Search Results (13,551)

Male fertility is important to ensure herd health and productivity. The camelid male breeding soundness examination (BSE) is strongly recommended because natural mating remains the primary breeding method due to the challenges in semen cryopreservation and artificial insemination. Guidelines for the BSE have been proposed but not adopted in practice. The investigation of male reproductive failure includes history, general health examination, examination of the genitalia, semen evaluation, and testing for contagious diseases. Difficulties in ejaculate collection and semen viscosity are challenges in camelid male fertility investigation. This review summarizes the outcomes of BSE in our practice on South American camelids (SACs) and camels. The results and discussion are presented under four main categories: congenital defects, impotentia coeundi, impotentia generandi, and male reproductive emergencies. There is a difference between camels and SACs in the incidence of various disorders. Congenital defects are common in SACs in particular cryptorchidism, testicular hypoplasia and rete testis cysts. Orchitis is more common in camels, particularly in areas where brucellosis is prevalent. Testicular degeneration occurs in all camelids and has been associated with heat stress, aging, systemic diseases and overuse of anabolic steroids. Precise diagnosis of fertility impairment may require disease testing, testicular biopsy, cytogenetics and endocrine evaluation. A significant proportion of males are referred because of reproductive emergencies, due to poor management, which results in loss of genetic potential. Implementation of regular BSE is possible in SACs but can be difficult in dromedaries because of the large variation in breed characteristics and management systems. Full article

Dementia is a growing problem of global relevance, currently affecting over 55 million people worldwide. The number of new dementia cases is still increasing, primarily due to the aging of society. Dementia is defined as a substantial decline in cognitive function, and it is inherently associated with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, frontotemporal dementia, and vascular dementia. Of note, most patients suffering from neurodegenerative conditions, in addition to cognitive impairment, often experience various types of sleep disorders, including insomnia, rapid eye movement sleep behavior disorder, sleep-disordered breathing, and circadian rhythm disturbances. There is increasing evidence of a bidirectional interaction between sleep disturbances and mental health. Disrupted sleep may directly aggravate neuropsychiatric symptoms, like depression, anxiety, agitation, and hallucinations, and conversely, such symptoms can make sleeping more difficult. This creates a feedback loop that inevitably leads to disease progression and deterioration in quality of life. In this review, we provide an up-to-date overview of the nature and mechanisms behind sleep disorders in major neurodegenerative diseases, summarize treatment strategies for handling sleep disturbances, and discuss the clinical relevance of sleep–mental health interactions in the context of neurodegeneration-associated dementia. Neurodegeneration is a complex problem on the border between neurology and psychiatry, and it poses a challenge to the healthcare system, as it requires multidisciplinary approaches for optimal management. Understanding the connection between sleep and neuropsychiatric symptoms offers further opportunities for better symptom control, improved quality of life, and slower cognitive decline. Full article

Schizophrenia is a prevailing yet severely debilitating psychiatric disorder characterized by a convoluted etiology. Although antipsychotics have been available for over half a century, they primarily mitigate symptoms rather than providing definitive care. This limitation suggests that the neurotransmitter systems targeted by these medications are not the root cause of the disorder. Ongoing research seeks to elucidate the cellular, molecular, and circuitry pathways that contribute to the development of schizophrenia. Unfortunately, its precise pathogenesis remains incompletely understood. Accumulating evidence implicates dysregulated neurogenesis and aberrant neurodevelopmental processes as key contributors to disease progression. Recent advances in proteomics and imaging technology have facilitated the emergence of novel models of schizophrenia, emphasizing the roles of neuroinflammation, sex steroids, and cortisol. This paper aims to organize and map the intercorrelations and potential causal effects between various mechanistic models to gain deeper insight on how these mechanisms contribute to the cause, risks, and symptoms of the disorder. Furthermore, we discuss the potential therapeutic strategies that target these pathological pathways. Elucidating these mechanisms may ultimately advance our understanding of schizophrenia’s etiological foundations and guide the development of curative interventions. Full article

Objectives: Chronic pain corresponds to hypersensitivity to painful stimuli; however, its relation to acute pain sensitivity in children is poorly understood. We explored this relationship by comparing acute and chronic pain measures, along with related factors, in children with chronic pain syndromes versus controls, before and after therapeutic intervention. Methods: This prospective controlled cohort study involved 57 children with chronic pain undergoing intensive interdisciplinary pain treatment in a hospital-based pain rehabilitation program and 50 controls. Participants, aged 7–18, were tested using a cold pressor task (CPT) at admission, discharge, and first follow-up visit. Data on sleep, anxiety, psychological distress, functional impairment, and pain were collected. Results: Significant differences were found between control and treatment groups in average pain threshold (p < 0.001), pain tolerance (p = 0.035), sleep visual analog scale (VAS) (p < 0.001), functional disability inventory (p < 0.001), patient reported outcomes information system anxiety assessment tool (p < 0.001), general anxiety disorder 7-item scale (p < 0.001), pain VAS (p < 0.001) and total brief symptom inventory (BSI) (p < 0.001) scores at admission with children with chronic pain scoring worse on all measures save the pain VAS during the CPT. After treatment and at follow-up, function and mental health measures improved but not acute pain threshold. Conclusions: At treatment completion, function and mental health significantly improved but acute pain threshold and sleep quality were unchanged. These findings suggest that while chronic pain treatment improves overall function and mental health, acute pain thresholds may not be a suitable indicator for evaluating the efficacy of interventions. Full article

Background: Autosomal dominant intellectual developmental disorder 51 (MIM #617788) is caused by pathogenic variants in KMT5B, a histone methyltransferase essential for transcriptional repression and central nervous system development. The disorder manifests as a complex neurodevelopmental syndrome with variable neurological and systemic features. Methods: Two adolescents with nonsense KMT5B variants underwent detailed clinical, neuropsychological, and neuroimaging evaluations, including MRI and ¹⁸FDG PET/CT, analyzed with Statistical Parametric Mapping against matched controls. RNA sequencing was performed, and the literature was reviewed to assess genotype–phenotype correlations. Results: Both patients showed global developmental delay, progressing to autism spectrum disorder (ASD) and developmental coordination disorder (DCD), without intellectual disability (ID). The MRI was normal, but neuropsychological testing revealed executive function impairment, expressive language deficits, and behavioral disturbances. PET/CT consistently demonstrated cerebellar and temporal lobe hypometabolism, correlating with symptom severity. RNA sequencing identified shared dysregulated pathways, notably DDIT4 upregulation, linked to synaptic dysfunction and neuronal atrophy in animal models. Conclusions: The findings highlight cerebellar involvement in DCD and ASD, medial temporal lobe contribution to ASD and executive dysfunction, and DDIT4 as a possible molecular signature of KMT5B loss-of-function. An integrative multimodal approach refined genotype–phenotype correlations and revealed novel brain regions and pathways implicated in KMT5B-related disorders. Full article

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and progressive cognitive decline. Recent evidence has highlighted the role of blood–brain barrier (BBB) dysfunction in the early stages of AD pathology. Objective: We sought to explore the histological structure and physiological function of the blood–brain barrier, and to identify the shared pathological mechanisms between BBB disruption and Alzheimer’s disease progression. Methods: This narrative review was conducted through a comprehensive search of peer-reviewed literature from 1997 to 2024, using databases such as PubMed, Elsevier, Scopus, and Google Scholar. Results: Multiple histological and cellular components—including endothelial cells, pericytes, astrocytes, and tight junctions—contribute to BBB integrity. The breakdown of this barrier in AD is associated with chronic inflammation, oxidative stress, vascular injury, pericyte degeneration, astrocyte polarity loss, and dysfunction of nutrient transport systems like Glucose Transporter Type 1 (GLUT1). These alterations promote neuroinflammation, amyloid-β (Aβ) accumulation, and progressive neuronal damage. Conclusions: BBB dysfunction is not merely a consequence of AD but may act as an early and active driver of its pathogenesis. Understanding the mechanisms of BBB breakdown can lead to early diagnostic markers and novel therapeutic strategies aimed at preserving or restoring barrier integrity in Alzheimer’s disease. Full article

Background/Objectives: Human epidermal growth factor receptor 2 (HER2) inhibitors have markedly improved outcomes in patients with HER2-positive breast cancer. Clinical treatment often involves the sequential or combined use of multiple HER2 inhibitors, making it essential to clarify their distinct adverse event (AE) profiles. However, AE trends remain insufficiently understood. This study aimed to comprehensively analyze characteristic AEs associated with HER2 inhibitors. Methods: Using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS, January 2004–September 2024), we conducted disproportionality analyses of AEs associated with HER2 inhibitors approved for breast cancer. Based on the natural logarithm of the reporting odds ratio (lnROR), hierarchical cluster analysis and principal component analysis (PCA) were performed. Results: Disproportionality analysis treating HER2 inhibitors as a single group identified several signals, with hair disorder (ROR 39.93 [95% CI: 37.68–42.32]) as a representative example. Hierarchical clustering showed that monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) diverged early in the dendrogram, and clusters broadly corresponded to pharmacological classes. The cluster of hair-related AEs closely corresponded to mAbs. PCA indicated that the first component reflected AE occurrence risk (R² = 0.655, p < 0.0001), the second component distinguished mAbs from TKIs (tucatinib: r = 0.667; trastuzumab: r = −0.567), and the third component separated molecular targeted agents from antibody–drug conjugates (neratinib: r = 0.521; T-DXd: r = −0.440). Conclusions: FAERS-based analyses enabled visualization of the distinct AE profiles of HER2 inhibitors. These findings may support safe drug selection, risk stratification, and improved AE management strategies. Full article

When exposed to high contact pressure and shear conditions, the sliding and/or rolling contact interfaces of moving mechanical systems can experience significant friction and wear losses, thereby impairing their efficiency, reliability, and environmental sustainability. Traditionally, these losses have been minimized using high-performance solid and liquid lubricants or surface engineering techniques like physical and chemical vapor deposition. However, increasingly harsh operating conditions of more advanced mechanical systems (including wind turbines, space mechanisms, electric vehicle drivetrains, etc.) render such traditional methods less effective or impractical over the long term. Looking ahead, an emerging and complementary solution could be tribocatalysis, a process that spontaneously triggers the formation of nanocarbon-based tribofilms in situ and on demand at lubricated interfaces, significantly reducing friction and wear even without the use of high-performance additives. These films often comprise a wide range of amorphous or disordered carbons, crystalline graphite, graphene, nano-onions, nanotubes, and other carbon nanostructures known for their outstanding friction and wear properties under the most demanding tribological conditions. This review highlights recent advances in understanding the underlying mechanisms involved in forming these carbon-based tribofilms, along with their potential applications in real-world mechanical systems. These examples underscore the scientific significance and industrial potential of tribocatalysis in further enhancing the efficiency, reliability, and environmental sustainability of future mechanical systems. Full article

First-trimester placental development comprises many critical yet understudied cellular events that determine pregnancy outcomes. Improper placentation leads to a host of health issues that not only impact the fetal period but also influence later-life offspring health. Thus, an experimental paradigm for studying early placental development is necessary and has spurred the development of new in vitro models. Organoid model systems are three-dimensional structures comprising multiple differentiated cell types that originate from a progenitor population. Trophoblasts are the progenitor cells that serve as the proliferative base for the differentiation and maintenance of the placenta. Due to research constraints, experimental studies on the causal mechanisms underlying pathological pregnancies cannot readily be performed in human subjects. The nonhuman primate (NHP) offers a solution to this problem as it circumvents the limitations of human pregnancy sampling. Importantly, NHPs share many developmental features of human pregnancy, including placenta type and a similar fetal growth trajectory, making longitudinal pregnancy studies feasible and relevant. Since perturbations made in vivo can be validated in vitro, an NHP model of early pregnancy would facilitate mechanistic studies of pregnancy disorders. Herein, we describe the methodology for the establishment of a first-trimester NHP placenta trophoblast organoid model system. Full article

Over the past two decades, immune–inflammatory dysregulation has emerged as a central paradigm in the biology of mood disorders. Patients with major depression (MDD) and bipolar disorder (BD) frequently display low-grade systemic inflammation. Elevated C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) identify clinically relevant subgroups of patients characterized by greater severity, cognitive impairment, and poor treatment response. Changes in the gut microbiota and disruptions of the blood–brain barrier (BBB) act as important gateways through which systemic immune activity can influence the brain. At the intracellular level, pattern-recognition receptors activate convergent hubs including NF-κB, JAK/STAT, and MAPK cascades, while the NLRP3 inflammasome integrates mitochondrial dysfunction and oxidative stress with IL-1β release and pyroptosis. These pathways converge on glial dysregulation, impaired BDNF/TrkB signaling, and kynurenine pathway (KP) alterations, fostering excitotoxicity and synaptic deficits. Translational studies demonstrate that elevated CRP and IL-6 predict poor antidepressant outcomes. Anti-inflammatory agents such as infliximab and celecoxib show efficacy in specific subgroups of patients. Emerging multi-omics approaches identify immuno-metabolic biotypes, supporting the rationale for biomarker-guided stratification. These findings define an ‘inflammatory biotype’ of mood disorders and highlight the need for biomarkers and precision-based trials to guide treatment. Full article

Both basic and preclinical research, as well as the development of new therapies, require tools that allow for the selective labelling of specific cell types and the targeted delivery of drugs. The developed tools must then be validated in biological systems. In view of the lack of effective therapies for many neurodevelopmental disorders, including neonatal brain injuries, we decided to use the newly described, innovative SPAchips^® (a4cell, Pozuelo de Alarcón, Spain) tool and test it in labelling neonatal rat neural cells. In our studies, rat primary cultures of neurons and glial cells (astrocytes, oligodendrocytes, and microglia) were incubated with different concentrations of SPAchips^®. At selected time points, uptake of the tested microchips by particular cell types was assessed using lineage-specific antibodies and visualized using a confocal microscope. Additionally, the potential cytotoxicity of added microparticles was verified, as was the possibility of microglia activation. The study indicates that the tested microdevices selectively label neonatal rat microglia and can be a useful tool for visualizing this cell type, as well as a non-toxic tool for developing innovative strategies based on the functionalization of microparticles aimed at modulating neuroinflammatory processes. Full article

Background/Objectives: This review article highlights the role of the nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing 3 protein (NLRP3) inflammasomes in various gastrointestinal and hepatic disorders in the pediatric age group. NLRP3 inflammasomes are one of the principal intracellular innate immune sensors. During inflammation, molecules such as caspase-1 and the release of IL-1β and IL-18 are produced. The NLRP3 inflammasome participates in the preservation of intestinal homeostasis and mucosal immune response. The objective is to evaluate the published articles related to the role of NLRP3 inflammasomes in common pediatric gastrointestinal and hepatic disorders in order to identify the future perspective regarding their possible therapeutic values. Methods: We searched Medline for NLRP3 inflammasomes and disorders of the digestive system during childhood. Results: Although the majority of articles were related to various disorders of adults, such as Alzheimer’s disease, Parkinson’s disease, atherosclerosis, as well as neurodevelopmental disorders, such as schizophrenia, a few published datasets were related to the roles of NLRP3 in the pediatric age group: they addressed autism, rheumatoid arthritis, and other autoimmune diseases, as well as inflammatory bowel diseases (IBD) and hepatic infection. Some research demonstrated that the NLRP3 inflammasome has a protective role; however, it also has a pathogenic function. Conclusions: This review focused on the comprehensive role of inflammasome NLRP3 in the most common pediatric and neonatal gastrointestinal and hepatic diseases, including clinical and experimental studies, as well as the pharmacological inhibitors for NLRP3 inflammasomes, which may provide future therapy for GIT problems, such as IBD. Full article

Background/Objectives: Individuals with anorexia nervosa (AN) are known to exhibit both reduced pain sensitivity—when assessed via thresholds and subjective ratings—and diminished facial expressions of emotion. Therefore, investigating the facial response to pain in this population is of particular interest. Method: Seventeen patients with AN and 18 age- and sex-matched healthy controls were assessed using a thermode to induce heat pain. Subjective pain measures included pain threshold, pain tolerance, and pain ratings of supra-threshold stimuli, rated on a numerical rating scale (NRS). Facial responses to the suprathreshold stimuli were analyzed using the Facial Action Coding System (FACS). Eating pathology was assessed using the Eating Attitudes Test (EAT-26), the Eating Disorder Inventory-2 (EDI-2) and the body mass index (BMI), while depression was measured using the Beck Depression Inventory-II (BDI-II). Results: Compared with healthy controls, AN patients showed altogether significantly reduced facial expressions of pain, with particularly pronounced reductions in Action Units AU 6_7 and AU 9_10. In contrast, subjective pain measures showed only marginal differences between groups. Importantly, the reduction in facial expression could not be accounted for by differences in pain thresholds or ratings, nor by levels of eating pathology or depression. Conclusions: Individuals with AN display a markedly reduced facial expression of pain, which was observed for the first time, consistent with similar findings regarding the facial expressions of emotions. As this reduction cannot be explained by subjective pain report, it suggests that the communication of pain is impaired on two levels in AN: both in verbal and in nonverbal signaling. This may hinder the ability of others to recognize and respond to their pain appropriately. Full article

Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are rare hematopoietic disorders that exhibit overlapping pathological and molecular features of both MDS and MPN. This study aimed to investigate the mutational profiles and prognostic implications of MDS/MPN subtypes in Korean patients. Methods: We retrospectively reviewed 53 patients with MDS/MPN who underwent bone marrow examination and next-generation sequencing panel testing. Overall survival was analyzed with 3-year censoring. The cohort included chronic myelomonocytic leukemia (CMML; N = 30); MDS/MPN with neutrophilia (N = 6); MDS/MPN with SF3B1 mutation and thrombocytosis (N = 4); and MDS/MPN, not otherwise specified (MDS/MPN-NOS; N = 13). Results: The most frequently mutated gene was ASXL1 (52.8%), followed by TET2 (39.6%) and U2AF1 (18.9%), in total MDS/MPN. U2AF1 mutations were particularly frequent in myelodysplastic CMML (33.3%) and MDS/MPN-NOS (30.8%). In CMML, ASXL1 and TET2 mutations were associated with a trend toward better prognosis compared with wild-type (HR 0.21, p = 0.052; HR 0.25, p = 0.057, respectively), while U2AF1 mutations were associated with adverse prognosis in univariate analysis with borderline significance (HR 12.20, p = 0.050). Clinical/Molecular CMML-Specific Prognostic Scoring System and Mayo Molecular Model showed stepwise survival patterns across risk groups without statistical significance. In univariate analysis, transfusion dependency was associated with poor prognosis (HR 7.78, p = 0.013). Conclusions: This study provides the first single-institution analysis in Korean patients with MDS/MPN and identified U2AF1 mutations as a potentially significant prognostic factor, enhancing the molecular understanding of MDS/MPN. Full article

RNA-based therapeutics offer transformative potential for treating devastating diseases. However, current RNA delivery technologies face significant hurdles, including inefficient tissue targeting, insufficient selectivity, and severe side effects, leading to the termination of many clinical trials. This review critically assesses the landscape of RNA-derived medicines, examining world-renowned mRNA vaccines (Spikevax, BNT162b2/Comirnaty) and RNA-based therapeutics like Miravirsen (anti-miR-122). It details the composition and clinical trial results of numerous modified short RNA drugs (e.g., siRNAs, miRNA mimetics/inhibitors) targeting various conditions. Prospects for RNA-based medicines are analysed for diseases with substantial societal impact, such as cancer, autoimmune disorders, and infectious diseases, with a focus on evolving delivery methods, including lipid nanoparticles, viral vectors, and exosomes. RNA-mediated macrophage reprogramming emerges as a promising strategy, potentially enhancing both delivery and clinical efficacy. This review highlights that while approved RNA therapies primarily target rare diseases due to delivery limitations, novel approaches in RNA modification, targeted delivery systems, and enhanced understanding of molecular mechanisms are crucial for expanding their application to prevalent diseases and unlocking their full therapeutic potential. Full article