Excitotoxic neuronal injury plays a central role in the pathological cascade which follows cerebral ischemia. Excessive glutamatergic signaling leads to calcium overload and the activation of apoptotic pathways, ultimately triggering neuronal death. Salvianolic acid B (Sal B), a water-soluble polyphenolic compound derived from Salvia miltiorrhiza, exhibits neuroprotective properties; however, its effects on excitotoxic neuronal injury following cerebral ischemia remain unclear. The present study used both in vitro and in vivo models of ischemic injury to investigate whether Sal B attenuated excitotoxic neuronal damage. Primary cortical neurons were exposed to cobalt chloride (CoCl2) to induce hypoxia-like injury, after which neuronal viability and apoptotic markers were evaluated. A middle cerebral artery occlusion (MCAO) rat model was constructed to examine the ischemia-induced alterations in excitatory neurotransmission-related proteins. Protein expression was analyzed using western blotting and immunofluorescence, while gene expression was assessed using quantitative real-time PCR. Sal B significantly improved neuronal viability and reduced CoCl2-induced apoptotic signaling, as indicated by the decreased cleavage of caspase-3 and PARP-1. In the MCAO model, ischemia altered the expression of glutamatergic markers, including glutamate receptor-1 (GluA1), vesicular glutamate transporter-2 (VGLUT2), and N-methyl-D-aspartate receptor-1 (NMDAR1). Sal-B treatment attenuated these alterations, reducing the GluA1 and VGLUT2 intensities in NeuN-positive cortical neurons. Furthermore, Sal B decreased mRNA expression of the hypoxia marker HIF1α and the pro-apoptotic factor Noxa, while increasing expression of the anti-apoptotic Bcl2 family members, Bcl-2 and Bcl-xL. SalB attenuates hypoxia- and ischemia-induced neuronal injury and modulates excitatory neurotransmission in the ischemic cortex. These findings indicate that Sal B exerts neuroprotective effects partly through the regulation of excitatory synaptic signaling following cerebral ischemia.
Lipopolysaccharide (LPS)-induced acute kidney injury (AKI) is characterized by oxidative stress, inflammation, and apoptotic injury. Theranekron (THERA) has been suggested to exert immunomodulatory effects; however, its impact on renal oxidative status and related molecular pathways remains unclear. Thirty-two male Wistar albino rats were allocated into four groups: Control, LPS, LPS+THERA, and THERA. Renal oxidative stress was assessed by measuring total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI). Serum creatinine and urea levels, histopathological alterations, and immunohistochemical expression of endothelial nitric oxide synthase (eNOS), interferon-gamma (IFN-γ), and interleukin-8 (IL-8) were evaluated. Sirtuin-1 (SIRT1), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), B-cell lymphoma-2 (BCL2), BCL2-associated X protein (BAX), aquaporin-2 (AQP2), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10) gene expression were measured. LPS significantly increased urea and creatinine levels and induced marked renal histopathological injury. Renal TAS was significantly decreased, and OSI was significantly increased. THERA treatment significantly increased TAS and reduced OSI compared with the LPS group. LPS significantly reduced SIRT1, NRF2, and HO-1 mRNA expression, and prophylactic THERA treatment significantly increased only HO-1 expression. LPS induced a pro-apoptotic shift and reduced AQP2 expression, all of which were significantly prevented by THERA. In parallel, THERA significantly reduced TNF-α expression and IL-10 levels, decreased IFN-γ and IL-8 immunoreactivity, and reduced eNOS immunoreactivity. Prophylactic THERA administration partially protected against early renal injury by improving renal antioxidant capacity, upregulating HO-1, and suppressing inflammatory and apoptotic responses, with preservation of AQP2 expression.
Cardiomyocyte-specific Cre driver lines such as Myh6-Cre are widely used in cardiovascular research, but Cre recombinase itself can induce cardiac toxicity independently of target gene deletion. Early biomarkers capable of identifying this injury before overt cardiac remodeling or dysfunction remain poorly defined. Here, we performed a longitudinal analysis of Myh6-Cre mice using circulating biomarkers, cardiomyocyte Ca²⁺ transient measurements, histology, echocardiography, organ pathology, and survival analysis. Circulating cardiac troponin T (cTnT) levels were unchanged at 7 and 8 weeks of age but increased significantly from 9 weeks onward, preceding detectable structural remodeling or global cardiac dysfunction. At 12 weeks, isolated ventricular cardiomyocytes from Myh6-Cre mice showed reduced Ca²⁺ transient amplitude and delayed Ca²⁺ decay, indicating early functional impairment at the cellular level. Histologically detectable myocardial fibrosis emerged from 20 weeks, systolic dysfunction became evident at approximately 30 weeks, and progressive myocardial degeneration, extracardiac pathology, and mortality developed at later stages. These findings define the temporal progression of cardiac injury in Myh6-Cre mice and identify circulating cTnT as an early biomarker of cardiomyocyte injury caused by cardiac-specific Cre expression. Routine assessment of cTnT may improve the interpretation of phenotypes and help identify early model-associated injury in widely used Cre-based cardiac models, thereby informing the suitability of cardiac-specific Cre systems for cardiovascular research.
Xin-Zi-Sheng-Wan Decoction (XZSWD) is a modified formulation derived from the classical prescription Zi-Sheng Pill, which was recorded in Xian Xing Zhai Yi Xue Guang Bi Ji from the Ming Dynasty. Traditionally, this formula is used to eliminate "turbid stagnation" and restore metabolic balance. Contemporary ethnopharmacological evidence indicates that XZSWD can reduce uric acid (UA) levels and ameliorate renal injury, although the molecular mechanism underlying these effects remains incompletely understood. The aim of this study was to determine whether XZSWD mitigates hyperuricemia-associated renal injury and to elucidate the underlying mechanisms, with a particular focus on RIPK1/RIPK3/MLKL-mediated necroptosis and oxidative stress in vivo and in vitro. UPLC-QTOF/MS was used to profile XZSWD constituents. A hyperuricemia mouse model was established in C57BL/6J mice using hypoxanthine plus potassium oxonate, followed by XZSWD or febuxostat treatment; serum SUA, Cr, and BUN and renal histopathology were assessed, together with Western blot and immunofluorescence. RNA-seq (GSE300922), network pharmacology, and molecular docking were performed to identify key targets and pathways. In vitro, HK-2 cells were treated with tumor necrosis factor-alpha (TNF-α), necroptosis inhibitors, apoptosis inhibitors and XZSWD-medicated serum, and cell viability and Annexin V-FITC/PI flow cytometry were conducted. XZSWD lowered serum UA and improved renal function, alleviating tubular injury and fibrosis in hyperuricemic mice. RNA-Seq and network analyses implicated TNF signaling and necroptosis. In HK-2 cells, XZSWD improved viability, reduced reactive oxygen species (ROS) accumulation, and suppressed RIPK1/RIPK3/MLKL phosphorylation, consistent with inhibition of necroptotic cell death. XZSWD ameliorates hyperuricemia-associated renal injury by attenuating TNF-α-driven RIPK1/RIPK3/MLKL-mediated necroptosis and oxidative stress.
Intermittent hypoxemia (IH) frequently occurs in preterm infants and is increasingly linked to adverse outcomes. We previously demonstrated a relationship between IH and S100B, a brain injury biomarker. Here, we assess these relationships with glial fibrillary acidic protein (GFAP), a protein released following astrocyte injury. Infants ≤32 weeks' gestation were prospectively enrolled. Oxygen saturation was continuously monitored. IH metrics were quantified using validated algorithms using multiple SpO₂ thresholds. Urine was collected at multiple time points, and GFAP concentrations were measured using an ultrasensitive immunoassay. Infants with severe intraventricular hemorrhage were excluded. Associations between IH metrics and urinary GFAP were examined using weighted Spearman correlation analyses (ρ). Twenty-nine infants contributed 71 urine samples with a median of 2.4 samples per infant [IQR 1.0-4.0] collected at a median postnatal age of 36.0 days [IQR 24.0-45.3]. Higher GFAP concentrations were associated with greater IH burden, including greater percent time in hypoxemia (ρ=0.45-0.47), increased IH frequency (ρ=0.42-0.44), longer IH duration (ρ=0.47-0.48), and lower nadir (ρ= -0.42 to -0.44), all p <0.001. When stratified by gestational age, extremely preterm infants (<28 weeks gestational age) demonstrated strong relationships between GFAP and IH events of both short (<1minute) and longer (≥1minute) duration, whereas very preterm infants (28-31 weeks gestational age) showed significant associations primarily with longer IH events. Urinary GFAP levels increase with greater IH exposure in preterm infants. Together with our prior findings for S100B, these results suggest that GFAP represents another astroglial biomarker associated with IH-related brain injury and may provide both mechanistic insight and a noninvasive tool for detecting early brain injury in this vulnerable population.
Extending previous research, this study examines distance runners' narrative accounts of sport injury and disordered eating, highlighting how these experiences intersect and unfold across their athletic careers. Ten regional to international level distance runners participated, who had experienced a range of injuries throughout their career (e.g., acute, chronic, overuse, career-ending). Life-story interviews (n=28) and visual methods (i.e., photographs) were used to facilitate the participants in telling their stories. Data were analysed using dialogical narrative analysis and represented through creative-non-fiction. Framed within narrative theory and taking a thick social-relational perspective, five stories were constructed that illustrate the complex and nuanced relationship between sport injury and disordered eating over time: Is it good for me?, I know I've gone too far, Maybe it wasn't too late for me?, Is this what normal feels like?, and I love food too much. This study deepens understanding of how injury and disordered eating unfold within performance-oriented cultures, pointing toward more supportive narrative and relational possibilities, and provides pedagogical resources that can promote a shared understanding across interdisciplinary practitioners who aim to work collaboratively to support athletes' well-being.
Acute lung injury (ALI) is a common and life-threatening critical illness with persistently high mortality, yet effective pharmacological therapies remain lacking. Norepinephrine (NE), a first-line vasopressor for septic shock, has been suggested to confer organ-protective and immunomodulatory effects in sepsis and related organ injury; however, its specific role and molecular mechanisms in ALI remain poorly defined. Here, we demonstrate both in vitro and in vivo that NE significantly attenuates ALI, and this protective effect is primarily attributable to the suppression of alveolar epithelial cell pyroptosis. Transcriptomic profiling and functional analyses reveal that NE activates the β2-adrenergic receptor (β2-AR)-cAMP/PKA signaling axis and, through the A-kinase anchoring protein AKAP1, preserves mitochondrial homeostasis, thereby interrupting the vicious cycle between mitochondrial damage and pyroptosis. Further mechanistic dissection identifies AKAP1 as an indispensable molecule for NE-mediated protection and caspase-11 as the critical downstream effector through which NE inhibits pyroptosis. Collectively, this study uncovers a novel mechanism by which NE suppresses alveolar epithelial pyroptosis and alleviates ALI via the β2-AR-AKAP1 axis, providing a potential therapeutic target for ALI.
Platycodon grandiflorum and Lonicera japonica are two plants that have been widely used in traditional ethnic medicine for both medicinal and edible purposes. They are commonly applied in the prevention and treatment of lung-heat-related and inflammatory diseases. However, the stems and leaves of these plants have historically been regarded as by-products, and their therapeutic potential has not been thoroughly explored. Recent studies have shown that the Platycodon grandiflorum stems and leaves, and Lonicera japonica stems and leaves are rich in bioactive compounds, including flavonoids, saponins and phenolic compounds and exhibit notable anti-inflammatory and antioxidant activities. In this study, we investigate the protective mechanism of Platycodon grandiflorum stems and leaves and Lonicera japonica stems and leaves (PLSL) against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. This work aims to provide a theoretical basis for resource development and the sustainable, high-value utilization of non-medicinal parts of traditional Chinese medicinal plants. In this study, an LPS-induced inflammatory model using RAW264.7 cells was employed to screen the optimal compatible ratio of PLSL. High-performance liquid chromatography (HPLC) was used to analyze its chemical composition and identify the main active components. In the animal experiment, a mouse model of ALI was established by intranasal instillation of LPS. The severity of lung injury was comprehensively evaluated based on the lung index, lung wet-to-dry (W/D) weight ratio, hematoxylin and eosin staining and Masson's staining. Levels of inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured using ELISA. The transcriptional levels of genes related to the Keap1/Nrf2 pathway were detected by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and the expression and nuclear translocation of Nrf2 and p65 proteins were assessed by immunofluorescence. Meanwhile, 16S rRNA high-throughput sequencing was applied to analyze the cecal microbiota composition in mice, and gas chromatography was used to determine short-chain fatty acid (SCFA) concentrations. Spearman correlation analysis was performed to explore correlations among inflammatory mediators, antioxidant markers and gut microbiota at the genus level. The in vitro results demonstrated that the 4:1 combination of PLSL promoted the migration and proliferation of RAW264.7 cells in a dose-dependent manner and effectively inhibited the overexpression of pro-inflammatory mediators, including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), as well as inflammatory cytokines such as TNF-α, IL-6 and IL-1β. Meanwhile, PLSL exhibited strong scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) cation radicals and hydroxyl radicals (·OH). HPLC analysis revealed that PLSL contained key active components, including platycodin D, lobetyolin, loganin and chlorogenic acid. In vivo experiments confirmed that PLSL significantly alleviated LPS-induced ALI in mice by regulating the NF-κB and Keap1/Nrf2 signaling pathways, reducing malondialdehyde (MDA) and nitric oxide (NO) levels, increasing glutathione (GSH) levels, suppressing the expression of COX-2, iNOS, TNF-α, IL-6 and IL-1β and modulating the mRNA expression of Keap1, Nrf2, heme oxygenase-1(HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). Furthermore, PLSL effectively improved intestinal microbial diversity, increased the relative abundance of beneficial bacteria, including Lachnospiraceae and Alistipes, and significantly elevated cecal short-chain fatty acids (SCFAs), such as acetic acid, propionic acid and butyric acid. This study preliminarily elucidates the multi-target synergistic anti-inflammatory effects of PLSL from the perspectives of inflammatory signaling pathways and gut microbiota. It provides experimental evidence for the whole-plant development and utilization of Platycodon grandiflorum and Lonicera japonica as ethnomedicines.
Hepatocellular ferroptosis is a key driver of acetaminophen (APAP)-induced acute liver injury (AILI). Although galangin has been reported to exert liver-protective effects by modulating ferroptosis, its role and mechanism in AILI remain poorly understood. In this study, galangin significantly attenuated APAP-induced liver injury and dysfunction. RNA-seq analysis suggested that galangin may mitigate AILI via ferroptosis- and autophagy-related pathways and identified FTH1 as a potential target. Molecular docking and CETSA confirmed a specific and stable interaction between galangin and FTH1. Furthermore, galangin significantly inhibited ferroptosis-related proteins (Cox2, Acsl4, and Lpcat3) and rescued antiferroptotic regulators (Gpx4, Slc7a11, Fsp1, and NADPH) in AILI mice, without altering autophagy-related proteins Ncoa4, LC3, and p62. Mechanistically, galangin inhibited the recognition and binding of HSC70 to FTH1 and downregulated the expression of LAMP2A, thereby reducing chaperone-mediated autophagy (CMA)-dependent degradation of FTH1 and ultimately inhibiting ferroptosis. Overall, this study supports galangin as a potential hepatoprotective supplement.
Extreme alpine summer sports are increasingly popular and expose participants to high-energy trauma in remote mountain environments. This pictorial essay reviews the emergency radiology of severe acute injuries associated with down-hill mountain biking, rock climbing, paragliding, BASE jumping, canyoning, and rafting, with emphasis on mechanism-based imaging interpretation. Injury patterns differ across disciplines but are largely determined by velocity, fall height, landing posture, impact surface, axial loading, torsional forces, and water-related hazards. Down-hill mountain biking commonly produces extremity, thoracic, craniofacial, abdominal, and spinal injuries after high-speed crashes or handlebar impact. Rock climbing and paragliding frequently involve falls from height and hard landings, leading to thoracolumbar fractures, pelvic trauma, calcaneal or ankle injuries, and, in severe cases, neurologic compromise or visceral injury. BASE jumping is associated with high-velocity landing trauma, particularly involving the lower limbs, pelvis, and spine. Canyoning and rafting combine blunt trauma with environmental risks such as submersion, aspiration, hypothermia, and drowning-related complications. In high-energy trauma or polytrauma, whole-body computed tomography is the cornerstone of emergency assessment, enabling rapid evaluation of head, spine, chest, abdomen, and pelvis. Radiography remains useful for isolated appendicular injuries, whereas magnetic resonance imaging is essential for spinal cord, ligamentous, marrow, and selected soft-tissue injuries. Awareness of sport-specific mechanisms helps radiologists optimize image selection, maintain an appropriate search pattern, recognize injuries that may coexist after axial loading, and communicate urgent findings promptly. A mechanism-oriented approach may improve diagnostic accuracy, guide multidisciplinary management, and reduce missed injuries in patients presenting after alpine summer extreme sports trauma.
The role of cerebral autoregulation in the management of traumatic brain injury (TBI) is of increasing interest. Though oxygen is potently vasoactive, its role in autoregulation is under-appreciated despite the importance of brain oxygen monitoring and pervasive availability of supplemental oxygen in clinical environments. This narrative review intends to provide historical scientific context for oxygen-driven cerebral autoregulation-hereby termed oxygenic autoregulation-and its therapeutic potential, particularly during intracranial pressure (ICP) crises. A review of original research from 1900-2025 identified sparse but consistent evidence, concentrated in the late 20th century, that hyperoxia and hypoxia have significant effects on cerebral vasomotion and ICP. Clinical studies of hyperoxia were conducted primarily using hyperbaric oxygen therapy (HBOT), which consistently reduced ICP, but often with a rebound to baseline levels or above both during and after treatment. Hypoxic high altitude cerebral edema was frequently associated with increased non-invasive estimates of ICP. The Brain Trauma Foundation's pre-hospital guidelines recommend the provision of supplemental oxygen to those suspected of having a brain injury. However much remains to be learned about the mechanism underlying this benefit, as well as the harms of hyperoxic therapy (such as oxidative stress or rebound ICP elevation), especially over the longer term. New research is needed to understand if supplemental oxygen reliably induces autoregulatory vasoconstriction which in turn reduces intracranial hypertension. At the present time, given the lack of recent research on this "oxygenic" mechanism of autoregulation, there is insufficient evidence for the therapeutic use of normobaric hyperoxic therapy for the treatment of intracranial hypertension.
Lutein and zeaxanthin (L/Z) are major components of macular pigment with established antioxidant and blue-light filtering properties. This study investigated the protective efficacy of a 20% marigold extract oil (L/Z complex) using both an A2E-mediated ARPE-19 cell in vitro phototoxicity model and a light-emitting diode (LED)-induced retinal injury rat model. In vitro, ARPE-19 cells were loaded with A2E and exposed to blue light (6,000 lux, 20 min). In vivo, rats were exposed to 750 lux LED for 48 h following 4-week oral administration of L/Z complex. Cell viability, inflammatory cytokines, antioxidant enzymes, retinal histopathology, and expression of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) and nuclear factor-κB (NF-κB) were evaluated. In ARPE-19 cells, A2E-mediated blue light exposure reduced viability to 28.15±3.67% and markedly increased inflammatory cytokines. L/Z complex significantly reduced NF-κB, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) expression while enhancing HO-1 and antioxidant enzyme levels. In the rat model, L/Z complex preserved outer nuclear layer (ONL) thickness, reduced pro-inflammatory cytokines, enhanced total antioxidant capacity (TAC) and glutathione peroxidase (GSH-Px) activities, and attenuated NF-κB expression. The L/Z complex confers retinal protection through coordinated antioxidant and anti-inflammatory mechanisms in both cellular and animal models of retinal injury, supporting its translational potential as a nutritional intervention for retinal degeneration.
Hyperpyrexia is a complication of burn injury, likely caused by systemic inflammation and infection, the pathophysiology of which is poorly understood. This study aimed to describe the patient cohort who developed hyperpyrexia (≥39.5°C) and evaluate the effectiveness of the Thermogard XP Icy®, an intravascular temperature management device, in restoring normothermia. This was a retrospective cohort study of adult patients admitted to Glasgow Royal Infirmary's intensive care unit with major burns (TBSA ≥20%) between January 2016 and October 2024. A central database and electronic medical records were used to collect data on demographics, burn severity, interventions and outcomes. Episodes of hyperpyrexia and Thermogard XP® use were also recorded. A multilevel interrupted time series analysis was used to assess the effectiveness of the Thermogard XP® device in reducing body temperature in comparison to historic controls. Fifty-six patients were analysed, of which 30 (56.3%) developed hyperpyrexia. This cohort were more likely to have sustained a flame burn (p = 0.003), have a greater burn TBSA (p = 0.006) and longer hospital stay (p = 0.005) when compared to non-hyperpyrexic patients; however, mortality rates did not differ significantly. Eight patients were managed with a Thermogard XP®; this appeared to achieve normothermia quicker than standard interventions. Hyperpyrexia was associated with more severe burn injuries and greater intervention requirements but not increased mortality. The Thermogard XP® seemed effective at controlling temperatures ≥ 39.5°C in this small single-centre observational study; future studies are needed to further explore its effectiveness and impact on outcomes such as survival.
Since the original descriptions by Giza and Hovda of the acute neurometabolic cascade of concussion 25 years ago, there has been a broad evolution in the understanding of concussion and other types of traumatic brain injuries (TBI) to include not only acute, neuro, and metabolic aspects of pathophysiology but also the impact and risk of TBI on numerous molecular and cellular processes, neural networks and physiologic systems. This review summarizes research and clinical advancements in the neurometabolic cascade of TBI, recognizing that evolution beyond this postinjury neuronal perspective is key to unlocking improved therapies and reduction of long-term risk.
Abusive head trauma (AHT) in children is challenging to diagnose due to unreliable histories and varying presentations and findings from additional examinations. Findings from additional examinations may help distinguish AHT from non-abusive head trauma (nAHT), but single studies report conflicting results. This systematic review (SR) synthesizes evidence on differences in additional examinations between children under 2 years with AHT and nAHT. We searched Ovid Medline, Web of Science, and the Cochrane Library for comparative observational studies to identify differences in cerebral, spinal, ophthalmological and skeletal findings between children with AHT and nAHT. Two reviewers independently selected studies, extracted data, and assessed risk of bias (RoB) using the Newcastle-Ottawa Scale. Random-effects meta-analyses and sensitivity analyses were performed. Forty (mostly retrospective) studies reported 51 clinical variables. Eighteen variables were associated with AHT: subdural hemorrhage (SDH), bilateral SDH, interhemispheric blood, mixed-density SDH, multilayered SDH, any intracranial hemorrhage (ICH), ICH without skull fracture, cerebral edema, ischemia, and atrophy, hydrocephalus, spinal SDH, cervical and thoracolumbar spinal SDH, retinal hemorrhages (RH), bilateral RH, vitreous hemorrhage and skeletal fracture. The variables skull fracture, isolated skull fracture, epidural hemorrhage (EDH), subgaleal hematoma, and long bone fracture were associated with nAHT. Moderate or high RoB was observed in 69% of the assessments. Certain cerebral, spinal, ophthalmological and skeletal features in children under 2 years with head injury may indicate AHT, with potential implications for accurate diagnosis and timely safeguarding. Results should be interpreted cautiously given the moderate to high RoB in the majority of assessments.
Sepsis during pregnancy is associated with increased risks of fetal growth restriction, preeclampsia, and placental abruption even after maternal recovery. Characterizing placental pathology after antepartum sepsis may clarify mechanisms linking infection to subsequent pregnancy complications. We performed placental histopathologic analysis on individuals delivering at a single institution. Cases had resolved antepartum sepsis (defined as clinical recovery ≥7 days before delivery), and controls were individuals without an antepartum infection hospitalization. Exclusion criteria included multifetal gestation, fetal anomalies, TORCH infections, and delivery <34 weeks' gestation (chosen to minimize gestational age-dependent histologic variability). All placentas were reviewed by a subspecialty placental pathologist and lesions characterized according to the Amsterdam criteria. Clinical characteristics and histopathologic findings were compared using Fisher's exact and Wilcoxon rank-sum tests. Twenty-two sepsis-exposed pregnancies and 49 controls were included. The most common infection sources were urinary tract (36.4%) and respiratory (36.4%), diagnosed at a mean (SD) gestational age of 25.3 (9.2) weeks. The sepsis group was younger (31.6 [4.6] vs 34.6 [4.7] years; p = 0.017) and had higher rates of tobacco use (13.6% vs 0%; p = 0.027) and pregestational diabetes (13.6% vs 0%; p = 0.027). Sepsis-exposed placentas had significantly higher rates of maternal vascular malperfusion (31.8% vs 0%; p < 0.001), placental infarction (13.6% vs 0%; p = 0.027), avascular villi (27.3% vs 4.1%; p = 0.009), histologic chorioamnionitis (50.0% vs 17.0%; p = 0.015), and meconium-staining (50.0% vs 14.3%; p = 0.003). Resolved antepartum sepsis is associated with increased placental vascular and inflammatory pathology, suggesting lasting placental injury after severe systemic infection that may underlie adverse pregnancy outcomes.
Wearable sensors and monitoring systems are increasingly used in clinical and home-care settings, often requiring prolonged contact with skin over bony prominences such as the sacrum. Tissue deformation beneath sustained loading is recognized as a key mechanical factor in pressure-induced tissue damage. However, device geometry influence on stress and strain distribution within underlying soft tissues remains insufficiently characterized. A three-dimensional finite element model of the sacral region was developed, incorporating skin, adipose tissue, muscle, and sacral bone. Two wearable-device geometries were simulated: a circular skin-mounted sensor and an elongated cable segment. Static pressures of 2, 6, 8, and 10 kPa were applied. Tissue stiffness was varied by ±10% and ±20% to represent inter-individual variability. Mechanical exposure was quantified using layer-resolved stress and strain distributions and a normalized risk index derived from cumulative histograms within a defined region of interest. Sensor loading produced predominantly superficial stress concentrations in skin, whereas cable loading redistributed mechanical exposure toward deeper tissues. At 10 kPa, strain-based risk indices in adipose tissue and muscle approached maximal values under cable loading across stiffness conditions, while stress-based risk remained highest in skin. Increasing tissue stiffness elevated stress-based risk but had limited influence on strain-based risk, especially in deeper tissues. We show that device geometry strongly determines tissue-level mechanical exposure. Sensor-like devices concentrate stress superficially, whereas cable-like geometries produce persistent strain in deeper tissues, which is relatively insensitive to moderate stiffness changes. Our results emphasize the need for geometry-aware, deformation-based assessment of wearable-device loading risk in pressure-vulnerable anatomical regions.
Poly rC binding proteins (PCBPs) 1 and 2 bind iron and ssDNA/RNA, acting as iron chaperones for enzyme metalation, ferritin storage, and iron toxicity prevention. Previously, we demonstrated that liver-specific PCBP1 deletion in mice increased unchaperoned iron, causing hepatic oxidative damage and steatosis. Little is known about the functions of PCBP2 in vivo. To define the roles of PCBP1 and PCBP2 in murine hepatic iron metabolism, we generated conditional (Alb-Cre) and vector-mediated (AAV8-TBG-iCre) deletion as models of chronic and acute PCBP deficiency, respectively. Conditional deletion in hepatocytes and cholangiocytes caused chronic, severe hepatic injury, with steatosis, necrosis, ductular reaction, increased plasma ALT and ALP, and Nrf2-dependent antioxidant gene activation. Vector-mediated PCBP1/PCBP2 double deletion in adult mice led to acute liver injury with periportal inflammation, apoptosis, and DNA damage, followed by compensatory hepatocyte proliferation. In contrast, single deletions caused mild or no acute liver abnormalities, suggesting a functional redundancy. Loss of both chaperones caused oxidative and ferroptosis-like injury, indicated by increased lipid peroxidation, 8-oxoguanine-modifcations of nucleic acids, and Nrf2 target gene expression. Dietary iron restriction, but not vitamin E, markedly improved liver pathology, normalized plasma markers, and reduced oxidative stress, demonstrating that iron toxicity, not general lipid peroxyl radicals, drives hepatocellular injury. Rescue experiments with PCBP1 variants demonstrated that wild-type PCBP1 restored normal hepatic function, while iron-binding-deficient (ΔFe) and RNA/DNA-binding-deficient (ΔRNA) variants failed. PCBP1ΔFe expression did not prevent liver damage or suppress ALT levels. PCBP1ΔRNA expression was, surprisingly, toxic to hepatocytes and caused more rapid cell death than transduction with no PCBP1 at all, suggesting that unbalanced iron- and RNA/DNA-binding activities are toxic to hepatocytes. These results establish PCBP1 and PCBP2 as essential, cooperative hepatic iron regulators whose loss causes ferroptosis-like injury through dysregulated iron and RNA/DNA homeostasis.
Ventilator-associated pneumonia (VAP) is a common intensive care unit (ICU) complication and a quality metric. Trauma patients may be uniquely predisposed to pulmonary infection from mechanisms intrinsic to injury (blunt chest trauma and pulmonary contusions) rather than ventilator exposure alone. This study hypothesized that trauma-specific factors would be associated with pneumonia in intubated trauma ICU patients. A review of patients admitted to the trauma ICU at a level I trauma center with ≥2 ventilator days from 2018 to 2022 was performed. Patients were stratified into VAP and non-VAP groups. Logistic regression models were used to analyze risk factors for VAP. During the 5-y study period, 444 patients met the inclusion criteria with 61 (13.7%) developing VAP. The VAP group had more blunt injury (98% versus 79%, P = 0.004), pulmonary contusions (ctx) (59% versus 35%, P < 0.001), ventilator (vent) days (12 versus 6 d, P < 0.001), and tracheostomies performed (53% versus 30%, P < 0.001). On logistic regression analysis, blunt injury (odds ratio [OR] 16.3), pulmonary ctx (OR 2.3), and vent days (OR 1.1) were associated with VAP in a multivariable model. Blunt injury and pulmonary ctx were associated with increased odds of VAP, while longer vent days only slightly associated. With unique predisposition, many trauma ICU pulmonary infections are likely not "ventilator-associated" and may require a new diagnosis, definition, and predicted incidence of these "trauma-associated" pneumonias.
An os subfibulare (OS) is frequently seen in adolescents with chronic lateral instability of the ankle, potentially impairing participation in sport and the quality of life. The aim of this study was to compare the clinical outcomes of the modified Broström-Gould procedure in adolescent patients with chronic lateral instability of the ankle with and without an OS. We retrospectively reviewed adolescent patients who underwent a modified Broström-Gould procedure for chronic instability of the ankle between August 2019 and July 2023. Propensity score matching (1:1) was undertaken based on age, sex, side, BMI, the duration of symptoms, pre-injury Tegner score, and joint hypermobility, yielding 82 matched cases (41 OS and 41 non-OS). Preoperative imaging parameters and intraoperative findings were recorded. Primary outcomes included patient-reported outcome measures (PROMs): a visual analogue scale (VAS) for pain, the Karlsson score, the Tegner score, and the Foot and Ankle Outcome Score (FAOS). Secondary outcomes included the incidence of re-sprain, the time to return to sport, satisfaction, and complications. Logistic regression analysis identified risk factors for re-sprain. The mean follow-up was 47.8 months (SD 11.2) in the OS group and 47.9 months (SD 9.6) in the non-OS group (p = 0.949). Both groups had significant improvements in all PROMs, with no differences between the groups for the VAS, Karlsson score, Tegner score, or FAOS. Re-sprain occurred in five in the OS group (12.2%) and 12 in the non-OS group (29.3%) (p = 0.081). Multivariate analysis identified higher pre-injury Tegner score (p = 0.001) and concomitant calcaneofibular ligament injury (p = 0.028) as significant independent risk factors for re-sprain. In adolescent patients with chronic lateral instabilty of the ankle, the presence of an OS does not compromise the outcomes of a modified Broström-Gould procedure. Excision of the OS combined with ligamentous repair provides improvements which are comparable to those of an isolated repair, representing a safe and effective form of surgical treatment. Nonetheless, greater attention should be given to patients with high sporting demands or concomitant calcaneofibular ligament injury, due to their increased risk of re-sprain postoperatively.