Role In Pathophysiology Research Articles

Associations between (pharmaco-)genetic markers and postoperative pain after inguinal hernia repair – a prospective study protocol

BackgroundPostoperative pain is a common complication following surgery, with severity and duration varying between patients. Chronic postoperative pain after inguinal hernia surgery has an incidence rate of approximately 10%. Risk factors for acute and chronic pain following hernia surgery include age, sex, psychosocial factors, and demographic background. Additionally, genetic polymorphisms in enzymes involved in pain mechanisms, as well as the metabolism of analgesics might influence pain perception, pain development, and response to pain medications. Key enzymes include the catechol-o-methyltransferase (COMT), the µ-opioid receptor 1 (OPRM1), and the cytochrome P450 2D6 (CYP2D6).CYP2D6 plays a crucial role in metabolizing analgesics such as tramadol, codeine, and oxycodone. It is also suspected to be involved in the synthesis of catecholamines and endogenous morphines suggesting a potential role in pathophysiology of pain. We hypothesize that the CYP2D6 activity influences the development of postoperative pain after hernia surgery.MethodsThis study is a prospective, observational, multicenter association study investigating adult patients scheduled for inguinal hernia surgery using a robotic-assisted (rTAPP) approach. Patients are enrolled during the preoperative surgical consultation. A buccal swab is collected for genetic testing at this time. Pain at the site of the hernia is assessed using the validated EuraHSQoL score preoperatively and at 2, 4, and 6 weeks postoperatively. Additionally, information on co-medication and details of the surgery will be collected. The planned number of participants is 350 patients. The primary objective is to analyze the association between different genotype-predicted CYP2D6 phenotypes and patient-reported pain intensity 6 weeks after surgery. Secondary objectives include the association between further genetic variants, such as the COMT rs4680 and OPRM1 rs1799971 genotype, and pain severity. Additionally, the potential of pharmacogenetic panel testing to optimize analgesic therapy in hernia surgery patients will be explored.DiscussionThe findings of this study are expected to provide valuable insights into identifying patients at higher risk for postoperative pain before surgery. This knowledge could pave the way for tailored interventions during and after surgery for these specific patients.Trial registrationDeutsches Register Klinischer Studien https://www.drks.de/DRKS00034796 Registered on August 07, 2024.

Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes

Anthracycline antitumor drug doxorubicin (DOX) induces severe cardiotoxicity. Deubiquitinating enzymes (DUBs) are crucial for protein stability and function and play a significant role in cardiac pathophysiology. By comparing RNA sequencing datasets and conducting functional screening, we determined that Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a key regulator of DOX-induced cardiotoxicity. In this study, we aimed to explore the function and regulatory mechanisms of MYSM1 in DOX-induced cardiotoxicity. Genetic knockdown of MYSM1 significantly mitigated DOX-induced cardiomyopathy. Correspondingly, cardiomyocyte-specific knockdown of MYSM1 by AAV9 protected the heart from DOX-induced cardiotoxicity. Gain- and loss-of-function analysis verified that MYSM1 mediated DOX-induced cardiomyocyte injury in vitro. Through a Co-IP combined with LC-MS/MS analysis, we discovered that MYSM1 directly interacted with tripartite motif-containing protein 21 (TRIM21). Mechanistic investigations revealed that MYSM1 regulates the deubiquitination and the stability of TRIM21 via its MPN domain. Furthermore, MYSM1 exacerbated DOX-induced cardiotoxicity by enhancing ferroptosis. This study identified MYSM1 as a potential therapeutic target for DOX-induced cardiotoxicity and illustrated a MYSM1-TRIM21-ferroptosis axis in regulating DOX-induced cardiotoxicity.

In-depth analysis of serum antibodies against Epstein-Barr virus lifecycle proteins, and EBNA1, ANO2, GlialCAM and CRYAB peptides in patients with multiple sclerosis

BackgroundA strong association between multiple sclerosis (MS) and Epstein-Barr virus (EBV) has been established but the exact role of EBV in MS remains controversial. Recently, molecular mimicry between EBNA1 and specific GlialCAM, CRYAB and ANO2 peptides has been suggested as a possible pathophysiological mechanism. The aim of this study was to analyse anti-EBV antibodies in MS patients against (I) EBV lifecycle proteins, (II) putative cross-reactive peptides, and (III) during treatment.MethodsIn this retrospective cross-sectional study, 258 serum samples were included consisting of EBV-negative (n = 25) and EBV-positive (n = 36) controls, 192 MS samples including untreated relapsing-remitting MS (RRMS) with and without relapses, secondary progressive MS (SPMS) and primary progressive MS (PPMS) patients, and 106 patients on 8 different treatment regimens. IgG and IgM antibody titers against EBV docking/fusion proteins (gp350, gh/gp42, gh/gL/gp42), immediate early antigen (BZLF1), early antigens (EA p85, EA P138, EA P54), capsid antigens (VCA P18, VCA P23, VCA gp125) and late antigens (EBNA1) were measured. Specific EBNA1 and GlialCAM, CRYAB and ANO2 peptides were synthesized and also incorporated in our custom magnetic bead based multiplex assay.ResultsWe observed significantly elevated IgG antibody titers in EBV-positive controls, RRMS with and without relapse, SPMS and PPMS patients for all lifecycle antigens except for several early antigens when compared to EBV-negative controls. Significantly higher IgG antibody titers were observed in RRMS patients for fusion proteins and EBNA1 peptides when compared to EBV-positive controls. An MS specific response was observed for ANO2 but not for GlialCAM or CRYAB. No significant treatment effects or a specific IgM response were detectable.ConclusionThe MS-specific, differential antibody response to EBV antigens confirms an altered immunological response to EBV in MS patients. EBV reactivation does not appear to play an important role in MS pathogenesis and no differential antibody signatures were observed between MS disease phases. The MS-specific anti-ANO2 antibody response suggests a potential role for EBNA1 as an antigenic driver, although the exact role of anti-ANO2 antibodies needs to be determined. The precise pathophysiological role of EBV in MS remains uncertain and requires further investigation.

Co-administration of coenzyme Q10 and curcumin mitigates cognitive deficits and exerts neuroprotective effects in aluminum chloride-induced Alzheimer's disease in aged mice.

Aluminum chloride (AlCl3), a known neurotoxic and Alzheimerogenic metal disrupts redox homeostasis which plays a pivotal role in pathophysiology of neurodegenerative disorders, particularly cognitive decline. The current study was designed to unveil the long-term neuroprotective outcomes and efficacy of CoQ10 and curcumin low dose (100 mg/kg each) combination in 18-months old geriatric male Balb/c mice subjected to AlCl3-prompted memory derangements (200 mg/kg in water bottles) for 28 days. The neuroprotective properties driven by antioxidant mechanisms were assessed via observing cellular pathology in key-memory related brain regions including the cornuammonis (CA3 and DG) and cortex 2/3 layer. Our outcomes revealed that AlCl3 exposure significantly reduced spatial learning and memory. In contrast, CoQ10 and curcumin combinatorial regime markedly mitigated cognitive deficits Vs. individual high-dose in AlCl3-treated animals as demonstrated by their improved performance in neurobehavioral tests such as the Y-maze, novel object recognition, passive avoidance and Morris-water maze test. Additionally, CoQ10 and curcumin co-administration restored redox balance by significantly reducing the levels of oxidative stressor (MDA) and increasing the anti-oxidant capacity (SOD,GPx). AchE is an enzyme involved in acetylcholine breakdown which negatively impacts acetylcholine levels and memory function. AlCl3 exposure elevated AchE levels in mice brains vs. treatment. This neurochemical alteration was notably reversed in the dual-treatment group. Furthermore, CoQ10 and curcumin ameliorated AlCl3-induced neurotoxicity by preserving neuronal cytoarchitecture in both cortical and hippocampal regions. In conclusion, CoQ10 and curcumin combination might attenuate memory loss induced by AlCl3-intoxication via restoring aberrant AchE activity, enhanced anti-oxidant defenses and salvaging the deleterious neuronal damage.

Integrated Analysis of Gene Expression and Immune Cell Infiltration Reveals Dysregulated Genes and miRNAs in Acute Kidney Injury.

Acute Kidney Injury (AKI) is a multifaceted condition characterised by rapid deterioration of renal function, often precipitated by diverse etiologies. A comprehensive understanding of the molecular underpinnings of AKI is pivotal for identifying potential diagnostic markers and therapeutic targets. This study utilised bioinformatics to elucidate gene expression and immune infiltration in AKI. Publicly available mRNA and miRNA datasets were harnessed to discern differentially expressed genes (DEGs) and miRNAs in AKI. The CIBERSORT algorithm was employed to quantify immune cell infiltration in AKI samples. Functional enrichment analyses were conducted to unravel the implicated biological processes. Furthermore, the expression of identified genes and miRNAs was validated by quantitative real-time PCR in an AKI model. Our study revealed significant dysregulation of three genes (Aspn, Clec2h, Tmigd1) and two miRNAs (mmu-miR-21a-3p, mmu-miR-223-3p) in AKI, each with p < 0.0001. These molecular markers are implicated in immune responses, tissue remodelling, and inflammation. We observed notable disturbances in specific immune cells, including activated and immature dendritic cells, M1 macrophages, and subsets of T cells (Treg, Th1, Th17). These alterations correlated significantly with AKI pathology, with dendritic cells and M1 macrophages showing p < 0.01, and T cell subsets demonstrating p < 0.05. These results highlight the intricate involvement of the immune system in AKI and indicate significant enrichment of pathways related to immune response, inflammation, and tissue remodelling, pointing to their pivotal roles in AKI pathophysiology. Our study underscored the significance of immune cell infiltration and dysregulated gene and miRNA expression in AKI. The identified genes (Clec2h, Aspn, and Tmigd1) and miRNAs (mmu-miR-21a-3p and mmu-miR-223-3p) offer potential diagnostic markers and therapeutic avenues for AKI. Subsequent investigations targeting these genes and miRNAs, along with the elucidated pathways, may augment the clinical management and outcomes for AKI patients.

Human papillomavirus E6 alters Toll-like receptor 9 transcripts and chemotherapy responses in breast cancer cells in vitro

BackgroundToll-like receptor 9 (TLR9) is a DNA recognizing receptor expressed also in several cancers. Decreased TLR9 expression is associated with poor prognosis in triple negative breast cancer (TNBC), but the role of TLR9 in breast cancer pathophysiology is currently unclear. Regulation of TLR9 expression in breast cancer is poorly understood. Human papillomavirus (HPV) infections suppress TLR9 expression in cervical cancers but the association between HPV and breast cancer has remained controversial. The aim of this study was to test if HPV16 can suppress TLR9 expression in breast cancer cells and affect cell behavior.Methods and resultsHuman T-47D and MDA-MB-231 breast cancer cells were transduced with lentivirus encoding HPV16 E6 oncoprotein. The effects of E6 on TLR9 mRNA and protein expression, and cell proliferation, migration, invasion and sensitivity to chemotherapy were studied in vitro. Breast cancer tissue samples (n = 37) were analyzed for the presence of HPV DNA. E6 expression decreased TLR9 mRNA expression in MDA-MB-231 and T-47D cells in hypoxia. E6 expression altered breast cancer cell proliferation and made cells significantly less sensitive to the growth inhibitory effects of chemotherapeutic agents. HPV L1 gene was not detected in a small pilot cohort of clinical breast cancer specimens.ConclusionHPV16 may influence breast cancer cell TLR9 transcription and chemotherapy responses and could thereby affect breast cancer prognosis. These results suggest that HPV may have a previously unrecognized role in breast cancer pathophysiology and warrant further studies on the topic.

Drug Treatments for Neurodevelopmental Disorders: Targeting Signaling Pathways and Homeostasis.

Preclinical and clinical evidence support the notion that neurodevelopmental disorders (NDDs) are synaptic disorders, characterized by excitatory-inhibitory imbalance. Despite this, NDD drug development programs targeting glutamate or gamma-aminobutyric acid (GABA) receptors have been largely unsuccessful. Nonetheless, recent drug trials in Rett syndrome (RTT), fragile X syndrome (FXS), and other NDDs targeting other mechanisms have met their endpoints. The purpose of this review is to identify the basis of these successful studies. Despite increasing evidence of disruption in synaptic homeostasis, most genetic variants associated with NDDs implicate proteins involved in cell regulation and not in neurotransmission. Metabolic processes, in particular mitochondrial function, appear to play a role in NDD pathophysiology. NDDs are also characterized by distinctive cell signaling abnormalities, which link cellular and synaptic homeostasis. Recent successful trials in NDDs, including those of trofinetide, the first drug specifically approved for one of these disorders (i.e., RTT), implicate the targeting of downstream processes (i.e., signaling pathways) rather than neurotransmitter receptors. Recent positive drug studies in NDDs and their underlying mechanisms, in conjunction with new knowledge on the pathophysiology of these disorders, support the concept that targeting signaling and cellular and synaptic homeostasis may be a preferred approach for ameliorating synaptic abnormalities in many NDDs.

Cell-free plasma telomere length correlated with the risk of cardiovascular events using machine learning classifiers

This retrospective study explored the association between circulating cell-free plasma telomere length (cf-TL) and coronary artery disease (CAD) and heart failure (HF). Data from 518 participants were collected, including clinical and laboratory data. cf-TL was measured in plasma samples and machine learning (ML) classification models were developed to differentiate between CAD, HF and control conditions. Our results showed that cf-TL was significantly prolonged in HF patients compared to controls, but no significant difference was observed between CAD patients and controls. Additionally, cf-TL was significantly correlated with nitric oxide metabolites (NOx) and flow-mediated dilation (FMD), suggesting a potential link with endothelial function. To avoid data leakage and ensure the model captured only relationships relevant to the research question, we utilized a temporal data split, holding out the last year’s data for testing (n = 81) and using the remaining data for training (n = 324) and validation (n = 109). The ML models using four variables achieved an area under the curve (AUC) of 0.795 in the validation dataset and 0.717 in the test dataset for CAD classification, and 0.829 in the validation dataset and 0.806 in the test dataset for HF classification. SHAP analysis revealed that cf-TL had minimal impact on the predictions of the CAD model, as indicated by consistently low SHAP values, whereas in the HF model, cf-TL exhibited a broader range of SHAP values, indicating a greater contribution to the model’s classification. These findings suggest that cf-TL may play a more prominent role in HF pathophysiology and could serve as a valuable biomarker for predicting HF risk. Further studies are warranted to explore cf-TL’s diagnostic and prognostic potential across different cardiovascular diseases.

Gender-specific inflammatory burden and headache risk in youth: a NHANES analysis

BackgroundHeadaches are a common and often debilitating condition among youth. The Inflammatory Burden Index (IBI), a simple surrogate marker of systemic inflammation, has been linked to various diseases. However, evidence for its relationship with headaches, particularly in youth, is lacking. This study aimed to investigate the association between IBI and persistent headache in youth, with a focus on evaluating gender-specific responses to IBI exposure.MethodsWe analyzed data from 2,210 young people in the 2001–2004 National Health and Nutrition Examination Survey (NHANES). The association between IBI and frequent or severe headaches in the past year was investigated using weighted logistic regression models. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated, and threshold effect analyses were performed.ResultsYouths in the highest IBI quartile (Q4) had a 46% higher risk of severe headaches compared to the lowest quartile (Q1) (OR: 1.46, 95% CI: 1.12–1.91, P = 0.0051). Gender-stratified analysis revealed a significant association between high IBI and headache risk in females (OR: 1.48; 95% CI: 1.03–2.11, P = 0.0324), but not in males. Threshold effect analysis identified an IBI breakpoint of 3.78, below which the headache risk increased significantly in females under 18 years (OR: 1.12, 95% CI: 1.01–1.25, P = 0.0385).ConclusionsOur findings demonstrate a significant association between elevated IBI and increased headache risk in youth, particularly in females. This gender-specific effect suggests that inflammatory processes may play a more prominent role in headache pathophysiology among female youth. These results underscore the importance of considering inflammatory markers in the early identification and prevention of youth headaches, especially in females.

The Aβ42:Aβ40 ratio modulates aggregation in beta-amyloid oligomers and drives metabolic changes and cellular dysfunction

The pathophysiological role of Aβ42 oligomers in the onset of Alzheimer’s disease (AD) is heavily disputed, pivoting research toward investigating mixed oligomers composed of Aβ42 and Aβ40, which is more abundant but less aggregation-prone. This study investigates Aβ42:Aβ40 oligomers in different ratios, examining their adverse effects on endothelial cells, neurons, astroglia, and microglia, as well as in a human blood–brain barrier (BBB) model. Combining label-free Raman microscopy with complementary imaging techniques and biochemical assays, we show the prominent impact of Aβ40 on Aβ42 fibrillation, suggesting an inhibitory effect on aggregation. Mixed oligomers, especially with low proportions of Aβ42, were equally detrimental as pure Aβ42 oligomers regarding cell viability, functionality, and metabolism. They also differentially affected lipid droplet metabolism in BBB-associated microglia, indicating distinct pathophysiological responses. Our findings demonstrate the overarching significance of the Aβ42:Aβ40 ratio in Aβ oligomers, challenging the traditional focus on Aβ42 in AD research.

EVALUATION OF GLUTATHIONE PEROXIDASE ACTIVITY, MALONYLALDEHYDE AND SELENIUM LEVELS IN SICKLE CELL ANAEMIA INDIVIDUALS ATTENDING NAUTH, NNEWI IN SOUTH-EASTERN NIGERIA.

Background: Oxidative stress is an imbalance between the production and clearance of toxic free radicals known as reactive oxygen species (ROS). It is associated with hemolysis, a hallmark of SCD. SCD has long been recognized as an inflammatory condition and oxidative stress play important role in pathophysiology of SCA. Imbalance between production and elimination of reactive oxygen species (ROS) damages cell structures, including lipids, membranes, proteins and nucleic acids resulting in cell death or altered cell function. Aim: The aim of this study was to measure the serum level of Glutathione peroxidase, Malonaldehyde and Selenium in SCA (HbSS) in their steady state, AA (Healthy adult) and AS (sickle cell carriers) Methods: This is a cross- sectional study. A total of one hundred and fifty aged matched participants were recruited for this study.50 SCA subjects with sickle cell anemia (SS). Glutathione peroxidase and Malonyaldehyde were measured using turbidometry and colorimetric methods respectively while Selenium was analysed using Atomic Absorption Spectrophotometry (AAS) Results: The result of analysis of variance (ANOVA) showed that the mean serum level of MDA concentration (2.97±0.29) was higher in the SS group and was statistically significant (p&lt; 0.05). MDA concentration was lower in the AS group. In the post hoc analysis MDA was statistically significant between SS vs AS and AA vs AA. The glutathione peroxidase activity was significantly lower in the SS group (0.85±0.12) compare with the mean values obtained in the AA and AS group. The GPx activity among the three groups was statistically significant while the post hoc analysis among the three groups showed statistical difference and was significant (p &lt; 0.005) The Selenium levels in the SS group is lower compared with the values observed between the AA and AS group. The Se levels in the SS group was statistically lower (5.73±1.34) (p &lt; 0.05) and showed significant difference. The comparison study between AS vs SS and AA vs AA were statistically significant. Conclusion: The decrease in selenium level potentiates low and weakened antioxidant activity and capacity which also is a reflection of low level of glutathione peroxidase observed which is supposed to attack free radicals to prevent oxidative stress. The findings from this study are in tandem with other researches suggesting that the pathophysiology of sickle cell disease is associated with oxidative stress

Advances in the Pathophysiology and Drug Discovery of Novel Therapeutics for Attention-Deficit/hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity and impulsivity. Psychostimulants such as methylphenidate are first-line treatments, but carry risks of severe side effects and addiction. Therefore, further research and the discovery of non-psychostimulant medications with novel mechanisms are urgently needed. We previously reported that juvenile stroke-prone spontaneously hypertensive rats (SHRSP/Ezo) are a suitable animal model of ADHD, and we identified N-methyl-D-aspartate (NMDA) receptor dysfunction in the prefrontal cortex of SHRSP/Ezo. D-Serine, a co-agonist for the glycine binding site of NMDA receptors, is synthesized from L-serine by serine racemase (SR) and degraded by D-amino acid oxidase (DAAO). Although D-serine dysregulation is implicated in psychiatric disorders, its pathophysiological role in ADHD is unclear. We measured D-serine in the medial prefrontal cortex (mPFC) of SHRSP/Ezo and addressed SR and DAAO expression. Additionally, we assessed cognitive function following DAAO inhibitor microinjection into the mPFC. SHRSP/Ezo showed a reduced D-serine/total serine (DL) ratio in the mPFC compared with the genetic control, Wistar Kyoto rat/Ezo (WKY/Ezo). DAAO expression in the mPFC was higher in SHRSP/Ezo rats compared with WKY/Ezo, however there was no difference in SR expression. The microinjection of a DAAO inhibitor into the mPFC of SHRSP/Ezo rats increased the DL ratio and ameliorated ADHD-like behaviors in the Y-maze test. These results suggest an association between abnormal D-serine metabolism and ADHD-like behaviors based on NMDA receptor dysfunction in the mPFC. Our findings provide insight into ADHD pathogenesis and should advance the development of new therapeutic approaches for the disorder.

Integrated data driven analysis identifies potential candidate genes associated with PCOS

Polycystic ovary syndrome (PCOS) is one of the most common anovulatory disorder observed in women presenting with infertility. Several high and low throughput studies on PCOS have led to accumulation of vast amount of information on PCOS. Despite the availability of several resources which index the advances in PCOS, information on its etiology still remains inadequate. Analysis of the existing information using an integrated evidence based approach may aid identification of novel potential candidate genes with a role in PCOS pathophysiology. This work focuses on integrating existing information on PCOS from literature and gene expression studies and evaluating the application of gene prioritization and network analysis to predict missing novel candidates. Further, it assesses the utility of evidence-based scoring to rank genes for their association with PCOS. The results of this study led to identification of ~2000 plausible candidate genes associated with PCOS. Insilico validation of these identified candidates confirmed the role of 938 genes in PCOS. Further, experimental validation was carried out for four of the potential candidate genes, a high-scoring (PROS1), two mid-scoring (C1QA and KNG1), and a low-scoring gene (VTN) involved in the complement and coagulation pathway by comparing protein levels in follicular fluid in women with PCOS and healthy controls. While the expression of PROS1, C1QA, and KNG1 was found to be significantly downregulated in women with PCOS, the expression of VTN was found to be unchanged in PCOS. The findings of this study reiterate the utility of employing insilico approaches to identify and prioritize the most promising candidate genes in diseases with a complex pathophysiology like PCOS. Further, the study also helps in gaining clearer insights into the molecular mechanisms associated with the manifestation of the PCOS phenotype by contributing to the existing repertoire of genes associated with PCOS.

Insights into Uromodulin and Blood Pressure.

We review the role of uromodulin, a protein exclusively expressed in the kidney, in blood pressure regulation and hypertension. The last few years have seen a shift of focus from genetic association to mendelian randomisation and uromodulin-salt interaction studies, thus confirming the causal role of uromodulin in blood pressure regulation and hypertension. This work has been complemented by phenome-wide association studies in a wider range of ethnicities. Important recent molecular work elucidated uromodulin trafficking and secretion and provided more insights into the pathophysiological roles of circulating and urinary uromodulin. Uromodulin has a causal role in blood pressure regulation and hypertensin. Recent studies show utility of the uromodulin as a biomarker and a possible precision medicine application based on genetically determined differential responses to loop diuretics.

Review of Tracheotomy Auxiliary Device Patents

Background: Tracheotomy is a surgical technique in which the trachea in the front of the neck is cut to construct an artificial airway. Bypassing blockage or lesions in the upper airway, this opening permits oxygen provision and carbon dioxide exhalation straight through the trachea. A more profound comprehension of the pathophysiologic role of the airway has made tracheotomy a crucial component of treatment for several illnesses. Medical devices used both during and after a tracheotomy are known as auxiliary devices for tracheotomies. These devices, which include dilators, cannulas, plugging devices for cannulas, and immobilization devices, ensure the procedure is completed safely and the patient recovers quickly. Objective: This paper aims to identify the key issues, summarize the many tracheotomy auxiliary device constructions in recent years, and serve as a resource for researchers working on related topics. Methods: Assess and evaluate the benefits and drawbacks of the tracheotomy auxiliary devices covered by the patents filed in the last several years and identify areas for development. Results: This patent research examines the shortcomings of current tracheotomy auxiliary devices and speculates about future directions for their advancement. Conclusion: Although they are challenging to use, the tracheotomy auxiliary devices now in use provide good stability and dependability. Enhancing the mechanical structure of tracheotomy auxiliary devices and strengthening clinical trials for various patient populations and intricate surgical settings are essential improvements. Furthermore, pertinent patents for auxiliary equipment used in tracheotomies have not yet been created.

Anticonvulsant effects of pentoxifylline on seizures induced by pentylenetetrazole and maximal electroshock in male mice: The role of the nitrergic pathway

IntroductionEpilepsy remains a challenge, with one-third of patients experiencing refractory seizures despite current anti-seizure medications. The nitrergic system, which involves nitric oxide (NO) and NO synthase (NOS) enzymes, plays a complex role in seizure pathophysiology. Pentoxifylline (PTPh), an FDA-approved phosphodiesterase inhibitor, has anticonvulsant effects; however, its relationship with the pathway is unclear. This study focused at how the nitrergic system could be involved in PTPh’s anticonvulsant effects. MethodsSeizures were induced in male mice by intravenous pentylenetetrazole (PTZ) infusion (absence-like seizures), intraperitoneal PTZ injection, and maximal electroshock (generalized tonic-clonic seizures). PTPh was administered at various doses, alone or in combination with the NO precursor L-arginine, as well as non-selective (L-NAME) and selective NOS inhibitors (nNOS inhibitor 7-NI and iNOS inhibitor aminoguanidine). Seizure thresholds, latencies, incidence, and mortality were assessed. Moreover, in the next paradigm, using maximal electroshock model, we evaluate possible protective effects of PTPh against generalized tonic-clonic seizures and subsequent mortality. ResultsIn the intravenous PTZ model, PTPh (≥150 mg/kg) increased the seizure threshold, potentiated by L-arginine but reduced by L-NAME and 7-nitroindazole. In the intraperitoneal PTZ model, 150 mg/kg PTPh decreased tonic seizure frequency, which was mitigated by aminoguanidine. However, PTPh failed to prolong clonic seizure latency. In the maximal electroshock test, 100 mg/kg PTPh protected against tonic seizure incidence (reduced by aminoguanidine). Although PTPh could not reduce mortality, its combination with L-NAME or 7-nitroindazole increased mortality compared with the vehicle-treated group. ConclusionPTPh exerted anticonvulsant effects against absence-like and generalized tonic-clonic seizures, likely through modulation of the nitrergic system involving neuronal, endothelial, and inducible NOS isoform. These findings provide novel insights into the complex interplay between NO signaling and the anticonvulsant actions of PTPh, highlighting the potential therapeutic implications of targeting the NO pathway in epilepsy management.

Correlations between SHBG, Sex Hormones, Inflammation, and Neurocognitive Decline in Alzheimer's Disease:A Retrospective Study.

Alzheimer's Disease (AD) is characterized by a progressive neurodegenerative process leading to cognitive decline and functional impairment. Endocrine factors, particularly sex hormones and their binding proteins, play a critical role in AD pathophysiology. Understanding the relationship between these factors and AD is essential for developing targeted interventions. To investigate the potential links between sex hormone binding globulin (SHBG) levels, sex hormone profiles, inflammatory markers, and neurocognitive decline in patients with AD. A retrospective case-control investigation was conducted with 110 AD patients who were admitted to our hospital from January 2021 to December 2023, and the patients were classified into either a mild neurocognitive impairment group (n=59) or a moderate to severe neurocognitive impairment group (n=51) according to their cognitive function. Correlation and regression analyses were conducted to examine relationships between variable factors. The study revealed a significant neurocognitive decline in AD patients with lower Mini-- Mental State Examination (MMSE) and higher AD Assessment Scale-Cognitive Subscale (ADAS- Cog) scores in the moderate to severe neurocognitive impairment group compared to the mild neurocognitive impairment group. Additionally, the moderate to severe neurocognitive impairment group significantly increased for SHBG, estradiol, progesterone inflammatory markers [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β)). It decreased for follicle-stimulating hormone (FSH) and luteinizing hormone (LH)]. Moreover, significant positive correlations were found between SHBG levels and ADAS-Cog scores, and significant negative correlations were found between SHBG levels and MMSE scores. FSH showed significant negative correlations with the MMSE score, while certain inflammatory markers demonstrated significant correlations with neurocognitive abilities. The correlation between sex hormones and inflammatory factors is weak. FSH, LH, SHBG, CRP, IL-6, TNF-α, and IL-1β are risk factors for neurocognitive impairment, while E2 and P are protective factors. The study provides evidence of significant correlations between SHBG levels, sex hormone profiles, inflammatory markers, and neurocognitive decline in AD patients.

Visfatin Enhances RANKL-Induced Osteoclastogenesis In Vitro: Synergistic Interactions and Its Role as a Mediator in Osteoclast Differentiation and Activation

Visfatin, an adipokine secreted by various cell types, plays multifaceted pathophysiological roles in inflammatory conditions, including obesity, which is closely associated with osteoclastogenesis, a key process underlying bone loss and increased osteoporosis (OP) risk. However, the role of visfatin in osteoclastogenesis remains controversial. This study was conducted to investigate the effects of visfatin on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation from precursor cells in vitro. Our results demonstrated that although visfatin exhibited a modest osteoclast-inductive effect relative to that of RANKL, co-stimulation of bone marrow-derived macrophages (BMDMs) with visfatin and RANKL led to significantly enhanced osteoclast differentiation and activation compared to individual stimulation. Neutralization of visfatin activity using blocking antibodies before differentiation markedly suppressed RANKL-induced osteoclastogenesis, as evidenced by a near-complete absence of tartrate-resistant acid phosphatase-positive multinucleated osteoclasts, decreased levels of nuclear factor of activated T cells cytoplasmic 1 and osteoclast-specific proteins, inhibition of nuclear factor-κB and mitogen-activated protein kinase signaling pathways, and a decrease in resorption pit formation. Our findings underscore the critical role of visfatin in RANKL-induced osteoclastogenesis in vitro and highlight the RANKL/visfatin signaling axis as a potential therapeutic target for destructive bone loss-related diseases.

Influence of gut and lung dysbiosis on lung cancer progression and their modulation as promising therapeutic targets: acomprehensive review.

Lung cancer (LC) continues to pose the highest mortality and exhibits a common prevalence among all types of cancer. The genetic interaction between human eukaryotes and microbial cells plays a vital role in orchestrating every physiological activity of the host. The dynamic crosstalk between gut and lung microbiomes and the gut-lung axis communication network has been widely accepted as promising factors influencing LC progression. The advent of the 16s rDNA sequencing technique has opened new horizons for elucidating the lung microbiome and its potential pathophysiological role in LC and other infectious lung diseases using a molecular approach. Numerous studies have reported the direct involvement of the host microbiome in lung tumorigenesis processes and their impact on current treatment strategies such as radiotherapy, chemotherapy, or immunotherapy. The genetic and metabolomic cross-interaction, microbiome-dependent host immune modulation, and the close association between microbiota composition and treatment outcomes strongly suggest that designing microbiome-based treatment strategies and investigating new molecules targeting the common holobiome could offer potential alternatives to develop effective therapeutic principles for LC treatment. This review aims to highlight the interaction between the host and microbiome in LC progression and the possibility of manipulating altered microbiome ecology as therapeutic targets.

Conduction system pacing in heart failure: Time for a paradigm shift?

Heart failure (HF) is a major clinical challenge characterized by significant morbidity and mortality. Electrical conduction abnormalities play a critical role in HF pathophysiology and progression, often leading to suboptimal outcomes with conventional pacing techniques. Con-duction system pacing (CSP), encompassing His bundle pacing and left bundle branch area pacing, has emerged as a novel approach. Despite data come from observational studies, recent guidelines recommend that a specific population may benefit from CSP. However, significant practical considerations and challenges need to be clarified before CSP can be routinely implemented in clinical practice. The reliance on observational studies means that long-term clinical outcomes for HF patients remain uncertain until data from randomized controlled trials (RCTs) become available. Current CSP practices face challenges with lead implantation, mechanical stress on leads, and the need for more advanced tools and artificial intelligence integration to improve procedure efficacy and safety. Future large-scale RCTs are essential to identify optimal candidates and address these technical challenges, potentially leading to a paradigm shift in HF management.