Despite existing strong evidence on oxidative markers overproduction following ischemia/reperfusion (I/R), the mechanism by which oxidative enzyme Cytochrome P450-2E1 (CYP2E1) contributes to I/R outcomes is not clear. In this study, we sought to evaluate the functional significance of CYP2E1 in I/R. CYP2E1 KO mice and controls were subjected to middle cerebral artery occlusion (MCAo-90min) followed by 24hr of reperfusion to induce focal I/R injury models. Then, histological and chemical analyses were conducted to investigate the role of CYP2E1 in lesion volume, oxidative stress, and inflammation exacerbation. Also, the role of CYP2E1 on the BBB integrity was investigated by measuring 20-Hydroxyecosatetraenoic acid (20-HETE) activity, as well as, in vivo BBB transfer rate. Following I/R, the CYP2E1 KO mice exhibited a significantly lower lesion volume, and neurological deficits compared to controls (p<0.005). Also, ROS production, apoptosis, and the neurodegeneration were significantly lower in the CYP2E1(-/-) I/R group (p<0.001). The BBB damage was significantly lower in CYP2E1(-/-) mice compared to WT (p<0.001), while 20-HETE production was increased by 41%. Besides, inflammatory cytokines expression and the number of activated microglia were significantly lower in CYP2E1(-/-) mice following I/R. CYP2E1 suppression ameliorates I/R injury and protects BBB integrity by reducing both oxidative stress and inflammation.

BACKGROUND: Lower limb skeletal muscle ischemia-reperfusion (IR) injury associated with increased morbidity and mortality is common in several clinical situations such as aortic aneurysms repairment, peripheral arterial surgery, vascular injury repairment, and shock. Although it is generally accepted that oxidative stress mediators have a significant role in IR injury, its precise mechanism is still unknown. Anecdotally, it is sustained not only by structural and functional changes in the organ it affects but also by damage to distant organs. The purpose of this report is to illustrate the effect of proanthocyanidin on IR injury. METHODS: In our study, 18 male Wistar albino rats were used. The subjects were divided into three groups of six each. (Group Control-C, Group Ischemia-Reperfusion -IR, Group Ischemia-Reperfusion and Proanthocyanidin-IR-PRO). Intraperitoneal proanthocyanidin was given to the IR and proanthocyanidin groups 30 minutes before laparotomy and 1-hour ischemia led to these two groups. After one hour, reperfusion started. Muscle atrophy-hypertrophy, muscle degeneration-congestion, fragmentation-hyalinization, muscle oval-central nucleus ratio, leukocyte cell infiltration, catalase enzyme activity, and TBARS were all examined in lower-limb muscle samples after one hour of reperfusion. RESULTS: When skeletal muscle samples were evaluated histopathologically, it was discovered that muscle atrophy-hypertrophy, muscle degeneration-congestion, fragmentation-hyalinization, and leukocyte cell infiltration with oval-central nucleus standardization were significantly higher in the IR group than group control and group IR-proanthocyanidin. Besides, oval-central nucleus standardization was significantly higher in the IR and proanthocyanidin group than in the control group. TBARS levels were significantly higher in the IR group than in the control and IR-proanthocyanidin groups while, catalase enzyme activity was found to be significantly lower in the IR group than in the control and IR and proanthocyanidin groups. CONCLUSION: As a consequence of our research, we discovered that proanthocyanidins administered before IR have a protective impact on skeletal muscle in rats. Further research in this area is required.

Myocardial ischemia/reperfusion injury (I/R) and the resulting heart failure is one of the main causes of mortality and morbidity worldwide. Camphene has been shown to have anti-inflammatory and hypolipidemic properties, however, its role in the protection of the heart from ischemia and reperfusion has not been investigated. The cardioprotective role of camphene and the mechanism that mediates its action against I/R injury was evaluated in the present study. A single dose of camphene was administered in adult rats prior to ex vivo I/R induction. Infarct size was measured using 2,3,5-triphenyltetrazolium chloride (TTC) staining and cardiomyocyte injury was assessed by determining the release of lactate dehydrogenase (LDH) enzyme. Camphene pretreatment provided significant protection reducing myocardial infarct size and cell death after I/R. The effect was correlated with the activation of antioxidant defense mechanisms, namely CAT, MnSOD, GPx and GR, and reduction of oxidative stress as evidenced by determination of protein carbonylation and GSH/GSSG ratio in cardiomyocytes. The results suggest that camphene can protect the heart against I/R injury by maintaining redox homeostasis and can hold therapeutic potential for mitigating the detrimental effects of I/R in the heart.

Background and Aim: It is generally accepted that oxidative stress mediators play an important role in ischemia-reperfusion injury(I/R), although the exact mechanism is not fully elucidated. While the impact of silymarin on I/R injury in several tissues, including the myocardial, cerebral, gastric and liver tissue, has been examined, the present state of research on this topic remains insufficient to provide a widely accepted understanding. For this purpose, our objective was to examine the effect of silymarin on muscle tissue in rats subjected to lower extremity I/R injury. Method: After ethics committee approval, 18 male Wistar albino rats weighing between 225-275 g were used. The rats were divided into three groups containing six mice each, Control,Ischemia-Reperfusion and Silymarin-Ischemia/Reperfusion groups. Silymarin was administered intraperitoneally 30 minutes before the procedure.( 100 mg/kg-1 ) In the I/R groups, an atraumatic microvascular clamp was placed in the infrarenal abdominal aorta. After 120 minutes, the clamp was removed and reperfusion was achieved for 120 minutes. In muscle tissue samples taken at the end of the reperfusion period; Malondialdehyde (MDA) levels, catalase (CAT) enzyme activity levels and histopathological parameters were compared. Results: In the histopathological examination, no degeneration was observed in the muscle fibers in the control group, while findings of striated muscle damage such as muscle atrophy hypertrophy, muscle degeneration-congestion, internal of the muscle nucleus-oval-central nucleus, fragmentation-hyalinization and leukocyte cell infiltration were observed in the I/R group. In the S-I/R group, muscle atrophy hypertrophy, internal of the muscle nucleus-oval-central nucleus, fragmentation-hyalinization and leukocyte cell infiltration were observed to improve these damaged areas compared to the I/R group. MDA levels in the I/R group were found to be significantly higher than in the control and S-I/R groups. CAT enzyme activity was found to be significantly higher in the I/R group than in the control group. Conclusion:Our study revealed that the administration of silymarin at a dosage of 100 mg/kg-1 by intraperitoneal injection 30 minutes before ischemia in rats effectively decreased lipid peroxidation and oxidative stress. Additionally, it successfully reduced the injury caused by ischemia/reperfusion in muscle histology.

The shortage of donor organs is a major global concern. Organ failure requires the transplantation of functional organs. Organ donors are preserved in warm or cold ischemia. Ischemia and reperfusion damage the organs, due to the lack of oxygen during the ischemia step and the oxidative stress during the reperfusion step. Different methodologies were developed to prevent or diminish the level of injuries. Preservation solutions were first developed, followed by the addition of chemical compounds. In addition of inhibitors of mitogen activated protein kinase, inhibitors of the proteasome, mesenchymal stem cells started to be used 13 years ago to prevent or diminish the organ’s injuries. Mesenchymal stem cells (e.g bone marrow stem cells, adipose derived stem cells) have proven to be powerful tools in repairing damaged organs. This review will focus on the use of some bone marrow stem cells, adipose derived stem cells and umbilical cord stem cells on preventing or decreasing the injuries due to ischemia-reperfusion.

Ischemic neuron loss contributes to brain dysfunction in patients with cardiac arrest (CA). Histidine–tryptophan–ketoglutarate (HTK) solution is a preservative used during organ transplantation. Can HTK also protect neurons from severe hypoxia (SH) following CA? We isolated rat primary cortical neurons and induced SH with or without HTK. Changes in caspase-3, hypoxia-inducible factor 1-alpha (HIF-1α), and NADPH oxidase-4 (NOX4) expression were evaluated at different time points till 72 h. Using a rat asphyxia model, we induced CA-mediated brain damage and then completed resuscitation. HTK or sterile saline was administered into the left carotid artery. Neurological deficit scoring and mortality were evaluated for 3 days. Then the rats were sacrificed for evaluating NOX4 and H2O2 level in blood and brain. In the in vitro study, HTK attenuated SH- and H2O2-mediated cytotoxicity in a volume- and time-dependent manner, associated with persisted HIF-1α expression, reductions in procaspase-3 activation and NOX4 expression. The inhibition of HIF-1α abrogated HTK’s effect on NOX4. In the in vivo study, neurological scores were significantly improved by HTK. H2O2 level, NOX4 activity and NOX4 gene expression were all decreased in the brain specimen of HTK-treated rats. Our results suggest that HTK acts as an effective neuroprotective solution.

Nutraceuticals are bioactive compounds present in foods, utilized to ameliorate health, prevent diseases, and support the proper functioning of the human body. They have gained attention due to their ability to hit multi-targets and act as antioxidants, anti-inflammatory agents, and modulators of immune response and cell death. Therefore, nutraceuticals are being studied to prevent and treat liver ischemia–reperfusion injury (IRI). This study evaluated the effect of a nutraceutical solution formed by resveratrol, quercetin, omega-3 fatty acid, selenium, ginger, avocado, leucine, and niacin on liver IRI. IRI was performed with 60 min of ischemia and 4 hours of reperfusion in male Wistar rats. Afterward, the animals were euthanized to study hepatocellular injury, cyto-kines, oxidative stress, gene expression of apoptosis-related genes, TNF-alpha and Caspase 3 proteins, and histology. Our results show that the nutraceutical solution was able to decrease apoptosis and histologic injury. The suggested mechanisms of action are a reduction in gene expression and the Caspase 3 protein and a reduction in the TNF-alpha protein in liver tissue. The nutraceutical solution was unable to decrease transaminases and cytokines. These findings suggest that the nutraceuticals used favored the protection of hepatocytes and their combination represent a promising therapeutic proposal against liver IRI.

Objective: Lower extremity ischemia-reperfusion injury (IRI) may occur with trauma-related vascular injury and various vascular diseases, during the use of a tourniquet, temporary clamping of the aorta in aortic surgery, and acute or bilateral acute femoral artery occlusion. Mitochondrial dysfunction and increased basal oxidative stress in diabetes may cause an increase in the effects of increased reactive oxygen species (ROS) and mitochondrial dysfunction due to IRI. It is of great importance to examine therapeutic approaches that can minimize the effects of IRI, especially for patient groups under chronic oxidative stress. Cerium oxide (CeO2) nanoparticles mimic the antioxidant enzymes and act as a catalyst that scavenges ROS. In this study, it was aimed to investigate whether CeO2 has protective effects on skeletal muscles in lower extremity IRI in mice with streptozocin-induced diabetes. Methods: A total of 38 Swiss albino mice were divided into six groups as follows: control group (group C, n=6), diabetes group (group D, n=8), diabetes-CeO2 (group DCO, n=8), diabetes-ischemia/reperfusion (group DIR, n=8), and diabetes-ischemia/reperfusion-CeO2 (group DIRCO, n=8). DCO and DIRCO groups were given doses of CeO2 0.5mg/kg intraperitoneally 30 minutes before the IR procedure. A 120-minute ischemia-120-minute reperfusion period with 100% O2 was performed. At the end of the reperfusion period, muscle tissues were removed for histopathological and biochemical examinations. Results: Total antioxidant status (TAS) levels were found to be significantly lower in group DIR compared with group D (p=0.047 and p=0.022, respectively). In group DIRCO and total oxidant status (TOS) levels were found to be significantly higher than in group DIR (p

Metformin（Met） is a commonly used drug in the treatment of type 2 diabetes. Currently, it has been found that Met can effectively reduce the incidence of stroke and exert anti-inflammatory effects. However, its role in ischemia-reperfusion (I/R) induced nerve injury remains unclear. This study aims to investigate the neuroprotective effects of Met in I/R-induced neuron injury as well as the underlying mechanism.A middle cerebral artery occlusion (MCAO) model was established in SD rats, which were then treated with different doses of Met.Neurological deficits of rats were measured at different times post-surgery. TTC staining to observe the volume of cerebral infarction.HE staining was performed to observe pathological changes of brain tissues .Immunohistochemistry was performed to observe the expression of inflammatory factors in the cerebral tissues .qRT-PCR method was used to detect the relative expression of PI3K、Akt mRNA in cells after 24 h of drug action.Western blot method was used to detect the expression of PI3K、p-PI3K、Akt and p-Akt in hippocampus.What’s more, in vitro experiments were performed on BV2 microglia to verify the role of Met against oxygen-glucose deprivation (OGD). As a result, Met dose-dependently attenuated neurological deficits and neuronal apoptosis. Besides, Met administration also significantly reduced BV2 cells apoptosis and inflammatory response. Mechanistically, Met inactivated PI3K/Akt pathway induced by I/R and OGD, while upregulated PI3K. In conclusion, Met protected rats from cerebral I/R injury via reducing neuronal apoptosis and microglial inflammation through PI3K/Akt pathway.

Regulated autophagy is involved in the repair of renal ischemia-reperfusion injury (IRI). ω3-Polyunsaturated fatty acids (ω3-PUFAs) show protective effects against various renal injuries. It was recently reported that ω3-PUFAs regulate autophagy. We assessed whether ω3-PUFAs attenuated IR-induced acute kidney injury (AKI) and evaluated associated mechanisms. C57Bl/6 background fat-1 mice and wild-type mice (wt) were divided into four groups: wt sham (n = 10), fat-1 sham (n = 10), wt IRI (reperfusion 35 min after clamping both the renal artery and vein; n = 15), and fat-1 IRI (n = 15). Kidneys and blood were harvested 24 h after IRI. Renal histological and molecular data were collected. The kidneys of fat-1 mice showed better renal cell survival, renal function, and pathological damage than those of wt mice after IRI. In addition, fat-1 mice showed less oxidative stress and autophagy impairment; greater amounts of LC3, Beclin-1, and Atg7; lower amounts of p62; and higher levels of renal cathepsin D and ATP6E than wt kidneys. They also showed more AMPK activation, which resulted in the inhibition of phosphorylation of the mammalian target of rapamycin (mTOR). Collectively, ω3-PUFAs in fat-1 mice contributed to AMPK mediated autophagy activation, leading to a renoprotective response.

Ischemia-reperfusion injury (IRI) is a complex pathophysiological process that can lead to severe and irreversible consequences, including the complete loss of renal function. While standardized strategies for preventing IRI during "back-table" and cold preservation are available, various intraoperative prevention methods have been proposed to mitigate the harmful effects of warm ischemia and reperfusion of the kidney. These methods include pharmacological agents, mechanical interventions, and surgical techniques such as renal capsulotomy, ischemic preconditioning, venous blood reperfusion, renal perfusion, and the use of tissue engineering techniques like mesenchymal stromal/stem cells and/or decellularization. In this comprehensive analysis, we provide a detailed overview of pharmacological agents and intraoperative methods and approaches for the prevention and treatment of renal IRI. We begin by discussing the mechanisms of IRI and the challenges of preventing it during surgery. Then using a bibliometric analysis and molecular docking of brand-new legends we showed eplerenone have the most binding affinity to Aldehyde dehydrogenase (AD), Estrogen receptor (ER), Klotho protein, Mineralocorticoid receptor (MR), and Toll-like receptor 4 (TLR4) for preventing IRI comparing with other available therapeutics, Benzodioxole, Hydrocortisone, Indoles, Nicotinamide adenine dinucleotide, and Niacinamide. Next, we provide a comprehensive analysis of the potential benefits and limitations of various prevention strategies, including an in-depth discussion of the mechanisms of action of pharmacological agents, mechanical interventions, and surgical techniques. Furthermore, we introduce a novel scoring system for the prevention methods of kidney IRI, which takes into account the effectiveness, feasibility, and safety of each method. We then analyze the current state of clinical research in this area and discuss the implications of these methods for future clinical practice. Overall, this article provides a valuable resource for clinicians and researchers seeking to prevent and treat renal IRI in surgical settings, and introduces a new scoring system that can be used to guide the selection of the most effective and safe prevention methods.

Objective: The purpose of this study was to investigate the effect of aerobic exercise on myocardial injury induced by I/ R in rats by regulating SIRT3/SOD2/NF-κB signaling pathway, and to provide theoretical guidance for clinical treatment of myocardial I/R injury.Methods:SPF Male Sprague-Dawley(SD) rats were randomly assigned to 4 groups: Sham operation group(n=10), I/R group(n=10), Aerobic exercise group(n=10)and Aerobic exercise+κ-receptor antagonist group(Pro DTC group，n=10). The left anterior descending coronary artery(LAD) of rats was ligated and re-canalized to establish I/R rat model. Hematoxylin-eosin(HE) staining was performed to examine histological morphology in myocardial tissues of each group. The biological analysis was performed to measure cTnI、CK-MB、BNP levels in blood samples of each group. The expression levels of SOD2, TLR4, and p65 in myocardial tissues were measured by immunohistochemical assay. The influence of aerobic exercise on Beclin-1 、LC3II/I、SIRT3, TLR4, and phosphorylated p65 was measured by Western blotting.Results: The result of histological morphology examination revealed that Aerobic exercise group exhibited integrated cardiac myofilament, less inflammatory cell infiltration, as much as significantly decreased cellular edema. Measurement of cTnI、CK-MB、BNP revealed that oxycodone post-treatment reduces the injury of myocardial tissues(P<0.05). Immunohistochemical staining results revealed that aerobic exercise clearly decreased the expression of TLR4 and p65, and increased the expression of SOD2(P<0.05). Besides, Western blotting revealed that aerobic exercise down-regulated the expression of Beclin-1 、LC3II/I、TLR4 and phosphorylated p65, up-regulated the expression of SIRT3(P<0.05).Conclusions: Aerobic exercise significantly improved myocardial I/R injury. The mechanisms may be associated with activating κ-receptor to regulate SIRT3/SOD2/NF-κB pathway.

Although a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) serve as the cleaving protease of vWF-multimers, its role in liver ischemia-reperfusion injury (IRI), as well as partial liver transplantation (pLT), remains unknown. First, ADAMTS13 deficient mice were subjected to IRI to investigate the impact on hepatic IRI. Hepatic IRI significantly decreased serum ADAMTS13 activity, while simultaneously up-regulated intrahepatic vWF expression. Ablation of ADAMTS13 aggravated liver IRI by promoting platelet aggregation and disturbing microcirculation in the liv-er accompanied by exacerbated transaminase release and enhanced pro-inflammatory cytokine/chemokines levels. Adjunctive supplementation of recombinant ADAMTS13 (rADAMTS13) improved hepatic microcirculatory failure observed in ADAMTS13-null mice. Immunohistochemistry revealed massive platelet aggregation within hepatic micro-vasculatures in ADAMTS13-null mice, which was attenuated by rADAMTS13 treatment. Consequently, peripheral platelet counts, transaminase release, and pro-inflammatory cytokines/chemokines levels deteriorated in ADAMTS13-null mice, while ameliorated by rADAMTS13 administration. Notably, rADAMTS13 improved IRI-induced pathologies even in WT mice compared with those without. Next, we tested rADAMTS13 in the rat pLT model. Similarly, in rat pLT, ADAMTS13 supplementation attenuated the aforementioned pathologies observed in the experimental mouse model. In conclusion, ADAMTS13 plays a pivotal role in alleviating both hepatic microcirculation and inflammatory responses, thus providing a novel therapeutic approach against LT-related stress.

Inflammatory reaction after ischemia-reperfusion contributes significantly to prognosis, and microglia activation is the main resource of inflammation in nervous system. STAT5 is proving to be a highly effective anti-inflammatory therapy with great potential, and inhibition of STAT5 has demonstrated significant anti-inflammation and therapeutic effects, but rarely focus on mechanism of neuroinflammation and brain injury from ischemia-reperfusion. It is the first time to found that the anti-inflammation of dauricine is mainly through STAT5-NF-κB pathway, might act as a STAT5 inhibitor. Dauricine suppressed the inflammation cytokines Eotaxin, KC, TNF-α, IL-1α, IL-1β, IL-6, IL-12β, IL-17α, and also inhibited the microglia activation. STAT5b mutant at Tyr-699 reversed the protective effect of dauricine on oxygen-glucose deprivation-reperfusion injury of neurons, and reactivated the suppression of dauricine on P-NF-κB of microglia. These results suggest that dauricine might suppress the neuroinflammation and protect the neuron from the injury of post-ischemia-reperfusion via mediating the microglia activation through STAT5-NF-κB pathway, and ss a potential therapeutic target for neuroinflammation, STAT5 needs to be raised concern in ischemic stroke.

Hyperleptinemia potentiates the effects of many atherogenic factors, such as inflammation, platelet aggregation, migration, hypertrophy, proliferation of vascular smooth muscle cells, and endothelial cell dysfunction. The present study analysed the effects of long-term hyperleptinemia in an in vivo myocardial ischemia-reperfusion model to demonstrate whether the in vivo deleterious effect also affects cardiac structure and function. Rats by were subcutaneously administered leptin for 8 days to estimate the involvement of the JAK/STAT pathway. Data from 58 male Wistar rats were included in the final analysis. Myocardial infarction (MI) was modelled by the 30-minute ligation of the main left coronary artery followed by 120-minute reperfusion. Hemodynamic measurements, electrocardiography monitoring, echocardiography, myocardial infarct size and area at risk, blood biochemical parameters, leptin, IL-6, TNF-alpha, FGF-21, and cardiomyocyte morphology were measured. Statistical analyses were performed using IBM SPSS Statistics v.26. Seven-day hyperleptinemia in rats led to increased an blood pressure and heart rate, myocardial hypertrophy, impaired LV function, an increased frequency of ischemic arrhythmias, dyslipidaemia, systemic inflammation, and an increased size of induced myocardial infarction. The blockade of the JAK/STAT signalling pathway effectively reversed the negative effects of leptin, including increased blood pressure and total cholesterol.

Coptisine (Cop) exerts a neuroprotective effect in central nervous system disease, particularly ischemic stroke. However, its protective mechanism is still unclear. This study aimed to investigate the protective effect of Cop on cerebral ischemia-reperfusion (IR) rats with a middle cerebral artery occlusion model by integrating a gas chromatography-mass spectrometry (GC-MS) based metabolomics approach with biochemical assessment. Our results showed that Cop could improve neurobehavioral function and decrease the ischemia size in IR rats. In addition, Cop was found to decrease inflammatory mediators (e.g., prostaglandin D2 (PGD2) and tumor necrosis factor-α (TNF-α) and attenuate oxidative stress response (e.g., increase the superoxide dismutase (SOD) expression and decrease 8-iso-PGF2α level). Furthermore, GC-MS based cerebrospinal fluid (CSF) metabolomics analysis indicated that Cop influenced the level of glycine, 2,3,4-trihydroxybutyric acid, oleic acid, glycerol, and ribose during IR injury. Cop exhibited a good neuroprotective effect against cerebral IR injury and metabolic alterations which might be mediated through its antioxidant and anti-inflammatory property.

Ischemia stroke is one of a clinically common cerebrovascular disease. And Inhibition of brain tissue ischemia and reperfusion-induced damage, especially apoptosis, has an irreplaceable protective effect on ischemic nerves, and has special significance for the treatment of patients after treatment. However, the development of neuroprotective drugs still has certain challenges. Radix scrophulariae as a valuable medicine, has been discovered to has neuroprotective effects. Our researches initially proved that Radix scrophulariae aqueous extract (RSAE) exerting a neuroprotective effects on cerebral ischemia and reperfusion (I/R) injury in oxygen glucose deprivation and reperfusion (OGD/R)-induced PC12 cells and middle cerebral artery occlusion/reperfusion (MCAO/R) model mice, were associated with attenuation of infarct volume, brain water content, nitric oxide (NO) and malondialdehyde (MDA), inhibiting I/R-induced damage by reducing the levels of LDH release, improving anti-oxidant capacity by upregulating the SOD, GSH-Px and CAT activity, stabilizing mitochondrial membrane potential, reducing neuronal apoptosis, necrosis and neuronal loss by regulating the expression of anti-apoptotic BCL-2and pro-apoptotic protein Bax, and elucidating downregulate the phosphorylation levels of MAPK pathways. Our findings may elaborate the neuroprotective effects and potential mechanisms of RSAE on focal cerebral I/R injury in mice. Since, Radix scrophulariae, as a potential neuroprotective natural plant, has originally been identified to, our results may offer directions and clues for discovering new active compounds or drugs for treatment of ischemic stroke, which allows us to discover many new natural active chemicals by chemical separation and identification, and provide new insights into therapeutic targets in stroke patients.

Cerebral ischemic stroke is one of the leading causes of death and disability worldwide. 2’-fucosyllactose (2’-FL), a human milk oligosaccharide, has anti-inflammatory effects and plays a protective role in arterial thrombosis, but its role in ischemic stroke remains unclear. This study aimed to investigate the neuroprotective effects of 2’-FL and its potential mechanisms in a mouse model of ischemic stroke. The administration of 2’-FL led to a reduction in the size of cerebral infarct and reactive oxygen species (ROS)-related products in the brain of MCAO mice. Further, 2’-FL promotes the recovery of neurological deficits and motor function in neurological scores and behavior tests. Biochemical studies showed that 2’-FL reduced upregulated IL-10 and downregu-lated TNF-α. Additionally,2’-FL enhanced M2-type microglial polar2’-FL upregulated IL-10 and downregulated TNF-α ization at 7 days after MCAO, with an increase in IL-4 levels and STAT6 activation at 3 days after MCAO. Our data showed that 2’-FL reduced the neurological symptoms of ischemic stroke and ROS accumulation in the brain through IL-4/STAT6-dependent M2-type mi-croglial polarization in MCAO mice. These results demonstrate that 2’-FL is a potentially effective therapeutic agent for ischemic stroke.

NCX 470, a nitric oxide (NO)-donating bimatoprost, was shown to ameliorate ocular hemodynamics and retinal physiology in rabbits following endothelin-1 (ET-1)-induced ischemia/reperfusion. Here we used the same model to compare NCX 470 (0.1% bid) to Lumigan® (bimatoprost 0.01% ophthalmic solution, LUM) and bimatoprost administered at equimolar dose as NCX 470 (0.072%, BIM). Intraocular pressure (IOP), ophthalmic artery resistive index (OA-RI) and electroretinogram (ERG) were computed prior to treatment and at various time-points thereafter. Gluthatione (GSH), 8-Hydroxy-2-deoxyguanosine (8-OH2dG), Interleukin-1beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6) and Caspase-3 protein expression and activity were determined in retina at week 6. ET-1 increased IOP (VEHIOP_Baseline=20.5±0.8 and VEHIOP_Week6=24.8±0.3mmHg) and OA-RI (VEHOA-RI_Baseline=0.36±0.02 and VEHOA-RI_Week6=0.55±0.01) while it reduced rod/cone responses. Oxidative stress, inflammation and apoptotic markers were also increased in ET-1-treated eyes. NCX 470 prevented IOP (NCX 470IOP_Week6=18.1±0.6mmHg) and OA-RI (NCX 470OA-RI_Week6=0.33±0.01) changes and restored ERG amplitude; these effects were only partially shared by LUM or BIM. Additionally, NCX 470 reduced oxidative stress, inflammation and apoptosis in retina of treated eyes. BIM and LUM were numerically less effective on these parameters. Data suggest that NCX 470 repeated ocular dosing ameliorates ocular hemodynamics and retinal cell dysfunction consequent to ischemia/reperfusion via both, NO- and bimatoprost-mediated mechanisms.

Many large-scale studies revealed that exogenous erythropoietin, erythropoie-sis-stimulating agents, have no renoprotective effects. We investigated the effects of en-dogenous erythropoietin on renal function in ischemic reperfusion injury (IRI) of kidney using prolyl hydroxylase domaine (PHD) inhibitor, Roxadustat (ROX). 4 hr hypoxia (7% O2) and 4 hr treatment by ROX prior to IRI did not improve renal function. In contrast, 24-72 hr pre-treatment by ROX largely improved the decline of renal function by IRI. Hy-poxia and 4 hr ROX increased interstitial cells-derived Epo production by 75 and 6-fold, respectively, before IRI and worked as exogenous Epo. 24-72 hr ROX treatment increased Epo production during IRI by 9-fold. Immunohistochemistry revealed that 24 hr ROX caused Epo production in proximal and distal tubules and worked as endogenous Epo. Our data show that 24-72 hr ROX-induced tubular endogenous Epo production results in renoprotection but peritubular exogenous Epo production by interstitial cells-derived in-duced by hypoxia and 4 hr ROX did not. Stimulation of tubular but not peritubular Epo production may link to renoprotection.

Acute myocardial infarction (AMI), which is characterized by severe and fatal arrhythmias resultant from cardiac ischemia/reperfusion (CIR), is the leading cause of morbidity and mortality in the world. Considering that epiisopiloturin (EPI), an imidazole alkaloid found in the leaves of Pilocarpus microphyllus produded anti-inflammatory and antioxidant effects in an animal model of peritonitis, paw edema and peritonitis in mice, we decided to investigate the potential cardioprotective activity of EPI in animal model of CIR. Then, adult rats submitted to CIR pretreated with EPI 10 mg/kg (EPI10+CIR group) or 15 mg/kg (EPI15+CIR group) were compared to control animals submitted to CIR treated with saline solution 0.9% (CIR group). To evaluate the incidence of ventricular arrhythmias (VA), atrioventricular block (AVB) and lethality (LET) induced by CIR in these rats, the ECG analysis was performed. Serum levels of cardiac damage markers, total creatine kinase (CK) and CK-MB, were measured. The results showed that the AVB incidence was reduced from 80% to 30%, and LET incidence was reduced from 70% to 20%, compared to CIR group. Serum levels of LDH, total CK and, CK-MB was similar in all groups studied. These results indicate that the treatment with EPI (15 mg/kg, IV) before CIR was effective to produce cardioprotective effects. Thus, the use of EPI could be a promisse strategy to reduce the incidence of severe and fatal arrhythmias associated with AMI.

It has been demonstrated that brief cycles of ischemia followed by reperfusion (IR) applied before exercise can improve performance and, IR intervention, applied immediately after exercise (post-exercise ischemic conditioning – PEIC) exerts a potential ergogenic effect to accelerate recovery. Thus, the purpose of this systematic review with meta-analysis was to identify the effects of PEIC on exercise performance, recovery and the responses of associated physiological parameters, such as creatine kinase, perceived recovery and muscle soreness, over 24 h after its application. From 3281 studies, six involving 106 subjects fulfilled the inclusion criteria. Compared to sham (cuff administration with low pressure) and control interventions (no cuff administration), PEIC led to faster performance recovery (p=0.004; ES=-0.49) and lower increase in creatine kinase (p&lt;0.001; ES=-0.71) and muscle soreness (p&lt;0.001; ES=-0.89) over 24 h. The effectiveness of this intervention is more pronounced in subjects with low/moderate fitness level and at least a total time of 10 min of ischemia (e.g. 2 cycles of 5 min) is necessary to promote positive effects.

Background: Previously, our laboratory has provided evidence that pre-administration of the antioxidant, lipoic acid covalently bonded to various naturally occurring antioxidants, enhanced neuroprotective capacity compared to the administration of lipoic acid on its own. The naturally occurring compound scopoletin, a coumarin derivative, has been shown in various in vitro studies to have both antioxidant and anti-inflammatory mechanism of actions. To date, the effect of scopoletin on neuronal cell death in an in vivo model of ischemia or ischemia-reperfusion has not been investigated. Therefore, the present investigation was designed to determine if scopoletin on its own, or a co-drug consisting of lipoic acid and scopoletin covalent bond, named UPEI-400, would be capable of demonstrating a similar neuroprotective efficacy. Methods: Using a rodent model of stroke in male rats (anesthetized with Inactin®; 100 mg/kg, iv), the middle cerebral artery was permanently occluded for 6 hours (pMCAO), or in separate animals, occluded for 30 min followed by 5.5 hrs of reperfusion (ischemia/reperfusion; I/R). Results: Pre-administration of either scopoletin or UPEI-400 significantly decreased infarct volume in the I/R model (p<0.05), but not in the pMCAO model of stroke. However, UPEI-400 was ~1000 times more potent as compared to scopoletin on its own. The optimal dose of UPEI-400 was then injected during the occlusion and at several time points during reperfusion and significant neuroprotection was observed for up to 150 mins following the start of reperfusion (p<0.05). Conclusion: The data suggest that synthetic combination of scopoletin with lipoic acid (UPEI-400) is a more effective neuroprotectant that either compound on their own. Also, since UPEI-400 was only effective in a model of I/R, it is possible that it may act to enhance neuronal antioxidant capacity and/or upregulate anti-inflammatory pathways to prevent the neuronal cell death.

Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo Rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the Rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with Rapamycin (10 ng/ml) for 1 hour before LPS. In contrast, Rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo Rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of Rapamycin treated DCs to WT recipients 24 hrs before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/ml) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.

The transient vanilloid receptor potential type 1 (TRPV1) regulates neuronal and vascular functions mediated by nitric oxide (NO) and by the calcitonin gene-related peptide (CGRP). Here we study the participation of TRPV1 in the regulation of myocardial injury caused by ischemia-reperfusion and in the regulation of NO, tetrahydrobiopterin (BH4), the cGMP pathway, CGRP, total antioxidant capacity (TAC), malondialdehyde (MDA) and phosphodiesterase-3 (PDE-3). Isolated hearts of Wistar rats were used (according to Langendorff) to study the effects of capsaicin (CS), capsazepine (CZ) and CZ+CS treatments. The hearts were divided into three subgroups; 1) perfusion, 2) ischemia and 3) ischemia-reperfusion. In all groups we studied cardiac work and levels of NO, cGMP, BH4, CGRP, TAC, MDA and PDE-3 in ventricular tissue. Western blots were used to determine the expressions of eNOS, iNOS and phosphorylated NOS (pNOS). Structural changes were determined by histological evaluation. CS prevented damage caused by ischemia-reperfusion by improving cardiac work and the levels of NO, cGMP, BH4, TAC and CGRP. TRPV1 and iNOS expression were increased under ischemic conditions, while eNOS and pNOS were not modified. We conclude that the activation of TRPV1 constitutes a therapeutic possibility to counteract the damage caused by ischemia and reperfusion by regulating the NO pathway through CGRP.

Background: Handheld cameras may increase access to teleretinal diabetic retinopathy screenings (TDRS), as they are more economical and nimbler than traditional desktop cameras. However, their use in safety-net clinical settings is less understood. Methods: The Los Angeles County Department of Public Health collaborated with the Los Angeles County Department of Health Services (DHS) to pilot the use of handheld cameras in DHS’s TDRS program. This study assessed screening metrics and interviewed TDRS coordinators and photographers about their experiences using these cameras. Results: Handheld cameras are harder to operate and performed less optimally on key screening metrics (e.g., image quality) compared to desktop cameras. However, this challenge appeared to be linked to the selected model, rather than to all handheld cameras. The adoption of handheld cameras in DHS was aided by their integration into an existing agency infrastructure that already supports the use of desktop cameras; these operational supports include an established workflow, a data platform, and experienced photographers. Conclusions: The use of handheld cameras for TDRS is a promising practice for assuring equitable access to screenings. Handheld cameras are portable, smaller in size, and lower in cost than desktop cameras. Future projects should invest in and assess the performance of higher-quality models of these cameras, especially their use in safety-net clinical settings.

Acute kidney injury (AKI) caused by ischemia followed by reperfusion (I/R) is characterized by intense anion superoxide (O2•-) production and oxidative damage. We investigated whether extracellular vesicles secreted by adipose tissue mesenchymal cells (EVs) administrated during reperfusion can suppress the exacerbated mitochondrial O2•- formation after I/R. We used Wistar rats submitted to bilateral renal arterial clamping (30 min) followed by 24 h of reperfusion. The animals received EVs (I/R+EVs group) or saline, I/R group) in the kidney subcapsular space. The 3rd group was of the false-operated rats (SHAM). Mitochondria were isolated from proximal tubule cells and immediately used. Amplex Red™ was used to measure mitochondrial O2•- formation and MitoTracker® Orange to evaluate Δψ. In vitro studies were carried out by using human renal proximal tubular cells (HK-2) co-cultured or not with EVs under hypoxia conditions. Administration of EVs restored O2•- formation to SHAM levels in all mitochondrial functional conditions. The expression of catalase and superoxide dismutase remained unmodified; transcription of heme oxygenase-1 (HO-1) was upregulated. The co-cultures of HK-2 cells with EVs revealed an intense decrease in apoptosis. We conclude that the mechanisms by which EVs recover the renal structure and function after I/R are related to the normalization of the mitochondrial redox environment. The intravesicular catalase is central in the preservation mechanisms that, with the aid of the upregulated antioxidant HO-1/Nuclear factor erythroid 2-related factor 2 system, depress early processes of cell death after I/R and open new vistas for the treatment of AKI.

Mesenteric ischemia diagnosis is challenging with an overall mortality in up to 50% of cases despite advances in treatment. The main problem that affects the outcome is the delayed diagnosis because of non-specific clinical presentation. Multi Detector CT Angiography (MDCTA) is the first line investigation for the suspected diagnosis of vascular abdominal pathologies and is the diagnostic test of choice in suspected mesenteric bowel ischemia. MDCTA can accurately detect the presence of arterial and venous thrombosis, determine the extension and the gastrointestinal tract involved, and provide detailed information determining the subtype and the stage progression of the diseases helping clinicians and surgeons for the proper management. CT can differentiate forms that are still susceptible to pharmacological or interventional treatment (NOM= non-operative management) from advanced disease with transmural necrosis in which a surgical approach is required. Knowledge of CT imaging patterns and corresponding vascular pathways is mandatory in Emergency settings to reach a prompt and accurate diagnosis. The aims of this paper are 1. to provide technical information about the optimal CTA protocol; 2. To empathize the CTA arterial and venous supply to gastrointestinal tract and relative ischemic pattern; 3. To describe vascular, bowel and extraintestinal CT findings for the diagnosis of acute mesenteric ischemia.

Background and Objectives: In recent years Electronic scooters (E-Scooters) have gained popularity, whether for private use or as a publicly available transportation method. With introduction of these vehicles, reports of E-Scooter related accidents have surged, sparking a public debate and concern. Aim of this study was to analyse epidemiological data, characteristics and severity of traumatic brain injury (TBI) related to E-Scooter accidents. Materials and Methods: This retrospective case series evaluated 28 patients who were admitted to three largest neurosurgery clinics in Riga, Latvia between time period from April to October in two separate years – 2022 and 2023 after an E-Scooter related accident. Data were collected on patient demographics, time of the accident, alcohol consumption, helmet use, type of TBI, other related injuries, treatment and assessment at discharge. Results: A total of 28 patients were admitted with TBI related to E-Scooter use, with median age 30 years (Q1-Q3, 20.25-37.25), four individuals under age of 18, majority (64%) were male. In 23 cases the injury mechanism was fall, in 5 cases collision. None were wearing a helmet at time of injury. Alcohol intoxication was evident in over half of the patients (51.5%), with severe intoxication (&gt;1.2ppm) in 75% cases among them. Neurological symptoms upon admission were noted in 50% of cases. All patients had intracranial trauma - 50% brain contusions, 43% traumatic subdural hematoma, almost 30% - epidural hematoma. Craniofacial fractures were evident in 71% of cases, fractures in other parts of body in 3 patients. 6 patients required emergency neurosurgical intervention. Neurological complications were noted in 2 patients, 1 patient died. Conclusions: E-Scooter related accidents result in a significant number of brain and other associated injuries, with notable frequency linked to alcohol influence and lack of helmet use. Prevention campaigns to raise awareness of potential risks and implementation of more strict regulations should be done.

Drug-induced liver disease represents one of the main problems in the therapeutic field. As with most pathologies, also in this case various risk factors can be recognised, such as age, sex, but also the gut microbiota. Therefore all drugs on the market can, in fact, cause hepatotoxicity of varying degrees. Drugs used in the treatment of IBD can also cause these adverse effects and even lead to DILI. In this review, the various classes of drugs used in the treatment of IBD were taken into consideration and the various adverse effects on the liver were illustrated. In particular, a major role has emerged regarding hepatotoxicity of immunosuppressants. Biological drugs, however, seem to be responsible for these complications to a much lesser extent.

Until recently, no disease-specific health-related quality of life (HRQoL) instrument existed for pediatric traumatic brain injury (TBI). In this revalidation study, the psychometric properties and the validity of the final German version of the 35-item QOLIBRI-KID/ADO questionnaire were examined in 300 children and adolescents. It is the first self-reported TBI-specific instrument for measuring pediatric HRQoL in individuals aged 8–17 years. The six-factor model fits the data adequately. Internal consistencies were excellent for the total score and satisfactory to excellent for the scale scores. Intraclass correlations indicated good test-retest reliability. Construct validity was supported by overlaps between the QOLBRI-KID/ADO and the PedsQL, which measures generic HRQoL. Discriminant validity indicated that HRQoL was significantly lower in older children and girls, and in those with anxiety, depression, and post-concussion symptoms than in comparison groups, replicating the results of the questionnaire’s first development study. Our results suggest that the QOLIBRI-KID/ADO is a valid and reliable multidimensional instrument for assessing disease-specific HRQoL after pediatric TBI in clinical and research settings, which can additionally be used across the lifespan in combination with the adult version. This may help to improve care, treatment, daily functioning and HRQoL after TBI.

Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.

Coronary revascularization is one of the most studied treatment modalities in cardiology, however, there is no consensus among experts about its indications in patients with stable coronary artery disease (SCAD). Contemporary data regarding the role of revascularization in SCAD are in clear conflict with the current European guidelines. This article discusses the main statements of the most significant American and European Guidelines on myocardial revascularization of the last decade, and also analyzes the appropriateness of revascularization to improve the prognosis and symptoms in CCS in the light of new research data, primarily the ISCHEMIA study (NCT01471522) and ACC/AHA 2021 Revascularization Guidelines based on them. Data on the revascularization in CCS obtained after the completion of ISCHEMIA (including the interim analysis of ISCHEMIA-EXTEND) and their potential significance are discussed. The results of ISCHEMIA sub-analyses in the most important ‘controversial’ subgroups (3-vessel disease, proximal left anterior descending artery (LAD) disease, strongly positive stress test, etc.) are reviewed, as well as the results of the ISCHEMIA-CKD substudy in patients with severe chronic kidney disease (CKD).

Drug-induced liver injury (DILI) stands as a significant cause of drug attrition. To mitigate clinical DILI risks, assessing drugs using human liver models is crucial since animal studies may fall short due to species-specific liver pathway variations. Cell-based preclinical hepatotoxicity testing is often pertinent. In the present study, cells from a human liver cancer line (HepG2, HepaRG) were cultured in both formats of 2D and 3D spheroids to explore their responses to drugs. Liver-specific marker expressions across cell lines and culture formats were also examined to assess disparities in drug-induced liver injury marker expressions. In cytotoxicity assays, HepG2 cells exhibited heightened sensitivity to amiodarone HCl, while HepaRG cells showed greater sensitivity to acetaminophen. Generally, 2D cultures were more responsive to drugs than 3D cultures. Consistency was observed between cytotoxicity assays and liver injury markers AST and ALT. Variations were also noted in liver cell marker secretion, with albumin and urea concentrations declining post-drug treatment, particularly with higher baseline expression in HepaRG cells and 3D cultures. Additionally, mRNA expression levels of CYP enzymes involved in hepatocellular drug metabolism were compared following treatment with enzyme inducers. CYP1A2 and CYP2C9 were not expressed in HepG2 cells. On the other hand, CYP3A4 was expressed higher in 3D culture than in 2D culture. HepaRG cells exhibited significantly increased expression of all three enzymes post-treatment. Notably, enzyme expression was notably higher in 3D cultures than in 2D cultures. Collectively, these findings suggest that HepaRG cells and 3D cultures hold promise for evaluating DILI during early-stage drug development.

Fever control is essential in patients with severe traumatic brain injury (TBI). The efficacy of therapeutic hypothermia (TH) in severe TBI has been investigated over the last few decades; however, in contrast to experimental studies showing benefits, no evidence of efficacy has been demonstrated in clinical practice. In this review, the mechanisms and history of hypothermia were briefly outlined, while the results of major randomized controlled trials (RCTs) and meta-analyses investigating TH for adult TBI are introduced and discussed. The retrieved meta-analyses showed conflicting results, with a limited number of studies indicating benefits of TH. Some studies have shown benefits of long-term TH compared with short-term TH. Although TH is effective at lowering elevated intracranial pressure (ICP), reduced ICP does not lead to favorable outcomes. Low-quality RCTs overestimated the benefits of TH, while high-quality RCTs showed no difference or worse outcomes with TH. RCTs assessing standardized TH quality demonstrated the benefits of TH. As TBI has heterogeneous and complicated pathologies, applying a uniform treatment may not be ideal. A meta-analysis of young patients who underwent early cooling and hematoma removal showed better TH results. TH should not be abandoned, and its optimal should be advocated on an individual basis.

Objective: To report time-loss match injuries in Portugal’s “Divisão de Honra” (Portuguese First Tier) 2022/23 season focusing on injury incidence, injury burden, anatomical region and type of injury. Methods: A cohort prospective observational study was conducted. Data was collected through an online form sent for every team medical department categorizing player position, injury type, location and severity. Injury incidence and burden were calculated per 1000-player-match-hours. Results: The overall injury incidence was 54.4 injuries per 1000 player-match-hours (CI95% 30.3-96.2). Forwards had a higher incidence comparing to backs. Lower limbs were the most affected location (52% of the injuries). Sprain/ligaments injuries were the most common type of injury followed by muscle injuries. Discussion: The injury incidence was higher than what is reported in amateur competitions and lower than professional ones. Injury severity was similar to other studies. Our study suggests a lower injury burden compared to other semi-professional and elite leagues. Further research with broader participation and training injury data is needed.

Traumatic brain injury (TBI) is a global healthcare concern affecting millions, with wide-ranging symptoms including sensory and behavioral changes that can persist long-term. Due to similarities with human brain cytoarchitecture and inflammation, minipig models are advantageous for translational TBI research. However, gaps in knowledge exist regarding their behavioral and sensory sequelae following injury. Therefore, in this study, we assessed changes in approachability using a forced human approach task (FHAT) and mechanical nociception using the von Frey Test in adult male and female Yucatan minipigs for up to one week following a sham or central fluid percussion injury (cFPI). Specifically, the FHAT assessed each animal’s response to a forced interaction with either a known or unknown experimenter. To evaluate changes in nociceptive sensory sensitivity, von Frey monofilaments ranging from 0.008 to 300 grams of force were applied to the pinna of the ear or base of the tail. We found that forced approachability was affected by experimenter familiarity as well as cFPI in a sex-specific manner at subacute timepoints. We also found reductions in sensitivity following cFPI on the ear in male minipigs and on the tail in female minipigs. Overall, the current study demonstrates that cFPI produces both behavioral and sensory changes in minipigs up to one-week post-injury.

Small interfering RNA (siRNA) holds significant therapeutic potential by silencing target genes through RNA interference. Current clinical applications of siRNA have been primarily limited to liver diseases, while achievements in delivery methods are expanding its applications to various organs, including the lungs. Cholesterol-conjugated siRNA emerges as a promising delivery approach due to its low toxicity and high efficiency. This study focuses on developing a cholesterol-conjugated anti-Il6 siRNA and the evaluation of its potency for the potential treatment of inflammatory diseases using the example of acute lung injury (ALI). The biological activities of different Il6-targeted siRNAs containing chemical modifications were evaluated in J774 cells in vitro. The lead cholesterol-conjugated anti-Il6 siRNA after intranasal instillation demonstrated dose-dependent therapeutic effects in a mouse model of ALI induced by lipopolysaccharide (LPS). The treatment significantly reduced Il6 mRNA levels, inflammatory cell infiltration, and the severity of lung inflammation. IL6 silencing by cholesterol-conjugated siRNA proves to be a promising strategy for treating inflammatory diseases, with potential applications beyond the lungs.

Introduction Blunt carotid injuries (BCI) in pediatric trauma are quite rare. Due to the low number of cases, only a few reports and studies have been conducted on this topic. This review will discuss how frequent BCI/ BCVI on pediatric patients after blunt trauma is, what routine diagnostics look like, if a CT/ CTA scan on pediatric patients after blunt trauma is always necessary and if there are any negative health effects? Methods This literature review includes reviews, systematic reviews, case reports and original studies in english language between 1999 and 2020 that have dealt with pediatric blunt trauma and the diagnostics of BCI and BCVI. Furthermore, publications on the risk of radiation exposure on children were included in the study. For literature research, Medline (PubMed) and the Cochrane library were used. Results Pediatric BCI/ BCVI, shows an overall incidence between 0.03 – 0.5% of confirmed BCI/ BCVI cases due to pediatric blunt trauma. 1.1 – 3.5% of pediatric blunt trauma patients underwent CTA to detect BCI. Only 0.17 – 1.2% of all CTA scans shows a positive diagnosis for BCI. In children, the median volume CT dose index on a non-contrast head CT is 33 milligray, a computed tomography angiography needs at least 138 mGy. A cumulative doses of about 50 mGy almost triples the risk of leukemia, and doses of about 60 mGy triples the risk of brain cancer. Discussion Knowing that a BCI could have extensive neurologic consequences for children, it is necessary to evaluate routine pediatric diagnostics after blunt trauma. Computed tomography scans (CT) and computed tomography angiography (CTA) are mostly used in routine BCI diagnostics. However, since radiation exposure in children should be as low as reasonably achievable, it should be asked if other diagnostic methods could be used to identify risk groups. Trauma guidelines and clinical scores like the McGovern score are reflect established BCI screening options, as well as using duplex ultrasound.

Electrolyte disturbances are common in patients with traumatic brain injury (TBI), particularly affecting sodium, potassium, chloride and calcium levels. This study aims to provide insights into these disturbances within the first 24 hours post-injury. We conducted a cross-sectional analysis of 50 TBI patients, excluding those with conditions affecting electrolyte balance. Electrolyte levels were measured, and correlations with demographic data, trauma mechanisms, imaging findings, and Glasgow Coma Scale (GCS) scores were analyzed. Results indicated that chloride levels inversely correlated with GCS scores (ρ = -0.515; p = 0.002), suggesting that elevated chloride may indicate severe neurological impairment. Potassium levels were significantly associated with subdural hematoma (p = 0.032) and subarachnoid hemorrhage (p = 0.043), highlighting their potential as markers for severe brain injuries. No significant associations were found between sodium or calcium levels and the studied variables. These findings underscore the importance of early monitoring of chloride and potassium levels in TBI patients to improve management and outcomes. Future research should focus on larger, multi-center studies to validate these findings and develop comprehensive guidelines for managing electrolyte imbalances in TBI patients.

Alcoholic liver disease (ALD) develops when the immunotolerant environment of the liver is compromised due to excessive alcohol consumption. ALD progression involves variations in the expression of multiple genes, resulting in liver inflammation and the development of a leaky gut. Molecular mechanism involved for ALD progression is still unclear, and due to that there are currently no FDA-approved drugs available for its treatment. In this study, the protective effects of Graphene oxide nanoparticles (GO) was investigated against ethanol-induced damage in the gut-liver axis in in vitro. GO was synthesized using a modified Hummer's method and characterization was done. Given the general concerns regarding nanoparticle toxicity, assessment of cell viability, lipid accumulation, DNA damage, cell death, and the generation of reactive oxygen species (ROS) were conducted using various techniques. Furthermore, gene expression of pro- and anti-inflammatory cytokines was done using RT-qPCR. The findings revealed that GOs promoted cell viability even against ethanol treatment. Additionally, lipid accumulation significantly decreased when cells were treated with GO alongside ethanol compared to ethanol treatment alone, with similar trends observed for other assays. Gene expression analysis indicated that GO treatment reduced the expression of proinflammatory cytokines while enhancing the expression of antioxidant genes. Moreover, GO treatment led to improvements in gut permeability and a reduction in proinflammatory cytokines in colon cells damaged by ethanol. These findings suggest that GO holds promise as a drug carrier, exhibiting no observed toxic effects. By shedding light on the protective effects of GO against ethanol-induced damage, this study contributes to the burgeoning field of nanoparticle-mediated therapy for ALD.

During the 90 days following hospitalization for acute heart failure, ejection fraction and type of discharge medications have been shown in clinical trials to have little effect on mortality. We examined the recent literature addressing brain-related etiologies of sudden death following heart failure. Two mechanisms of sudden unexpected death have been suggested to possibly result from 4 significant influences on pathophysiology in the brain. The two causes of death are severe cardiac arrhythmia, and neurogenic pulmonary edema. They are both mediated through the brainstem autonomic nuclei generally, and executed specifically through the dorsal motor nucleus of the vagus nerve. The four significant influences on pathophysiology in the brainstem autonomic nuclei are: 1) Hyper-stimulation of neurons in the solitary tract nucleus, increasing their metabolic requirements; 2) Inadequate blood flow at a vascular watershed terminus; 3) Additionally decreased blood flow following vasoconstriction related to relative hyperventilation and decreased pCO2 levels; 4) Gravitational ischemia in the brain—caused by the weight of the brain mass sitting above the brainstem. Changes in head tilt release gravitational ischemia in the brain. There is no specific head position (relative to gravity) that is considered favorable or unfavorable for an extended period of time (i.e. more than 24 hours). Even a small degree of head elevation, used in managing pulmonary congestion, may increase gravitational ischemia in the posterior fossa and brainstem. In this paper we suggest a new and important research avenue for intervening in cardiac arrhythmias, and preventing their occurrence, through the non-invasive use of head-tilting, and other head repositioning maneuvers. This could potentially help many geriatric patients with heart failure, who have decreased mobility in bed, and who tend to stay in one position longer, thereby increasing gravitational ischemia in the brain.

There is evidence that kidney involvement is frequently observed in COVID-19 patients, and can manifest as mild proteinuria to advancing acute kidney injury (AKI). One of the mechanisms is microvascular and macrovascular thrombosis caused by the hypercoagulation phase of the disease. Thromboelastography (TEG) is a valuable examination to detect significant hemostatic abnormalities, including the hypercoagulable state. This study analyzed the coagulation profiles, including TEG parameters, in COVID-19 patients who developed AKI compared to those who did not during their intensive care unit (ICU) stay, to identify predictors of AKI. Our single-center cohort retrospective study involved adult patients of COVID-19 in the ICU of Sardjito Hospital in Yogyakarta, Indonesia between May and September 2021. Patients were divided into two groups of AKI and non-AKI based on 2012 KDIGO definition and the elaboration by Indonesian Society of Nephrology. Variables showing a significant difference in the two groups were then analyzed using univariate and multivariate binary logistic regression. A total of 60 COVID-19 patients were included in the study, and 35% of them developed AKI. Compared to non-AKI patients, those with AKI exhibited a greater prevalence of diabetes mellitus (66.7% versus 35.9%, P = 0.023), higher D-Dimer levels (970 versus 685 ng/mL, P = 0.045), and higher values in TEG parameters of maximum amplitude/MA (74.6 versus 65.9 mm, P = 0.001) and coagulation index/CI (2.3 versus 1.0, P = 0.033). TEG parameter of MA emerged as the sole significant predictor for the development of AKI (OR, 6.33; 95% CI, 1.56 to 25.64). Our study validated the kidney involvement of COVID-19 infection, and showed that diabetes mellitus, high D-Dimer levels, and hypercoagulability serve as prominent risk factors in the development of AKI. Furthermore, TEG parameter of MA exceeding 70 mm is the single independent significant predictor of AKI.

Peripheral nerve injuries (PNI) can have several etiologies, such as trauma and iatrogenic interventions that can lead to the loss of structure and/or function impairment. These changes can cause a partial or complete loss of motor and sensory functions, physical disability, and neuropathic pain, what in turn can affect the quality of life. For those reasons, PNI is a major public health concern. This review aims to revisit the concepts associated with the PNI. First, the anatomy of the peripheral nerve is detailed to explain the different types of injury. Then, some of the available therapeutic strategies are explained, including surgical methods, pharmacological therapies, and the use of cell-based therapies alone or in combination with biomaterials in the form of tube guides. Nevertheless, even with the various available treatments, it is difficult to achieve a perfect outcome with complete functional recovery. This review aims to explain the urge for new approaches and to understand the methods to evaluate nerve regeneration in a One Health perspective. In vitro models followed by in vivo models are very important to be able to translate the achievements to human medicine.

Myocardial infarction (MI) remains the leading cause of death in the western world. Although medical advancements have been made in interventional revascularization technologies, a large percentage of patients are not candidates for them due to co-morbidities or lack of local resources. Thus, there remains a need for the development of novel non-invasive strategies to treat MI. Approaches to accelerate revascularization within ischemic tissues through angiogenesis by providing Vascular Endothelial Growth Factor (VEGF) in protein or gene form has been shown to be effective in animal models but not in humans likely due to its short half-life and systemic toxicity. We previously showed that a small peptide (PR1P) we developed stabilizes VEGF in its active dimer state, increases VEGF binding to its receptors and potentiates VEGF activity. Here we show that systemic PR1P treatment targeted, stabilized and upregulated endogenous VEGF within ischemic myocardium following left coronary artery surgery in mice and rats. Targeted VEGF upregulation led to augmentation of heart function at two weeks following surgery. We conclude that PR1P is a potential candidate therapeutic for MI.

Background: Injury of the spinal cord causes motor and sensory dysfunction, and pathological reflexes, leading to paraplegia or tetraplegia. The sequelae of traumatic spinal cord injury (SCI) is a significant burden and impact on healthcare systems. Despite constant progress in medicine, traumatic SCI still remains irreversible. Till now, no satisfying treatment that can enable neuronal regeneration and recovery of function at the damaged level has been found. Hundreds of experiments have been conducted on various possibilities of influencing spinal regeneration, some of them have yielded promising results, but unfortunately, the successes obtained in experimental animals have not translated into humans. Methods: This narrative review article presents the application of Extracorporeal Shock Wave Therapy (eSWT) in Spinal Cord Injury. The article has been divided into parts: 1. Use of extracorporeal Shock Wave Therapy for regeneration of the spinal cord after traumatic Spinal Cord Injury. 2. Application of extracorporeal Shock Wave Therapy in spasticity after Spinal Cord Injury. In both cases, the hypotheses of possible mechanisms of action will be described. Results and conclusions: A small number of clinical trials have demonstrated the potential of eSWT to influence the regeneration of the spine, as an innovative, safe, and cost-effective treatment option for patients with SCI. Some reports have shown that eSWT can improve spasticity, walking ability, urological function, quality of life, and independence in daily life.

Epigenetic mechanisms, including histone post-translational modifications (PTMs), play a critical role in regulating pain perception and the pathophysiology of burn injury. However, the epigenetic regulation and molecular mechanisms underlying burn injury-induced pain remain insufficiently explored. Spinal dynorphinergic (Pdyn) neurons contribute to heat hyperalgesia induced by severe scalding-type burn injury through p-S10H3-dependent signaling. Beyond p-S10H3, burn injury may impact various other histone H3 PTMs. Double immunofluorescent staining and histone H3 protein analyses demonstrated significant hypermethylation at H3K4me1 and H3K4me3 sites and hyperphosphorylation at S10H3 within the spinal cord. By analyzing Pdyn neurons in the spinal dorsal horn, we found evidence of chromatin activation with a significant elevation in p-S10H3 immunoreactivity. We used RNA-seq analysis to compare the effects of burn injury and forma-lin-induced inflammatory pain on spinal cord transcriptomic profiles. We identified 98 DEGs for burn injury and 86 DEGs for formalin-induced inflammatory pain. A limited number of shared differentially expressed genes (DEGs) suggest distinct central pain processing mechanisms between burn injury and formalin models. KEGG pathway analysis supported this divergence, with burn injury activating Wnt signaling. This study enhances our understanding of burn injury mechanisms and uncovers converging and diverging pathways in pain models with different origins.

Background: Acute kidney disease (AKD) is a known risk factor for increased mortality and evolution towards chronic kidney disease (CKD) in adults. The data regarding children are scarce. The purpose of our study is to explore the risk factor for AKD and impact of AKD following an acute kidney injury (AKI) episode in children on mortality and new-onset CKD. Methods: We retrospectively evaluated 736 children with ages between 2 and 18 years old with AKI admitted in a tertiary care hospital from the west Romania over a 9 years period. Results: AKD incidence following AKI was 17%. Patients that developed AKD were older, with higher baseline serum creatinine values, urea, C reactive protein and lower proteins, haemoglobin and sodium. They were more often exposed to sepsis, critical illness and nephrotoxic medications and presented certain susceptibilities like CKD, neoplasia, anemia, heart failure, arterial hypertension, stem cell transplant and female gender. AKI causes that increased the risk of AKD were intrinsic ones. AKD increased the overall mortality by three times. The factors that independently increased the risk of evolution towards CKD were AKD, acute tubular necrosis and higher baseline serum creatinine values. Conclusions: AKD is an independent risk factor for mortality and new-onset CKD in children.

Τhis study aims to assess changes in the fovea avascular zone (FAZ) in treatment naïve patients receiving aflibercept or ranibizumab injections for diabetic macular edema (DME). This is a prospective study recruiting patients with treatment-naïve DME. Best corrected visual acuity (BCVA) testing, OCT and OCT-angiography (OCTA) imaging were performed at baseline and 1 month after each injection. Injections of either aflibercept or ranibizumab were administered monthly for 6 consecutive months. FAZ in the superficial (SCP) and the deep capillary plexus (DCP) using OCTA was recorded for each visit. Fifty eyes from 50 patients with a mean age of 67.010.7 years were included in the study Twenty-five patients received aflibercept and 25 received ranibizumab. BCVA was 40.810.0 and increased to 52.17.9 ETDRS letters at the last visit (p&lt;0.001). CRT was 295.634.0 at baseline and 247.929.7 at the last study visit (p&lt;0.001). SCP FAZ was 350.679.5μm2 at baseline and 339.071.3μm2 after 6 monthly injections (p=0.132). DCP FAZ was 558.6199.0μm2 at baseline and 459.5156.1μm2 after 6 monthly injections (p&lt;0.001). There was no effect of the choice of ranibizumab or aflibercept on DCP FAZ change (p=0.277). In conclusion, treatment with 6 monthly injections of ranibizumab and aflibercept led to an increase in BCVA and a decrease in CRT and DCP FAZ area. Both drugs led to an improvement in DCP ischemia.

Cerebral ischemia, which is a leading cause of disability and mortality worldwide, sets off a chain of molecular and cellular pathologies that are associated with some central nervous system (CNS) disorders, mainly including ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy and other CNS diseases. In recent times, despite significant advancements in the treatment of the pathological processes underlying various neurological illnesses, effective therapeutic approaches specifically targeted at minimizing the damage of such diseases remain absent. Remarkably, ischemia causes severe damage to cells in Ischemia-associated CNS Diseases. Cerebral ischemia initiates oxygen and glucose deprivation, which subsequently promotes mitochondrial dysfunction, including MPTP opening, mitophagy dysfunction, and excessive mitochondrial fission, triggering various forms of cell death, such as autophagy, apoptosis, as well as ferroptosis. Ferroptosis, a novel type of regulated cell death (RCD), is characterized by iron-dependent accumulation of lethal reactive oxygen species and lipid peroxidation. Mitochondrial dysfunction and ferroptosis both play critical roles in the pathogenic progression of Ischemia-associated CNS Diseases. In recent years, growing evidence has indicated that mitochondrial dysfunction interplays with ferroptosis to aggravate cerebral ischemia injury. However, the potential connections between mitochondrial dysfunction and ferroptosis in Cerebral Ischemia have not yet been clarified. Thus, we analyze the underlying mechanism between mitochondrial dysfunction and ferroptosis in Ischemia-associated CNS Diseases. We also discovered that GSH depletion and GPX4 inactivation cause lipoxygenase activation and calcium influx following cerebral ischemia injury, resulting in MPTP opening and mitochondrial dysfunction. Additionally, dysfunction in mitochondrial electron transport and an imbalanced fusion-to-fission ratio can lead to the accumulation of reactive oxygen species and iron overload, which further contribute to the occurrence of ferroptosis. This creates a vicious cycle that continuously worsens cerebral ischemia injury. In this study, our focus is on exploring the interplay between mitochondrial dysfunction and ferroptosis, which may offer new insights into potential therapeutic approaches for the treatment of Ischemia-associated CNS Diseases.

Traumatic Brain Injury (TBI) is one of the leading causes of death and disability worldwide. Patient treatment and management pose a challenge for healthcare systems. The prognosis of these patients may be influenced by factors such as sex. This study aims to describe the clinical parameters of patients hospitalized in the Intensive Care Unit (ICU) of a Spanish hospital due to Trauma Brain Injury and to establish differences based on sex. Methodology: An observational, cross-sectional, and analytical study was conducted from March 2015 to December 2019. All patients admitted to the ICU during this period who presented isolated significant Traumatic Brain Injury, defined as an abbreviated injury scale (AIS) ≥ 3, were included. Data on baseline characteristics, mechanism of injury, substance use, and acute management in the prehospital and hospital stages (including the need for hospitalization) were recorded. A descriptive and in-ferential analysis was conducted using the chi-square test. Results: A total of 950 patients were ultimately included. The majority of the patients were men (723) with a mean age of 45.16 (± 17.55). There were statistically significant differences in terms of the mechanism of injury (p

Chronic Mesenteric Ischemia (CMI) arises from the inability to achieve adequate intestinal blood flow after meals, leading to an imbalance between oxygen and metabolite supply and demand. The true incidence of CMI remains uncertain. However, the occurrence of mesenteric artery occlusive disease (MAOD) is relatively common among the elderly population. Delays in diagnosing CMI can often be attributed to several factors, including the variability of patient symptoms, the range of potential causes for chronic abdominal pain with weight loss. Mikkelson pioneered the introduc-tion of a surgical treatment for occlusive lesions of the superior mesenteric artery (SMA) in 1957. The inaugural performance of endovascular revascularization (ER) for visceral vessels took place in 1980. The literature has documented two types of endovascular revascularization (ER) methods: percutaneous transluminal angioplasty (PTA) and primary stenting (PMAS). Despite the limited quality of available evidence, the consensus among experts is strongly in favor of PMAS over PTA alone for the treatment of atherosclerotic mesenteric artery stenosis. There are several key areas of focus for chronic mesenteric ischemia (CMI) treatment. Randomized controlled trials comparing different stent types, such as covered stents versus bare metal stents, are needed to evaluate effi-cacy, patency rates, and long-term outcomes in CMI patients.

Background: Ventilatory strategies in acute respiratory distress syndrome patients aim to mitigate the risk of acute lung injury (ALI). However, prolonged utilization of these strategies may precipitate alveolar carbon dioxide elevation and pH reduction. This scoping review endeavors to present extant knowledge concerning hypercapnia effects in experimental models, with or without ALI, specifically focusing on delineating the immunologically mediated pulmonary tissue damage; Methods: A systematic exploration encompassing PubMed, Web of Science, ScienceDirect, Cochrane Reviews, and Scielo databases was undertaken. Articles published between January 1, 2008, and December 31, 2022, were screened for their elucidation of hypercapnia's immunological impact on lung tissue, utilizing experimental or biological models, irrespective of ALI presence; Results: Following duplicate removal and predefined criteria filtering, 30 pertinent articles scrutinizing hypercapnia's influence on pulmonary epithelium were identified. It was observed that hypercapnia induces perturbations in innate immune response gene transcription, mediated via Nuclear Factor-kappa B attenuation. Furthermore, a compromised innate immune response against injurious agents was noted. Concurrently, disruption and subsequent resealing of alveolar epithelial cells were evidenced, primarily through Na/K-ATPase endocytosis, impeding fluid reabsorption at the alveolar epithelium level; Conclusions: In experimental settings, with or without ALI, hypercapnia's immunomediated mechanisms exacerbate innate immune system impairment and disrupt the respiratory epithelium's repair and healing processes.

Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have severe impact on the patient’s quality of life. The current review summarizes evidence for utility of amantadine in TBI in connection to its mechanism of action. Amantadine combining multiple mechanisms of action may offer both neuroprotective and neuroactivating effects in TBI patients. Indeed, use of amantadine in TBI has been encouraged by several clinical practice guidelines/recommendations. Amantadine is also available as infusion which may be of particular benefit in unconscious patients with TBI, due to immediate delivery to the central nervous system and the possibility of precise dosing. In other situations, orally administered amantadine may be used. There are several questions that remain to be addressed: Can amantadine be effective in disorders of consciousness requiring long-term treatment and in combination with drugs approved for treatment of TBI? Do the observed beneficial effects of amantadine extend to disorders of consciousness due to factors other than TBI? Well controlled clinical studies are warranted to ultimately confirm its utility in the TBI and provide answers these questions.

The present review aimed to identify through what means neurologic injury can predispose individuals to Post-Traumatic Stress Disorder (PTSD). In recent years, comprehensive studies have helped to clarify which structures in the central nervous system (CNS) that, when damaged, lead to distinct PTSD symptoms–namely dissociative reactions or flashbacks. Our review narrowed its focus to three common neurologic injuries including traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), and stroke. Beyond discussing the potential mechanisms by which neurotrauma may lead to PTSD, we summarized our current understanding of the pathophysiology of the disorder and discussed predicted associations between the limbic system and PTSD. In particular, the role of noradrenergic neuromodulatory signaling on the HPA axis as it pertains to fear memory recall needs to be further explored to better understand its effects on limbic structures in PTSD patients. This paper also described how damage to the CNS can alter the function of the limbic system and result in characteristic symptoms of PTSD like intrusive memories and acute psychological distress. Further, our review intended to draw attention to a lack of PTSD prognosis in TBI, SAH, and stroke patients who could benefit from early treatment. PTSD symptoms often compound with pre-existing issues further deteriorating health outcomes for these patients. It is ultimately our goal to clarify the relationship between neurotrauma and PTSD such that earlier diagnoses and appropriate treatment are observed in clinic.

Ischemia, the inadequate blood flow, can arise from pre-existing or traumatic events, remain an undetectable issue, and impact the body's ability to provide oxygen to necessary limbs, organs, muscles, or tissue. New technology involving wearable ultrasonic devices allows medical professionals to gain real-time insight into the cardiovascular system of their patients. A non-invasive, postage-stamp-sized ultrasonic sensor can be attached to a patient, allowing for continuous monitoring of the patient’s blood pressure outside of the hospital. After reviewing 16 papers on ultrasonic sensors, this paper intends to review the current use of wearable ultrasonic sensors and the advantages and limitations of the technology used to obtain accurate blood pressure readings. This review will bring attention to the evolving and expanding world of wearable ultrasonic sensors for medical applications.

Introduction: Despite the introduction of increasingly multifaceted diagnostic techniques and the general progress of emergency abdominal and vascular surgery, the outcome of treatment of patients with acute impaired intestinal circulation remains unsatisfactory. The non-invasive and high-resolution technique of optical coherence tomography (OCT) can be used intraoperatively to assess intestine viability and associated conditions that frequently emerge under conditions of impaired blood circulation. This study aims to demonstrate the effectiveness of multimodal (MM) OCT for intraoperative diagnostics of both the microstructure (cross-polarization OCT mode) and microcirculation (OCT angiography mode) of the small intestine wall in patients with acute mesenteric ischemia (AMI). Methods and Participants: A total of 18 patients were enrolled in the study. Nine of them suffered from AMI in segments II-III of the superior mesenteric artery (AMI group), where the ischemic segments of the intestine were examined. Nine others were operated for adenocarcinoma of the colon (control group), thus allowing areas of their normal small intestine to be examined for comparison. Data on the microstructure and microcirculation in the walls of the small intestine were obtained intraoperatively from the side of the serous membrane using the MM OCT system (IAP RAS, Russia) before bowel resection. The MM OCT data were compared with the results of histological examination. Results: The study finds that MM OCT visualized the damage to serosa, muscularis externa, and blood vessels localized in these layers in 100% of AMI cases. It also visualized the submucosa in 33.3% of AMI cases. The MM OCT image of non-ischemic (control group), viable ischemic and necrotic small intestines (AMI group) differed significantly across stratification of the distinguishable layers, the severity of intermuscular fluid accumulations and the type and density of the vasculature. Conclusion: The MM OCT diagnostic procedure optimally meets the requirements of emergency surgery. Data on the microstructure and microcirculation of the intestinal wall can be obtained simultaneously in real time without requiring contrast agent injections. The depth of visualization of the intestinal wall from the side of the serous membrane is sufficient to assess the volume of the affected tissues. However, the methodology for obtaining MM OCT data needs to be improved to minimize the motion artefacts generated in actual clinical conditions.

Background: The treatment of peripheral arterial disease (PAD) is focused on improving perfusion and oxygenation in the affected limb. Standard revascularization methods include bypass surgery, endovascular interventional procedures, or hybrid revascularization. Cell-based therapy can be an alternative strategy for patients with no-option critical limb ischemia who are not eligible for endovascular or surgical procedures. Aims: This review offers an up-to-date critical overview of the knowledge and data of evidence-based medicine on the position of cell therapy in the treatment of PAD. It provides an overview of current evidence and appraises the future perspectives of cell-based therapy, emphasizing the potential of exosomal cell-free approaches in patients with critical limb ischemia. Results: Meta-analyses focused on cell therapy problems in PAD treatment confirm a significantly greater chance of limb salvage in the first year after the cell therapy administration. The opportunity of defect healing is at least two times higher when compared with the standard conservative therapy. Secondary endpoints of the available meta-analyses are also included in this review. Improvement of perfusion and oxygenation parameters in the affected limb, pain regression, and claudication interval prolongation are discussed. Conclusions: The available evidence-based medicine data show that this technique is safe, associated with minimum complications or adverse events, and effective.

NaoMaiTong (NMT: Radix et Rhi-zoma Rhei, Radix Ginseng, Radix Puerariae, and Rhizoma Ligustici Chuanxiong as 9: 9: 6: 6) is a traditional Chinese medicine prescription for treating ischemia cerebral apoplexy. In this work, four cell injury models of ischemic stroke were establish, namely hypoxic injury, glutamate damage, injury of potassium chloride and hydrogen peroxide damage model. The protective effects of NMT and its single herbs-containing sera of different time points on PC12 cell damage were evaluated respectively, and the corresponding efficacy-time curves were drawn. Cell viability was measured by MTT (3-(4,5)-Dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide) assay. Furthermore, an statistical methods of support vector machine (SVM) were used to establish the correlation between concentration-time-efficacy for the first time. These results revealed that NMT-containing serum has obvious protective effect on the four injury models and can significantly improve cell viability. The PK-PD correlation between fifteen ingredients in the NMT compound with four model efficacy indexes indicated that rhein, puerarin, and 3'-methoxy puerarin might be the most important constituents controlling the pharmacological effects of NMT. The study suggested that these fifteen components are likely to be the material basis of NMT and recommended to increase the amounts of Pueraria in the NMT compound. That provided the scientific basis and demonstration for the research of efficacy material base of Traditional Chinese Medicine (TCM).

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase- (PI3K-) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K- remain unclear. We hypothesized MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K- pathway. Five days after receiving a single bolus of 0.075 units bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-1, oxidative loads, Masson’s trichrome staining, extracellular collagen levels, positive staining of -smooth muscle actin, PI3K- expression, and myonuclear apoptosis (P &lt; 0.05). Decreased diaphragm contractility and peroxisome proliferator activated receptor- coactivator-1 levels were also observed (P &lt; 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K- activity (P &lt; 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated through PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.

Traumatic brain injury (TBI) is among the leading causes of mortality and long-term impairment globally. TBI has a dynamic pathology encompassing a variety of metabolic and molecular events that occur in two phases, primary and secondary. An external forceful blow to the brain initiates the primary phase, which is followed by a secondary phase that involves the release of calcium ions (Ca2+) and the initiation of a cascade of inflammatory processes, including mitochondrial dysfunction, rise in oxidative stress, activation of glial cells, and damage to the blood-brain barrier (BBB), resulting in paracellular leakage. There is currently no FDA-approved drug for TBI, but existing approaches rely on delivering small and macromolecular treatments, which are severely constrained by the BBB, poor retention, off-target toxicity, and complex pathology of TBI. Therefore, there is a demand for innovative and alternative therapeutics with effective delivery tactics for diagnosis and treatment of TBI. Tissue engineering and use of biomaterials is one such alternative approach. With this approach, neuronal stem cell therapy is combined with synthetically generated tissue materials such as hydrogels, self-assembling peptides, and electrospun nanofibers, which may induce neurite outgrowth, differentiation of human neural stem cells, and nerve gap bridging in TBI. This review examines tissue engineering and the use of biomaterials as potential treatments for TBI, including their synthesis, mechanisms of action, and limitations. The review also discusses challenges facing tissue engineering and biomaterial technology including survival rate of transplanted stem cells and the development of biodegradable, biocompatible, and mechanically flexible biomaterials. A better understanding of the mechanisms and drawbacks of these novel therapeutic approaches will help guide the design of future TBI therapies.

Embryonic genetic mechanisms are present in the brain and ready to be placed into action upon cellular injury termed the response to injury wound healing (RTIWH) mechanism. When injured, regional brain endothelial cells initially undergo activation and dysfunction with initiation of hemostasis, inflammation (peripheral leukocytes and innate microglia and perivascular macrophage cells), proliferation (astrogliosis), remodeling, repair, and resolution phases if the injurious stimuli are removed. In conditions wherein the injurious stimuli are chronic as occurs in obesity, metabolic syndrome, and type 2 diabetes mellitus this process does not undergo resolution and there is persistent RTIWH with remodeling. Indeed, the brain is unique, in that it utilizes its neuroglia: the microglia cell along with peripheral inflammatory cells and its astroglia instead of peripheral scar-forming fibrocytes/fibroblasts. The brain undergoes astrogliosis to form a gliosis scar instead of a fibrosis scar to protect the surrounding neuropil from regional parenchymal injury. One of the unique and evolving remodeling changes in the brain is the development of enlarged perivascular spaces (EPVS), which is the focus of this brief review. EPVS are important since they serve as a biomarker for cerebral small vessel disease and also represent an impairment of the effluxing glymphatic system that is important for the clearance of metabolic waste from the interstitial fluid to the cerebrospinal fluid and disposal. Therefore, it is important to better understand how the RTIWH mechanism is involved in the development of EPVS that are closely associated with and important to the development of premature and age-related cerebrovascular and neurodegenerative diseases with impaired cognition.

Glial fibrillary acidic protein (GFAP) is the major intermediate filament III protein of astroglia cells which is upregulated in traumatic brain injury (TBI). Here we reported that GFAP is truncated at both the C- and N-terminals by cytosolic protease calpain to GFAP breakdown products (GBDP) of 46-40K then 38K following pro-necrotic (A23187) and pro-apoptotic (staurosporine) challenges to primary cultured astroglia or neuron-glia mixed cells. In addition, with another pro-apoptotic challenge (EDTA) where caspases are activated but not calpain, GFAP was fragmented internally, generating a C-terminal GBDP of 20 kDa. Following controlled cortical impact in mice, GBDP of 46-40K and 38K were formed from day 3 to 28 post-injury. Purified GFAP protein treated with calpain-1 and -2 generates (i) major N-terminal cleavage sites between A-56 and A-75, and (ii) major C-terminal cleavage sites between T-383 and Q-388, producing a limit fragment of 38K. Caspase-6 treated GFAP was cleaved at D-78, R-79, D-266 and A-267, where GFAP was relatively resistant to caspase-3. We also derived a GBDP-38K N-terminal-specific antibody which only labels injured astroglia cell body in both cultured astroglia and mouse cortex and hippocampus after TBI. As a clinical translation, we observed that CSF samples collected from severe human TBI have elevated levels of GBDP-38K as well as two C-terminally released GFAP peptides (DGEVIKES and DGEVIKE). Thus, in addition to intact GFAP, both the GBDP-38K as well as unique GFAP released C-terminal proteolytic peptides species might have the potential in tracking brain injury progression.

Background: Inflammation is an important mechanism in atherosclerosis and plaque formation. C-reactive protein (CRP) is a common inflammatory biomarker associated with the risk of coro-nary heart disease. We investigated the relationship of CRP with findings from myocardial per-fusion imaging (MPI). Methods: In this retrospective study, 102 consecutive patients (mean age 71 years, 68% males) that underwent MPI (for diagnostic reasons or quantification of myocardial ischemia) and CRP determination (upper limit: 6mg/L) within 1 month from MPI, were included. Patients had no infection or recent acute coronary syndrome. Results: the median CRP level was 4mg/L (2,10) among the study population. Patients with raised CRP had higher summed stress score (SSS) (P = 0.006) and summed rest score (SRS) (P = 0.001) and higher risk for SSS > 3 (OR 9.25, 95% CI 2.03-42.13, P = 0.001) compared to those with low CRP. The association of SSS and SRS with CRP levels was more evident in patients over 70 years (P = 0.027 and P = 0.005 respectively). No significant difference in summed difference score was shown. The two groups had no difference in other risk factors (p > 0.05 for all comparisons). Conclusion: A high level of CRP was associated with the presence and extent of stress-induced myocardial ischemia in MPI.

Introduction: The COVID-19 pandemic challenged people with spinal cord injury (SCI) regarding a variety of mental and physical issues. New challenges may arise as the effects of the pandemic continue. The objective of the present study was to explore the social participation of Canadians with SCI during the second wave of COVID-19. Methods: Participants with SCI from two Canadian provinces (Quebec and British Columbia) were interviewed. Results: Eighteen participants completed interviews. Facilitators of social participation remain similar since the first wave of COVID-19, such as the use of technology, help received by relatives and the use of delivery services to obtain groceries and other essentials. Obstacles to mobility due to winter conditions and lack of considerations related to COVID-19 public health measures specific to wheelchair users were also discussed by participants. Conclusions: People with SCI perceived participation restrictions, little changes in life habits, and uncertainty about the future during the second wave of COVID-19. The unique living conditions of people with SCI, ability to adapt life habits, and the lived experiences of people with SCI may have contributed to an overall resilience during the pandemic. Adaptive families, social contacts and technology made a difference during the pandemic.

Despite ongoing efforts, the relationship between groin strength and injury remains unclear. The challenge of accurately predicting injuries presents an opportunity for researchers to develop pre-vention strategies to reduce the occurrence of such injuries. Consequently, this issue requires further investigation to obtain insights into effective mitigation strategies. In 120 male soccer players the maximum isometric strength of the hip muscle groups was measured, and the strength ratios were calculated. Previous injury and anthropometric data were registered. Injury data were collected following the FIFA/UEFA consensus. The K- Nearest Neighbour (k-NN), was used to predict the incidence of injury, while the significant predictive variables of the k-NN algorithm were fitted into a multivariate logistic regression model (LR) to analyze the likelihood of players sustaining a groin injury. The LR model determined two variables as significant predictors of groin injury. Players were less likely to sustain a groin injury by 76% for each decrease of the Adductors/Abductors isometric strength ratio in the non-dominant limb (OR = 0.238, CI 95%= [(0.098-0.572]). Players with a history of previous injury had a 67% greater risk of sustaining an injury (OR = 0.333, CI 95%= [(0.1068-1.038]). Isometric hip adductor and abductor strength im-balances of the non-dominant lower limb and a history of previous injury were risk factors for groin injury in soccer players.

Capsinoids (CAP) are potential antioxidant agents capable of reducing oxidative damage and the resulting complications triggered by obesity. Thus, the aim of this study was to investigate the effects of CAP on adiposity and biomarkers of cardiac oxidative stress in rats with obesity induced by a high-fat diet. Male Wistar rats were exposed to a high-fat diet for 27 consecutive weeks. After characterization of obesity (week 19), some of the obese (Ob) animals began to receive capsinoids (10 mg/kg/day) by orogastric gavage. Adiposity and comorbidities were assessed. In the heart, remodeling, injury and biomarkers of oxidative stress were determinated. The treatment did not reduce the adiposity induced d by obesity, but they were efficient in reducing cholesterol levels. CAP treatment did not cause a difference in heart and LV mass, despite having reduced troponin I concentrations. Furthermore, capisinoids did not reduce the increase in advanced oxidation of proteins products (AOPP) and carbonylated proteins (CBO) caused by obesity in cardiac tissue. Besides that, it was observed that ObCap rats presented high levels of malondialdehyde and greater activity of antioxidant enzymes compared to Ob. In conclusion, treatment with capsinoids did not lead to significant positive effects in reducing obesity-induced oxidative stress.

Ultrasound imaging is a vital imaging tool in musculoskeletal medicine, with the number of publications on ultrasound-guided surgery increasing in recent years. However, ultrasound imaging has drawbacks, such as operator dependency and image obscurity. Artificial Intelligence (AI) and Deep Learning (DL), a subset of AI, can address these issues. DL methods, including segmentation, detection, and localization of target tissues and medical instruments, potentially allow physicians and surgeons to perform ultrasound-guided procedures more accurately and efficiently. This review summarizes recent advances in ultrasound-guided procedures for musculoskeletal diseases and provides a comprehensive overview of the utilization of AI/DL in ultrasound for musculoskeletal medicine, particularly focusing on ultrasound-guided surgery.

Genetics plays an integral role in athletic performance and is increasingly becoming recognised as an important risk factor for injury. Ankle and knee injuries are the most common injuries sustained by soccer players. Often these injuries result in players missing training and matches, which can incur significant costs to clubs. This study aimed to identify genotypes associated with ankle and knee injuries in soccer players and how these impacted the number of matches played. 289 soccer players including 46 professional, 98 semi-professional and 145 amateur players were genetically tested. Ankle and knee injuries and the number of matches played were recorded during the 2014/15 season. Four genes were assessed in relation to injury. Genotypes found to be associated with injury included the TT genotype of the GDF5 gene, TT and CT genotypes of AMPD1 gene, TT genotype of COL5A1 and GG genotype of IGF2 gene. These genes were also associated with a decrease in the number of matches played.

Exoskeleton technology has been shown to be useful for individuals with spinal cord injury (SCI), potentially facilitating their recovery of motor function and social reintegration. However, studies on the safety and usability of exoskeletons are limited. This study aimed to design a powered exoskeleton for SCI and evaluate its safety and usability. Ten healthy adults participated in this study. The prototype exoskeleton featured an adjustable frame, computer-controlled hip and knee joint actuators, and a gait-trigger sensor. The experimental actions included walking, standing, and sitting, with and without the prototype. Safety outcomes included adverse events, vital signs, numerical rating scale (NRS) scores for pain, discomfort, and fatigue, and prototype-human body clearance. Usability outcomes included donning and doffing times, subjective ratings, gait speed, stride length, and kinematic parameters of hip and knee joint angles. Safety outcomes showed no serious adverse events, stable vital signs, minimal NRS scores, and acceptable clearance. Usability outcomes showed high efficiency and received positive ratings. Kinematic parameters showed significant positive correlations between normal walking and walking with the prototype for both hip and knee joint angles, confirming its effectiveness in assisting walking. However, further device improvements and gait parameter tuning are necessary for future clinical application.

Chronic Limb Threatening Ischemia (CLTI) represents the end stage form of peripheral arterial disease (PAD) and is associated to very poor prognosis with high risk of limb loss and mortality. It can be considered very similar to a terminal cancer disease reflecting a large impact on quality of life and healthcare costs. The aim of this study is to offer an overview of the relationship between CLTI, limb salvage and mortality with a focus on the need of a fast-track team-based management, that’s a driver to achieve better survival results. This review can be useful to improve management of this growing impact disease, and promote standardisation of care and communication between specialist and non-specialist health care professionals.

The sensitivity of exercise ECG is marginally sufficient for detection of mild reduction of coronary blood flow in patients with early coronary atherosclerosis. Here we describe the application of new technique of ECG registration/analysis – ultrahigh resolution ECG (UHR ECG) – for early detection of myocardial ischemia (MIS). The utility of UHR ECG vs. conventional ECG (C ECG) was tested in anesthetized rats and pigs. Transmural MIS was induced in rats by the ligation of the left coronary artery (CA). In pigs, subendocardial ischemia of variable extent was produced by stepwise inflation of balloon within the right CA causing 25-100% reduction of its lumen. In rats, a reduction in power spectral density (PSD) in high-frequency (HF) channel of UHR ECG was registered at 60 s after ischemia (power 0.81±0.14 vs. 1.25±0.12 mW at baseline, p<0.01). This was not accompanied by any ST segment elevation on C ECG. In pigs, PSD in HF channel of UHR ECG was significantly decreased at 25% reduction of CA lumen, while ST segment on C ECG remained unchanged. In conclusion, UHR ECG enabled earlier detection of transmural MIS compared to C ECG. PSD in HF-channel of UHR ECG demonstrated greater sensitivity in the settings of subendocardial ischemia.

Sports traumatic brain injury (TBI) accounts for up to 20% of all sports injuries, and the number of cases is growing year by year due to an increase in the number of people involved in sports, the growing popularity of extreme and contact sports, as well as a high level of motivation to achieve record results. Mild TBI dominates, which can provoke the development of a very wide range of complications and negative consequences. In the programs for the prevention of complications and the rehabilitation of athletes after TBI, TBI features are not sufficiently considered, which significantly differ from household, road or criminal injuries. There are no instrumental methods for diagnosing the severity of the injury. Sports TBI is characterized by repeated frequent TBI, elevated body and brain temperature, peripheral redistribution of blood flow and hypocapnia, which significantly affect cerebral blood flow. Brain injury is an independent cause of the development of cerebral hyperthermia, which significantly worsens the consequences of TBI. To diagnose sports TBI, the method of microwave radiometry of the brain (MWR) can be used. For the prevention of complications, the technology of craniocerebral hypothermia (CCH), which allows for to reduce of physical general and cerebral hyperthermia, and increases the resistance of cerebral cortex neurons to hypoxia and trauma could be used However, these approaches in sports medicine are used sporadically, which, is due to the lack of awareness of coaches and doctors of sports teams. The purpose of the review is to present MWR and CCH in sports TBI.

(1) Background: This study aims to investigate differences in the perspectives of exercise intensity for resistance exercise of healthcare professionals (HCPs) and adults living with spinal cord injury (SCI) in Asian countries. Also, it verifies the appropriateness of the conventional indicators for resistance exercise intensity in an Asian context; (2) Methods: 121 certified HCPs and 107 adults with SCI participated in a survey conducted in Indonesian, Japanese, Korean and Thai languages. The survey asked what principles are important for prescribing resistance exercise, and if ‘moderate’ and ‘vigorous’ were appropriate terms for indicating an intensity level. Perspective differences were examined between both groups and, further, between countries from a psychosocial perspective; (3) Results: Of the HCPs, 92% perceived that resistance exercise intensity was far more important than frequency, time or type of exercise while frequency (61%) followed by intensity (58%) was perceived as important by respondents with SCI. Only Japanese respondents with SCI agreed with HCP’s perception of intensity. Both HCPs and respondents with SCI showed unfavorable responses on the usage of ‘moderate’ and ‘vigorous’ for describing resistance exercise intensity, especially Japanese HCP and respondents with SCI from Indonesia; (4) Conclusion: Our findings suggest that non-HCPs must improve their perceptions of exercise intensity. Findings also suggest the need for more explicit and user-friendly terms or expressions indicating the level of intensity in a local (Asian) context.

Hamstring injuries present a notable challenge to the performance and durability of soccer athletes, particularly those situated in rural areas where access to specialized training facilities may be scarce. This literature review delves into the amalgamation of resistance and flexibility training as a holistic strategy for averting hamstring injuries among rural-based soccer athletes. Utilizing existing scholarly works, this review underscores the significance of resistance training in enhancing hamstring strength, power, and stamina, while flexibility training augments muscle pliability and range of motion, thus diminishing the likelihood of injuries. Furthermore, it scrutinizes a range of resistance and flexibility routines customized to meet the specific requirements of soccer and the limitations of rural settings. Through the amalgamation of evidence-based methodologies, this review puts forth the mechanisms of injury and pragmatic suggestions for coaches, trainers, and athletes to implement efficient injury prevention protocols. Highlighting the collaborative advantages of resistance and flexibility training, this methodology strives to enhance performance and shield against hamstring injuries in rural-based soccer athletes.

A risk of ischemic stroke increases exponentially after menopause. Even a mild-ischemic stroke can result in increased frailty. Frailty is a state of increased vulnerability to adverse outcomes, which subsequently increases risk of cerebrovascular events and severe cognitive decline, particularly after menopause. Several interventions to reduce frailty and subsequent risk of stroke and cognitive decline have been proposed in laboratory animals and patients. One of them is whole body vibration (WBV). WBV recuperates cerebral function and cognitive ability that deteriorates with increased frailty. The goal of the current study is to test the efficacy of WBV in reducing post-ischemic stroke frailty and brain damage in reproductively senescent female rats. Reproductively senescent Sprague–Dawley female rats were exposed to transient middle cerebral artery occlusion (tMCAO) and randomly assigned to either WBV or control groups. Animals placed in the WBV group underwent 30 days of WBV (40 Hz) treatment performed twice daily for 15 min each session, 5 days each week. The motor functions of animals belonging to both groups were tested intermittently and at the end of treatment period. Brains were then harvested for inflammatory markers and histopathological analysis. The results demonstrate a significant reduction in inflammatory markers and infarct volume with significant increases in brain-derived neurotrophic factor and improvement in functional activity after tMCAO in middle-aged female rats that were treated with WBV as compared to the control group. Our results may facilitate a faster translation of the WBV intervention for improved outcome after stroke, particularly among frail women.

Background/Objectives: Infectious Endocarditis often requires surgical intervention, with postoperative acute kidney injury (AKI) posing a significant concern. This retrospective study aimed to investigate AKI incidence, its impact on short-term mortality, and identify modifiable factors in patients with endocarditis scheduled for valve surgery. Methods: This single center study enrolled 130 consecutive endocarditis patients from 2013 to 2021 undergoing valve surgery. Creatinine levels were monitored pre- and postoperatively, and AKI was defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Patient demographics, comorbidities, procedural details, and complications were recorded. Primary outcomes included AKI incidence, the relevance of creatinine levels for AKI detection, and the association of AKI with 30-, 60- and 180-day mortality. Modifiable factors contributing to AKI were explored as secondary outcomes. Results: Postoperatively, 35.4% developed AKI. The highest creatinine elevation occurred on the 2nd postoperative day. Best predictive value for AKI was a creatinine level of 1.35 mg/dl on the 2nd day (AUC: 0.901; sensitivity: 0.89, specificity: 0.79). Elevated creatinine levels on the 2nd day were robust predictors for short-term mortality at 30, 60 and 180 days postoperatively (AUC ranging from 0.708 to 0.789). CK-MB levels at 24 hours postoperatively and minimum hemoglobin during surgery were identified as independent predictors for AKI in logistic regression. Conclusions: This study highlights the crucial role of creatinine levels in predicting short-term mortality in surgical endocarditis patients. A specific threshold (1.35 mg/dl) provides a practical marker for risk stratification, offering insights for refining perioperative strategies and optimizing outcomes in this challenging patient population.

The nuclear factor-ĸB (NF-ĸB) transcriptional system is a major effector pathway involved in inflammatory responses. Previous studies found that a Gardenia decoction (GD) inhibited the expression of NF-κB in a lipopolysaccharide (LPS)-stimulated mouse intestinal injury model. Herein, we hypothesized that geniposide (GE), a component of Gardenia jasminoides Ellis, also exerts anti-inflammatory effects and inhibits NF-ĸB activity in LPS-induced intestinal epithelial cells (IEC-6). IEC-6 cells were stimulated with LPS, following which the effects of GE on NF-ĸB signaling in the IEC-6 cells were examined by western blotting to detect IĸB phosphorylation/degradation. The expression of NF-κB was determined by immunofluorescence assay (IFA). Enzyme-linked immunosorbent assay (ELISA) was used to detect the inhibitory effect of GE on the release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) activated by LPS in IEC-6 cells. In addition, the migration ability of IEC-6 cells was observed by the scratch method. These results showed that GE dose-dependently downregulated levels of the proinflammatory cytokines TNF-α, IL-6 and IL-1β that had been upregulated by LPS and suppressed the phosphorylation of IĸB and NF-ĸB induced by LPS. Our findings indicated that GE could reduce LPS-induced NF-ĸB signaling and proinflammatory expression in IEC-6 cells and significantly enhance the migration of IEC-6 cells. Moreover, GE inhibited the expression of NF-κB, nuclear transfer, and transcriptional activity in IEC-6 cells. GE could block the synthesis of inflammatory factors of IEC-6 cells by inhibiting activation of the IĸB/NF-κB signaling pathway induced by LPS.

Delineating the epidemic of vaccine injury from the coterminous condition long covid is a challenging prospect, but one with many implications not just for treatment, but also has important legal considerations for settlements of vaccine injury. The shared etiological factor of the spike protein in both vaccine injury and long covid make differentiation difficult, and while treatment is largely similar between vaccine injury and long covid, there are important distinctions. Furthermore, diagnostics are important for monitoring treatment progress and assessing the extent of subclinical vaccine injury in population having received a covid-19 vaccine. The development of rigorous diagnostics is an important step towards the recognition of both long covid and vaccine injury, as those suffering these conditions have faced immense challenges in having their conditions recognized, treated, and compensated by insurance companies or national health services.

Spinal Cord Injury in children can be a devastating condition in children with profound implications for their overall health and quality of life. In this review we aim to provide a concise overview of the key aspects associated with SCI in pediatric population. Firstly, we discuss the etiology and epidemiology of SCI in children, highlighting the diverse range of causes. We explore the unique anatomical and physiological characteristics of the developing spinal cord that contribute to the specific challenges faced by pediatric patients. Next, we delve into the clinical presentation and diagnostic methods, emphasizing the importance of prompt and accurate diagnosis to facilitate appropriate interventions. Furthermore, we approach the multidisciplinary management of pediatric SCI, encompassing acute medical care, surgical interventions, and ongoing supportive therapies. Finally, we explore emerging research and innovative therapies in the field and we emphasize the need for continued advancements in understanding and treating SCI in children to improve their functional independence and overall quality of life.

Background. Sarcopenia and spinal cord injury (SCI) often coexist, but little is known about the associations of these two pathologies. This study aimed to assess the impact of SCI on muscle and bone mass and the correlations between clinical characteristics of SCI patients and sarcopenia. Methods: 136 patients diagnosed with SCI admitted to rehabilitation hospital were included in the study. The type and severity of injury (AIS), the level of spasticity (MAS), bone mineral density and Appendicular Lean Muscle Mass (ALM) were assessed. Sarcopenia was diagnosed according to the recommended EWGSOP2 cut-off points for ALM. Results: There was a statistically significant association between the ALM value and the gender, 75% of women developing sarcopenia. Among men, 42.9% had sarcopenia. Over 55% of AIS Grades A and B cases had sarcopenia. Mean age of sarcopenic patients was 35.8 years and they had multiple comorbidities. 51.6% of the patients with osteoporosis had sarcopenia. 69.7% of MAS level 0 cases had sarcopenia, while this was diagnosed in about 40% of patients with MAS levels 1-4. Conclusions: Gender, type of injury, presence of multiple comorbidities and age were directly associated with sarcopenia, while surprisingly, spasticity level and the presence of immobilization osteoporosis were not.

Traumatic nerve injuries are common lesions that affect several hundred thousand humans, as well as dogs and cats. The assessment of nerve regeneration trough animal models may provide information for translational research and future therapeutic options that can be applied mutually in veterinary and human medicine, in a one health perspective. This review offers a hands-on vision about the non-invasive and conservative approaches on peripheral nerve injury, focusing the role of neurorehabilitation in nerve repair and regeneration. The peripheral nerve injury may lead to hypersensitivity, allodynia and hyperalgesia, with the possibility of joint contractures, decreasing functionality and impairing the quality of life. The question remains regarding how to improve nerve repair with surgical possibilities, but also considering electrical stimulation modalities by modulating sensory feedback, upregulation BDNF, GFNF, TrKB and adenosine monophosphate, maintaining muscle mass and modulating fatigue. This could be improved by the positive synergetic effect of exercises and physical activity with locomotor training, and other physical modalities, such as low-level laser therapy and ultrasounds. In addition, the use of cell-based therapies is an innovative treatment tool in this field. These strategies may help avoiding situations of permanent monoplegic limbs that could lead to amputation.

Acute kidney injury (AKI) is a clinical syndrome where a rapid decrease in kidney function and/or urine output is observed, which may result in the imbalance of water, electrolyte and acid base, and is associated with poor prognosis and prolonged hospitalization. Therefore, early diagnosis and treatment to avoid the severe AKI stage is important. While several biomarkers, such as urinary L-FABP and NGAL, can be clinically useful, there is still no gold standard for early detection of AKI and there are limited therapeutic options against AKI. miRNAs are non-coding and single-stranded RNAs that silence their target genes in the post-transcriptional process and are involved in a wide range of biological processes. Recent accumulated evidence has revealed that miRNAs may be potential biomarkers and therapeutic targets for AKI. In this review article, we summarize the current knowledge about miRNAs as promising biomarkers and potential therapeutic targets for AKI, as well as the challenges in their clinical use.

Ischemic stroke (IS) is a group of vascular disease concomitant with high morbidity and mortality. Berberine is a bioactive substance and it has known to improve stroke, but the mechanism is yet to be proven. Mice were fed with BBR for 14 days. Then, mice were made into MCAO/R models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were detected. We tested the changes of intestinal flora in model mice after BBR administration by 16SrRNA sequencing. Chromatography-mass spectrometry was used to detect butyrate chemically. Tissue immunofluorescence was used to detect the changes of microglia and astroglia in mice brain. Our findings suggest that berberine improves stroke outcomes by modulating gut microbiota. Specifically, after MCAO/R mice were given berberine, beneficial bacteria producing butyric acid increased significantly, and the mice also had significantly higher levels of butyric acid. Administration of butyric acid and an inhibitor of butyric acid synthesis, heptyl-coA, showed that butyric acid improved stroke outcomes in model mice. In addition, butyric acid could inhibit the activation of microglia and astrocytes in the brain of model mice, thereby inhibiting the release of inflammatory cytokines IL-6, IL-1β, TNF-α and improving stroke outcomes. Our results suggest that berberine may improve stroke outcomes by modulating the gut flora to increase the abundance of butyric acid. These findings elucidate the mechanisms by which berberine improves stroke outcomes and provide some basis for clinical treatment.

Background: Inflammatory demyelination and impaired recovery processes result in permanent neurodegeneration and neurological disability in patients with multiple sclerosis (MS). In terms of smoldering MS, chronic neuroinflammation develops in the early period of the disease and leads to confirmed disability accumulation. There is a great need to identify biomarkers of neuro-degeneration and disease progression. Methods: We evaluated the concentrations of the param-eters of brain injury (NF-H, GPAF, S100B, UCHL1) in the cerebrospinal fluid (CSF) and the se-lected interleukins (ILs) in serum of 123 relapsing-remitting MS (RRMS) and 88 progressive MS (PMS) patients. Results: The levels of GFAP, S100B and UCHL were higher in the PMS group compared to RRMS as opposed to the levels of NF-H. We observed a positive correlation be-tween the selected pro-inflammatory cytokines and the parameters of brain injury. The Ex-panded Disability Status Scale score (EDSS) increased with GFA and NF-H levels and correlated with the selected ILs. The concentrations of S100B, UCHL1 and NF-H reflected the duration of MS symptoms. Conclusions: The levels of brain injury parameters in the CSF and the selected serum ILs in MS patients seem to be promising biomarkers to determine neurodegeneration and neuroinflammation in smoldering MS. Further studies are warranted in this respect.

Anemia is a well-known disorder in CKD dogs, but its frequency in AKI dogs has been poorly investigated. The aim of the present study was to retrospectively evaluate the frequency of anemia, its degree of severity, and regeneration rate in relation to IRIS grade, etiology, therapy, and out-come. Medical records of dogs (2017-2023) with historical, laboratory, and ultrasound findings consistent with AKI were retrospectively reviewed. According to etiology, AKI was classified as ischemic/inflammatory (IS), infectious INF), nephrotoxic (NEP), obstructive (OBS), and unknown (UK). AKI dogs were also classified according to therapeutical management (medical vs hemo-dialysis), survival to hospital discharge (survivors vs non-survivors). AKI dogs were considered anemic in case of HCT 38 g/dL). Regeneration rate was considered absent (RET< 60,000/μL), mild 61,000- 150,000/μL), and moderate (> 150,000/μL). A total of 120 AKI dogs were included the study, and anemia was found in 86/120 dogs (72%). The severity of anemia was mild in 32/86 dogs (37%), moderate in 40/86 dogs (47%), severe in 11/86 dogs (13%), and very severe in 3/86 (3%). Anemia was normo-chromic in 71/86 dogs (83%), hyperchromic in 12/86 dogs (14%), and hypochromic in 3/86 dogs (3%). Normocytic anemia was present in 56/86 dogs (65%), microcytic anemia in 27/86 dogs (31%), and macrocytic anemia in 3/86 dogs (4%). Non-regenerative anemia was found in 76/86 dogs (88%). The frequency of anemia increased significantly (p

This study aimed to describe the injury profiles of young Korean baseball players according to position and age as the proportion and distribution of injuries based on playing position and age remains unclear. A total of 271 elite youth baseball players aged 8 to 16 years were divided into two groups: elementary school (ES) (n=135) and middle school (MS) (n=136). The participants' basic, baseball practice, and injury information were collected. Injuries in the MS group were not limited to the elbow and shoulder, and the injury prevalence varied by age group and baseball position. The most injured body region in the ES group was the elbow joint, regardless of the position. In contrast, the most injured body region in the MS group was the lower back, except for infielders whose elbows were the most injured. Additionally, the MS group was more likely to experience injuries of the lower back (OR=4.27, 95% CI=2.47–7.40), shoulder (OR=1.93, 95% CI=1.08–3.43; P=0.024), and knee (OR=2.15, 95% CI=1.17–3.94; P=0.012). Our findings indicate that excessive practice and lack of rest during MS (growth spurt period) can significantly increase the risk of lower back problems in young baseball players.

The combined muscle-skeletal traumas (MST) are very frequent over the last few years. The emergency care try to save the life of the patient and to receive resuscitation treatment. The role of Trauma surgeon is to choose the right moment for surgery. Aim: To present the management of patient with combined height injury, fracture stabilization, partial foot amputation, local flaps, skin grafting and HIFU – thermotherapy as scar treatment. Materials and methods: 40 years old mail patient, injured after a fall from 8 meters in an elevator shaft. After resuscitation treatment to control the shock the Imaging results are: burst fracture of L3 with spinal canal stenosis, fracture of the sacral bone Denis I, fracture of the right humerus in the proximal third, Monteggia fracture of the left arm, fracture of the proximal third of the right tibia as well as comminuted fractures of both calves and of both heel bones. Results: After a few operations his final result was well healed bone fractures and a good quality soft tissue coverage allowing the patient a satisfactory quality of life. Conclusions: Combined traumas of the muscle- skeletal system are severe, serious and difficult to manage. The good outcome in their treatment requires a team approach between the different medical specialists.

The meniscus is a meniscus-shaped fibrocartilage tissue located between the femur and tibia，it is mainly composed of meniscus cells and related extracellular matrix.The synovial limbus area of the knee joint capsule near the meniscus is divided into red areas with rich blood vessels and white areas with less blood supply according to the distribution of blood vessels,there is a transition zone called the red and white zone between the two;Red zone has better self-repair ability,The injury in this area can be treated by conservative treatment or surgical suture;Once the white area of the meniscus is torn and involves the free edge area,It is often necessary to partially remove the damaged meniscus.When most of the entire meniscus is severely torn and involved,not only the course of the disease is very long, but it cannot be repaired by sutures,Often a subtotal or total meniscus resection is required,whether it is a partial meniscus resection, a subtotal meniscus resection or a complete resection.In the later period, it may cause quadriceps atrophy and osteoarthritis (OA）.OA is a refractory multi-system disease,involve the patient’s peripheral joints,it has high disability and teratogenicity, and is very harmful to human health.Chondrocyte pyrolysis, degradation, and inflammation play a vital role in the destruction of OA articular cartilage and chondrocyte apoptosis.Meniscus stem cells have strong proliferation and differentiation ability,has become one of the hot spots in the field of meniscus repair,this article studies the role of meniscal stem cells in the development of OA.

Objective: The aim of this study was to evaluate the clinical outcome of patients suffering from chronic limb threatening ischemia (CLTI) and tissue loss treated with primary isolated femoral bifurcation endarterectomy (FBE) or with FBE combined with bypass surgery. Methods: This retrospective study was performed in a tertiary university based care center. Between January 2008 and December 2019 a prospectively collected database of patients suffering from CLTI and tissue loss and undergoing either primary FBE (group A) or FBE in combination with bypass surgery (group B) was analysed. Study endpoints were ulcer healing, primary and secondary patency rate, limb salvage and survival. Results: In total, FBE was performed in 73 and FBE with bypass in 60 patients. Between both groups there were no significant differences regarding demographic data or the Global Limb Anatomic Staging System (GLASS) grade III and IV of femoropopliteal lesions. After 3 years, ulcer healing could be achieved in 72% of FBE and in 75% of FBE with bypass patients. The primary patency rate was 95% and 91% for FBE and 83% and 80% for FBE with bypass after one and three years, respectively. The 3-year limb salvage rate was 78% for FBE and 84% for FBE with bypass. The secondary patency rate after one and three years was 99% and 97% for FBE and 93% and 88% for FBE with bypass. Conclusion: FBE and FBE with bypass are equally effective for ulcer healing in cases of combined CFA and superficial femoral artery lesions. There was no significant difference between both groups regarding primary and secondary patency

Endovascular techniques are currently considered as a first line treatment options for lower limb chronic limb-threatening ischemia (CLTI), defined by the presence of ischemic rest pain and severe tissue loss such as ulcers or gangrene. Although the technical success rate of endovascular revascularization is high, in specific patients with advanced infrapopliteal disease and absence of run-off tibial vessels ("desert foot"), the chance of successful revascularization is minimal. In order to avoid primary amputation several treatment option are currently being investigated, including different strategies such as gene therapy or venous arterialization techniques. This review focuses on the percutaneous deep venous arterialization technique, recently introduced in everyday clinical practice, as a promising, minimally invasive treatment option for limb salvage in CLTI patients presenting with “desert foot”.

Background: Vascular inflammation plays a crucial role in peripheral arterial disease (PAD), although the role of the mediators involved has not yet been properly defined. The aim of this work is to investigate gene expression and plasma biomarkers in chronic limb-threating ischemia (CLTI). Methods: Using patients from the GHAS trial, both blood and ischemic muscle samples were obtained to analyze plasma markers and mRNA expression, respectively. Statistical analy-sis was performed by using univariate (Spearman, t-Student, X2) and multivariate (multiple lo-gistic regression) tests. Results: 35 patients were available at baseline (29 for mRNA expression). Baseline characteristics (mean): Age:71.4±12.4 (79.4% male); TNF-α:10.7±4.9; hs-CRP:1.6±2.2; Neutrophil-to-lymphocyte ratio (NLR):3.5±2.8. Plasma TNF-α was found elevated (≥8.1) in 68.6% of patients, while high hs-CRP (≥0.5) in 60.5%. Diabetic patients with high level of inflammation showed significantly higher levels of NOX4 expression at baseline (p=0.0346). Plasma TNF-α had a negative correlation with eNOS expression (-0.5, p=0.015) and hs-CRP with VEGF-A (-0.63, p=0.005). The expression of NOX4 was parallel to that of plasma TNF-α (0.305, p=0.037), especial-ly in DM. Cumulative mortality at 12-month was related to NLR ≥3 (p=0.019) and TNF-α ≥8.1 (p=0.048). The best cut-off point for NLR to predict mortality was 3.4. Conclusions: NOX4 and TNF-α are crucial for the development and complications of lower limb ischemia, especially in DM. hs-CRP could have a negative influence on angiogenesis too. NLR and TNF-α represent suita-ble markers of mortality in CLTI. These results are novel because they connect muscle gene expres-sion and plasma information in patients with advanced PAD, deepening the search of new and ac-curate targets for this condition.

Non-alcoholic steatohepatitis (NASH) is a clinically serious stage of non-alcoholic fatty liver disease (NAFLD). Histologically characterized by hepatocyte ballooning, immune cell infiltration and fibrosis, NASH at a molecular level involves lipid induced hepatocyte death and cytokine production. Currently, there are very few diagnostic biomarkers available to screen NASH, and no pharmacological intervention is available for its treatment. In this study, we show that hepatocyte damage by lipotoxicity results in the release of extracellular RNAs (eRNAs) which serve as damage-associated molecular patterns (DAMPs) that stimulate the expression of pro-apoptotic and pro-inflammatory cytokines, aggravating inflammation, and cell death in HepG2 cells. Furthermore, the inhibition of eRNA activity by RNase 1 significantly increased cellular viability and reduced NF-kB mediated cytokine production. Similarly, RNase 1 administration significantly improved hepatic steatosis, inflammatory and injury markers in a murine NASH model. This study, therefore, for the first time, underscores the therapeutic potential of inhibiting eRNA action as a novel strategy for NASH treatment.

Extracorporeal membrane oxygenation (ECMO), in conjunction with its life-saving benefits, carries a significant risk of acute brain injury (ABI). Hypoxic-ischemic brain injury (HIBI) is one of the most common types of ABI in ECMO patients. Various risk factors such as history of hypertension, high day 1 lactate level, low pH, cannulation technique, large peri-cannulation PaCO2 drop (∆PaCO2), and early low pulse pressure, have been associated with the development of HIBI in ECMO patients. The pathogenic mechanisms of HIBI in ECMO are complex and multifactorial, attributing to the underlying pathology requiring initiation of ECMO and the risk of HIBI associated with ECMO itself. HIBI is likely to occur in the peri-cannulation or peri-decannulation time secondary to underlying refractory cardiopulmonary failure before or after ECMO. Current therapeutics target pathological mechanisms, cerebral hypoxia and is-chemia, by employing targeted temperature management in the case of extracorporeal cardiopulmonary resuscitation (eCPR), and optimizing cerebral O2 saturations and cerebral perfusion. This review describes the pathophysiology, neuromonitoring, and therapeutic techniques to improve neurological outcomes in ECMO patients so as to prevent and minimize the morbidity of HIBI. Further studies aimed at stand-ardizing the most relevant neuromonitoring techniques, optimizing cerebral perfusion, and minimizing the severity of HIBI once it occurs will improve long-term neurological outcomes in ECMO patients.

A Traumatic brain injury (TBI) is among the main causes of sudden death after head trauma. These injuries can result in severe degeneration and neuronal cell death in the CNS, including the retina which is a crucial part of the brain responsible for perceiving and transmitting visual information. The long-term effects of mild-repetitive TBI (rmTBI) are far less studied thus far, even though damages induced by repetitive injuries occurring in the brain are more common, especially amongst athletes. rmTBI can also have a detrimental effect on the retina and the pathophysiology of these injuries are likely to differ from the severe TBI (sTBI) retinal injury.Here we showed how rmTBI and sTBI can dissimilarly affect the retina. Our results indicate an increase in the number of activated microglial cells and Caspase3-positive cells in the retina in both traumatic models, suggesting a rise in the level of inflammation and cell death after TBI. The pattern of microglial activation appears evenly distributed and widespread but differs amongst the various retinal layers. sTBI induced microgial activation in both the superficial and deep retinal layers. In contrast to sTBI, no significant change occurred following the repetitive mild injury in the superficial layer, only the deep layer (spanning from the inner nuclear layer to the outer plexiform layer) shows microglial activation. This difference suggests that alternate response mechanisms play a role in the case of the different TBI incidents. The Caspase3 activation pattern showed a uniform increase in both the superficial and deep layers of the retina. This suggests a different action in the course of the disease in sTBI and rmTBI models and points to the need for new diagnostic procedures.Our present results suggest that the retina might serve as such a model of head injuries since the retinal tissue reacts to both forms of TBI and is the most accessible part of the human brain.

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macro-phages and reactive M1 microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in a the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlight the time-dependent transformation of reactive mi-croglia (M1) and astrocytes (A1) into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide sug-gestions on how to increase functional outcome after SCI and discuss key therapeutic approaches.

ACL injuries present significant challenges in sports medicine, particularly in restoring knee joint function and preventing further complications like subsequent injuries or post-traumatic osteoarthritis. Traditional rehabilitation techniques, which often rely on pre-planned exercises and standardized assessments, may not adequately prepare athletes for the unpredictable nature of sports. This paper argues for a comprehensive approach that recognizes ACL injuries as failures of complex nonlinear systems rather than merely biomechanical deficiencies. The complexity of ACL injuries involves a dynamic interplay of individual skills, team dynamics, and external conditions. Traditional rehabilitation approaches that focus solely on biomechanical factors overlook the critical role of interpersonal dynamics and sensorimotor control. The brain’s integration of sensory information to form a comprehensive environmental representation is vital for motor actions. Disruptions in this sensorimotor feedback loop can impair motor control, increasing the risk of ACL injuries. Effective rehabilitation should enhance sensory integration and feedback mechanisms, improving motor control and reducing re-injury risk. Addressing proprioceptive deficits and arthrogenic muscle inhibition (AMI) is crucial for successful rehabilitation. Neurocognitive training, focusing on enhancing decision-making and motor responses, is essential for sports performance and injury prevention. Techniques like neurofeedback training can optimize brain activity patterns, leading to better motor responses and adaptation to dynamic environments. Psychological factors such as motivation, anxiety, and fear significantly influence recovery. Integrating psychological support into rehabilitation programs can address these factors, leading to more comprehensive and effective recovery strategies. Innovative rehabilitation approaches, including EMG biofeedback, motor imagery, and virtual reality-based training, can enhance reactive motor planning and adaptability, preparing athletes for the demands of their sport. The future of ACL rehabilitation lies in embracing the complexity of the sensorimotor system and developing multidisciplinary interventions that promote beneficial neuroplasticity. Advances in neuroscience and technology, such as artificial intelligence, can lead to more personalized and effective rehabilitation programs. Recognizing and addressing the multifaceted nature of ACL injuries can significantly improve rehabilitation outcomes, ensuring athletes can safely and effectively return to their sports.

This study examined the association between pressure injuries and complexity of abdominal temperature measured in residents of a nursing facility. The temperature served as a proxy measure for skin thermoregulation. Refined multiscale sample entropy and bubble entropy were used to measure the complexity of the temperature time series measured over two days at 1-minute intervals. Robust summary measures were derived for the multiscale entropies and used in predictive models for pressure injuries that were built with adaptive lasso regression and neural networks. Both types of entropies were lower in the group of participants with pressure injuries (n=11) relative to the group of non-injured participants (n=15). This was generally true at the longer temporal scales, with the effect peaking at scale τ=23 minutes. Predictive models for pressure injury on the basis of refined multiscale sample entropy and bubble entropy yielded 92% accuracy, outperforming predictions based on any single measure of entropy. Combining entropy measures with a widely used risk assessment score led to the best prediction accuracy. Complexity of abdominal temperature series could therefore serve as an indicator of risk of pressure injury.

Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks after optic nerve crush (ONC) and analyzed the data from the Genomic Fabric Paradigm (GFP) to bring additional insights into the molecular mechanisms of the retinal remodeling after induction of RGC degeneration. GFP considers for the expression of each gene 3 independent characteristics: level, variability and correlation with each other gene. Thus, the 17,657 quantified genes our study generated a total of 155,911,310 values to analyze. This represents 8,830x more data per condition than a traditional transcriptomic analysis. ONC led to a 57% reduction in RGC numbers as detected by retrograde labeling with DiI. We observed a higher Relative Expression Variability after ONC. Gene expression stability was used as a measure of transcription control and disclosed a robust reduction in the number of very stably expressed genes. Predicted Protein-Protein interaction (PPI) analysis with STRING revealed axon and neuron projection as mostly decreased processes, consistent with RGC degeneration. Conversely, immune response PPIs were found among up-regulated genes. Enrichment analysis showed that Complement Cascade and Notch Signaling Pathway, as well as Oxidative Stress and Kit Receptor Pathway were affected after ONC. To expand our studies of altered molecular pathways, we examined the pair-wise coordination of gene expressions within each pathway and within the entire transcriptome using Pearson correlations. ONC increased the number of synergistically coordinated pairs of genes and the number of similar profiles mainly in Complement Cascade and Notch Signaling Pathway. This deep bioinformatic study provides novel insights beyond the regulation of individual gene expression and discloses changes in the control of expression of Complement Cascade and Notch Signaling functional pathways that may be relevant for both RGC degeneration and remodeling of the retinal tissue after ONC.

Following an initial mechanical insult, traumatic spinal cord injury (SCI) induces a secondary wave of injury, resulting in a toxic lesion environment inhibitory to axonal regeneration. This review focuses on the glial cell line-derived neurotrophic factor (GDNF) and its application, also in combination with other factors and cell transplantations, for repairing the injured spinal cord. As recent decades of studies strongly suggest combinational treatment approaches hold the greatest therapeutic potential for the central nervous system (CNS) trauma, future directions of combinational therapies will also be discussed.