Irreversible Injury Research Articles

The trans-differentiation promotion of parietal epithelial cells by magnesium isoglycyrrhizinate to improve podocyte injury induced by high fructose consumption

BackgroundPodocytes have limited proliferative capacity, which leads to irreversible glomerular injury in diverse kidney diseases. Magnesium isoglycyrrhizinate (MgIG), a hepatoprotective agent in clinic, has been reported to improve glomerular podocyte injury. However, the underlying mechanism of MgIG in ameliorating podocyte injury remains unclear. PurposeGlomerular parietal epithelial cells (PECs) are recognized as podocyte progenitors and play a pivotal role in the recovery following glomerular injury. This work aims to investigate the protective mechanisms of MgIG in mitigating glomerular injury by promoting PEC trans-differentiation. Study DesignA rat model of progressive glomerular podocyte injury, and in vitro models using the primary podocytes and primary PECs, were established to further explore the pharmacological mechanism of MgIG. MethodsFour-week-old male Sprague-Dawley (SD) rats were fed a 10% fructose solution for 3, 6, 9 and 12 weeks to induce glomerular injury. The effect of MgIG on the progressive changes in podocytes and PECs, and the correlation between PEC density and podocyte loss, were analyzed. The mechanism of MgIG in triggering PEC trans-differentiation was investigated, by examining adenosine secretion in injured podocytes, as well as the expression of cluster of differentiation 44 (CD44), nephrin, adenosine receptor A2B (ARA2B) and glucocorticoid receptor (GR) in PECs were examined both in vivo and in vitro. ResultsRats fed a high fructose diet exhibited progressive changes in glomerular PECs, including increased cell density and a preference for trans-differentiation. A positive correlation was observed between PEC density and podocyte loss. Co-culture experiments demonstrated that extracellular adenosine accumulation in injured podocytes induced by high fructose exposure promoted PEC trans-differentiation via ARA2B. MgIG significantly improved podocyte injury and exhibited effects similar to dexamethasone on nephrin upregulation activation and CD44 inhibition. Moreover, the inhibitory effect of MgIG on PEC ARA2B activation was more effective than that of dexamethasone. The co-expression of paired box 2 (PAX2)+-Nephrin+ in glomeruli indicated that MgIG induced PEC trans-differentiation and podocyte regeneration in model rats. Accordingly, podocyte loss and increased urine albumin-to-creatinine ratio (UACR) were also alleviated. Moreover, MgIG, which acts as a GR agonist to activate GR, reversed the upregulation of CD44 and decreased ARA2B induced by tumor necrosis factor-α (TNF-α) in primary PECs. The siRNA interference experiment manifested that MgIG exhibited a more pronounced enhancement of GR upregulation, in contrast to ARA2B activation, to promote PEC trans-differentiation. ConclusionThis work reports for the first time that PECs respond to the accumulation of extracellular adenosine from injured podocytes via activating ARA2B and focuses on the role of adenosine and adenosine receptors in the trans-differentiation of PECs. Furthermore, this study provides the first evidence that MgIG may promote podocyte regeneration by enhancing PEC trans-differentiation through GR activation, providing a research basis for investigating the glucocorticoid-like activity of MgIG in ameliorating glomerular podocyte injury.

Cortistatin exerts an immunomodulatory and neuroprotective role in a preclinical model of ischemic stroke

Ischemic stroke is the result of a permanent or transient occlusion of a brain artery, leading to irreversible tissue injury and long-term sequelae. Despite ongoing advancements in revascularization techniques, stroke remains the second leading cause of death worldwide. A comprehensive understanding of the complex and interconnected mechanisms, along with the endogenous mediators that modulate stroke responses is essential for the development of effective interventions. Our study investigates cortistatin, a neuropeptide extensively distributed in the immune and central nervous systems, known for its immunomodulatory properties. With neuroinflammation and peripheral immune deregulation as key pathological features of brain ischemia, cortistatin emerges as a promising therapeutic candidate. To this aim, we evaluated its potential effect in a well-established middle cerebral artery occlusion (MCAO) preclinical stroke model. Our findings indicate that the peripheral administration of cortistatin at 24h post-stroke significantly reduces neurological damage and enhances recovery. Importantly, cortistatin-induced neuroprotection was multitargeted, as it modulated the glial reactivity and astrocytic scar formation, facilitated blood-brain barrier recovery, and regulated local and systemic immune dysfunction. Surprisingly, administration of cortistatin at immediate and early post-stroke time points proved to be not beneficial and even detrimental. These results emphasize the importance of understanding the spatio-temporal dynamics of stroke pathology to develop innovative therapeutic strategies with appropriate time windows. Premature interruption of certain neuroinflammatory processes might inadvertently compromise neuroprotective mechanisms. In summary, our study highlights cortistatin as a novel pleiotropic therapeutic approach against ischemic stroke, offering new treatment options for patients for whom early revascularization intervention is unsuccessful.

Interprétation d’une valeur élevée de troponine en dehors des syndromes coronariens aigus

AbstractApart from acute coronary syndrome, increased troponin represents 40 % of requests. In acute myocardial infarction (AMI), the increase in cardiac troponin is linked to cardiomyocyte necrosis. But any reversible or irreversible cardiomyocyte injury can be accompanied with an increase in cardiac troponin. It is important to know how to distinguish causes without any real deleterious ­impact, such as intense physical exercise, from the numerous pathological causes where the high value of cardiac troponin constitutes a prognostic factor : renal failure, pulmonary embolism, sepsis, non-cardiac surgery. The increase in cardiac troponin T alone in various muscular disorders seems more and more frequent and leads us to question the necessity of having the dosage of both cardiac troponin T and cardiac troponin l.

Pathophysiology of Normal Pressure Hydrocephalus

The current perspective for the pathophysiology of normal pressure hydrocephalus is focusing on stiffness of the central nervous tissue, especially on a type of cerebrovascular disorder. Rigid intracranial vessels and tissues derived by either vascular risk factors or aging may lead into impaired dynamics of the cerebrospinal fluid such as increased pulsatility and decreased absorption of the cerebrospinal fluid. Enlarged ventricle may result in a decrease of blood perfusion in brain parenchyma, and in turn global hypoxia and neuro-inflammation along with a breakdown of the blood-brain-barrier. Deterioration of the glymphatic pathway, the crucial disposal pathway of the waste product of the brain, also might contribute to the irreversible injury of the nervous tissue by deposition of abnormal toxic proteins including amyloid beta. Of note, the pathophysiology of the normal pressure hydrocephalus is moving to a type of cerebrovascular disorder instead of the etiology of idiopathic.

B-Lines in the Assessment of Interstitial Lung Disease Associated with Scleroderma: The Role of Handheld Devices.

Background: Timely detection and aggressive management of interstitial lung disease (ILD) in systemic sclerosis (SSc) are essential to improving outcomes and reducing risks of irreversible lung injury. Objective: to explore the usefulness of an ultraportable ultrasound device for the management of SSc-related ILD and to compare it with clinical and instrumental data. Methods: A total of 19 consecutive SSc patients underwent a comprehensive pulmonary evaluation: clinical, pulmonary function tests (PFTs) (spirometry, DLCO), lung CT (1.5 mm slice thickness reconstruction; HRCT), and lung ultrasound (LUS). A total score was calculated based on the number of color-coded B-lines recorded for each lung sliding. B-lines were analyzed against dyspnea, cough, Velcro, CT imaging (Warrick's score), and PFTs. Global and subgroup analysis were performed (diffuse versus limited cutaneous SSc, Warrick's < 7 versus >7). Results: Symptomatic lung involvement with varying degrees of dyspnea was reported in about 74% of cases (functional NYHA > 2 in more than half), chronic dry cough in one-third, Velcro rales in 42%. A total of 84.24% were classified as SSc with ILD on CT imaging. Statistically significant mild-to-moderate correlations between B-lines and clinical manifestations were demonstrated, as well as PFTs and Warrick's scores (more B-lines, lower pulmonary function, but higher extent and severity on CT) (p < 0.05); there were differences between SSc patients without and with ILD in terms of the number and distribution of B-lines (p < 0.05), as well as different B-lines patterns and numbers in diffuse versus limited SSc (p < 0.05). Conclusions: Ultraportable handheld LUS is a promising method suitable for the management (screening, early detection, and evaluation) of SSc patients.

Tubulointerstitial injury in proteinuric chronic kidney diseases.

Proteinuria is an independent risk factor for chronic kidney disease progression and cardiovascular diseases. Apart from its prognostic role, the load of proteins that pass across the disrupted glomerular capillary wall trigger multiple pathophysiologic processes. These include, among others, intratubular complement activation and excessive proximal tubular reabsorption of filtered proteins, especially albumin and albumin-bound free fatty acids, which can set off several pathways of cellular damage. The activation of these pathways can cause apoptosis of proximal tubular cells and paracrine effects that incite the development of interstitial inflammation and fibrosis, ultimately leading to irreversible kidney injury. In this review, we provide a comprehensive overview of the current understanding on the mechanisms underlying the tubular toxicity of ultrafiltered proteins in the setting of proteinuric chronic kidney diseases. The acquired knowledge is expected to be instrumental for the development of novel therapeutic classes of medications to be tested on top of standard of care with optimized renin-angiotensin-aldosterone blockade and sodium-glucose cotransporter-2 inhibition, in order to further improve the clinical outcomes of patients with proteinuric chronic kidney diseases.

Potential Player of Platelet in the Pathogenesis of Cardiotoxicity: Molecular Insight and Future Perspective.

Cancer patients may encounter the onset of cardiovascular disease due to tumor advancement or chemotherapy, commonly known as "cardiotoxicity." In this respect, the conventional chemotherapy treatment protocol involves a mixture of different medications. These medications can be detrimental to cardiac tissue, consequently exposing the patient to the possibility of irreversible cardiac injury. The enhancement of oxidative stress and inflammation is an important mechanism of chemotherapeutic agents for developing cardiotoxicity. Regarding their dual pro- and anti-inflammatory functions, platelets can significantly influence the progression or suppression of cardiotoxicity. Therefore, the expression of platelet activatory markers can serve as valuable prognostic indicators for cardiotoxicity. The primary objective of this study is to examine the significance of platelets in cardiotoxicity and explore potential strategies that could effectively target malignant cells while minimizing their cytotoxic impact, such as cardiotoxicity and thrombosis.

Role for NLRP3 inflammasome-mediated, Caspase1-dependent response in glaucomatous trabecular meshwork cell death and regulation of aqueous humor outflow

PurposeAcute ocular hypertension (AOH) is the defining feature of acute glaucoma. The mechanical stress and excessive production of reactive oxygen species (ROS) during episodes can directly or indirectly damage the trabecular meshwork (TM). Despite its significance, a clear understanding of its pathogenesis and an effective therapeutic target remain lacking in acute glaucoma. In the present study, we explored the potential molecular mechanisms underlying TM cell death following oxidative damage and AOH. The use of NAC/VX-765 as a potential pharmaceutical intervention for reducing intraocular pressure (IOP) was discussed. MethodsThe levels of NLRP3 and caspase-1 were compared between normal and glaucomatous TM samples. An in vitro oxidative damage model and an AOH rat model were used to investigate the potential molecular mechanism behind TM cell death. The ROS scavenger N-acetyl-L-cysteine (NAC) and caspase-1 inhibitor VX-765 were used to counteract TM damage. ResultsElevated levels of NLRP3 and caspase-1 were observed in patients with acute glaucoma. H2O2 exposure decreased the viability of human trabecular meshwork (HTM) cells and increased intracellular ROS levels. Both Gene and protein expressions of NLRP3, caspase-1, GSDMD-N, and IL-1β were notably upregulated in H2O2-induced HTM cells and the rodent AOH model. Both NAC and VX-765 demonstrated protective effects against TM injury by inhibiting pyroptosis. The IOP-lowering effects of NAC and VX-765 persisted for 7 days. ConclusionsOur findings indicate that the classical pyroptosis pathway, NLRP3/caspase-1/IL-1β, plays a key role in acute glaucomatous TM injury. Targeting pyroptosis provides novel therapeutic avenues for treating AOH-induced irreversible TM injury. This provides not only a promising therapeutic target for glaucoma but also introduces a new approach to intervention.

Severe pancytopenia at the presentation of Imerslund-Gräsbeck syndrome in a 23-month-old Italian boy

BackgroundImerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder characterized by megaloblastic anemia due to selective cobalamin malabsorption and benign proteinuria. IGS is caused by a disfunction of the cubam receptor, which mediates the reabsorption of cobalamin in the ileum and the reuptake of albumin in renal proximal tubules.Case presentationWe describe the case of a 23-month-old-italian infant presenting with severe pancytopenia and failure to thrive in whom the diagnosis of IGS was made and vitamin B12 replacement therapy was resolutive. Genetic analysis (NGS with CNV analysis including 214 genes involved in bone marrow failure and anemia), showed the presence of two pathogenetic variants in the AMN gene (c-208–2 A > G and c.1006 + 34_1007-31del). These variants have been previously described in the literature, but their combination has never been reported.ConclusionsImerslund-Gräsbeck syndrome should be considered in the differential diagnosis of children with severe pancytopenia even in those without neurological involvement. This case emphasizes the importance of an early diagnosis and prompt treatment, to prevent irreversible neurological injury.

Time varying characteristic in somatosensory evoked potentials as a biomarker of spinal cord ischemic-reperfusion injury in rat.

Spinal cord ischemic-reperfusion injury (SCIRI) could occurs during surgical procedures without detection, presenting a complex course and an unfavorable prognosis. This may lead to postoperative sensory or motor dysfunction in areas innervated by the spinal cord, and in some cases, permanent paralysis. Timely detection of SCIRI and immediate waring can help surgeons implement remedial intervention to prevent irreversible spinal cord injury. Therefore, it is crucial to develop a precise and effective method for early detection of SCIRI. This study utilized rat models to simulate intraoperative SCIRI and employed somatosensory evoked potentials (SEP) for continuous monitoring during surgery. In this study, SEP signal changes were examined in six groups with varying severities of SCIRI and one normal control group. SEP signal changes were examined during operations in different groups and correlated with postoperative behavioral and histopathological data. The result demonstrated specific changes in SEP signals during SCIRI, termed as time-varying characteristics, which are associated with the duration of ischemia and subsequent reperfusion. Time-varying characteristics in SEP could potentially serve as a new biomarker for the intraoperative detection of SCIRI. This finding is significant for clinical surgeons to identify and guide early intervention of SCIRI timely. Additionally, this measurement is easily translatable to clinical application.

Sub-zero non-freezing of vascularized composite allografts in a rodent partial hindlimb model

Ischemia is a major limiting factor in Vascularized Composite Allotransplantation (VCA) as irreversible muscular injury can occur after as early as 4–6 h of static cold storage (SCS). Organ preservation technologies have led to the development of storage protocols extending rat liver ex vivo preservation up to 4 days. Development of such a protocol for VCAs has the added challenge of inherent ice nucleating factors of the graft, therefore, this study focused on developing a robust protocol for VCA supercooling. Rodent partial hindlimbs underwent subnormothermic machine perfusion (SNMP) with several loading solutions, followed by a storage solution with cryoprotective agents (CPA) developed for VCAs. Storage occurred in suspended animation for 24h and VCAs were recovered using SNMP with modified Steen. This study shows a robust VCA supercooling preservation protocol in a rodent model. Further optimization is expected to allow for its application in a transplantation model, which would be a breakthrough in the field of VCA preservation.

Targeting CNS myeloid infiltrates provides neuroprotection in a progressive multiple sclerosis model

Demyelination and axonal injury in chronic-progressive Multiple Sclerosis (MS) are presumed to be driven by a neurotoxic bystander effect of meningeal-based myeloid infiltrates. There is an unmet clinical need to attenuate disease progression in such forms of CNS-compartmentalized MS. The failure of systemic immune suppressive treatments has highlighted the need for neuroprotective and repair-inducing strategies. Here, we examined whether direct targeting of CNS myeloid cells and modulating their toxicity may prevent irreversible tissue injury in chronic immune-mediated demyelinating disease. To that end, we utilized the experimental autoimmune encephalomyelitis (EAE) model in Biozzi mice, a clinically relevant MS model. We continuously delivered intracerebroventricularly (ICV) a retinoic acid receptor alpha agonist (RARα), as a potent regulator of myeloid cells, in the chronic phase of EAE. We assessed disease severity and performed pathological evaluations, functional analyses of immune cells, and single-cell RNA sequencing on isolated spinal CD11b+ cells. Although initiating treatment in the chronic phase of the disease, the RARα agonist successfully improved clinical outcomes and prevented axonal loss. ICV RARα agonist treatment inhibited pro-inflammatory pathways and shifted CNS myeloid cells toward neuroprotective phenotypes without affecting peripheral infiltrating myeloid cell phenotypes, or peripheral immunity. The treatment regulated cell-death pathways across multiple myeloid cell populations and suppressed apoptosis, resulting in paradoxically marked increased neuroinflammatory infiltrates, consisting mainly of microglia and CNS / border-associated macrophages. This work establishes the notion of bystander neurotoxicity by CNS immune infiltrates in chronic demyelinating disease. Furthermore, it shows that targeting compartmentalized neuroinflammation by selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury, and may serve as a novel disease-modifying approach.

Necroptosis in alveolar epithelial cells drives lung inflammation and injury caused by SARS-CoV-2 infection

COVID-19, caused by SARS-CoV-2 infection, results in irreversible or fatal lung injury. We assumed that necroptosis of virus-infected alveolar epithelial cells (AEC) could promote local inflammation and further lung injury in COVID-19. Since CD8+ lymphocytes induced AEC cell death via cytotoxic molecules such as FAS ligands, we examined the involvement of FAS-mediated cell death in COVID-19 patients and murine COVID-19 model. We identified the occurrence of necroptosis and subsequent release of HMGB1 in the admitted patients with COVID-19. In the mouse model of COVID-19, lung inflammation and injury were attenuated in Fas-deficient mice compared to Fas-intact mice. The infection enhanced Type I interferon-inducible genes in both groups, while inflammasome-associated genes were specifically upregulated in Fas-intact mice. The treatment with necroptosis inhibitor, Nec1s, improved survival rate, lung injury, and systemic inflammation. SARS-CoV-2 induced necroptosis causes cytokine induction and lung damage, and its inhibition could be a novel therapeutic strategy for COVID-19.

Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage: Location, Distribution Patterns, Infarct Load, and Effect on Outcome.

Delayed cerebral ischemia (DCI) is one of the main contributing factors to poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). Unsuccessful treatment can cause irreversible brain injury in the form of DCI-related infarction. We aimed to assess the association between the location, distribution, and size of DCI-related infarction in relation to clinical outcome. Consecutive patients with SAH treated at 2 university hospitals between 2014 and 2019 (Helsinki, Finland) and between 2006 and 2020 (Aachen, Germany) were included. Size of DCI-related infarction was quantitatively measured as absolute volume (in milliliters). In a semiquantitative fashion, infarction in 14 regions of interest (ROIs) according to a modified Alberta Stroke Program Early CT Score (ASPECTS) was noted. The association of infarction in these ROIs along predefined regions of eloquent brain, with clinical outcome, was assessed. For this purpose, 1-year outcome was measured by the Glasgow Outcome Scale (GOS) and dichotomized into favorable (GOS 4-5) and unfavorable (GOS 1-3). Of 1,190 consecutive patients with SAH, 155 (13%) developed DCI-related infarction. One-year outcome data were available for 148 (96%) patients. A median overall infarct volume of 103 mL (interquartile range 31-237) was measured. DCI-related infarction was significantly associated with 1-year unfavorable outcome (odds ratio [OR] 4.89, 95% CI 3.36-7.34, p < 0.001). In patients with 1-year unfavorable outcome, vascular territories more frequently affected were left middle cerebral artery (affected in 49% of patients with unfavorable outcome vs in 30% of patients with favorable outcome; p = 0.029), as well as left (44% vs 18%; p = 0.003) and right (52% vs 14%; p < 0.001) anterior cerebral artery supply areas. According to the ASPECTS model, the right M3 (OR 8.52, 95% CI 1.41-51.34, p = 0.013) and right A2 (OR 7.84, 95% CI 1.97-31.15, p = 0.003) regions were independently associated with unfavorable outcome. DCI-related infarction was associated with a 5-fold increase in the odds of unfavorable outcome, after 1 year. Ischemic lesions in specific anatomical regions are more likely to contribute to unfavorable outcome. Data collection in Aachen was registered in the German Clinical Trial Register (DRKS00030505); on January 3, 2023.

Development of A 3D Lung Tumor Model For Cell Death Assessment in Microwave Ablation

AbstractPrimary lung cancer is the leading cause of cancer‐related death worldwide. Recent statistics estimate 1.8 million new cases and 1.6 million deaths per year. Despite significant advances in surgery, chemotherapy, and radiotherapy, the 5‐year survival rate remains at just 18%. Thermal ablation is an established treatment that is safe and effective. It refers to the local application of controlled heat to induce irreversible cell injury and ultimately tumor apoptosis and necrosis. This approach is particularly suitable for the treatment of small tumors in patients who are not suitable for surgery. However, the lack of suitable benchtop models to assess ablation devices complicates prognostic prediction and the development of effective treatment strategies. In this context, the development of a 3D lung tumor model is presented using a cancer cell‐laden hydrogel composed of 2% hyaluronic acid–tyramine (HA‐TA) and 0.5% agarose, resulting in a tumor mimetic of clinically relevant size. This innovative model provides a valuable platform for testing ablation devices and provides insights that can significantly improve prognostic ability and refine treatment approaches for lung cancer patients.

The current epidemiology of vascular injuries associated with knee dislocation in the United States from 2010 to 2022

IntroductionDespite the recognized importance of managing vascular injury associated with knee dislocation, studies have been limited by small patient sizes, data older than five years, and lack of inclusion of newer procedural and diagnoses codes. This has been reflected in the reported frequency of knee dislocation associated with vascular injury ranging from 1.6 % to 64 %. As such, we sought to determine: (1) the frequency of knee dislocations associated with vascular injuries; (2) the frequency of knee dislocations associated with vascular injuries that required repair; as well as (3) independent risk factors for knee dislocation with vascular injury that require repair, across different age groups, sexes, and United States geographic regions. MethodsA national, all-payer database was queried from January 1, 2010 to June 31, 2022. The frequency of a vascular injury was calculated by dividing the number of vascular injuries within 30 days of all knee dislocations by the total number of knee dislocations in each category. The frequency of a vascular injury that required repair was calculated by dividing the number of vascular injuries that required repair associated with knee dislocation by the total number of vascular injuries associated with knee dislocations. Patients were categorized by year of diagnosis, age, sex, and US geographic region. Multivariable logistic regressions were calculated to determine independent risk factors for knee dislocation with vascular injury. ResultsFrom 2010 to 2022, there were 99,688 knee dislocations. Of the total knee dislocations, there were 1066 (1.1 %) vascular injuries associated with knee dislocations, 96,530 (96.8 %) were closed dislocations, and 3158 (2.2 %) were open dislocations. Of the 1066 vascular injuries associated with knee dislocations, 262 (24.6 %) vascular injuries required repair. Male sex (P < 0.001), Elixhauser Comorbidity Index (ECI) > 3 (P < 0.001), alcohol abuse (P = 0.006), congestive heart failure (P = 0.01), hypothyroidism (P = 0.003), and obesity (P < 0.001), were independent risk factors for knee dislocation with vascular injuries. ConclusionOur study provides a refined understanding of the historically low incidence of knee dislocation with vascular injury as well as an increase in vascular injuries requiring repair from 2010 to 2022. Given the large expense of irreversible injury in these patients, vulnerable patient populations identified in our study, such as obese patients with additional comorbidities, should be a focus of future intervention. These findings can guide physicians in a clinical setting to appropriately manage the expectations of patients as well as minimize the morbidity and mortality associated with this presentation.

Biomarkers in Kidney Transplantation: A Rapidly Evolving Landscape.

The last decade has seen an explosion in clinical research focusing on the use of noninvasive biomarkers in kidney transplantation. Much of the published literature focuses on donor-derived cell-free DNA (dd-cfDNA). Although initially studied as a noninvasive means of identifying acute rejection, it is now clear that dd-cfDNA is more appropriately described as a marker of severe injury and irrespective of the etiology, elevated dd-cfDNA ≥0.5% portends worse graft outcomes. Blood gene expression profiling is also commercially available and has mostly been studied in the context of early identification of subclinical rejection, although additional data is needed to validate these findings. Torque teno virus, a ubiquitous DNA virus, has emerged as a biomarker of immunosuppression exposure as peripheral blood Torque teno virus copy numbers might mirror the intensity of host immunosuppression. Urinary chemokine tests including C-X-C motif chemokine ligand 9 and C-X-C motif chemokine ligand 10 have recently been assessed in large clinical trials and hold promising potential for early diagnosis of both subclinical and acute rejection, as well as, for long-term prognosis. Urinary cellular messenger RNA and exosome vesicular RNA based studies require additional validation. Although current data does not lend itself to conclusion, future studies on multimodality testing may reveal the utility of serial surveillance for individualization of immunosuppression and identify windows of opportunity to intervene early and before the irreversible allograft injury sets in.

Mechanisms of oxidative stress in myocardial ischemia-reperfusion injury and protective effects of traditional Chinese medicines

Myocardial ischemia is a disease characterized by high morbidity and mortality rates, restoring blood supply to the ischemic area through reperfusion is an effective intervention method. However, numerous studies have shown that reperfusion may cause severe myocardial damage, resulting in myocardial systolic and diastolic dysfunction and seriously affecting myocardial function. This phenomenon is called myocardial ischemia reperfusion injury(MIRI). The physiological and pathological mechanisms of MIRI include oxidative stress, calcium overload, autophagy, pyrolysis, endoplasmic reticulum stress, apoptosis, etc. Oxidative stress plays an important role in MIRI-related cell death and is considered to be the main mechanism of MIRI. The occurrence of oxidative stress is mainly due to the excessive production of reactive oxygen species(ROS), which disrupts the balance of the redox system of the body or tissue. A large number of highly reactive ROS exceed the antioxidant defense capacity of cardiomyocytes, causing modifications in biological macromolecules such as DNA and proteins and resulting in severe reactions like DNA damage, protein dysfunction, cell damage or death, and local inflammation. Oxidative stress mediates apoptosis, autophagy, and inflammatory injury through various pathways, resulting in irreversible cardiomyocyte injury and myocardial dysfunction, which brings significant challenges for clinical treatment and prognosis. In recent years, remarkable progress has been made in understanding oxidative stress in ischemia reperfusion(I/R) injury of different organs and tissue. However, the injury mechanism caused by oxidative stress in restoring blood supply to the ischemic area and the protective effect of TCM remain largely unexplored. This article reviewed the role of oxidative stress in MIRI, the main production pathways of ROS, and the protective effects of TCM on oxidative stress injury during ischemic myocardial reperfusion, so as to provide a reference for future research and clinical treatment in this field.

Meta-analysis of Clinical High-risk Factors for the Development of Neonatal Hypoglycemia

GDM is a common clinical complication of pregnancy, the incidence rate has been increasing in recent years and the risk of neonatal development of neonatal hypoglycemia (NH) has significantly increased. Studies have shown that the incidence of NH in GDM-delivered newborns is up to 27%. Severe hypoglycemia can cause irreversible brain injury and neurological sequelae in newborns, NH is one of the most common metabolic diseases in neonatal intensive care units. However, many scholars have discussed the related risk factors of neonatal hypoglycemia, but the risk factors and research results are different among the studies and there are some controversies. Therefore, this study aims to conduct a Meta-analysis through the domestic and foreign published studies on the risk factors for neonatal hypoglycemia, to identify the main risk factors for neonatal hypoglycemia, and to provide a basis for early clinical prevention and timely development of scientific and effective interventions. Through health and interest Engineering, the computer conducted a literature search in the medical databases of Wanfang Medical, PubMed database, domestic medical research journals, and biomedical medical literature, and conducted a Meta-analysis using Rev Man 5.2 software based on the clinical risk factors of neonatal hypoglycemia. The retrieved literature was screened according to the criteria of study subjects, methods, disease type, and so on, and a total of 9 documents meeting the criteria were finally included, with low bias. The results of the Meta-analysis showed statistical differences in the incidence of pregnant and maternal gestational diabetes, neonatal asphyxia and low birth weight infants in the hypoglycaemic and non-hypoglycaemic neonatal groups, Moreover, the incidence of pregnant and maternal gestational diabetes, neonatal asphyxia, and low birth weight infants was significantly lower in the hypoglycemic neonatal group(P&lt;0.05); Studies evaluated maternal gestational diabetes, neonatal asphyxia and low birth weight infants with neonatal hypoglycemia, The results showed that maternal gestational diabetes, neonatal asphyxia, and low birth weight infants all increase the risk of neonatal hypoglycemia(P&lt;0.001). Therefore, for children with neonatal hypoglycemia, pregnant mothers and gestational diabetes, neonatal asphyxia, and low-weight children are all high-risk factors for hypoglycemia, clinicians should do a good job in prevention and control, and intervention to reduce the incidence of neonatal hypoglycemia.

Tensor-valued diffusion MRI detects brain microstructure changes in HIV infected individuals with cognitive impairment.

Despite advancements, the prevalence of HIV-associated neurocognitive impairment remains at approximately 40%, attributed to factors like pre-cART (combination antiretroviral therapy) irreversible brain injury. People with HIV (PWH) treated with cART do not show significant neurocognitive changes over relatively short follow-up periods. However, quantitative neuroimaging may be able to detect ongoing subtle microstructural changes. This study aimed to investigate the sensitivity of tensor-valued diffusion encoding in detecting such changes in brain microstructural integrity in cART-treated PWH. Additionally, it explored relationships between these metrics, neurocognitive scores, and plasma levels of neurofilament light (NFL) chain and glial fibrillary acidic protein (GFAP). Using MRI at 3T, 24 PWH and 31 healthy controls underwent cross-sectional examination. The results revealed significant variations in b-tensor encoding metrics across white matter regions, with associations observed between these metrics, cognitive performance, and blood markers of neuronal and glial injury (NFL and GFAP). Moreover, a significant interaction between HIV status and imaging metrics was observed, particularly impacting total cognitive scores in both gray and white matter. These findings suggest that b-tensor encoding metrics offer heightened sensitivity in detecting subtle changes associated with axonal injury in HIV infection, underscoring their potential clinical relevance in understanding neurocognitive impairment in PWH.