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Science Advances Jun 2024Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and...
Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 () by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
Topics: Animals; Glycolysis; Liver Cirrhosis; Hepatic Stellate Cells; Extracellular Vesicles; Mice; rab GTP-Binding Proteins; Humans; Disease Models, Animal; Liver; Mice, Inbred C57BL; Male
PubMed: 38941469
DOI: 10.1126/sciadv.adn5228 -
Science Advances Jun 2024Functional deficits in basal ganglia (BG) circuits contribute to cognitive and motor dysfunctions in alcohol use disorder. Chronic alcohol exposure alters synaptic...
Functional deficits in basal ganglia (BG) circuits contribute to cognitive and motor dysfunctions in alcohol use disorder. Chronic alcohol exposure alters synaptic function and neuronal excitability in the dorsal striatum, but it remains unclear how it affects BG output that is mediated by the substantia nigra pars reticulata (SNr). Here, we describe a neuronal subpopulation-specific synaptic organization of striatal and subthalamic (STN) inputs to the medial and lateral SNr. Chronic alcohol exposure (CIE) potentiated dorsolateral striatum (DLS) inputs but did not change dorsomedial striatum and STN inputs to the SNr. Chemogenetic inhibition of DLS direct pathway neurons revealed an enhanced role for DLS direct pathway neurons in execution of an instrumental lever-pressing task. Overall, we reveal a subregion-specific organization of striatal and subthalamic inputs onto the medial and lateral SNr and find that potentiated DLS-SNr inputs are accompanied by altered BG control of action execution following CIE.
Topics: Animals; Neuronal Plasticity; Basal Ganglia; Substantia Nigra; Ethanol; Corpus Striatum; Male; Mice; Neurons; Alcoholism; Neural Pathways
PubMed: 38941461
DOI: 10.1126/sciadv.adm6951 -
Medicine Jun 2024This study investigated recurrence rates and treatment efficacy based on tomographic findings during a long-term follow-up after primary spontaneous pneumothorax (PSP)...
Is there a change in the view of treatment for primary spontaneous pneumothorax?: The effect of thoracic CT and autologous blood pleurodesis: a retrospective cohort study.
This study investigated recurrence rates and treatment efficacy based on tomographic findings during a long-term follow-up after primary spontaneous pneumothorax (PSP) treatment. We retrospectively analyzed patients with PSP treated at our hospital between 2003 and 2020. Patients were categorized into 2 groups based on computed tomography (CT) findings: group 1 (no bulla/bleb) and group 2 (bullae-bleb <3 cm). Data on demographics, recurrence, treatment methods, and outcomes were also collected and compared. A total of 251 PSP cases were evaluated, predominantly male (93.6%) with a mean age of 29.23 ± 1.14 years. Most cases (57%) occurred on the right side. Recurrence rates were highest within the first year (77.8%), with the first and second recurrences occurring at rates of 26% and 27.3%, respectively. In group 1 (n = 117), conservative treatment was applied in 15 cases, tube thoracostomy in 81, autologous blood pleurodesis (ABP) in 19, and surgery in 12. Recurrence rates were 46.6%, 21%, 5.3%, and 8.3%, respectively. In group 2 (n = 134), the recurrence rates were 50%, 32.7%, 20%, and 3.1%, respectively (P < .001). No mortality was observed for any patient. The treatment groups included conservative (n = 19), thoracostomy (n = 179), ABP (n = 34), and surgical (n = 44) groups. Recurrence rates were 47.3%, 27.4%, 11.8% (group 1: 5.3%, group 2: 20%, P = .035), and 4.5% (0% vs 6.3%), respectively. ABP effectively reduced recurrence in group 1 PSP patients without bullae or blebs on CT, potentially avoiding surgery. Video-assisted thoracoscopic surgery should be preferred in group 2 cases with bullae or blebs to minimize recurrence. These results underscore the importance of tailoring treatment strategies based on CT findings to optimize PSP management outcomes.
Topics: Humans; Pneumothorax; Male; Pleurodesis; Female; Retrospective Studies; Adult; Tomography, X-Ray Computed; Recurrence; Treatment Outcome; Thoracostomy
PubMed: 38941434
DOI: 10.1097/MD.0000000000038639 -
Medicine Jun 2024Acute pancreatitis (AP) is a common emergency condition with high morbidity, mortality, and socio-economic impact. Soluble urokinase plasminogen activator receptor...
BACKGROUND
Acute pancreatitis (AP) is a common emergency condition with high morbidity, mortality, and socio-economic impact. Soluble urokinase plasminogen activator receptor (suPAR) is a potential biomarker for AP prognosis. This study systematically reviews the literature on suPAR's prognostic roles in assessing AP severity, organ failure, mortality, and other pathological markers.
METHODS
A comprehensive search of 5 databases up to March 19, 2023, was conducted, selecting cohort studies that examined suPAR's relationship with AP outcomes. Outcome variables included AP severity, organ failure, mortality, hospital stay length, and suPAR's association with other inflammatory markers. Our paper has been registered on Prospero (ID: CRD42023410628).
RESULTS
Nine prospective observational studies with 1033 AP patients were included. Seven of eight studies found suPAR significantly elevated in severe acute pancreatitis (P < .05). Four studies showed suPAR effectively predicted organ failure risk, and 4 studies concluded suPAR significantly predicted mortality (P < .05). The review had no high-risk studies, enhancing credibility.
CONCLUSION
suPAR is a valuable prognostic marker in AP, significantly predicting severity, organ failure, hospital stay length, and mortality. Further large-scale studies are needed to explore suPAR's role in other clinical outcomes related to AP disease course, to establish it as a mainstay of AP prognosis.
Topics: Humans; Pancreatitis; Receptors, Urokinase Plasminogen Activator; Prognosis; Biomarkers; Systematic Reviews as Topic; Severity of Illness Index; Length of Stay; Acute Disease
PubMed: 38941433
DOI: 10.1097/MD.0000000000037064 -
Medicine Jun 2024Schizophrenia (SPR) is the most devastating mental illness that causes severe deterioration in social and occupational functioning, but, the etiology remains unknown....
Schizophrenia (SPR) is the most devastating mental illness that causes severe deterioration in social and occupational functioning, but, the etiology remains unknown. The objective of this study is to explore the genetic underpinnings of novelty seeking behavior in schizophrenic family within the Korean population. By conducting a family-based genome-wide association study, we aim to identify potential genetic markers and variations associated with novelty seeking traits in the context of SPR. We have recruited 27 probands (with SPR) with their parents and siblings whenever possible. DNA was extracted from blood sampling of 58 individuals in 27 families and analyzed in an Illumina core exome single nucleotide polymorphism (SNP) array. A family-based association test (qFAM) was used to derive SNP association values across all chromosomes. Although none of the final 800,000 SNPs reached the genome-wide significant threshold of 8.45 × 10-7, the most significant 4 SNPs were within the 10-5 to 10-7. This study identifies genetic associations between novelty seeking behavior and SPR within families. RAPGEF5 emerges as a significant gene, along with other neuropsychiatric-related genes. Noteworthy genes like DRD4 and COMT did not show associations, possibly due to the focus on schizophrenic family. While shedding light on this complex relationship, larger studies are needed for robust conclusions and deeper mechanistic insights.
Topics: Humans; Genome-Wide Association Study; Schizophrenia; Male; Female; Polymorphism, Single Nucleotide; Republic of Korea; Pilot Projects; Exploratory Behavior; Adult; Middle Aged; Genetic Predisposition to Disease; Young Adult
PubMed: 38941432
DOI: 10.1097/MD.0000000000038694 -
Medicine Jun 2024Primary sclerosing cholangitis (PSC), a chronic cholestatic liver condition, is frequently associated with inflammatory bowel disease. Specific immune cells have been...
Primary sclerosing cholangitis (PSC), a chronic cholestatic liver condition, is frequently associated with inflammatory bowel disease. Specific immune cells have been implicated in PSC pathogenesis with the emergence of the "microbiota" and "gut lymphocyte homing" hypotheses, albeit their identities remain controversial. The first genome-wide association analysis leveraged nonoverlapping data from 3757 Europeans to evaluate 731 immunophenotypes. A genome-wide association analysis comprising 2871 cases and 12,019 controls yielded summary statistics for PSC. An inverse-variance weighted (IVW) analysis was performed to identify immunophenotypes causally related to PSC, and the results were validated using weighted mode, MR-Egger, and weighted median methods. Comprehensive sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. IVW analysis revealed 26 immune traits exhibiting causal associations with PSC. CD3 on HLA-DR+ CD4+ (IVW odds ratio [OR]: 0.904; 95% confidence interval [CI]: 0.828-0.986, P = .023) and CD3 on secreting Treg (IVW OR: 0.893; 95% CI: 0.823-0.969, P = .007) were negatively associated with PSC susceptibility and demonstrated high consistency across the 3 validation methods. Moreover, 7 other immune traits, including CD39+ resting Treg absolute cell (IVW OR = 1.083, 95% CI: 1.013-1.157, P = .019), CD39+ secreting Treg absolute cell (IVW OR = 1.063, 95% CI: 1.012-1.118, P = .015), CD3 on naive CD8br (IVW OR = 0.907, 95% CI: 0.835-0.986, P = .022), CD3 on CD39+ activated Treg (IVW OR = 0.927, 95% CI: 0.864-0.994, P = .034), CD28 on resting Treg (IVW OR = 0.724, 95% CI: 0.630-0.833, P = 5.95E-06), and CD39 on CD39+ CD4+ (IVW OR = 1.055, 95% CI: 1.001-1.112, P = .044) exhibited consistent results in the Weighted Median and Weighted Mode validation methods. Moreover, no significant heterogeneity or horizontal pleiotropy was observed across the single nucleotide polymorphisms. The leave-one-out results revealed that sequentially eliminating each single nucleotide polymorphism had no significant influence on model effect estimates or qualitative inference. This study evaluated potential causal links between 731 immune traits and PSC susceptibility. Twenty-six immune traits were identified using the IVW method. Verification across multiple methods revealed 9 immune traits with a plausible causal connection to PSC. These findings may uncover mechanistic pathways and novel therapeutic approaches.
Topics: Cholangitis, Sclerosing; Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Immunophenotyping; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide
PubMed: 38941430
DOI: 10.1097/MD.0000000000038626 -
Medicine Jun 2024We hypothesized that the triglyceride-glucose (TyG)-alanine aminotransferase (ALT) index, which combines the TyG index with ALT, may enhance sensitivity and specificity... (Observational Study)
Observational Study
We hypothesized that the triglyceride-glucose (TyG)-alanine aminotransferase (ALT) index, which combines the TyG index with ALT, may enhance sensitivity and specificity in detecting the severity of nonalcoholic fatty liver disease (NAFLD). A total of 131 NAFLD patients with a mean age of 11.5 ± 2.29 years were enrolled, and severity was assessed by ultrasound fatty liver index (US-FLI) scoring. The TyG-ALT index was defined as ln(fasting triglyceride [mg/dL] × fasting glucose [mg/dL] × ALT [IU/L]/2). Multiple linear regression analysis revealed a significant association between the TyG-ALT index and US-FLI (β = 0.317, P < .001) after controlling for sex, age, and body mass index. The TyG-ALT index showed a more stable and superior ability to detect the severity of NAFLD compared to both ALT and the TyG index. The area under the curve values, listed in the order of ALT, TyG index, and TyG-ALT index, were as follows: 0.737 (P < .001), 0.599 (P = .055), and 0.704 (P < .001) at US-FLI ≥ 4 points; 0.717 (P < .001), 0.720 (P < .001), and 0.775 (P < .001) at US-FLI ≥ 5 points; and 0.689 (P < .05), 0.748 (P < .01), and 0.775 (P < .001) at US-FLI ≥ 6 points. The TyG-ALT index is associated with US-FLI score and superior to both ALT and the TyG index in predicting NAFLD severity. These findings indicate the potential of the TyG-ALT index in the management of pediatric NAFLD progression.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Male; Female; Triglycerides; Child; Alanine Transaminase; Severity of Illness Index; Blood Glucose; Adolescent; Ultrasonography; Biomarkers; Sensitivity and Specificity
PubMed: 38941428
DOI: 10.1097/MD.0000000000038241 -
Medicine Jun 2024Rosacea is a chronic and recurrent inflammatory skin disease affecting the center of the face that causes burning and itching sensations and changes in aesthetics. Liang...
Rosacea is a chronic and recurrent inflammatory skin disease affecting the center of the face that causes burning and itching sensations and changes in aesthetics. Liang Xue Wu Hua Tang (LXWHT) is a classic herbal formulation that is efficacious and has been widely used in the clinical treatment of rosacea; however, the pharmacological mechanisms remain unclear. The aim of the present study was to investigate the mechanism of action of LXWHT using network pharmacology and molecular docking. The Traditional Chinese Medicine System Pharmacology database was searched to identify the active ingredients and pharmacological targets of LXWHT, and the GeneCard, Disgenet, and Gene Expression Omnibus databases were applied to screen rosacea-related targets. Cytoscape software was used to visualize the protein-protein interaction network, and network topology analysis was used to identify core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed for the core targets. Molecular docking simulations and visualization were performed using Maestro and PyMOL, respectively. A total of 43 active compounds and 28 potential targets for LXWHT treatment of rosacea were selected for analysis. The Gene Ontology/Kyoto Encyclopedia of Genes and Genomes results indicated that LXWHT may exert therapeutic effects on rosacea by intervening in immune pathways including tumor necrosis factor pathway, interleukin-17 pathways, and Toll-like receptor signaling pathways. Chemokine ligand 2, interferon-γ, interleukin-1ß, peroxisome proliferator-activated receptor-γ, and matrix metallopeptidase 9 may be the core therapeutic target. Quercetin, stigmasterol, kaempferol, beta-sitosterol, luteolin, beta-carotene, baicalein, acetin, and isorhamnetin were predicted to be the key active ingredients. LXWHT may exert therapeutic effects in the treatment of rosacea by modulating immunity and angiogenesis, laying the foundation for further research.
Topics: Rosacea; Molecular Docking Simulation; Humans; Drugs, Chinese Herbal; Network Pharmacology; Protein Interaction Maps; Medicine, Chinese Traditional
PubMed: 38941423
DOI: 10.1097/MD.0000000000038705 -
Medicine Jun 2024Reproductive health issues, including unsafe pregnancy termination, remain a significant concern for women in developing nations. This study focused on investigating and...
Reproductive health issues, including unsafe pregnancy termination, remain a significant concern for women in developing nations. This study focused on investigating and predicting pregnancy termination in Bangladesh by employing a hybrid machine learning approach. The analysis used data from the Bangladesh Demographic and Health Surveys conducted in 2011, 2014, and 2017 to 2018. Ten independent variables, encompassing factors such as age, residence, division, wealth index, working status, BMI, total number of children ever born, recent births, and number of living children, were examined for their potential associations with pregnancy termination. The dataset undergoes preprocessing, addressing missing values and balancing class distributions. To predict pregnancy termination, 8 classical machine learning models and hybrid models were used in this study. The models' performance was evaluated based on the area under the curve, precision, recall, and F1 score. The results highlighted the effectiveness of the hybrid models, particularly the Voting hybrid model (area under the curve: 91.97; precision: 84.14; recall: 83.87; F1 score: 83.84), in accurately predicting pregnancy termination. Notable predictors include age, division, and wealth index. These findings hold significance for policy interventions aiming to reduce pregnancy termination rates, emphasizing the necessity for tailored approaches that consider regional disparities and socioeconomic factors. Overall, the study demonstrates the efficacy of hybrid machine learning models in comprehending and forecasting pregnancy termination, offering valuable insights for reproductive health initiatives in Bangladesh and similar contexts.
Topics: Bangladesh; Humans; Machine Learning; Female; Pregnancy; Abortion, Induced; Adult; Young Adult; Socioeconomic Factors; Adolescent; Middle Aged
PubMed: 38941421
DOI: 10.1097/MD.0000000000038709 -
Medicine Jun 2024Observational studies have reported a relationship between multiple common dermatoses and mental illness. To assess the potential bidirectional causality between 3 skin...
Observational studies have reported a relationship between multiple common dermatoses and mental illness. To assess the potential bidirectional causality between 3 skin disorders (psoriasis, eczema, and urticaria) and 4 psychiatric disorders (bipolar disorder, schizophrenia, major depressive disorder, and anxiety) in the European population, we used Mendelian randomization (MR) analysis, which provides definitive evidence for causal inference. Eligible single nucleotide polymorphisms were screened for dermatological and psychiatric disorders using a genome-wide association study database. We conducted bidirectional, 2-sample MR analysis using instrumental variables related to psoriasis, eczema, and urticaria as exposure factors, and bipolar disorder, schizophrenia, major depression, and anxiety as outcomes. Reverse MR analysis with bipolar disorder, schizophrenia, major depression, and anxiety as exposure and psoriasis, eczema, and urticaria as outcomes were also performed, and the causality was analyzed using inverse-variance weighting (IVW), MR-Egger, and weighted median methods. To thoroughly assess causality, sensitivity analyses were conducted using the IVW, MR-PRESSO, and MR-Egger methods. The results showed that bipolar disorder increased the incidence of psoriasis (odds ratio = 1.271, 95% confidence interval = 1.003-1.612, P = .047), heterogeneity test with Cochran Q test in the IVW showed P value > .05, (P = .302), the MR-Pleiotropy and MR-PRESSO (outlier methods) in the multiplicity test showed P value > .05, (P = .694; P = .441), and MR-Pleiotropy evidence showed no apparent intercept (intercept = -0.060; SE = 0.139; P = .694). Major depression increased the risk of eczema (odds ratio = 1.002, 95% confidence interval = 1.000-1.004, P = .024), heterogeneity test showed P value > .05, (P = .328), multiplicity detection showed P value > .05, (P = .572; P = .340), and MR-Pleiotropy evidence showed no apparent intercept (intercept = -0.099; SE = 0.162; P = .572). Sensitivity analyses of the above results were reliable, and no heterogeneity or multiplicity was found. This study demonstrated a statistically significant causality between bipolar disorder and psoriasis, major depression, and eczema in a European population, which could provide important information for physicians in the clinical management of common skin conditions.
Topics: Humans; Mendelian Randomization Analysis; Psoriasis; Eczema; Europe; Polymorphism, Single Nucleotide; Urticaria; Mental Disorders; Genome-Wide Association Study; Bipolar Disorder; Female; Schizophrenia; Depressive Disorder, Major; Causality; Male
PubMed: 38941419
DOI: 10.1097/MD.0000000000038586