Local Ischemia Research Articles

Smartphone-Based Rigid Endoscopy Device with Hemodynamic Response Imaging and Laser Speckle Contrast Imaging.

Modern smartphones have been employed as key elements in point-of-care (POC) devices due to remarkable advances in their form factor, computing, and display performances. Recently, we reported a combination of the smartphone with a handheld endoscope using laser speckle contrast imaging (LSCI), suggesting potential for functional POC endoscopy. Here, we extended our work to develop a smartphone-combined multifunctional handheld endoscope using dual-wavelength LSCI. Dual-wavelength LSCI is used to monitor the changes in dynamic blood flow as well as changes in the concentration of oxygenated (HbO2), deoxygenated (Hbr), and total hemoglobin (HbT). The smartphone in the device performs fast acquisition and computation of the raw LSCI data to map the blood perfusion parameters. The flow imaging performance of the proposed device was tested with a tissue-like flow phantom, exhibiting a speckle flow index map representing the blood perfusion. Furthermore, the device was employed to assess the blood perfusion status from an exteriorized intestine model of rat in vivo during and after local ischemia, showing that blood flow and HbO2 gradually decreased in the ischemic region whereas hyperemia and excess increases in HbO2 were observed in the same region right after reperfusion. The results indicate that the combination of LSCI with smartphone endoscopy delivers a valuable platform for better understanding of the functional hemodynamic changes in the vasculatures of the internal organs, which may benefit POC testing for diagnosis and treatment of vascular diseases.

Abstract P3063: Selective Release Of Mitochondrial Dna After Brief Myocardial Ischemia

Objective: Mitochondrial DNA (mtDNA) is one of several pro-inflammatory damage-associated molecular patterns released from necrotic myocytes during myocardial infarction (MI). Based on our recent observation of a ~50-fold rise in circulating mtDNA after brief whole-body ischemia in a porcine model of cardiac arrest without ongoing MI, we hypothesized that ischemia-induced mtDNA release can occur in the absence of necrosis. Accordingly, we measured circulating mtDNA levels before and after localized myocardial ischemia of insufficient duration to produce myocyte necrosis in swine. Methods: Swine (n=6) were subjected to a 10-minute occlusion of the left anterior descending (LAD) coronary artery based on prior evidence that this duration of ischemia elicits myocardial injury without necrosis. Peripheral venous and coronary sinus (CS) blood samples collected at baseline (BL) as well as 1-hour and 24-hours after reperfusion were analyzed via qPCR to quantify mtDNA and nuclear DNA (nucDNA) release. Results were compared to a separate group of swine (n=6) subjected to a 75-minute LAD occlusion to produce MI. Results: Prolonged ischemia led to a significant rise in CS levels of mtDNA (6.2 ± 3.6-fold vs. BL; p<0.05) and nucDNA (5.4 ± 2.0-fold vs. BL; p<0.05) 1 hour after reperfusion, consistent with rapid non-selective DNA release after myocyte necrosis. In contrast, brief ischemia was associated with detectable elevations in CS mtDNA (4.6 ± 1.4-fold vs. BL; p<0.05) but not nucDNA (2.1 ± 0.5-fold vs. BL; p=0.35) at this timepoint. However, the magnitude of DNA release after brief or prolonged ischemia was not sufficient to increase circulating mtDNA or nucDNA, as peripheral venous levels of mtDNA and nucDNA did not differ from BL at 1-hour or 24-hours post-reperfusion in either group. Conclusion: Brief myocardial ischemia is associated with selective release of mtDNA into circulation, providing a potential mechanism by which immune activation may occur after myocardial injury even when myocyte necrosis is absent. The magnitude of mtDNA release after brief myocardial ischemia is ~10-fold lower than that detected in peripheral blood after resuscitation from cardiac arrest, suggesting that mtDNA is released from other organs after brief whole-body ischemia.

Study of morphological transformation and features of vascular blood flow of the wall of the small and large intestine in the simulation of ischemia in the experiment

Introduction. Ischemia of the small and large intestine of various degree was simulated in 45 sexually mature male rats of the Wistar line weighing 150-200 g on the basis of the Department of Experimental Medicine with vivarium at Privolzhsky Research Medical University. Аim. To present in an experiment the effect of different degrees of occlusive ischemia on the morphological transformation of the intestinal wall and the level of changes in blood flow.Materials and methods. The anesthetized animals underwent a median laparotomy with subsequent differentiation of the intestinal divisions: the jejunal section was selected in the small intestine, the ascending section was selected in the large intestine. With the help of a nylon thread (5-0), the blood supplying arcades of these zones were ligated and further exposed for 40, 60 and 120 minutes. During the indicated periods of ischemia, the average rate of blood supply in capillary microvessels located at a depth of 0.5-1.0 mm was estimated in relative units on 1.0 mm2-area (LACC-02, NPP Lazma, Russia). After the assessment of vascular blood flow was completed, ischemic intestinal areas were sampled for morphological examination. The study results were processed using Excel application and STADIA statistical package. Results. In the course of study, the authors registered clear relationships between blood flow parameters in different parts of the intestine and the duration of ischemia. Local trophic disturbance was combined with a transformation in the histoarchitectonics of the intestinal wall. It is noted that adaptive-regenerative mechanisms provide tissue stress reduction in 120 min. due to compensatory mechanisms of blood supply contributing to the restoration of the "villus-crypt" system of the mucous membrane.Conclusion. Thus, in case of local ischemia in the small and large intestine, the tissue structure is restored due to adaptive mechanisms of blood supply, this preserves the viability and functionality of the intestinal wall.

Immune regulation of the gut-brain axis and lung-brain axis involved in ischemic stroke.

Local ischemia often causes a series of inflammatory reactions when both brain immune cells and the peripheral immune response are activated. In the human body, the gut and lung are regarded as the key reactional targets that are initiated by brain ischemic attacks. Mucosal microorganisms play an important role in immune regulation and metabolism and affect blood-brain barrier permeability. In addition to the relationship between peripheral organs and central areas and the intestine and lung also interact among each other. Here, we review the molecular and cellular immune mechanisms involved in the pathways of inflammation across the gut-brain axis and lung-brain axis. We found that abnormal intestinal flora, the intestinal microenvironment, lung infection, chronic diseases, and mechanical ventilation can worsen the outcome of ischemic stroke. This review also introduces the influence of the brain on the gut and lungs after stroke, highlighting the bidirectional feedback effect among the gut, lungs, and brain.

Calcitonin gene-related peptide: a potential protective agent in cerebral ischemia-reperfusion injury.

Ischemic stroke is the most common type of cerebrovascular disease with high disability and mortality rates, which severely burdens patients, their families, and society. At present, thrombolytic therapy is mainly used for the treatment of ischemic strokes. Even though it can achieve a good effect, thrombolytic recanalization can cause reperfusion injury. Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a neuroprotective role in the process of ischemia-reperfusion injury. By combining with its specific receptors, CGRP can induce vasodilation of local cerebral ischemia by directly activating the cAMP-PKA pathway in vascular smooth muscle cells and by indirectly activating the NO-cGMP pathway in an endothelial cell-dependent manner,thus rapidly increasing ischemic local blood flow together with reperfusion. CGRP, as a key effector molecule of neurogenic inflammation, can reduce the activation of microglia, downregulates Th1 classical inflammation, and reduce the production of TNF-α, IL-2, and IFN-γ and the innate immune response of macrophages, leading to the reduction of inflammatory factors. CGRP can reduce the overexpression of the aquaporin-4 (AQP-4) protein and its mRNA in the cerebral ischemic junction, and play a role in reducing cerebral edema. CGRP can protect endothelial cells from angiotensin II by reducing the production of oxidants and protecting antioxidant defense. Furthermore, CGRP-upregulated eNOS can further induce VEGF expression, which then promotes the survival and angiogenesis of vascular endothelial cells. CGRP can also reduce apoptosis by promoting the expression of Bcl-2 and inhibiting the expression of caspase-3. These effects suggest that CGRP can reduce brain injury and repair damaged nerve function. In this review, we focused on the role of CGRP in cerebral ischemia-reperfusion injury.

The New Ice Age of Musculoskeletal Intervention: Role of Percutaneous Cryoablation in Bone and Soft Tissue Tumors.

In the rapidly evolving field of interventional oncology, minimally invasive methods, including CT-guided cryoablation, play an increasingly important role in tumor treatment, notably in bone and soft tissue cancers. Cryoablation works using compressed gas-filled probes to freeze tumor cells to temperatures below -20 °C, exploiting the Joule-Thompson effect. This cooling causes cell destruction by forming intracellular ice crystals and disrupting blood flow through endothelial cell damage, leading to local ischemia and devascularization. Coupling this with CT technology enables precise tumor targeting, preserving healthy surrounding tissues and decreasing postoperative complications. This review reports the most important literature on CT-guided cryoablation's application in musculoskeletal oncology, including sarcoma, bone metastases, and bone and soft tissue benign primary tumors, reporting on the success rate, recurrence rate, complications, and technical aspects to maximize success for cryoablation in the musculoskeletal system.

The Role of Mitochondrial Biogenesis in Ischemic Stroke.

Ischaemic stroke is a sudden neurological disorder caused by localised cerebral ischaemia and persistent cerebral infarction. Occlusion of large arteries due to atherothrombosis, cerebral embolism (i.e., embolic infarction), no thrombotic occlusion in small, deep cerebral arteries (i.e., lacunar infarction), and stenosis of proximal arteries due to hypotension leading to decreased cerebral blood flow in arterial supply zones are the most common causes of ischemic stroke (i.e., hemodynamic stroke). It is now known that organelles play an important role in various signaling events and cellular functions. The molecular mechanisms of mitochondria are involved in cerebral ischemia by generating and scavenging reactive oxygen species, apoptosis, biogenesis, mitochondrial dynamics, and inflammation are all examples of electron transport chain dysfunction. More knowledge about the involvement of mitochondria in ischemia-induced neuronal death and neuronal protection will contribute to the development of better treatment programs for stroke syndromes such as ischemic stroke.

PEG-SH-GNPs-SAPNS@miR-29a delivery system promotes neural regeneration and recovery of motor function after spinal cord injury

Spinal cord injury (SCI) is a serious disease characterized by hemorrhage, edema, local ischemia and hypoxia, inflammatory reaction, and degeneration of the injured spinal cord, which lacks effective clinical treatments. We design a PEG-SH-GNPs-SAPNS@miR-29a delivery system to repair impaired spinal cord by building a regenerative microenvironment for the recruitment of endogenous neural stem cells. The miR-29a, as an axonal regeneration-related miRNA that overexpression of miR-29a significantly inhibits the expression of PTEN and promotes axonal regeneration of the injured spinal cord. The gold nanoparticles and self-assembling peptide hydrogel composite scaffold (PEG-SH-GNPs-SAPNS@miR-29a delivery system) applied to deliver miR-29a, which recruit endogenous neural stem cells simultaneously. Sustained release of miR-29a and recruitment of endogenous neural stem cells give rise to favorable axonal regeneration and recovery of motor function after spinal cord injury. These findings suggest that the PEG-SH-GNPs-SAPNS@miR-29a delivery system may be an alternative strategy for the treatment of SCI.

Effect and Mechanism of Sodium Butyrate on Neuronal Recovery and Prognosis in Diabetic Stroke.

Ischemic stroke is a cerebrovascular lesion caused by local ischemia and hypoxia. Diabetes mellitus (DM) is a chronic inflammatory disease that disturbs immune homeostasis and predisposes patients to ischemic stroke. The mechanism by which DM exacerbates stroke remains unclear, although it may involve disturbances in immune homeostasis. Regulatory T cells (Tregs) play a regulatory role in many diseases, but the mechanism of Tregs in diabetes complicated by stroke remains unclear. Sodium butyrate is a short-chain fatty acid that increases Treg levels. This study examined the role of sodium butyrate in the prognosis of neurological function in diabetic stroke and the mechanism by which Tregs are amplified in the bilateral cerebral hemispheres. We evaluated the brain infarct volume, observed 48-h neuronal injury and 28-day behavioral changes, and calculated the 28-day survival rate in mice. We also measured Treg levels in peripheral blood and brain tissue, recorded changes in the blood‒brain barrier and water channel proteins and neurotrophic changes in mice, measured cytokine levels and peripheral B-cell distribution in bilateral hemispheres and peripheral blood, and examined the polarization of microglia and the distribution of peripheral T-cell subpopulations in bilateral hemispheres. Diabetes significantly exacerbated the poor prognosis and neurological deficits in mice with stroke, and sodium butyrate significantly improved infarct volume, prognosis, and neurological function and showed different mechanisms in brain tissue and peripheral blood. The potential regulatory mechanism in brain tissue involved modulating Tregs/TGF-β/microglia to suppress neuroinflammation, while that in peripheral blood involved improving the systemic inflammatory response through Tregs/TGF-β/T cells.

Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients.

Coronary artery disease (CAD) is the leading cause of mortality worldwide. In chronic and myocardial infarction (MI) states, aberrant levels of circulating microRNAs compromise gene expression and pathophysiology. We aimed to compare microRNA expression in chronic-CAD and acute-MI male patients in peripheral blood vasculature versus coronary arteries proximal to a culprit area. Blood from chronic-CAD, acute-MI with/out ST segment elevation (STEMI/NSTEMI, respectively), and control patients lacking previous CAD or having patent coronary arteries was collected during coronary catheterization from peripheral arteries and from proximal culprit coronary arteries aimed for the interventions. Random coronary arterial blood was collected from controls; RNA extraction, miRNA library preparation and Next Generation Sequencing followed. High concentrations of microRNA-483-5p (miR-483-5p) were noted as 'coronary arterial gradient' in culprit acute-MI versus chronic-CAD (p = 0.035) which were similar to controls versus chronic-CAD (p < 0.001). Meanwhile, peripheral miR-483-5p was downregulated in acute-MI and chronic-CAD, compared with controls (1.1 ± 2.2 vs. 2.6 ± 3.3, respectively, p < 0.005). A receiver operating characteristic curve analysis for miR483-5p association with chronic CAD demonstrated an area under the curve of 0.722 (p < 0.001) with 79% sensitivity and 70% specificity. Using in silico gene analysis, we detected miR-483-5p cardiac gene targets, responsible for inflammation (PLA2G5), oxidative stress (NUDT8, GRK2), apoptosis (DNAAF10), fibrosis (IQSEC2, ZMYM6, MYOM2), angiogenesis (HGSNAT, TIMP2) and wound healing (ADAMTS2). High miR-483-5p 'coronary arterial gradient' in acute-MI, unnoticed in chronic-CAD, suggests important local mechanisms for miR483-5p in CAD in response to local myocardial ischemia. MiR-483-5p may have an important role as a gene modulator for pathologic and tissue repair states, is a suggestive biomarker, and is a potential therapeutic target for acute and chronic cardiovascular disease.

Pituitary Apoplexy causing Panhypopituitarism

We present an atypical presentation of pituitary apoplexy as a pontine mimic with drowsiness and pin-point pupils. The patient had a known pituitary macroadenoma with suprasellar extension with hypogonadism and hypothyroidism. Initial investigations revealed hyponatraemia and imaging suggested a localised cerebral ischaemia in the basal ganglia and no change in the pituitary adenoma. Only further assessment with MRI showed the extent of the haemorrhage. Management was conservative, although close involvement of neurosurgery and ophthalmology teams is essential. We believe, that awareness of such unusual association is important for clinicians to consider apoplexy in the differential, even if the initial CT imaging is not suspicious.

Venous, Arterial, and Neuropathic Leg Ulcers With Emphasis on the Geriatric Population.

Leg ulcers are a common and often serious problem in older adults. Underlying conditions that increase risk include age-related increases in chronic venous insufficiency, peripheral artery disease, connective tissue and autoimmune conditions, reduced mobility, and diabetes mellitus (DM). Geriatric patients have a higher risk of multiple wound-related complications including infection, cellulitis, ischemia, and gangrene, any of which may lead to further complications including amputation. The very presence of these lower extremity ulcers in the elderly negatively impacts their quality of life and ability to function. Understanding and early identification of the underlying conditions and wound features are important for effective ulcer healing and complication mitigation. This targeted review focuses on the three most common types of lower extremity ulcers: venous, arterial, and neuropathic.The goal of this paper is to characterize and discuss the general and specific aspects of these lower extremity ulcers and their relevancy and impact on the geriatric population. The top five main results of this study can be summarized as follows. (1) Venous ulcers, caused by inflammatory processes secondary to venous reflux and hypertension, are the most common chronic leg ulcer in the geriatric population. (2) Arterial-ischemic ulcers are mainly due to lower extremity vascular disease, which itself tends to increase with increasing age setting the stage for an age-related increase in leg ulcers. (3) Persons with DM are at increased risk of developing foot ulcers mainly due to neuropathy and localized ischemia, both of which tend to increase with advancing age. (4) In geriatric patients with leg ulcers, it is important to rule out vasculitis or malignancy as causes. (5) Treatment is best made on a case-by-case basis, considering the patient's underlying condition, comorbidities, overall health status, and life expectancy.

Butylphthalide protects against ischemia-reperfusion injury in rats via reducing neuron ferroptosis and oxidative stress.

Local ischemia in the cerebra leads to vascular injury and necrosis. Ferroptosis is involved in the pathophysiological process of many diseases and widely exists when ischemia-reperfusion injury occurs in many organs. The aim of this study was to evaluate the effect of Butylphthalide (NBP) on middle cerebral artery occlusion (MCAO) rats model-caused neuron injury. Sprague Dawley Rats were randomly allocated to receive sham and MCAO operation. NBP low-dose (40 mg/kg b.w), and high-dose (80 mg/kg b.w) were administrated in MACO rats. Results showed NBP improves infarct volume, attenuates neuronal apoptosis in the brain tissue of MCAO rats. The tumor necrosis factor (TNF-α), IL-6, and malondialdehyde (MDA) levels decreased after NBP administration, while the activity of superoxide dismutase (SOD) and the ratio of GSH/GSSG in MACO rats increased. MACO caused non-heme iron accumulation in the brain tissue and Perl's staining confirmed NBP attenuates ferroptosis in MACO rats. The protein expressions of SCL7A11 and glutathione peroxidase 4 (GPX4) decreased following MCAO, and NBP treatment subsequently increased the expression of SCL7A11 and GPX4. In vitro analysis in cortical neuron cells indicated that the GPX4 inhibitor reverses the inhibition of ferroptosis by NBP, which suggested that the SCL7A11/GPX4 pathway majorly contributed to the NBP ferroptosis protection effect.

Features of hemodynamic and immunological parameters in patients with recurrent uveitis complicated by hypertension, Fuchs heterochromic uveitis and Posner-Schlossman syndrome.

Introduction: Uveitis is a disease that manifests with increased vascular permeability and occlusion, with some ischemia and inflammatory mediators. It is characterized by a wide range of pathological processes, including inflammation, increased vascular permeability and occlusion, local ischemia and cell alteration by inflammatory mediators, and is characterized by the presence of complications. Aim: To study the state of ocular hemodynamics by rheoophthalmography, as well as the immune status in patients with idiopathic recurrent anterior uveitis complicated by intraocular hypertension, Fuchs heterochromic uveitis, Posner-Schlossman syndrome, during the relapse period. Materials and methods: 93 patients with idiopathic recurrent anterior uveitis were included in this study, 8 patients with Fuchs' uveitis, and 6 patients with Posner-Schlossman syndrome. According to clinical signs, relapse and remission were considered. The control group (healthy volunteers of the same age) consisted of 27 people. In this regard, 5 groups of subjects were formed. The mean age of the patients was (M ± SD) 39.2 ± 14.6 years. According to the Median (range), the duration of the disease in patients was 2033 (350-3285) days, intraocular hypertension being recorded at P0 > 20 mm Hg. Statistical analysis was carried out in spreadsheets using STATISTICA 8.0 (StatSoft.Inc) program. Quantitative indicators were evaluated according to the correspondence to the normal distribution and to the Kolmogorov-Smirnov criterion. With a normal distribution, arithmetic means (M) and standard deviations (SD), limits of the 95% confidence interval (95% CI) and Student's t-test were calculated. Results: The volumetric blood filling of the eye according to the rheoophthalmographic indicator RQ during the period of remission of uncomplicated and complicated by hypertension anterior uveitis was reduced by 32.4%-40.5%, respectively, compared with the norm. During the period of relapse, RQ was significantly higher by 28% (p<0.05) than in remission, in the group of uncomplicated uveitis, and in the group of uveitis with increased IOP, no significant differences between the periods of remission and relapse were observed, which reflected the ischemic process in the relapse period. Volumetric blood filling in Fuchs and Posner-Schlossman syndromes in the acute period did not differ from the norm. Cellular immunity in the groups of uncomplicated and complicated by intraocular hypertension idiopathic uveitis, as well as with Fuchs and Posner-Schlossman syndromes, had a higher level of CD4 helper lymphocytes and a lower level of CD8 suppressor lymphocytes, which reflected higher values of the immunoregulatory index. The increase in the immunoregulatory index is most pronounced in Fuchs and Posner-Schlossman syndromes. Discussion: In the presented study, the incidence of idiopathic recurrent anterior uveitis complicated by intraocular hypertension was 9,9% among all cases of idiopathic recurrent anterior uveitis in one-time period. According to literature, this complicated form of uveitis occurs in 11,5%-46,1% of cases. Most often (up to 92% of cases), the anterior chamber angle was open. Conclusions: Different activity of the mechanisms regulating the balance of cellular and humoral immunity, sensitivity of T-cells to eye antigens in idiopathic anterior uveitis, Fuchs and Posner-Schlossman syndromes was assumed. Peculiarities of eye hemodynamics in these forms of uveitis were also revealed. Abbreviations: IOP = intraocular pressure, IOHS = inflammatory ocular hypertension syndrome, HSV = herpes simplex virus, CMV = cytomegalovirus, OCT = optical coherence tomography, OD = right eye, OS = left eye.

The case of arrhythmic equivalent of myocardial ischemia in the practice of family doctor

In the practice of the family physician (general practitioner) there are patients with recurrent cardiac arrhythmia (most commonly ventricular extrasystoles) accompanying angina pectoris attacks associated with local myocardial ischemia and manifested by ST-segment depression or elevation on the electrocardiogram. At the same time, there are patients with ischemic heart disease who may have palpable or insensible episodes of cardiac arrhythmia without ST-segment displacement and typical retrosternal pain during exercise. This clinic requires a detailed approach to diagnosing the equivalent of myocardial ischemia, including, exercise tests and coronarography, especially if a diagnosis of ischemic heart disease has been confirmed before.&#x0D; The case of cardiac arrhythmia as an equivalent of angina pectoris in a 67-year-old male patient with a history of myocardial infarction with postinfarction angina pectoris is presented in the article. Stenting of the right coronary artery was performed twice during ischemic heart disease treatment.&#x0D; Knowledge of the signs of myocardial ischemia equivalents determined the tactics of patient management by a general practitioner already at the stage of interview of ischemic heart disease history. Examination and referral of the patient for coronarography contributed to timely angioplasty with stenting of the affected left circumflex coronary artery, which caused local myocardial ischemia and arrhythmia.

Clinical effect of magnetic compression anastomosis on ureterostenosis after kidney transplantation.

Clinical effect of magnetic compression anastomosis on ureterostenosis after kidney transplantation.

Distinct MicroRNAs Identified in Rabbit Blood Arising from Induced Diabetes and a Surgically Simulated Diabetic Ischemia Complication.

Diabetic complications have been studied extensively in recent years. There are very few biomarkers in body fluids that can pinpoint a distinct diabetic complication due to insufficient known specific biomarkers for ischemia. Identifying microRNA in animal models for each complication could enable early diagnosis of a given complication if verified in humans. MicroRNA (miRNA) profiling has been done in rodent models for a number of diabetic complications, like diabetic glomerular injury, atherosclerosis, cognitive impairment, diabetic wound healing, angiopathy and other complications. Due to multiple differences between rodents and humans, the changes in rabbit skin, considered closer to humans than even pigs, may better simulate human diabetic complications of ischemia. To study the miRNA profile of rabbits in which diabetes was induced or ischemia was surgically generated, we studied whether diabetes or ischemia-induced specific miRNA could be detected. MicroRNA from the blood of diabetic rabbits and rabbits with local ischemia was collected in PAXgene Blood RNA tubes specifically designed for miRNA isolation and extracted using the PAX gene miRNA extraction kit. The isolated RNA was quality controlled using an RNA analyzer, and further, using RNA seq technology, it was analyzed for distinct miRNAs that were detected in diabetic and non-diabetic rabbits induced with ischemia. A miRNA that was found to be expressed in diabetic rabbits and ischemic rabbits but not in untreated rabbits was miRNA-183. Several miRNAs were differentially expressed across comparison groups, and several upregulated miRNAs were identified being unique to each comparison. In rabbits with a potential diabetic complication of a long-term ischemic model, there was one distinct microRNA, which was highly significantly upregulated in ischemia rabbit (miRNA-133-3p). One miRNA that was highly significantly upregulated in diabetic rabbit but not in ischemic rabbits was miRNA-3074-5p. Only statistically significant results have been considered and analyzed. These findings could lead to a precise and timely diagnosis of a potential single diabetic complication without invasive tissue biopsies and could be a novel tool in the management of diabetic patients developing complications due to the progression of diabetes.

Rose Bengal Induced Photothrombosis in CAM Integrated Human Split Skin Grafts—A Feasibility Study

Wound healing is a complex process requiring an adequate supply of the wound area with oxygen and nutrients by neo-vascularization, to renew tissue. Local ischemia can result in the formation of chronic wounds. Since there is a lack of wound healing models for ischemic wounds, we aimed to develop a new one, based on chick chorioallantoic membrane (CAM) integrated split skin grafts and induction of ischemia with photo-activating Rose Bengal (RB) in a two-part study: (1) investigation of the thrombotic effect of photo-activated RB in CAM vessels and (2) investigation of the influence of photo-activated RB on CAM integrated human split skin xenografts. In both study phases, we observed a typical pattern of vessel changes after RB activation with a 120 W 525/50 nm green cold light lamp in the region of interest: intravascular haemostasis and a decrease in vessel diameter within 10 min of treatment. In total, the diameter of 24 blood vessels was measured before and after 10 min of illumination. Mean relative reduction of vessel diameter after treatment was 34.8% (12.3%-71.4%; p < 0.001). The results indicate that the present CAM wound healing model can reproduce chronic wounds without inflammation due to the statistically significant reduction of blood flow in the selected area using RB. Combined with xenografted human split skin grafts, we established the set up for a new chronic wound healing model for the research of regenerative processes following ischemic damage of the tissue.

Responses to Hypoxia: How Fructose Metabolism and Hypoxia-Inducible Factor-1a Pathways Converge in Health and Disease.

Oxygen is critical for the high output of energy (adenosine triphosphate) generated by oxidative phosphorylation in the mitochondria, and when oxygen delivery is impaired due to systemic hypoxia, impaired or reduced delivery of red blood cells, or from local ischemia, survival processes are activated. One major mechanism is the activation of hypoxia-inducible factors (HIFs) that act to reduce oxygen needs by blocking mitochondrial function and stimulating glucose uptake and glycolysis while also stimulating red blood cell production and local angiogenesis. Recently, endogenous fructose production with uric acid generation has also been shown to occur in hypoxic and ischemic tissues where it also appears to drive the same functions, and indeed, there is evidence that many of hypoxia-inducible factors effects may be mediated by the stimulation of fructose production and metabolism. Unfortunately, while being acutely protective, these same systems in overdrive lead to chronic inflammation and disease and may also be involved in the development of metabolic syndrome and related disease. The benefit of SGLT2 inhibitors may act in part by reducing the delivery of glucose with the stimulation of fructose formation, thereby allowing a conversion from the glycolytic metabolism to one involving mitochondrial metabolism. The use of hypoxia-inducible factor stabilizers is expected to aid the treatment of anemia but, in the long-term, could potentially lead to worsening cardiovascular and metabolic outcomes. We suggest more studies are needed on the use of these agents.

Osteochondritis dissecans of the knee: Epidemiology, etiology, and natural history.

Osteochondritis dissecans of the knee is a disease that typically affects skeletally immature patients. Clinically manifested with knee pain, limping, and joint disfunction, this condition has remained misunderstood and undervalued for a long period. Although being a rare condition, its awareness is of utmost clinical interest because of the possible severe consequences it can bring when misrecognized or inadequately treated. Its etiology remains unclear and is still debated. Many theories have been proposed, including inflammation, local ischemia, subchondral ossification abnormalities, genetic factors, and repetitive mechanical microtrauma, with a likely interplay of the same. This review article aims to deliver and discuss current and up-to-date concepts on epidemiology, etiology, and natural history of this pediatric condition. Level of evidence: level V.