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BackgroundThe pharmacoinvasive (PhI) strategy is the standard-of-care for ST-elevation myocardial infarction (STEMI) patients when primary percutaneous coronary intervention (pPCI) is unfeasible. Optimal timing for post-fibrinolytic PCI (lysis-PCI) remains elusive. Therefore, this study aimed to assess the clinical and economic impacts of early vs. delayed lysis-PCI in patients with STEMI.MethodsThis retrospective cohort study included 1,043 STEMI patients classified by lysis-PCI timing. The primary outcome was in-hospital major adverse cardiovascular events (4p-MACE), with secondary outcomes such as 3p-MACE, in-hospital mortality, and costs. Multivariable logistic regression models were used to assess the association between lysis-PCI timing and outcomes. Cost analyses were conducted from the perspective of Brazilian public healthcare system, with values converted to international dollars (Int$) for broader applicability.ResultsEvery 4-h delay in lysis-PCI was associated with a 44% reduction in in-hospital mortality [OR = 0.560 (95% CI: 0.381–0.775); p = 0.001] and a 13% decrease in 4p-MACE [OR = 0.877 (95% CI: 0.811–0.948); p = 0.001]. Additionally, 4-h delay in lysis-PCI was also associated with a significant reduction in in-hospital costs (Int$916.20 ± 99) and disease-induced years of productivity lost (β = −41.79 ± 151 years; p = 0.001). These significant trends remained consistent even after adjusting for confounders and applying propensity score matching. Older adults (aged ≥80) experienced an increase in 3p-MACE with earlier lysis-PCI.ConclusionDelaying lysis-PCI was found to be associated with reduced in-hospital cardiovascular adverse events and lower costs, particularly among older adults. Further research should develop evidence-based lysis-PCI protocols that optimize both clinical outcomes and cost-effectiveness.

The intensification of production processes, resulting from the rise in pork production, contributes to environmental changes and increased interaction between humans, animals, and wildlife. This favorable scenario promotes the spread of potent viral species, such as PCV3, increasing the potential for the emergence of new pathogenic agents and variants. These changes in the epidemiology and manifestation of PCV3 highlight the need for enhanced understanding and control. The current literature presents challenges in the classification of PCV3, with different groups proposing diverse criteria. Establishing common terminology is crucial to facilitate comparisons between studies. While consensus among experts is valuable, new approaches must be transparent and comparable to existing literature, ensuring reproducible results and proper interpretation, and positively impacting public health. This study aims to review the literature on PCV3 infection, exploring its key aspects and highlighting unanswered questions.

Sodium glucose cotransporter 2 inhibitors (SGLT2) have been increasingly pursued as a promising target for addressing residual cardiovascular risk. Prior trials demonstrated that SGLT2i not only promotes glucose-lowering, but also improves endothelial dysfunction, adiposity, fluid overload, and insulin sensitivity thus contributing to hemodynamic changes implicated in its cardiorenal benefits. The mechanisms in the effect of SGLT2i on blood pressure and their potential role in preventing cardiovascular events are hereby revised.

BackgroundAccurate measurement of ventricular volumes is an important clinical imaging goal. Three-dimensional echocardiography (3DEcho) is used increasingly as it is more available and less costly than cardiac magnetic resonance (CMR). For the right ventricle (RV), the current practice is to acquire 3DEcho volumes from the apical view. However, in some patients the RV may be better seen from the subcostal view. Therefore, this study compared RV volume measurements from the apical vs. the subcostal view, using CMR as a reference standard.MethodsPatients

Effective secondary response to antigen is a hallmark of immunological memory. However, the extent of memory CD8 T cell response to secondary boost varies at different times after a primary response. Considering the central role of memory CD8 T cells in long-lived protection against viral infections and tumors, a better understanding of the molecular mechanisms underlying the changing responsiveness of these cells to antigenic challenge would be beneficial. We examined here primed CD8 T cell response to boost in a BALB/c mouse model of intramuscular vaccination by priming with HIV-1 gag-encoding Chimpanzee adenovector, and boosting with HIV-1 gag-encoding Modified Vaccinia virus Ankara. We found that boost was more effective at day(d)100 than at d30 post-prime, as evaluated at d45 post-boost by multi-lymphoid organ assessment of gag-specific CD8 T cell frequency, CD62L-expression (as a guide to memory status) and in vivo killing. RNA-sequencing of splenic gag-primed CD8 T cells at d100 revealed a quiescent, but highly responsive signature, that trended toward a central memory (CD62L+) phenotype. Interestingly, gag-specific CD8 T cell frequency selectively diminished in the blood at d100, relative to the spleen, lymph nodes and bone marrow. These results open the possibility to modify prime/boost intervals to achieve an improved memory CD8 T cell secondary response.

Background: Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing this risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy since they are as effective and overall safer than warfarin in preventing AF-related stroke. Although patients bleed less from DOACs compared to warfarin, bleeding remains the primary safety concern with this therapy.Hypothesis: Genetic variants known to modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs could increase the risk of bleeding.Aim: To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes (ABCB1, ABCG2, CYP2J2, CYP3A4, CYP3A5) with the risk of bleeding from DOACs in non-valvular AF patients.Methods: A retrospective cohort study was carried out with 2,364 self-identified white non-valvular AF patients treated with either rivaroxaban or apixaban. Genotyping was performed with Illumina Infinium CoreExome v12.1 bead arrays by the Michigan Genomics Initiative biobank. The primary endpoint was a composite of major and clinically relevant non-major bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of the eight PK-related SNVs with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. The pre-specified primary analysis was the covariate-adjusted, additive genetic models. Six tests were performed in the primary analysis as three SNVs are in the same haplotype, and thus p-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant.Results: In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all p > 0.1). In exploratory analyses with other genetic models, the ABCB1 (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban [HR: 1.391 (95%CI: 1.019–1.900); p = 0.038] but not from apixaban (p = 0.487).Conclusion: Eight functional PK-related genetic variants were not significantly associated with bleeding from either rivaroxaban or apixaban in more than 2,000 AF self-identified white outpatients.

Mycophenolate rapidly substituted azathioprine (AZA) in transplant immunosuppression regimens since the 1990s, when early clinical trials indicated better outcomes, although opposite results were also observed. However, none of these trials used the well-established optimization methods for AZA dosing, namely, thiopurine methyltransferase pharmacogenetics combined with monitoring of the thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). Resistance to optimize AZA therapy remains today in transplant therapy, despite the fact that thiopurine metabolite testing is being used by other medical disciplines with evident improvement in clinical results. In a previous analysis, we found that active 6-TGN metabolites were not detectable in about 30% of kidney transplant patients under continuous use of apparently adequate azathioprine dosage, which demonstrates the need to monitor these metabolites for therapeutic optimization. Two of four case studies presented here exemplifies this fact. On the other hand, some patients have toxic 6-TGN levels with a theoretically appropriate dose, as seen in the other two case studies in this presentation, constituting one more important reason to monitor the AZA dose administered by its metabolites. This analysis is not intended to prove the superiority of one immunosuppressant over another, but to draw attention to a fact: there are thousands of patients around the world receiving an inadequate dose of azathioprine and, therefore, with inappropriate immunosuppression. This report is also intended to draw attention, to clinicians using thiopurines, that allopurinol co-therapy with AZA is a useful therapeutic pathway for those patients who do not adequately form active thioguanine metabolites.

Cryptococcosis is an invasive mycosis caused by Cryptococcus spp. that affects the lungs and the central nervous system (CNS). Due to the severity of the disease, it may occur concomitantly with other pathogens, as a coinfection. Pseudomonas aeruginosa (Pa), an opportunistic pathogen, can also cause pneumonia. In this work, we studied the interaction of C. gattii (Cg) and Pa, both in vitro and in vivo. Pa reduced growth of Cg by the secretion of inhibitory molecules in vitro. Macrophages previously stimulated with Pa presented increased fungicidal activity. In vivo, previous Pa infection reduced morbidity and delayed the lethality due to cryptococcosis. This phenotype was correlated with the decreased fungal burden in the lungs and brain, showing a delay of Cg translocation to the CNS. Also, there was increased production of IL-1β, CXCL-1, and IL-10, together with the influx of iNOS-positive macrophages and neutrophils to the lungs. Altogether, Pa turned the lung into a hostile environment to the growth of a secondary pathogen, making it difficult for the fungus to translocate to the CNS. Further, iNOS inhibition reverted the Pa protective phenotype, suggesting its important role in the coinfection. Altogether, the primary Pa infection leads to balanced pro-inflammatory and anti-inflammatory responses during Cg infection. This response provided better control of cryptococcosis and was decisive for the mild evolution of the disease and prolonged survival of coinfected mice in a mechanism dependent on iNOS.

Lipopolysaccharide (LPS) is a peculiar component of the outer membrane (OM) of many Gram-negative bacteria that renders these bacteria highly impermeable to many toxic molecules, including antibiotics. LPS is assembled at the OM by a dedicated intermembrane transport system, the Lpt (LPS transport) machinery, composed of seven essential proteins located in the inner membrane (IM) (LptB2CFG), periplasm (LptA), and OM (LptDE). Defects in LPS transport compromise LPS insertion and assembly at the OM and result in an overall modification of the cell envelope and its permeability barrier properties. LptA is a key component of the Lpt machine. It connects the IM and OM sub-complexes by interacting with the IM protein LptC and the OM protein LptD, thus enabling the LPS transport across the periplasm. Defects in Lpt system assembly result in LptA degradation whose stability can be considered a marker of an improperly assembled Lpt system. Indeed, LptA recruitment by its IM and OM docking sites requires correct maturation of the LptB2CFG and LptDE sub-complexes, respectively. These quality control checkpoints are crucial to avoid LPS mistargeting. To further dissect the requirements for the complete Lpt transenvelope bridge assembly, we explored the importance of LPS presence by blocking its synthesis using an inhibitor compound. Here, we found that the interruption of LPS synthesis results in the degradation of both LptA and LptD, suggesting that, in the absence of the LPS substrate, the stability of the Lpt complex is compromised. Under these conditions, DegP, a major chaperone–protease in Escherichia coli, is responsible for LptD but not LptA degradation. Importantly, LptD and LptA stability is not affected by stressors disturbing the integrity of LPS or peptidoglycan layers, further supporting the notion that the LPS substrate is fundamental to keeping the Lpt transenvelope complex assembled and that LptA and LptD play a major role in the stability of the Lpt system.

Neutrophils play an important role in the outcome of leishmaniasis, contributing either to exacerbating or controlling the progression of infection, a dual effect whose underlying mechanisms are not clear. We recently reported that CD4+ and CD8+ T cells, and dendritic cells of Leishmania amazonensis-infected mice present high expression of PD-1 and PD-L1, respectively. Given that the PD-1/PD-L1 interaction may promote cellular dysfunction, and that neutrophils could interact with T cells during infection, we investigated here the levels of PD-L1 in neutrophils exposed to Leishmania parasites. We found that both, promastigotes and amastigotes of L. amazonensis induced the expression of PD-L1 in the human and murine neutrophils that internalized these parasites in vitro. PD-L1-expressing neutrophils were also observed in the ear lesions and the draining lymph nodes of L. amazonensis-infected mice, assessed through cell cytometry and intravital microscopy. Moreover, expression of PD-L1 progressively increased in neutrophils from ear lesions as the disease evolved to the chronic phase. Co-culture of infected neutrophils with in vitro activated CD8+ T cells inhibits IFN-γ production by a mechanism dependent on PD-1 and PD-L1. Importantly, we demonstrated that in vitro infection of human neutrophils by L braziliensis induced PD-L1+ expression and also PD-L1+ neutrophils were detected in the lesions of patients with cutaneous leishmaniasis. Taken together, these findings suggest that the Leishmania parasite increases the expression of PD-L1 in neutrophils with suppressor capacity, which could favor the parasite survival through impairing the immune response.

Bacterial species able to produce proteins that are toxic against insects have been discovered at the beginning of the last century. However, up to date only two of them have been used as pesticides in mosquito control strategies targeting larval breeding sites: Bacillus thuringensis var. israelensis and Lysinibacillus sphaericus. Aiming to expand the arsenal of biopesticides, bacterial cultures from 44 soil samples were assayed for their ability to kill larvae of Aedes albopictus. A method to select, grow and test the larvicidal capability of spore-forming bacteria from each soil sample was developed. This allowed identifying 13 soil samples containing strains capable of killing Ae. albopictus larvae. Among the active isolates, one strain with high toxicity was identified as Brevibacillus laterosporus by 16S rRNA gene sequencing and by morphological characterization using transmission electron microscopy. The new isolate showed a larvicidal activity significantly higher than the B. laterosporus LMG 15441 reference strain. Its genome was phylogenomically characterized and compared to the available Brevibacillus genomes. Thus, the new isolate can be considered as a candidate adjuvant to biopesticides formulations that would help preventing the insurgence of resistance.

Arginase catalyzes the hydrolysis of l-arginine into l-ornithine and urea, acting as a key enzyme in the biosynthesis of polyamines. Leishmania growth and survival is dependent on polyamine biosynthesis; therefore, inhibition of Leishmania arginase may be a promising therapeutic strategy. Here, we evaluated a series of thirty-six chalcone derivatives as potential inhibitors of Leishmania infantum arginase (LiARG). In addition, the activity of selected inhibitors against L. infantum parasites was assessed in vitro. Seven compounds exhibited LiARG inhibition above 50% at 100 μM. Among them, compounds LC41, LC39, and LC32 displayed the greatest inhibition values (72.3 ± 0.3%, 71.9 ± 11.6%, and 69.5 ± 7.9%, respectively). Molecular docking studies predicted hydrogen bonds and hydrophobic interactions between the most active chalcones (LC32, LC39, and LC41) and specific residues from LiARG's active site, such as His140, Asn153, His155, and Ala193. Compound LC32 showed the highest activity against L. infantum promastigotes (IC50 of 74.1 ± 10.0 μM), whereas compounds LC39 and LC41 displayed the best results against intracellular amastigotes (IC50 of 55.2 ± 3.8 and 70.4 ± 9.6 μM, respectively). Moreover, compound LC39 showed more selectivity against parasites than host cells (macrophages), with a selectivity index (SI) of 107.1, even greater than that of the reference drug Fungizone®. Computational pharmacokinetic and toxicological evaluations showed high oral bioavailability and low toxicity for the most active compounds. The results presented here support the use of substituted chalcone skeletons as promising LiARG inhibitors and antileishmanial drug candidates.

The outer membrane (OM) of Gram-negative bacteria is a highly selective permeability barrier due to its asymmetric structure with lipopolysaccharide (LPS) in the outer leaflet. In Escherichia coli, LPS is transported to the cell surface by the LPS transport (Lpt) system composed of seven essential proteins forming a transenvelope bridge. Transport is powered by the ABC transporter LptB2FGC, which extracts LPS from the inner membrane (IM) and transfers it, through LptC protein, to the periplasmic protein LptA. Then, LptA delivers LPS to the OM LptDE translocon for final assembly at the cell surface. The Lpt protein machinery operates as a single device, since depletion of any component leads to the accumulation of a modified LPS decorated with repeating units of colanic acid at the IM outer leaflet. Moreover, correct machine assembly is essential for LPS transit and disruption of the Lpt complex results in LptA degradation. Due to its vital role in cell physiology, the Lpt system represents a good target for antimicrobial drugs. Thanatin is a naturally occurring antimicrobial peptide reported to cause defects in membrane assembly and demonstrated in vitro to bind to the N-terminal β-strand of LptA. Since this region is involved in both LptA dimerization and interaction with LptC, we wanted to elucidate the mechanism of inhibition of thanatin and discriminate whether its antibacterial effect is exerted by the disruption of the interaction of LptA with itself or with LptC. For this purpose, we here implemented the Bacterial Adenylate Cyclase Two-Hybrid (BACTH) system to probe in vivo the Lpt interactome in the periplasm. With this system, we found that thanatin targets both LptC–LptA and LptA–LptA interactions, with a greater inhibitory effect on the former. We confirmed in vitro the disruption of LptC–LptA interaction using two different biophysical techniques. Finally, we observed that in cells treated with thanatin, LptA undergoes degradation and LPS decorated with colanic acid accumulates. These data further support inhibition or disruption of Lpt complex assembly as the main killing mechanism of thanatin against Gram-negative bacteria.

Twenty-nine pediatric patients (age range, 10–16 years) with working memory (WM) deficits, including children with pediatric bipolar disorder (PBD) with and without attention-deficit hyperactivity disorder (ADHD) comorbidity and children with ADHD, underwent a Cogmed WM training program. For both patient groups, WM performance on Cogmed tasks and on the Digit Span test improved significantly after training. Moreover, the PBD group improved on Trails Making Test A and on the Inhibition Scale, the Behavior Regulation Index, and the Global Executive Composite of the Behavioral Rating Inventory of Executive Function. The ADHD group improved significantly on the Trails Making Test B, the Spatial Span Test, and the Reading Fluency Test of the Woodcock–Johnson III, as well as on depressive symptoms. The present findings suggest that working memory training is beneficial not only in youths with ADHD but also in youths with PBD. They also show evidence of near and far transfer of WM improvement in these patients, although in different ways for the two patient groups. Future studies examining the mechanisms of cognitive remediation in pediatric patients will aid in creating tailored illness-specific cognitive interventions.

The genome is reprogrammed during development to produce diverse cell types, largely through altered expression and activity of key transcription factors. The accessibility and critical functions of epidermal cells have made them a model for connecting transcriptional events to development in a range of model systems. In Arabidopsis thaliana and many other plants, fertilization triggers differentiation of specialized epidermal seed coat cells that have a unique morphology caused by large extracellular deposits of polysaccharides. Here, we used DNase I-seq to generate regulatory landscapes of A. thaliana seeds at two critical time points in seed coat maturation (4 and 7 DPA), enriching for seed coat cells with the INTACT method. We found over 3,000 developmentally dynamic regulatory DNA elements and explored their relationship with nearby gene expression. The dynamic regulatory elements were enriched for motifs for several transcription factors families; most notably the TCP family at the earlier time point and the MYB family at the later one. To assess the extent to which the observed regulatory sites in seeds added to previously known regulatory sites in A. thaliana, we compared our data to 11 other data sets generated with 7-day-old seedlings for diverse tissues and conditions. Surprisingly, over a quarter of the regulatory, i.e. accessible, bases observed in seeds were novel. Notably, plant regulatory landscapes from different tissues, cell types, or developmental stages were more dynamic than those generated from bulk tissue in response to environmental perturbations, highlighting the importance of extending studies of regulatory DNA to single tissues and cell types during development.

Lynch syndrome (LS) is a dominantly inherited condition with incomplete penetrance, characterized by high predisposition to colorectal cancer (CRC), endometrial and ovarian cancers, as well as to other tumors. LS is associated with constitutive DNA mismatch repair (MMR) gene defects, and carriers of the same pathogenic variants can show great phenotypic heterogeneity in terms of cancer spectrum. In the last years, human gut microbiota got a foothold among risk factors responsible for the onset and evolution of sporadic CRC, but its possible involvement in the modulation of LS patients’ phenotype still needs to be investigated. In this pilot study, we performed 16S rRNA gene sequencing of bacterial DNA extracted from fecal samples of 10 postoperative LS female patients who had developed colonic lesions (L-CRC) or gynecological cancers (L-GC). Our preliminary data show no differences between microbial communities of L-CRC and L-GC patients, but they plant the seed of the possible existence of a fecal microbiota pattern associated with LS genetic background, with Faecalibacterium prausnitzii, Parabacteroides distasonis, Ruminococcus bromii, Bacteroides plebeius, Bacteroides fragilis and Bacteroides uniformis species being the most significantly over-represented in LS patients (comprising both L-CRC and L-GC groups) compared to healthy subjects.

In vitro studies of liver stage (LS) development of the human malaria parasite Plasmodium falciparum are technically challenging; therefore, fundamental questions about hepatocyte receptors for invasion that can be targeted to prevent infection remain unanswered. To identify novel receptors and to further understand human hepatocyte susceptibility to P. falciparum sporozoite invasion, we created an optimized in vitro system by mimicking in vivo liver conditions and using the subcloned HC-04.J7 cell line that supports mean infection rates of 3–5% and early development of P. falciparum exoerythrocytic forms—a 3- to 5-fold improvement on current in vitro hepatocarcinoma models for P. falciparum invasion. We juxtaposed this invasion-susceptible cell line with an invasion-resistant cell line (HepG2) and performed comparative proteomics and RNA-seq analyses to identify host cell surface molecules and pathways important for sporozoite invasion of host cells. We identified and investigated a hepatocyte cell surface heparan sulfate proteoglycan, glypican-3, as a putative mediator of sporozoite invasion. We also noted the involvement of pathways that implicate the importance of the metabolic state of the hepatocyte in supporting LS development. Our study highlights important features of hepatocyte biology, and specifically the potential role of glypican-3, in mediating P. falciparum sporozoite invasion. Additionally, it establishes a simple in vitro system to study the LS with improved invasion efficiency. This work paves the way for the greater malaria and liver biology communities to explore fundamental questions of hepatocyte-pathogen interactions and extend the system to other human malaria parasite species, like P. vivax.

Autism spectrum disorders (ASD) represent a complex group of neurodevelopmental conditions characterized by deficits in communication and social behaviors. We examined the functional connectivity (FC) of the default mode network (DMN) and its relation to multimodal morphometry to investigate superregional, system-level alterations in a group of 22 adolescents and young adults with high-functioning autism compared to age-, and intelligence quotient-matched 29 healthy controls. The main findings were that ASD patients had gray matter (GM) reduction, decreased cortical thickness and larger cortical surface areas in several brain regions, including the cingulate, temporal lobes, and amygdala, as well as increased gyrification in regions associated with encoding visual memories and areas of the sensorimotor component of the DMN, more pronounced in the left hemisphere. Moreover, patients with ASD had decreased connectivity between the posterior cingulate cortex, and areas of the executive control component of the DMN and increased FC between the anteromedial prefrontal cortex and areas of the sensorimotor component of the DMN. Reduced cortical thickness in the right inferior frontal lobe correlated with higher social impairment according to the scores of the Autism Diagnostic Interview-Revised (ADI-R). Reduced cortical thickness in left frontal regions, as well as an increased cortical thickness in the right temporal pole and posterior cingulate, were associated with worse scores on the communication domain of the ADI-R. We found no association between scores on the restrictive and repetitive behaviors domain of ADI-R with structural measures or FC. The combination of these structural and connectivity abnormalities may help to explain some of the core behaviors in high-functioning ASD and need to be investigated further.

The cause of Alzheimer’s disease (AD) remains uncertain. The accumulation of amyloid peptides (Aβ) is the main pathophysiological hallmark of the disease. Spatial deficit is an important initial sign of AD, while other types of memory impairments that appear in later stages. The Barnes maze allows the detection of subtle alterations in spatial search by the analysis of use of different strategies. Previous findings showed a general performance deficit in this task following long-term (35 days) infusion of Aβ, which corresponds to the moderate or severe impairments of the disease. In the present study, we evaluated the effects of a low-dose 15-day long treatment with Aβ peptides on spatial and non-spatial strategies of rats tested in the Barnes maze. Aβ peptides (0.5 μL/site/day; 30 pmoL solution of Aβ1–40:Aβ1–42 10:1) or saline were bilaterally infused into the CA1 (on the first treatment day) and intraventricularly (on the following 15 days) in 6-month-old Wistar male rats. Aβ infusion induced a deficit in the performance (increased latency and distance traveled to reach the target compared to saline group). In addition, a significant association between treatment and search strategy in the retrieval trial was found: Aβ group preferred the non-spatial search strategy, while saline group preferred the spatial search. In conclusion, the protocol of Aβ infusion used here induced a subtle cognitive deficit that was specific to spatial aspects. Indeed, animals under Aβ treatment still showed retrieval, but using non-spatial strategies. We suggest that this approach is potentially useful to the study of the initial memory deficits in early AD.

Genetic susceptibility contributes to the etiology of sporadic Parkinson’s Disease (PD) and worldwide studies have found positive associations of polymorphisms in the alpha-synuclein gene (SNCA) with the risk for PD. However, little is known about the influence of variants of SNCA in individual traits or phenotypical aspects of PD. Further, there is a lack of studies with Latin-American samples. We evaluated the association between SNCA single nucleotide polymorphisms (single nucleotide polymorphisms, SNPs – rs2583988, rs356219, rs2736990, and rs11931074) and PD risk in a Brazilians sample. In addition, we investigated their potential interactions with environmental factors and specific clinical outcomes (motor and cognitive impairments, depression, and anxiety). A total of 105 PD patients and 101 controls participated in the study. Single locus analysis showed that the risk allele of all SNPs were more frequent in PD patients (p < 0.05), and the associations of SNPs rs2583988, rs356219, and rs2736990 with increased PD risk were confirmed. Further, the G-rs356219 and C-rs2736990 alleles were associated with early onset PD. T-rs2583988, G-rs356219 and C-2736990 alleles were significantly more frequent in PD patients with cognitive impairments than controls in this condition. In addition, in a logistic regression model, we found an association of cognitive impairment with PD, and the practice of cognitive activity and smoking habits had a protective effect. This study shows for the first time an association of SNCA polymorphism and PD in a South-American sample. In addition, we found an interaction between SNP rs356219 and a specific clinical outcome, i.e., the increased risk for cognitive impairment in PD patients.

The intensification of production processes, resulting from the rise in pork production, contributes to environmental changes and increased interaction between humans, animals, and wildlife. This favorable scenario promotes the spread of potent viral species, such as PCV3, increasing the potential for the emergence of new pathogenic agents and variants. These changes in the epidemiology and manifestation of PCV3 highlight the need for enhanced understanding and control. The current literature presents challenges in the classification of PCV3, with different groups proposing diverse criteria. Establishing common terminology is crucial to facilitate comparisons between studies. While consensus among experts is valuable, new approaches must be transparent and comparable to existing literature, ensuring reproducible results and proper interpretation, and positively impacting public health. This study aims to review the literature on PCV3 infection, exploring its key aspects and highlighting unanswered questions. [ABSTRACT FROM AUTHOR]

The intensification of production processes, resulting from the rise in pork production, contributes to environmental changes and increased interaction between humans, animals, and wildlife. This favorable scenario promotes the spread of potent viral species, such as PCV3, increasing the potential for the emergence of new pathogenic agents and variants. These changes in the epidemiology and manifestation of PCV3 highlight the need for enhanced understanding and control. The current literature presents challenges in the classification of PCV3, with different groups proposing diverse criteria. Establishing common terminology is crucial to facilitate comparisons between studies. While consensus among experts is valuable, new approaches must be transparent and comparable to existing literature, ensuring reproducible results and proper interpretation, and positively impacting public health. This study aims to review the literature on PCV3 infection, exploring its key aspects and highlighting unanswered questions. [ABSTRACT FROM AUTHOR]

Autism Spectrum Disorder (ASD) affects millions of individuals worldwide, presenting challenges in social communication, repetitive behaviors, and sensory processing. Despite its prevalence, diagnosis can be lengthy, and access to appropriate treatment varies greatly. This project utilizes the power of Artificial Intelligence (AI), particularly Machine Learning (ML) and Deep Learning (DL), to improve Autism Spectrum Disorder diagnosis and treatment. A central data hub, the Master Data Plan (MDP), will aggregate and analyze information from diverse sources, feeding AI algorithms that can identify risk factors for ASD, personalize treatment plans based on individual needs, and even predict potential relapses. Furthermore, the project incorporates a patient-facing chatbot to provide information and support. By integrating patient data, empowering individuals with ASD, and supporting healthcare professionals, this platform aims to transform care accessibility, personalize treatment approaches, and optimize the entire care journey. Rigorous data governance measures will ensure ethical and secure data management. This project will improve access to care, personalize treatments for better outcomes, shorten wait times, boost patient involvement, and raise ASD awareness, leading to better resource allocation. This project marks a transformative shift toward data-driven, patient-centred ASD care in Italy. This platform enhances treatment outcomes for individuals with ASD and provides a scalable model for integrating AI into mental health, establishing a new benchmark for personalized patient care. Through AI integration and collaborative efforts, it aims to redefine mental healthcare standards, enhancing the well-being for individuals with ASD.

Minimally invasive medical treatments for peripheral nerve stimulation are critically needed to minimize surgical risks, enhance the precision of therapeutic interventions, and reduce patient recovery time. Magnetoelectric nanoparticles (MENPs), known for their unique ability to respond to both magnetic and electric fields, offer promising potential for precision medicine due to their dual tunable functionality. In this study a multi-physics modeling of the MENPs was performed, assessing their capability to be targeted through external magnetic fields and become electrically activated. In particular, by integrating electromagnetic, fluid dynamics, and biological models, the efficacy of MENPs as wireless nano-tools to trigger electrical stimulation in the peripheral Nervous system present within the dermal microenvironment was assessed. The simulations replicate the blood venous capillary network, accounting for the complex interactions between MENPs, blood flow, and vessel walls. Results demonstrate the precise steering of MENPs (>95%) toward target sites under a low-intensity external magnetic field (78 mT) even with a low susceptibility value (0.45). Furthermore, the extravasation and electrical activation of MENPs within the dermal tissue are analyzed, revealing the generation of high-induced electric fields in the surrounding area when MENPs are subjected to external magnetic fields. Overall, these findings predict that MENPs can be targeted in a tissue site when intravenously administrated, dragged through the microvessels of the venous system, and activated by generating high electric fields for the stimulation of the peripheral nervous system.

Alternating hemiplegia of childhood (AHC) is a rare neurological disorder that usually manifests before 18 months of age and is characterized by recurrent, alternating episodes of hemiparesis with variable frequency and can last from a few minutes to several days. We present a case of AHC in a little girl carrying a sporadic mutation in the ATP1A3 gene (p.Glu815Lys) refractory to flunarizine and non-compliant to topiramate due to adverse effects treated with oral compound of adenosine-5′-triphosphate (ATP) capsules. Outcome was evaluated through the follow-up and side effects and safety were monitored regularly. Compounded drug showed effectiveness and safety. Indeed, during the four-year follow-up, with the dose of adenosine-5′-triphosphate gradually increasing up to 21 mg/kg, the patient showed a substantial benefit in controlling the frequency and duration of hemiplegic episodes and an improvement in neurological deterioration.

Religious beliefs can shape how people process fear. Yet the psychophysiological mechanisms underlying this phenomenon remain poorly understood. We investigated fear learning and extinction processes in a group of individuals who professed a belief in God, compared to non-believers. Using a virtual reality Pavlovian fear conditioning/extinction task, we measured neurovegetative activity associated with these forms of associative learning. Our finding shows reduced fear extinction among God believers, compared to non-believers. This suggests that the general mechanism of fear extinction learning is suppressed in these individuals. Importantly, this effect was not explained by state or trait anxiety scores. These findings align with previous evidence linking religiosity and spirituality with the neural circuit of fear and suggest that religiosity may be associated with weaker inhibitory learning processes related to fear.

Mycobacterium bovis (M. bovis) is the primary agent of bovine tuberculosis (TB) in Mediterranean buffalo, which has a negative economic impact on buffalo herds. Improving TB diagnostic performance in this species represents a key step to eradicate efficiently this disease. We have recently shown the utility of the IFN-γ assay in the diagnosis of M. bovis infection in Mediterranean buffaloes (Bubalus bubalis), but other cytokines might be useful immunological biomarkers of this infection. We therefore investigated the utility of key immune cytokines as diagnostic biomarkers of M. bovis infection in this species. Thirty-six Italian Mediterranean buffaloes were used in this study: healthy animals (N = 11), infected (IFN-γ test positive, no post-mortem lesions, no M. bovis detection; N = 14), and affected (IFN-γ test positive, visible post-mortem lesions; N = 11). Heparin blood samples were stimulated with bovine purified protein derivative (PPD-B), alongside controls, and 18–24 h later plasma were collected. Levels of 14 key cytokines were measured: IFN-γ, IL-17, IL-4, IL-10, TNF, IL-1α, IL-1β, IL-6, IP-10, MIP-1α, MIP-1β, MCP-1, IL-36Ra, and VEGF-A. We observed that both infected and affected animals released higher levels of IFN-γ, IL-17, IL-10, TNF, IL-1α, IL-6, MIP-1β, in response to PPD-B compared to healthy subjects. Mycobacterium bovis infected animals released also higher levels of IL-1β and IP-10 in response to PPD-B compared to healthy subjects, whereas only tendencies were detected in affected animals. Affected animals only released MIP-1α in response to PPD-B compared to healthy subjects and in this group higher values of PPD-B specific TNF was also observed. Finally, canonical discriminant analysis (CDA) was used to generate predictive cytokine profiles by groups. Our data suggest that IL-10, TNF, IL-1α, IL-6, MIP-1β could be useful biomarkers of TB in Mediterranean Buffalo and can improve the TB diagnostic performance in this specie.

Effective secondary response to antigen is a hallmark of immunological memory. However, the extent of memory CD8 T cell response to secondary boost varies at different times after a primary response. Considering the central role of memory CD8 T cells in long-lived protection against viral infections and tumors, a better understanding of the molecular mechanisms underlying the changing responsiveness of these cells to antigenic challenge would be beneficial. We examined here primed CD8 T cell response to boost in a BALB/c mouse model of intramuscular vaccination by priming with HIV-1 gag-encoding Chimpanzee adenovector, and boosting with HIV-1 gag-encoding Modified Vaccinia virus Ankara. We found that boost was more effective at day(d)100 than at d30 postprime, as evaluated at d45 post-boost by multi-lymphoid organ assessment of gag-specific CD8 T cell frequency, CD62L-expression (as a guide to memory status) and in vivo killing. RNA-sequencing of splenic gag-primed CD8 T cells at d100 revealed a quiescent, but highly responsive signature, that trended toward a central memory (CD62L+) phenotype. Interestingly, gag-specific CD8 T cell frequency selectively diminished in the blood at d100, relative to the spleen, lymph nodes and bone marrow. These results open the possibility to modify prime/ boost intervals to achieve an improved memory CD8 T cell secondary response. [ABSTRACT FROM AUTHOR]

Galectin-3 (Gal-3) is a β-galactoside-binding lectin expressed in cells of the placental microenvironment. This lectin is involved in various biological processes, such as modulation of the immune system and control of parasitic illness. Toxoplasma gondii infection can lead to congenital transmission and cause miscarriages, prematurity and fetal anomalies. However, little is known about the role of Gal-3 in T. gondii infection in the placental microenvironment. This study aimed to unravel the underlying mechanisms of Gal-3 during T. gondii infection. For this purpose, we promoted the knockdown of Gal-3 expression by using RNA interference (RNAi) in BeWo cells or by using a synthetic inhibitor (GB1107) in human villous explants. We showed that the decreased Gal-3 expression in BeWo cells and human villous explants increases the invasion and proliferation of T. gondii probably by downregulating MIF and IL6 levels, highlighting thus the role of this lectin in modulating the immune response. Collectively, our study reveals Gal-3 as a promising target protein during congenital toxoplasmosis.

The objective of this review was to verify the therapeutic effect of polysaccharides derived from algae in neurodegenerative disease models involving the basal ganglia. To achieve this goal, a literature search was conducted in PubMed, Science Direct, Scopus, Web of Science, Embase, and Google Scholar databases. The descriptors “neuroprotective or neural regenerative or immunomodulatory activity or neuroprotection,” “polysaccharide or carbohydrate or carbohydrate polymers,” “marine algae or seaweed,” and “basal ganglia” according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology were used. This methodology involved the steps of searching, pre-selection, and inclusion of articles. A total of 737 records were identified. Following the data analysis, 698 studies were excluded, resulting in a final sample of 8 studies. Species such as Turbinaria decurrens, Gracilaria cornea, Chlorella pyrenoidosa, Arthrospira (Spirulina) platensis, Fucus vesiculosus, and Laminaria japonica have demonstrated significant neuroprotective effects. This review suggests that polysaccharides derived from marine algae possess therapeutic potential for neuroprotection, modulation of inflammation, and amelioration of functional deficits. Their use in neurodegenerative disease models warrants further consideration.

Cytotoxic activity is a hallmark of the immunopathogenesis in human cutaneous leishmaniasis (CL). In this study, we identified accumulation of CD4+ granzyme B producing T cells with increased cytotoxic capacity in CL lesions. These cells showed enhanced expression of activating NK receptors (NKG2D and NKG2C), diminished expression of inhibitory NKG2A, along with the upregulation of the senescence marker CD57. Notably, CD4+ T cells freshly isolated from CL lesions demonstrated remarkable capacity to mediate NL-like bystander cytolysis. Phenotypic analyses revealed that lesional CD4+ T cells are mainly composed of late-differentiated effector (CD27-CD45RA-) and terminally differentiated (senescent) TEMRA (CD27-CD45RA+) subsets. Interestingly, the TEMRA CD4+ T cells exhibited higher expression of granzyme B and CD107a. Collectively, our results provide the first evidence that senescent cytotoxic CD4+ T cells may support the skin pathology of human cutaneous leishmaniasis and, together with our previous findings, support the notion that multiple subsets of cytotoxic senescent cells may be involved in inducing the skin lesions in these patients.

The use of artificial intelligence in law represents one of the biggest challenges across different legal systems. Supporters of predictive systems believe that decisionmaking could be more efficient, consistent and predictable by using AI. European legislation and legal scholars, however, identify areas where AI developments are at high risk or too dangerous to be used in judicial proceedings. In this article, we contribute to this debate by problematizing predictive systems based on previous judgments and the growing use of Generative AI in judicial proceedings. Through illustrations from real criminal cases in Italian courts and prosecution offices, we show misalignments between the functions of AI systems and the essential features of legal decision-making and identify possible legitimate usages. We argue that current predictive systems and Generative AI crunch the complexity of judicial proceedings, the dynamics of fact-finding and legal encoding. They reduce the delivery of justice to statistical connections between data or metadata, cutting off the emotive-cognitive process that lies at the core of legal decision-making.

IntroductionHereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is an ultra-rare autosomal dominant inherited disease that affects 1 in 67,000 people in the world. The attacks are based on subcutaneous and submucosal edema that can lead to death if not properly managed. Considering the lack of information on the clinical management of Brazilian patients with HAE, this study aimed to identify and characterize patients with HAE-C1-INH that used danazol prophylactic treatment in the Brazilian Public Health System (SUS) and the healthcare resource utilization (HCRU).MethodsThis was an observational retrospective database study with patients treated with danazol from January 2011 until December 2021 within the SUS. The HAE cohort included patients with 12 years or older with at least one record for ICD-10 D84.1, one claim for danazol record, and at least 6 months of available history in the database.ResultsOur study included 799 patients treated in the SUS, with a mean (SD) age at danazol initiation of 40 years (16). The number of patients with HAE showed a similar distribution over this 10-year period analyzed with the highest number of patients in 2015 (n = 509) and 2016 (n = 480). A total of 253 (32%) patients had a record of at least one attack. Of those, 45 (17.8%) had at least one procedure HAE-related hospital admission, and 128 (50.6%) had at least one HAE-related hospital admission. The mean (SD) hospitalization length of stay was 5 (8) days. Over 14% (n = 36) of HAE patients with attack (n = 253) had at least one HAE-related ICU admission.ConclusionThis database study is the strategy used to allow us to find and describe the characteristics of patients with HAE who use danazol for long-term prophylaxis in the SUS and identify HCRU outcomes of interest such as hospitalizations, inpatient, and outpatient settings. The high rate of attacks, hospitalizations, and general resource uses highlights the necessity to increase awareness of new strategies and accurate approaches to treat HAE patients. Therefore, our findings are important indicators that our health system and guidelines need to be revised and improved to properly diagnose, treat, and assist patients with HAE.

Background: Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing this risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy since they are as effective and overall safer than warfarin in preventing AF-related stroke. Although patients bleed less from DOACs compared to warfarin, bleeding remains the primary safety concern with this therapy. Hypothesis: Genetic variants known to modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs could increase the risk of bleeding. Aim: To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes (ABCB1, ABCG2, CYP2J2, CYP3A4, CYP3A5) with the risk of bleeding from DOACs in non-valvular AF patients. Methods: A retrospective cohort study was carried out with 2,364 self-identified white non-valvular AF patients treated with either rivaroxaban or apixaban. Genotyping was performed with Illumina Infinium CoreExome v12.1 bead arrays by the Michigan Genomics Initiative biobank. The primary endpoint was a composite of major and clinically relevant non-major bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of the eight PK-related SNVs with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. The pre-specified primary analysis was the covariate-adjusted, additive genetic models. Six tests were performed in the primary analysis as three SNVs are in the same haplotype, and thusp-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. Results: In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all p > 0.1). In exploratory analyses with other genetic models, the ABCB1 (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban [HR: 1.391 (95%CI: 1.019-1.900); p = 0.038] but not from apixaban (p = 0.487). Conclusion: Eight functional PK-related genetic variants were not significantly associated with bleeding from either rivaroxaban or apixaban in more than 2,000 AF self-identified white outpatients. [ABSTRACT FROM AUTHOR]

Mycophenolate rapidly substituted azathioprine (AZA) in transplant immunosuppression regimens since the 1990s, when early clinical trials indicated better outcomes, although opposite results were also observed. However, none of these trials used the well-established optimization methods for AZA dosing, namely, thiopurine methyltransferase pharmacogenetics combined with monitoring of the thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). Resistance to optimize AZA therapy remains today in transplant therapy, despite the fact that thiopurine metabolite testing is being used by other medical disciplines with evident improvement in clinical results. In a previous analysis, we found that active 6-TGN metabolites were not detectable in about 30% of kidney transplant patients under continuous use of apparently adequate azathioprine dosage, which demonstrates the need to monitor these metabolites for therapeutic optimization. Two of four case studies presented here exemplifies this fact. On the other hand, some patients have toxic 6-TGN levels with a theoretically appropriate dose, as seen in the other two case studies in this presentation, constituting one more important reason to monitor the AZA dose administered by its metabolites. This analysis is not intended to prove the superiority of one immunosuppressant over another, but to draw attention to a fact: there are thousands of patients around the world receiving an inadequate dose of azathioprine and, therefore, with inappropriate immunosuppression. This report is also intended to draw attention, to clinicians using thiopurines, that allopurinol co-therapy with AZA is a useful therapeutic pathway for those patients who do not adequately form active thioguanine metabolites. [ABSTRACT FROM AUTHOR]

ObjectiveThe prognosis of colorectal cancer has continuously improved in recent years thanks to continuous progress in both the therapeutic and diagnostic fields. The specific objective of this study is to contribute to the diagnostic field through the evaluation of the correlation between superior hemorrhoidal vein (SHV) ectasia detected on computed tomography (CT) and Tumor (T), Node (N), and distant metastasis (M) examination and mesorectal fascia (MRF) invasion in the preoperative staging of rectal cancer.MethodsBetween January 2018 and April 2022, 46 patients with histopathological diagnosis of rectal cancer were retrospectively enrolled, and the diameter of the SHV was evaluated by CT examination. The cutoff value for SHV diameter used is 3.7 mm. The diameter was measured at the level of S2 during portal venous phase after 4× image zoom to reduce the interobserver variability. The parameters evaluated were tumor location, detection of MRF infiltration (defined as the distance < 1 mm between the tumor margins and the fascia), SHV diameter, detection of mesorectal perilesional lymph nodes, and detection of metastasis.ResultsA total of 67.39% (31/46) of patients had SHV ectasia. All patients with MRF infiltration (4/46, 7.14%) presented SHV ectasia (average diameter of 4.4 mm), and SHV was significantly related with the development of liver metastases at the moment of primary staging and during follow-up.ConclusionSHV ectasia may be related to metastasis and MRF involvement; therefore, it could become a tool for preoperative staging of rectal cancer.

IntroductionEating Disorders (EDs) affect individuals globally and are associated with significant physical and mental health challenges. However, access to adequate treatment is often hindered by societal stigma, limited awareness, and resource constraints.MethodsThe project aims to utilize the power of Artificial Intelligence (AI), particularly Machine Learning (ML) and Deep Learning (DL), to improve EDs diagnosis and treatment. The Master Data Plan (MDP) will collect and analyze data from diverse sources, utilize AI algorithms for risk factor identificat io n, treatment planning, and relapse prediction, and provide a patient-facing chatbot for information and support. This platform will integrate patient data, support healthcare professionals, and empower patients, thereby enhancing care accessibility, personalizing treatment plans, and optimizing care pathways. Robust data governance measures will ensure ethical and secure data management.ResultsAnticipated outcomes include enhanced care accessibility and efficiency, personalized treatment plans leading to improved patient outcomes, reduced waiting lists, heightened patient engagement, and increased awareness of EDs with improved resource allocation.DiscussionThis project signifies a pivotal shift towards data-driven, patient-centered ED care in Italy. By integrat ing AI and promoting collaboration, it seeks to redefine mental healthcare standards and foster better well- being among individuals with EDs.

Securing a consistent food supply remains a pressing global challenge, particularly for small-scale farmers grappling with obstacles in enhancing agricultural yields, especially in tropical soils. Integrated Nutrient Management (INM) techniques, employing organic manures like vermicompost and bio-enriched rock phosphate, emerge as recommended solutions. Vermicompost is lauded for its nutrient richness and positive soil health impacts. At the same time, bio-enriched rock phosphate serves as a sustainable alternative to conventional phosphorus fertilisers, specifically tailored for tropical soil conditions. Despite individual studies assessing the effects of vermicompost, bio-enriched rock phosphate, and soluble fertilisers on plant growth, a comprehensive overview of their combined application is noticeably lacking. To fill this gap, this study employs the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) method to explore the synergies of combining these elements and their impacts on crop production and the environment. This review is among the first to comprehensively summarize the complexities of combining vermicompost, bio-enriched rock phosphate, and chemical fertilisers on various crops. It thoroughly examines potential advantages, disadvantages, effects on agricultural systems, socio-economic implications, and existing policies governing their usage. Our findings reveal that the combined application of vermicompost, bio-enriched rock phosphate, and soluble fertilisers leads to significant improvements in plant growth, yield, and soil properties. The optimal impact is observed when vermicompost constitutes 25% and soluble fertiliser comprises 75 or 100% of the recommended fertiliser dosage. Moreover, incorporating a mixture of phosphate-solubilizing bacteria (PSB) strains in rock phosphate further enhances its positive effects. Despite these positive findings, we identified gaps in comprehensive approaches addressing socio-cultural dimensions and the lack of literature on prevailing policies regarding vermicompost use in agricultural systems highlighting the need for a more holistic understanding of vermicompost incorporation and a better grasp of the institutional frameworks guiding these practices. However, to secure sustainable crop production, farmers need to integrate vermicompost and biofertilisers with chemical fertilisers. In fostering the adoption of sustainable and inclusive agricultural practices on small rural properties, it is advisable to incorporate agricultural education into farmer training programs.

Proinflammatory cytokines are implicated in promoting neurodegeneration in multiple sclerosis (MS) by affecting excitatory and inhibitory transmission at central synapses. Conversely, the synaptic effects of anti-inflammatory molecules remain underexplored, despite their potential neuroprotective properties and their presence in the cerebrospinal fluid (CSF) of patients. In a study involving 184 newly diagnosed relapsing–remitting (RR)-MS patients, we investigated whether CSF levels of the anti-inflammatory interleukin (IL)-10 were linked to disease severity and neurodegeneration measures. Additionally, we examined IL-10 impact on synaptic transmission in striatal medium spiny neurons and its role in counteracting inflammatory synaptopathy induced by IL-1β in female C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Our findings revealed a significant positive correlation between IL-10 CSF levels and changes in EDSS (Expanded Disability Status Scale) scores one year after MS diagnosis. Moreover, IL-10 levels in the CSF were positively correlated with volumes of specific subcortical brain structures, such as the nucleus caudate. In both MS patients’ CSF and EAE mice striatum, IL-10 and IL-1β expressions were upregulated, suggesting possible antagonistic effects of these cytokines. Notably, IL-10 exhibited the ability to decrease glutamate transmission, increase GABA transmission in the striatum, and reverse IL-1β-induced abnormal synaptic transmission in EAE. In conclusion, our data suggest that IL-10 exerts direct neuroprotective effects in MS patients by modulating both excitatory and inhibitory transmission and attenuating IL-1β-induced inflammatory synaptopathy. These findings underscore the potential therapeutic significance of IL-10 in mitigating neurodegeneration in MS.

BackgroundGross motor function impairments and manual dexterity deficits are frequently observed in children and adolescents with Cerebral Palsy (CP), having a major impact on their activity level and autonomy. Improving manual dexterity and activity level of patients with CP is often the focus of rehabilitation. Novel and adjuvant treatment methods that could support the standard training also in chronic conditions are a research priority. The transcutaneous Vagus Nerve Stimulation (tVNS) is a non-invasive brain stimulation technique, which provides a bottom-up stimulation of subcortical and cortical brain structures, enhancing brain GABA and Noradrenaline levels. This technique may play a pivotal role in brain plasticity, which has not been tested in CP patients before.Methods44 children and adolescents with CP will be involved, treated in pairs in a randomized, double-blind, pre-post test study. The two groups will undergo the Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) for 2 consecutive weeks, with 3 h daily sessions for 5 days per week, for an overall time interval of 30 h; the training will be combined with the application for 75 min/day of active or sham tVNS, in separate, randomly allocated groups. The primary outcome measure will include the scores at the Assisting Hand Assessment and Box and Block Test, and at an ad-hoc visuomotor task evaluating manual visuomotor control. Secondary outcomes will include the scores at the Children’s Hand Experience Questionnaire, Canadian Occupational Performance Measure, Melbourne Assessment of Unilateral Upper Limb Function, Gross Motor Function Measure, Vineland, Pediatric quality of life inventory. The evaluation points will include pre (T0), post (T1) and 3-month follow up (T2) assessments. Safety and tolerability will also be assessed.ResultsThe results of this trial will assess whether tVNS can effectively boost the effects of an intensive two-week bimanual training, in improving manual dexterity in children and adolescents with cerebral palsy, ensuring safety and tolerability throughout the intervention period.Clinical trial registration: ClinicalTrials.gov, NCT06372028.

Solitary primary extraosseous plasmacytoma is a rare disease in the gastrointestinal tract, recently classified as an “exceptional” tumor of the colon site. The real incidence (one case/population/year) is unknown but reasonably less than 1/10,000,000 cases/year with very few descriptions in the literature. The rare cases described in the literature are often diagnosed after surgery for perforation and with predominant localization of the left colon. The main endoscopic presentation mimics colon carcinoma with ulcerated mass and obstructing lumen. In this paper, we report a rare case of isolated mass mimicking a submucosal lesion of the ascending colon diagnosed in an older female patient by colonoscopy. The patient was almost asymptomatic; she reported only a history of hematochezia without anemia. This mass was successfully treated by surgery and followed by hematological investigations, including bone marrow biopsy, specific laboratory tests, and CT/PET scan, which confirmed primary isolated plasmacytoma of the colon.

Metabolic adaptations to negative energy balance, as well as lipomobilization, influence inflammatory responses, immune function, and oxidative stress in animals. This study aimed to evaluate the biochemical profile of Mediterranean buffaloes with different levels of lipomobilization from the prepartum to the postpartum period. A total of 76 Mediterranean buffaloes were enrolled, and a weekly blood sample was taken from 7 weeks before to 6 weeks after calving. The concentration of non-esterified fatty acids (NEFAs) was determined in serum and was used to categorize buffaloes into three lipomobilization groups 7 weeks before calving: mild (NEFA-I; NEFA ≤ 0.29 mEq/L; n = 18), medium (NEFA-II; 0.29 0.29 mEq/L; NEFA-II and NEFA-III) at 7 weeks before calving should be monitored more closely to reduce the risk of metabolic diseases. Furthermore, the medium (NEFA-II) and severe (NEFA-III) lipomobilization groups could be associated with differences in the animals’ ability to manage their metabolic status. Specifically, the severe mobilization group was most associated with a greater energy deficit during both the prepartum and postpartum periods without oxidative stress. On the contrary, the medium mobilization group was associated with a less severe energy deficit but was also associated with an inflammatory status and oxidative stress during the prepartum period. These distinctions highlight the need for tailored management strategies to address varying levels of metabolic stress in dairy buffaloes.