Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsinyD V Vankov, O V Obukhova, I A Deev, M A Ivanova
The diseases of circulatory system represent one of the main problems of the population health due to corresponding high morbidity and mortality and load on health care. The purpose of the study is to evaluate direct and indirect costs of medical care under acute coronary syndrome depending on level of medical organization. The study used content-analysis, statistical and analytical methods scientific publications on the research topic, copying of data from the medical documentation of the Vologda Regional Clinical Hospital for the period 2012-2021. The significant number of publications confirm that diseases of circulatory system develop due to multitude of risk factors. Also economic and medical effectiveness of timely applied medical care of diseases of the circulatory system is proved. It is demonstrated that medical care and cardiac rehabilitation under acute coronary syndrome are the most resource-wasteful types of medical care, while prevention of development of disease allows to save human, material and financial resources. In the medium perspective, economic damage under the worst scenario of development of disease when disability is set in makes up to about 400.000 rubles and in case of death of patient, more than five million rubles. Under acute coronary syndrome, medical, social and economic efficiency of emergency medical care is higher in medical organizations of the 3rd level. However, it is more economically advantageous to implement preventive measures.
Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsinyM V Botnaryuk, Y A Lepekhina
The sailors more often than other professional groups are forced to work in extreme conditions associated with heat, humidity and low temperatures (passage of tropical and northern latitudes). Therefore, they are at risk of development of various diseases and the most dangerous are cardiovascular ones. Despite taken protective measures, the number of crew members of merchant marine vessel complaining on poor well-being continues to increase, including at the expense of disorders of heart and vascular functioning. With purpose to enhance measures preventing development of cardiovascular diseases that currently are not always detected during pre-voyage medical examination and result in health deterioration and lethal outcomes, the article proposes a number of practical recommendations. It is relevant to carry out genetic examination before starting voyage in order to identify risks of development of occupational diseases in sailors older than 40 years. To equip vessel with portable cardiograph will contribute to timely detection of physiological changes in heart functioning of of crew member and will reduce possibility of occurrence of life-threatening conditions. The issuing of voluntary medical insurance program will permit to apply more in-depth diagnostics with purpose to increase possibility to detect cardiovascular diseases at early stage.
Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsinyA B Dzhanaliev, N K Kasiev, M Kulzhanov
The diseases of circulatory system continue to occupy leading positions in structure of morbidity and mortality of population, remaining one of key public health problems. The purpose of the study is to investigate dynamics of primary morbidity and prevalence of diseases of circulatory system by main nosological forms among adult and adolescent population of the Kyrgyz Republic in 2018-2024. The study used official data from the Center for E-Health Care that was analyzed using retrospective, statistical and comparative analytical methods. It was found that indicators of primary morbidity and prevalence were characterized by pronounced variability with greatest increase in 2022, against the background of decrease in 2020-2021, that may be due to changes in availability of medical care in period of COVID-19 pandemic. The highest levels of morbidity and prevalence were found for hypertension, coronary heart disease and cerebrovascular diseases. Some nosologies, including myocardial infarction and other peripheral vascular diseases, demonstrated sharp increase in indicators, suggesting changes in disease detection and health care seeking behavior of population. The obtained results confirm necessity to improve system of monitoring, prevention and early detection of cardiovascular diseases, especially among high-risk groups.
Annals of medicineDan He, Hua Li, Chunling Wei, Chen Chen, Juanjuan Li
BACKGROUND: Retinal ischemia-reperfusion (RIR) injury impairs vision through microvascular damage and inflammation. While astrocyte-derived exosomes (ADEs) offer neuroprotection, their role in protecting retinal microvasculature is unclear. This study investigates ADEs' effects on retinal microvascular endothelial cells (RMECs) in RIR. METHODS: ADEs were isolated from astrocytes. Mouse RIR and cellular oxygen-glucose deprivation/reoxygenation (OGD/R) models were used. We assessed ADEs' impact on retinal microcirculation, microglial activation, and RMEC function. The roles of neurogranin and the CaMKII-autophagy pathway were examined using inhibitors. RESULTS: ADEs, rich in neurogranin, alleviated RIR-induced microvascular damage and suppressed OGD/R-triggered pro-inflammatory microglial activation. This was associated with increased neurogranin, CaMKII phosphorylation, and autophagy in microglia. Consequently, ADEs counteracted the harmful effects of activated microglia on RMEC proliferation, migration, and tube formation. Inhibiting CaMKII or autophagy blocked ADEs' protective benefits without altering neurogranin, placing the CaMKII-autophagy axis downstream. CONCLUSION: ADEs protect RMECs from RIR injury by modulating microglial responses via a neurogranin-CaMKII-autophagy mechanism, revealing their therapeutic potential for retinal microvascular protection.
PulmonologyDavid Jimenez, Behnood Bikdeli, Victor Tapson, Cecilia Becattini, Lisa Moores, Geoffrey D Barnes, Manuel Monreal, Stavros Konstantinides, Gregory Piazza, Raque…
BACKGROUND: For patients with acute pulmonary embolism (PE), assessment of prognosis helps with risk stratification, triage for level of care, management strategy, and communication among healthcare workers and patients. We sought to identify prognostic models and individual factors associated with short-term outcomes after acute symptomatic PE. METHODS: We performed a systematic review of prognostic factors for PE, searching MEDLINE, Embase, and Web of Science for records up to 1 June 2024. Studies of any design evaluating potential prognostic models or individual variables (not contained in the models) associated with short-term mortality after acute PE were included. RESULTS: We identified 314 studies that included 2,495,115 patients. Of these, 225 studies included 2,267,952 patients and evaluated 24 prognostic models for patients with acute PE. The most frequently used validated models were the simplified Pulmonary Embolism Severity Index (sPESI) (127 studies), the original PESI (79 studies), and the European Society of Cardiology risk schema (34 studies). Each model-development study had a c-index ≥ 0.7. Individual factors associated with prognosis included older age, presence of coexisting conditions, abnormal clinical signs and symptoms, clot burden, markers of right‑ventricle dilatation/dysfunction and myocardial injury, altered laboratory results indicating impaired haemodynamics, and tests that assess for systemic inflammation. Pooled odds ratios for variables not contained in any eligible prognostic model ranged from 1.43 (for D-dimer) to 2.65 (for right heart thrombi). CONCLUSIONS: This systematic review identified 24 prognostic models and 18 individual variables distinct from the prognostic models associated with short-term mortality after acute PE.
BACKGROUND: Left ventricular thrombus (LVT) is a significant complication in ischemic cardiomyopathy (ICM). However, factors associated with LVT have mainly been reported in patients with recent myocardial infarction (MI), while data in chronic ICM remain limited. This study aimed to identify factors associated with CMR-detected LVT in patients with chronic ICM (left ventricular ejection fraction [LVEF] < 50% of ischemic etiology, >40 days post-MI), develop a CMR-based risk score, and evaluate the prognostic implications of LVT on major adverse cardiovascular events (MACE). METHODS: This study included 790 patients with ICM who underwent CMR at an academic hospital in Thailand between 2016 and 2023. Factors associated with LVT were identified using logistic regression analyses. A CMR-based risk score was developed and validated, with discriminative performance assessed by the area under the receiver operating characteristic curve (AUC-ROC). MACE, defined as a composite of cardiovascular death, ischemic stroke, transient ischemic attack, systemic embolism, nonfatal MI, or heart failure hospitalization, was also evaluated. Factors associated with MACE were assessed using Cox regression analysis. RESULTS: The mean age was 66.9 ± 11.3 years, and 75.3% were male. LVT was detected in 116 patients. Independent factors associated with LVT included apical aneurysm, apical late gadolinium enhancement (LGE), and the number of LGE segments. The CMR-LVT Score, incorporating these variables, demonstrated an AUC of 0.73 (95%CI, 0.68-0.77;p < 0.001) in the derivation cohort and 0.79 (95%CI, 0.69-0.90;p < 0.001) in the validation cohort. During a median follow-up of 3.2 years (IQR, 1.6-5.5), 150 MACE occurred. Baseline LVT was independently associated with MACE (adjusted HR 2.38, 95%CI 1.31-4.30;p = 0.004). CONCLUSIONS: In patients with ICM undergoing CMR, apical aneurysm, apical LGE, and LGE extent were independently associated with LVT. The CMR-LVT Score demonstrated acceptable discriminative performance for identifying higher-risk patients who may benefit from more intensive follow-up. LVT was also independently associated with MACE.
Clinical and experimental hypertension (New York, N.Y. : 1993)Gulsum Ozkan, Caner Celik, Hilmi Tozkir, Semih Asıkovali, Nergiz Bayrakci
OBJECTIVE: Hyponatremia is one of the most common electrolyte disorders in clinical practice and is frequently observed following thiazide use. Advanced age and female gender are implicated in the etiology of hydrochlorothiazide (HCTZ)-associated hyponatremia. There has also recently been mention of a genetic disposition. This study evaluated the genetic component, and particularly the clinical significance, of variants in the SLC12A3 gene in the development of hyponatremia in hypertensive patients using HCTZ-group diuretics. METHOD: Ninety-five patients presenting to the Tekirdağ Namık Kemal University nephrology clinic and receiving antihypertensive therapy including HCTZ for at least one month were examined. Peripheral blood specimens were collected from hyponatremic (n = 62) and non-hyponatremic (n = 33) individuals. Variants in the SLC12A3 gene were analyzed using next generation sequencing and were compared with the clinical data. RESULTS: A total of 947 variants were detected in the SLC12A3 gene, the majority of which were classified as of uncertain significance. Hyponatremia was determined at a higher rate in patients with c.506-276A>G (75.00%), c.282+492G>A (85.70%), c.282+499G>C (87.00%), c.282+495G>A (85.00%), and c.505+375G>A (92.30%) variants in particular. The risk of hyponatremia development increased 9.2-fold in the presence of the c.282+492G>A variant (OR = 9.243; 95% CI: 2.259-37.818; p = 0.002). CONCLUSION: In conclusion, we think that HCTZ-associated hyponatremia cannot be predicted by clinical and biochemical parameters alone, and that genetic factors should also be considered. Further multi-center prospective studies involving larger populations will clarify the clinical significance of variants in SLC12A3 and other genes and will make a significant contribution to individualized therapeutic approaches.
Annals of medicineKo Eun Kim, Yerin Lee, Hyunyoung Kang, Dai Hyun Kim, Hwan Kyu Roh, Sejung Yang, Beom Suk Kim
BACKGROUND: Chronic venous insufficiency (CVI) produces heterogeneous lower-extremity skin changes that often mimic inflammatory dermatoses, complicating the differentiation between venous etiologies and conditions requiring dermatologic care. Coexisting venous signs further confound visual interpretation, leading to diagnostic variability. To address this unmet clinical need, we developed and externally validated a pose-guided, high-resolution deep learning pipeline to classify CVI-related skin lesions from routine clinical photographs. MATERIALS AND METHODS: A deep learning framework was developed using a multicentre dataset (8672 images) from Korea University Guro Hospital, Chung-Ang University Gwangmyeong Hospital and Heartwell Vein Clinic. The pipeline integrated Sapiens-based pose estimation for limb localization and a U-Net model refined with Segment Anything Model 2 (SAM2) for skin segmentation. Multiple backbone architectures were evaluated, and ResNet-34 was selected based on optimal performance, taking refined masks and RGB images as input. Performance was evaluated on an internal test set, an independent clinical dataset (n = 183), and the Fitzpatrick17k dataset. RESULTS: ResNet-34 emerged as the optimal architecture, achieving an internal AUROC of 0.922 with balanced sensitivity (0.679) and specificity (0.943) at 1024 × 1024 resolution. Pose-guided skin segmentation improved discrimination compared to using raw images (AUROC 0.920) or skin masking alone (AUROC 0.905). Multicentre training enhanced generalizability, yielding an external AUROC of 0.877 and maintaining high performance on the Fitzpatrick17k dataset (sensitivity 0.918). CONCLUSIONS: Our pose-guided, high-resolution pipeline enables robust, objective detection of CVI-related skin lesions. By demonstrating high generalizability across multicentre and public datasets, this framework serves as a reliable decision-support tool to standardize clinical phenotyping and facilitate consistent triage and management of chronic venous disease across diverse care settings.
Although cardiovascular complications are the most common cause of morbidity and mortality in chronic kidney disease (CKD), the detection of subclinical cardiorenal remodeling is still limited. This is a single-center, exploratory observational study of 127 patients with CKD of various etiologies (hypertensive nephropathy, diabetic nephropathy and chronic glomerulonephritis) and 30 healthy controls. In addition to transthoracic echocardiography at rest and after exercise, biomarkers of podocyte injury (urinary nephrin), fibrosis (urinary type IV collagen and serum galectin-3), cardiac wall stress (serum NT-proBNP) and renal filtration/cardiovascular risk integration (serum cystatin C) were assessed. Biomarker abnormalities were consistent across all CKD groups, even in the absence of overt heart-failure symptoms and preserved ejection fraction. Urinary nephrin and type IV collagen were significantly increased, as were galectin-3 and NT-proBNP concentrations. All CKD groups had resting E/e' values above the normal range and these values were further elevated following exercise. Nephrin showed a strong positive correlation with E/e' and post-exercise echocardiography was associated with greater discrimination of an operationally defined subclinical cardiorenal phenotype than resting imaging. These exploratory findings indicate that a combined biomarker and echocardiographic profile is associated with an early cardiorenal phenotype and may assist in risk stratification of patients with CKD exhibiting early cardiorenal remodeling prior to the development of overt heart failure; they are hypothesis-generating and not intended to set diagnostic criteria. Prior to implementing this multimarker strategy clinically, larger, multicenter prospective studies with multivariable adjustment and external validation should be performed.
Annals of medicineChieh-Sen Chuang, Chew-Teng Kor, Shu-Yi Wang, Ying-Lin Hsu
OBJECTIVES: To evaluate the effectiveness and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in elderly patients with type 2 diabetes mellitus, with particular focus on renal and cardiovascular outcomes. METHODS: This retrospective cohort study analyzed data from 9,915 diabetic patients aged ≥65 years who received antihyperglycemic therapy at Changhua Christian Hospital, Taiwan, between January 2021 and September 2023. Patients were categorized as SGLT2 inhibitor users (n = 3,345) or non-users (n = 6,570). After 1:1 propensity score matching, 1,529 patients remained in each group. Primary outcomes included renal function (measured by eGFR decline), coronary artery disease, ischemic stroke, and heart failure. Secondary outcomes included urinary tract infection, genital infection, diabetic ketoacidosis, and hypoglycemia. RESULTS: SGLT2 inhibitor use was associated with significant renoprotective effects, demonstrated by reduced risk of 30% eGFR decline (HR 0.69, 95% CI 0.59-0.80, p < 0.001) and 50% eGFR decline (HR 0.60, 95% CI 0.45-0.80, p < 0.001). Subgroup analyses revealed that renoprotective effects were more pronounced in patients with higher baseline eGFR (≥50 mL/min/1.73 m2), suggesting greater benefit with early initiation of SGLT2 inhibitors for kidney protection. However, SGLT2 inhibitor use was associated with an increased risk of genital infections (HR 4.29, 95% CI 1.02-18.04, p = 0.047) in patients without prior history of such infections. CONCLUSIONS: In elderly patients with type 2 diabetes, SGLT2 inhibitors demonstrate significant renal protective effects, particularly among those with preserved renal function (eGFR ≥50 mL/min/1.73 m2). These findings highlight the importance of considering patient characteristics when evaluating potential benefits of SGLT2 inhibitor therapy. The differential risk patterns suggest that clinicians should consider individual patient profiles and medical histories when prescribing these medications. The occurrence of major adverse cardiovascular events (MACE) did not exhibit a statistically significant difference between the cohort administered SGLT2 inhibitors and the cohort not receiving SGLT2 inhibitors (log-rank p-value = 0.160). Conversely, the recurrence of MACE was markedly reduced in the cohort receiving SGLT2 inhibitors (log-rank p-value < 0.001). These findings should be interpreted in the context of a single-center retrospective design and the inherent limitations of propensity-score-matched observational analyses.
Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) reduces thrombotic risk in acute coronary syndrome (ACS) but may increase bleeding, especially in chronic kidney disease (CKD). This study evaluated the impact of different DAPT durations on cardiovascular and bleeding outcomes in ACS patients with and without CKD. Using the Taiwan National Health Insurance Research Database (2001-2018), patients ≥20 years with ACS who underwent PCI and received clopidogrel plus aspirin for ≥1 month were analyzed. Primary outcomes were cardiovascular events and bleeding events. Subgroup analysis was conducted by CKD status, which was defined using claims-based International Classification of Diseases, Ninth and Tenth Revision (ICD-9/ICD-10) diagnostic codes. Among 4,800 patients with ACS identified (median age: 62 years; 77% male), there were no significant differences in cardiovascular events across DAPT duration groups. No associations between DAPT duration and cardiovascular outcomes were identified in patients with or without CKD. However, DAPT duration ≥7 months was associated with a higher incidence of other major bleeding in patients with CKD (adjusted odds ratio [aOR] = 29.7, 95% confidence interval [CI]: 1.80-491.05, p = 0.018). In patients undergoing PCI for ACS, no clear association was observed between longer DAPT duration and reduced cardiovascular events. In prespecified subgroup analyses, prolonged DAPT was associated with a higher incidence of bleeding events among patients with claims-defined CKD; however, this finding should be interpreted as exploratory given the observational design and low event rates. These results highlight the importance of individualized decision-making regarding DAPT duration, particularly in patients with increased bleeding susceptibility.
Hematology (Amsterdam, Netherlands)Ojan Ghodsi, Ali Ghasemi, Saleh Ahangari
OBJECTIVE: Gastrointestinal bleeding (GIB) is a major cause of morbidity in von Willebrand disease (vWD), most commonly resulting from angiodysplasia. Current obscure gastrointestinal bleeding (OGIB) algorithms are primarily anatomy-based and often overlook underlying hemostatic disorders, delaying diagnosis and promoting recurrent bleeding. This review summarizes current evidence on the molecular basis, diagnosis, and management of vWD-associated GIB and proposes a mechanism-oriented diagnostic framework. METHODS: A comprehensive narrative review of experimental, translational, and clinical studies was conducted, focusing on inherited vWD, acquired von Willebrand syndrome (AvWS), gastrointestinal angiodysplasia, endothelial biology, and diagnostic and therapeutic strategies. RESULTS: Deficiency or dysfunction of high-molecular-weight von Willebrand factor (vWF) multimers promotes angiodysplasia by disrupting Weibel-Palade body homeostasis, enhancing Ang-2/Tie2 and VEGF signaling, impairing integrin αvβ3 function, and fostering pro-inflammatory endothelial activation. Genetic and epigenetic modifiers, including FLI1, STXBP5, ABO blood group, and miR-24, further influence vascular susceptibility. Based on these mechanisms, we propose a four-stage diagnostic framework integrating bleeding assessment, platelet function screening, and targeted vWF testing with conventional endoscopic evaluation to facilitate earlier recognition of vWD/AvWS in patients with recurrent or obscure GIB. This strategy supports mechanism-based treatment combining hemostatic replacement therapies with selected anti-angiogenic approaches. CONCLUSION: vWD-associated GIB should be regarded as a systemic vascular-hemostatic disorder rather than an isolated structural gastrointestinal disease. Integrating hemostatic evaluation into OGIB pathways may improve diagnostic accuracy, reduce unnecessary procedures, and enable personalized management of patients with recurrent bleeding.
Retinal ischemia-reperfusion injury (RIR) is the main pathogenic mechanisms of acute glaucoma, diabetic retinopathy, central retinal vein occlusion. As a common post-transcriptional modification of eukaryotic RNAs, N6-methyladenosine (m6A) is associated with the pathogenesis of different diseases, including angiogenesis, through the regulation of RNA metabolism and functions. The aim of this study was to identify the potential relevance of m6A RNA methylation in pathogenesis of RIR. A total of 10,851 mRNAs and 23,270 associated m6A methylation modified peaks were identified in the RIR group. Similarly, 10,391 mRNAs and 22,935 associated m6A methylation modified peaks were detected in the Sham group. MeRIP-seq identified 3,871 RIR-specific m6A peaks and 3,624 Sham-specific m6A peaks, in addition to 19,399 shared peaks between groups. Gene ontology (GO) analysis showed that hypermethylated mRNAs were enriched in cellular process, cellular anatomical entity, and binding, while hypomethylated mRNAs were enriched in synaptic signaling, synapse, and gated channel activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that hypermethylated mRNAs were involved in tight junction, hippo signaling pathway, and PI3K-Akt signaling pathway, while hypomethylated mRNAs were involved in Neuroactive ligand-receptor interaction, glutamatergic synapses, cholinergic synapses. Joint analysis identified mRNAs with differential m6A methylation and expression simultaneously. Among them, the expression patterns of Irx4, Kdr, and Lyz2 were confirmed by RT-qPCR to be consistent with the sequencing results. The results revealed an altered m6A epitranscriptome in RIR retinas. These methylated RNAs may act as novel modulators and targets in RIR.
BACKGROUND: Patients undergoing dialysis are at an elevated risk of cardiovascular events. This study aimed to develop machine learning (ML) prediction models to identify risk factors for major adverse cardiovascular events (MACE) in dialysis patients. MATERIALS AND METHODS: This retrospective study included 203 patients undergoing dialysis with a median age of 45.0 years and 64.0% male. The participants were divided into training and test sets in a 7:3 ratio. LASSO regression selected characteristic variables from patients'general information, laboratory tests, and echocardiographic parameters (including global longitudinal strain [GLS]). Eight ML models were constructed,and SHAP analysis evaluated feature importance. RESULTS: The incidence of MACE (including myocardial infarction, unstable angina, heart failure, and cardiovascular death) in dialysis patients was 38.92%. The average follow-up period was 18 months. LASSO regression identified eight feature variables. Among the ML models, AdaBoost demonstrated superior performance, with an AUC of 0.883 (95% CI: 0.830-0.937), accuracy of 0.804, sensitivity of 0.864 and specificity of 0.762 in the training set, and an AUC of 0.809 (95% CI: 0.706-0.912), accuracy of 0.750, sensitivity of 0.90 and specificity of 0.675 in the test set. The SHAP analysis identified N-terminal pro-brain natriuretic peptide (NT-proBNP) level, estimated glomerular filtration rate (eGFR), GLS and age as the four most important features for predicting MACE in patients undergoing dialysis (mean absolute SHAP values: 0.199, 0.176, 0.096 and 0.091, respectively). CONCLUSION: Elevated NT-proBNP, advanced age, reduced eGFR and impaired GLS were independently associated with an increased risk of MACE in patients undergoing dialysis.
Gynecological endocrinology : the official journal of the International Society of Gynecological EndocrinologyPaul Charles M Piette, James A Simon
OBJECTIVE: Identify estradiol serum levels associated with vasomotor symptom relief and assess their effects on osteoporosis and cardiovascular prevention using an estradiol hydro-alcoholic gel formulation. METHODS: Estradiol serum concentrations from two pivotal efficacy and safety trials with transdermal (TdL) estradiol gel were compared to those reported in the KEEPS and ELITE trials regarding skeletal and cardiovascular disease prevention. RESULTS: A total of 567 patients were included in the intent-to-treat efficacy population. In the first study (n = 216), the daily 2.5 g dose of TdL E2 gel reduced the moderate to severe hot flash frequency from a baseline of 10.5 to 2.0 ± 4.2 (-82%). In the second study (n = 351), a daily 2.5 g dose of TdL E2 gel reduced moderate-to-severe hot flushes from 11.8 to 2.3 ± 3.8, similar to the TdL E2 patch, which decreased them from 10.9 to 1.3 ± 3.2. The serum concentrations of E2 from patients receiving the TdL E2 gel once daily were within the normal range of young premenopausal women in the mid-follicular phase, with a proportional dose‒response effect. CONCLUSIONS: These results on vasomotor symptoms are consistent with the optimal cardiovascular and skeletal benefits observed in KEEPS (TdL estradiol) and ELITE (oral estradiol), corresponding to serum levels of approximately 60 pg/mL.
EpigeneticsYang Liu, Zijun Wang, Youxiao Zhao, Yanyan Ma, Jing Yi, Yingnan Song, Yanqiu Liu, Li An, Zhijun Pan, Hong Gao, Ying Cao
DNA methylation has traditionally been regarded as a stable epigenetic modification. However, emerging evidence indicates that oxidative and genotoxic stress can induce locus-specific methylation changes that modulate transcriptional responses. The contribution of such dynamic regulation to cardiac gene expression during myocardial ischemia/reperfusion injury (MIRI) remains incompletely understood. This study investigated whether altered methylation changes within the Gja1 promoter region are associated with connexin43 (Cx43) remodeling during MIRI. Male C57BL/6 mice were underwent global hypothermic I/R using a Langendorff-perfused heart model, with or without pretreatment using the DNA methyltransferase inhibitor 5-azacytidine (5-Aza, 3 μg/g body weight, i.p.). Gja1 promoter methylation was analyzed by BSP and MSP, while Dnmt1 enrichment was assessed by chromatin immunoprecipitation. Cx43 expression and localization were examined by qRT-PCR, Western blotting, and immunofluorescence, together with electrophysiological and histological analyses. MIRI was associated with Dnmt1 upregulation and nuclear enrichment, accompanied by altered methylation signals at selected CpG sites within the examined Gja1 promoter region and transcriptional repression. These changes coincided with reduced Cx43 expression, altered subcellular localization, impaired electrical conduction and increased arrhythmia susceptibility. Pretreatment with 5-Aza partially attenuated Gja1 promoter methylation signals and preserved Cx43 expression and localization during subsequent MIRI. These findings support an association between Dnmt1 enrichment, alteredGja1promoter CpG methylation, and Cx43 remodeling under reperfusion stress, suggesting that methylation-related epigenetic regulation may participate in Gja1 transcriptional responses during MIRI. Further temporal and gene-specific validation will be required to establish the kinetics and causal specificity of this pathway.
Gut microbesGautham Siddarth Ragunagam, Anand Anbarasu, Gothandam Kodiveri Muthukaliannan
Fusobacterium nucleatum has emerged as a pathobiont that associates oral dysbiosis with systemic diseases through coaggregation, hematogenous dissemination, and immune modulation. This review provides molecular insights through which they are involved in systemic diseases such as colorectal cancer, adverse pregnancy outcomes, cardiovascular diseases, neurodegenerative disorders, and diabetes mellitus. Key virulence factors include the adhesins of FadA, Fap2, and RadD, lipopolysaccharides, and outer membrane vesicles, which mediate epithelial invasion and endothelial permeafbility and facilitate immune suppression through TLR4-NF-κB, β-catenin/Wnt, and MAPK signaling pathways. These interactions result in impaired tissue homeostasis, propagate chronic inflammation, and promote oncogenic and metabolic modulation. Systemic pleiotropy of F. nucleatum is further substantiated by its involvement in chemoresistance, placental dysfunction, vascular inflammation, and neuronal injury, substantiating its systemic pleiotropy. Emerging therapeutic strategies, such as blocking adhesins, neutralizing outer membrane vesicles, microbiome manipulation, and using CRISPR-based clearance, provide precision techniques for mitigating diseases. Therefore, this review identifies F. nucleatum as the primary microbial mediator of oral-systemic pathology and its translational significance in the development of targeted antimicrobial and host-directed therapies.
Clinical and experimental hypertension (New York, N.Y. : 1993)Keng Zhong, Libo Zhao, Chengliang Cai, Jianhui Peng, Shangyi Yu, Jiajun Pan, Xuechao Zhang, Yanren Lu, Qing Xue, Guanxin Zhang
OBJECTIVE: Aortic dissection (AD) is a fatal cardiovascular emergency that is predominantly induced by long-term uncontrolled hypertension. MATERIALS AND METHODS: The mouse AD model was established by combining β-aminopropionitrile with angiotensin II. The incidence rate, rupture rate, and survival status of the mice were evaluated. The structural damage of the aorta was observed using tissue staining technology, the extracellular matrix status, and macrophage pyroptosis were evaluated by immunofluorescence staining, the infiltration of inflammatory cells was detected by immunohistochemistry, the expression of pyroptosis-related molecules, and inflammatory factors was analyzed by Western blotting and enzyme-linked immunosorbent assay (ELISA). Cell proliferation was detected by EdU staining, and cell apoptosis was detected by flow cytometry. RESULTS: In the aortic tissues of AD model mice, the expression of APN, and the content of APN in the serum were significantly decreased. APN intervention can alleviate the thickening of the aortic media, rupture of elastic fibers, and degradation of the extracellular matrix. APN inhibits the proliferation, apoptosis, and phenotypic transformation of vascular smooth muscle cells (VSMCs). At the same time, it can inhibit the infiltration of neutrophils and macrophages and the inflammatory response. Underlying mechanism, it was found that APN inhibited NLRP3-mediated pyroptosis by reducing the release of inflammatory factors; this effect was dependent on the phosphorylation activation of AMPKα and APN receptor. CONCLUSION: APN plays a protective role in AD. Its underlying mechanism is related to the activation of the AMPK pathway, which in turn inhibits macrophage pyroptosis and vascular inflammation. This study offers a new perspective for the pathological mechanism of AD.
Gynecological endocrinology : the official journal of the International Society of Gynecological EndocrinologyKatalin Widmann, Marlene Hager, Lisa-Maria Windischbauer, Robert Krysiak, Johannes Ott
OBJECTIVE: Women with Turner syndrome (TS) are at increased risk of reduced bone mineral density (BMD) due to primary ovarian insufficiency. This study aimed to assess longitudinal changes in BMD in TS patients receiving oral or transdermal hormone replacement therapy (HRT) and to identify factors associated with bone density decline. METHODS: This retrospective pilot study included 40 TS patients treated with oral or transdermal estradiol. The median age was 22 years in both the transdermal (20-30) and oral (20-27) groups. Median BMI was 23.1 (21.1-25.5) and 25.4 (22.1-29.1), respectively. Dual-energy X-ray absorptiometry (DEXA) of the lumbar spine and femoral neck was performed at baseline and follow-up. The primary outcome was the t-score at both sites. Univariable and multivariable logistic regression analyses were used to identify factors associated with declining t-scores. RESULTS: At baseline, 38.3% of patients had osteopenia, and 3.3% had osteoporosis. During follow-up, a decline in t-scores at at-least one skeletal site was observed in 47.5% of patients. No significant differences were found between oral and transdermal estradiol therapy regarding absolute t-scores, t-score changes, or the proportion of patients with declining t-scores (all p > 0.05). In multivariable analysis, lower vitamin D levels at follow-up were independently associated with declining t-scores. CONCLUSIONS: In TS patients, the route of estradiol administration did not significantly affect long-term BMD outcomes. Despite HRT, a substantial proportion of patients experienced bone loss. Vitamin D status has emerged as the most relevant modifiable factor associated with declining BMD, highlighting the need for bone health management beyond HRT.
Gut microbiota and bile acids are increasingly recognized to regulate blood pressure, but the mechanisms remain unclear. Takeda G-protein coupled receptor 5 (TGR5) is a major receptor for secondary bile acids. We hypothesized that loss of TGR5 function remodels gut microbiota and influences blood pressure. Using CRISPR/Cas9, TGR5 knockout (Tgr5KO) rats on the Dahl Salt-Sensitive (S) background were generated and characterized. Compared to the control S rats, Tgr5KO rats demonstrated significantly lower blood pressure, a distinct shift in gut microbiota composition, and an increase in the secondary bile acid, particularly, glycodeoxycholic acid. Supplementation of glycodeoxycholic acid to the control S rats produced a similar gut microbial shift and lowered blood pressure. Furthermore, cecal microbiota transplantation from Tgr5KO to control S rats lowered blood pressure in the recipient rats. This first loss-of-function study demonstrates that deletion of TGR5 remodels gut microbiota, increases glycodeoxycholic acid, and lowers blood pressure regardless of TGR5 signaling status, identifying a promising gut-liver axis target for lowering hypertension.