Bosnian Journal of Basic Medical Sciences
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Rare liver diseases — Etiology, diagnosis and management: A review
Full text linkRare liver diseases (RLDs) are diverse and often misdiagnosed conditions that impose significant clinical and public health challenges due to their variable presentations and limited treatment options. This study aims to synthesize contemporary evidence on the etiology, classification, diagnostics, and management of RLDs and to identify near-term research and implementation priorities. We conducted a systematic search of PubMed and Scopus for the years 2015 to 2025 using predefined keywords. We included peer-reviewed human studies, such as guidelines, randomized trials, and large registries, focusing on mechanisms, diagnostic strategies, and treatments. We excluded animal studies and non-peer-reviewed reports, extracting data on disease biology, diagnostic tools, outcomes, and molecular therapies. RLDs can be categorized into genetic/inherited, autoimmune cholestatic, and other vascular/metabolic entities. Care for these diseases is increasingly guided by structured pathways that integrate biochemistry and serology with magnetic resonance cholangiopancreatography (MRCP), elastography, targeted next-generation sequencing (NGS), and selective biopsy. Emerging biomarkers, such as circulating microRNAs, alongside machine learning in imaging techniques, enhance disease staging and prognostication. Key management strategies include the use of bile-acid modulators, surgical interventions, and ileal bile acid transporter (IBAT) inhibitors for progressive familial intrahepatic cholestasis (PFIC). Lifelong copper chelation is recommended for Wilson disease, with trientine preferred for neurologic phenotypes. Supportive care in alpha-1 antitrypsin deficiency (A1ATD) is complemented by the investigation of molecular chaperones. Additionally, gene-directed therapies, gene editing, RNA-based approaches, and cell therapies show early promise but raise concerns regarding durability, safety, and ethical considerations, particularly for pediatric patients. In conclusion, implementing precision medicine frameworks that rely on standardized diagnostics, multicenter registries, and equitable access is crucial for facilitating earlier detection and translating mechanism-targeted therapies into sustainable, globally accessible benefits
Dantrolene use across surgical and medical care at Mayo Clinic from 2010 to 2024: Indications, frequency, and value for identifying malignant hyperthermia
Full text linkDantrolene is the definitive treatment for malignant hyperthermia (MH), a rare and life-threatening disorder. This retrospective study aimed to achieve two objectives: (1) to characterize the indications and frequency of dantrolene administration in both medical and surgical settings, and (2) to evaluate whether perioperative dantrolene may serve as a surrogate marker for identifying MH cases. Using pharmacy records, we identified hospitalized patients who received dantrolene between 2010 and 2024. Each recipient underwent a chart review to examine the clinical context of dantrolene administration. A total of 1,199,450 inpatient pharmacy records were reviewed, revealing 118 patients who received dantrolene, resulting in an incidence rate of 1 in 10,165 hospital admissions (95% CI: 1 in 8,488 to 1 in 12,280). Among these, 87 patients (74%) received oral dantrolene: 84 for chronic spasticity, two for neuroleptic malignant syndrome, and one as preoperative prophylaxis due to a history of MH. The remaining 31 patients (26%) received intravenous dantrolene. Seventeen patients received perioperative dantrolene for suspected MH; of these, nine cases (53%) were subsequently clinically confirmed as MH. Based on these findings and the total number of surgical procedures involving general anesthesia (n=885,127), the estimated prevalence of MH following general anesthesia was calculated to be 1 in 98,328 exposures (95% CI: 1 in 51,813 to 1 in 215,054). Dantrolene was administered at an approximate rate of 1 per 10,000 hospital admissions, primarily in oral formulation for chronic spasticity. Among the patients who received perioperative dantrolene, approximately half were confirmed to have MH, resulting in an estimated MH prevalence of 1 in 100,000 patients exposed to general anesthesia
HbA1c variability and risk of incident heart failure: A systematic review and meta-analysis
Full text linkVisit-to-visit variability in glycated hemoglobin (HbA1c) reflects long-term instability in glycemic control, potentially contributing to cardiovascular complications. However, the association between HbA1c variability and heart failure (HF) risk remains unclear. This meta-analysis aimed to quantify the relationship between HbA1c variability and the risk of incident HF in adults. A systematic search of PubMed, Embase, and Web of Science was conducted to identify relevant studies. Observational studies and post-hoc analyses of clinical trials evaluating the association between visit-to-visit HbA1c variability and incident HF were included. Random-effects models were employed to pool hazard ratios (HRs) with 95% confidence intervals (CIs), accounting for potential heterogeneity. A total of nine studies (n = 342,123) were included in the analysis. Overall, high HbA1c variability was associated with an increased risk of HF (pooled HR = 1.78, 95% CI: 1.39–2.27, p < 0.001; I² = 87%). Sensitivity analyses restricted to patients with type 2 diabetes (HR = 1.73, 95% CI: 1.35–2.22), high-quality studies (HR = 1.82, 95% CI: 1.32–2.50), or studies adjusting for mean HbA1c (HR = 1.68, 95% CI: 1.31–2.16) produced consistent results. Subgroup analyses indicated a stronger association in prospective cohorts (HR = 2.51) compared to retrospective or post-hoc studies (p for subgroup difference < 0.001). Meta-regression analysis revealed no significant modifying effects of age, sex, follow-up duration, or study quality (p all > 0.05). In conclusion, greater visit-to-visit HbA1c variability may be associated with an increased risk of incident HF, underscoring the prognostic importance of maintaining stable long-term glycemic control in patients with type 2 diabetes
Comparing del Nido and St. Thomas II cardioplegia in a rat ischemia–reperfusion model: Histopathology, mitochondria, and TEM analysis
Full text linkMyocardial ischemia–reperfusion (IR) injury remains a major challenge in cardiac surgery, and comparative histological and ultrastructural data on cardioplegia solutions are limited. This study compared the myocardial protective effects of St. Thomas II and del Nido cardioplegia in a controlled rat IR model, focusing on inflammation, mast cell dynamics, and subcellular preservation. Twenty-four Wistar Albino rats were randomized to Control, St. Thomas II, or del Nido groups. After 90 minutes of ischemia and 30 minutes of passive reperfusion, myocardial tissue was analyzed by hematoxylin–eosin, toluidine blue, and transmission electron microscopy. Outcomes included mast cell counts, leukocyte infiltration, karyolysis, and ultrastructural measures (Flameng score, crista density, basement membrane thickness). Both cardioplegia groups preserved myocardial morphology and attenuated inflammatory changes versus control. Light microscopy revealed a consistent mast cell density and reduced karyolysis in hearts treated with cardioplegia, with no significant differences observed between St. Thomas II and del Nido solutions. Conversely, transmission electron microscopy (TEM), the primary endpoint of this study, demonstrated enhanced mitochondrial and endothelial preservation in the del Nido group, as evidenced by significantly lower Flameng scores and increased crista density compared to both St. Thomas II and control groups (p < 0.05). In conclusion, both solutions reduced early IR-related injury, but del Nido provided a significant ultrastructural advantage on TEM despite similar routine light-microscopic findings
TBRG4 as a prognostic biomarker and key regulator of cell cycle and EMT in lung cancer
Full text linkTransforming growth factor β regulator 4 (TBRG4) is upregulated in lung cancer, but its biological role and underlying mechanisms remain poorly understood. In this study, we analyzed pancancer gene expression profiles and clinical data from University of California, Santa Cruz Xena (UCSC Xena) to evaluate the prognostic significance of TBRG4 using univariate and multivariate Cox regression analyses. Genes with a Pearson correlation coefficient above 0.4 with TBRG4 in lung cancer were identified via UALCAN, followed by pathway enrichment analyses to explore their functional associations. To investigate TBRG4’s role in lung cancer progression, we assessed cell proliferation, colony formation, and cell cycle alterations in lung cancer cells following TBRG4 knockdown. Western blot analysis was performed to examine the effects of TBRG4 depletion on key cell cycle regulators and epithelial-mesenchymal transition (EMT) markers. Additionally, the biological significance of TBRG4 was evaluated in vivo using a mouse xenograft model. TBRG4 knockdown significantly inhibited cell proliferation and colony formation while inducing cell cycle arrest and apoptosis in lung cancer cells. Analysis of co-expressed genes in the The Cancer Genome Atlas - Lung Adenocarcinoma (TCGA-LUAD) cohort revealed enrichment in cell cycle-related pathways, aligning with our experimental findings. Furthermore, TBRG4 depletion reduced EMT marker expression and suppressed tumor growth in vivo. Collectively, these findings suggest that TBRG4 may serve as a promising prognostic biomarker and therapeutic target in lung cancer
Predictive value of TGF-β1 and SMAD-7 expression at diagnosis for treatment response in low-risk myelodysplastic syndrome
Full text linkMyelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease. Supportive treatments, such as erythropoiesis-stimulating agents (ESAs), are commonly used in patients with low-risk MDS. This study aimed to retrospectively assess the impact of bone marrow Mothers against decapentaplegic homolog 7 (SMAD-7) and transforming growth factor beta 1 (TGF-β1) protein expression on prognosis and response to ESA treatment in patients with low-risk MDS. We retrospectively analyzed patients diagnosed with low-risk MDS at the adult hematology department of Bursa Uludağ University Hospital. A total of 56 patients classified as low or very low risk were included in the study. Immunohistochemical analysis of bone marrow specimens at diagnosis showed that only five patients (9.8%) exhibited low SMAD-7 staining, while 51 patients (90.2%) showed no staining. Regarding TGF-β1 staining, 18 patients (32.1%) demonstrated moderate to high staining, whereas 38 patients (67.9%) exhibited low (36/38) or no staining (2/38). A statistically significant correlation was found between TGF-β1 staining levels and ESA treatment administration (P = 0.011). Additionally, a significant relationship was observed between lower erythropoietin (EPO) levels and moderate to high TGF-β1 staining (P = 0.04). However, when TGF-β1 staining status was compared with first- and third-month treatment responses in patients receiving ESA therapy, no significant difference was detected between groups. These findings suggest that while TGF-β1 alone may not be sufficient to predict ESA treatment response, additional parameters related to the TGF-β/SMAD pathway should be considered. Strong TGF-β1 staining, alongside EPO levels, may influence the decision to initiate ESA therapy
Enhancing predictions of health insurance overspending risk through hospital departmental performance indicators
Full text linkThe substantial rise in health insurance expenditures, combined with delayed feedback on overspending from administrative departments, highlights the urgent need for timely reporting of such data. This study analyzed a large cohort of 549,910 discharged patients\u27 medical records from the Wuxi Health Commission, covering the period from January 2022 to November 2023. We applied four widely recognized machine learning techniques—Logistic Regression (LR), LightGBM, Random Forest (RF), and Artificial Neural Networks (ANN)—alongside departmental performance indicators (DPIs) to develop Insurance Overspending Risk Prediction (IORP) models at both regional and hospital levels. The dataset was divided into training and testing sets in a 7:3 ratio. Experimental results showed that LightGBM outperformed the other models, achieving an accuracy of 0.82 for both regional and hospital-level predictions. Its weighted F1-score reached 0.78 at the regional level and 0.82 at the hospital level, with corresponding AUC-ROC (Area Under the Receiver Operating Characteristic Curve) values of 0.91 and 0.94, demonstrating strong performance in identifying overspending risks. The model’s high recall and precision further ensure reliable predictions and minimize misclassifications. Notably, four key DPIs—Total Amount of Discharged Patients (TADP), Average Inpatient Stay (AIS), Medicine Expenses Percentage (MEP), and Consumable Expenses Percentage (CEP)—were strongly correlated with overspending risks. The integration of IORP models into the Health Insurance Management System (HIMS) at the Affiliated Hospital of Jiangnan University has significantly improved departmental managers\u27 ability to anticipate overspending. By effectively leveraging HIMS in combination with this advanced model, managers can perform timely, accurate assessments, thereby enhancing financial oversight and resource allocation
The impact of MITF expression on tumor-infiltrating lymphocytes in melanoma: Insights into immune microenvironment dynamics
Full text linkMelanoma progression is influenced by complex interactions between tumor cells and the immune microenvironment. This study examined the relationship between microphthalmia-associated transcription factor (MITF) expression and the immune microenvironment in primary melanoma using a modified classification of tumor-infiltrating lymphocytes (TILs) based on conventional BRISK categories. Archival formalin-fixed, paraffin-embedded tissue samples from 81 primary melanoma patients were analyzed via tissue microarray immunohistochemistry to assess MITF protein levels. TIL patterns were categorized into six groups, refining the traditional BRISK classification to distinguish between continuous and discontinuous infiltration, as well as peripheral vs intratumoral distribution. The analysis revealed that melanomas classified under the BRISK B category exhibited the highest MITF expression, often exceeding 50%. In contrast, tumors in the NON-BRISK and ABSENT TIL groups showed significantly lower MITF expression (mean values: 32.73% ± 16.98% and 22.00% ± 10.54%, respectively), with statistically significant differences (Kruskal–Wallis test, P = 0.027; modified classification, P = 0.011). Additionally, the presence of CD20+ B lymphocytes correlated with increased MITF expression (P = 0.009). MITF gene amplification was detected in 29% of cases, though its association with protein expression showed only a trend (P = 0.058). These findings highlight the complex interplay between MITF expression and TIL distribution in melanoma, suggesting that refined TIL classification may offer deeper insights into tumor immunobiology and help predict responses to immunotherapy
Hormonal predictors of the insulin sensitive phenotype in humans
Full text linkClinical obesity, a chronic condition marked by excessive fat accumulation, often leads to insulin resistance and a heightened risk of comorbidities. This study aimed to identify hormonal predictors of an insulin-sensitive phenotype (ISP) in patients undergoing body contouring surgeries, focusing on the relationship between gut hormones, adipokines, and fat mass. ISP was defined as the highest tertile of HOMA insulin sensitivity. We prospectively followed patients undergoing abdominoplasty, lower body lift, or thigh lift at Hamad General Hospital from January 2021 to December 2023. Body composition, glycemic indices, and hormonal levels were assessed, with data analyzed using descriptive statistics and regression models. The study included 34, 22, and 27 subjects at visits 1, 2, and 3, respectively. Fat percentage decreased slightly at visits 2 and 3 compared to baseline, though not significantly. Median levels of glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), pancreatic polypeptide (PP), liver-expressed antimicrobial peptide 2 (LEAP2), and amylin varied significantly across visits, initially rising at visit 2 before declining at visit 3. Logistic regression revealed that ISP was negatively associated with serum GIP. LEAP2, and leptin levels while positively associated with PP. History of bariatric surgery was only weakly associated with the ISP after hormonal associations were accounted for. Notably, total body fat percentage did not predict ISP after accounting for hormonal factors. This study highlights GIP, PP, leptin, and LEAP2 as key predictors of ISP, with GIP being the primary negative regulator. These findings underscore the importance of hormonal interplay in insulin sensitivity, emphasizing the role of gut hormones and adipokines in predicting ISP in humans
Vitamin D and depression in adults: A systematic review
Full text linkDepression is one of the most prevalent psychiatric disorders and a leading cause of disability worldwide. Although the pathogenesis of depression remains far from fully understood, current research suggests a potential role for vitamin D due to its involvement in brain functioning. Moreover, vitamin D supplementation has shown promising results in the treatment of patients with depression. Therefore, the present study aimed to systematically review the available research investigating the association between vitamin D levels and the onset of depression. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the protocol was registered in the PROSPERO database (registration number: CRD42024515918). A search was performed across PubMed/Medline, SCOPUS, and Web of Science databases, yielding a total of 8,052 potentially eligible articles. After the removal of duplicates and ineligible records, and exclusion based on title and abstract screening, 297 original full-text articles were assessed according to the inclusion and exclusion criteria. Ultimately, 66 articles were included in this systematic review. Most of the included studies employed a cross-sectional design (N = 46). Overall, the data analyzed in this review indicate an association between depression and vitamin D serum levels, particularly in studies using cross-sectional designs. Only a few longitudinal studies demonstrated that lower vitamin D levels are associated with an increased risk of developing depressive symptoms or major depressive disorder, highlighting an important research gap. However, it remains to be established through future research whether acute or chronic vitamin D supplementation could have a protective effect against the development of depression