dataset of reproductive data collected from a population of a long-lived seabird, the Scopoli's shearwater, to analyze (i) how a set of parental traits (i.e., reproductive success, body mass and egg size) change with maternal and paternal age, and (ii) potential age-dependent parental effects on the body mass and skeletal traits of the offspring. We found that age strongly affected reproductive success. Early-life improvement was steeper in females than in males, whereas both sexes showed the typical late-life decline expected with advancing age. Adult body mass followed a similar, though partially reversed, pattern: males gained mass more rapidly than females early in life before reaching a plateau. Age also affected female egg volume and width, with older and heavier females laying larger and wider eggs. Parental effects on offspring body mass were mainly driven by pair experience, whereas skeletal traits depended only on chick age and sex. Our study shows that reproductive aging varies across traits in long-lived species, providing support for the asynchronous theory of aging, and reveals unexpected sex-specific patterns of age-related reproductive changes in monogamous species. Moreover, it suggests that advanced parental age is not necessarily associated with negative effects on offspring fitness.

The bidirectional relationship between epilepsy and sleep is well established. People with epilepsy frequently experience sleep and wake disturbances, which may be more frequent in older adults. With 15%-20% of epilepsy cases presenting as late-onset epilepsy of unknown etiology (LOEU), this study aimed to assess subjective sleep quality and daytime sleepiness in LOEU patients compared to older adults without neurological and psychiatric diseases. This observational study included 78 LOEU patients (55.1% males, mean age 68.29 ± 8.01 y.o.) diagnosed at Epilepsy Centers in Rome Tor Vergata, Perugia, and Chieti, and 55 older controls (38.2% males, mean age 69.76 ± 14.99 y.o.). Patients and controls completed the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI), and a subgroup of patients also answered the Quality of Life in Epilepsy Inventory (QOLIE-31) and the Beck Depression Inventory-II (BDI-II). Following the adjustment for age and epilepsy centers, LOEU patients showed significantly poorer global sleep quality (p = .046) and lower sleep quality and efficiency (p < .001) compared to controls. ESS scores were similar between groups. Patients with generalized seizures reported lower sleep quality than patients with other types of seizures. BDI-II scores correlated positively with poor sleep quality and negatively with quality of life. LOEU patients reported lower subjective sleep quality than older controls. Sleep disturbances correlated with depressive symptoms, which in turn were associated with a more impaired quality of life. These findings highlight the importance of addressing sleep issues in this population to prevent seizure recurrence and to improve well-being and quality of life.