Search Results (668)

The study aims to reconstruct the life history of an individual whose skeleton was recovered during the excavation of the late medieval Pauline monastery of the Blessed Virgin Mary on Moslavina Mountain, Croatia. The monastery was one of the most important ecclesiastical centres in continental Croatia during the 14th/15th centuries CE and was abandoned between 1520 and 1544 due to fear of imminent Ottoman attacks. The inscription and coat of arms on the tombstone of a tomb located in the chancel, next to the main altar, indicate that the skeleton belongs to Sofia Kaštelančić née di Prata (di Pordenone), a member of Croatian late medieval high-ranking nobility. We conducted a conventional bioarchaeological study, carbon and nitrogen stable isotopes analysis, paleoradiological imaging (CT/CBCT scanning), and three-dimensional facial reconstruction. The skeleton belongs to a middle-aged woman between 40 and 50 years old with an estimated stature of about 161 cm. Numerous pathological changes, such as ante mortem tooth loss, caries, abscess, linear enamel hypoplasia, dysodontiasis, and osteophytosis were observed, with the most notable pathology being the fracture of the right ankle, a fact also confirmed by CT scanning. Carbon and nitrogen isotopic values are consistent with a terrestrial diet based on C₃ plants with no marine input, and the consumption of large quantities of animal-based proteins. Three-dimensional facial reconstruction made it possible for the first time in over 500 years to obtain the approximate physical appearance of the individual. The presented results are consistent with the hypothesis that the skeleton probably belongs to Sofia Kaštelančić. Nevertheless, none of the observed osteological traits are individually or collectively diagnostic of Sofia, so, in the absence of individualising evidence, the identification remains hypothetical rather than demonstrative. Full article

Alzheimer’s disease (AD) is neuropathologically characterized by tau-immunopositive neurofibrillary tangles (NFTs) and amyloid-β (Aβ)-immunopositive senile plaques. According to the widely accepted amyloid cascade hypothesis, Aβ pathology represents the upstream event in AD pathophysiology and induces tau aggregation. However, numerous studies have suggested that tau aggregates correlate more closely with neuronal loss and regional brain atrophy than with Aβ depositions. Tau aggregation in AD demonstrates a hierarchical spreading pattern beginning in the transentorhinal cortex, but the mechanisms underlying this spreading manner of lesions remain to be elucidated. This review aims to address current controversies regarding tau pathology in AD from the perspectives of both the ‘amyloid cascade’ and ‘tauopathy’ hypotheses. From the ‘amyloid cascade’ viewpoint, Aβ deposition prominently involves distal axon and axon terminals, and in some regions, there are anatomical correspondences between axonal Aβ pathology and cytoplasmic tau aggregations (e.g., a close relationship between senile plaques in the molecular layer of the hippocampal dentate gyrus and NFTs in the transentorhinal cortex). Nevertheless, this model cannot explain the whole body of hierarchical spreading of tau aggregation because notable spaciotemporal discrepancies also exist in many regions. From the ‘tauopathy’ perspective, the distribution of tau aggregates in AD involves key nodes within the memory circuits. Also, experimental studies have suggested that patient-derived tau exhibits seeding and neuron-to-neuron propagation properties. Interestingly, tau aggregation in AD appears to spread laterally in a proximity-dependent, cortico-cortical fashion rather than along long-range memory circuits. This contrasts with the system-selective, poly-nodal degenerations seen in four-repeat tauopathies, amyotrophic lateral sclerosis, or spinocerebellar degenerations. Moreover, the proportions of three-repeat and four-repeat isoforms shift during the maturation of NFTs in AD. Overall, spreading patterns of tau-pathology in AD cannot be fully explained by Aβ pathology and also differ from the system degeneration seen in other tauopathies. Full article

Background and Objectives: Perioperative myocardial infarction (PMI) after coronary artery bypass grafting (CABG) remains difficult to diagnose due to varying biomarker thresholds and ECG criteria. This study aimed to evaluate the predictive value of ECG changes and cardiac biomarkers for identifying pathological findings in repeat coronary angiography after CABG. Materials and Methods: This retrospective study included 137 patients who underwent repeat coronary angiography due to suspected PMI. ECG changes and serial measurements of CK, CK-MB, and hsTnT were analyzed at 4, 8, and 18 h postoperatively. The primary endpoint was the identification of graft-related complications or new coronary lesions. Results: Pathological angiographic findings were detected in 85.4% (n = 117) of cases, predominantly graft-related complications (96.6%). ST-segment elevation (p < 0.01) and ST-segment depression (p = 0.02) were significantly associated with pathological findings. The combination of ST-segment elevation and CK-MB > 1.0 µkat/L also showed a high predictive accuracy (p < 0.01). HsTnT demonstrated the strongest diagnostic performance, with a threshold of 1231 ng/L at 18 h (AUC = 1.0; p < 0.01). Earlier postoperative biomarker elevations did not show significant discriminatory value. Conclusions: ECG remains the most accessible and fastest predictive tool for PMI detection. However, cardiac biomarkers only gain diagnostic relevance beyond 8 h postoperatively. A multimodal approach integrating biomarker kinetics and ECG changes may enhance early decision-making and improve patient outcomes, as ST-segment elevation in combination with CK-MB > 1.0 µkat/L serves as a relevant predictor. Notably, hsTnT levels > 1231 ng/L at 18 h reliably identified patients with pathological angiographic findings. These findings were derived from a highly selected cohort (~2% of all CABG patients) referred for coronary angiography and should therefore be interpreted as hypothesis-generating rather than directly generalizable to the broader surgical population. Full article

Italian Court of Cassation Ruling Decree 30032 of 30 October 2023 discusses a medical malpractice case concerning the diagnosis of dermatofibrosarcoma protuberans and the alleged diagnostic and therapeutic delay. By examining how the ruling frames the role of histopathology in proving pathology benignity, authors prompt to reflect on diagnostic path, the allocation of the burden of proof, and the role of dermatologist’s expertise in professional liability issues. Over a four-year period, five health professionals were involved in a claim concerning an initial diagnosis of an epidermoid cyst and a subsequent diagnosis of dermatofibrosarcoma protuberans. The plaintiff questioned the delay in diagnosis, and the Court of Cassation found two physicians liable because they could not prove that the treated pathology was initially benign. We argue that equating diagnostic correctness exclusively with histological confirmation is unnecessary, both clinically and legally, in typical cases, if the reasoning and findings are adequately documented. Additionally, we examine the value of dermatologists’ experience and the scope of professional competence as measures of liability. Finally, we outline the minimum standards of clinical documentation necessary to make the diagnostic pathway traceable and verifiable. The diagnostic process is a discretionary effort that integrates multiple sources of information, both instrumental and experiential, to reach the most reasonable hypothesis. While histopathology is a crucial tool, it is not the sole gateway to a correct diagnosis of every cutaneous alteration. Adequate disclosure and structured documentation of the diagnostic reasoning are fundamental to the care process and fair assessment of professional responsibility. Full article

The thymus and parathyroid glands share a common embryological origin from the third pharyngeal pouch, yet their potential morphological and functional interconnections remain insufficiently explored. We conducted a comparative study integrating immunohistochemistry (IHC) and SEM on human thymic tissue, parathyroid adenomas, and parathyroid tissue excised during thyroidectomy. IHC staining targeted Thymosin-α1, CaSR, and PTH1R, with semi-quantitative evaluation of staining intensity and distribution. SEM analysis was performed at multiple magnifications to assess stromal organization and microvascular relief. Non-parametric statistical tests (Kruskal–Wallis with Mann–Whitney post hoc comparisons) were applied to clinical and laboratory data across the three cohorts. Scanning electron microscopy (SEM) revealed convergent ultrastructural features between thymus and parathyroid, including reticular stromal meshes and vascular grooves suggestive of comparable microcirculatory organization. IHC demonstrated robust Thymosin expression in thymus, with heterogeneous/apical distribution in parathyroid tissue; CaSR showed strong membranous and cytoplasmic expression in parathyroid, but weak diffuse signal in thymus; PTH1R exhibited low-to-moderate expression in thymus and moderate heterogeneous expression in parathyroid, with apical accentuation in adenomas. Statistical analysis confirmed significant differences in ionized calcium, PTH, and anti-AChR titers among the three cohorts (all p < 0.001), while TSH and calcitonin did not differ significantly. Our findings strengthen the hypothesis of a morpho-functional parathyroid–thymus axis. The robust parathyroid expression of CaSR and PTH1R aligns with established roles in calcium–PTH homeostasis, while the novel detection of Thymosin in parathyroid tissue suggests an expanded functional repertoire. These results highlight a continuum between embryological proximity and adult tissue cross-talk, with potential clinical implications for parathyroid pathology and immune regulation. Full article

We aimed to develop and internally validate a nomogram to estimate axillary pathological complete response (pCR, ypN0) after neoadjuvant systemic therapy (NAST) in clinically node-positive (cN1–2) breast cancer. In a single-center retrospective cohort of 144 consecutive patients treated with NAST (anti-HER2 as indicated), all underwent standardized pre- and post-NAST 18F-FDG PET/CT and axillary staging (sentinel lymph node biopsy [SLNB], targeted axillary dissection [TAD], or axillary lymph node dissection [ALND]). Axillary pCR occurred in 51.4% (74/144). In a multivariable analysis, independent positive determinants of ypN0 included the triple-negative subtype, Modified PERCIST (SUVmax-based) reduction ≥ 80.70%, pre-NAST tumor-to-axilla SUVmax ratio ≥ 1.21, and residual breast tumor size < 0.5 mm; conversely, conglomerate/matted nodal morphology at diagnosis was inversely associated. The model showed good internal discrimination (AUC 0.857, 95% CI 0.797–0.917) and acceptable calibration (Hosmer–Lemeshow p = 0.425). Exploratory, subtype-restricted signals were observed for inflammatory indices within Luminal B (HER2+) but were not retained in the final model. The resulting nomogram—combining tumor biology, PET/CT response, and pre-NAST nodal features—may support risk stratification for axillary de-escalation after NAST; however, prospective external validation—ideally embedded in ongoing de-escalation frameworks—remains essential before clinical implementation, and the tool should currently be regarded as hypothesis-generating rather than a stand-alone decision aid for routine practice. Full article

Background and Objectives: Neuropsychiatric disorders pose a major global health challenge, marked by high prevalence, limited diagnostic precision, and suboptimal therapeutic outcomes. Current diagnoses remain primarily clinical, lacking objective biomarkers, while many patients experience poor remission rates and frequent relapse. The endocannabinoid system (ECS), a central regulator of synaptic plasticity, neuroinflammation, and stress responses, is increasingly implicated in depression, anxiety, schizophrenia, and neurodegenerative diseases. In parallel, extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication and promising biomarker sources, as they reflect the physiological or pathological status of their cells of origin. This review examines the hypothesis that interactions between ECS signaling and EV-mediated communication form a convergent pathway shaping vulnerability and resilience in neuropsychiatric disorders, with potential implications for biomarker identification and therapeutic innovation. Methods: This hypothesis-driven review was developed using a narrative approach, focusing on the interface between cannabinoids and EVs in neuropsychiatric conditions. Relevant publications were identified through PubMed, Scopus, and Web of Science searches up to September 2025. Results: Emerging evidence indicates a bidirectional relationship between ECS activity and EV biology: endocannabinoids can be loaded into EVs to facilitate intercellular signaling, while phytocannabinoids such as THC and CBD can alter EV release and cargo composition. Conclusions: We propose a hypothesis-driven framework in which the possible interplay between cannabinoids and EVs may stimulate new research and support the development of biomarker-guided, personalized therapeutic strategies for neuropsychiatric disorders. Full article

Microplastics and nanoplastics (MNPs) are pervasive contaminants infiltrating water, food, and human tissues. The sharp rise in plastic production—with over half manufactured between 2003 and 2022—has heightened concerns about their health impacts. Methods included: (1) a literature review of clinical studies on MNPs focusing on human health and (2) analysis of Standardized Mortality Rates (SMRs) for 44 groups of diseases in Italy (2003–2022, Italian National Institute of Statistics, ISTAT data). The outcomes suggest that MNPs have been connected to pathological alterations in a number of organ systems, such as the gastrointestinal tract (intestine, liver, and pancreas), breathing system, eyes, brain, and vascular structures. SMRs increased significantly in only eight of the 46 illness categories examined between 2003 and 2022. The analysis of clinical and epidemiological data allows us to identify a possible clinical assessment consisting of a 30-variable diagnostic questionnaire (Chicago Cluster Evaluation System, CCES), encompassing laboratory markers, clinical signs, and ultrasound findings. A binomial distribution model suggests that more than 8 positive responses may indicate a presumptive diagnosis of Microplastic Syndrome (MP-Sy). This framework reflects observed clinical/epidemiological patterns and provides a foundation for hypothesis-driven research. Prospective longitudinal studies are warranted to validate the proposed definition and its diagnostic utility. The aim of the present study is to propose a preliminary clinical framework for a potential MP-Sy integrating toxicological evidence with epidemiological data, define diagnostic criteria and assess their consistency with observed disease trends. Full article

Mutations in genes encoding sarcomeric proteins are a common cause of cardiomyopathy and sudden cardiac death in humans. We evaluated the hypothesis that myofilament dysfunction is coupled to morphological and functional alterations of cardiomyocyte nuclei in a Tnnc1-targeted knock-in (Tnnc1-p.A8V) mouse model of hypertrophic cardiomyopathy (HCM). Tnnc1 is the gene that codes for the isoform of the Ca²⁺-regulatory protein troponin C (cTnC) that is expressed in cardiomyocytes and slow skeletal muscle fibers and resides on thin filaments of sarcomeres in those muscles. This pathogenic mutation in a sarcomere gene alters many aspects of cardiomyocyte function, including sarcomere contractility, cytoplasmic Ca²⁺ buffering, and gene expression. Analysis of myocardial histological sections and isolated cardiomyocytes from adult Tnnc1-p.A8V mouse hearts revealed significantly smaller (cross-sectional area and volume) and rounder nuclei compared to those from age-matched, wild-type control mice. Changes in nuclear morphology could not be explained by differences in cardiomyocyte size or ploidy. Isolated wild-type and mutant cardiomyocyte nuclei, which are embedded centrally within myofibrils, undergo compression during contraction of the cardiomyocyte, indicating that during each heartbeat cardiomyocyte nuclei would be mechanically deformed as well as being exposed to elevated cytoplasmic Ca²⁺. Immunoblotting analysis indicated decreased nuclear localization of cardiac troponin C and decreased histone H4 expression in Tnnc1-p.A8V mouse hearts. Next, we investigated the influence of nucleocytoplasmic transport by immunofluorescence microscopy, and we could not confirm nuclear localization of cardiac troponin C in fixed myocardial tissue from adult mice. However, cardiac troponin C could be detected in healthy human-induced pluripotent stem cell-derived cardiomyocyte nuclei. We conclude that pathological myofilament dysfunction due to a pathogenic, cardiomyopathy-associated mutation can be linked to altered protein composition of cardiomyocyte nuclei and aberrant nuclear morphology. Full article

Feline calicivirus (FCV) is widespread in multi-cat environments and typically causes acute upper respiratory tract disease (URTD). FCV also causes outbreaks of virulent systemic disease (VSD), mainly in adults, with multiple organ involvement. In this study, an FCV-VSD infection was described in a less-one-month-old Maine Coon kitten originating from a cattery where an outbreak of FCV-URTD had previously been reported. After spontaneous death, post-mortem examination as well as histopathological, immunohistochemical, bacteriological and virological investigations were carried out. Pathological findings were consistent with severe pneumonia and cutaneous oedema of the footpads. No concomitant bacterial infection was detected. FCV RNA was detected in several organs and the highest amount of viral RNA was observed in the lung sample, in which the presence of the FCV antigen was confirmed by immunohistochemistry. With the same immunohistochemical technique, the IBA-1 antibody detected sparse alveolar macrophages, the main viral target cell and pulmonary replication site. The nucleotide sequences of the viral ORF2 gene amplified from all positive tissues were identical with each other and phylogeny confirms that highly virulent FCV strains are not distinguishable from FCV-URTD phenotypes. Our findings reinforce the hypothesis that VSD outbreaks can occur even in small populations, due to the high genetic variability of FCV. Full article

The streptozotocin (STZ) experimental model of sporadic Alzheimer’s disease (SAD), the most prevalent form of this type of dementia, has become a valuable tool to study the behavioral and morphological changes that occur during the gradual development of this pathology. We used the STZ experimental model in combination with the novel object recognition test (NORT) and immunohistochemical techniques to evaluate the recognition memory decline and morphological alterations in memory-related structures (hippocampus and cortex). Our analysis included five different time points after intracerebroventricular (ICV) administration of 3 mg/kg of STZ or artificial cerebrospinal fluid (aCSF) as a control. The time points included three distinct stages: early (15 and 30 days), intermediate (60 days), and late (90 and 120 days). We found that recognition memory impairment started in the intermediate stage and persisted through the later stages. Morphologically, we detected significant astrogliosis starting in the early stages, whereas cholinergic changes began in the intermediate stage. No neuronal loss was observed at any of the time points analyzed. Our results further support the hypothesis that astrogliosis constitutes an initial pathological event that may compromise the hippocampal cholinergic system and can contribute to the onset of recognition memory deficits. Full article

Epilepsy is one of the most prevalent neurological disorders, severely impacting quality of life. The burden of epilepsy is exacerbated by high rates of neuropsychiatric comorbidities such as depression, anxiety, and post-traumatic stress disorder. The molecular mechanisms linking epilepsy to these comorbidities remain unclear. Epileptogenesis and recurrent seizures implicate multiple processes including changes in the extracellular matrix, structural and functional neuroplasticity, neuroinflammation, and neurodegeneration. The plasminogen activation (PA) system—a complex system of proteins that function as both proteases and signaling molecules—modulates these processes in the central nervous system (CNS) under normal conditions and following potentially epileptogenic insults. Notably, the PA system is also dysregulated in stress-related psychiatric disorders. In this review, we first provide an overview of the role of PA system in the CNS with an emphasis on the mechanisms related to epilepsy. We then explore the hypothesis that the components of the PA system components constitute a shared pathological link implicated in both epileptogenesis and psychiatric disorders. We summarize clinical and preclinical evidence demonstrating that seizures and other brain insults disrupt the PA system, and that similar dysregulation is observed in stress-related psychiatric conditions. We propose that PA system dysregulation is a potential molecular substrate linking epileptogenesis and neuropsychiatric comorbidities, presenting a promising target for future research aimed at understanding the mechanisms underlying the development of behavioral comorbidities in epilepsy. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming more common among adolescents, but non-invasive biomarkers for early detection are still limited. Liver-expressed antimicrobial peptide-2 (LEAP-2), a ghrelin receptor antagonist, has been connected to obesity and liver fat buildup in adults, but pediatric data are limited. This study investigates the hypothesis that higher levels of LEAP-2 are associated with hepatic steatosis and the role of LEAP-2 serum levels in the earlier and easier diagnosis of MASLD in children. Methods: In this cross-sectional study, 51 adolescents aged 12–18 were divided into three groups: one with MASLD and obesity (MASLD-Ob) (confirmed hepatosteatosis by imaging studies such as magnetic resonance or ultrasound, along with at least one cardiometabolic criterion and a body mass index (BMI) > 2 SD) (n = 19), another with obesity without any liver pathology or MASLD (BMI > 2 SD) (n = 14), and healthy controls (n = 18). The controlled attenuation parameter (CAP) was measured using FibroScan^® Mini + 430 (Echosens SA, Créteil, France), and serum ghrelin and LEAP-2 levels were determined via ELISA. Correlations between LEAP-2, ghrelin, CAP, BMI z-score, and metabolic parameters were analyzed. Results: LEAP-2 and ghrelin levels among the three groups were similar (p = 0.148, p = 0.515). A positive correlation was observed between LEAP-2 levels and CAP values in the obese group (both the MASLD-Ob and obesity groups) (r = 0.379, p = 0.030). When a cutoff of 240 dB/m was used, the median LEAP-2 level in cases above this value was 2.20 ng/mL, compared to 1.37 ng/mL in cases below it (p = 0.021), which was significantly different. When analyzing the obese group (both the MASLD-Ob and obese groups) a statistically significant correlation was found between serum LEAP-2 levels and CAP, AST, GGT, and total bilirubin values (r = 0.379, p = 0.030; r = 0.369, p = 0.035; r = 0.369, p = 0.035; r = 0.357, p = 0.049, respectively). Conclusions: Interventional imaging methods and biomarkers for diagnosing and monitoring hepatosteatosis have become well-established in the literature. However, since these tests are not available at all centers and can be costly, there is an increasing search for other easily accessible diagnostic and follow-up parameters. LEAP-2 could be a promising non-invasive biomarker for pediatric MASLD, especially when used alongside CAP measurements. The application of this biomarker in pediatric MASLD provides valuable data to help identify and monitor the condition in adolescents. We believe our study offers strong evidence to support further research and the development of drug treatments for MASLD that aim to reduce plasma LEAP-2. Full article

Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease caused by a CTG repeat expansion in the DMPK gene. The toxic mutant mRNA sequesters MBNL proteins, disrupting global RNA metabolism. Although alternative splicing in DM1 skeletal muscle pathology has been extensively studied, early-stage transcriptomic changes remained uncharacterized. To gain deeper and contextual insight into DM1 transcriptome, we performed the first Weighted Gene Co-expression Network Analysis (WGCNA) on skeletal muscle RNA sequencing data from the widely used DM1 mouse model HSA^LR (~250 CTG repeats). We identified 532 core genes using data from 16-week-old mice, an age before the onset of muscle weakness. Additional differential expression analysis across multiple HSA^LR datasets revealed 42 common up-regulated coding and non-coding genes. Within identified core genes, the pathway gene-pair signature analysis enabled contextual selection of functionally related genes involved in maintaining proteostasis, including endoplasmic reticulum (ER) protein processing, the ubiquitin-proteasome system (UPS), macroautophagy and mitophagy, and muscle contraction. The enrichment of ER protein processing with prevailing core genes related to ER-associated degradation suggests adaptive chaperone and UPS activation, while core genes such as Ambra1, Mfn2, and Usp30 indicate adaptations in mitochondrial quality control. Coordinated early alterations in processes maintaining protein homeostasis, critical for muscle mass and function, possibly reflect a response to cellular stress due to repeat expansion and appears before muscle weakness development. Although the study relies exclusively on transcriptomic analyses, it offers a comprehensive, hypothesis-generating perspective that pinpoints candidate pathways, preceding muscle weakness, for future mechanistic validation. Full article

Among mouse models of neurological disease, Theiler’s murine encephalomyelitis virus (TMEV) provides a unique platform by using a naturally occurring viral trigger, paralleling the role of infections like Epstein–Barr virus in multiple sclerosis (MS). Just as not all individuals with predisposing viral infections develop the same neurological disease, not all mouse strains develop the same diseases following TMEV infection, so susceptibility is dictated by genetic background. For example, certain sets of alleles, called haplotypes, of the major histocompatibility complex (MHC) region have been associated with susceptibility to TMEV-induced demyelination (TVID) and MS. However, our previous work revealed that these MHC susceptibility haplotypes are not the sole contributors to TMEV-induced diseases in all mice. We infected mice from the genetically diverse Collaborative Cross (CC), a resource designed to reflect human population-level genetic variation. All 15 CC strains tested exhibited some form of neurological phenotype or CNS lesion following TMEV infection. However, chronic radiculoneuropathy characterized by axonal degeneration with myelin loss was observed in the CNS of only two strains, CC002 and CC023, which had markedly different immune responses and clinical profiles throughout the course of infection. Moreover, the pathology seen in CC002 and CC023 was not the same as what is typically seen in TVID. We used previous results from RNA sequencing of the hippocampus and spinal cord to test our hypothesis that myelin loss in these strains resulted from the convergent biological effects of multiple genetic risk variants, many previously unassociated with TMEV-induced diseases. These findings identify novel genetic targets and demonstrate the utility of genetically diverse models for uncovering complex neuroimmune interactions. Full article