Early Therapeutic Intervention Research Articles

Risk factors for neonatal cholestasis in small gestational age infants: case report and literature review

Cholestatic jaundice, defined as conjugated bilirubin levels higher than 1 mg/dl, is a bile formation and excretion disturbance. Its incidence is estimated at 1 case in 2500 live births, being 100-200 times higher in preterm infants less than 28 weeks gestational age. It occurs in biliary atresia, infectious diseases, endocrine and inherited metabolic diseases, Alagille Syndrome, preterm and intrauterine growth-restricted newborns, lack of enteral feeding, and is more frequent in male gender. It is a frequent complication of parenteral nutrition. In preterm and small for gestational age (SGA) infants, the etiology of cholestasis is multifactorial. Early diagnosis enables early therapeutic intervention. We report the case of an SGA male preterm infant. He was born by C-section for fetal distress at 30 weeks gestational age with an 800 g birth weight. He developed mild respiratory distress, hypoglycemia, meconium ileus, and early cholestasis. Complex hematological, serological, and immunological tests were carried out; ultrasound evaluations were performed. The final diagnosis was cholestasis of multifactorial etiology in a preterm infant with severe intrauterine growth restriction (IUGR). Treatment with ursodeoxycholic acid was started. Three months later, the transaminases, bilirubin, gammaglutamyl transferase (GGT), and alkaline phosphatase (ALP) triglycerides returned to normal. Conclusion. Cholestasis in SGA infants is a severe condition potentially associated with life-threatening complications, requiring complex diagnostic evaluation.

Portable Detection of Lysine Acetyltransferase Activity in Lung Cancer Cells Based on a Miniature Electrochemical Sensor.

The detection of lysine acetyltransferases is crucial for diagnosing and treating lung cancer, highlighting the necessity for highly efficient detection methods. We developed a portable, highly accurate, and sensitive technique using fast-scan cyclic voltammetry (FSCV) to determine the activity of the lysine acetyltransferase TIP60, employing a novel miniature electrochemical sensor. This approach involves a compact electrochemical cell, merely 3 mm in diameter, that holds solutions up to 50 μL, equipped with a conductive indium tin oxide working electrode. Uniquely, this system operates on a two-electrode model compatible with the FSCV, obviating the traditional requirement for a reference electrode. The system detects TIP60 activity through the continuous generation of CoA molecules that engage in reactions with Cu(II), thereby significantly improving the accuracy of the acetylation analysis. Remarkably, the detection limit achieved for TIP60 is notably low at 3.3 pg/mL (S/N = 3). The results show that the reversible dynamic acetylation can be effectively regulated by inhibitor incubation and glucose stimulation. This cutting-edge strategy enhances the analysis of a broad spectrum of biomarkers by modifying the responsive unit, and its miniaturization and portability significantly amplify its applicability in biomedical research, promising it to be a versatile tool for early diagnostic and therapeutic interventions in lung cancer.

Functions of Differentially Regulated miRNAs in Breast Cancer Progression: Potential Markers for Early Detection and Candidates for Therapy.

Breast cancer remains a major global health concern, emphasizing the need for reliable biomarkers to enhance early detection and therapeutic interventions. MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNA (~22 nt in length) molecules, which are aberrantly expressed in cancer and seem to influence tumor behavior and progression. Specific miRNA dysregulation has been associated with breast cancer initiation, proliferation, invasion, and metastasis. Understanding the functional roles of these miRNAs provides valuable insights into the intricate molecular mechanisms underlying breast cancer progression. The diagnostic potential of miRNAs as non-invasive biomarkers for early breast cancer detection is a burgeoning area of research. This review aims to elucidate the functions of differentially regulated miRNAs in breast cancer progression and assess their potential as markers for early detection, stage-specific biomarkers, and therapeutic targets. Furthermore, the ability of specific miRNAs to serve as prognostic indicators and predictors of treatment response highlights their potential clinical utility in guiding personalized therapeutic interventions.

Cachexia-Affected Survival Based on Inflammatory Parameters Compared to Complex Conventional Nutritional Assessments in Patients with Pancreatic Cancer and Other Gastrointestinal Tumors-The CONKO 020 Investigation.

Pancreatic adenocarcinoma (PDAC) is still a complex, devastating disease. Cachexia symptoms frequently impair patient survival. This accompanying syndrome is commonly diagnosed late, when clinical signs become evident. Early diagnosis using conventional measurement methods is often difficult, and the discrimination of this disease from cancer progression is challenging and often overlaps. The aim of this study was to analyze whether conventional nutritional assessments or laboratory biomarkers are better predictive tools for the early detection of patients at risk of reduced survival. We analyzed a prospective predefined cohort of 182 patients with gastrointestinal cancer, 120 patients with PDAC and-as controls-62 patients with other gastrointestinal adenocarcinoma (oAC), from whom we have sufficient data of protocol-defined conventional nutritional assessments, clinical data, and specific laboratory parameters. at the time of tumor diagnosis, high inflammatory biomarkers (c-reactive protein (CRP), interleukin-6 (IL-6)) and albumin serum levels were associated with impaired OS in PDAC patients, but not in patients with oAC. Hemoglobin, body mass index (BMI), and bioelectrical assessments alone did not have a prognostic impact at the time of diagnosis. In a multivariate analysis, only CRP (HR 1.91 (1.25-2.92), p = 0.003) was found to be an independent prognostic factor in PDAC patients. Over the course of the disease in PDAC patients, inflammatory biomarkers, albumin, hemoglobin, and bioelectrical assessments were associated with impaired OS. In multivariate testing, CRP (HR 2.21 (1.38-3.55), p < 0.001) and albumin (HR 1.71 (1.05-2.77), p = 0.030) were found to be independent prognostic factors in PDAC patients. Specifically for PDAC patients, high inflammatory index and albumin serum levels potentially represent a sufficient early surrogate marker to detect patients at high risk of impaired OS better than complex conventional methods. These findings could help to identify patients who may benefit from early therapeutic interventions.

MicroRNA-150 Deletion Reduces the Occurrence and Severity of Rheumatoid Arthritis by Inhibiting IL-17.

Understanding the effects of epigenetic factors on the pathogenesis of rheumatoid arthritis (RA) is important for the early diagnosis and therapeutic intervention of this disease. MicroRNA-150 (miR-150) exerts an important influence on the development and function of lymphocytes. However, the role of miR-150 in the pathogenesis of RA remains unclear. To explore the role of miR-150 in the pathogenesis of RA and the related immune mechanism. In this study, we used miR-150 knock-out (miR-150KO) and created animal models of RA. Flow cytometry, immunohistochemistry, and real-time RT-PCR were employed to assess the frequency of T cell subsets and cytokines expression. Compared to wild-type (WT) mice, the onset of RA was postponed and the incidence of RA was reduced in miR-150KO mice. The expression of IL-4 and IFN-γ significantly increased while the expression of IL-17 decreased significantly in NKT and CD4+ T cells of KO mice compared to that of WT mice after RA induction. In addition, the expression of IL-4 and IFN-γ increased while the expression of IL-17 decreased significantly in the joint tissues of KO mice compared to that of WT mice. Furthermore, the mRNA expression of TNF-α and IL-17 decreased significantly in the synovial fluid cells of KO mice compared to that of the WT mice after RA induction. MiR-150 deficiency decreases the expression of IL-17 in T cells and joint tissues, and alleviates the occurrence and progression of RA in mice.

Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey.

We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.

Nanotheranostics: A Cutting-Edge Technology for Cancer Management.

Cancer is the second-leading cause of death in the 21st century, where early detection and appropriate therapeutic interventions are two components essential for effective cancer management. Despite the availability of several conventional diagnostics and therapeutic agents, cancer mortality rates are rising due to an increase in the frequency of recurrence and metastasis in cancer patients. Therefore, tremendous efforts have been expended to address this significant clinical issue and improve therapeutic efficacy. In this regard, nanotheranostic is a multipotential single platform for both cancer diagnosis and treatment through enhanced aqueous solubility and bioavailability of the encapsulated agent, stimulus responsiveness, tumor-specific targeting ability, precise tumor imaging, and real-time drug delivery. Nonetheless, the translational success of nanotheranostic platforms is still in its infancy and requires more extensive research in the context of tumor heterogeneity, safety profile, and regulatory issues, which pose one of the largest technological limitations. The present review summarizes different nanotheranostic platforms and nanotheranostic candidates in clinical trials (AGuIX® , NBTXR3, Ferumoxtran, MM-398, EndoTAG-1, etc.), along with disadvantages and challenges to improving cancer diagnosis and treatment. Overall, the concept, platform, and technical knowledge of nanotheranostics are really helpful to academic and pharmaceutical researchers.

Development of a fluorescence and quencher-based FRET assay for detection of endogenous peptide:N-glycanase/NGLY1 activity

Cytosolic peptide:N-glycanase (PNGase/NGLY1 in mammals) catalyzes deglycosylation of N-glycans on glycoproteins. A genetic disorder caused by mutations in the NGLY1 gene leads to NGLY1 deficiency, with symptoms including motor deficits and neurological problems. Effective therapies have not been established, though a recent study used the administration of an adeno-associated viral vector expressing human NGLY1 to dramatically rescue motor functions in young Ngly1–/– rats. Thus, early therapeutic intervention may improve symptoms arising from central nervous system dysfunction, and assay methods for measuring NGLY1 activity in biological samples are critical for early diagnostics. In this study, we established an assay system for plate-based detection of endogenous NGLY1 activity using a FRET-based probe. Using this method, we revealed significant changes in NGLY1 activity in rat brains during aging. This novel assay offers reliable disease diagnostics and provides valuable insights into the regulation of PNGase/NGLY1 activity in diverse organisms under different stress conditions.

534 - Incidence of venous thromboembolic events and atherosclerotic cardiovascular disease risk factors in adolescents and adults with atopic dermatitis in Denmark: a population-based cohort study

Abstract Background Atopic dermatitis (AD) is associated with substantial impairment in quality of life, including sleep disturbances, anxiety, and depression, which may increase the risk of cardiovascular disease (CVD). However, the association between CVD and AD is not well established. Objectives To evaluate incidence rates (IRs) of venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) in patients with and without AD in a population-based cohort study in Denmark, and to assess IRs of malignancies, major adverse cardiovascular events (MACE), VTE, and the distribution of Atherosclerotic Cardiovascular Disease (ASCVD) risk factors in patients with AD and rheumatoid arthritis (RA) in a nested cohort analysis. Methods Data from all individuals aged ≥12 years (≥18 years in the nested cohort analysis) between January 1, 2000, and December 31, 2018, were extracted from the Danish National Patient Registry. Patients with ≥1 AD diagnosis during the study period were matched on sex and age with 10 individuals from the general population. The nested cohort analysis included patients diagnosed with RA as an additional comparison population. In the overall cohort, IRs of VTE, DVT, and PE were assessed; the nested cohort analysis evaluated the distribution of ASCVD risk factors and incidence of malignancies, MACE, and VTE in patients with and without ASCVD risk factors (age ≥65 years, and history of smoking, coronary artery disease, stroke, DVT, PE, and malignancy). The follow-up period was from the first diagnosis during the study period until the occurrence of death or an endpoint, the first instance of migration, or December 31, 2018. IRs are shown per 100 patient-years (PY) of exposure with 95% confidence intervals. Results The population-based cohort comprised 190,751 patients, including 17,341 patients with AD and 173,410 age- and sex-matched controls. The IR/100 PY of VTE was similar between the AD cohort (0.14 [95% CI, 0.12-0.16]) and the general population (0.11 [0.11-0.12]). The IR/100 PY for VTE was higher in patients with AD aged ≥65 years (0.71 [0.56-0.90]) than the age-matched general population (0.50 [0.46-0.54]) and lower in the younger AD cohorts (12 to &amp;lt;18 years, 0.02 [0.00-0.08]; 18 to &amp;lt;65 years, 0.12 [0.09-0.13]). The IRs/100 PY of DVT and PE were comparable between the AD cohort (DVT, 0.08 [0.06-0.09]; PE, 0.06 [0.05-0.08]) and the general population (DVT, 0.06 [0.06-0.07]; PE, 0.05 [0.05-0.05]).. The nested cohort analysis comprised 195,807 patients, including 13,432 with AD, 48,055 with RA, and 134,320 age- and sex-matched controls. Distribution of risk factors for malignancies (excluding nonmelanoma skin cancer [NMSC]), MACE, and VTE was comparable in the AD cohort and general population, but higher in patients with RA. The IR/100 PY for malignancies (excluding NMSC) was higher in patients with AD with a history of malignancy (11.41 [9.83-13.25]) than those without (0.44 [0.40-0.48]), and in those aged ≥65 years (3.09 [2.75-3.48]) versus &amp;lt;65 years (0.36 [0.33-0.40]). Similarly, the IR/100 PY for MACE was higher in patients with AD aged ≥65 years (2.30 [2.01-2.63]) versus &amp;lt;65 years (0.15 [0.13-0.17]), and patients with a history of ASCVD (5.02 [4.37-5.76]) versus without (0.15 [0.13-0.18]). Patients with AD with a history of VTE (including DVT/PE) and inherited thrombophilia had a greater risk of VTE than patients without these risk factors. Conclusions In these 2 large cohort studies of adults and adolescents with AD, IRs of VTE, DVT, and PE were comparable with the general Danish population. The risk of VTE, malignancy, and MACE was higher in patients with AD with a history of risk factors for ASCVD. This underscores the need for appropriate monitoring and reporting of cardiovascular events in patients with AD, and active management of risk factors with early and effective therapeutic intervention.

Clinical Implications of Various Electroencephalographic Patterns in Post-Stroke Seizures. The Utility of Routine Electroencephalogram.

Objective: Post-stroke seizures (PSS) are one of the major stroke-related complications. Early therapeutic interventions are critical therefore using electroencephalography (EEG) as a predictive tool for future recurrence may be helpful. We aimed to assess frequencies of different EEG patterns in patients with PSS and their association with seizure recurrence and functional outcomes. Methods: All patients admitted with PSS were included and underwent interictal EEG recording during their admission and monitored for seizure recurrence for 24 months. Results: PSS was reported in 106 patients. Generalized slow wave activity (GSWA) was the most frequent EEG pattern observed (n = 62, 58.5%), followed by Focal sharp wave discharges (FSWDs) (n = 57, 55.8%), focal slow wave activity (FSWA) (n = 56, 52.8%), periodic discharges (PDs) (n = 13, 12.3%), and ictal epileptiform abnormalities (n = 6, 5.7%). FSWA and ictal EAs were positively associated with seizure recurrence (p < .001 and p = .015 respectively) and it remained significant even after adjusting for age, sex, stroke severity, stroke subtype, or use of anti-seizure medications (ASMs). Other positive associations were status epilepticus (SE) (p = .015), and use of older ASM (p < .001). FSWA and GSWA in EEG were positively associated with severe functional disability (p = .055, p = .015 respectively). Other associations were; Diabetes Mellitus (p = .034), Chronic Kidney Disease (p = .002), use of older ASMs (p = .037), presence of late PSS (p = .021), and those with Ischemic stroke (p = .010). Conclusions: Recognition and documentation of PSS-related EEG characteristics are important, as certain EEG patterns may help to identify the patients who are at risk of developing recurrence or worse functional outcomes.

Inflammatory Biomarkers, Cognitive Functioning, and Brain Imaging Abnormalities in Bipolar Disorder: A Systematic Review.

Recent studies have pointed to neuroinflammation and neurotrophic factors as crucial mediators in the pathophysiology origins of mood disorders. The aim of this review is to assess the potential association between cognitive impairment, brain imaging abnormalities, and inflammatory biomarkers in patients affected by bipolar disorder (BD). Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, we systematically searched PubMed, Google Scholar, Scopus, and Web of Science databases, with no year restriction, up until August 2023, for human studies that examined the relationship between inflammatory markers and cognitive impairment in BD patients. Studies based on neuroimaging, such as MRI, DTI, and fMRI, were also included, along with those examining the moderating role of specific inflammatory markers in the alteration of the brain. 59 human clinical studies satisfied the criteria for consideration. Most of the studies reviewed concur that inflammatory state, measured by peripheral blood levels of CRP and cytokines, constitutes an important contributor to cognitive impairment observed in patients with BD. Robust evidence indicates an association between cognitive impairment and CRP, IL-1RA, IL-6, and TNF-α with its receptors, whereas there is no convincing evidence for the involvement of other neuroinflammatory biomarkers. Neuroimaging studies suggest that brain structural/functional abnormalities seen in BD could also be linked to a neuroinflammatory condition. Current data provide evidence of a link between cognitive impairments observed in BD patients and mechanisms of neuroinflammation. Emerging evidence indicates that systemic inflammation might also play an important role in the deterioration of brain structures critical to cognitive functions in patients with BD. The convergence of findings across these studies strengthens our understanding of the complex neurobiological underpinnings of these disorders. Identification of BD specific inflammatory markers may be of assistance for future early therapeutic interventions.

Modified pustulotic arthro-osteitis diagnostic guidance 2022 - Modified Sonozaki criteria - Secondary publication.

The concept of pustulotic arthro-osteitis (PAO) was first reported by Sonozaki et al. in 1979, with diagnostic criteria (Sonozaki criteria) proposed in 1981. These criteria have served as the gold standard for PAO diagnosis for over 40 years. In recent years, there has been an increasing emphasis on maximizing the quality of life of patients with PAO. This is achieved by striving for clinical remission, structural remission, and functional remission through early diagnosis and appropriate therapeutic intervention from an early stage. This article is an English translation of a summary of the 'Modified PAO Diagnostic Guidance 2022', edited by the Japan Ministry of Health, Labour and Welfare's Research Group on improvement of medical standard and quality of life of patients with spondyloarthritis and related diseases represented by ankylosing spondylitis and the Japan Spondyloarthritis Society. This guidance is intended to be helpful to both Japanese and global communities in rheumatology and spondyloarthritis.

Assessment Of The Status And Challenges Of The Linkage Between Universities And Industries In Ethiopia: The Case Of Two Universities And Six Industries

The primary objective is to report and document the case of a collodion baby, a rare congenital condition, emphasizing the importance of early and appropriate therapeutic intervention. By presenting this infrequent incidence, the aim is to contribute to the existing medical knowledge regarding the clinical symptoms and complications associated with collodion baby syndrome. Specifically, the goal is to highlight the significance of prompt and adequate management in minimizing potential complications due to skin barrier disruption. This involves implementing a treatment approach focused on eliminating scaling and reducing xerosis without causing excessive irritation to the delicate skin of the affected newborn. Furthermore, the report seeks to enhance clinical awareness among healthcare professionals, providing valuable insights into the symptoms that should be monitored closely and the multidisciplinary care required. Collaboration between pediatricians, dermatologists, otorhinolaryngologists, ophthalmologists, plastic surgeons, and physiotherapists is crucial for comprehensive care, addressing immediate concerns, and ensuring long-term survival and well-being. In summary, the objective is twofold: first, to contribute to the medical literature by documenting a rare collodion baby syndrome, and second, to underscore the importance of early intervention and multidisciplinary care in managing this congenital condition and minimizing associated complications.

Fabry App: the value of a portable technology in recording day-to-day patient monitored information in patients with Fabry disease

BackgroundFabry disease is a rare inherited disorder resulting from deficient α-galactosidase A enzyme activity. Common disease manifestations are sweating abnormalities, neuropathic pain, gastrointestinal symptoms and fatigue. Challenges are faced by health care professionals in evaluating symptom burden in the current clinical setting, and the demand for alternative methods for monitoring disease-specific symptoms has seen an acceleration in recent years. Smartphone technologies offer the potential for continuity of care and surveillance. As a part of a quality improvement project, a disease specific app was developed in collaboration with a software company (Health Touch Ltd) and made available for patient use in May 2018. The Fabry mobile app records five categories: pain, gastrointestinal symptoms, sweating, activity levels, medications. Fabry disease patients with gastrointestinal and pain symptoms attending the Lysosomal Storage Disorders Unit of the Royal Free London NHS Foundation Trust were reviewed to assess eligibility and invited to download the app for recording their symptoms (activity, sweating, pain and gastrointestinal) and medications. Patient-generated data were transmitted to a secure website for clinicians to review.ResultsOne-hundred and thirty-nine symptomatic Fabry disease patients who had a smartphone (iPhone or android) were invited to download the app. Sixty-seven patients (26 males and 41 females; median age, 49 years [range, 20–81]) downloaded and tracked the Fabry App at least once. The median frequency of use per patient was 6 (range, 1–629). Pain in the hands and abdominal pain were significantly higher (p = 0.009 and p = 0.007, respectively) in patients with classic phenotype compared with patients with non-classic phenotypes.ConclusionsWe demonstrated the feasibility and acceptability of a smartphone app to facilitate the remote assessment and monitoring of Fabry disease symptom burden on a daily/weekly basis, as an alternative to the current standard of care that requires patients to recall their symptoms during 6 to 12 monthly annual clinic visits. Patients who were more likely to use the app had greater disease burden. This innovation has the potential to assess disease progression, early therapeutic intervention, thereby decreasing the burden of morbidity and mortality among Fabry patients, and to record long-term effects of Fabry-specific therapies.

MarsGT: Multi-omics analysis for rare population inference using single-cell graph transformer

Rare cell populations are key in neoplastic progression and therapeutic response, offering potential intervention targets. However, their computational identification and analysis often lag behind major cell types. To fill this gap, we introduce MarsGT: Multi-omics Analysis for Rare population inference using a Single-cell Graph Transformer. It identifies rare cell populations using a probability-based heterogeneous graph transformer on single-cell multi-omics data. MarsGT outperforms existing tools in identifying rare cells across 550 simulated and four real human datasets. In mouse retina data, it reveals unique subpopulations of rare bipolar cells and a Müller glia cell subpopulation. In human lymph node data, MarsGT detects an intermediate B cell population potentially acting as lymphoma precursors. In human melanoma data, it identifies a rare MAIT-like population impacted by a high IFN-I response and reveals the mechanism of immunotherapy. Hence, MarsGT offers biological insights and suggests potential strategies for early detection and therapeutic intervention of disease.

E. Coli LPS-induced calcium signaling regulates the expression of hypoxia-inducible factor 1α in periodontal ligament fibroblasts in a non-hypoxia-dependent manner

Periodontitis, an inflammatory disease, can cause significant damage to the oral tissues which support the teeth. During the early development of periodontitis, periodontal ligament fibroblasts (PDLFs) undergo metabolic reprogramming regulated by hypoxia-inducible factor 1α (HIF-1α), which is strongly linked to the progression of inflammation. However, the precise mechanisms by which PDLFs regulate HIF-1α and its associated metabolic reprogramming during early inflammation remain unclear. This study illustrated that brief and low-dose exposure to Escherichia coli (E. coli) lipopolysaccharide (LPS) can serve as a non-hypoxic stimulus, effectively replicating early periodontal inflammatory reactions. This is evidenced by the upregulation of HIF-1α expression and the activation of HIF-1α-mediated crucial glycolytic enzymes, namely lactate dehydrogenase a, pyruvate kinase, and hexokinase 2, concomitant with an augmentation in the inflammatory response within PDLFs. We observed that the effects mentioned and their impact on macrophage polarization were notably attenuated when intracellular and extracellular stores of Ca2+ were depleted using BAPTA-AM and Ca2+-free medium, respectively. Mechanistically, our findings demonstrated that the transcriptional process of HIF-1α is regulated by Ca2+ during E. coli LPS stimulation, mediated through the signal transducer and activator of transcription 3 (STAT3) pathway. Additionally, we observed that the stabilization of intracellular HIF-1α proteins occurs via the endothelin (ET)-1-endothelin A receptor pathway, independent of hypoxia. Taken together, our research outcomes underscore the pivotal involvement of Ca2+ in the onset of early periodontitis by modulating HIF-1α and glycolysis, thereby presenting novel avenues for early therapeutic interventions.

Single-cell and Spatial Transcriptomics Reveals Ferroptosis as The Most Enriched Programmed Cell Death Process in Hemorrhage Stroke-induced Oligodendrocyte-mediated White Matter Injury.

Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Programmed cell death (PCD) is crucial for immunological balance, and includes necroptosis, pyroptosis, apoptosis, ferroptosis, and necrosis. However, the distinctions between these programmed cell death modalities after ICH remain to be further investigated. We used single-cell transcriptome (single-cell RNA sequencing) and spatial transcriptome (spatial RNA sequencing) techniques to investigate PCD-related gene expression trends in the rat brain following hemorrhagic stroke. Ferroptosis was the main PCD process after ICH, and primarily affected mature oligodendrocytes. Its onset occurred as early as 1 hour post-ICH, peaking at 24 hours post-ICH. Additionally, ferroptosis-related genes were distributed in the hippocampus and choroid plexus. We also elucidated a specific interaction between lipocalin-2 (LCN2)-positive microglia and oligodendrocytes that was mediated by the colony stimulating factor 1 (CSF1)/CSF1 receptor pathway, leading to ferroptosis induction in oligodendrocytes and subsequent neurological deficits. In conclusion, our study highlights ferroptosis as the primary PCD mechanism, emerging as early as 1 hour post-ICH. Early therapeutic intervention via the suppression of microglial LCN2 expression may alleviate ferroptosis-induced damage in oligodendrocytes and associated neurological deficits, thus offering a promising neuroprotective strategy following ICH.

The Correlation of MicroRNA-21 With the Nephrin, Podocin, and Urinary Albumin-Creatinine Ratio in Patients With Type 2 Diabetes and Albuminuria: A Cross-Sectional Study.

Diabetic kidney disease (DKD) is the most common and deranging microvascular complication of diabetes mellitus (DM). Podocytopathy is a key component of glomerular damage in DKD. Micro RNA-21 (miRNA-21) is an epigenetic regulator that plays a role in podocyte damage; however, the results of previous studies have not resolved the controversy about the role of miRNA-21 in the pathogenesis of DKD. The objective was to investigate the correlation between miRNA-21 levels and urinary nephrin, podocin, and urinary albumin-creatinine ratio (UACR) in patients with type 2 DM and albuminuria. This is a cross-sectional study. This study was carried out in internal medicine outpatient clinic of Cipto Mangunkusumo Hospital Jakarta, Indonesia. This study consisted of 42 adults with type 2 DM and albuminuria. The measurements include (1) Serum miRNA-21; (2) urinary podocin, nephrin, and albumin-creatinine ratio; and (3) serum miRNA-21 correlated to urinary podocin, nephrin, and albumin-creatinine ratio. The Spearman bivariate analysis to assess the correlation of miRNA-21 with nephrin, podocin, and UACR. The mean relative expression of miRNA-21 was 0.069 (0.024), the median for nephrin, podocin, and UACR was 35.5 (15.75-51.25) ng/mL, 0.516 (0.442-0.545) ng/mL, and 150 (94.56-335.75) ng/mL, respectively. A correlation between miRNA-21 and nephrin was observed (r = 0.598; P < .0001). There was a correlation between miRNA-21 and UACR (r = 0.604; P < .0001). No correlation was found between miRNA-21 and podocin. A lack of non-DM and non-albuminuric control population and small sample size. We could not exclude concurrent disease, and all other potential confounding variables, particularly those related to inflammation. The miRNA-21 can be considered an early biomarker for podocytopathy and albuminuria in DM, highlighting its potential for early diagnostic and therapeutic interventions. Further research is required to confirm these findings and explore their clinical applications, which could significantly alter management strategies for DKD.

Peripheral neuropathy associated with severe glial fibrillary acidic protein (GFAP) astrocytopathy: a case report

A 44-year-old man was admitted due to a fever. He developed unconsciousness and respiratory failure, necessitating mechanical ventilation. After the administration of methylprednisolone and intravenous immunoglobulin for suspected autoimmune encephalitis, his consciousness and respiratory state improved. However, he exhibited pronounced tetraparalysis and impaired sensation below the neck. A spinal MRI revealed swelling of the entire spinal cord, indicating myelitis. Deep tendon reflexes were diminished in all extremities, and a nerve conduction study confirmed motor-dominant axonal polyneuropathy. Subsequently, he developed a fever and headache. Brain MRI demonstrated FLAIR hyperintensities in the basal ganglia and brain stem. CSF analysis for anti-glial fibrillary acidic protein (GFAP) antibody turned out positive, leading to the diagnosis of GFAP astrocytopathy. Although the steroid re-administration improved muscle strength in his upper limbs and reduced the range of diminished sensation, severe hemiparalysis remained. Severe GFAP astrocytopathy can be involved with polyneuropathy. Early detection and therapeutic intervention for this condition may lead to a better prognosis.

Serum Amyloid A3 Fuels a Feed-Forward Inflammatory Response to the Bacterial Amyloid Curli in the Enteric Nervous System

BackgroundMounting evidence suggests a role for the gastro-intestinal microbiome as a determinant of peripheral immunity and central neurodegeneration, but the local disease mechanisms remain unknown. Given its potential relevance for early diagnosis and therapeutic intervention, we set out to map the pathogenic changes induced by bacterial amyloids in the gastro-intestinal tract and its enteric nervous system. MethodsTo examine the early response, we challenged primary murine myenteric networks with curli, the prototypic bacterial amyloid, and performed shotgun RNA sequencing and multiplex ELISA. Using enteric neurosphere-derived glial and neuronal cell cultures, as well as in vivo curli injections into the colon wall, we further scrutinized curli-induced pathogenic pathways. ResultsCurli induced a pro-inflammatory response, with marked upregulation of Serum Amyloid A3 (Saa3) and the secretion of several cytokines. This pro-inflammatory state was primarily induced in enteric glia, was accompanied by elevated levels of DNA damage and replication, and triggered the influx of immune cells in vivo. The addition of recombinant SAA3 was sufficient to recapitulate this specific pro-inflammatory phenotype while Saa3 knock-out attenuated curli-induced DNA damage and replication. Like curli, recombinant SAA3 caused a strong upregulation of Saa3 transcripts, indicating a feed-forward loop. Colonization of curli-producing Salmonella and Dextran Sulphate Sodium (DSS)-induced colitis caused a significant increase in Saa3 transcripts, indicating a central role for SAA3 in enteric dysfunction. Inhibition of dual leucine zipper kinase (DLK), an upstream regulator of the c-Jun N-terminal kinase (JNK) pathway responsible for SAA3 production, attenuated curli- and SAA3-induced Saa3 upregulation, DNA damage and replication in enteric glia. ConclusionsOur results position SAA3 as an important mediator of gastro-intestinal vulnerability towards bacterial-derived amyloids and demonstrate the potential of DLK inhibition to dampen enteric pathology.