Mechanical analysis of the femoral head is mostly conducted through finite element analysis (FEA), the operation of which is relatively complex. In this study, the correlation between computed tomography (CT) quantitative analysis and FEA in the diagnosis of osteonecrosis of the femoral head (ONFH) was analyzed. This retrospective study involved 30 hips from patients with Steinberg stage II ONFH who had not received treatment. The average CT density was measured, and an FEA model was constructed on the basis of the CT images of each case. The correlation between the average CT density and the FEA measurements was analyzed. The average CT density of the coronal midline plane was 370.47 ± 16.85 HU, and that of the maximum necrotic layer was 420.73 ± 22.24 HU. According to the FEA results, the maximum total displacement was 0.42 ± 0.04 mm, the maximum displacement in the Z direction was 0.25 ± 0.02 mm, the maximum equivalent stress in the stress concentration zone of the head was 1.81 ± 0.02 MPa, and the failure coefficient was 0.34 ± 0.02. The average CT density of the maximum necrotic layer was not correlated with the maximum total displacement or maximum displacement in the Z direction but was correlated with the maximum equivalent stress (r = 0.65; P < 0.1001) and failure coefficient (r=-0.58; P < 0.001). The average CT intensity of the maximum slice (P = 0.004) and the average failure coefficient (P = 0.020) significantly differed between the collapse and noncollapse groups. CT quantification can reflect the load distribution and bearing capacity of ONFH to some extent. The higher the average CT density of the maximum slice, the lower are the average failure coefficient of the femoral head and the clinical risk of collapse.
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a leading global health burden, yet its diagnosis and staging rely heavily on invasive liver biopsies. Liquid biopsy, utilizing circulating cell-free DNA (cfDNA), offers a promising noninvasive alternative to capture hepatic genomic instability. This review consolidates current knowledge on cfDNA biomarkers in MASLD, moving from established quantitative metrics to emerging epigenetic insights. The role of mitochondrial DNA copy number (mtDNAcn) is examined as a dynamic marker of oxidative stress, highlighting its biphasic response: compensatory upregulation in early disease versus depletion in advanced fibrosis. Furthermore, key nuclear copy number variations (CNVs) specifically the XPO4 duplication (13q12.11), CES1 deletion (16q12.2), and ACOT1 deletion (14q24.3) are discussed regarding their mechanistic drivers of fibrogenesis and lipid metabolism dysregulation. Addressing the complexity of MASLD pathogenesis, the discussion extends to emerging multi-modal metrics, including DNA methylation and fragmentomics. These modalities offer superior specificity by tracing the "tissue of origin" and distinguishing apoptotic from necrotic fragmentation patterns, effectively addressing the diagnostic challenges posed by the "burnout" phenomenon in advanced cirrhosis. Finally, critical future directions are outlined, emphasizing the necessity for standardized pre-analytical protocols and the integration of multi-omics data with machine learning. This comprehensive approach will shed light on the transition cfDNA from a research tool to a precise clinical instrument for early risk stratification and therapeutic monitoring.
Fat embolism syndrome (FES) is a rare but likely underdiagnosed complication of sickle cell disease (SCD) characterised by multi- or single- organ involvement secondary to embolism of fat and/or necrotic bone marrow. It is one of the most devastating acute complications of SCD and historically the diagnosis has often been made on the basis of post-mortem findings. Literature on FES in SCD is scarce although most reported cases are individuals with non-HbSS genotypes for reasons which have not yet been fully elucidated. Even fewer data exist regarding the potential association with parvovirus B19 (B19V) and the mechanisms by which B19V infection could trigger FES in SCD. Management is largely supportive with early intensive care team involvement for close monitoring and potential organ support. Emerging evidence, albeit limited, suggests that early exchange transfusion has an important role in improving clinical outcomes. We describe two life-threatening cases of FES in SCD of differing genotypes who required intensive care unit admission but who both recovered with supportive management and early exchange transfusion.
HMGB1 acts as an alarmin when released from stressed or dying cells. In vitro, HMGB1 has previously been demonstrated to readily form complexes with other molecules and through intermolecular disulfide bond formation form homodimers. Recently, dimerized HMGB1 was identified in serum of LPS-challenged mice. In cancer, HMGB1 has been described as having both tumour-promoting and tumour-suppressing features, possibly dependent on the form of HMGB1 released into the tumour microenvironment. Factors determining the form in which HMGB1 is released remain, however, largely unexplored. We therefore investigated the form of HMGB1 released during different cell death modes and in response to LPS stress using various tumour cell lines. Supernatants were collected from ten non- and LPS-treated tumour cell lines and necrotic, apoptotic and pyroptotic THP-1 monocytic cells, to assess active and passive secretion of HMGB1. Released proteins were concentrated by TCA-precipitation and analysed by Western blotting under reducing and non-reducing conditions to detect monomeric, dimeric, or HMGB1-protein complexes. Co-immunoprecipitation and LC-MS/MS were used to identify binding partners of extracellular HMGB1. Tumour cells were found to release monomeric HMGB1 and HMGB1 heterocomplexes in the 50-60 kDa range, as indicated by their persistent high molecular weight under reducing conditions. Furthermore, we identified that HMGB1 interacts with ribosomal proteins, histone H2B, and SRP9 following LPS treatment of microglial SIM-A9 cells. HMGB1 readily formed heterocomplexes, but not homodimers in vitro across multiple cell lines, with differences between LPS-treated and untreated conditions. The form of released HMGB1 was influenced by cell type, cell death mode, and LPS stress.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a group of small-vessel necrotizing vasculitides with minimal immune complex deposition. Hypertrophic cranial pachymeningitis, a rare complication of AAV, is characterized by focal/diffuse dural thickening and fibrosis, causing neurological dysfunction such as headache and optic nerve injury. While AAV-associated hypertrophic cranial pachymeningitis is well documented, reports of concurrent spinal dural involvement remain scarce. This case highlights the rare co-occurrence of cranial and spinal dural involvement in AAV, providing new clinical evidence to expand the understanding of AAV-related dural manifestations and improve diagnostic awareness among clinicians. A 57-year-old male presented with fever, headache, otalgia, and hearing loss, and was diagnosed with granulomatosis with polyangiitis based on positive anti-proteinase 3 antibodies (664.3), cytoplasmic anti-neutrophil cytoplasmic antibody (1:10). Symptoms resolved with glucocorticoids, disease-modifying antirheumatic drugs, and anti-infective therapy. He later developed recurrent headache and lumbodorsal pain. Thoracic magnetic resonance imaging (MRI) revealed a T10 to 12 epidural lesion, which was surgically resected. Pathology confirmed epidural vasculitis with necrotic/fibrous tissue, granulation, and inflammatory cell infiltration. Methylprednisolone and cyclophosphamide relieved back pain, but headaches persisted. Cranial MRI showed dural thickening in the cerebellar, posterior fossa, and foramen magnum regions, consistent with pachymeningitis. Cerebrospinal fluid analysis showed elevated mononuclear cells (35.00 × 106/L), nucleated cells (40.00 × 106/L), and protein (1.49 g/L), with negative cultures. The final diagnosis was granulomatosis with polyangiitis complicated by concurrent cranial and spinal dural involvement. Initial management included glucocorticoids, disease-modifying antirheumatic drugs, and anti-infective therapy, which resolved the patient's fever, otalgia, and hearing loss. Surgical resection was performed for the T10 to 12 epidural lesion, followed by immunosuppressive therapy with methylprednisolone and cyclophosphamide. After adjustment of the treatment regimen, the patient's headache improved. Initial therapy resolved the patient's fever, otalgia, and hearing loss. Surgical resection combined with immunosuppressive therapy relieved lumbodorsal pain but failed to resolve headaches initially; cranial MRI confirmed pachymeningitis, and cerebrospinal fluid analysis indicated inflammatory changes. After adjustment of the treatment regimen, the patient's headache improved, and he has remained clinically stable during follow-up. This case demonstrates that AAV can involve both cranial and spinal dura mater. Clinicians should consider dural involvement in AAV patients presenting with lumbodorsal pain.
Micro- and nanoplastics have been recognized to pose potential threat for human environment and health. Plastic particles of different, sizes, forms and composition have already been detected in human tissue, but little information is available so far on how particle numbers are relating to cellular effects in dependence of size. We here set out to utilize a mast-cell/basophilic cell model to investigate the role of different polystyrene bead numbers and sizes on mast-cells under conditions that allow for local accumulation of auto- and paracrine released cytokines and mediators, resembling the conditions in inflamed tissue. Cultured RBL-2H3 cells responded to spherical polystyrene (PS) microplastic particles with degranulation and release of inflammatory mediators. Our results indicate a non-linear dose response curve for mast-cell mediator release, due to induction of apoptosis at high particle counts for all tested particle sizes. Cellular uptake of larger (1µm) particles was found to enhance necrotic cell death.
Jack Bean Urease (JBU) is a urease isoform from the plant Canavalia ensiformis with recognized insecticidal properties, although its full entomotoxic potential remains poorly understood. In this study, we used Rhodnius prolixus, a vector of Chagas disease, as a model to investigate the effects of JBU on reproduction. Injection of a sublethal dose in vitellogenic females significantly reduced oviposition and delayed ovarian development, with ovarioles displaying degenerating follicles. Microscopy analyses revealed signs of apoptosis, autophagy, and necrosis in the ovarian tissue of JBU-treated insects. The fat body-the main sites of vitellogenin and lipophorin synthesis-exhibited necrotic features, enlarged adiposomes, and increased triacylglycerol content. qPCR analysis showed increased transcript levels of the lipid metabolism-related genes acetyl-CoA carboxylase, perilipin, and Brummer lipase in JBU-treated females. ELISA assays indicated that JBU induced changes in the amounts of vitellogenin and lipophorin in the fat body and the ovary, as well as in their levels in the hemolymph. JBU treatment impaired vitellogenin uptake and lipophorin-mediated lipid transfer to the oocytes while promoting lipid accumulation in the fat body. An in vivo approach using fluorescently labeled JBU showed its presence in the fat body and ovarian tissues, with no detectable proteolytic processing of JBU in the hemolymph under the conditions tested. Altogether, these findings indicate that JBU-induced reproductive impairment is, at least in part, mediated by disruptions in lipid metabolism along the fat body-ovary axis. These results contribute to understanding the entomotoxic effects of JBU and highlight its potential impact on insect population dynamics.
This study aimed to investigate the clinical characteristics and imaging features of walled-off pancreatic necrosis (WOPNs) involving the pancreatic parenchyma in patients with no documented pancreatitis, and to establish a diagnostic prediction nomogram using Lasso regression to differentiate WOPNs from mucinous cystic neoplasms (MCNs). A total of 247 cases were retrospectively collected from three independent hospitals, including surgically confirmed post-inflammatory necrotic collections meeting imaging criteria for WOPNs and pathologically confirmed MCNs. Clinical and imaging features were analyzed, and independent predictors were identified using Lasso regression. Clinical, imaging, and combined diagnostic models were constructed and assessed using ROC, calibration, and decision curve analyses (DCA). A diagnostic nomogram was developed from the best model. Univariate analysis revealed significant differences between WOPNs and MCNs in the training cohort for age, sex, clinical symptoms, lesion location, shape, lesion margin, cyst category, incomplete septation, peripancreatic fat space, density/signal, cyst wall and/or septal thickness, mural nodule, lesion calcification, peripancreatic inflammatory changes, MPD morphology, location of ductal dilation, vascular involvement, and organ involvement (p < 0.05). Lasso regression identified three clinical features, eight imaging features, and five combined clinical and imaging features as independent risk factors, which were subsequently used to construct clinical, imaging, and combined models. The combined model achieved the highest diagnostic performance, with AUC values of 0.880 in the training cohort and 0.858 and 0.856 in the two external validation cohorts, respectively, demonstrating good sensitivity, specificity, and overall accuracy. We established a reliable, non-invasive diagnostic prediction nomogram based on Lasso regression to differentiate WOPNs with no documented pancreatitis from MCNs.
Vibrio vulnificus is a highly virulent gram-negative aquatic bacterium found in warm brackish waters and in molluscum shellfish worldwide that can cause sepsis after ingestion of raw oysters or undercooked molluscum shellfish as well as deadly skin and soft-tissue infections from immersion in contaminated seawater. Populations at a higher risk of infections are men older than 60 years with diabetes mellitus, liver cirrhosis, renal disease, or elevated iron levels and those who are immunocompromised. Three severe syndromes caused by V. vulnificus are gastroenteritis, primary septicemia, and wound infections. Gastroenteritis caused by ingestion is self-limited; however, sepsis can develop rapidly with a mean survival rate of 50%, and wound infections can progress to necrotizing skin and soft-tissue infections with 24 hours. Early identification, prevention of hypotension, initiation of antibiotics, and surgical debridement of necrotic wound tissue is paramount to survival. Public education and awareness of this deadly pathogen is necessary to prevent exposure and improve clinical outcomes, especially for high-risk populations.
SMARCB1-deficient sinonasal carcinoma (SDSC) is a rare, highly aggressive malignancy with limited therapeutic options and no established preclinical models. Here, single-nucleus RNA sequencing (snRNAseq), spatial transcriptomics, and ex vivo patient-derived tissue slice culture (TSC) were combined to resolve intratumoral heterogeneity, niche organization, and treatment vulnerabilities in an index SDSC. snRNAseq identified three malignant subpopulations, including two specialized states marked by ALDH1A1 and NTN4. Spatial profiling mapped these states to distinct niches. The ALDH1A1+ compartment localized to a basal-associated niche with intermingled p63-positive basal cells adjacent to stroma, showed reduced proliferative activity, and displayed stem-like transcriptional features. Ex vivo drug testing revealed a striking response: the mTOR inhibitor Sapanisertib induced extensive tumor necrosis and was associated with near-complete depletion of ALDH1A1+ and NTN4+ states, accompanied by strong stress/apoptosis signatures and reduced endothelial cells. In an additional retrospective cohort of 12 SDSC, ALDH1A1 was present in all cases with heterogeneous spatial patterns and higher levels in recurrences. Mesothelin was expressed in the index case and a subset of tumors, supporting mesothelin-directed therapeutic strategies.
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Obstructive sleep apnea (OSA), characterized by recurrent apneic/hypopneic events and intermittent hypoxia, exhibits a high yet underrecognized prevalence (40%-65%) among patients with acute myocardial infarction (MI), compounded by suboptimal performance of conventional screening modalities. A defining epidemiological feature is the pronounced nocturnal predominance of MI onset in OSA cohorts, diverging from the diurnal pattern observed in non-OSA populations.Pathophysiologically, OSA manifests a paradoxical duality in the context of MI: acute cardioprotective effects, including reduced in-hospital mortality, attenuated infarct size (evidenced by lower peak troponin levels), and enhanced coronary collateralization, are attributed to ischemic preconditioning induced by chronic intermittent hypoxia. Conversely, OSA independently exacerbates long-term post-MI risk, with severe nocturnal hypoxemia driving elevated rates of major adverse cardiovascular events (MACE), alongside maladaptive ventricular remodeling, electrical instability, and endothelial dysfunction-mechanisms underpinned by synergistic activation of inflammatory pathways and cell death signaling.Therapeutically, the role of OSA-directed interventions in post-MI management remains contentious. Observational data suggest potential benefits of continuous positive airway pressure (CPAP), but large randomized controlled trials fail to demonstrate incremental cardioprotection in broader cardiovascular cohorts. Emerging proof-of-concept evidence suggests that early adaptive servo-ventilation (ASV) may influence myocardial salvage after acute MI in carefully selected patients with sleep-disordered breathing, particularly those without reduced ejection fraction. However, these findings should be interpreted cautiously given the small trial size and prior safety concerns regarding ASV in patients with heart failure and reduced ejection fraction. Resolving these uncertainties necessitates targeted research incorporating optimized adherence strategies and enhanced screening protocols to reconcile OSA's acute phenotypic associations with its long-term prognostic implications.
High-fat diet (HFD), characterized by an increased proportion of palmitic acid (PA), can induce inflammatory responses in Sertoli cells, trigger apoptosis, and cause spermatogenic dysfunction. Endoplasmic reticulum stress (ERS) is intimately linked to inflammation, but whether ERS contributes to HFD-induced Sertoli cell inflammatory injury remains unclear. This study investigated how HFD and PA mediated Sertoli cell injury by upregulating inflammatory response at the in vivo and cellular levels. Obese mice and TM4 cell models were established using HFD and PA, respectively. The sperm quality of mice was systematically assessed. Key regulatory pathways were identified via transcriptome sequencing, and the mechanism underlying HFD-induced Sertoli cell injury was validated using Western blot and flow cytometry. The results showed that HFD could upregulate the expression of inflammatory cytokines in Sertoli cells by activating the NF-κB signaling pathway, ultimately leading to a reduction in Sertoli cell numbers. Through transcriptome sequencing, we found that PA could activate ERS in TM4 cells. After inhibiting the activity of ERS transmembrane protein inositol-requiring 1α (IRE1α), the apoptosis rate, inflammatory cytokine production, and the expression levels of NF-κB signaling pathway proteins in PA-stimulated TM4 cells were significantly decreased. Notably, inhibition of IRE1α protein activity significantly downregulated the expression of adaptor protein tumor necrosis factor 2 (TRAF2). Knocking down TRAF2 reduced the expression of both NF-κB signaling pathway proteins and inflammatory cytokines. Overall, this study provides a theoretical basis for preventing and treating HFD-induced male reproductive dysfunction by targeting the IRE1α/ TRAF2/NF-κB axis.
Fluorene is biotransformed into the more toxic 2-hydroxyfluorene in the Perinereis aibuhitensis. However, the underlying toxicological mechanisms remain poorly defined. This study aims to decipher the mechanisms of intestinal injury in P. aibuhitensis under 2-hydroxyfluorene exposure. This study employed an integrated multi-endpoint approach to evaluate the dose-dependent effects of 2-hydroxyfluorene (0, 5, 50, and 500 μg/L) on P. aibuhitensis over a 28-day period. Results demonstrated that escalating concentrations triggered pronounced metabolic stress, indicating a shift in energy allocation toward detoxification and repair. Histopathological analysis identified the intestine as the primary target, showing mucosal necrosis and fragmented muscle fibers. These structural aberrations were mechanistically linked to sustained oxidative stress, which compromised intestinal permeability and paralyzed digestive and neurological functions. 16S rRNA sequencing further revealed that 2-hydroxyfluorene exposure reduced gut microbial diversity and the abundance of the beneficial genus, while promoting the abundance of the harmful genus. In conclusion, 2-hydroxyfluoreneinduces severe intestinal injury and metabolic dysfunction in P. aibuhitensis by initiating a vicious cycle: direct oxidative damage compromises gut barrier integrity, which in turn fosters dysbiosis microbiota. This dysbiosis characterized then likely exacerbates the initial host injury. This host-microbe interplay likely exacerbated the initial intestinal injury. These findings highlight the significant ecological risks posed by hydroxylated polycyclic aromatic hydrocarbon (PAH) metabolites to marine benthic invertebrates and underscore the crucial contribution of the gut microbiome in mediating environmental toxicity.
This study investigated perioperative Th1/Th2 cytokine polarization and biochemical changes in cats undergoing ovariohysterectomy under three different anesthesia protocols. Twenty-four healthy mixed-breed female cats were randomly allocated into three groups (n = 8/group): propofol-isoflurane (Group I), xylazine-ketamine hydrochloride (Group II), and xylazine-isoflurane (Group III). Venous blood samples were collected preoperatively (0 h) and at 6 and 12 h postoperatively. Serum concentrations of TNF-α, IFN-γ, IL-2, IL-4, IL-5, and IL-10 were quantified using feline-specific ELISA kits, and biochemical variables were measured with an automated analyzer. In Group I, tumor necrosis factor (TNF)-α, increased postoperatively (12.64 ± 2.28 ng/mL) compared to preoperative levels (6.79 ± 0.74 ng/mL; p < 0.05). In Group II, both interferon (IFN)-γ and interleukin (IL)-2 levels decreased after the operation compared to pre-op 0 h (p < 0.05). Group III showed a decrease in IL-4 and IL-10 postoperatively (124.21 ± 23.45 pg/mL and 106.05 ± 5.25 ng/mL, respectively) compared to pre-op 0 h (197.28 ± 14.40 pg/mL and 113.14 ± 11.19 ng/mL, respectively; p < 0.05). IL-5 concentrations did not change significantly in any group. Postoperative biochemical changes were transient and remained within reference ranges, with no clinical complications observed. These findings indicate that anesthesia protocols differentially influence perioperative immune responses in cats. The xylazine-ketamine combination induced the greatest cytokine fluctuations, whereas xylazine-isoflurane best preserved Th1/Th2 balance. Anesthetic selection may play a critical role in minimizing perioperative immune modulation. The xylazine-isoflurane protocol may be a preferable option for feline ovariohysterectomy, particularly in patients where immune stability is clinically relevant. These findings indicate that anesthesia protocols are associated with distinct short-term perioperative immune profiles in cats undergoing elective ovariohysterectomy. The observed differences should be interpreted as preliminary and hypothesis-generating, and larger studies with standardized pain assessment and longer follow-up are warranted to clarify clinical implications.
Decreased time to cardiac catheterization improves survival and limits cardiac tissue damage in ST Elevation myocardial infarction (STEMI). Emergency medical services delays account for half of treatment delays in STEMI. Helicopter air ambulance (HAA) can reduce the time to percutaneous intervention (PCI), and therefore may reduce mortality. The impact of physical distance between the PCI hospital helipad and the PCI laboratory on the door-to-door-to-balloon time (DDBT) for cardiac intervention in STEMI patients transported through HAA from remote community hospitals to PCI facilities was assessed. This was a retrospective chart review of interfacility STEMI patients where HAA was activated to reduce DDBT from January 1, 2020, to January 1, 2023. The HAA agency under review transports STEMI patients to 2 PCI centers. There is a significant difference in the distance between the helipad and the PCI laboratory at the 2 hospitals. Descriptive statistics were used to compare DDBT as well as the time from HAA arrival at the PCI hospital helipad to the cardiac catheterization laboratory. Data were available for 91 STEMI cases. The median time for DDBT was 89.9 minutes with a median time of 10.5 minutes from helipad arrival to catheterization laboratory (Table 1). Of the 91 cases, 69 (76%) were from hospital A and 22 (24%) were from hospital B. There was no detectable difference in the distribution of DDBT times between hospitals (P = .47). Helipad arrival times to cardiac catheterization laboratory were significantly longer for hospital A than hospital B (P < .001). The median time for hospital A was 11.0 minutes (interquartile range, 9.2-14.0) compared with hospital B, which had a median of 5.4 minutes (5.0-7.3). The physical distance a PCI laboratory is located from the helipad can be a significant addition to ischemic time for STEMI patients.
Preterm neonates with short bowel syndrome represent one of the most challenging populations in pediatric intestinal rehabilitation. Autologous intestinal reconstruction is frequently delayed in this group because insufficient bowel dilation precludes safe lengthening, prolonging dependence on parenteral nutrition and increasing the risk of intestinal failure-associated liver disease, sepsis, and growth failure. We conducted a retrospective single-center cohort study of preterm neonates with short bowel syndrome managed with a standardized protocol of controlled bowel expansion (CBE) followed by serial transverse enteroplasty (STEP) between 2018 and 2025. Eligible patients had pediatric intestinal failure requiring parenteral nutrition for ≥60 consecutive days. Primary outcomes were bowel length gain and achievement of enteral autonomy. Secondary outcomes included complications and resolution of intestinal failure-associated liver disease (IFALD). Nine preterm neonates were included (median gestational age 27 weeks [IQR, 25-28]; median birth weight 880 g [IQR, 820-1080]; underlying aetiology predominantly necrotizing enterocolitis [78%]). Baseline bowel length was a median of 33 cm (18% of expected for gestational age). During the CBE phase, bowel length increased by a median of 20 cm (IQR, 14.5-30), allowing progression to definitive STEP after a median expansion period of 27 weeks (IQR, 18.1-33). STEP provided an additional median gain of 20 cm (IQR, 14-40), with a cumulative median gain of 54.5 cm (IQR, 42-61) and a final bowel length of 61% of expected. Eight of nine patients (88%) achieved full enteral autonomy at a median of 29.3 weeks post-STEP (IQR, 24.1-52.5). IFALD resolved in all affected patients, and no mortality or post-STEP surgical complications occurred. In preterm neonates with short bowel syndrome, CBE was incorporated as part of a staged surgical pathway prior to STEP, during which bowel length increased. This approach was feasible and was associated with progression to STEP, with high rates of enteral autonomy observed in the cohort. . These findings suggest that CBE may serve as a preconditioning strategy to enable timely reconstruction in a population traditionally considered unsuitable for early lengthening. Prospective multicentre studies are warranted to validate these outcomes and standardize patient selection.
The combined effects of water acidification and lead (Pb) pollution have become a significant ecological risk factor for freshwater aquaculture systems. In this study, we systematically evaluated the effects of acidification and Pb exposure on juvenile Eriocheir sinensis through three interrelated laboratory experiments. First, the effects of different pH levels (7.8, 6.5 and 5.5) and of Pb (1.435 mg/L), alone and in combination, on bioaccumulation, tissue damage, antioxidant enzyme activity and gut microbiota composition were investigated. In addition, a plant-derived feed additive (FYK) was applied to assess its mitigating potential under a representative combined stress condition (pH 6.5 + Pb). The results indicate that Pb accumulated in the gills and hepatopancreas of E. sinensis, with significantly increased bioaccumulation in these tissues at low pH (P < 0.05). Combined exposure to low pH and Pb resulted in severe histopathological damage, including gill lamella distortion, epithelial necrosis and hepatopancreatic cell vacuolation. Antioxidant enzyme activities were also significantly altered. SOD, CAT and GSH-PX activities increased with Pb exposure, but decreased with acidification, suggesting that acidification impaired the antioxidant defence capacity of juvenile crabs under Pb stress. Pb exposure altered the structure of the gut microbiota, reducing the abundance of key groups such as Candidatus Bacilloplasma. Notably, dietary supplementation with FYK, particularly at 1%, significantly alleviated tissue damage, improved antioxidant and immune-related enzyme activities, and enhanced stress tolerance. This study provides new insights into the effects of water acidification and Pb pollution on crustaceans, offering a scientific basis for the management of aquaculture water and the development of functional feed.
Curcumin, a polyphenolic compound exhibits various bioactivities, including antimalarial and anti-inflammatory effects. This study investigated the long-term antimalarial effects of curcumin through in vivo experiments using Plasmodium berghei NK65-infected mice, complemented by in vitro and in silico analyses targeting the plasmodial GSK3 protein. Through in vitro, the antimalarial activity of curcumin was assessed on P. falciparum K1 (multi-drug resistant strain) and 3D7 (sensitive strain) as well as P. knowlesi A1H1 of Plasmodium lactate dehydrogenase (pLDH) assay, alongside cytotoxic effects on Vero cells using the MTT assay. Curcumin demonstrated its bioactivity to disrupt the parasite's growth and replication based on the effective inhibition on both P. falciparum (3D7 EC50=8.11µM; K1 EC50=31.21µM) and P. knowlesi (EC50=4.51µM). Molecular docking studies explored curcumin's interaction with the ATP-binding pocket of P. falciparum glycogen synthase kinase-3 (PfGSK3) with favourable binding affinity (-8.72kcal/mol), revealing it potential as a selective inhibitor. Further, in vivo experiments validated curcumin's immunomodulatory activities and therapeutic effects in P. berghei-infected mice. Prolonged curcumin treatment has shown to significantly reduce the parasitaemia compared to the controls. Cytokine profiling via ELISA showed enhanced levels of anti-inflammatory cytokines (IL-10, IL-4) and decreased pro-inflammatory markers (TNF-α, IFN-γ), mitigating systemic inflammation associated with malaria. Histopathological analysis revealed reduction of tissue damage in the curcumin-treated mice, including decreasing parasite sequestration, inflammatory cell infiltration, hepatocyte necrosis and hemorrhages. This study highlights curcumin's potentials in inhibiting PfGSK3, regulating immune responses, and attenuating tissue damage which support its therapeutic role against malarial infection.
ST-elevation myocardial infarction (STEMI) in very elderly patients (≥85 years) poses a major clinical challenge due to frailty and comorbidities. In the general population, left anterior descending (LAD) artery involvement predicts adverse outcomes, but data in the very elderly are limited. We aimed to evaluate the impact of LAD culprit lesions on 30-day mortality in this population. In this multicenter registry (six Italian Hub hospitals, 2010-2023), 586 consecutive STEMI patients aged ≥85 years undergoing coronary angiography and percutaneous coronary intervention (PCI) were retrospectively analyzed. Patients were stratified by culprit vessel: LAD (n = 288) vs. non-LAD (n = 298). Demographic, clinical, procedural characteristics, and 30-day outcomes, including mortality and major adverse cardiovascular events, were collected. Multivariable analysis identified independent predictors of mortality. Baseline differences included prior myocardial infarction (MI) (9.4% vs. 18.5%, P < 0.01), prior CABG (0.3% vs. 4.7%, P < 0.01), and dyslipidemia (35.4% vs. 45.6%, P = 0.02), less frequent in LAD STEMI. Single-vessel disease was more common in LAD STEMI (42.0% vs. 31.5%, P = 0.01). Overall, 30-day mortality was 19.3% (113/586), higher in the LAD group [hazard ratio (HR) 1.57; 95% confidence interval (CI) 1.06-2.33; P = 0.024]. In LAD STEMI, cardiogenic shock at presentation was the strongest independent predictor of death (HR 6.10; 95% CI 3.70-10.35; P = 0.01), while dyslipidemia was associated with lower mortality (HR 0.51; 95% CI 0.28-0.92; P = 0.03). In very elderly STEMI patients, LAD culprit lesions are associated with higher short-term mortality. Cardiogenic shock at presentation and absence of dyslipidemia identify a high-risk subgroup, emphasizing the need for tailored risk stratification and careful procedural planning in this vulnerable population.