Search Results (1,045)

Myeloid neoplasms (MNs) with germline predisposition represent a distinct, increasingly recognized category in the WHO classification, encompassing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) arising in the context of an inherited genetic alteration or mutation. While often presenting at a younger age or with characteristic cytopenias with or without organ dysfunction, some can manifest in adulthood, highlighting the need for vigilance regardless of age or family history. Key predisposing genes include transcription factors (e.g., RUNX1, CEBPA) and genes involved in RNA splicing and telomere biology disorders. Identification of these germline mutations is critical as MNs with germline predisposition dictate specific therapeutic strategies—particularly for hematopoietic stem cell transplantation (HSCT)—and require genetic counseling and surveillance for at-risk relatives. Accurate diagnosis often requires non-hematopoietic germline DNA testing, which provides important biological insights into the development of different myeloid neoplasms and directs personalized patient care. Full article

Down Syndrome Regression Disorder (DSRD) is a rare but severe neuropsychiatric condition characterized by abrupt loss of speech, autonomy, and cognitive abilities in individuals with Down syndrome, often associated with immune dysregulation and gut–brain axis dysfunction. We report the case of an 11-year-old girl with Down syndrome who developed developmental regression at age five, in temporal proximity to a family transition (the birth of a younger sibling), with loss of continence, language, and comprehension, alongside persistent behavioral agitation and gastrointestinal symptoms. Laboratory assessment revealed Giardia duodenalis infection, elevated fecal calprotectin and secretory IgA, and microbial imbalance with overgrowth of Streptococcus anginosus and S. sobrinus. The patient received a single oral dose of tinidazole (2 g), daily folinic acid (1 mg/kg), and a 90-day course of transcranial and abdominal photobiomodulation (PBM) (1064 nm, 10 min per site). Post-treatment, stool analysis showed normalized inflammation markers and restoration of beneficial bacterial genera (Bacteroides, Bifidobacterium, Lactobacillus) with absence of Enterococcus growth. Behaviorally, she exhibited marked recovery: CARS-2-QPC decreased from 106 to 91, ABC from 63 to 31, and ATEC from 62 to 57, alongside regained continence, speech, and fine-motor coordination. These outcomes suggest that abdominal and transcranial PBM, by modulating mitochondrial metabolism, mucosal immunity, and microbiota composition, may facilitate systemic and neurobehavioral recovery in DSRD. This translational case supports further investigation of PBM as a non-invasive, multimodal therapy for neuroimmune regression in genetic and developmental disorders including validation through future randomized controlled clinical trials. Full article

Sudden cardiac death (SCD) remains a major challenge in forensic medicine, representing a leading cause of natural mortality and frequently occurring in individuals without antecedent symptoms. Although conventional autopsy and histology remain the cornerstones of investigation, up to 10–15% of cases are classified as “autopsy-negative sudden unexplained death,” underscoring the need for complementary diagnostic tools. In recent years, post-mortem biochemistry and molecular approaches have become essential to narrowing this gap. Classical protein markers of myocardial necrosis (cardiac troponins, CK-MB, H-FABP, GPBB) continue to play a fundamental role, though their interpretation is influenced by post-mortem interval and sampling site. Peptide biomarkers reflecting hemodynamic stress (BNP, NT-proBNP, copeptin, sST2) offer additional insight into cardiac dysfunction and ischemic burden, while inflammatory and immunohistochemical markers (CRP, IL-6, fibronectin, desmin, C5b-9, S100A1) assist in detecting early ischemia and myocarditis when routine histology is inconclusive. Beyond these traditional markers, molecular signatures—including cardiac-specific microRNAs, exosomal RNA, proteomic alterations, and metabolomic fingerprints—provide innovative perspectives on metabolic collapse and arrhythmic mechanisms. Molecular autopsy through next-generation sequencing has further expanded diagnostic capability by identifying pathogenic variants associated with channelopathies and cardiomyopathies, enabling both cause-of-death clarification and cascade screening in families. Emerging multi-omics and artificial intelligence frameworks promise to integrate these heterogeneous data into standardized and robust interpretive models. Pre- and post-analytical considerations, together with medico-legal implications ranging from malpractice evaluation to the management of genetic information, remain essential components of this evolving field. Overall, the incorporation of validated biomarkers into harmonized international protocols, increasingly supported by AI, represents the next frontier in forensic cardiology. Full article

Background: Gut barrier dysfunction and altered gut microbial metabolism are emerging signatures of chronic gut disorders. Considering growing interest in combining structurally and mechanistically distinct bioactives, we investigated the individual and combined effects of serum-derived bovine immunoglobulin (SBI) and N-acetylglucosamine (NAG) on the gut microbiome and barrier integrity. Methods: The validated ex vivo SIFR^® (Systemic Intestinal Fermentation Research) technology, using microbiota from healthy adults (n = 6), was combined with a co-culture of epithelial/immune (Caco-2/THP-1) cells. Results: While SBI and NAG already significantly improved gut barrier integrity (TEER, transepithelial electrical resistance, +21% and +29%, respectively), the strongest effect was observed for SBI_NAG (+36%). This potent combined effect related to the observation that SBI and NAG each induced distinct, complementary shifts in microbial composition and metabolite output. SBI most selectively increased propionate (~Bacteroidota families) and health-associated indole derivatives (e.g., indole-3-propionic acid), while NAG most specifically boosted acetate and butyrate (~Bifidobacteriaceae, Ruminococcaceae, and Lachnospiraceae). The combination of SBI_NAG displayed effects of the individual ingredients, thus, for instance, enhancing all three short-chain fatty acids (SCFA) and elevating microbial diversity (CMS, community modulation score). Conclusions: Overall, SBI and NAG exert complementary, metabolically balanced effects on the gut microbiota, supporting combined use, particularly in individuals with gut barrier impairment or dysbiosis linked to lifestyle or early-stage gastrointestinal disorders. Full article

Background: Fatty acid-binding protein 3 (FABP3) is released in circulation following myocardial infarction, and an increased level of circulatory FABP3 has also been reported in peripheral artery disease patients, exposing endothelial cells to higher levels of FABP3. Recently, loss of endothelial FABP3 was shown to protect endothelial cells against inflammation-induced endothelial dysfunction; however, the effect of FABP3 exposure on endothelial cells is unknown. Accordingly, to study the effect of FABP3 exposure on endothelial cells, we performed transcriptomic profiling following recombinant human FABP3 (rhFABP3) treatment of endothelial cells. Methods: Cultured human endothelial cells were treated with either a vehicle or rhFABP3 (50 ng/mL, 6 h); then, RNA sequencing was performed. Gene expression analysis followed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses was performed to identify differentially expressed genes and affected cellular functions and pathways. Results: Differential gene expression analysis revealed kinesin family member 26b (KIF26B) to be the most upregulated and survival of motor neuron 2 (SMN2) to be the most downregulated genes in rhFABP3-treated compared to vehicle-treated endothelial cells. Most of the differentially expressed genes were associated with endothelial cell motility, immune response, and angiogenesis. GO and KEGG analyses indicated that rhFABP3 exposure impacts several crucial pathways, predominantly “Regulation of leukocyte mediated cytotoxicity” and “Natural killer cell mediated cytotoxicity”, suggesting its involvement in endothelial cell physiology and response mechanisms to cardiovascular stress. Conclusions: This is the first study to evaluate rhFABP3-induced transcriptomics in human endothelial cells. Our data reveal novel genes and pathways affected by the exposure of endothelial cells to FABP3. Further research is necessary to validate these findings and fully understand FABP3’s role in endothelial biology and in cardiovascular diseases like myocardial infarction and peripheral artery disease. Full article

Background/Objectives: Current studies have shown that caregiving anxiety is associated with an individual’s dysfunctional thoughts. The aim of this study was to assess the mediating effect of caregivers’ forgiveness (benevolence, lack of avoidance and lack of revenge) on the relationship between dysfunctional thoughts and anxiety in the informal caregivers of dependent older adults. Methods: Participants were 222 family caregivers. We conducted path analysis to test the hypothesized model. Results: We found a model that showed a good fit (χ² = 3.410; χ²/gL = 5; p = 0.63; GFI = 0.994; CFI = 0.999; RMSEA = 0.001). It showed a direct and negative association between dysfunctional thoughts and lack of revenge, and this variable was related positively with both benevolence and lack of avoidance. In turn, benevolence was associated with lower levels of anxiety. The associations between dysfunctional thoughts and anxiety were mediated by caregiver forgiveness. Conclusions: Our research suggests the importance of health workers seeking to understand how individuals judge their avoidance, revenge and lack of benevolence, which affect individuals’ anxiety, for change. This study demonstrates the relevance of forgiving strategies in developing and testing informal caregiving assessments. It is necessary to detect and reduce avoidance and revenge related to caregivers. It is also necessary to detect and improve benevolence. Full article

Variants of the MYO5B gene, which encodes the molecular motor protein myosin-Vb, have gained prominence as a causative factor in familial intrahepatic cholestasis (FIC). Understanding the disease mechanism is pivotal for therapy development and clinical decision-making. The prevailing theory for the mechanism underlying MYO5B-associated cholestasis implicates faulty trafficking of the ABCB11-encoded bile salt export pump (BSEP) in hepatocytes due to dysfunctional myosin-Vb. This is supported by cell and mouse studies. However, while BSEP localization was abnormal in some patients’ liver biopsies, BSEP appeared normally localized in others, raising questions with regard to the role of BSEP in MYO5B-associated FIC. We present a focused systematic narrative review of all cases of MYO5B variant-associated isolated FIC reported in the MEDLINE database. We assembled a comprehensive patient dataset and assessed clinical features of MYO5B-associated FIC, their relationship with MYO5B genotype, the clinical value and significance of BSEP abnormalities, and the relationship of MYO5B-associated FIC to ABCB11 variant-associated FIC. Our review revealed that aberrant BSEP localization correlated with the absence of one MYO5B allele carrying a truncating nonsense or frameshift variant. Notably, biochemical and clinical parameters including treatment outcome were indistinguishable between patients presenting with normal and aberrant BSEP localization. Further, myosin-Vb and BSEP deficiency-associated FIC patient cohorts showed distinct biochemical and clinical phenotypes, indicating different underlying mechanisms. This suggests that whether or not BSEP localization was abnormal depended on the MYO5B genotype without a predictable effect on clinical parameters and treatment response. Treatment decisions should be guided by clinical parameters rather than by genotype or immunohistochemistry findings. Full article

Type 2 diabetes mellitus (T2D) affects hundreds of millions worldwide, with recent estimates indicating approximately 589 million adults living with diabetes, most with type 2 disease. Beyond classical insulin signaling pathways, increasing evidence implicates altered protein glycosylation in metabolic dysfunction. The solute carrier 35 (SLC35) family of nucleotide sugar transporters mediates the import of activated sugars into the endoplasmic reticulum and Golgi lumen, thereby influencing global glycosylation patterns. Dysregulation of these transporters can perturb glucose homeostasis, insulin responsiveness, and nutrient-sensing pathways through changes in glycosylation flux. In this review, we dissect the molecular mechanisms by which these transporters modulate glucose homeostasis, insulin signaling pathways, protein O-GlcN acylation, and broader glycosylation processes. We integrate findings from human genetic studies, rodent models, and in vitro functional analyses to characterize how altered SLC35 activity is associated with T2D and metabolic syndrome. Four members demonstrate particularly compelling evidence: SLC35B4 modulates hepatic glucose metabolism, SLC35D3 mutations impair dopaminergic signaling and energy balance, and SLC35F3 variants interact with high-carbohydrate intake to increase metabolic-syndrome risk. SLC35A3, though less studied, may influence glycosylation-dependent insulin signaling through its role in N-glycan biosynthesis. Beyond these characterized transporters, this review identifies potential metabolic roles for understudied family members, suggesting broader implications across the entire SLC35 family. We also discuss how such alterations can lead to disrupted hexosamine flux, impaired glycoprotein processing, aberrant cellular signaling, and micronutrient imbalances. Finally, we evaluate the therapeutic potential of targeting SLC35 transporters, outlining both opportunities and challenges in translating these insights into novel T2D treatments. Full article

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a leading cause of end-stage renal disease worldwide. Despite advances in metabolic and blood pressure control, the prevalence of DKD continues to rise, creating a significant clinical and socioeconomic burden. Recent studies have revealed that non-coding RNAs, particularly microRNAs (miRNAs), play an important role in the development and progression of DKD. Distinct patterns of miRNA dysregulation have been identified in specific renal cell types, including podocytes, mesangial cells, tubular epithelial cells, endothelial cells, fibroblasts, and macrophages. These alterations drive characteristic cellular injuries such as podocyte loss, mesangial matrix expansion, tubular epithelial–mesenchymal transition, endothelial dysfunction, and interstitial fibrosis. Certain miRNAs, such as miR-21, miR-192, and miR-214, reinforce profibrotic TGF-β/Smad signaling, whereas protective groups, including the miR-29 and miR-30 families, maintain epithelial stability and restrict matrix deposition. Beyond their regulatory roles, circulating and urinary miRNAs have emerged as stable, non-invasive biomarkers that reflect renal injury and disease progression. This review summarizes recent progress in elucidating cell-specific miRNA networks in DKD and highlights their potential as diagnostic indicators and therapeutic targets for precision management of diabetic kidney disease. Full article

Sensory processing differences, reported in up to 97% of individuals with autism spectrum disorder (ASD), are increasingly recognized as a defining feature of the condition, shaping perception, cognition, and adaptive behavior. Atypical sensory responsivity, ranging from hyper- to hypo-reactivity and sensory seeking, emerges early in development and contributes to the clinical and neurobiological heterogeneity of autism. Alterations in neural connectivity, the balance of excitation and inhibition, and multisensory integration are thought to underlie these sensory profiles, influencing emotional regulation, attention, and social interaction. Sensory features also interact with co-occurring conditions such as anxiety, attention deficit hyperactivity disorder, and sleep and feeding difficulties, thereby shaping developmental trajectories and influencing adaptive behavior. Clinically, these sensory dysfunctions have a significant impact on daily participation and quality of life, extending their effects to family functioning. Understanding individual sensory phenotypes is therefore essential for accurate assessment and personalized intervention. Current therapeutic approaches include Sensory Integration Therapy, Sensory-Based Interventions, Sequential Oral Sensory Approach, and structured physical activity programs, often complemented by behavioral and mindfulness-based techniques. Emerging neuroplasticity-oriented methods for targeted modulation of sensory processing networks include neurofeedback and non-invasive brain stimulation. Overall, current evidence highlights the central role of sensory processing in ASD and underscores the need for multidisciplinary, individualized approaches to optimize developmental trajectories and enhance adaptive functioning. This review provides an updated synthesis of sensory processing in ASD, integrating neurobiological, developmental, and clinical evidence to highlight established knowledge, unresolved questions, and priorities for future research. Full article

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease characterized by abnormal lipid metabolism. The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor involved in regulating multiple physiological processes. Recent studies have demonstrated that AHR exerts a multifaceted regulatory role in liver diseases by integrating metabolic and immune signaling pathways; however, the specific role of AHR in MAFLD is not clear. In our work, a rat model of MAFLD was established by feeding wild-type (WT) and AHR knockout (AHR^−/−) rats with a high-fat, high-fructose, and high-cholesterol diet (HFHFrHCD) for 10 weeks, and then the liver injury markers, lipid-related biochemical indices and liver histopathology were examined to elucidate the effect of AHR on MAFLD progression. We discovered that AHR deficiency can elevate plasma transaminase levels, increase hepatic triglyceride (TG) and total cholesterol (TC), and exacerbate insulin resistance (IR) under an overnutrition environment. Subsequently, liver transcriptome and RT-qPCR were performed to investigate the underlying mechanism, which revealed that the hepatic bile acid synthesis was inhibited because of lower Cytochrome P450 Family 7 Subfamily A Member 1 (CYP7A1) expression in the liver when AHR was knockout. Additionally, intestinal flora dysbiosis occurred in AHR^−/− rats fed with HFHFrHCD, which might also contribute to the hepatic cholesterol accumulation. Taken together, our results suggested that AHR might play an important role in regulating cholesterol metabolism by inhibiting bile acid synthesis and breaking the steady state of the gut microbiota during the MAFLD progression. Full article

Background/Objectives: Eustachian Tube Dysfunction (ETD) is a prevalent condition affecting middle ear pressure regulation, yet nationwide epidemiological data in Saudi Arabia remain limited. This study aimed to assess the prevalence of ETD and identify its associated factors among Saudi adults using a validated screening tool. Methods: A nationwide cross-sectional study was conducted between June 2024 and March 2025 among 1124 Saudi adults (aged ≥ 18 years) across five geographic regions. ETD was assessed using the validated Arabic version of the seven-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7), with scores ≥ 14.5 indicating dysfunction. Data on demographic, anthropometric, clinical, and lifestyle characteristics were collected via an online questionnaire. Multiple linear regression analysis identified independent predictors of ETDQ-7 scores, with statistical significance set at p < 0.05. Results: The prevalence of ETD was 33.9% (95% CI: 31.1–36.8%), substantially higher than the 7% self-reported rate. Of affected participants, 29.6% had mild-to-moderate ETD and 4.3% had severe dysfunction. Multivariable regression analysis identified four significant independent predictors: higher body mass index (BMI) (β = 0.08; 95% CI: 0.03–0.16; p = 0.049), family history of hearing loss (β = 1.87; 95% CI: 0.90–2.83; p < 0.001), prior bariatric bypass surgery (β = 14.37; 95% CI: 3.33–25.41; p = 0.011), and allergies (β = 3.19; 95% CI: 2.30–4.07; p < 0.001). No significant associations were found with demographic factors, smoking, or other comorbidities. Conclusions: ETD affects approximately one-third of Saudi adults, with significant underdiagnosis. Obesity, genetic predisposition, bariatric surgery, and allergic conditions represent key modifiable and non-modifiable risk factors. These findings support implementing routine ETDQ-7 screening in primary care and targeted interventions for high-risk populations. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now one of the most common chronic liver diseases in children and closely parallels the rising prevalence of severe pediatric obesity. Methods: This review synthesizes current evidence (2019–2025) and landmark studies on the diagnosis and management of pediatric MASLD, integrating contemporary guidelines and future directions. Results: Based on current data, we propose practical algorithms for screening and management of pediatric MASLD. Screening with alanine aminotransferase (ALT) as the initial test should be initiated in all children aged 9–11 years with obesity, in those who are overweight with additional risk factors, and in children with severe obesity or a family history of MASLD. Non-invasive imaging techniques show important limitations in children with increased amount of subcutaneous tissue requiring cautious interpretation. Lifestyle modification remains the cornerstone of therapy, while pharmacological treatments are investigational. In adolescents with severe obesity and significant comorbidities, bariatric surgery represents an effective therapeutic option with durable metabolic effects. Conclusions: Early identification of high-risk children, especially those with severe obesity, and implementation of multidisciplinary management are essential to prevent MASLD progression. Refinement of screening strategies and development of validated non-invasive biomarkers remain key priorities for future pediatric care. Full article

Background: Prehospital emergency professionals are exposed to high psychosocial demands that may impact their mental health, but pre-COVID-19 baseline data from Spanish services are scarce. This study aimed to assess the general health and psychosocial risk factors in a regional prehospital emergency service before the COVID-19 pandemic. Methods: We conducted a cross-sectional descriptive study (September–December 2019) including 51 physicians, nurses, and emergency medical technicians working at the 061 Health Emergency Center in Granada (Andalusia, Spain). General health and chronic problems were assessed with the Goldberg General Health Questionnaire (GHQ-28/CGHQ-28), and work-related psychosocial risks were evaluated using the COPSOQ-ISTAS21 questionnaire. Descriptive statistics, group comparisons, and exploratory Spearman correlations between health indicators and psychosocial dimensions were performed. Results: Most participants reported good self-perceived general health, but the chronic coding of the GHQ (CGHQ-28) indicated long-term difficulties mainly related to social dysfunction, somatic symptoms, and anxiety/insomnia. Exposure to unfavorable psychosocial risk was frequent, particularly in psychological demands, double presence (work–family conflict), and low esteem, with intermediate–unfavorable patterns in active job/development, insecurity, and social support/leadership. Exploratory correlations suggested that double presence was the psychosocial factor most consistently associated with chronic distress. Conclusions: In this pre-COVID-19 cohort of prehospital emergency professionals, good perceived general health coexisted with chronic psychological strain and high exposure to adverse psychosocial work factors. These findings support the need for organizational measures to reduce psychological demands and work–family conflict and to strengthen social support and leadership in prehospital emergency teams. Full article

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Yet, its treatment has serious challenges and is unsuccessful in a considerable fraction of patients. One reason may be a limited understanding of the molecular mechanisms underlying AF. Recent studies suggest that oxidative stress is involved in AF pathogenesis. Enhanced oxidative stress is largely determined by disrupted mitochondrial homeostasis, as cardiomyocytes heavily rely on mitochondrial energy production and calcium transfer between mitochondria and the sarcoplasmic reticulum. Atrial fibrillation involves metabolic, structural, and electrical remodeling, all of which are influenced by mitochondrial mechanisms. Mitochondrial homeostasis is controlled by mitochondrial quality control (mtQC), which is a multi-pathway mechanism to maintain integrity and functionality of mitochondria. Impaired mtQC may result in disturbed mitochondria-related calcium handling, decreased energy production, mitochondria-related inflammation and fibrosis, and impaired mitophagy. Sirtuins (SIRTs) are a family of seven members of histone deacetylases which have antioxidant properties, and three of them are localized to mitochondria. Therefore, at least some SIRTs may ameliorate enhanced oxidative stress related to damaged mitochondria. SIRTs have shown potential to improve AF outcomes in studies on AF patients and animal models. Therefore, SIRTs may have potential to ameliorate AF by decreasing oxidative stress and restoring mitochondrial homeostasis disrupted in AF. In this narrative review, we provide information on how mitochondrial dysfunctions, expressed as a disturbance in mtQC, contribute to AF through oxidative stress, calcium handling abnormalities, energy deficiency, inflammation and fibrosis, and genetic changes. In addition, we present the protective potential of sirtuins in AF. Full article