Occlusion Of Blood Vessels Research Articles

Enhancing foundational validity of forensic findings in nonlethal medico-legal strangulation examinations.

Nonlethal strangulation occurs when the brain is deprived of oxygen because of external compression leading to the occlusion of the neck's blood vessels and/or airway. The current state of strangulation science confines expert testimony to merely describing injuries attributed to strangulation 'based on the expert's experience and training.' Expert testimony that can quantify the likelihood that observed injuries are attributable to strangulation would strengthen the scientific validity of such testimony. This study aims to identify those documented features, or clusters of features, that are associated with cases where strangulation is reported versus cases where strangulation is not reported. This study is a retrospective analysis of medical record data from patients seeking forensic examinations for strangulation and/or sexual assault who presented to the emergency department of an academic medical center from January 2018 to June 2022. Among the 170 cases, 77 were documented as strangulation-absent and 93 were documented as strangulation-present. A simple classification algorithm was developed to identify these cases where strangulation was present. Prominent features of this algorithm included: presence of petechiae, observed number of injuries around the mouth, face, head and neck, and total number of injuries. This algorithm has a false positive rate of 5% and a false negative rate of 32%. To our knowledge, this is the first medico-legal research study to produce an algorithm to assist with classifying cases of strangulation given specific forensic examination characteristics. The study demonstrates the value of data collection in medico-legal research for developing an algorithm that enables forensic examiners to use data-driven methods to verify victims' reports of strangulation.

Pathological roles of mitochondrial dysfunction in endothelial cells during the cerebral no-reflow phenomenon: A review.

Emergency intravascular interventional therapy is the most effective approach to rapidly restore blood flow and manage occlusion of major blood vessels during the initial phase of acute ischemic stroke. Nevertheless, several patients continue to experience ineffective reperfusion or cerebral no-reflow phenomenon, that is, hypoperfusion of cerebral blood supply after treatment. This is primarily attributed to downstream microcirculation disturbance. As integral components of the cerebral microvascular structure, endothelial cells (ECs) attach importance to regulating microcirculatory blood flow. Unlike neurons and microglia, ECs harbor a relatively low abundance of mitochondria, acting as key sensors of environmental and cellular stress in regulating the viability, structural integrity, and function of ECs rather than generating energy. Mitochondria dysfunction including increased mitochondrial reactive oxygen species levels and disturbed mitochondrial dynamics causes endothelial injury, further causing microcirculation disturbance involved in the cerebral no-reflow phenomenon. Therefore, this review aims to discuss the role of mitochondrial changes in regulating the role of ECs and cerebral microcirculation blood flow during I/R injury. The outcomes of the review will provide promising potential therapeutic targets for future prevention and effective improvement of the cerebral no-reflow phenomenon.

Molecular Links and Clinical Effects of Inflammation and Metabolic Background on Ischemic Stroke: An Update Review.

Stroke is a major global health concern, with 12.2 million new cases and 6.6 million deaths reported in 2019, making it the second leading cause of death and third leading cause of disability worldwide. Ischemic stroke, caused by blood vessel occlusion, accounts for 87% of stroke cases and results in neuronal death due to oxygen and nutrient deprivation. The rising global stroke burden is linked to aging populations and increased metabolic risk factors like high blood pressure, obesity, and elevated glucose levels, which promote chronic inflammation. This article explores the intricate molecular and clinical interplay between inflammation and metabolic disorders, emphasizing their role in ischemic stroke development, progression, and outcomes.

Clinical features and prognosis of children with multiple Takayasu's arteritis complicated with carotid artery occlusion

This study aimed to analyze the clinical characteristics and prognosis of Takayasu's arteritis (TA) with carotid artery occlusion in children. This study collected clinical data and follow-up information on the first diagnosis and treatment of c-TA combined with carotid artery occlusion in pediatric patients at the Children's Hospital affiliated with the Capital Institute of Pediatrics and Inner Mongolia Medical University Affiliated Hospital from 2013 to 2023. This study included four female patients with a mean age of (13.25±1.71) years old. The time from onset to diagnosis was (8.14±11.19) months. Their main clinical symptoms and signs were dizziness, headache, chest discomfort, aphasia, dyskinesia, impaired mobility of the limbs, hypertension, asymmetry of blood pressure in the limbs, vascular murmurs or tremors, weakened radial artery pulsation, and decreased muscle strength. All four children showed elevated levels of C-reactive protein and erythrocyte sedimentation rate. The medical imaging results showed that among the four patients, three had bilateral carotid artery occlusion, and one had unilateral carotid artery occlusion. There were three cases of cerebrovascular involvement, accompanied by arterial involvement in multiple parts of the body, mainly involving bilateral subclavian arteries, cephalic trunk arteries, bilateral renal arteries, bilateral iliac arteries, and middle cerebral arteries. Four children were effectively treated with glucocorticoids and immunosuppressants. These children were followed up for a period of (42.25±52.54) months, which showed that the original affected artery still had varying degrees of occlusion, with no progression from the pre-treatment period and no new arterial involvement. The condition of three children with pre-existing physical and language disorders gradually improved. In summary, children with c-TA combined with carotid artery occlusion can cause involvement of multiple blood vessels. Their clinical manifestations are mostly systemic symptoms and ischemia of corresponding supply organs caused by vascular lesions, which are prone to be combined with cerebral infarction, and their occluded blood vessels are difficult to recover.

The application of thermolysis and sonophoresis for vascular closure. Case report

Modern skin care cosmetology provides an extensive array of techniques to enhance skin condition, particularly those related to dilated blood vessels. The study aimed to assess the efficacy of combined therapy of thermolysis for occluding blood vessels and sonophoresis using ultrasound for skin regeneration and enhancement. The conducted skin analyses indicated that the integration of these two procedures yields satisfactory outcomes in the management of erythema and in the occlusion of blood vessels.

Novel Self-Expandable Laser-Cut Device for Effective Thrombus Retrieval: Overcoming Limitations in Thrombectomy for Deep Vein Thrombosis, Peripheral Artery Disease and Pulmonary Embolism

Pulmonary embolism (PE) is a serious complication of deep vein thrombosis (DVT) and peripheral artery disease, often leading to fatal outcomes. The first line of treatment for DVT and PAD is anticoagulation: preventing the thrombus, occlusion of blood vessels, and propagation of PE especially in the case of DVT where limb or life-threatening complications are at risk. Clots retrieved from vessels include mechanical and manual interventions such as catheter-directed thrombolysis and thrombectomy. Yet the risks involved with thrombotic and embolic vascular occlusions are high because they cause occlusion of blood flow in crucial vessels; this may lead to tissue damage, organ failure, and death. Most of the existing thrombectomy devices do not remove the organized thrombus completely while prevention of clot fragmentation is also lacking. The study presents a new, self-expanding laser-cut clot retrieval device specifically designed to remove both hard and soft thrombi with no trauma at all to the vessel wall. This is one of the promising advancements in thrombectomy that overcomes the disadvantages of other existing technologies and offers a stronger approach for the removal of occlusions in the vascular system associated with DVT, PAD, and PE. The simulation test in vitro and a trackability test have been conducted with the developed device together with its delivery system for validation. These tests were envisaged to demonstrate how the device can operate, for example, navigate through the vasculature, and retrieve thrombi safely and accurately.

Mechanistic insights into the regression of atherosclerotic plaques.

Atherosclerosis is a major contributor to cardiovascular diseases and mortality globally. The progression of atherosclerotic disease results in the expansion of plaques and the development of necrotic cores. Subsequent plaque rupture can lead to thrombosis, occluding blood vessels, and end-organ ischemia with consequential ischemic injury. Atherosclerotic plaques are formed by the accumulation of lipid particles overloaded in the subendothelial layer of blood vessels. Abnormally elevated blood lipid levels and impaired endothelial function are the initial factors leading to atherosclerosis. The atherosclerosis research has never been interrupted, and the previous view was that the pathogenesis of atherosclerosis is an irreversible and chronic process. However, recent studies have found that the progression of atherosclerosis can be halted when patients' blood lipid levels are reversed to normal or lower. A large number of studies indicates that it can inhibit the progression of atherosclerosis lesions and promote the regression of atherosclerotic plaques and necrotic cores by lowering blood lipid levels, improving the repair ability of vascular endothelial cells, promoting the reverse cholesterol transport in plaque foam cells and enhancing the ability of macrophages to phagocytize and clear the necrotic core of plaque. This article reviews the progress of research on the mechanism of atherosclerotic plaque regression. Our goal is to provide guidance for developing better therapeutic approaches to atherosclerosis by reviewing and analyzing the latest scientific findings.

Analysis of Predictor Factors and Comorbidities About Lower-Extremity Repetitive Amputation in Diabetic Foot Ulcer and Infection: A Retrospective Study

Category: Diabetes Introduction/Purpose: About 12-25% of diabetic patients had foot ulcers during their lifetime, which has been reported in several studies that not only reduce the quality of life but also increase the risk of amputation due to infection and increase mortality. However, there are insufficient studies on risk factors and comorbidities on re-amputation due to uncontrolled infection and necrosis after amputation. Therefore, the purpose of this study is to investigate the predictors of lower-extremity amputation or re-amputation in diabetic foot ulcer patients and the effects of comorbidities. Methods: Among the patients who underwent amputation or re-amputation for diabetic foot ulcer at a single institution from April 2019 to March 2021, 60 cases, who were followed up for at least 1 year, were investigated. The group that underwent amputation and the group that had more than one amputation were divided into two groups, and the clinical characteristics and comorbidities of each group were comparatively evaluated. Clinical factors were Wagner stage, the anatomical level of the amputation, the presence or absence of osteomyelitis in radiology, glycated hemoglobin, the difference in results according to the bacterial culture test, and the presence or absence of peripheral blood vessel occlusion, and the reperfusion procedure. Results: The average follow-up period was 12.7 (6-24 months), and the higher the Wagner stage, the higher the rate of re-amputation was statistically significant (OR 1.8, 95%CI 1.4 to 2.4; p=.001). The rate of re-amputation was significantly higher in the group that failed to re-perfuse peripheral blood vessels preoperatively than in the group that succeeded (OR 7.4, 95% CI 2.0 to 27.5; p=.003). Uncontrolled diabetes was confirmed by glycated albumin was predicted the need for repetitive amputation (OR 1.08, 95% CI 0.8 to 2.7; p=.001). In addition, there was a high rate of re-amputation in diabetic foot ulcers and infections identified by polymicrosomal infection. (OR 8.4, 95% CI 1.0 to 69.5; p=.026) Conclusion: In patients with diabetic foot ulcers and severe infections, who have a peripheral vascular obstruction, which failed vascular intervention, and who had high glycated albumin was performed from the initial amputation below the major joint in the proximal lower extremity, resulting in reduced patient mortality and morbidity. In addition, the results of the treatment varied depending on the infected bacteria. Re-amputation free survival of diabetic foot ulcer Kaplan-Meier curves for reamputation-free survival of diabetes patients with diabetic foot ulcers over 3 year, depending on enterococal infection (log-rank test p= 0.03).

Albumin adjuvant therapy for acute ischemic stroke with large vessel occlusion (AMASS-LVO): rationale, design, and protocol for a phase 1, open-label, clinical trial.

Acute ischemic stroke (AIS) is an acute brain injury caused by sudden occlusion of a blood vessel. Endovascular therapy is the most effective way to restore blood flow. However, despite the restoration of blood flow in some patients, their clinical prognosis often remains unsatisfactory. Albumin has shown neuroprotective effects in animal models of AIS. Therefore, this study aims to evaluate the safety, feasibility, and efficacy of local arterial infusions of 20% human serum albumin solution as an adjuvant therapy after endovascular therapy in patients with AIS. This study is a prospective, therapeutic exploratory, non-randomized, open-label, phase 1 clinical trial testing the use of 20% human serum albumin solution injected via the artery immediately after successful reperfusion in patients with AIS. The study is divided into two stages. In the first stage, a single-dose-finding will explore the maximum safe dose according to the 3 + 3 dose escalation principle;, with the maximum dose being 0.60 g/kg. After recanalizing the occluded blood vessel, human serum albumin solution will be injected into the internal carotid artery region through a guiding catheter for 30 min. The second stage involves an albumin adjuvant therapy cohort (AT) and an endovascular treatment lonely cohort (ET). The AT cohort will encompass at least 15 additional participants to complete safety trials at the maximum safe dose determined in the first stage. The ET cohort will include well-matched patients receiving endovascular therapy alone, derived from a contemporaneous prospective registry, who will be excluded from having cardiopulmonary disorders and from receiving any neuroprotective therapy. The primary outcome of this study will be symptomatic intracranial hemorrhage. Efficacy outcomes will include the proportion of patients with the progression of cerebral infarction volume, a modified Rankin Scale of 0-2 on day 90 after randomization. An exploratory secondary outcome will be the analysis of thromboinflammatory and neuroprotective molecule profiles. This pilot trial aims to explore the safety and efficacy of arterial infusion of an albumin solution after occlusive vessel opening in AIS. The results will provide data parameters for subsequent tests on the arterial infusion of albumin solutions. ClinicalTrials.gov, NCT05953623.

Remote ischemic conditioning slows blood-retinal barrier damage in type 1 diabetic rats

Diabetic retinopathy (DR) is one of the major complications of diabetes and can cause severe visual impairment. Blood-retina barrier (BRB) destruction resulted from chronic hyperglycemia underlines its major pathological process. However, current treatments have limited efficacy and may even cause serious complications. Remote ischemic conditioning (RIC), through repeated transient mechanical occlusion of limb blood vessels, has been confirmed to promote blood–brain barrier integrity after stroke, but its role in BRB disruption has not been elucidated. This study aimed to investigate the protective effects of RIC on the BRB in diabetic rats and its potential mechanisms. 48 Sprague-Dawley rats were randomly assigned to the Sham group, Sham + RIC group, diabetes mellitus (DM) group and DM+RIC group. The diabetic model was successfully induced by intraperitoneal injection of streptozotocin. RIC treatment was administered daily and lasted for 9 weeks. In functional analysis, RIC improved the retinal function based on electroretinogram data and reduced the leakage of BRB in diabetic rats. In proteomic analysis, tight junction pathway was enriched after RIC treatment, in which Patj gene was significantly increased. We also found that RIC increased mRNA levels of Patj, claudin-1 and zonula occludens (ZO)-1, protein expression of claudin-1 when compared with diabetic models. In conclusion, RIC slowed BRB damage in diabetic rats, which may be related to the preservation of tight junction proteins. RIC may be a promising protective strategy for the treatment of DR.

Metagenomic analysis of atheroma plaques for identification of microorganisms indicates presence of Toxoplasma gondii as a possible etiological agent

BackgroundCardiovascular diseases (CVDs) are the leading cause of death worldwide. Vital organs like the heart are affected by the occlusion of blood vessels due to atherosclerotic plaque formation. However, the role of infectious agents has always been an essential subject of investigation. This study investigated the presence of microorganisms, including nanobacteria, in atherosclerotic plaques removed from human carotid arteries by microbiological and metagenomic examination. MethodsAtheroma plaque samples were obtained from 20 patients with carotid artery stenosis who had atherectomy by surgery or percutaneous intervention. Nanobacteria were grown by culturing homogenates of the atheroma plaques. Whole genome sequencing was done for samples. Because of the high percentage of Toxoplasma gondii (T. gondii) DNA, PCR investigation was applied to detect T. gondii DNA in the samples. ResultsA molecular analysis of nanobacteria revealed them to be made of human proteins, supporting the theory that they are not living organisms. According to sequencing results, samples showed that more than 50 % of the metagenomic sequences belonged to Toxoplasma gondii. PCR investigation indicated that T. gondii DNA was positive in 8 (40 %) of 20 plaques. ConclusionsFurther evidence regarding the role of T. gondii in the etiology of plaque formation may help determine the strategy for prevention and treatment of infections in preventing atheroma plaque formation in the future.

Evaluation of the Quality and Readability of Web-Based Information Regarding Foreign Bodies of the Ear, Nose, and Throat: Qualitative Content Analysis.

Foreign body (FB) inhalation, ingestion, and insertion account for 11% of emergency admissions for ear, nose, and throat conditions. Children are disproportionately affected, and urgent intervention may be needed to maintain airway patency and prevent blood vessel occlusion. High-quality, readable online information could help reduce poor outcomes from FBs. We aim to evaluate the quality and readability of available online health information relating to FBs. In total, 6 search phrases were queried using the Google search engine. For each search term, the first 30 results were captured. Websites in the English language and displaying health information were included. The provider and country of origin were recorded. The modified 36-item Ensuring Quality Information for Patients tool was used to assess information quality. Readability was assessed using a combination of tools: Flesch Reading Ease score, Flesch-Kincaid Grade Level, Gunning-Fog Index, and Simple Measure of Gobbledygook. After the removal of duplicates, 73 websites were assessed, with the majority originating from the United States (n=46, 63%). Overall, the quality of the content was of moderate quality, with a median Ensuring Quality Information for Patients score of 21 (IQR 18-25, maximum 29) out of a maximum possible score of 36. Precautionary measures were not mentioned on 41% (n=30) of websites and 30% (n=22) did not identify disk batteries as a risky FB. Red flags necessitating urgent care were identified on 95% (n=69) of websites, with 89% (n=65) advising patients to seek medical attention and 38% (n=28) advising on safe FB removal. Readability scores (Flesch Reading Ease score=12.4, Flesch-Kincaid Grade Level=6.2, Gunning-Fog Index=6.5, and Simple Measure of Gobbledygook=5.9 years) showed most websites (56%) were below the recommended sixth-grade level. The current quality and readability of information regarding FBs is inadequate. More than half of the websites were above the recommended sixth-grade reading level, and important information regarding high-risk FBs such as disk batteries and magnets was frequently excluded. Strategies should be developed to improve access to high-quality information that informs patients and parents about risks and when to seek medical help. Strategies to promote high-quality websites in search results also have the potential to improve outcomes.

Exploring the effects of lateral pressure to the soft tissue of the buttocks during seating to preserve tissue perfusion

AimPressure-ulcer occurrence in the seated patient is understudied. Preventative devices have been developed and are prescribed commonly, but there is little quantitative evidence of their effectiveness. This study explores the concept of a lateral pressure device, a prevention device that applies pressure to the sides of the seated buttocks, to reduce the amount of tissue distortion and blood-vessel occlusion. It is hypothesized that this device will reduce deep tissue injury by reducing the pressure at the bone-muscle interface, as demonstrated computationally in previous research. This study aimed to use oximetry to investigate the efficacy of the device in maintaining transcutaneous gas tensions of the tissue as close to baseline as possible. MethodsOximetry electrodes were attached to participants' ischial tuberosity and greater trochanter for different amounts of lateral pressure. The amount of lateral pressure is a given percentage of the pressure due to the participants’ underbody pressure. ResultsThe results show that 50 % lateral pressure is sufficient to produce an improvement in participants’ gas tensions at their ischial tuberosity, without negatively impacting the tissue at their greater trochanter, relative to the control of sitting with no application of lateral pressure. ConclusionDespite a rudimentary prototype device design, and that participants each placed their own oximetry sensors, results support the application of lateral pressure as a method to maintain transcutaneous gas tensions. Further work should be carried out on a larger sample to consolidate these findings.

A Study on the Effects of Different Positions on the Clinical Prognosis of Patients with Acute Ischemic Stroke.

The key to treating Acute Ischemic Stroke (AIS) is to rapidly reopen occluded blood vessels, restore blood flow, and rescue the ischemic penumbra. Treatment methods mainly include thrombolysis, endovascular intervention, etc. However, these treatments are limited by strict time windows and technical conditions. Simpler and more feasible methods to improve cerebral blood flow are currently a hot topic in clinical research. In recent years, several studies have shown that changes in body position can effectively improve cerebral blood flow in patients. However, the effect on the neurological functional prognosis of AIS remains inconclusive. This review has examined the effects of changes in body position on the clinical prognosis of AIS, combining relevant guidelines and the latest research. The study has provided evidence of an improvement in the clinical prognosis of AIS.

Therapeutic Strategies for Ischemic Stroke: Modulating the Adult Neural Stem Cell Niche through the Wnt/β-catenin Pathway.

Stroke is a prominent contributor to mortality and impairment on a global scale. Ischemic stroke accounts for approximately 80% of stroke cases and is caused by occlusion of cerebral blood vessels. Enhancing neurogenesis through the modulation of the neural stem cell niche in the adult brain is a promising therapeutic strategy for individuals afflicted with ischemic stroke. Neurogenesis results in the generation of newborn neurons that serve as replacements for deceased neural cells within the ischemic core, thereby playing a significant role in the process of neural restoration subsequent to cerebral ischemia. Research has shown that activation of the Wnt/β-catenin pathway can augment neurogenesis following cerebral ischemia, suggesting that this pathway is a potentially beneficial therapeutic target for managing ischemic stroke. This review provides an extensive analysis of the current knowledge regarding the involvement of the Wnt/β-catenin pathway in promoting neurogenesis, thereby offering a promising avenue for therapeutic intervention in the context of ischemic stroke or other neurological impairments.

Disturbance in cerebral blood microcirculation and hypoxic-ischemic microenvironment are associated with the development of brain metastasis.

Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occurs through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that are dependent on Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF). In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and postmortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcomes were analyzed in BM patients. Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human BM negatively correlated with survival. Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevents the outgrowth of macrometastases.

Vascular Damage and Repair - Are Small-Diameter Vascular Grafts Still the "Holy Grail" of Tissue Engineering?

Cardiovascular diseases are the most important cause of morbidity and mortality in the civilized world. Stenosis or occlusion of blood vessels leads not only to events that are directly life-threatening, such as myocardial infarction or stroke, but also to a significant reduction in quality of life, for example in lower limb ischemia as a consequence of metabolic diseases. The first synthetic polymeric vascular replacements were used clinically in the early 1950s. However, they proved to be suitable only for larger-diameter vessels, where the blood flow prevents the attachment of platelets, pro-inflammatory cells and smooth muscle cells on their inner surface, whereas in smaller-diameter grafts (6 mm or less), these phenomena lead to stenosis and failure of the graft. Moreover, these polymeric vascular replacements, like biological grafts (decellularized or devitalized), are cell-free, i.e. there are no reconstructed physiological layers of the blood vessel wall, i.e. an inner layer of endothelial cells to prevent thrombosis, a middle layer of smooth muscle cells to perform the contractile function, and an outer layer to provide innervation and vascularization of the vessel wall. Vascular substitutes with these cellular components can be constructed by tissue engineering methods. However, it has to be admitted that even about 70 years after the first polymeric vascular prostheses were implanted into human patients, there are still no functional small-diameter vascular grafts on the market. The damage to small-diameter blood vessels has to be addressed by endovascular approaches or by autologous vascular substitutes, which leads to some skepticism about the potential of tissue engineering. However, new possibilities of this approach lie in the use of modern technologies such as 3D bioprinting and/or electrospinning in combination with stem cells and pre-vascularization of tissue-engineered vascular grafts. In this endeavor, sex-related differences in the removal of degradable biomaterials by the cells and in the behavior of stem cells and pre-differentiated vascular cells need to be taken into account. Key words: Blood vessel prosthesis, Regenerative medicine, Stem cells, Footprint-free iPSCs, sr-RNA, Dynamic bioreactor, Sex-related differences.

Outcomes of surgical revascularization for pediatric moyamoya disease and syndrome

PurposeMoyamoya disease and syndrome represent rare entities characterized by progressive stenosis and/or occlusion of the intracranial blood vessels. We present our series of patients with moyamoya disease and syndrome stratified by underlying disease and analyze differences in presentation and outcome following surgical revascularization.MethodsThis was an Institutional Review Board (IRB) approved, retrospective review of all patients surgically revascularized by the senior author (SNM) while at Children’s National Hospital in Washington, DC. Demographic data, presenting symptoms and severity, surgical details, and functional and radiographic outcomes were obtained and analyzed for differences among the underlying cohorts of moyamoya disease and syndrome as well as by unilateral or bilateral disease and index or non-index surgeries.ResultsTwenty-two patients were identified with the following underlying diseases: six with idiopathic moyamoya disease, six with sickle cell anemia, five with trisomy 21, and five with neurofibromatosis type 1. Thirty hemispheres were revascularized with a significantly reduced rate of stroke from 3.19 strokes/year (SD = 3.10) to 0.13 strokes/year (SD = 0.25), p = 0.03. When analyzed by underlying cause of moyamoya syndrome, patients with neurofibromatosis type 1 were found to be significantly less likely than the other subtypes of moyamoya syndrome to have had either a clinical stroke (0.0% neurofibromatosis type 1 vs. 100.0% sickle cell, 60.0% trisomy 21, or 83.3% moyamoya disease, p < 0.01) or radiographic stroke (0.0% neurofibromatosis type 1 vs. 100.0% sickle cell, 60.0% trisomy 21, or 83.3% moyamoya disease, p < 0.01) at time of presentation. Patients with moyamoya syndrome associated with sickle cell disease were more likely to present with clinical and radiographic strokes. Additionally, patients with bilateral disease demonstrated no difference in final functional outcome compared to patients with unilateral disease (mRS 0.73 (SD = 1.33) vs. 1.29 (SD = 1.60), p = 0.63).ConclusionIndirect surgical revascularization decreases stroke risk for pediatric patients with different forms of moyamoya disease and moyamoya syndrome. Additionally, these data suggest that sickle cell anemia-associated moyamoya syndrome may represent a more aggressive variant, while neurofibromatosis type 1 may represent a more benign variant.

Novel Method to Assess Treatment Effcacy in Preclinical Peripheral Arterial Disease Studies

Background: Peripheral arterial disease (PAD), a condition caused by atherosclerotic narrowing or occlusion of blood vessels in the lower extremities, affects ~200 million adults globally and lacks effective treatment options to improve limb function. Cilostazol is the only approved pharmacological treatment option for PAD patients, but its effect on walking performance is modest and the drug is not widely used clinically. Over the past several decades, numerous therapies (drug, gene, and cell-based) have shown promise in the preclinical setting but failed to achieve primary outcomes in clinical trials. While the failure of therapeutic translation is complex, most preclinical studies have employed perfusion recovery as a primary outcome variable whereas most clinical trials in PAD patients employ the six-minute walk test. Although perfusion is an important contributor to limb function and walking performance, assessing preclinical therapeutics solely via perfusion recovery may be a flawed approach. Objective: To address the need for a more comprehensive method to assess the effcacy of preclinical PAD therapeutics, we aimed to develop a protocol to assess hindlimb function that incorporates assessment of muscle power and perfusion across a six-minute testing period. Methods: To assess muscle contractile performance, the tibialis anterior or plantarflexor muscles were carefully exposed and the distal tendon mounted to the force-length controller (Aurora Scientific) and the muscles were stimulated via the sciatic nerve in anesthetized C57BL6 mice. After obtaining isometric forces, a six-minute functional test was performed using repeated isotonic (shortening) contractions against a submaximal load (30% or 45% of the reference force). Muscle fatigue was measured as a change in power across the testing period. Throughout the test, laser Doppler flowmetry was used to measure muscle blood flow. Hindlimb ischemia was used as an experimental model of PAD. Results: In healthy mice without PAD, the test produced the expected dose-dependent relationship between fatigue and workload with contractions performed at 30% of the reference force having less fatigue compared to 45% of the reference force ( P=0.0051), without a significant difference in muscle blood flow between the conditions. Compared the mice that received a sham surgery, those subjected to hindlimb ischemia displayed significantly lower maximal isometric forces (1514 ± 118 mN vs. 880 ± 85 mN, P=0.0001) and power at 35% maximal force (280 ± 12 vs. 105 ± 46 watts/kg, P=0.0002). Whereas sham mice lost ~25% power across the six-minute test, HLI mice displayed a ~70% loss of power. Regarding muscle blood flow, sham mice increased blood flow ~250% whereas HLI mice were only able to increase blood flow to ~105% ( P&lt;0.001). Conclusions: This newly developed protocol successfully combines isotonic muscle function and limb perfusion assessments in the hindlimb of mice and can detect differences between healthy and PAD mice. Future work is needed to fully evaluate the accuracy and sensitivity of this method to select therapeutics in preclinical PAD models. This study was supported by National Institutes of Health (NIH) grant R01-HL149704 (T.E.R.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Single-Nuclei RNA-Sequencing Uncovers Alterations in the Transcriptional Profile of Skeletal Muscle in Peripheral Artery Disease

BACKGROUND: Lower extremity peripheral artery disease (PAD) is caused by atherosclerotic occlusion of lower limb blood vessels, impacting &gt;200 million people worldwide. PAD causes life-altering symptomatology such as claudication, ischemic rest pain, and gangrene, with limited effective treatment options. Herein, we performed single-nuclei RNA-sequencing (snRNAseq) to facilitate a better understanding of the complex pathobiological environment within the PAD limb and intercellular communication. METHODS: Gastrocnemius muscle specimens were collected from 20 patients with PAD and 12 non-PAD controls. Patients with PAD were classified as Rutherford category 3 (severe claudication). Non-PAD participants were of similar age, body mass index and medication usage as patients with PAD. Nuclei were isolated and snRNAseq was performed. Bioinformatic analysis was conducted to determine differences in gene expression between PAD and non-PAD nuclei, as well as analysis of intercellular signaling networks. Histological analysis of muscle specimens assessed the following: myosin heavy chain fiber distributions, myofiber cross-sectional area and myofiber denervation. RESULTS: 57,364 high-quality nuclei were captured (21,417 PAD; 35,947 non-PAD) and unsupervised clustering revealed 12 distinct nuclei populations based on their transcriptional profile. Quantification of the relative abundance of nuclei populations identified several differences, including PAD muscles having a lower percentage of type I myonuclei, muscle stem cells, and endothelial cells but a higher proportion of type II and regenerating myonuclei. Differentially expressed gene analysis of myonuclei populations uncovered upregulation of genes involved in stress response, autophagy, and atrophy in patients with PAD. Ligand-receptor interactions were used to determine how PAD alters the communication between identified nuclei populations. The inferred strength of interactions was greater in non-PAD compared to PAD patients. Further, intercellular communication network analysis revealed fibro-adipogenic progenitors as a primary signaling hub in PAD muscle. CONCLUSION: snRNAseq uncovered novel transcriptional differences and intercellular communication pathways unique to PAD muscle. This study was supported by National Institutes of Health (NIH) grant R01-HL149704 (T. Ryan). K. Kim supported by the American Heart Association grant POST903198. T. Thome supported by NIH grant F31-DK128920. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.