Punan Hospital

Traumatic brain injury (TBI) triggers complex pathological cascades, including inflammation, oxidative stress, apoptosis, and gliosis, particularly during the acute phase after injury. Trigonelline has been reported to exert neuroprotective effects in experimental models; however, its molecular mechanisms in acute TBI remain insufficiently defined. This study aimed to elucidate the molecular targets and mechanisms by which trigonelline attenuates acute TBI using an integrated network pharmacology and experimental validation approach. A trigonelline-target interaction network was constructed based on network pharmacology, followed by GO/KEGG analyses to predict the biological processes and pathways involved. Molecular docking was conducted to validate the binding affinity of trigonelline with key targets. Animal experiments were carried out to confirm the mechanistic predictions. Network pharmacology identified GAPDH, IL6, ALB, TNF, and IL1B as major hub genes associated with trigonelline. GO/KEGG analyses suggested that the neuroprotective effects of trigonelline against TBI primarily involved the MAPK and PI3K-Akt pathways. Invivo assays demonstrated that trigonelline treatment significantly reduced brain water content, inflammation, and oxidative stress levels within 72 h post-injury, while ameliorating histopathological damage, as confirmed by ELISA, HE, and LFB staining. TUNEL, NeuN, and FJB staining further revealed that trigonelline attenuated TBI-induced neuronal apoptosis. Western blotting demonstrated that trigonelline suppressed MMP-9 and AQP4 expression and attenuated the triggering of the MAPK signaling pathway. By attenuating MAPK signaling and apoptosis, trigonelline mitigates neural damage following TBI. The present findings provide experimental evidence supporting the neuroprotective effects of trigonelline in an acute TBI model.

Hypoxemia during sedated gastrointestinal endoscopy affects over 40% of morbidly obese (BMI ≥ 35 kg/m2) patients. High-flow nasal cannula (HFNC) alone often fails due to persistent airway collapse. The COMBO endoscopy oropharyngeal airway provides mechanical support while delivering oxygen. This study aimed to assess the efficacy of combined COMBO-HFNC oxygenation for preventing hypoxemia in this high-risk population. In a prospective, single-centre, Simon two-stage trial, 50 adults with morbid obesity scheduled for gastrointestinal endoscopy under propofol-alfentanil sedation received COMBO-HFNC oxygenation. The primary endpoint was hypoxemia (SpO₂ 75–90% for < 60 s) compared with a historical rate of 40%. Secondary endpoints were subclinical respiratory depression (SpO₂ 90–95%) and severe hypoxemia (SpO₂ < 75% or 75–90% ≥ 60 s). Rates were analysed with an exact one-sided binomial test (α = 0.05). All 50 participants completed the study. No patient developed hypoxemia (0%), significantly lower than the historical 40% (P < 0.001). Subclinical respiratory depression occurred in 8 patients (16%), and no severe hypoxaemic episodes were recorded. Transient hypotension occurred in 3 patients (6%), with no other complications. COMBO-HFNC oxygenation was associated with a 0% hypoxemia rate in morbidly obese patients undergoing sedated endoscopy without increasing adverse events. These findings suggest potential clinical value compared with historical conventional oxygenation strategies, but require confirmation in future multicentre randomized controlled trials to establish causal inference. The trial was registered at the ClinicalTrials.gov on 1 February 2025 (NCT06812403).

Fecal contamination of coastal waters threatens human and ecosystem health. Microbial source tracking (MST) methods offer a strategy to identify sources of fecal contamination through the measurement of genetic markers associated with a particular animal host. In this study, we measured fecal indicator bacteria (FIB) and employed MST methods to evaluate the sources of fecal contamination in a coupled stream-beach system in Kailua Bay, Hawai'i where residents adjacent to the shoreline use onsite cesspools for sewage management. In a baseline campaign, we measured enterococci concentrations in surface water samples from the stream and beach (n = 36). Results indicated that the stream contained enterococci in exceedance of the state standard (50% of samples) and therefore represented a potential source of contamination to the coastal ocean. To identify potential fecal sources, five MST genetic markers - three indicative of human feces (HF183/BacR287, CPQ_056, and ToBRFV), one of dog feces (DG3), and one of avian feces (GFD) - were measured alongside enterococci concentrations and environmental parameters (water temperature, salinity, tidal stage, and rainfall) in stream and beach water samples from longitudinal (n = 78) and spatial (n = 25) sampling campaigns. During the two-week longitudinal campaign, detections were observed for the avian marker (78% of samples positive), human marker ToBRFV (40%), and dog marker (10%), while HF183/BacR287 and CPQ_056 were not detected. Marker detection frequency varied by sampling location, with GFD most frequently detected in the stream and ToBRFV most frequently detected at the site adjacent to cesspools. In the spatial campaign, enterococci concentrations significantly decreased along the stream towards the beach (p < 0.001) but similar trends were not observed for MST markers. The occurrence of human, avian, and canine MST genetic markers in this study confirms these are important sources of fecal contamination in the Kailua Bay area. This study is the first to implement the RNA-based ToBRFV digital PCR assay in tropical coastal waters.

Ischemic stroke (IS), a multifaceted neurodegenerative disorder characterized by neuroinflammation and neuronal damage, is critically linked to the cGAS-STING pathway, a key mediator of neuroinflammatory responses during cerebral ischemia. However, the specific role of the STING agonist 2’,3’-cGAMP (cGAMP) in modulating ischemic brain injury remains poorly understood. In this study, we investigated the therapeutic effects of cGAMP in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and in BV2 microglial cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R). Network pharmacology analysis was further employed to predict potential molecular targets and mechanisms underlying cGAMP’s action in IS. To validate these findings, TREM2-specific small interfering RNA (siRNA) was utilized to suppress TREM2 expression, enabling mechanistic exploration of cGAMP’s activity. Our results demonstrate that cGAMP exerts neuroprotective effects in IS through a noncanonical STING signaling pathway. Specifically, we reveal that cGAMP enhances microglial/macrophage phagocytic function via TREM2-dependent mechanisms. These findings provide novel insights into the therapeutic potential of cGAMP in IS and identify TREM2 as a promising target for modulating neuroinflammation and neuronal recovery in ischemic stroke.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10753-025-02427-w.

BackgroundAutoimmune encephalitis (AE) is a severe neurological disorder, but limited evidence comparing the efficacy of double filtration plasmapheresis (DFPP) and intravenous methylprednisolone (IVMP) as first-line treatments in the acute phase. This study aimed to evaluate the clinical outcomes of DFPP versus IVMP in antibody-positive patients with AE.MethodsA prospective observational cohort study was conducted at Renji Hospital from July 2018 to May 2024. Thirty-eight patients with antibody-confirmed AE in the acute phase who received either DFPP (n=22) or IVMP (n=16) as first-line therapy were included. The primary outcome was improvement in the Modified Rankin Scale (mRS), and the secondary outcome was improvement in the Clinical Assessment Scale for Autoimmune Encephalitis (CASE). Adverse events were recorded for safety assessment. Univariate and multivariate logistic regression analyses were performed.ResultsThe DFPP group demonstrated significantly higher rates of functional improvement, with 68.2% (15/22) achieving mRS reduction compared to 31.3% (5/16) in the IVMP group (p=0.047). Similarly, symptomatic improvement (CASE score reduction) was observed in 72.7% (17/22) of DFPP patients versus 43.8% (7/16) with IVMP (p=0.099). Multivariate analysis identified DFPP as the sole independent predictor of better outcomes (OR: 5.234, 95% CI: 1.179–23.235, p=0.030). Adverse events were limited to the DFPP group (3/22), including manageable deep venous thrombosis and hepatic impairment.ConclusionDFPP demonstrated superior short-term efficacy compared to IVMP in improving functional and symptomatic outcomes in acute-phase AE, suggesting its potential as a preferred first-line therapy. Further large-scale randomized trials are warranted to validate these findings.

Abstract It is now understood that oxidative stress, characterized by an excess of reactive oxygen species (ROS) within growth plate injury sites, can impede cartilage repair through various mechanisms. Morinda officinalis (MO), a traditional Chinese herbal medicine, possesses potent antioxidant properties. Furthermore, extracellular vesicles (EVs) derived from plants exhibit comparable physical and chemical characteristics to their parent plants, along with favorable tissue permeability and biocompatibility. Herein, it develops a ROS‐sensitive hydrogel by self‐crosslinking two natural extracellular matrix (ECM)‐derived components: polyvinyl alcohol (PVA) and chondroitin sulfate grafted with phenylboric acid (CSBA). The hydrogel is subsequently combined with MO‐derived EVs (MO‐EVs) to eliminate excess ROS from the damaged microenvironment and release MO‐EVs as needed to facilitate growth plate damage healing. In vitro studies revealed that a CSBA‐PVA hydrogel containing MO‐EVs facilitated the restoration of chondrocyte mitochondrial function by activating the NRF2‐HO‐1/NQO1 pathway, thereby enhancing endogenous antioxidant capacity. Furthermore, in vivo results reveal that implantation of CSBA‐PVA hydrogel loaded with MO‐EVs significantly inhibited bone bridge development and facilitated cartilage restoration within the growth plate. CSBA‐PVA@MO‐EVs therapy brings huge prospects as a therapeutic approach, offering novel insights and therapeutic strategies for treating growth plate injuries.

BackgroundGiven the increased risk factors such as the wide application of various dose forms of corticosteroids and broad-spectrum antibiotics in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in recent years, the incidence of invasive Candida pneumonia secondary to AECOPD tends to increase. However, Candida infections secondary to AECOPD are often neglected in clinical practice, or even misdiagnosed as bacterial infections, resulting in disease deterioration due to delayed diagnosis. Knowing that early diagnosis and timely treatment can obviously improve the prognosis of pulmonary candidiasis, improving the early diagnosis rate is the key to reduce the mortality of AECOPD-associated candidiasis. The present study was intended to develop a new model that can early and accurately predict the occurrence of Candida infections secondary to AECOPD.MethodsClinical data of 164 hospitalized patients with AECOPD who received treatment in the department of respiratory medicine of Yiwu Central Hospital between January 2022 and January 2024 were reviewed retrospectively, including the diagnosis, gender, age, BMI, use of inhaled corticosteroids, the duration of using antibiotics, use of carbapenem antibiotics, random blood glucose, albumin level, the presence or absence of cerebral infarction aspiration, cancer chemoradiotherapy, complicated cardiovascular disease, procalcitonin level, pulmonary function grade, and surviving time. Data were treated and analyzed by R language statistical software.ResultsOf the 164 AECOPD patients, 87 were male and 77 were female, with a mean age of 77.28 ± 8.10 years. The model group consisted of 127 AECOPD patients, including 64 with candidiasis secondary to AECOPD and 63 with no candida infection; the validation group consisted of 37 patients, including 14 with secondary candidiasis and 23 with no Candida infection. Single factor logistic regression analysis of the patients in the model group showed that BMI, use of antibiotics ≥2 weeks, cancer chemoradiotherapy and pulmonary function grade were four independent predictors for the occurrence of secondary candida infection. The weigh factor of the four risk factors was further determined by Multivariate logistic regression analysis as follows: Probability of infection (P) = EXP (−17.7063452 + 1.8265388*pulmonary function grade + 1.8443357*cancer chemoradiotherapy + 4. 1749059*use of antibiotics ≥ 2 weeks + 0.4527216*BMI), and P > 0.5 suggests the probability of developing secondary candidiasis in the AECOPD patient.ConclusionThe result demonstrated that this new model could accurately predict the occurrence of secondary candidiasis in AECOPD patients, with an accuracy rate of 84%, thus providing a simple and accurate tool for predicting the probability of secondary candidiasis in AECOPD patients, especially in cancer patients complicated with AECOPD. This model can only be used as an auxiliary assessment tool for the possibility of secondary candidal infection and cannot be used as a diagnostic basis.

Serum AQP4 antibody (AQP4-IgG) is the causative antibody of neuromyelitis optica spectrum disorder (NMOSD) but AQP4-IgG in cerebrospinal fluid (CSF) has been seldom studied. We aimed to explore the clinical value and influencing factors of CSF AQP4-IgG in NMOSD. In this study, we screened 137 patients with NMOSD diagnosed according to the 2015 International Consensus Diagnostic Criteria (IPND criteria). From this cohort, paired CSF and serum samples were simultaneously collected from 82 patients (including seropositive and seronegative subgroups) for antibody titer measurement. We explored the relationship between CSF AQP4-IgG and patient's clinical features. Their demographic, clinical, laboratory data and MRI images were collected and analyzed. 74 patients were seropositive for AQP4-IgG and 8 patients were seronegative. Among the 74 patients seropositive for AQP4-IgG, 46 were CSF-positive and 28 were CSF-negative, while none of the 8 seronegative patients were CSF-positive. CSF AQP4-IgG positive and negative patients showed significant differences in EDSS and relapse status. Out of the 82 patients, 67 patients were during relapse and only patients during relapse were included in the next analysis. Between the CSF-positive and CSF-negative patients, no significant differences were found in EDSS, relapse manifestation, CSF indicators, serum cytokine levels, lymphocyte subsets or MRI lesions. Responses to treatment during relapse and length of hospital stay showed no significant differences either. A positive correlation between the serum and CSF titers (rs: 0.64, p < 0.001) was found. Further binary logistic regression analysis revealed that CSF AQP4-IgG positivity was associated with serum AQP4-IgG titers and EDSS scores. CSF AQP4-IgG positivity primarily results from passive diffusion of serum antibodies across the blood-brain barrier, which is different from the CNS-restricted antibody production in MOG-IgG associated disorders (MOGAD). Limited prognostic value of CSF AQP4-IgG was revealed in this study.

This study investigates distinct neuroinflammatory patterns in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) using multi-tracer PET and MR imaging. Eight NMOSD (5F/3M; median age 36.5) and six MOGAD patients (2F/4M; median age 34.0) underwent PET scans with [18F]FDG (glucose metabolism), the translocator protein (TSPO) ligand [18F]PBR06 (glial activation), and [11C]acetate (astrocyte metabolism), integrated with synchronous 3T MRI sequences. Standardized uptake value ratios (SUVRs) referenced to contralateral white matter (WM) or whole brain were statistically compared across specific anatomic regions: active lesions, normal-appearing WM (NAWM), and periventricular zones. Both groups exhibited elevated [18F]PBR06 SUVR within lesions compared to contralateral WM, marking microgliosis. Crucially, NMOSD lesions showed significantly lower [18F]FDG SUVR (p ​= ​0.01; metabolic impairment) and [11C]acetate SUVR (astrocyte dysfunction) than MOGAD lesions. Lesional [18F]PBR06 uptake correlated significantly with [18F]FDG uptake. Beyond lesions, NMOSD patients had higher [18F]FDG SUVR in cerebellar WM (p ​< ​0.01) and periventricular regions near the fourth ventricle (p ​= ​0.01), and higher [18F]PBR06 SUVR in cerebral WM (p ​= ​0.03), contrasted with MOGAD. With lesions in both disorders demonstrating microgliosis, NMOSD exhibited more severe lesion-specific metabolic suppression and astrocyte dysfunction, reflected in reduced [11C]acetate uptake, coupled with regional inflammation (microgliosis) and hypermetabolism. These differential multi-tracer PET patterns, especially the combined reduction in lesional astrocytic ([11C]acetate) and metabolic ([18F]FDG) markers in NMOSD versus MOGAD, highlight multimodal PET/MRI as a powerful tool for differentiating NMOSD and MOGAD pathophysiology.

For critically ill patients in the intensive care unit (ICU), acute respiratory failure (ARF) stands as a prominent cause of mortality. Anion gap (AG) denotes the disparity between unmeasured cations and anions. Adjusting AG for albumin levels results in the albumin corrected anion gap (ACAG), which provides a more accurate representation of the body's acid-base status. Elevated ACAG may arise from ARF-induced cellular hypoxia and metabolic acidosis. However, limited research has investigated the association between ACAG and the 28-day all-cause mortality of ARF patients in critical care. Using the Medical Information Mart for Intensive Care (MIMIC-IV 2.2) database, a retrospective data analysis was conducted, specifically targeting critically ill patients diagnosed with ARF. Serum ACAG was collected within 24 hours of the patient's admission to the ICU. The association between ACAG levels and 28-day all-cause mortality was investigated using smooth curve fitting, a multivariate Cox proportional hazard regression model, and Kaplan-Meier survival curve analysis. Furthermore, the consistency of these relationships was assessed through interaction and subgroup analyses. The study involved the enrollment of 3888 eligible participants in total. After adjusting for confounding variables in the multivariable Cox regression analysis model, we noticed a positive linear relationship between the ACAG value and the ICU's 28-day all-cause mortality rate. When ACAG was used as a continuous variable, a 3.1% increase in 28-day all-cause mortality was associated with a 1.0-mmol/L increase in ACAG (adjusted HR = 1.037, 95% CI: 1.025-1.048, p < 0.001). In the 28-day all-cause mortality, the highest and intermediate ACAG groups (adjusted HR 1.483, 95% CI: 1.244-1.768 and adjusted HR 1.244, 95% CI: 1.062-1.457, respectively) were notably higher than the lowest ACAG group when ACAG was utilized as a tertiles categorical variable. The substantial association between ACAG and 28-day all-cause mortality in the ICU was consistently demonstrated through subgroup analysis. Among ICU patients with ARF, an elevated ACAG is linked to an elevated risk of 28-day all-cause mortality. There exists a linearly positive relationship between the 28-day all-cause mortality and ACAG.