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Acute kidney injury (AKI) is an underestimated, yet important risk factor for development of chronic kidney disease (CKD). Even after initial total recovery of renal function, some patients develop progressive and persistent deterioration of renal function and these patients are more likely to progress to end-stage renal disease (ESRD). Animal models are indispensable for unravelling the mechanisms underlying this progression towards CKD and ESRD and for the development of new therapeutic strategies in its prevention or treatment. Ischemia (i.e. hypoperfusion after surgery, bleeding, dehydration, shock, or sepsis) is a major aetiology in human AKI, yet unilateral ischemia-reperfusion is a rarely used animal model for research on CKD and fibrosis. Here, we demonstrate in C57Bl/6J mice, by both histology and gene expression, that unilateral ischemia-reperfusion without contralateral nephrectomy is a very robust model to study the progression from acute renal injury to long-term tubulo-interstitial fibrosis, i.e. the histopathological hallmark of CKD. Furthermore, we report that the extent of renal fibrosis, in terms of Col I, TGFβ, CCN2 and CCN3 expression and collagen I immunostaining, increases with increasing body temperature during ischemia and ischemia-time. Thus, varying these two main determinants of ischemic injury allows tuning the extent of the long-term fibrotic outcome in this model. Finally, in order to cover the whole practical finesse of ischemia-reperfusion and allow model and data transfer, we provide a referenced overview on crucial technical issues (incl. anaesthesia, analgesia, and pre- and post-operative care) with the specific aim of putting starters in the right direction of implementing ischemia in their research and stimulate them, as well as the community, to have a critical view on ischemic literature data.

Following the success of recent endovascular trials, endovascular therapy has emerged as an exciting addition to the arsenal of clinical management of patients with acute ischemic stroke (AIS). In this paper, we present an extensive overview of intravenous and endovascular reperfusion strategies, recent advances in AIS neurointervention, limitations of various treatment paradigms, and provide insights on imaging-guided reperfusion therapies. A roadmap for imaging guided reperfusion treatment workflow in AIS is also proposed. Both systemic thrombolysis and endovascular treatment have been incorporated into the standard of care in stroke therapy. Further research on advanced imaging-based approaches to select appropriate patients, may widen the time-window for patient selection and would contribute immensely to early thrombolytic strategies, better recanalization rates, and improved clinical outcomes.

Background Hyperoxemia may aggravate reperfusion brain injury after cardiac arrest. The aim of this study was to study the associations between different levels of hyperoxemia in the reperfusion period after cardiac arrest and 30-day survival. Methods Nationwide observational study using data from four compulsory Swedish registries. Adult in- and out-of-hospital cardiac arrest patients admitted to an ICU, requiring mechanical ventilation, between January 2010 and March 2021, were included. The partial oxygen pressure (PaO 2 ) was collected in a standardized way at ICU admission (± one hour) according to the simplified acute physiology score 3 reflecting the time interval with oxygen treatment from return of spontaneous circulation to ICU admission. Subsequently, patients were divided into groups based on the registered PaO 2 at ICU admission. Hyperoxemia was categorized into mild (13.4–20 kPa), moderate (20.1–30 kPa) severe (30.1–40 kPa) and extreme (> 40 kPa), and normoxemia as PaO 2  8–13.3 kPa. Hypoxemia was defined as PaO 2  < 8 kPa. Primary outcome was 30-day survival and relative risks (RR) were estimated by multivariable modified Poisson regression. Results In total, 9735 patients were included of which 4344 (44.6%) were hyperoxemic at ICU admission. Among these, 2217 were classified as mild, 1091 as moderate, 507 as severe, and 529 as extreme hyperoxemia. Normoxemia was present in 4366 (44.8%) patients and 1025 (10.5%) had hypoxemia. Compared to the normoxemia group, the adjusted RR for 30-day survival in the whole hyperoxemia group was 0.87 (95% CI 0.82–0.91). The corresponding results for the different hyperoxemia subgroups were; mild 0.91 (95% CI 0.85–0.97), moderate 0.88 (95% CI 0.82–0.95), severe 0.79 (95% CI 0.7–0.89), and extreme 0.68 (95% CI 0.58–0.79). Adjusted 30-day survival for the hypoxemia compared to normoxemia group was 0.83 (95% CI 0.74–0.92). Similar associations were seen in both out-of-hospital and in-hospital cardiac arrests. Conclusion In this nationwide observational study comprising both in- and out-of-hospital cardiac arrest patients, hyperoxemia at ICU admission was associated with lower 30-day survival.

To clarify whether the relaxation period during stretching affects the degree of elevated shear rate and the degree of reduction of arterial stiffness, we examined relaxation duration to build an adequate stretching protocol. In Experiment 1, the changes in cardiac output, the shear rate in the posterior tibial artery, and blood volume in the calf muscle were measured during recovery (0–60 s) from a single bout of one-legged passive calf stretching in 12 healthy young men. In Experiment 2, the effects of different relaxation periods (5-, 10-, 20-, and 60-s) of passive one-legged intermittent calf stretching (30-s × 6 sets) on the femoral-ankle pulse wave velocity (faPWV) as an index of peripheral arterial stiffness were identified in 17 healthy young men. As a result, the stretched leg’s shear rate significantly increased from 0 to 10 th s after stretching. The muscle blood volume in the stretched leg significantly reduced during stretching, and then significantly increased during the recovery period after stretching; however, cardiac output remained unchanged during stretching and recovery. Additionally, the reduction in faPWV from the pre-stretching value in the stretched leg was significantly larger in the protocol with 10-s and 20-s relaxation periods than that in the non-stretched leg, but this did not differ in the 5-s and 60-s relaxation periods. These findings suggest that the relaxation periods of intermittent static stretching that cause a high transient increase in shear rate (via reperfusion after microvascular compression by the stretched calf muscles) are effective to reduce arterial stiffness.

Background and Objectives: The majority of cardiac surgical procedures are performed using cardiopulmonary bypass and cardioplegia-induced cardiac arrest. Cardiac arrest and reperfusion may lead to ischemia-reperfusion injury of the myocardium. The aim of this study was to investigate whether gradual reperfusion with a slow increase in oxygen partial pressure leads to a reduction in reperfusion injury. Materials and Methods: Fifty patients undergoing elective cardiac surgery were included in this prospective randomized study. Patients in the hyperoxemic (control) group received conventional reoxygenation (paO2 250–300 mmHg). Patients in the normoxemic (study) group received gradual reoxygenation (1st-minute venous blood with paO2 30–40 mmHg, 2nd-minute arterial blood with paO2 100–150 mmHg). Periprocedural blood samples were taken serially, and markers of myocardial injury were analyzed. In addition, the influence of gradual reoxygenation on hemodynamics, inflammation, and the overall perioperative course was evaluated. Results: There was a trend toward higher CK levels in the hyperoxemia group without statistical significance; however, CK-MB and troponin T levels did not show any statistical difference between the two groups. Potassium concentrations in the coronary sinus were significantly higher in the hyperoxemia group at 3 and 8 min after opening of the aortic cross-clamp (6.88 ± 0.87 mmol/L vs. 6.30 ± 0.91 mmol/L and 5.87 ± 0.73 mmol/L vs. 5.43 ± 0.42 mmol/L, respectively; p = 0.03 and p = 0.02). All other measurements did not show a statistical difference between the two groups. Conclusions: The use of gradual reperfusion in cardiac surgery with cardiopulmonary bypass and cardiac arrest is safe. However, it does not reduce ischemia-reperfusion injury compared to standard hyperoxemic reperfusion.

Hemorrhagic transformation can complicate ischemic strokes after recanalization treatment within a time window that requires early intervention. To determine potential therapeutic effects of matrilin-3, rat cerebral ischemia-reperfusion was produced using transient middle cerebral artery occlusion (tMCAO); intracranial hemorrhage and infarct volumes were assayed through hemoglobin determination and 2,3,5-triphenyltetrazoliumchloride (TTC) staining, respectively. Oxygen-glucose deprivation (OGD) modeling of ischemia was performed on C8-D1A cells. Interactions between matrilin-3 and YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) were determined using RNA immunoprecipitation assay and actinomycin D treatment. Reperfusion after tMCAO modeling increased hemorrhage, hemoglobin content, and infarct volumes; these were alleviated by matrilin treatment. Matrilin-3 was expressed at low levels and YTHDF2 was expressed at high levels in ischemic brains. In OGD-induced cells, matrilin-3 was negatively regulated by YTHDF2. Matrilin-3 overexpression downregulated p-PI3K/PI3K, p-AKT/AKT, ZO-1, VE-cadherin and occludin, and upregulated p-JNK/JNK in ischemic rat brains; these effects were reversed by LY294002 (a PI3K inhibitor). YTHDF2 knockdown inactivated the PI3K/AKT pathway, inhibited inflammation and decreased blood-brain barrier-related protein levels in cells; these effects were reversed by matrilin-3 deficiency. These results indicate that YTHDF2-regulated matrilin-3 protected ischemic rats against post-reperfusion hemorrhagic transformation via the PI3K/AKT pathway and that matrilin may have therapeutic potential in ischemic stroke.

Background Cerebrolysin could mitigate reperfusion injury and hemorrhagic transformation (HT) in animal models of acute ischemic stroke. Methods This was a prospective, randomized, open-label, parallel-group with active control, multicenter pilot study. Cerebrolysin (30 mL/day over 14 days) was administered concurrently with alteplase (0.9 mg/kg) in 126 patients, whereas 215 control patients received alteplase alone. The primary outcomes were the rate of any and symptomatic HT assessed from day 0 to 14. The secondary endpoints were drug safety and functional outcome measured with the National Institutes of Health Stroke Scale (NIHSS) on day 1 and 14, and the modified Rankin scale (mRS) on day 90. Advanced brain imaging analysis was applied on day 1 and 14 as a marker for in vivo pharmacology of Cerebrolysin. Results Cerebrolysin treatment resulted in a substantial decrease of the symptomatic HT rate with an odds ratio (OR) of 0.248 (95% CI: 0.072–0.851; p  = 0.019). No serious adverse events attributed to Cerebrolysin occurred. On day 14, the Cerebrolysin arm showed a significant decrease in the NIHSS score ( p  = 0.045). However, no difference in the mRS score was observed on day 90. A substantial improvement in the advanced brain imaging parameters of the infarcted area was evident in the Cerebrolysin group on day 14. Conclusions Early add-on of Cerebrolysin to reperfusion therapy was safe and significantly decreased the rate of symptomatic HT as well as early neurological deficit. No effect on day 90 functional outcome was detected. Improvements in the imaging metrics support the neuroprotective and blood–brain barrier stabilizing activity of Cerebrolysin. Trial registration Name of Registry: ISRCTN. Trial Registration Number: ISRCTN87656744 . Trial Registration Date: 16/02/2021.

Brief moments of blood flow occlusion followed by reperfusion may promote enhancements in exercise performance. Thus, this study assessed the 24-h effect of post-exercise ischemic conditioning (PEIC) on exercise performance and physiological variables in trained cyclists. In a randomized, single-blind study, 28 trained cyclists (27.1 ± 1.4 years) performed a maximal incremental cycling test (MICT). The outcome measures were creatine kinase (CK), muscle soreness and perceived recovery status, heart rate, perceived exertion and power output. Immediately after the MICT, the cyclists performed 1 of the following 4 interventions: 2 sessions of 5-min occlusion/5-min reperfusion (PEIC or SHAM, 2 x 5) or 5 sessions of 2-min occlusion/2-min reperfusion (PEIC or SHAM, 5 x 2). The PEIC (50 mm Hg above the systolic blood pressure) or SHAM (20 mm Hg) treatment was applied unilaterally on alternating thighs. At 24 h after the interventions, a second MICT was performed. In all the groups, the CK levels were increased compared with the baseline (p < 0.05) after the 24-h MICT. The PEIC groups (2 x 5 and 5 x 2) felt more tired at 24 h post intervention (p < 0.05). However, both PEIC groups maintained their performance (2 x 5: p = 0.819; 5 x 2: p = 0.790), while the SHAM groups exhibited decreased performance at 24 h post intervention compared to baseline (2 x 5: p = 0.015; 5 x 2: p = 0.045). A decrease in the maximal heart rate (HR) was found only in the SHAM 2 x 5 group (p = 0.015). There were no other significant differences in the heart rate, power output or perceived exertion after 24 h compared with the baseline values for any of the interventions (p > 0.05). In conclusion, PEIC led to maintained exercise performance 24 h post intervention in trained cyclists.

Mitochondrial dysfunction has been implicated in the cell death observed after cerebral ischemia, and several mechanisms for this dysfunction have been proposed. Reperfusion after transient cerebral ischemia may cause continued and even more severe damage to the brain. Many lines of evidence have shown that mitochondria suffer severe damage in response to ischemic injury. The purpose of this study was to observe the features of mitochondrial dysfunction in isolated mitochondria during the reperfusion period following focal cerebral ischemia. Male Wistar rats were subjected to focal cerebral ischemia. Mitochondria were isolated using Percoll density gradient centrifugation. The isolated mitochondria were fixed for electron microscopic examination; calcium-induced mitochondrial swelling was quantified using spectrophotometry. Cyclophilin D was detected by Western blotting. Fluorescent probes were used to selectively stain mitochondria to measure their membrane potential and to measure reactive oxidative species production using flow cytometric analysis. Signs of damage were observed in the mitochondrial morphology after exposure to reperfusion. The mitochondrial swelling induced by Ca(2+) increased gradually with the increasing calcium concentration, and this tendency was exacerbated as the reperfusion time was extended. Cyclophilin D protein expression peaked after 24 hours of reperfusion. The mitochondrial membrane potential was decreased significantly during the reperfusion period, with the greatest decrease observed after 24 hours of reperfusion. The surge in mitochondrial reactive oxidative species occurred after 2 hours of reperfusion and was maintained at a high level during the reperfusion period. Reperfusion following focal cerebral ischemia induced significant mitochondrial morphological damage and Ca(2+)-induced mitochondrial swelling. The mechanism of this swelling may be mediated by the upregulation of the Cyclophilin D protein, the destruction of the mitochondrial membrane potential and the generation of excessive reactive oxidative species.

Hemorrhagic transformation (HT) is a severe complication occurring in acute ischemic stroke (AIS) patients. Stress hyperglycemia is frequent in patients with acute illness such as stroke. We aimed to explore the association between stress hyperglycemia and HT in AIS patients. A total of 287 consecutive participants with HT and 285 age- and sex-matched stroke patients without HT were enrolled in this study. Baseline glucose and glycated hemoglobin (HbA1c) levels were collected to measure stress hyperglycemia. The stress hyperglycemia ratio (SHR) was calculated by dividing the fasting plasma glucose at admission with HbA1c. HT was diagnosed by follow-up imaging assessment, and was radiologically classified as hemorrhagic infarction type (HI) 1 or 2 or parenchymal hematoma type (PH) 1 or 2. Univariate analysis showed that SHR is significantly higher among patients with HT than those without HT. Compared to the patients in the lower three quartiles of SHR, the incidence of HT was significantly higher among patients with the highest quartile of SHR in total population, diabetic and non-diabetic population. We also observed that patients with the highest SHR quartile were associated with an increased risk of hemorrhagic transformation after adjusted for potential covariates (68.4% versus 39.1%; adjusted odds ratio, 2.320; 95% confidence interval, 1.207-4.459; =0.012). The stress hyperglycemia ratio, representing the state of stress hyperglycemia, was significantly associated with an increased risk of hemorrhagic transformation in patients with acute ischemic stroke.