bluuebunny/crossref_metadata_2025 huggingface dataset:
The Composition of the HDL Particle and Its Capacity to Remove Cellular Cholesterol Are Associated with a Reduced Risk of Developing Active Inflammatory Rheumatoid Arthritis
Authors: Giacaglia Marcia Benacchio , Felix Vitoria Pires , Santana Monique de Fatima Mello , Amendola Leonardo Szalos , Lerner Perola Goberstein , Fernandes Sibelle D. Elia , Camacho Cleber Pinto , Passarelli Marisa
Published: October 2024

In rheumatoid arthritis (RA), the risk of cardiovascular death is 50% higher compared to the general population. This increased risk is partly due to the systemic inflammation characteristic of RA and changes in the lipoprotein profiles. This study investigated plasma lipid levels, lipid ratios, and the composition and functionality of high-density lipoprotein (HDL) in control individuals and RA subjects based on the disease’s inflammatory score (DAS28). This study included 50 control (CTR) individuals and 56 subjects with RA, divided into remission/low-activity disease (DAS28 < 3.2; n = 13) and active disease (DAS28 ≥ 3.2; n = 43). Plasma lipids (total cholesterol, TC; triglycerides, TG) and the HDL composition (TC; TG; phospholipids, PL) were determined using enzymatic methods; apolipoprotein B (apoB) and apoA-1 were measured by immunoturbidimetry. HDL-mediated cholesterol efflux and anti-inflammatory activity were assessed in bone marrow-derived macrophages. Comparisons were made using the Mann–Whitney test, and binary logistic regression was used to identify the predictors of active RA. A p-value < 0.05 was considered significant. TC, HDLc, and the TC/apoB ratio were higher in RA subjects compared to the CTR group. Subjects with active disease exhibited higher levels of TG and the TG/HDLc ratio and lower levels of HDLc, the TG/apoB ratio, TC, and apoA-1 in HDL particles compared to those with remission/low-activity RA. Increased levels of HDLc [odds ratio (OR) 0.931, 95% CI = 0.882–0.984], TC/apoB (OR 0.314, 95% CI = 0.126–0.78), HDL content in TC (OR 0.912, 95% CI = 0.853–0.976), PL (OR 0.973, 95% CI = 0.947–1.000), and apoA-1 (OR 0.932, 95% CI = 0.882–0.985) were associated with a decreased risk of active disease, but BMI (OR 1.169, 95% CI = 1.004–1.360) and TG (OR 1.031, 95% CI = 1.005–1.057) were positively associated with active disease. A reduction in HDL-mediated cholesterol efflux increased the OR for active RA by 26.2%. The plasma levels of HDLc, along with the composition and functionality of HDL, influence the inflammatory score in RA and may affect the development of cardiovascular disease.
Acetylation of Histone H3 in Cancer Progression and Prognosis
Authors: Miziak Paulina , Baran Marzena , Borkiewicz Lidia , Trombik Tomasz , Stepulak Andrzej
Published: October 2024

Cancer is a multifactorial disease resulting from both genetic factors and epigenetic changes. Histone acetylation, a post-translational modification, which alters chromatin architecture and regulates gene expression is associated with cancer initiation, development and progression. Aberrations in global histone acetylation levels are observed in various cancer cells and are also associated with patients’ tumor aggressiveness. Therefore, histone acetylation may have prognostic utility and serve as a potential biomarker of cancer progression and patients’ prognosis. The reversible modification of histones by an acetyl group is versatile. One particular histone can be acetylated on different lysine residues, subsequently resulting in different biological outcomes. Here, we discuss recent findings on the acetylation of the highly conserved histone protein H3 in the context of cancer biology. Specifically, we review the acetylation of particular H3 residues in various cancer types. We further highlight the significance of H3 acetylation levels as a potential cancer biomarker with prognostic implications.
Interleukin-1 Beta (IL1B) and Nerve Growth Factor (NGF): Key Players in Rabbit Reproductive Regulation
Authors: Guelfi Gabriella , Dall’Aglio Cecilia , Bufalari Antonello , Mercati Francesca , Anipchenko Polina , Capaccia Camilla , Cocci Paolo , Palermo Francesco Alessandro , Acuti Gabriele , Troisi Alessandro , Tomassoni Daniele , Boiti Cristiano , Zerani Massimo , Maranesi Margherita
Published: October 2024

Several seminal plasma components, besides NGF, are implicated as ovulation-inducing factors in mammals. This study investigated the IL1B and its receptor IL1R1 in the testis (T), male accessory glands, prostate (P) and seminal vesicles (SV), and uterus (U) of adult rabbits using immunohistochemistry (IHC) and quantitative reverse transcription PCR (RT-qPCR). We also assessed the presence of IL1B in seminal plasma through Western blotting (WB) and examined the interaction between IL1B and NGF in vitro by measuring their production with enzyme-linked immunosorbent assay (ELISA) in the presence of NGF and IL1B alone or with their respective receptor antagonists. IHC revealed IL1B system expression in all reproductive organs studied, with IL1B and IL1R1 localized to the germinative epithelium of the T and the epithelial cells of the accessory glands and U. IL1B gene transcript levels were significantly higher (p < 0.01) in the P and SV compared to the T, while IL1R1 levels were significantly higher (p < 0.001) in the P compared to the other tissues, while IL1R1 levels were three times higher (p < 0.001) in the P. WB confirmed the presence of IL1B in seminal plasma with a 30–35 kDa band. The in vitro study demonstrated that IL1B increased (p < 0.05) basal NGF production in the U, whereas NGF had no effect on IL1B production. These findings provide evidence of the expression of the IL1B/IL1R1 system in both male and female rabbit reproductive tracts and suggest that IL1B in seminal plasma may influence uterine endocrine activity. The results propose a potential role for IL1B in ovulation, in conjunction with NGF, supporting that ovulation may involve inflammatory-like processes.
Changes in Cx43 and AQP4 Proteins, and the Capture of 3 kDa Dextran in Subpial Astrocytes of the Rat Medial Prefrontal Cortex after Both Sham Surgery and Sciatic Nerve Injury
Authors: Bretová Karolína , Svobodová Viktorie , Dubový Petr
Published: October 2024

A subpopulation of astrocytes on the brain’s surface, known as subpial astrocytes, constitutes the “glia limitans superficialis” (GLS), which is an interface between the brain parenchyma and the cerebrospinal fluid (CSF) in the subpial space. Changes in connexin-43 (Cx43) and aquaporin-4 (AQP4) proteins in subpial astrocytes were examined in the medial prefrontal cortex at postoperative day 1, 3, 7, 14, and 21 after sham operation and sciatic nerve compression (SNC). In addition, we tested the altered uptake of TRITC-conjugated 3 kDa dextran by reactive subpial astrocytes. Cellular immunofluorescence (IF) detection and image analysis were used to examine changes in Cx43 and AQP4 protein levels, as well as TRITC-conjugated 3 kDa dextran, in subpial astrocytes. The intensity of Cx43-IF was significantly increased, but AQP4-IF decreased in subpial astrocytes of sham- and SNC-operated rats during all survival periods compared to naïve controls. Similarly, the uptake of 3 kDa dextran in the GLS was reduced following both sham and SNC operations. The results suggest that both sciatic nerve injury and peripheral tissue injury alone can induce changes in subpial astrocytes related to the spread of their reactivity across the cortical surface mediated by increased amounts of gap junctions. At the same time, water transport and solute uptake were impaired in subpial astrocytes.
Assessment of the Antioxidant and Photoprotective Properties of Cornus mas L. Extracts on HDF, HaCaT and A375 Cells Exposed to UVA Radiation
Authors: Zagórska-Dziok Martyna , Mokrzyńska Agnieszka , Ziemlewska Aleksandra , Nizioł-Łukaszewska Zofia , Sowa Ireneusz , Feldo Marcin , Wójciak Magdalena
Published: October 2024

The influence of UV radiation on skin discoloration, skin aging and the development of skin cancer is widely known. As a part of this study, the effect of extracts from three varieties of Cornus mas L. (C. mas L.) on skin cells exposed to UVA radiation was assessed. The analyses were performed on both normal and cancer skin cells. For this purpose, the potential photoprotective effects of the obtained extracts (aqueous and ethanolic) was assessed by performing two cytotoxicity tests (Alamar blue and Neutral red). Additionally, the antioxidant capacity was compared using three different assays. The 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) probe was used to evaluate the intracellular level of free radicals in cells exposed to the simultaneous action of UVA radiation and dogwood extracts. Additionally, the ability to inhibit excessive pigmentation was determined by assessing the inhibition of melanin formation and tyrosinase activity. The obtained results confirmed the strong antioxidant properties of dogwood extracts and their photoprotective effect on normal skin cells. The ability to inhibit the viability of melanoma cells was also observed. Additionally, a reduction in oxidative stress in skin cells exposed to UVA radiation and a strong inhibition of melanin formation and tyrosinase activity have been demonstrated. This study shows that dogwood extract could be a valuable cosmetic raw material that can play both a photoprotective and antihyperpigmentation role in cosmetic preparations.
In Vitro Methylene Blue and Carboplatin Combination Triggers Ovarian Cancer Cells Death
Authors: da Veiga Moreira Jorgelindo , Schwartz Laurent , Jolicoeur Mario
Published: October 2024

Ovarian cancer presents a dire prognosis and high mortality rates, necessitating the exploration of alternative therapeutic avenues, particularly in the face of platinum-based chemotherapy resistance. Conventional treatments often overlook the metabolic implications of cancer, but recent research has highlighted the pivotal role of mitochondria in cancer pathogenesis and drug resistance. This study delves into the metabolic landscape of ovarian cancer treatment, focusing on modulating mitochondrial activity using methylene blue (MB). Investigating two epithelial ovarian cancer (EOC) cell lines, OV1369-R2 and OV1946, exhibiting disparate responses to carboplatin, we sought to identify metabolic nodes, especially those linked to mitochondrial dysfunction, contributing to chemo-resistance. Utilizing ARPE-19, a normal retinal epithelial cell line, as a control model, our study reveals MB’s distinct cellular uptake, with ARPE-19 absorbing 5 to 7 times more MB than OV1946 and OV1369-R2. Treatment with 50 µM MB (MB-50) effectively curtailed the proliferation of both ovarian cancer cell lines. Furthermore, MB-50 exhibited the ability to quell glutaminolysis and the Warburg effect in cancer cell cultures. Regarding mitochondrial energetics, MB-50 spurred oxygen consumption, disrupted glycolytic pathways, and induced ATP depletion in the chemo-sensitive OV1946 cell line. These findings highlight the potential of long-term MB exposure as a strategy to improve the chemotherapeutic response in ovarian cancer cells. The ability of MB to stimulate oxygen consumption and enhance mitochondrial activity positions it as a promising candidate for ovarian cancer therapy, shedding light on the metabolic pressures exerted on mitochondria and their modulation by MB, thus contributing to a deeper understanding of mitochondrial dysregulation and the metabolic underpinnings of cancer cell proliferation.
Unveiling the Molecular Mechanisms of Browning in Camellia hainanica Callus through Transcriptomic and Metabolomic Analysis
Authors: Wu Kunlin , Liu Yanju , Xu Yufen , Yu Zhaoyan , Cao Qiulin , Gong Han , Yang Yaodong , Ye Jianqiu , Jia Xiaocheng
Published: October 2024

Camellia hainanica is one of the camellia plants distributed in tropical regions, and its regeneration system and genetic transformation are affected by callus browning. However, the underlying mechanism of Camellia hainanica callus browning formation remains largely unknown. To investigate the metabolic basis and molecular mechanism of the callus browning of Camellia hainanica, histological staining, high-throughput metabolomics, and transcriptomic assays were performed on calli with different browning degrees (T1, T2, and T3). The results of histological staining revealed that the brown callus cells had obvious lignification and accumulation of polyphenols. Widely targeted metabolomics revealed 1190 differentially accumulated metabolites (DAMs), with 53 DAMs annotated as phenylpropanoids and flavonoids. Comparative transcriptomics revealed differentially expressed genes (DEGs) of the T2 vs. T1 associated with the biosynthesis and regulation of flavonoids and transcription factors in Camellia hainanica. Among them, forty-four enzyme genes associated with flavonoid biosynthesis were identified, including phenylalaninase (PAL), 4-coumaroyl CoA ligase (4CL), naringenin via flavanone 3-hydroxylase (F3H), flavonol synthase (FLS), Chalcone synthase (CHS), Chalcone isomerase (CHI), hydroxycinnamoyl-CoA shikimate transferase (HCT), Dihydroflavonol reductase (DFR), anthocyanin reductase (LAR), anthocyanin synthetase (ANS), and anthocyanin reductase (ANR). Related transcription factors R2R3-MYB, basic helix-loop-helix (bHLH), and WRKY genes also presented different expression patterns in T2 vs. T1. These results indicate that the browning of calli in Camellia hainanica is regulated at both the transcriptional and metabolic levels. The oxidation of flavonoids and the regulation of related structural genes and transcription factors are crucial decisive factors. This study preliminarily revealed the molecular mechanism of the browning of the callus of Camellia hainanensis, and the results can provide a reference for the anti-browning culture of Camellia hainanica callus.
Lipoprotein (a) as a Cardiovascular Risk Factor in Controversial Clinical Scenarios: A Narrative Review
Authors: Abdalla Hesham M. , Mahmoud Ahmed K. , Khedr Ahmed E. , Farina Juan M. , Scalia Isabel G. , Abbas Mohammed Tiseer , Awad Kamal A. , Baba Ali Nima , Bismee Nadera N. , Attaripour Esfahani Sogol , Javadi Niloofar , Pereyra Milagros , Alsidawi Said , Lester Steven J. , Ayoub Chadi , Arsanjani Reza
Published: October 2024

Lipoprotein (a) is a complex lipid molecule that has sparked immense interest in recent years, after studies demonstrated its significant association with several cardiovascular conditions. Lp(a) promotes cardiovascular disease through its combined proatherogenic, pro-inflammatory, and prothrombotic effects. While the measurement of Lp(a) has become widely available, effective methods to reduce its concentration are currently limited. However, emerging data from ongoing clinical trials involving antisense oligonucleotides have indicated promising outcomes in effectively reducing Lp(a) concentrations. This may serve as a potential therapeutic target in the management and prevention of myocardial infarction, calcific aortic stenosis, and cerebrovascular accidents. In contrast, the role of Lp(a) in atrial fibrillation, in-stent restenosis, cardiac allograft vasculopathy, and bioprosthetic aortic valve degeneration remains unclear. This review article aims to thoroughly review the existing literature and provide an updated overview of the evidence surrounding the association of Lp(a) and these cardiovascular diseases. We seek to highlight controversies in the existing literature and offer directions for future investigations to better understand Lp(a)’s precise role in these conditions, while providing a summary of its unique molecular characteristics.
The Green Extraction of Blueberry By-Products: An Evaluation of the Bioactive Potential of the Anthocyanin/Polyphenol Fraction
Authors: Capaldi Giorgio , Aimone Clelia , Calcio Gaudino Emanuela , Radošević Kristina , Bagović Martina , Grillo Giorgio , Cravotto Giancarlo
Published: October 2024

In the context of a circular economy, this study explores the valorization of blueberry pomace (BP) as a source of bioactive compounds using sustainable extraction methods. Microwave-assisted extraction (MAE) and microwave-assisted subcritical water extraction (MASWE) were employed to obtain two distinct fractions: MAE 1° and MASWE 2°. The first extract, MAE 1°, obtained at 80 °C, had a high total anthocyanin content (21.96 mgCya-3-glu/gextract), making it suitable as a natural pigment. Additionally, MAE 1° exhibited significant enzyme inhibition, particularly against α-amylase and β-glucosidase, suggesting potential anti-diabetic and anti-viral applications. The second extract, MASWE 2°, obtained at 150 °C, contained a higher total phenolic content (211.73 mgGAE/gextract) and demonstrated stronger antioxidant activity. MASWE 2° showed greater inhibition of acetylcholinesterase and tyrosinase, indicating its potential for use in Alzheimer’s treatment, skincare, or as a food preservative. MASWE 2° exhibited cytotoxicity against HeLa cells and effectively mitigated H2O2-induced oxidative stress in HaCat cells, with MAE 1° showing similar but less pronounced effects. A tested formulation combining MAE 1° and MASWE 2° extracts in a 3:2 ratio effectively enhanced anthocyanin stability, demonstrating its potential as a heat-stable pigment. The extract characteristics were compared with a conventional method (MeOH-HCl in reflux condition), and the protocol’s sustainability was assessed using several green metric tools, which provided insights into its environmental impact and efficiency.
SPROUTY2, a Negative Feedback Regulator of Receptor Tyrosine Kinase Signaling, Associated with Neurodevelopmental Disorders: Current Knowledge and Future Perspectives
Authors: Puranik Nidhi , Jung HoJeong , Song Minseok
Published: October 2024

Growth-factor-induced cell signaling plays a crucial role in development; however, negative regulation of this signaling pathway is important for sustaining homeostasis and preventing diseases. SPROUTY2 (SPRY2) is a potent negative regulator of receptor tyrosine kinase (RTK) signaling that binds to GRB2 during RTK activation and inhibits the GRB2-SOS complex, which inhibits RAS activation and attenuates the downstream RAS/ERK signaling cascade. SPRY was formerly discovered in Drosophila but was later discovered in higher eukaryotes and was found to be connected to many developmental abnormalities. In several experimental scenarios, increased SPRY2 protein levels have been observed to be involved in both peripheral and central nervous system neuronal regeneration and degeneration. SPRY2 is a desirable pharmaceutical target for improving intracellular signaling activity, particularly in the RAS/ERK pathway, in targeted cells because of its increased expression under pathological conditions. However, the role of SPRY2 in brain-derived neurotrophic factor (BDNF) signaling, a major signaling pathway involved in nervous system development, has not been well studied yet. Recent research using a variety of small-animal models suggests that SPRY2 has substantial therapeutic promise for treating a range of neurological conditions. This is explained by its function as an intracellular ERK signaling pathway inhibitor, which is connected to a variety of neuronal activities. By modifying this route, SPRY2 may open the door to novel therapeutic approaches for these difficult-to-treat illnesses. This review integrates an in-depth analysis of the structure of SPRY2, the role of its major interactive partners in RTK signaling cascades, and their possible mechanisms of action. Furthermore, this review highlights the possible role of SPRY2 in neurodevelopmental disorders, as well as its future therapeutic implications.
The Impact of Different Anesthetics on the Distribution and Cytotoxic Function of NK Cell Subpopulations: An In Vitro Study
Authors: Vulcano Tristan J. , Abdulahad Wayel H. , van Meurs Matijs , Jongman Rianne M. , Struys Michel M. R. F. , Bosch Dirk J.
Published: October 2024

Only some subpopulations of natural killer (NK) cells have cytotoxic functionality, and the effects of anesthetics on these subpopulations are unknown. This study aimed to evaluate the in vitro effects of various anesthetics, both alone and in combination, on the distribution and cytotoxic function of NK cells and their subpopulations. Peripheral blood mononuclear cells (PBMCs) from eight healthy volunteers were treated for 4 h in vitro with dexmedetomidine, remifentanil, lidocaine, propofol, sevoflurane, and combinations in clinically relevant concentrations or left untreated. Flow cytometry was used to quantify the percentage of sampled NK cells and evaluate their distribution (CD56brightCD16neg, CD56brightCD16dim, CD56dimCD16neg, CD56dimCD16bright, and CD56negCD16bright) and cytotoxicity (Granzyme B (GrzB) and perforin) of NK cell subpopulations. Although the percentage of total NK cells did not change following exposure to anesthesia, the most important cytotoxic subpopulation (CD56dimCD16bright NK cells) decreased after exposure to both propofol (−3.58%, p = 0.045) and sevoflurane (−16.10%, p = 0.008) alone, and most combinations, especially in combination with lidocaine (propofol with lidocaine (−9.66%, p = 0.002) and sevoflurane with lidocaine (−21.90%, p < 0.001)). Dexmedetomidine and remifentanil had no effect on CD56dimCD16bright NK cells. Furthermore, no anesthetic regimen or combination altered the expression of GrzB and perforin in NK cells or NK cell subpopulations. In short, propofol and sevoflurane suppressed the highly cytotoxic phenotype (CD56dimCD16bright) of NK cells, with those exposed to sevoflurane combinations showing greater reductions. Immunosuppression was intensified with the inclusion of lidocaine in the anesthetic regimen.
Variable Message Signs in Traffic Management: A Systematic Review of User Behavior and Future Innovations
Authors: Lagoa Paula , Galvão Teresa , Campos Ferreira Marta
Published: October 2024

Effective traffic management is crucial in addressing the growing complexities of urban mobility, and variable message signs (VMSs) play a vital role in delivering real-time information to road users. Despite their widespread application, there is limited comprehensive understanding of how VMS influence user behavior and optimize traffic flow. This systematic literature review aims to address this gap by examining the effectiveness of VMS in shaping user interactions and enhancing traffic management systems. Using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) methodology, a thorough analysis of relevant studies was conducted to identify key factors influencing VMS impact, including message content and characteristics, complementary sources of information, user demographics, VMS location, and users’ reliance on these signs. Additionally, the review explores the implications of displaying non-critical information on VMS and introduces virtual dynamic message signs (VDMSs) as an innovative approach for delivering public traveler information. The study identifies several research gaps, such as the integration of VMS with vehicle-to-everything (V2X) technologies, navigation systems, the need for validation in real-world scenarios, and understanding behavioral responses to non-critical information on VMS. This review highlights the importance of optimizing VMS for improved user engagement and traffic management, providing valuable insights and directions for future research in this evolving field.
Innovative Pavement Solutions: A Comprehensive Review from Conventional Asphalt to Sustainable Colored Alternatives
Authors: Riaz Anisa , Yasir Nof , Badin Gul , Mahmood Yasir
Published: October 2024

Climate change significantly impacts transportation infrastructure, particularly asphalt pavements. Similarly, the heat absorption of paved surfaces, especially conventional black pavements, significantly intensifies the urban microclimate. Paved surfaces, including asphalt pavements, account for over 30% of the covered surfaces and are vulnerable to rising temperatures, which cause not only pavement distress, such as rutting and cracking, but also urban heat islands (UHI). Sustainable pavement solutions, specifically colored pavements, have been investigated for their potential to mitigate these effects. This review presents an extensive overview of current pavement technologies, emphasizing conventional asphalt’s economic, environmental, and functional characteristics. A discussion of the benefits and challenges of colored pavements is also provided, including their ability to reduce UHI, enhance safety, and contribute to sustainable urban growth. This paper discusses advancements in pavement material science, the use of recycled materials, and the application of reflective coatings, providing insights into sustainable infrastructure development. Transitioning from conventional black pavements to sustainable colored alternatives is not merely a matter of material choice but a strategic transition toward resilient urban planning. Increasing demand for environmentally friendly infrastructure could prompt the construction industry to adopt colored pavements as a tool to promote environmental stewardship.
Clinical and Serological Profiles in Cryoglobulinemia: Analysis of Isotypes and Etiologies
Authors: Codes-Méndez Helena , Jeria Sicylle , Park Hye-Sang , Moya Patricia , Magallares-López Berta , Moltó Elisabeth , Álvaro Yolanda , Mariscal Anais , Moga Esther , Tandaipan Jose Luis , Díaz-Torne César , Laiz Ana , Sainz Luis , Castellví Ivan , Corominas Hector
Published: October 2024

Objectives: Cryoglobulinemia (CG) is marked by abnormal immunoglobulins (Ig) in serum, precipitating at temperatures below 37 °C. Current classification categorizes CG into three subtypes (types I, II, and III) based on Ig clonality. The features distinguishing patients with CG based on their etiology remain unidentified. Aiming to characterize clinical and serological profiles of CG individuals, we conducted an observational analysis of a large cohort of patients and compared their characteristics based on underlying causes: hepatovirus (HV) infections, rheumatic diseases (RD), hematological disorders, and unidentified etiology (essential CG). Methods: We analyzed 252 cryoglobulin-positive serum samples from 182 patients and classified these into the four etiological groups. A separate sub-analysis was carried out for 10 patients meeting criteria for multiple diseases. We collected demographic, clinical, and laboratory data: CG characterization, complement (C3 and C4) levels, antinuclear antibodies (ANA), and rheumatoid factor (RF). Kruskal–Wallis and Wilcoxon–Mann–Whitney U-tests were used for comparisons. Results: Most patients (93.3%) had mixed cryoglobulinemia (types II + III), with 6.7% having type I. HV infection, predominantly hepatitis C, was the main (52.9%) associated condition within the cohort, followed by rheumatic (27.3%) and hematological (9.8%) disorders. In our cohort, ANA were frequent (45.3%) and often associated with RF positivity (43.6%) and decreased complement levels (C3: 42.4%, C4: 32.5%). Essential CG and CG associated with RD had a higher prevalence of cutaneous manifestations (p < 0.01) and renal involvement (p = 0.017). Hematological disorder-related CG showed higher cryoglobulin and RF concentrations (p < 0.01), despite milder symptoms. Conclusions: Our study underscores a mixed prevalence of CG across disease subgroups, with hepatitis-C virus as the primary factor, followed by rheumatic and hematological disorders. Four clinical and serological profiles of CG were identified based on their etiologies.
The Effect of Extreme Alkalemia upon Presentation to the Emergency Department on Patient Outcomes
Authors: Gur Ivan , Gutgold Amichai , Milo Gai , Miller Asaf
Published: October 2024

Background/Objectives: The prognostic significance of alkalemia found in an initial emergency department (ED) evaluation has not been described thus far. Methods: We retrospectively reviewed the records of all patients aged 18 years or older evaluated in the ED of one large academic referral center during 2000–2023. Included patients were those with at least one measurement of pH ≥ 7.55 upon initial ED presentation. Alkalemia was deemed primarily metabolic (PM) if PCO2 was ≥35 mmHg and primarily respiratory (PR) if bicarbonate levels were ≤24 mEq/L. The primary outcome was survival 30 days from ED presentation. Results: Of 2440 patients included, 199 (8.1%) had PM and 1494 (61.2%) had PR. Alkalemia severity was not correlated with prognosis. Survival at 30 days was significantly (p < 0.001) lower in the PM group (78.9%) compared with that of either the PR (95.3%) or the combined etiology (92.2%) groups. Multivariate survival analysis after balancing potential observed confounders using propensity score matching revealed the type of alkalemia (PM vs. PR) to be a significant predictor of 30-day mortality (aHR 1.73; 95% C.I. = [1.07 to 2.82]; p = 0.026), irrespective of age, other laboratory values obtained on ED evaluation (including pH), past medical history, or vital signs on presentation. Conclusions: In patients presenting to the ED with significant alkalemia, the mechanism of alkalemia, i.e., primarily metabolic versus primarily respiratory, rather than the absolute degree of alkalemia, is associated with increased mortality.
Multi-Ancestry Causal Association between Rheumatoid Arthritis and Interstitial Lung Disease: A Bidirectional Two-Sample Mendelian Randomization Study
Authors: Kim Bo-Guen , Yoon Sanghyuk , Lee Sun Yeop , Kim Eun Gyo , Kim Jung Oh , Kim Jong Seung , Lee Hyun
Published: October 2024

Abstract: Background: Rheumatoid arthritis (RA) is associated with diverse extra-articular manifestations, including interstitial lung disease (ILD). No previous studies have examined the bidirectional relationship between RA and ILD using the Mendelian randomization (MR) analyses. Therefore, we aimed to investigate this subject using a two-sample bidirectional MR method. Methods: We performed bidirectional two-sample MR using summary statistics from genome-wide association studies (GWASs). The data are publicly available, de-identified, and from European (EUR) and East Asian (EAS) ancestries. Results: A total of 474,450 EUR participants and 351,653 EAS participants were included for either forward or reverse MR analysis. In our primary analysis, we found significant evidence of an increased risk of ILD associated with RA among individuals of EUR ancestry (ORMR-cML = 1.08; 95% confidence interval [CI] = 1.03–1.14; p = 0.003) and EAS ancestry (ORMR-cML = 1.37; 95% CI = 1.23–1.54; p < 0.001). Additionally, the reverse MR showed significant evidence of an increased risk of RA associated with ILD among those of EUR ancestry (ORMR-cML = 1.12; 95% CI = 1.05–1.19; p < 0.001). However, only one instrumental variable was selected in the EAS ILD GWAS, and there was no increased risk of RA associated with ILD in those of EAS ancestry (ORMR-cML = 1.02; 95% CI = 0.91–1.14; p = 0.740). Conclusions: Our findings indicate that RA and ILD have a bidirectional causal inference when using the MR analysis of GWAS datasets. The findings are only relevant for genetic predisposition; thus, further research is needed to determine the impact of non-genetic predispositions.
Targeting KDM1A in Neuroblastoma with NCL-1 Induces a Less Aggressive Phenotype and Suppresses Angiogenesis
Authors: Sprüssel Annika , Suzuki Takayoshi , Miyata Naoki , Astrahantseff Kathy , Szymansky Annabell , Toedling Joern , Thole-Kliesch Theresa M. , Ballagee Annika , Lodrini Marco , Künkele Annette , Truss Matthias , Heukamp Lukas C. , Mathia Susanne , Hertwig Falk , Rosenberger Christian , Eggert Angelika , Deubzer Hedwig E. , Schulte Johannes H.
Published: October 2024

Background: The KDM1A histone demethylase regulates the cellular balance between proliferation and differentiation, and is often deregulated in human cancers including the childhood tumor neuroblastoma. We previously showed that KDM1A is strongly expressed in undifferentiated neuroblastomas and correlates with poor patient prognosis, suggesting a possible clinical benefit from targeting KDM1A. Methods: Here, we tested the efficacy of NCL-1, a small molecule specifically inhibiting KDM1A in preclinical models for neuroblastoma. Results: NCL-1 mimicked the effects of siRNA-mediated KDM1A knockdown and effectively inhibited KDM1A activity in four neuroblastoma cell lines and a patient-representative cell model. KDM1A inhibition shifted the aggressive tumor cell phenotypes towards less aggressive phenotypes. The proliferation and cell viability was reduced, accompanied by the induction of markers of neuronal differentiation. Interventional NCL-1 treatment of nude mice harboring established neuroblastoma xenograft tumors reduced tumor growth and inhibited cell proliferation. Reduced vessel density and defects in blood vessel construction also resulted, and NCL-1 inhibited the growth and tube formation of HUVEC-C cells in vitro. Conclusions: Inhibiting KDM1A could attack aggressive neuroblastomas two-fold, by re-directing tumor cells toward a less aggressive, slower-growing phenotype and by preventing or reducing the vascular support of large tumors.
The Gut Microbiome in Sepsis: From Dysbiosis to Personalized Therapy
Authors: Piccioni Andrea , Spagnuolo Fabio , Candelli Marcello , Voza Antonio , Covino Marcello , Gasbarrini Antonio , Franceschi Francesco
Published: October 2024

Sepsis is a complex clinical syndrome characterized by an uncontrolled inflammatory response to an infection that may result in septic shock and death. Recent research has revealed a crucial link between sepsis and alterations in the gut microbiota, showing that the microbiome could serve an essential function in its pathogenesis and prognosis. In sepsis, the gut microbiota undergoes significant dysbiosis, transitioning from a beneficial commensal flora to a predominance of pathobionts. This transformation can lead to a dysfunction of the intestinal barrier, compromising the host’s immune response, which contributes to the severity of the disease. The gut microbiota is an intricate system of protozoa, fungi, bacteria, and viruses that are essential for maintaining immunity and metabolic balance. In sepsis, there is a reduction in microbial heterogeneity and a predominance of pathogenic bacteria, such as proteobacteria, which can exacerbate inflammation and negatively influence clinical outcomes. Microbial compounds, such as short-chain fatty acids (SCFAs), perform a crucial task in modulating the inflammatory response and maintaining intestinal barrier function. However, the role of other microbiota components, such as viruses and fungi, in sepsis remains unclear. Innovative therapeutic strategies aim to modulate the gut microbiota to improve the management of sepsis. These include selective digestive decontamination (SDD), probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT), all of which have shown potential, although variable, results. The future of sepsis management could benefit greatly from personalized treatment based on the microbiota. Rapid and easy-to-implement tests to assess microbiome profiles and metabolites associated with sepsis could revolutionize the disease’s diagnosis and management. These approaches could not only improve patient prognosis but also reduce dependence on antibiotic therapies and promote more targeted and sustainable treatment strategies. Nevertheless, there is still limited clarity regarding the ideal composition of the microbiota, which should be further characterized in the near future. Similarly, the benefits of therapeutic approaches should be validated through additional studies.
Thrombotic, Cardiovascular, and Microvascular Complications of Myeloproliferative Neoplasms and Clonal Hematopoiesis (CHIP): A Narrative Review
Authors: Schafer Andrew I. , Mann Douglas L.
Published: October 2024

The most common causes of morbidity and mortality in the myeloproliferative neoplasms (MPNs), with the exception of myelofibrosis, are venous and arterial thrombosis, as well as more recently discovered cardiovascular disease (CVD). Clonal hematopoiesis of indeterminate potential (CHIP) is the subclinical finding in an individual of somatic mutations that are also found in clinically overt MPNs and other myeloid malignancies. The prevalence of “silent” CHIP increases with age. CHIP can transform into a clinically overt MPN at an estimated rate of 0.5 to 1% per year. It is likely, therefore, but not proven, that many, if not all, MPN patients had antecedent CHIP, possibly for many years. Moreover, both individuals with asymptomatic CHIP, as well as clinically diagnosed patients with MPN, can develop thrombotic complications. An unexpected and remarkable discovery during the last few years is that even CHIP (as well as MPNs) are significant, independent risk factors for CVD. This review discusses up-to-date information on the types of thrombotic and cardiovascular complications that are found in CHIP and MPN patients. A systemic inflammatory state (that is often subclinical) is most likely to be a major mediator of adverse reciprocal bone marrow–cardiovascular interplay that may fuel the development of progression of MPNs, including its thrombotic and vascular complications, as well as the worsening of cardiovascular disease, possibly in a “vicious cycle”. Translating this to clinical practice for hematologists and oncologists who treat MPN patients, attention should now be paid to ensuring that cardiovascular risk factors are controlled and minimized, either by the patient’s cardiologist or primary care physician or by the hematologist/oncologist herself or himself. This review is intended to cover the clinical aspects of thrombosis and cardiovascular complications in the MPN, accompanied by pathobiological comments.
Myositis-Associated Interstitial Lung Disease: The Experience of a Tertiary Center
Authors: Correia Bianca Paulo , Campanilho-Marques Raquel , Dourado Eduardo , Silva Mariana , Silva Augusto , Costa Filipa , Bandeira Matilde , Melo Ana Teresa , Barreira Sofia C. , Fonseca João E.
Published: October 2024

Background: Interstitial lung disease (ILD) is a common extra-muscular manifestation of idiopathic inflammatory myopathies (IIMs), often associated with a poorer prognosis and increased mortality risk. Methods: This retrospective study aimed to characterize lung involvement and treatment response in an IIM cohort at a Portuguese tertiary center, followed between June 2016 and March 2024. We analyzed data from high-resolution computed tomography (HRCT) scans and pulmonary function tests (PFTs) to assess associations with autoantibody profiles and treatment regimens. Results: A total of 198 patients were included, with 69 (34.8%) exhibiting ILD. Antisynthetase syndrome (ASyS) and dermatomyositis were the most common diagnoses among IIM-ILD patients, with ASyS being significantly more frequent in this group than in non-ILD patients (p < 0.001). Anti-Jo1 and anti-MDA-5 antibodies were more frequent in ILD patients (p < 0.001 and p = 0.021), while anti-Mi2 antibodies were less common (p = 0.002). Non-specific interstitial pneumonia (NSIP) was the most common radiological pattern (69.5%). IIM-ILD patients presented with significantly lower forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) compared to non-ILD patients (p < 0.001 for all values). Longitudinal analysis showed improved DLCO (p = 0.022) and stable or improved FVC (p = 0.097), especially with intravenous immunoglobulin (IVIg) and azathioprine (AZA). Combination therapies including IVIg with mycophenolate mofetil (MMF) or rituximab (RTX) also improved DLCO and FVC. Most ILD patients (89.6%) had stable HRCT patterns over time. Conclusions: Our findings highlight the potential for stabilizing or even improving lung function in IIM-ILD with appropriate immunosuppressive therapy, particularly with regimens incorporating IVIg and AZA, and combination therapies.
Particularities of a Cardiac Amorphous Left Ventricular Tumor in a Patient with Coronary Artery Disease—Diagnostic and Therapeutic Challenges: A Case Report and Literature Review
Authors: Streian Caius Glad , Tudoran Cristina , Staicu Raluca Elisabeta , Negru Alina Gabriela , Mederle Alexandra Laura , Borza Claudia , Lascu Ana
Published: October 2024

Background: Cardiac calcified amorphous tumors (CATs) are rare non-neoplastic formations containing amorphous fibrinous material and calcifications. In our research, we present the case of a 42-year-old male patient who developed, during his 6-months monitoring for coronary artery disease, a left ventricular (LV) CAT raising diagnostic challenges. Methods: To gather additional information on CATs, we researched the international medical literature for scientific articles published with the full text in English, on PubMed, ResearchGate, Clarivate, and Google Scholar between 2020 and 2024. Results: Compared to most described cases, our patient was a young male, without mitral annular calcification or chronic renal disease, but he was suffering from chronic peripheral and coronary artery disease, and genetic testing revealed a higher risk for thromboembolic events. During 6 months, he developed a LV CAT of 4.5/3.5/3 cm. Although we found in the medical literature 16 case reports of patients with CAT, only six authors could specify a precise postoperative evolution of the CAT, most of them sustaining that if completely removed, it would not relapse, an aspect observed also in our patient during 3 years of follow-up. Conclusions: CATs are rare heart tumors with slow growth, but with a high embolization risk that raises diagnostic and therapeutic challenges.
Impact of Virtual Reality Intervention on Anxiety and Level of Cooperation in Children and Adolescents with Autism Spectrum Disorder during the Dental Examination
Authors: Al Kheraif Abdulaziz Abdullah , Adam Tasneem Rashed , Wasi Aisha , Alhassoun Raghad Khalid , Haddadi Rawan Mohammed , Alnamlah Mohammed
Published: October 2024

Background: Individuals with Autism Spectrum Disorder (ASD) frequently encounter increased levels of anxiety and display resistant behaviors during dental examinations, which negatively affects their oral care and maintenance. This study employed a cross-sectional design to evaluate the impact of virtual reality (VR) intervention on the anxiety and level of cooperation in children and adolescents with ASD during dental examinations. Methods: A total of 140 participants diagnosed with ASD, aged from 4- to 18-years-old, were selected from two specialized ASD management centers in Riyadh/Saudi Arabia. The participants were randomly allocated into either the control group or the VR group. Control group participants were subjected to a conventional dental examination, while the VR group utilized VR intervention to immerse themselves in a simulated natural and soothing environment. The Venham anxiety and behavior scale (VABS) was utilized to measure anxiety levels, while the Frankl behavior rating scale (FBRS) was employed to assess the level of cooperation. Data were analyzed using a Mann–Whitney U test with a significance level of p < 0.05. Results: The baseline anxiety and level of cooperation between the groups were comparable (p > 0.05). During the dental examination, the VR group had significantly reduced anxiety scores (2.48 ± 1.76) compared to the control group (1.50 ± 1.74) (p < 0.001). Regarding the level of cooperation, the VR group exhibited significantly greater levels of cooperation (3.41 ± 0.96) than the control group (2.86 ± 1.03) (p = 0.002). Conclusions: These findings suggest that VR intervention is a successful technique for decreasing anxiety and enhancing cooperation among children with ASD during dental examination. Integrating VR technology in dental environments can potentially improve the dental experience and results for children diagnosed with ASD.
Amiodarone Therapy: Updated Practical Insights
Authors: Șorodoc Victorița , Indrei Lucia , Dobroghii Catinca , Asaftei Andreea , Ceasovschih Alexandr , Constantin Mihai , Lionte Cătălina , Morărașu Bianca Codrina , Diaconu Alexandra-Diana , Șorodoc Laurențiu
Published: October 2024

Amiodarone, a bi-iodinated benzofuran derivative, is among the most commonly used antiarrhythmic drugs due to its high level of effectiveness. Though initially categorized as a class III agent, amiodarone exhibits antiarrhythmic properties across all four classes of antiarrhythmic drugs. Amiodarone is highly effective in maintaining sinus rhythm in patients with paroxysmal atrial fibrillation while also playing a crucial role in preventing a range of ventricular arrhythmias. Amiodarone has a complex pharmacokinetic profile, characterized by a large volume of distribution and a long half-life, which can range from several weeks to months, resulting in prolonged effects even after discontinuation. Side effects may include thyroid dysfunction, pulmonary fibrosis, and hepatic injury, necessitating regular follow-ups. Additionally, amiodarone interacts with several drugs, including anticoagulants, which must be managed to prevent adverse effects. Therefore, a deep understanding of both oral and intravenous formulations, as well as proper dosage adjustments, is essential. The aim of this paper is to provide a comprehensive and updated review on amiodarone’s indications, contraindications, recommended dosages, drug interactions, side effects, and monitoring protocols.
Endothelial Keratoplasty Following Glaucoma Filtration Surgery: A UK Tertiary Eye Care Referral Centre Experience
Authors: Aiello Francesco , Matarazzo Francesco , Phylactou Maria , Muthusamy Kirithika , Maurino Vincenzo
Published: October 2024

Purpose: To compare the postoperative complications and clinical outcomes of Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping automated endothelial keratoplasty (DSAEK) in eyes with previous glaucoma filtering surgery. Methods: In this retrospective comparative case series, we analysed postoperative visual acuity and intraocular pressure, graft survival, rate of graft detachment and/or dislocation, number of rebubbling and/or graft repositioning procedures, and graft rejection or failure (primary and secondary). Results: Sixteen eyes with DMEK and 80 eyes with DSAEK with previous glaucoma surgery were studied. The results were recorded at 3 and 12 months postoperatively. No statistically significant differences in postoperative visual acuity were found between the two groups at any stage of the follow-up. Intraocular pressure was lower in the DMEK group at the follow-up stage of 3 (p = 0.0022) and 12 months (p = 0.0480). Visually significant graft detachment was recorded in 31.3% and 22.5% of DMEK and DSAEK cases, respectively (p = 0.4541). All DMEK detachments (n = 5) were managed with slit-lamp rebubbling. Out of 18 graft detachments in the DSAEK group, 2 grafts were observed due to small graft detachment, 6 large graft detachments underwent rebubbling performed in the operating theatre, and 10 eyes needed primary graft repositioning for graft dislocation. Conclusions: DMEK is a feasible option to treat endothelial failure in complex eyes with previous glaucoma surgery. In the DMEK group, visual acuity outcomes and possibly postoperative intraocular pressure control were better compared with the DSAEK group.