Impaired Blood Flow Research Articles

The Nociceptin/Orphanin FQ peptide receptor antagonist, SB-612111, improves cerebral blood flow in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) affects more than 2.5 million people in the U.S. each year and is the leading cause of death and disability in children and adults ages 1 to 44. Approximately 90% of TBI cases are classified as mild but may still lead to acute detrimental effects such as impaired cerebral blood flow (CBF) that result in prolonged impacts on brain function and quality of life in up to 15% of patients. We previously reported that nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonism reversed mild blast TBI-induced vestibulomotor deficits and prevented hypoxia. To explore mechanisms by which the NOP receptor-N/OFQ pathway modulates hypoxia and other TBI sequelae, the ability of the NOP antagonist, SB-612111 (SB), to reverse TBI-induced CBF and associated injury marker changes were tested in this study. Male Wistar rats randomly received sham craniotomy or craniotomy + TBI via controlled cortical impact. Injury severity was assessed after 1h (modified neurological severity score (mNSS). Changes in CBF were assessed 2h post-injury above the exposed cortex using laser speckle contrast imaging in response to the direct application of increasing concentrations of vehicle or SB (1, 10, and 100µM) to the brain surface. TBI increased mNSS scores compared to baseline and confirmed mild TBI (mTBI) severity. CBF was significantly impaired on the ipsilateral side of the brain following mTBI, compared to contralateral side and to sham rats. SB dose-dependently improved CBF on the ipsilateral side after mTBI compared to SB effects on the respective ipsilateral side of sham rats but had no effect on contralateral CBF or in uninjured rats. N/OFQ levels increased in the cerebral spinal fluid (CSF) following mTBI, which correlated with the percent decrease in ipsilateral CBF. TBI also activated ERK and cofilin within 3h post-TBI; ERK activation correlated with increased CSF N/OFQ. In conclusion, this study reveals a significant contribution of the N/OFQ-NOP receptor system to TBI-induced dysregulation of cerebral vasculature and suggests that the NOP receptor should be considered as a potential therapeutic target for TBI.

Botanical Mixture Containing Nitric Oxide Metabolite Enhances Neural Plasticity to Improve Cognitive Impairment in a Vascular Dementia Rat Model.

Vascular dementia (VD), caused by impaired cerebral blood flow, is the most common form of dementia after Alzheimer's disease (AD) in the elderly and is characterized by severe neuronal damage and cognitive decline. Nitric oxide (NO) is an important determinant of vascular homeostasis, and its deficiency is associated with the progression of VD. In this study, we investigated the role of nitrite ion, a NO metabolite in a botanical mixture (BM) of fermented garlic, fermented Scutellaria baicalensis, and Rhodiola rosea on neuron loss and cognitive impairment using a VD rat model. The BM containing the NO metabolite alleviated cognitive deficits and enhanced neural plasticity, as reflected by an increase in long-term potentiation. The BM also alleviated neuron apoptosis, decreased GFAP expression, and oxidative stress, and increased parvalbumin and brain-derived neurotrophic factor (BDNF) levels. These results indicate that BM exerts neuroprotective effects and alleviates cognitive dysfunction while enhancing neuroplasticity, and thus has therapeutic potential against VD.

Mobilization of Stroke Patients to Prevent Decubitus: A Systematic Review

Stroke is a disease or nerve disorder that occurs suddenly due to impaired blood flow to the brain. Stroke is known to cause various complications including the occurrence of decubitus wounds. Decubitus is one of the most frequent complications experienced by stroke patients. One of the therapies that can be given to prevent these complications is to take mobilization actions. The purpose of this literature review has been to analyze the provision of mobilization measures in stroke patients to prevent decubitus. The search method uses the Mendeley, PubMed, and Google Scholar databases between 2017 and 2021, with the keyword "Mobilization and Patient Stroke and Pressure Sores" obtained from 100 journals, from the Mendeley 82, PubMed 1 and Google Scholar 17 databases, then from these 100 journals a selection was made and 5 articles were obtained that can be reviewed according to the inclusion criteria. Results and Discussion of a review of literature review in 5 articles stated that mobilization measures can prevent decubitus in stroke patients. Mobilization can facilitate circulatory circulation, maintain muscle tone, and maintain and increase joint range of motion. Mobilization can be given to stroke patients with mobilization actions in the form of changes in the right tilt position, left tilt, and changes in tilt position 30 degrees. This position change can be done every 2 hours. The conclusions and recommendations of this literature review suggest that the administration of mobilizing measures is effective in preventing the occurrence of decubitus in stroke patients. For this reason, this research recommendation is that patients with bed rest be mobilized and given olive oil smears.

Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis.

Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR. Ninety-five patients with severe AS without coronary artery disease awaiting AVR (30 AS-T2D and 65 AS-noT2D) were recruited (mean, 71 years of age [95% CI, 69, 73]; 34 [37%] women). Thirty demographically matched healthy volunteers (HVs) and 30 patients with T2D without AS (T2D controls) were controls. One month before and 6 months after AVR, cardiac PCr/ATP, adenosine stress MBF, global longitudinal strain, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and 6-minute walk distance were assessed in patients with AS. T2D controls underwent identical assessments at baseline and 6-month follow-up. HVs were assessed once and did not undergo 6-minute walk testing. Compared with HVs, patients with AS (AS-T2D and AS-noT2D combined) showed impairment in PCr/ATP (mean [95% CI]; HVs, 2.15 [1.89, 2.34]; AS, 1.66 [1.56, 1.75]; P<0.0001) and vasodilator stress MBF (HVs, 2.11 mL min g [1.89, 2.34]; AS, 1.54 mL min g [1.41, 1.66]; P<0.0001) before AVR. Before AVR, within the AS group, patients with AS-T2D had worse PCr/ATP (AS-noT2D, 1.74 [1.62, 1.86]; AS-T2D, 1.44 [1.32, 1.56]; P=0.002) and vasodilator stress MBF (AS-noT2D, 1.67 mL min g [1.5, 1.84]; AS-T2D, 1.25 mL min g [1.22, 1.38]; P=0.001) compared with patients with AS-noT2D. Before AVR, patients with AS-T2D also had worse PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.66 [1.56, 1.75]; P=0.04) and vasodilator stress MBF (AS-T2D, 1.25 mL min g [1.10, 1.41]; T2D controls, 1.54 mL min g [1.41, 1.66]; P=0.001) compared with T2D controls at baseline. After AVR, PCr/ATP normalized in patients with AS-noT2D, whereas patients with AS-T2D showed no improvements (AS-noT2D, 2.11 [1.79, 2.43]; AS-T2D, 1.30 [1.07, 1.53]; P=0.0006). Vasodilator stress MBF improved in both AS groups after AVR, but this remained lower in patients with AS-T2D (AS-noT2D, 1.80 mL min g [1.59, 2.0]; AS-T2D, 1.48 mL min g [1.29, 1.66]; P=0.03). There were no longer differences in PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.51 [1.34, 1.53]; P=0.12) or vasodilator stress MBF (AS-T2D, 1.48 mL min g [1.29, 1.66]; T2D controls, 1.60 mL min g [1.34, 1.86]; P=0.82) between patients with AS-T2D after AVR and T2D controls at follow-up. Whereas global longitudinal strain, 6-minute walk distance, and NT-proBNP all improved after AVR in patients with AS-noT2D, no improvement in these assessments was observed in patients with AS-T2D. Among patients with severe AS, those with T2D demonstrate persistent abnormalities in myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function after AVR; AVR effectively normalizes myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function in patients without T2D.

Vascular deficits contributing to skeletal fragility in type 1 diabetes.

Over 1 million Americans are currently living with T1D and improvements in diabetes management have increased the number of adults with T1D living into later decades of life. This growing population of older adults with diabetes is more susceptible to aging comorbidities, including both vascular disease and osteoporosis. Indeed, adults with T1D have a 2- to 3- fold higher risk of any fracture and up to 7-fold higher risk of hip fracture compared to those without diabetes. Recently, diabetes-related vascular deficits have emerged as potential risks factors for impaired bone blood flow and poor bone health and it has been hypothesized that there is a direct pathophysiologic link between vascular disease and skeletal outcomes in T1D. Indeed, microvascular disease (MVD), one of the most serious consequences of diabetes, has been linked to worse bone microarchitecture in older adults with T1D compared to their counterparts without MVD. The association between the presence of microvascular complications and compromised bone microarchitecture indicates the potential direct deleterious effect of vascular compromise, leading to abnormal skeletal blood flow, altered bone remodeling, and deficits in bone structure. In addition, vascular diabetic complications are characterized by increased vascular calcification, decreased arterial distensibility, and vascular remodeling with increased arterial stiffness and thickness of the vessel walls. These extensive alterations in vascular structure lead to impaired myogenic control and reduced nitric-oxide mediated vasodilation, compromising regulation of blood flow across almost all vascular beds and significantly restricting skeletal muscle blood flow seen in those with T1D. Vascular deficits in T1D may very well extend to bone, compromising skeletal blood flow control, and resulting in reduced blood flow to bone, thus negatively impacting bone health. Indeed, several animal and ex vivo human studies report that diabetes induces microvascular damage within bone are strongly correlated with diabetes disease severity and duration. In this review article, we will discuss the contribution of diabetes-induced vascular deficits to bone density, bone microarchitecture, and bone blood flow regulation, and review the potential contribution of vascular disease to skeletal fragility in T1D.

FRI625 Diabetic Ischemic Skeletal Muscle Injury Occurs Through Pkc-beta/sp1 Regulation Of Bag3 Expression

Abstract Disclosure: A. Mani: None. V. Lamin: None. T. Wong: None. M.V. Singh: None. A.O. Dokun: None. Peripheral arterial disease (PAD) affects more than 200 million people worldwide and is characterized by impaired blood flow to the lower extremities. Individuals with diabetes (DM) and PAD have more severe ischemic limb injuries and increased limb amputations, but the mechanisms involved are poorly understood. Following experimental PAD, C57Bl/6 mice develop limited ischemic limb injury largely due to protective effect of genes within the limb salvage QTL-1 (LSq-1) a genetic locus on chromosome 7. However, when diabetes is induced in C57Bl/6 mice they develop severe ischemic limb injuries following experimental PAD, akin to the findings in humans. Previously, we identified BAG3 as a gene within LSq-1 that is protective against ischemic limb injuries. BAG3 is upregulated in ischemic limbs from non-DM C57Bl/6 mice but poorly expressed in ischemic limbs of DM mice. The mechanism of BAG3 upregulation in ischemia is not known however the BAG3 promoter has a Specificity protein 1 (Sp1) transcription factor binding site suggesting its possible role. Moreover, how DM impairs BAG3 expression in ischemic skeletal muscles in not known. PKCβ regulates expression of transcription factors, and its phosphorylation has been implicated in the vascular pathology in DM but a role in ischemic diabetic skeletal muscle injury has not been established. Here we assessed the role of Sp1 in BAG3 upregulation in ischemic skeletal muscle cells (HSMC), we found Sp1 is upregulated in ischemic HSMCs and overexpression of Sp1 enhanced BAG3 promoter luciferase activity while knock down of Sp1 impaired BAG3 upregulation in ischemia. However, in vitro, ischemic HSMCs under DM conditions (High glucose or HG, 25mM + Palmitic acid or PA, 200µM) express lower BAG3 (fold change: Vehicle, 1.0±0.02 vs HG+PA, 0.57±0.04; n=4; p&amp;lt;0.05) and Sp1 (fold change: Vehicle, 1.0±0.15 vs HG+PA, 0.22±0.03; n=4; p&amp;lt;0.05). Overexpression of BAG3 improved survival of ischemic HSMCs in DM conditions in vitro (fold change: Vehicle, 1.0±0.02 vs HG+PA, 1.3±0.02 vs BAG3+HG+PA, 1.03±0.03; n=4-5; p&amp;lt;0.05) and improved extent of limb injury in vivo (Necrosis Score; DM mice without BAG3 2.67±0.29 vs DM mice + BAG3, 0.87±0.29; n=8-9; p&amp;lt;0.05). Additionally, under DM conditions ischemic HSMCs showed increased phosphorylation of PKCβ on the Ser661. Blocking PKCβ activation with Ruboxistaurin (Rbx), a specific inhibitor of PKCβ phosphorylation prevented the DM induced phosphorylation of PKCβ on the Ser661 (p-PKCβ/PKCβ ratio: Vehicle, 0.08±0.006 vs HG±PA, 0.19±0.03 vs Rbx+HG+PA, 0.10±0.006; n=4; p&amp;lt;0.05) and rescued BAG3 and Sp1 expression (BAG3, fold change: Vehicle, 1.0±0.06 vs HG±PA, 0.50±0.02 vs Rbx+HG+PA, 0.76±0.03; SP1, fold change: Vehicle, 1.0±0.02 vs HG±PA, 0.57±0.03 vs Rbx+HG+PA, 0.85±0.02; n=4; p&amp;lt;0.05). We conclude that impaired BAG3 expression in ischemic HSMC is mediated by impaired Sp1 expression due to increased PKCβ phosphorylation in DM. Presentation: Friday, June 16, 2023

Predictors of Adverse Clinical Outcomes after Endovascular Thrombectomy in Acute Ischemic Stroke

Introduction. Stroke is recognized as one of the most significant global socio-economic issues. Endovascular interventions, including mechanical thrombectomy of cerebral arteries, have been increasingly performed during the past decade to restore impaired cerebral blood flow in the first hours from the onset of the disease. However, it has been observed that the technical success of the procedure does not always imply an improvement in the clinical condition of a patient.Materials and methods. The study retrospectively analyzes the outcomes of interventions in 86 acute ischemic stroke patients in order to identify factors that can exert an adverse effect on the first hours of the disease and potentially worsen the results of reperfusion therapy. The study involves patients aged 35–85 years (mean age 66.82±1.52 years), predominantly males (57 males versus 29 females). 42 patients (49%) suffered atrial fibrillation, of which 28 (66.7%) had permanent, 11 (26.2%) — paroxysmal, 3 — persistent atrial fibrillation (7.1%), and 27 (31.4%) suffered diabetes mellitus.Results and discussion. Based on the study, factors affecting outcome and one-year long-term results were identified. The predictors included severity of neurological deficit according to Rankin and NIH Stroke scales, time between symptom onset and reperfusion, TICI thrombectomy score, age, diabetes mellitus, and haemorrhagic transformation after thrombectomy.Conclusion. In order to ensure better outcomes, medical specialists should develop an efficient patient routing, pay special attention to the initial severity of neurological deficit, time from the onset of the disease, age of patients, concomitant diabetes mellitus, development of hemorrhagic transformation after endovascular thrombectomy, and, which is particularly important, to the combination of adverse factors.

Characteristics of SPECT/CT-derived pulmonary perfusion imaging in chronic pulmonary vascular stenosis with different etiologies

Objective: To explore the characteristics of pulmonary blood flow perfusion imaging of single photo emission computer tomography/computer tomography (SPECT/CT) in chronic pulmonary vascular Stenosis (CPVS) caused by different etiological factors. Methods: This is a retropective study. Present study screened 50 consecutive cases diagnosed with chronic pulmonary vascular stenosis from January 2019 to January 2020 in the department of cardiology of Gansu Provincial Hospital and underwent SPECT/CT pulmonary blood flow perfusion examination. Thirteen patients were excluded because of pulmonary vascular lesions with a disease course of less than 3 months and poor image quality. According to the etiology, patients were divided into fibrosing mediastinitis (FM) group, Takyasu's arteritis (PTA) group, and chronic thromboembolic pulmonary hypertension/chronic thromboembolic pulmonary disease (CTEPH/CTED) group. The severity of pulmonary blood flow perfusion was evaluated in accordance with the Begic scoring principle in the three groups. The overall Begic score, lung lobe scores among three groups were compared. CT signs of lung SPECT/CT, such as enlargement of hilar lymph node, atelectasis, bronchial stenosis, were also analyzed in three groups. Results: A total of 37 patients with chronic pulmonary vascular stenosis were finally enrolled (18 in the FM group, 5 in the PTA group, and 14 in the CTEPH/CTED group). The total Begic score of pulmonary perfusions was similar among the three groups (F=0.657,P>0.05). There was a statistically significant difference in the left upper lobe Begic score among the three groups (H=4.081, P<0.05). The left upper lobe Begic score was higher in the FM group than in the PTA group (3.44±2.50 vs. 1.60±0.55, P<0.05). As compared to other two groups, patients in FM group were featured with CT signs of higher percent of hilar enlargement (FM group vs. PTA group: 16/18 vs. 1/5, P=0.008; FM group vs. CTEPH/CTED group: 16/18 vs. 3/14, P=0.000 2), enlargement of the pulmonary hilum lymph nodes (FM group vs. PTA group: 14/18 vs. 1/5, P=0.033; FM group vs. CTEPH/CTED group: 14/18 vs. 2/14, P=0.001), and calcification of mediastinal soft tissue (FM group vs. PTA group: 11/18 to 0/5, P=0.037; FM group vs. CTEPH/CTED group: 11/18 vs. 1/14, P=0.003). The proportion of CT signs of bronchial stenosis (9/18 vs. 0/14, P=0.002) and atelectasis (9/18 vs. 1/14, P=0.002) was also higher in the FM group than in the CTEPH/CTED group. In case of abnormal pulmonary blood flow perfusion, the diagnostic accuracy of CT signs hilar enlargement, hilar lymph node enlargement, mediastinal soft tissue calcification, bronchial stenosis, and atelectasis for the diagnosis of FM were 81.1%, 83.8%, 78.4%, 75.7%, and 73.0%, respectively. Conclusion: There is no significant difference in the Begic score of SPECT/CT pulmonary blood flow perfusion imagines among the three groups of patients. Impaired pulmonary blood flow perfusion combined with typical CT signs is useful for identifying patients with FM.

Abstract 064: CD4+ T Cells Mediate Pregnancy-induced Renal Damage In The Dahl SS In A Process Dependent Upon NADPH Oxidase 2 (NOX2)

Previous work from our lab demonstrated that adoptive transfer of Dahl SS splenocytes into rats lacking T cells (SS CD247-/- ) led to significant renal damage and impairment in uterine artery blood flow during pregnancy. In contrast, transfer of SS p67phox-/- splenocytes, which lack the ability to generate NOX2-derived ROS, did not amplify pregnancy-induced renal damage. It is unknown what cell type in splenocytes mediates these effects. The present study tested the hypothesis that adoptive transfer of Dahl SS CD4+ T cells would induce a preeclamptic-like phenotype in the SS CD247-/- in a process dependent on NOX2. CD4+ T cells from Dahl SS or SS p67phox-/- were transferred into SS CD247-/- rats by intraperitoneal injection at postnatal day 5 to investigate the oxidative capacity of CD4+ T cells. Injected SS CD247-/- rats were aged to 10 weeks when they were mated with naïve littermate males. Prior to mating, baseline MAP and protein excretion rates were comparable between the groups (136±6 vs 134±3 mmHg, 33±5 vs 28±3 mg/day, p&gt; 0.05, n=5/group, SS vs SS p67phox-/- , respectively). At the end of the pregnancy, the SS treated rats develop significant proteinuria that is not observed in the rats that received SS p67phox-/- CD4+ T cells (138±14 vs 83±16 mg/day, p&lt; 0.05) despite no difference in MAP. In addition, there was an increase in uterine artery resistance index as assessed by Doppler ultrasound at GD20 in the SS treated relative to SS p67phox-/- (0.70±0.03 vs 0.62±0.02, p &lt;0.05) indicating an impairment in blood flow leading to the placenta. There was a trending reduction in placental efficiency (fetal/placental weight) observed in the rats injected with SS CD4+ T cells versus those injected with SS p67phox-/- CD4+ T cells (3.99±0.3 vs 4.57±0.1, p=0.06) suggesting there is an impairment in placental function. Taken together, the present data suggest a causal role for NOX2 in CD4+ T cells in pregnancy-associated renal damage and impairment of vascular function.

Relationship Between Perioperative Factors and Splenic Artery Steal Syndrome After Orthotopic Liver Transplant: A Retrospective Clinical Study.

After orthotopic liver transplant, ischemia of biliary tract and graft loss may occur due to impaired hepatic arterial blood flow. This situation with hypersplenism and impaired hepatic arterial blood flowis defined as splenic artery steal syndrome.The aim of this study was to investigate the relationship between perioperative factors and splenic artery steal syndrome in orthotopic liver transplant patients. Forty-five patients who underwent orthotopic liver transplant between 2014 and 2022 were included in the study. The data for the patients were obtained from the hospital database, including the intraoperative anesthesiology and postoperative intensive care records. Eleven patients were diagnosed with splenic artery steal syndrome. Patients with splenic artery steal syndrome had higher need for intraoperative vasopressor agents (P = .016) and exhibited lower intraoperative urine output (P = .031). In the postoperative intensive care follow-up, patients with splenic artery steal syndrome had higher levels of C-reactive protein during the first 48 hours (P = .030). Intraoperative administration of vasopressor drugs, low urine output, and early postoperative high C-reactive protein levels were associated with the development of splenic artery steal syndrome in patients undergoing orthotopic liver transplant. Future studies should focus on investigation of biomarkers associated systemic hypoperfusion that may contribute to the development of splenic artery steal syndrome.

Abstract P422: CD4+ T Cells From Preeclamptic Patients During Pregnancy Causes Cognitive Dysfunction Postpartum In A Pregnant Rat Model

Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with impaired cognitive function and increased cerebral blood flow (CBF). Although we have previously shown adoptive transfer of placental CD4+ T cells from PE women into athymic nude pregnant rats causes HTN and circulating factors associated with PE, we do not know the role of CD4+ T cells in contributing to impaired cerebral blood flow and cognitive dysfunction in the postpartum period. Therefore, we hypothesize that adoptive transfer of placental CD4+ T cells from PE patients into pregnant athymic nude recipient rats will cause maternal hypertension and cognitive dysfunction and impaired CBF postpartum. Placental CD4+ T cells were isolated from normotensive (NP) and preeclamptic (PE) pregnant women at delivery. One million CD4+ T cells were injected interperitoneally (i.p.) into normal pregnant nude athymic rats on gestational day (GD) 12. Dams were allowed to deliver and aged 12-weeks after delivery. Blood pressure (MAP) was measured by carotid catheter and at 12-weeks postpartum CBF autoregulation was measured by laser Doppler flowmetry. The Barnes maze and the novel object recognition behavioral assays were used to assess cognitive function on gestational day (GD) 15-19 and 12-weeks postpartum. A student’s t-test was used for statistical analysis. MAP increased during pregnancy in PE recipient rats (115±2 mmHg, n=5) compared to NP recipient rats (99±3 mmHg, n=4, p&lt; 0.05). MAP significantly increased in the postpartum period in PE recipient rats (114±2 mmHg, n=5) compared to NP controls (98±2 mmHg, n=7, p&lt;0.05). PE recipient rats exhibited latency with errors navigating in the Barnes maze compared to NP controls during pregnancy and postpartum. Locomotor activity was decreased in PE recipient rats compared to NP controls during pregnancy (p&lt;0.05) and postpartum. PE recipient rats had increased CBF autoregulation compared to NP rat recipients in the postpartum period. Our findings indicate that rat recipients of CD4+ T cells from PE patients demonstrate maternal HTN and increased CBF and cognitive dysfunction in the postpartum period compared to recipients of NP CD4 + T cells. These data indicate long-term cognitive and cerebral dysfunction as a result of preeclampsia.

Necrotizing Raynaud's phenomenon after recurrent COVID-19 infection

Raynaud's phenomenon (RP), which can be primary or secondary, is a common vascular clinical syndrome due to abnormal arteriolar vasospasm. Its treatment is most often conservative depending on the etiology. In recent years, there have been reports of RP as a syndrome after a previous SARS-CoV-2 infection, in patients of different genders and ages. As an etiological factor for the development of vascular pathology in these cases, two main mechanisms are assumed: an autoimmune process or the thrombosis of arterial vessels, leading to tissue ischemia, and the so-called necrotizing Raynaud's phenomenon. In the pathogenesis of Raynaud's phenomenon, the influence of local, neuronal and hormonal mediators is emphasized. Some studies prove the role of estrogens, which explains the higher incidence of RP among women. At present, there is no convincing evidence for "candidate genes" to be associated with Raynaud's phenomenon, despite studies by some authors (Susol et al., 2000; Pistorius et al., 2006). Vasospasm in digital ischemia may be further complicated by COVID-19 infection. Another potential component is hypercoagulation (further complicated by the presence of antiphospholipid antibodies in certain patients) and elevated levels of D-dimer. A state of hypercoagulation is caused by the so-called cytokine storm. This inflammatory state, as a result of endovascular damage, increased platelet activity and coagulation cascade, causes the so-called phenomenon of immunothrombosis. Overactivation of the coagulation pathway during cytokine storm results from increased activity of thrombin, which has an additional role in the inflammatory process through proteinase-activated receptors (PARs). Acrocyanosis due to excessive coagulation status has been described in critically ill patients with COVID-19. In these patients, gangrene may arise from impaired blood flow and insufficient healing of digital wounds, which is associated with elevated levels of C-reactive protein (CRP). Ischemic limb lesions, usually seen in older patients with severe clinical course of the disease, represent a dangerous, although rare, complication associated with COVID-19 and are due to arterial occlusions. They are extremely difficult to treat and often lead to amputations. In patients with antiphospholipid syndrome, arterial and venous thrombi are primarily caused by the formation of neutrophil extracellular traps (NET), which in turn activate platelets, and their excessive formation can lead to local thrombosis. In addition to platelet activation, neutrophils release tissue factor, which initiates the coagulation cascade. NETs bind coagulation factor XII and activate it, and also induce an inflammatory reaction in the vessel wall. According to the available knowledge to date, the hypothesis that digital necrosis in patients with COVID-19 is primarily related to the formation of NETs has been developed.&#x0D; Necrotizing Raynaud's phenomenon (NRP) is a vascular clinical syndrome characterized by vasoconstriction of distal resistance vessels following low temperatures or states of anxiety and stress. The first symptom is pain, due to lack of oxygen, which leads to tissue ischemia. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause endotheliopathy with microvascular and macrovascular thrombotic events. COVID-19 induces hypercoagulation, thrombosis, endothelial damage, and inflammation leading to vasculitis. The coagulopathy, inflammation, and thrombosis seen in COVID-19 are potentiated by increased activity of clotting factors, loss of protective glycocalyx function, and decreased nitric oxide levels. The effects of COVID-19 in patients with RP are still being elucidated.&#x0D; This review presents a series of selected clinical cases associated with Raynaud's phenomenon (necrotic, new-onset, exacerbated, or as part of another systemic connective tissue disease) secondary to past COVID-19 infection or vaccination.&#x0D;

Avascular Necrosis

Osteonecrosis can be defined as bone cell death resulting from impaired blood flow to the bone due to traumatic or non-traumatic events. Case Presentation: We present a case in which a 62-year-old female came to the Orthopedic Surgery Polyclinic with complaints of pain in her groin. The pain is intermittent and worsens when the patient moves his legs. This makes it difficult for patients to sit and have pain when walking, so they need a cane as a tool. This complaint has been felt for ± 1.5 years and has been getting worse since this 1 month. During the pain the patient said he was taking pain relievers but his complaints did not decrease. On local examination in the left Hip Joint region, it was found that on look examination there was no visible deformity, swelling and skin color that was the same as the surrounding area. On examination of the feel found positive tenderness. On AP pelvic X-ray examination, there was a fracture of the left femoral head with superior displacement. Treatment for this patient includes non-surgical and surgical (total hip replacement). Conclusion: The patient was diagnosed with Avascular necrosis.

Morphologic characteristic of rat myocardium in comorbid pathology

Diabetic cardiomyopathy is a serious complication of diabetes mellitus (DM). Aim. Therefore, we aimed to study myocardial changes in adult rats with streptozotocin (STZ)-induced DM exposed to chronic immobilization stress (CIS). Materials and methods. A total of 26 adult albino male rats weighing 180–200 g were examined. All the animals were divided into three groups: Group I included 10 rats with STZ-induced DM exposed to CIS; Group II comprised 10 rats with STZ-induced DM; Group III included 6 intact animals. The samples were collected on the 14th and 56th days of the experiment. Histological, histochemical, electron microscopy, and biochemical methods were used. Results. On the 14th day of the experiment, in Group I and Group II, increased blood flow was observed in the capillaries, venules, and veins, while an arteriolar spasm in the microcirculation was found. In addition, cardiomyocyte surface area in different myocardial regions reduced due to low glycogen content as confirmed by histochemical and ultrastructural studies. On the 56th day of the experiment, in Group I and Group II, hyperemia occurred due to red blood cell aggregation and microthrombi. The surface area of all microcirculatory vessels increased as compared to that of intact animals, as evidenced by an increase in their wall surface area leading to an increase in their wall-to-lumen ratio. Such morphometric changes in the microcirculatory vessels were indicative of decreased vascular permeability and impaired myocardial blood flow. At the histological level, in Group I and Group II, focal cardiomyocyte lysis, moderate to diffuse stromal edema, lymphohistiocytic infiltration were seen. Such changes pointed to sterile inflammation, probably due to myocardial infraction secondary to diabetic microangiopathy. In cardiomyocytes, karyolysis, vacuolar degeneration, apical ballooning, subsarcolemmic edema, fibrosis and lysis of myofibrils, colliquative necrosis were observed. Conclusions. STZ-induced DM and stress resulted in pronounced destructive changes in the myocardium of rats, including interstitial edema, focal cardiosclerosis, myolysis. Such changes occurred on the background developing diabetic microangiopathy. The most pronounced myocardial changes were recorded in animals with a comorbidity.

Long-Term Change in Flow Rates in Patients with Coronary Slow Flow

Introduction: Coronary slow flow (CSF) is a condition characterized by impaired blood flow rates in the coronary arteries. It can result in severe cardiovascular outcomes. There is no sufficient evidence regarding the certain etiology and reversibility of slow flow patterns and changes in frame counts with long-term management. Methods: We retrospectively enrolled 48 patients with chronic coronary syndrome and CSF who underwent a second angiography. A corrected coronary frame rate (CFR) >27 was defined as CSF. We created 3 groups according to the change in CSF status as the improved, not changed, and worsened groups. We compared the CFR and CSF status of the patients between the first and second angiographies within a median of 2.6 years. Results: We determined a nonsignificant change in cCFR in left anterior descending (LAD) artery (34.4 [18.9] vs. 31.59 [10.3], p = 0.35), circumflex (Cx) artery (42.84 [12.56] vs. 40.66 [13.2], p = 0.35), and right coronary artery (RCA) (57.80 [30.13] vs. 50.32 [19.5], p = 0.11). In the comparison of CSF status of LAD (75% vs. 63%, p = 0.27), Cx (96% vs. 83%, p = 0.09), RCA (94% vs. 94%, p = 1.0) between first and second angiographies, there was no significant change. In the comparison of the 3 groups according to the improvement of CSF status, there was no significant difference in demographic features, change in laboratory parameters, and time between the groups. Conclusion: There was no significant change in the median CFR and CSF status in the overall group between the two angiographies after 3 years.

Transcranial Doppler Sonography in Children with Congenital Heart Disease Undergoing Cardiac Catheterization

Background Children with congenital heart disease (CHD) are at high risk for neurodevelopmental disabilities. Acute neurologic complications, such as seizures, transient ischemic attack, intracranial hemorrhage, and ischemic stroke might occur in the setting of cardiac surgery and cardiac catheterization. Cardiac catheterization is important in the diagnosis and assessment of hemodynamic function in children with congenital heart disease. The incidence of neurologic complications (occurring within 48 hours) in interventional cardiac catheterization is significantly higher than those in diagnostic. Objective The Aim of this study is to evaluate the effect of cardiac catheterization on TCD Commented [RM1]: transcranial doppler (TCD) in children with congenital heart disease. Methods This is a prospective study. 40 children were enrolled; at Children’s hospital, Ain Shams University over 6 months. TCD parameters, clinical data, neurologic examination were done before and after cardiac catheterization. Results In the present study, 33 patients (82.5%) had interventional catheter and 7 (17.5%) had diagnostic catheter. Middle cerebral artery TCD parameters of the patients in the diagnostic group showed lower peak systolic (PS), and time average mean of the maximal velocities (TAMX), also called mean velocity, before catheterization and lower PS, end diastolic (ED), and TAMX post catheterization. All patients showed statistically significant lower TAMX post catheterization. Conclusion Cardiac catheterization lower middle cerebral artery time average mean of the maximal velocities in children with congenital heart disease. This impairment in blood flow might be a risk for cerebrovascular diseases in this population.

Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury

Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical spreading depolarization (CSD) are metabolically demanding processes that may worsen secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis, reduced ATP production, and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. Here, we explored this association using a rodent closed head injury model. CSD is associated with neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation or to induce seizures via 4-aminopyridine application. We measured vascular dysfunction following CSDs and seizures in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. CSD resulted in mitochondrial dysfunction and pathological signs of increased oxidative stress adjacent to the vasculature. We explored these findings further using electron microscopy and found that TBI and CSDs resulted in vascular morphological changes and mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI.

Assessment of cerebral autoregulatory function and inter-hemispheric blood flow in older adults with internal carotid artery stenosis using transcranial Doppler sonography-based measurement of transient hyperemic response after carotid artery compression

Unhealthy vascular aging promotes atherogenesis, which may lead to significant internal carotid artery stenosis (CAS) in 5 to 7.5% of older adults. The pathogenic factors that promote accelerated vascular aging and CAS also affect the downstream portion of the cerebral microcirculation in these patients. Primary treatments of significant CAS are eversion endarterectomy or endarterectomy with patch plasty. Factors that determine adequate hemodynamic compensation and thereby the clinical consequences of CAS as well as medical and surgical complications of carotid reconstruction surgery likely involve the anatomy of the circle of Willis (CoW), the magnitude of compensatory inter-hemispheric blood flow, and the effectiveness of cerebral microcirculatory blood flow autoregulation. This study aimed to test two hypotheses based on this theory. First, we hypothesized that patients with symptomatic and asymptomatic CAS would exhibit differences in autoregulatory function and inter-hemispheric blood flow. Second, we predicted that anatomically compromised CoW would associate with impaired inter-hemispheric blood flow compensation. We enrolled older adults with symptomatic or asymptomatic internal CAS (>70% NASCET criteria; n = 46) and assessed CoW integrity by CT angiography. We evaluated transient hyperemic responses in the middle cerebral arteries (MCA) after common carotid artery compression (CCC; 10 s) by transcranial Doppler sonography (TCD). We compared parameters reflecting autoregulatory function (e.g., transient hyperemic response ratio [THRR], return to baseline time [RTB], changes of vascular resistance) and inter-hemispheric blood flow (residual blood flow velocity). Our findings revealed that CAS was associated with impaired cerebral vascular reactivity. However, we did not observe significant differences in autoregulatory function or inter-hemispheric blood flow between patients with symptomatic and asymptomatic CAS. Moreover, anatomically compromised CoW did not significantly affect these parameters. Notably, we observed an inverse correlation between RTB and THRR, and 49% of CAS patients exhibited a delayed THRR, which associated with decreased inter-hemispheric blood flow. Future studies should investigate how TCD-based evaluation of autoregulatory function and inter-hemispheric blood flow can be used to optimize surgical techniques and patient selection for internal carotid artery revascularization.

Successful treatment of nonocclusive mesenteric ischemia in a reconstructed jejunum after esophagectomy and remnant gastric tube resection: a case report

BackgroundNonocclusive mesenteric ischemia (NOMI), an ischemic bowel disease without a disruption of the mesenteric blood flow or strangulation of the mesentery or intestine, may cause a lethal clinical course. We report a very rare case of jejunal necrosis caused by NOMI in the pedicled mesentery of the reconstructed jejunum after remnant gastric tube resection for heterochronous gastric tube cancer after esophagectomy.Case presentationAn 80-year-old man visited our department with chief complaints of fever and appetite loss after 4 months from gastric tube resection and digestive reconstruction with pedicled jejunum. Contrast-enhanced computed tomography (CT) revealed impaired blood flow without torsion of the mesentery, severe wall thickness, and micro-penetration in the reconstructed jejunum and combined pyothorax in the right thoracic cavity. Esophagogastroduodenoscopy demonstrated extensive mucosal necrosis confined to the jejunum, which was elevated in the thoracic cavity. The jejunal necrosis due to NOMI occurring in the reconstructed jejunum was suspected, and lifesaving small bowel resection with right thoracotomy was considered necessary. However, radical operation with right thoracotomy was considered to be excessively invasive and not valid due to the patient’s poor physical status, advanced age, and presence of left adrenal metastasis from the remnant gastric cancer. Therefore, we selected the conservative treatment with fasting, transnasal drainage, and administration of antibiotics due to the patient’s intention. CT-guided right thoracic drainage for the intrathoracic abscess was needed 10 days after starting treatment and the inflammatory response rapidly improved. Follow-up CT and esophagogastroduodenoscopy revealed the improvement in the ischemic changes in jejunal mucosa without perforation. Intake was initiated at 20 days after symptom onset, and the patient was discharged at 40 hospital days without any complications and sequelae.ConclusionsTo the best of our knowledge, this is the first case of NOMI occurring in the reconstructed jejunum after remnant gastric tube resection that was successfully treated with a conservative treatment. For NOMI, it is important to make appropriate diagnosis based on imaging findings and perform proper assessment of the patient’s condition. Conservative treatments may be also useful depending on the patient’s condition.

Chronic hypoxia of endothelial cells boosts HIF-1α-NLRP1 circuit in Alzheimer's disease.

Cerebral microvasculature of patients with Alzheimer's disease (AD) exhibits reduced capillary diameter and impaired blood flow. Molecular mechanisms of ischemic vessels affecting AD progressions have not been well established yet. In the present study, we found that in vivo triple (PS1M146V, APPswe, tauP301L) transgenic AD mouse model (3x-Tg AD) brains and retinas showed hypoxic vessels expressing hypoxyprobe and hypoxia inducible factor-1α (HIF-1α). To mimic in vivo hypoxic vessels, we used in vitro oxygen-glucose deprivation (OGD)-treated endothelial cells. HIF-1α protein was increased through reactive oxygen species (ROS) producing NADPH oxidases (NOX) (i.e., Nox2, Nox4). OGD-induced HIF-1α upregulated Nox2 and Nox4, demonstrating crosstalk between HIF-1α and NOX (i.e., Nox2, Nox4). Interestingly, NLR family pyrin domain containing 1 (NLRP1) protein was promoted by OGD, and such effect was blocked by downregulation of Nox4 and HIF-1α. Knockdown of NLRP1 also diminished OGD-mediated protein levels of Nox2, Nox4, and HIF-1α in human brain microvascular endothelial cells. These results showed interplay among HIF-1α, Nox4 and NLRP1 in OGD-treated endothelial cells. Expression of NLRP3 was not detected well in hypoxic endothelial cells of 3x-Tg AD retinas or OGD-treated endothelial cells. Instead, hypoxic endothelial cells of 3x-Tg AD brains and retinas markedly expressed NLRP1, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and interleukin-1β (IL-1β). Taken together, our results suggest that AD brains and retinas can trigger chronic hypoxia especially in microvascular endothelial cells, consequently leading to NLRP1 inflammasome formation and upregulation of ASC-caspase-1-IL-1β cascades. In addition, NLRP1 can stimulate HIF-1α expression and form HIF-1α-NLRP1 circuit. These consequences might further destroy vascular system in AD.