Elevated Markers Research Articles

Vasculitic involvement of the skeletal muscle and the peripheral nervous system: clinical and neuropathologic perspective

The peripheral nervous system is a classic target organ in systemic vasculitis. In addition, the skeletal muscle can also be affected. Myalgia, muscle weakness and sensory deficits are typical signs, which can lead to severe functional limitations and impaired of quality of life. Vasculitic involvement of the skeletal muscle (vasculitic myopathy [VM]) and peripheral nerves (vasculitic neuropathy [VN]) occurs predominantly in polyarteritis nodosa and small-vessel vasculitis. VM presents with elevated markers of inflammation and is typically characterized by immobilizing myalgia with normal creatine kinase activity and diffuse or patchy areas of hyperintensity on T2-weighted MRI ("MRI myositis without myositis"). In VN, sensor motor deficits predominantly affect the lower extremity in the area supplied by several peripheral nerves (e.g., mononeuritis multiplex) with acute to subacute history. The histopathological examination of nerve and muscle biopsies is the gold standard for the diagnosis of vasculitic manifestations and has a significant impact on the therapeutic approach.

Post-hospitalisation COVID-19 cognitive deficits at one year are global and associated with elevated brain injury markers and grey matter volume reduction.

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers, and reduced anterior cingulate cortex volume one year after COVID-19. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies.

Reactive oxygen species-sensitive fenofibrate-loaded dextran nanoparticles in alleviation of osteoarthritis

Osteoarthritis (OA) stands as a prevalent chronic joint pathology, emerging as a leading cause of disability on a global scale. However, the current therapeutic efficacy in OA treatment remains unsatisfactory. Chondrocyte ferroptosis has become to a critical target for OA treatment, while the fabrication of nanomedicines emerges as a promising strategy for OA treatment. Nevertheless, there exists a paucity of reported nanomedicine systems designed to combat chondrocyte ferroptosis for OA alleviation. In light of this, our study introduced a reactive oxygen species (ROS)-sensitive fenofibrate-loaded targeted nanoparticle (FN-CNPs) as a means of alleviating OA by suppressing chondrocyte ferroptosis. In vitro investigations demonstrated the FN-CNPs can achieve this through the reduction of lipid peroxidation and ROS levels, as well as the elevation of anti-ferroptosis markers (GPX4, FSP1, and ACSL3). Consequently, FN-CNPs exhibited significant anti-inflammatory effects and downregulated the expression of key catabolic mediators in vitro. Furthermore, in vivo studies underscored the ability of FN-CNPs to alleviate OA progression and protect cartilage. Collectively, these findings highlight the efficacy of FN-CNPs in mitigating OA progression by suppressing chondrocyte ferroptosis via regulating ROS levels, antioxidant systems and lipid metabolism of chondrocytes.

Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement.

Despite the extraordinary anti-tubercular activity of isoniazid (INH), the drug-induced hepatotoxicity and peripheral neuropathy pose a significant challenge to its wider clinical use. The primary cause of INH-induced hepatotoxicity is in vivo metabolism involving biotransformation on its terminal -NH2 group owing to its high nucleophilic nature. The human N-acetyltransferase-2 enzyme (NAT-2) exploits the reactivity of INH's terminal -NH2 functional group and inactivates it by transferring the acetyl group, which subsequently converts to toxic metabolites. This -NH2 group also tends to react with vital endogenous molecules such as pyridoxine, leading to their deficiency, a major cause of peripheral neuropathy. The elevation of liver functional markers is observed in 10%-20% of subjects on INH treatment. INH-induced risk of fatal hepatitis is about 0.05%-1%. The incidence of peripheral neuropathy is 2%-6.5%. In this review, we discuss the genesis and historical development of INH, and different reported mechanisms of action of INH. This is followed by a brief review of various clinical trials in chronological order, highlighting treatment-associated adverse events and their occurrence rates, including details such as geographical location, number of subjects, dosing concentration, and regimen used in these clinical studies. Further, we elaborated on various known metabolic transformations highlighting the involvement of the terminal -NH2 group of INH and corresponding host enzymes, the structure of different metabolites/conjugates, and their association with hepatotoxicity or neuritis. Post this deliberation, we propose a hydrolysable chemical derivatives-based approach as a way forward to restrict this metabolism.

Dissecting depression symptoms: Multi-omics clustering uncovers immune-related subgroups and cell-type specific dysregulation

In a subset of patients with mental disorders, such as depression, low-grade inflammation and altered immune marker concentrations are observed. However, these immune alterations are often assessed by only one data type and small marker panels. Here, we used a transdiagnostic approach and combined data from two cohorts to define subgroups of depression symptoms across the diagnostic spectrum through a large-scale multi-omics clustering approach in 237 individuals. The method incorporated age, body mass index (BMI), 43 plasma immune markers and RNA-seq data from peripheral mononuclear blood cells (PBMCs). Our initial clustering revealed four clusters, including two immune-related depression symptom clusters characterized by elevated BMI, higher depression severity and elevated levels of immune markers such as interleukin-1 receptor antagonist (IL-1RA), C-reactive protein (CRP) and C-C motif chemokine 2 (CCL2 or MCP-1). In contrast, the RNA-seq data mostly differentiated a cluster with low depression severity, enriched in brain related gene sets. This cluster was also distinguished by electrocardiography data, while structural imaging data revealed differences in ventricle volumes across the clusters. Incorporating predicted cell type proportions into the clustering resulted in three clusters, with one showing elevated immune marker concentrations. The cell type proportion and genes related to cell types were most pronounced in an intermediate depression symptoms cluster, suggesting that RNA-seq and immune markers measure different aspects of immune dysregulation. Lastly, we found a dysregulation of the SERPINF1/VEGF-A pathway that was specific to dendritic cells by integrating immune marker and RNA-seq data. This shows the advantages of combining different data modalities and highlights possible markers for further stratification research of depression symptoms.

Unraveling the Liver-Brain Axis: Resveratrol's Modulation of Key Enzymes in Stress-Related Anxiety.

Stress-related anxiety disorders and anxiety-like behavior in post-traumatic stress disorder (PTSD) are associated with altered neurocircuitry pathways, neurotransmitter systems, and the activities of monoamine and glucocorticoid-metabolizing enzymes. Resveratrol, a natural polyphenol, is recognized for its antioxidant, anti-inflammatory, and antipsychiatric properties. Previous studies suggest that resveratrol reduces anxiety-like behavior in animal PTSD models by downregulating key enzymes such as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and monoamine oxidases (MAOs). However, the underlying mechanisms remain unclear. In this study, we explored the efficacy of resveratrol in treating stress-induced anxiety using a chronic predator stress model in rats. Resveratrol was administered intraperitoneally at 100 mg/kg following a 10-day stress exposure, and anxiety behavior was assessed with an elevated plus maze. Our results indicated that stress-related anxiety correlated with increased activities of brain MAO-A, MAO-B, and hepatic 11β-HSD-1, alongside elevated oxidative stress markers in the brain and liver. Resveratrol treatment improved anxiety behavior and decreased enzyme activities, oxidative stress, and hepatic damage. We demonstrate that resveratrol exerts antianxiogenic effects by modulating glucocorticoid and monoamine metabolism in the brain and liver. These findings suggest resveratrol's potential as a therapeutic agent for anxiety disorders, warranting further clinical investigation.

Mitochondrial dysfunction and oxidative stress in selective fetal growth restriction

IntroductionPlacental dysfunction is the primary cause of selective fetal growth restriction (sFGR), and the specific role of mitochondria remains unclear. This study aims to elucidate mitochondrial functional defects in sFGR placentas and explore the roles of mitochondrial genomic and epigenetic alterations in its pathogenesis. MethodsThe placental villi of MCDA twins with sFGR were collected and the morphology and number of mitochondria were observed by transmission electron microscopy. Meanwhile, the levels of reactive oxygen species (ROS), ATP and oxidative damage markers were assessed. Mitochondrial DNA (mtDNA) copy number detection, targeted sequencing and methylation sequencing were performed. The expression of placental cytochrome c oxidase subunit I (COX I) and mitochondrial long non-coding RNAs (lncRNAs) were evaluated by Western blotting and qPCR. ResultsCompared with placentae from normal fetuses, pronounced mitochondrial damage within cytotrophoblast was revealed in sFGR placentae, alongside augmented mitochondrial number in syncytiotrophoblast. Enhanced oxidative stress in these placentae was evidenced by elevated markers of oxidative damage, accompanied by increased ROS production and diminished ATP generation. In sFGR placentae, a notable rise in mitochondrial copy number and one heterozygous mutation in the MT-RNR2 gene were observed, along with decreased COX Ⅰ levels, increased lncND5, lncND6, lncCyt b, and MDL1 synthesis, and decreased RMRP synthesis. DiscussionFindings collectively confirmed an exacerbation of oxidative stress within sFGR placentae, coinciding with mitochondrial dysfunction, compromised energy production, and ultimately the failure of compensatory mechanisms to restore energy balance, which may result from mutations in the mitochondrial genome and abnormal expression of epigenetic regulatory genes.

A Case of Raoultella Ornithinolytica Cholangitis in A Liver Transplant Recipient.

We present the first documented case of Raoultella ornithinolytica bacteraemia in a patient with liver transplantation. R. ornithinolytica is a Gram-negative anaerobic bacterium found in aquatic environments in fish and birds, and is source of nosocomial infection causing pneumonia, enteritis, cholangitis or urinary infections, associated with surgical interventions in a hospital setting. A 44-year-old female presented with a 2-day history of fever, rigors, and headache. Her past medical history was significant for having received three orthotopic liver transplants due to Wilson's disease over a 20-year period. Her physical examination was unremarkable besides stigmata of prior liver transplantation. Blood tests revealed mild elevations in liver function markers and raised inflammatory markers. R. ornithinolytica was eventually isolated from blood cultures. Subsequent magnetic resonance cholangiopancreatography (MRCP) demonstrated new left intrahepatic ductal dilation with heterogeneous peripheral enhancement. The proximal location of the cholangitis explained the lack of abdominal pain or tenderness. The patient was treated with appropriate antibiotic therapy and cultures were negative on day 2. The patient recovered without further intervention. Seldom encountered R. ornithinolytica is uncommonly pathogenic but should be considered in patients receiving immunosuppressants and those with complex surgical anatomy. This is the first case of Raoultella cholangitis in a liver transplant recipient described in the literature.Atypical clinical presentation and atypical infections are common in this patient group.Cholangitis should be suspected in all liver transplant recipients due to immunosuppression.

Clinical presentations and diagnostic approaches of pediatric necrotizing tracheobronchitis with influenza A virus and Staphylococcus aureus co-infections

In March 2023, our pediatric intensive care unit (PICU) retrospectively examined six cases of pediatric necrotizing tracheobronchitis (NTB), focusing on co-infections with influenza A virus (IAV) and Staphylococcus aureus (S. aureus). This study aimed to elucidate NTB’s clinical characteristics, diagnostics, and therapeutic approaches. Diagnostics included symptom assessment, microbiological testing that confirmed all patients were positive for IAV H1N1 with a predominant S. aureus co-infection, and bronchoscopy. The patients predominantly exhibited fever, cough, and dyspnea. Laboratory analysis revealed decreased lymphocyte counts and elevated infection markers like C-reactive protein and procalcitonin. Chest computed tomography (CT) scans detected tracheobronchial obstructions in half of the cases, while bronchoscopy showed severe mucosal congestion, edema, necrosis, and purulent-hemorrhagic exudates. Treatments encompassed comprehensive strategies like oxygen therapy, intubation, bronchoscopic interventions, thoracentesis, oseltamivir, and a regimen of antibiotics. Our findings suggested potential correlations between clinical markers, notably lymphocyte count and procalcitonin, and clinical interventions such as the number of rescues and intensive care unit (ICU) duration. This research highlights the importance of early detection and the role of bronchoscopy and specific markers in assessing NTB, advocating for continued research in larger cohorts to better understand its clinical trajectory and refine treatment approaches for this challenging pediatric disease.

Hypothesis paper: GDF15 demonstrated promising potential in Cancer diagnosis and correlated with cardiac biomarkers

BackgroundCardiovascular toxicity represents a significant adverse consequence of cancer therapies, yet there remains a paucity of effective biomarkers for its timely monitoring and diagnosis. To give a first evidence able to elucidate the role of Growth Differentiation Factor 15 (GDF15) in the context of cancer diagnosis and its specific association with cardiac indicators in cancer patients, thereby testing its potential in predicting the risk of CTRCD (cancer therapy related cardiac dysfunction).MethodsAnalysis of differentially expressed genes (DEGs), including GDF15, was performed by utilizing data from the public repositories of the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Cardiomyopathy is the most common heart disease and its main clinical manifestations, such as heart failure and arrhythmia, are similar to those of CTRCD. Examination of GDF15 expression was conducted in various normal and cancerous tissues or sera, using available database and serum samples. The study further explored the correlation between GDF15 expression and the combined detection of cardiac troponin-T (c-TnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), assessing the combined diagnostic utility of these markers in predicting risk of CTRCD through longitudinal electrocardiograms (ECG).ResultsGDF15 emerged as a significant DEG in both cancer and cardiomyopathy disease models, demonstrating good diagnostic efficacy across multiple cancer types compared to healthy controls. GDF15 levels in cancer patients correlated with the established cardiac biomarkers c-TnT and NT-proBNP. Moreover, higher GDF15 levels correlated with an increased risk of ECG changes in the cancer cohort.ConclusionGDF15 demonstrated promising diagnostic potential in cancer identification; higher GDF15, combined with elevated cardiac markers, may play a role in the monitoring and prediction of CTRCD risk.

Influence of Postoperative Insulin Resistance on Short-Term Outcomes of Radical Gastrectomy for Gastric Cancer: A Microbiome and Metabolome-Based Prospective Cohort Study.

Gastrectomy is one of the main treatment modalities for gastric cancer (GC) and induces pathophysiological changes that significantly affect patients' postoperative recovery. In this study, we investigated the relationships between altered insulin resistance (IR), inflammation, and gut microbiota associated with gastrectomy. This study was a single-center prospective cohort investigation involving 60 patients with GC who underwent gastrectomy between May 2023 and April 2024. Monitoring encompassed IR, inflammation, and nutrition-related markers via blood assays, while gut microbiota analysis employed high-throughput sequencing, and short-chain fatty acids (SCFAs) were examined through targeted metabolomics. The study is registered under the number ChiCTR2300075653. The patients exhibited a significant increase in post-gastrectomy IR markers (P < 0.001), accompanied by elevated inflammation markers (P < 0.001), and also showeddecreased nutrition-related indicators (P < 0.001). Notable alterations were observed in the gut microbiota, including reductions in Bifidobacterium and Faecalibacterium, an increase in Streptococcus, and a noteworthy decrease in fecal butyrate. Patients with postoperative IR exhibited poorer inflammation markers (P < 0.05), nutritional indicators (P < 0.05), and postoperative recovery parameters (P < 0.05). Furthermore, significant negative correlations were observed between IR and Bifidobacterium,Faecalibacterium,as well as butyrate. Patients with GC post-gastrectomy displayed heightened IR, exacerbated inflammation, and compromised nutritional status. Disturbed gut microbiota and reduced fecal butyrate were observed. Gut microbiota and metabolite butyrate production may be predictors of postoperative IR and short-term outcomes in patients with GC.

Assessment of the toxic influence of locally formulated pesticides on hepatic and renal biomarkers in male Wistar rats.

There is growing concern of the potential damage to vital organs after long term exposure to locally formulated pesticides in rural area of Nigeria. This study was designed to assessed the effects of the individual chemical compound and their combination on the kidney and liver of rats' model. Fifty-four rats divided into six groups and three sub-groups were exposed to 25, 50 and 75% dose of each of the pesticide's LD50 for 4h at 3days interval in an inhalation chamber for 28days. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TOT_BIL), creatinine and urea assay showed significant increase at the aforementioned doses in comparison to the control group. The red blood cell counts, hematocrit and hemoglobin concentrations were significantly altered in the rats administered varying doses of the pesticides when compared with the control. Similar result was obtained for the differential white blood cell counts. Histopathological examinations of the liver tissue of rats showed infiltrated sinusoids, traces of karypyknosis, vacuolar degeneration and microvesicular steatosis while that of the renal tissue showed glomeruli atrophy leading to widened Bowman's spaces as well as few shrunken glomeruli and varied level of degenerative tubular changes to tubular necrosis. This study established that individual pesticides and their mixture is toxic to the liver and kidney, as evidenced by the elevated markers of renal and liver functions and distortion of the structure of both organs as revealed by their photomicrographs. Therefore, it is a matter of public health significance to regularly monitor pesticide residues in foods and humans in order to assess the food safety risk and population exposure to pesticides.

Herpes simplex reactivation triggers symptom exacerbation in patients with major depressive disorder

BackgroundHerpes Simplex Virus (HSV) infection has been linked to depression, but the underlying mechanism remains largely unknown. We hypothesized that recurring HSV infection could exacerbate depressive symptomatology via activation of the immune response and the kynurenine pathway in patients with Major Depressive Disorder (MDD). Methods32 MDD patients and 17 psychiatrically healthy individuals with a history of HSV recurrence were enrolled into the study. Blood samples were obtained, and psychiatric symptom severity was assessed at three separate visits- asymptomatic, active infection, and follow-up. Plasma levels of tryptophan metabolite levels were measured using ultra-high performance liquid chromatography-mass spectrometry (LC-MS), and inflammation-associated proteins were measured using high sensitivity electrochemiluminescence. ResultsThere was a significant effect of infection recurrence on IFN-γ and sICAM-1 levels, the latter being influenced by MDD diagnosis. This indicates that the effect of infection on sICAM-1 levels differs between control and depressed groups, although post hoc analysis suggests that interaction effect might be subtle. Infection recurrence had a significant effect on the reactivity of psychiatric symptoms. Finally, there was a positive correlation between levels of anti-inflammatory cytokines IL-10 and IL-13 and depression severity in the cohort during infection recurrence. LimitationsRelatively small sample size, limited number of male participants, and the relatively weak inflammatory stimuli studied. ConclusionsMDD patients might react with an exacerbation of symptoms along with elevations of inflammatory markers during HSV recurrence. Further, the association with symptom severity indicates that therapeutic modulation of inflammation may be beneficial in patients with MDD, especially during active infections.

Preventive Effect of Alpha-pinene on Cisplatin-induced Kidney Injury by Oxidative Stress, Inflammation and Apoptosis via NF-κB Signaling Pathway

Introduction: The chemotherapy medication cisplatin is highly effective and is used in treating a wide variety of cancers. Tumor resistance and dose-related severe side effects, including kidney and hearing damage and suppressed bone marrow function, limit its clinical utility. This study aimed to investigate the nephroprotective effect of alpha-pinene against cisplatin-induced nephrotoxicity in male albino Wistar rats. Methods: A total of 24 rats were divided into four groups containing six animals. Alpha-pinene (50 mg/kg) was administered orally for 14 days, and cisplatin (50 mg/kg) was given intraperitoneally for the last two consecutive days (13th and 14th day). Kidney function markers, lipid peroxidative markers, antioxidant status, inflammatory markers, and apoptotic gene expressions were analyzed. The cisplatin-induced rats significantly elevated kidney function markers, inflammatory markers, and pro-apoptotic genes in kidney tissues. Further, the antioxidant level/activities and antiapoptotic gene expression were significantly diminished in cisplatin-induced rats. Results: Pretreatment with alpha-pinene significantly decreased kidney function markers, inflammatory markers, and pro-apoptotic genes and increased antioxidant status and antiapoptotic genes. Conclusion: These findings provide the protective effect of alpha-pinene against CP-induced nephrotoxicity, as measured by potent antioxidant and antiapoptotic properties.

Angiopoietin-like 4 facilitates human aortic smooth muscle cell phenotype switch and dysfunctions through the PI3K/Akt signaling in aortic dissection

PurposeVascular smooth muscle cell (VSMC) phenotype switch and dysfunctions have been reported to participate in aortic dissection (AD) progression. This study was aimed to investigate the role of angiopoietin-like 4 (ANGPTL4) in regulating VSMCs phenotype switch. Materials and methodsKey genes were analyzed in AD using public datasets, and it was found that the central differential gene ANGPTL4 was up-regulated in AD. The KEGG signaling pathway annotation was performed to validate the associated pathways, and the expression of ANGPTL4 was verified using multiple datasets and clinical samples. Furthermore, the specific functions of ANGPTL4 on platelet-derived growth factor-BB (PDGF-BB)-treated human aortic smooth muscle cell (HASMC) phenotypes were investigated. The dynamic effects of ANGPTL4 and core signaling antagonists on HASMC phenotypes were examined. ResultsHub gene ANGPTL4 was significantly up-regulated in AD. ANGPTL4 was linked to the PI3K/Akt signaling, angiogenesis, and neovascularization and remodeling. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotypes, including promoted cell viability and migration, decreased contractile VSMC markers α-SMA and SM22α, elevated ECM degradation markers MMP-2 and MMP-9, and promoted phosphorylation of PI3K and Akt. ANGPTL4 knockdown partially abolished PDGF-BB-induced contractile/synthetic VSMCs imbalance and HASMC dysfunctions. Furthermore, in ANGPTL4-overexpressing HASMCs pre-treated with PDGF-BB, the PI3K/Akt signaling inhibitor LY294002 also partially eliminated the effects caused by the PDGF-BB treatment and ANGPTL4 overexpression. ConclusionsANGPTL4 is significantly up-regulated in AD. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotype switch and dysfunctions, which might be involved in the PI3K/Akt signaling.

Altered Liver Enzyme Markers in Patients with Asymptomatic, and Mild Omicron Infection: A Retrospective Study.

The emergence of the SARS-CoV-2 Omicron variant has posed a significant global public health challenge. Elucidating the laboratory profiles of individuals infected with this variant is crucial for assessing organ damage. This study aimed to investigate the variations in liver function tests and their correlation with demographic characteristics and inflammatory markers in patients with early Omicron variant infections. A retrospective cohort study was conducted on 1133 mild or asymptomatic COVID-19 cases at Tianjin First Central Hospital. Data on age, gender, body mass index (BMI), and serum markers were collected and analyzed. Statistical analyses were performed using SPSS software, version 24.0. Abnormal liver function parameters, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (TBIL), were observed in 314 (27.71%) patients. "Hepatocellular type" was identified in 56 (4.94%) patients, "cholestatic type" in 185 (16.33%) patients, and "mixed type" in 73 (6.44%) patients. In the mixed group, we observed a pronounced elevation in the levels of ALT, AST, and GGT. Moreover, the hepatocellular group exhibited a statistically significant increase in AST and ALT concentrations relative to both the normal and cholestatic groups. Notably, the cholestatic group demonstrated a substantial increment in ALP levels. Males had a significantly higher prevalence of "abnormal liver enzyme markers" compared to females. Patients with "abnormal liver enzyme markers" exhibited significantly decreased immunoglobulin G (IgG) levels and elevated levels of inflammatory markers, including procalcitonin (PCT), interleukin-6 (IL6), as well as C-reactive protein (CRP) compared to normal group. Logistic regression analysis revealed that male gender and PCT levels were significantly associated with the risk of abnormal liver enzyme markers. Patients in hepatocellular group were likely accompanied with high CRP levels, whereas those in the cholestatic type were associated with high IL6 levels. Early Omicron infection might cause liver stress response. Elevated liver enzyme marker levels were correlated with age, gender, inflammatory factors, and IgG.

Anti‐synthetase syndrome complicated by multifocal tuberculosis: A thought‐provoking differential diagnosis with tumors

AbstractMycobacterium tuberculosis, which mainly affects the lungs but can also invade other systems, presents a diagnostic challenge when co‐existing with autoimmune disease. We report a case of 31‐year‐old Asian woman with anti‐synthetase syndrome who developed abdominal and subcutaneous lumps during treatment, along with elevated tumor markers, raising suspicion of malignancy. Pathological examination revealed M. tuberculosis infection, changing the diagnosis to multifocal extrapulmonary tuberculosis. This case highlights the need for prompt and detailed evaluations, and the importance of broad differential diagnosis.

Hindlimb immobilization induces insulin resistance and elevates mitochondrial ROS production in the hippocampus of female rats.

Alzheimer's disease (AD) is the fifth leading cause of death in older adults, and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a threefold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse [via a model of hindlimb immobilization (HLI)] on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-mo-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of amyloid precursor protein (APP) and tau protein in the hippocampus, 4) and reduced brain-derived neurotrophic factor (BDNF) expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.NEW & NOTEWORTHY Muscle disuse via hindlimb immobilization increased oxidative stress and insulin resistance in the hippocampus. These findings were in association with muscle iron overload in connection with iron dysregulation in the brain. Overall, our work identifies muscle disuse as a contributor to hippocampal dysfunction, potentially through an iron-based muscle-brain axis, highlighting iron dysregulation as a potential novel mechanism in the relationship between muscle health, cognitive function, and Alzheimer's disease risk.

Probiotic therapy modulates the brain-gut-liver microbiota axis in a mouse model of traumatic brain injury

The interplay between gut microbiota and host health is crucial for maintaining the overall health of the body and brain, and it is even more crucial how changes in the bacterial profile can influence the aftermath of traumatic brain injury (TBI). We studied the effects of probiotic treatment after TBI to identify potential changes in hepatic lipid species relevant to brain function. Bioinformatic analysis of the gut microbiota indicated a significant increase in the Firmicutes/Bacteroidetes ratio in the probiotic-treated TBI group compared to sham and untreated TBI groups. Although strong correlations between gut bacteria and hepatic lipids were found in sham mice, TBI disrupted these links, and probiotic treatment did not fully restore them. Probiotic treatment influenced systemic glucose metabolism, suggesting altered metabolic regulation. Behavioral tests confirmed memory improvement in probiotic-treated TBI mice. While TBI reduced hippocampal mRNA expression of CaMKII and CREB, probiotics reversed these effects yet did not alter BDNF mRNA levels. Elevated pro-inflammatory markers TNF-α and IL1-β in TBI mice were not significantly affected by probiotic treatment, pointing to different mechanisms underlying the probiotic benefits. In summary, our study suggests that TBI induces dysbiosis, alters hepatic lipid profiles, and preemptive administration of Lactobacillus helveticus and Bifidobacterium longum probiotics can counter neuroplasticity deficits and memory impairment. Altogether, these findings highlight the potential of probiotics for attenuating TBI's detrimental cognitive and metabolic effects through gut microbiome modulation and hepatic lipidomic alteration, laying the groundwork for probiotics as a potential TBI therapy.

Monitoring pediatric CNS non-germinomatous germ cell tumors via cerebrospinal fluid circulating tumor DNA.

Accurate molecular and clinical stratification of patients with central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) remains challenging, impeding the development of personalized therapeutic approaches. Herein, we investigated the translational significance of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) in pediatric NGGCTs to identify characteristic features of CNS NGGCTs and to identify a subset of patients for whom the presence of residual disease is a risk factor and an indicator of shorter progression-free survival (PFS) and overall survival (OS). Medical records of patients with CNS NGGCTs between January 1, 2018 and December 31, 2022 were reviewed retrospectively. The cohort consisted of 11 male and six female patients. Tumor markers were elevated in four of the five people who underwent surgery. The remaining 12 patients were diagnosed with malignant NGGCTs according to elevated tumor markers. Among them, ctDNA before chemotherapy as well as ctDNA clearance were consistently associated with PFS and OS (p<.05). By setting a ctDNA positivity threshold of 6%, patients with high ctDNA (above the threshold) levels, which had limitation due to the selection based on optimal statistic from the survival analysis, had significantly inferior 5-year PFS and OS compared to those with low levels (below the threshold). ctDNA or ctDNA clearance combined with the presence of residual disease predicted significantly worse OS and PFS (p<.05). CSF ctDNA might allow the study of genomic evolution and the characterization of tumors in pediatric NGGCTs. CSF ctDNA analysis may facilitate the clinical management of pediatric NGGCT patients, and aid in designing personalized therapeutic strategies.