Vascular Damage Research Articles

Palliative effects of carnosol on lung-deposited pollutant particles-induced thrombogenicity and vascular injury in mice.

The toxicity of inhaled particulate air pollution perseveres even at lower concentrations than those of the existing air quality limit. Therefore, the identification of safe and effective measures against pollutant particles-induced vascular toxicity is warranted. Carnosol is a bioactive phenolic diterpene found in rosemary herb, with anti-inflammatory and antioxidant actions. However, its possible protective effect on the thrombotic and vascular injury induced by diesel exhaust particles (DEP) has not been studied before. We assessed here the potential alleviating effect of carnosol (20 mg/kg) administered intraperitoneally 1 h before intratracheal (i.t.) instillation of DEP (20 μg/mouse). Twenty-four hours after the administration of DEP, various parameters were assessed. Carnosol administration prevented the increase in the plasma concentrations of C-reactive protein, fibrinogen, and tissue factor induced by DEP exposure. Carnosol inhibited DEP-induced prothrombotic effects in pial microvessels invivo and platelet aggregation invitro. The shortening of activated partial thromboplastin time and prothrombin time induced by DEP was abated by carnosol administration. Carnosol inhibited the increase in pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor α) and adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin) in aortic tissue. Moreover, it averted the effects of DEP-induced increase of thiobarbituric acid reactive substances, depletion of antioxidants and DNA damage in the aortic tissue. Likewise, carnosol prevented the decrease in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) caused by DEP. We conclude that carnosol alleviates DEP-induced thrombogenicity and vascular inflammation, oxidative damage, and DNA injury through Nrf2 and HO-1 activation.

Umbilical Cord Mesenchymal Stem Cells Combined with Fufang Xueshuantong Capsule Attenuate Oxidative Stress and Vascular Lesions in Diabetic Rats by Activating Nrf-2/HO-1 Signaling Pathway

Background:: Macrovascular lesions are the main cause of death and disability in diabetes mellitus, and excessive accumulation of cholesterol and lipids can lead to long-term and repeated damage of vascular endothelial cells. Umbilical cord mesenchymal stem cells (UCMSCs) can attenuate vascular endothelial damage in type 1 diabetic mice, while Fufang Xueshuantong capsule (FXC) has a protective effect on endothelial function; however, whether FXC in combination with UCMSCs can improve T2DM macrovascular lesions as well as its mechanism of action are not clear. Therefore, the aim of this study was to reveal the role of FXC + UCMSCs in T2DM vasculopathy and their potential mechanism in the treatment of T2DM. Methods:: The control and T2DM groups were intragastrically administered with equal amounts of saline, the UCMSCs group was injected with UCMSCs (1×106, resuspended cells with 0.5 mL PBS) in the tail vein, the FXC group was intragastrically administered with 0.58 g/kg FXC, and the UCMSCs + FXC group was injected with UCMSCs (1×106) in the tail vein, followed by FXC (0.58 g/kg), for 8 weeks. Results:: We found that FXC+UCMSCs effectively reduced lipid levels (TG, TC, and LDL-C) and ameliorated aortic lesions in T2DM rats. Meanwhile, Nrf2 and HO-1 expression were upregulated. We demonstrated that inhibition of Nrf-2 expression blocked the inhibitory effect of FXC+UCMSCs-CM on apoptosis and oxidative stress injury. Conclusion:: Our data suggest that FXC+UCMSCs may attenuate oxidative stress injury and macroangiopathy in T2DM by activating the Nrf-2/HO-1 pathway.

Catastrophic rupture of an internal carotid aneurysm in a neurofibromatosis type 1 patient: A critical case study

Catastrophic rupture of an internal carotid aneurysm in a neurofibromatosis type 1 patient: A critical case study

Coenzyme Q10 eyedrops conjugated with vitamin E TPGS alleviate neurodegeneration and mitochondrial dysfunction in the diabetic mouse retina

Diabetic retinopathy (DR) is a leading cause of blindness and vision impairment worldwide and represents one of the most common complications among diabetic patients. Current treatment modalities for DR, including laser photocoagulation, intravitreal injection of corticosteroid, and anti-vascular endothelial growth factor (VEGF) agents, target primarily vascular lesions. However, these approaches are invasive and have several limitations, such as potential loss of visual function, retinal scars and cataract formation, and increased risk of ocular hypertension, vitreous hemorrhage, retinal detachment, and intraocular inflammation. Recent studies have suggested mitochondrial dysfunction as a pivotal factor leading to both the vascular and neural damage in DR. Given that Coenzyme Q10 (CoQ10) is a proven mitochondrial stabilizer with antioxidative properties, this study investigated the effect of CoQ10 eyedrops [in conjunction with vitamin E d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS)] on DR-induced neurodegeneration using a type 2 diabetes mouse model (C57BLKsJ-db/db mice). Utilizing a comprehensive electroretinography protocol, supported by immunohistochemistry, our results revealed that topical application of CoQ10 eyedrops conjugated with vitamin E TPGS produced a neuroprotective effect against diabetic-induced neurodegeneration by preserving the function and histology of various retinal neural cell types. Compared to the control group, mice treated with CoQ10 exhibited thicker outer and inner nuclear layers, higher densities of photoreceptor, cone cell, and rod-bipolar cell dendritic boutons, and reduced glial reactivity and microglial cell density. Additionally, the CoQ10 treatment significantly alleviated retinal levels of MMP-9 and enhanced mitochondrial function. These findings provide further insight into the role of mitochondrial dysfunction in the development of DR and suggest CoQ10 eyedrops, conjugated with vitamin E TPGS, as a potential complementary therapy for DR-related neuropathy.

Association between anti-Topoisomerase I antibody and organ damage in systemic sclerosis at the National Hospital of Dermatology and Venereology

Objectives: To evaluate the association between anti-Topoisomerase (Topo) I antibody and damage of some organs in systemic sclerosis (SSc). Materials and methods: Cross-sectional descriptive study of 100 patients diagnosed with SSc and were tested for anti-Topo I antibodies by ELISA technique at the National Hospital of Dermatology and Venereology. Results: The average score of general effects, thickened skin lesions, peripheral vascular damages, and lung damages according to the Medsger scale of the group of SSc patients with positive anti-Topo I was higher than SSc patients with negative anti-Topo I (0.93±1.07 vs 0.24±0.44; 1.6±0.7 vs 1.16±0.37; 1.88±0.61 vs 1.36±0.49, and 1.23±0.67 vs 0.84±0.94, respectively). The proportion of patients with joint contractures in the positive anti-Topo I group was higher than in the anti-Topo I negative group (32 vs 12%). The proportion of patients with severe and very severe organ damage in the anti-Topo I positive group was higher than in the anti-Topo negative group. There was no association between the presence of anti-Topo I and heart or digestive damage. Conclusions: Anti-Topo I antibodies were associated with the level of general effects, peripheral vascular damage, skin thickening, and pulmonary fibrosis. The presence of anti-Topo I antibodies would be a poor prognostic factor for patients with SSc.

#2052 Reciprocal interplay between miR-155-5p and SOCS1 in the development of renal and vascular damage in experimental diabetes

Abstract Background and Aims Chronic kidney disease and atherosclerosis are common vascular complication of diabetes and a global health issue. Hyperglycemia, dyslipidemia, and cytokines activate Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway to induce mediators of inflammation and oxidative stress, which are critical events in the progression of renal and vascular damage in diabetic patients. MicroRNAs are small, non-coding molecules and key regulators of gene expression. There is evidence of microRNA-155 (miR-155) involvement in diabetes complications, but the underlying mechanisms are unclear. In this study, gain- and loss-of-function experiments were applied to investigate the interplay between miR-155-5p and suppressor of cytokine signaling 1 (SOCS1) in the regulation of JAK/STAT pathway during renal and vascular injury in diabetes. Method Mesangial, tubuloepithelial, and vascular smooth muscle cells were transfected with miR-155-5p mimic or inhibitor, SOCS1 expression plasmid or siRNA, before stimulation with cytokines or high-glucose. Apolipoprotein E deficient mice with streptozotocin-induced diabetes were treated with either SOCS1-encoding adenovirus or miR-155-5p inhibitor. Samples were analyzed for the expression of miR-155-5p, SOCS1, and mediators of renal and vascular damage. Results In diabetic mice, the expression of miR-155-5p correlated inversely with SOCS1 levels and positively with markers of renal dysfunction, atherosclerosis, inflammation and oxidative stress. In renal cells, transfection with miR-155-5p mimic downregulated SOCS1, activated STAT1 and cytokine expression, and stimulated cell proliferation and migration. Mimic transfection also promoted the transition from contractile to synthetic phenotype in vascular smooth muscle cells. Conversely, both miR-155-5p antagonism and SOCS1 overexpression protected cells from inflammatory damage. In vivo SOCS1 gene delivery in diabetic mice decreased miR-155-5p and prevented kidney and vascular injury. Finally, therapeutic inhibition of miR-155-5p alleviates albuminuria, renal inflammation and fibrosis in diabetic mice, and also reduced atherosclerosis burden and improved plaque stability. Conclusion The modulation of miR-155/SOCS1 axis protects against diabetic renal and vascular damage in mice, thus highlighting its potential as therapeutic target for chronic complications of diabetes.

#2810 Exploring non-renal vasculature: therapeutic implications of proton pump inhibitor and anthelmintic treatment in PCK rat model

Abstract Background and Aims Cystic kidney diseases represent ciliopathies that can cause vascular damage through renal hypertension. Additionally, there is growing experimental evidence of endothelial cell abnormalities associated with ciliary protein deficiencies. PCK rats, a strain derived from Sprague-Dawley (SD) rats that develops both polycystic kidney disease (PKD) and liver disease, serve as a model for recessive PKD. The PCK rat model also presents abnormalities in non-renal vascular function. Another study from our group suggests a potential therapeutic benefit of repurposed therapy with a proton pump inhibitor (PPi) and an anthelmintic agent in attenuating the progression of PKD in a PCK rat model. Here, we investigated whether these drugs can also improve endothelial function. Method The compounds were administered to 3-week-old male and female PCK rats (n = 5-6) for a total of 10 weeks. Untreated PCK rats and age-matched SD rats (n = 5-6) served as controls. After perfusion fixation, the aorta was harvested and its thoracic rings were used to evaluate the contraction/relaxation responses ex vivo by organ bath experiments. Additional rings were preserved for histological and molecular biological analyses. Results Male PCK rats exhibited impaired endothelial function compared to healthy controls. Endothelium-dependent relaxation to acetylcholine was improved by 10% after treatment with PPi, while the anthelmintic administration had no protective effect. PKD also impaired endothelial function in female PCK rats compared to healthy SD controls. There was an improvement in endothelium-dependent relaxation to acetylcholine after treatment with PPi by 5.5%, while administration of the anthelmintic agent further impaired endothelial function. Conclusion 13-week-old PCK rats show endothelial dysfunction in non-renal vasculature. Treatment with a proton pump inhibitor improved endothelial function in male PCK rats to the level of healthy SD controls. By contrast, in a parallel study, the anthelmintic had a positive effect on renal function but a detrimental impact on endothelial function. These intricate relationships underscore the need for further exploration to understand the underlying mechanisms and broader implications of our findings, illustrating the challenges and potential avenues for the development of effective treatments for PKD.

#198 Different patterns of renal thrombotic microangiopathy

Abstract Background and Aims Thrombotic microangiopathy (TMA) is a renal lesion often associated with microangiopathic hemolysis. However, there are cases of TMA that present without hemolysis, hematuria or even proteinuria, sometimes being an incidental histopathological finding. In these situations, little is known about the long-term effects on renal function. The aim of our study is to describe the clinical and histopathological presentation of patients with renal TMA biopsied in our center, focusing on those without hemolysis and with low clinical suspicion of TMA. Method We conducted a retrospective observational unicentric study. Clinical and histological parameters were collected from patients biopsied between 2015 and 2023, whose renal biopsy (RB) showed TMA, with a minimum follow-up of 6 months. We excluded renal transplant recipients. Results Data were collected from 41 patients (17 men, 24 women), with a mean age at the time of RB of 54 ± 16 years and a mean eGFR of 80 ± 23 ml/min/1.72 m2. 12 of them (29%) had chronic kidney disease (CKD). Twenty-seven patients (66%) did not have hemolysis at diagnosis. Compared to patients with hemolysis, they were of older age (58 vs 47 years, p = 0.030) and had higher prevalence of CKD (41% vs 7%, p = 0.028). They had a milder clinical presentation, with lower creatinine (168 vs 419 μmol/L, p = 0.029), lower need for renal replacement therapy (RRT) (4% vs 50%, p = 0.001), less hematuria (33% vs 79%, p = 0.008) and proteinuria (67% vs 100%, p = 0.035). Histologically, patients without hemolysis had less fibrosis (56% vs 86%, p = 0.084) and fewer chronic TMA lesions (double contours, wrinkling of the basement membrane) (52% vs 93%, p = 0.009), despite delayed renal biopsy compared to patients with hemolysis (99 ± 118 vs 28 ± 30 days since clinical presentation, p = 0.036). The causes of TMA that were most commonly associated with the absence of hemolysis were drugs (89% without hemolysis) and glomerulopathies such as IgA nephropathy, minimal change disease and fibrillary glomerulonephritis (100% without hemolysis). Within this group of patients without hemolysis, 13 (32%) had a low clinical suspicion of TMA, defined as the absence of hemolysis, hypertension and predisposing factors, in some cases being an incidental finding in the RB. As expected, they also had a mild presentation and did not require RRT. In some cases, they even presented without proteinuria (7 patients, 64%). When comparing the severity of the lesions in renal tissue with patients with high clinical suspicion of TMA, patients with low clinical suspicion presented a similar prevalence of mesangiolysis, vascular damage and a similar proportion of affected glomeruli. Chronic TMA lesions were present in both groups (Table 1). When analysing the evolution of renal function, there are several confounding factors to consider (higher prevalence of CKD in patients without hemolysis, targeted treatment in patients with hemolysis, different time of follow-up between groups...). In our results, there were no statistically significant differences in the evolution of creatinine and proteinuria between groups, even when TMA was an incidental finding. In our sample, these findings were not attributable to a larger number of other histopathological lesions in patients with low suspicion of TMA, as there were no differences between groups (see Table 1). Conclusion Renal TMA should be suspected even in the absence of hemolysis, hypertension or proteinuria, as in our sample one third of diagnoses were incidental and their mild presentation may have delayed renal biopsy. The severity of histological lesions and the evolution of renal function in these cases are comparable to those of patients with a high clinical suspicion. Therefore, its prompt identification, etiological study and treatment are equally important. Currently, we have insufficient data to provide the different clinical scenarios in which TMA should be suspected. However, based on our findings, in the presence of drugs TMA should be considered in the differential diagnosis along with Acute Interstitial Nephritis, even in the absence of urinary abnormalities.

#2387 Case study of a patient with gouty nephropathy treated with immunosorbent therapy

Abstract Background and Aims Gouty nephropathy is a kidney disease caused by chronic hyperuricemia, in which uric acid crystals are deposited in the kidneys leading to tubular and glomerular damage, which in turn affects kidney function. Patient female, 68 years old, 7 years ago, no obvious cause of the first toe joint of the right foot, the right ankle joint redness, swelling and pain, the local skin temperature increases, serious limitation of activities, had checked the high uric acid (specific unknown), diagnosed as “gout”, simple treatment after the symptoms are relieved, but did not have systematic treatment, and gradually appeared in the left foot, the first toe joint, the left ankle joint, double knee joint redness, swelling and pain, oral pain medication treatment, pain disappears after still no systematic treatment. After that, redness, swelling and pain appeared gradually in the first toe joint of the left foot, left ankle joint and both knee joints, and the pain disappeared without systematic treatment after taking pain-relieving medicines. He was admitted to our hospital as an outpatient with the diagnosis of “gout”. Method Immunosorbent therapy was given once/day on days 1-3, along with Jinshuibao and urotoxin clearing granules. Immunosorbent therapy was given again three times on the 8th-10th day of admission. Results Before admission, uric acid: 899.3 µmol/L; creatinine: 586.1 µmol/L, both seriously out of the normal range. 3 days later, uric acid: 770.4 µmol/L, creatinine: 468.7 µmol/L. At the time of discharge, serum uric acid: 298.5 µmol/L and creatinine: 182.6 µmol/L were detected and restored to the normal range. Conclusion The case demonstrated the presence of gout with arthritic symptoms, vascular damage, anemia, and hepatic and renal impairment. The patient's gout progressively worsened due to prolonged absence of systemic treatment. After admission, the levels of uric acid and creatinine were effectively controlled and restored by immunosorbent therapy. This indicates that immunosorbent therapy plays a positive role in removing uric acid from the body and improving renal function. Meanwhile, the management and control of gout was further strengthened by combining the comprehensive treatment with Jinshuibao and uremic acid granules.

Features of the Background EEG of Alcohol Dependent Patients with Comorbid Exogenous Organic Brain Damage

Background: the range and prevalence of complicating pathologies in alcoholism indicate the need for a thorough examination of patients using modern diagnostic approaches. The aim was to study the indicators of spontaneous electrical activity of the brain in patients with alcohol dependence with comorbid exogenous organic brain damage non-alcoholic nature. Patients and methods: a study of electroencephalograms of 148 men with alcohol dependence using the classification of E.A. Zhirmunskaya (1984) was conducted. Results: based on the hystory data, 85 (57.4%) patients were found to have exogenous organic vascular brain damage (including hypertension in 57 (38.5%) cases, chronic cerebral circulation disorder — in 8 (5.4%), somatoform autonomic dysfunction — in 7 (4.7%)) and traumatic character (mild traumatic brain injury) in 13 (8.8%)) patients. The analysis using Fisher’s exact criterion revealed statistically significant differences between patients with alcohol dependence and alcoholism patients with comorbid exogenous organic brain damage in the frequency of occurrence of various types of electroencephalograms (p < 0.001). The study clearly showed that the presence of exogenous organic brain damage in patients with alcoholism leads to more pronounced functional changes in the brain. Conclusion: early detection of pathological activity on the EEG in patients with alcohol dependence will allow clinicians to carry out appropriate therapeutic and diagnostic measures in a timely manner and will provide additional information necessary for the development of personalized medical rehabilitation programs for patients taking into account their neurophysiological profile.

#49 Uremic toxins and inflammation: Metabolic pathways affected in stage 5 kidney disease

Abstract Background and Aims Chronic kidney disease (CKD) is a global health threat, affecting around 12% of the population. The uremic phenotype associated with CKD is considered a predictor for the high cardiovascular and overall mortality in these patients and inflammation is regarded as an essential contributor to it. We seek to discover new inflammation-related metabolites in the CKD population through the use of semitargeted metabolomics, in order to gain insight into the pathways involved and identify potential biomarkers. Method The study employed an observational prospective design to investigate metabolite impact on inflammation in 50 non-dialysis-dependent stage 5 CKD patients. Blood samples were collected before the start of the first haemodialysis session. A semitargeted metabolomic approach was followed, utilising liquid chromatography and high-resolution mass spectrometry with an in-house library of polar compounds. Univariate (Mann-Whitney test) and multivariate (logistic regression with LASSO regularization) analyses identified metabolomic variables associated with inflammation. Results Univariate analysis revealed that adenosine-5′-phosphosulfate (APS) (p-value (p) 0.0211), dimethyglycine (p 0.0015), pyruvate (p 0.0066), lactate (p 0.0156) and 2-ketobutyric acid (p 0.0458) were significantly increased with inflammation, with differences over 1,5-fold changes (inflammation = yes vs inflammation = no). Cholic acid (p 0.01655), homogentisic acid (p 0.0007), 2-phenylpropionic acid (p 0.0351) and 3-indoxylsulfate (p 0.0087) show similar patterns but in the opposite direction, as observed in the volcano plot in Fig. 1. Multivariate analysis revealed significant associations between metabolites and inflammation in CKD stage 5 patients. Specifically, odds ratios for N-Butyrylglycine (OR: 1.87), dimethylglycine (OR: 1.81), 2-Oxoisopentanoic acid (OR: 1.70), and pyruvate (OR: 1.71) were related to a higher probability of experiencing inflammation. Conversely, homogentisic acid (OR: 072), 2-Phenylpropionic acid (OR: 0.77), and 2-Methylglutaric acid (OR: 0.78) exhibited an OR<1, suggestive of decreased probability. This is graphically represented in Fig. 2. Conclusion In our semi-targeted metabolomics study on stage 5 CKD patients, we pinpointed various metabolites linked to inflammation. Notably, dimethylglycine, a uremic toxin, may contribute to vascular damage, while pyruvate's abnormal metabolism is a known feature in heart failure and chronic kidney disease. N-butyrilglycine and 2-oxoisopentanoic acid were also associated with inflammation, potentially tied to mitochondrial fatty acid beta oxidation and incomplete breakdown of branched-chain amino acids. APS, impacting bone development and intestinal permeability, showed a positive correlation with inflammation. Conversely, homogentisic acid and phenylpropionic acid were negatively correlated. While homogentisic acid's anti-inflammatory role isn't clear, phenylpropionic acid exhibits protective effects against hepatotoxicity by reducing immune response. 2-methylglutaric acid and cholic acid were inversely correlated with inflammation, suggesting a protective effect related to fatty acid metabolism and bile acid regulation. These identified metabolites enhance our understanding of CKD-associated inflammation and present strong candidates for future biomarker validation with potential for clinical translation.

#1372 Association of plasma beta-2-microglobulin with risk of cardiovascular disease in patients with chronic kidney disease

Abstract Background and Aims In patients with chronic kidney disease(CKD), beta 2 microglobulin (B2MG) can be used to assess renal function, and predialysis serum B2MG levels can predict mortality risk. In addition to the kidney, B2MG regulates the expression of interleukin 1 and tumor necrosis factor, participates in the pathogenesis of vascular damage, and is a marker that can detect the formation of amyloid, therefore it is important in the diagnosis of cardiovascular disease (CVD). To assess the correlation of serum B2MG levels with some metabolic and cardiovascular function factors in patients with chronic kidney disease. Method 119 people with chronic kidney disease and 52 healthy control groups were selected as a case-control study and blood samples were analyzed for creatinine, urea, cholesterol, triglycerides, LDL, calcium, phosphorus, albumin, total protein, and B2MG with Cobas 6000 fully automatic analyzer and echocardiography was performed. Renal function was evaluated by CKD EPI crea-cys combined calculation. In the group with CKD, a person with eGFR <90 ml/min/1.73 m² was not included in the study due to the study exclusion criteria. Results The average age of the group with CKD was 54.92, and the average age of the healthy group was 50.66. B2MG has a significantly higher (P < 0.000) statistically significant correlation in the group with CKD compared to the control group. B2MG was significantly associated with creatinine (g = 0.516, P < 0.000), phosphorus (g = 0.342, P < 0.000), cystatin C (g = 0.700, P < 0.000), urea (g = 0.326, P < 0.000), and echocardiography with directly indicators LVMI(g = 0.113, P < 0.000), LVESD (r = 0.265, P < 0.000), thus BMI (g = −0.274, P < 0.000), tTSH (r = −0.516, P < 0.000), calcium ( g = −0.137, P < 0.000), albumin (g = −0.180, P < 0.000), total protein (r = −0.080, P < 0.000), cholesterol (g = −0.215, P < 0.000), BNLP (r = −0.163, P < 0.000), triglycerides (g = −0.142, P < 0.000), and EV of echocardiography (g = −0.292, P < 0.000) have inverse statistical significance. Conclusion B2MG levels have been shown to predict CVD risk and CVD-related mortality in all stages of chronic kidney disease. According to our study, B2MG is directly related to kidney function biomarkers, phosphorus, LVMI, and LVESD indicators of cardiac echocardiography, and inversely correlated with parameters of eGFR, protein, triglycerides, calcium, and cardiac echocardiogram EV indicators, which is similar to studies conducted in other countries. Therefore, B2MG can be used to detect the risk of CVD in people with severe CKD. Figure: Will be uploaded on our poster if accepted.

Chronic Thromboembolic Pulmonary Hypertension Becoming of a Patient Followed Since the Age Of 10

Chronic thromboembolic pulmonary hypertension occurs after one or more episodes of pulmonary embolism. A rigorous diagnostic approach makes it possible to identify this condition, to evaluate its functional and hemodynamic impact and to determine the degree of extension of the vascular damage. Surgical pulmonary endarterectomy in specialized centers remains the treatment of choice in certain cases. Other therapeutic modalities include transplantation, pulmonary angioplasty, and pharmacological treatments with pulmonary vasodilators. We report the case of OA aged 25, followed since the age of 10 for post-embolic PAH. She was hospitalized at this age in pediatrics for the first episode of pulmonary embolism. The initial etiological assessment was without abnormalities. One year after pulmonary embolism, pulmonary pressures were still elevated despite effective anticoagulation. The patient was started on sildenafil at the age of 11. The evolution was stable. At the age of 16, she was referred to us for care. Her cardiovascular assessment revealed suprasystemic PAH; the patient was then put on a combination of sintrom, sildenafil and bosentan. The thrombophilia assessment is without abnormalities. Currently, she is 25 years old, she is in NYHA functional class II on dual therapy, she has presented several right heart decompensations following non-compliance with treatment and dietary deviation. We discussed a surgical endarterectomy at her home but unfortunately the damage is distal and old. Through this case, we will review this entity of PAH by discussing the different modes of expression and the medical, surgical and interventional therapeutic management (pulmonary angiopalstia with a balloon).

Blood biomarkers for occupational hand-arm vibration exposure.

Hand-arm vibration is a common occupational exposure that causes neurological impairment, myalgia, and vibration-induced Raynaud's phenomena or vibration white fingers (VWF). The pathological mechanism is largely unknown, though several mechanisms have been proposed, involving both immunological vascular damage and defective neural responses. The aim of this study was to test whether the substances interleukin-33 (IL-33), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), endothelin-1 (ET-1), C-C motif chemokine ligand 20 (CCL20), calcitonin, and thromboxane (TXA2) changed before and after occupational hand-arm vibration exposure. 38 full-time shift workers exposed to hand-arm vibration were recruited. All the participants underwent medical examinations regarding symptoms of Raynaud's phenomena. In 29 of the participants, the concentration of IL-33, MDC, IL-10, ET-1, CCL20, calcitonin, and TXA2 was measured before and after a workday. There was a significant increase in ET-1 and calcitonin concentration and a decrease in the CCL20 concentration after the work shift in all participants. In the group suffering from VWF, but not in the non-VWF group, MDC was statistically significantly lower before the work shift (p = .023). The VWF group also showed a significant increase in MDC after the work shift. Exposure to occupational hand-arm vibration is associated with changes in ET-1, calcitonin, and MDC concentration in subjects suffering from vibration white fingers, suggesting a role of these biomarkers in the pathophysiology of this condition.

Pathogenesis of Pulmonary Manifestations in ANCA-Associated Vasculitis and Goodpasture Syndrome.

Pulmonary manifestations of vasculitis are associated with significant morbidity and mortality in affected individuals. They result from a complex interplay between immune dysregulation, which leads to vascular inflammation and tissue damage. This review explored the underlying pathogenesis of pulmonary involvement in vasculitis, encompassing various forms such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and anti-GBM disease. Mechanisms involving ANCA and anti-GBM autoantibodies, neutrophil activation, and neutrophil extracellular trap (NETs) formation are discussed, along with the role of the complement system in inducing pulmonary injury. Furthermore, the impact of genetic predisposition and environmental factors on disease susceptibility and severity was considered, and the current treatment options were presented. Understanding the mechanisms involved in the pathogenesis of pulmonary vasculitis is crucial for developing targeted therapies and improving clinical outcomes in affected individuals.

Integrin-linked kinase mRNA expression in circulating mononuclear cells as a biomarker of kidney and vascular damage in experimental chronic kidney disease

BackgroundTraditional biomarkers of chronic kidney disease (CKD) detect the disease in its late stages and hardly predict associated vascular damage. Integrin-linked kinase (ILK) is a scaffolding protein and a serine/threonine protein kinase that plays multiple roles in several pathophysiological processes during renal damage. However, the involvement of ILK as a biomarker of CKD and its associated vascular problems remains to be fully elucidated.MethodsCKD was induced by an adenine-rich diet for 6 weeks in mice. We used an inducible ILK knockdown mice (cKD-ILK) model to decrease ILK expression. ILK content in mice's peripheral blood mononuclear cells (PBMCs) was determined and correlated with renal function parameters and with the expression of ILK and fibrosis and inflammation markers in renal and aortic tissues. Also, the expression of five miRNAs that target ILK was analyzed in whole blood of mice.ResultsThe adenine diet increased ILK expression in PBMCs, renal cortex, and aortas, and creatinine and urea nitrogen concentrations in the plasma of WT mice, while these increases were not observed in cKD-ILK mice. Furthermore, ILK content in PBMCs directly correlated with renal function parameters and with the expression of renal and vascular ILK and fibrosis and inflammation markers. Finally, the expression of the five miRNAs increased in the whole blood of adenine-fed mice, although only four correlated with plasma urea nitrogen, and of those, three were downregulated in cKD-ILK mice.ConclusionsILK, in circulating mononuclear cells, could be a potential biomarker of CKD and CKD-associated renal and vascular damage.Graphical ILK content in circulating mononuclear cells reflects renal and vascular damage in a CKD experimental model.

The Use of the Galea Flap for the Reconstruction of Forehead Defects

The forehead, a vital anatomical unit of the face, is delimited by the anterior hairline superiorly and by the nasal root, eyebrows, and a horizontal line through the lateral canthus inferiorly. Malignant tumors like basal cell carcinomas frequently afflict this region, necessitating meticulous reconstruction techniques to preserve aesthetics and functionality. This article presents an in-depth exploration of the galea flap graft’s efficacy in addressing tissue defect on the forehead, especially in cases of basal cell carcinomas. The surgical procedure involves a wide excision with a 1 cm safety margin, including the frontal muscle and periosteum, followed by exposing the frontal bone. A meticulous approach is taken in tracing the midline, marking the hairline, and planning the left hemi coronal incision to ensure optimal outcomes. The galea flap, vascularized by branches of the superficial temporal artery, is meticulously lifted and transposed downwards to cover the tissue defect, while ensuring the viability of the flap. Postoperative monitoring reveals no signs of cutaneous or vascular damage, with preserved sensory and motor functions attributed to the preservation of the frontal branch of the facial nerve. The discussion delves into the intricate anatomy of the forehead, emphasizing its vascularization, innvervation, and aesthetic subunits such as the glabella and eyebrows. Various surgical techniques, including direct suturing, directed healing, skin grafts, advancement flaps, and two-stage scalp flaps, are examined in light of their efficacy and limitations in forehead reconstruction. The galea flap emerges as a preferred option due to its reliable vascular supply, ease of lifting, and versatility in covering tissue defects while preserving aesthetics. Future research directions are suggested, focusing on refining surgical techniques to achieve optimal outcomes in forehead tissue reconstruction, balancing esthetic results with functional integrit.

Preliminary Exploration of Potential Active Ingredients and Molecular Mechanisms of Yanggan Yishui Granules for Treating Hypertensive Nephropathy Using UPLC-Q-TOF/MS Coupled with Network Pharmacology and Molecular Docking Strategy.

Hypertensive nephropathy (HN) is a prevalent complication of hypertension and stands as the second primary reason for end-stage renal disease. Research in clinical settings has revealed that Yanggan Yishui Granule (YGYSG) has significant therapeutic effects on HN. However, the material basis and action mechanisms of YGYSG against HN remain unclear. Consequently, this study utilized a comprehensive method integrating ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), network pharmacology, and molecular docking to delineate the active ingredients and potential therapeutic mechanisms of YGYSG for treating HN. Firstly, sixty distinct components were recognized in total as potential active ingredients in YGYSG by UPLC-Q-TOF/MS. Subsequently, the mechanisms of YGYSG against HN were revealed for the first time using network pharmacology. 23 ingredients played key roles in the complete network and were the key active ingredients, which could affect the renin-angiotensin system, fluid shear stress and atherosclerosis, HIF-1 signaling pathway, and AGE-RAGE signaling pathway in diabetic complications by regulating 29 key targets such as TNF, IL6, ALB, EGFR, ACE, and MMP2. YGYSG could treat HN through the suppression of inflammatory response and oxidative stress, attenuating the proliferation of renal vascular smooth muscle cells, lessening glomerular capillary systolic pressure, and ameliorating renal dysfunction and vascular damage through the aforementioned targets and pathways. Molecular docking results revealed that most key active ingredients exhibited a high affinity for binding to the key targets. This study pioneers in clarifying the bioactive compounds and molecular mechanisms of YGYSG against HN and offers scientific reference into the clinical application.

Astrogliosis in the GFAP-CreERT2:Rosa26iDTR Mouse Model Does Not Exacerbate Retinal Microglia Activation or Müller Cell Gliosis under Hypoxic Conditions.

Diabetic retinopathy (DR) affects over 140 million people globally. The mechanisms that lead to blindness are still enigmatic but there is evidence that sustained inflammation and hypoxia contribute to vascular damage. Despite efforts to understand the role of inflammation and microglia in DR's pathology, the contribution of astrocytes to hypoxic responses is less clear. To investigate the role of astrocytes in hypoxia-induced retinopathy, we utilized a 7-day systemic hypoxia model using the GFAP-CreERT2:Rosa26iDTR transgenic mouse line. This allows for the induction of inflammatory reactive astrogliosis following tamoxifen and diphtheria toxin administration. We hypothesize that DTx-induced astrogliosis is neuroprotective during hypoxia-induced retinopathy. Glial, neuronal, and vascular responses were quantified using immunostaining, with antibodies against GFAP, vimentin, IBA-1, NeuN, fibrinogen, and CD31. Cytokine responses were measured in both the brain and serum. We report that while both DTx and hypoxia induced a phenotype of reduced microglia morphological activation, DTx, but not hypoxia, induced an increase in the Müller glia marker vimentin. We did not observe that the combination of DTx and hypoxic treatments exacerbated the signs of reactive glial cells, nor did we observe a significant change in the expression immunomodulatory mediators IL-1β, IL2, IL-4, IL-5, IL-6, IL-10, IL-18, CCL17, TGF-β1, GM-CSF, TNF-α, and IFN-γ. Overall, our results suggest that, in this hypoxia model, reactive astrogliosis does not alter the inflammatory responses or cause vascular damage in the retina.

Incorporation of Inclusion Complexes in the Dissolvable Microneedle Ocular Patch System for the Efficiency of Fluconazole in the Therapy of Fungal Keratitis.

Fluconazole (FNL) is one of the first-line treatments for fungal keratitis as it is an effective broad-spectrum antimicrobial commonly administered orally or topically. However, FNL has a very low water solubility, limiting its drug formulation, therapeutic application, and bioavailability through tissues. To overcome these limitations, this study aimed to develop FNL inclusion complexes (FNL-IC) with cyclodextrin (α-cyclodextrin, sulfobutylether-β-cyclodextrin, and hydroxypropyl-γ cyclodextrin) and incorporate it into a dissolvable microneedle (DMN) system to improve solubility and drug penetration. FNL-IC was evaluated for saturation solubility, Fourier transform infrared spectroscopy, differential scanning calorimetry, in vitro release, minimum inhibitory concentration, minimum fungicidal concentration, and time-killing assay. DMN-FNL-IC was evaluated for mechanical and insertion properties, surface pH, moisture absorption ability, water vapor transmission, and drug content recovery. Moreover, ocular kinetic, ex vivo antimicrobial, in vivo antifungal, and chorioallantoic membrane (HET-CAM) assays were conducted to assess the overall performance of the formulation. Mechanical strength and insertion properties revealed that DMN-FNL-IC has great mechanical and insertion properties. The in vitro release of FNL-IC was significantly improved, exhibiting a 9-fold increase compared to pure FNL. The ex vivo antifungal activity showed significant inhibition of Candida albicans from 6.54 to 0.73 log cfu/mL or 100-0.94%. In vivo numbers of colonies of 0.87 ± 0.13 log cfu/mL (F2), 4.76 ± 0.26 log cfu/mL (FNL eye drops), 3.89 ± 0.24 log cfu/mL (FNL ointments), and 8.04 ± 0.58 log cfu/mL (control) showed the effectiveness of DMN preparations against other standard commercial preparations. The HET-CAM assay showed that DMN-FNL-IC (F2) did not show any vascular damage. Finally, a combination of FNL-IC and DMN was developed appropriately for ocular delivery of FNL, which was safe and increased the effectiveness of treatments for fungal keratitis.