Edema Formation Research Articles

Nephrotic syndrome and adrenoleukodystrophy in a 5-year-old boy.

Nephrotic syndrome is a common condition characterized by filtration of large amounts of protein, hypoalbuminemia, reduced plasma oncotic pressure, sodium retention, and edema. The mechanism responsible for sodium retention in this condition is still controversial. Two different pathophysiological pathways have been proposed to explain edema formation: activation of neurohumoral effector mechanisms, including the renin-angiotensin-aldosterone system, or abnormal intrinsic/primary renal sodium retention. A 5-year-old boy with X-linked adrenoleukodystrophy presented with bilateral leg swelling, massive proteinuria, and hypoalbuminemia. Minimal change disease was diagnosed. The patient was initially treated with corticosteroids and experienced several relapses. The progression of fractional excretion of sodium correlated with proteinuria and undetectable aldosterone levels. This unusual finding suggests that the mechanism of tubular sodium avidity in this child with mineralocorticoid insufficiency was independent of the renin-angiotensin-aldosterone system.

Normothermic Perfusion is Superior to Cold Perfusion in Porcine Ex Situ Lung Perfusion

BackgroundCold ex situ lung perfusion (ESLP) has demonstrated improved preservation in small animal ESLP compared to normothermic ESLP and cold static preservation. We hypothesized that cold negative pressure ventilation (NPV)-ESLP would improve graft function in a porcine transplantation model. MethodsFour perfusate temperatures were examined with 12 hours NPV-ESLP in a large animal transplantation model. Pig lungs were allotted to four groups: (1) Normothermia (38°C, n = 6); (2) profound hypothermia (10°C, n = 6); (3) moderate hypothermia (20°C, n = 3); (4) subnormothermia (32°C, n = 3). A fifth group subnormothermic low-flow (SNLF) perfusion was examined to assess the effect of reduced cardiac output with cold perfusion (32°C, 10% cardiac output, n = 6). ResultsOnly Normothermic and SNLF groups demonstrated acceptable oxygenation after 12 hours NPV-ESLP and were transplanted. All other groups failed prematurely. After 12 hours of ESLP, Normothermic lungs demonstrated significantly greater dynamic compliance compared to SNLF lungs (P = .03). Edema formation post-ESLP was significantly worse in the SNLF group (P = .01). There was no significant difference in pulmonary artery pressures after ESLP (P = .10); however, pulmonary vascular resistance was significantly greater in the SNLF (P = .04). Isolated left lung oxygenation 4-hours post-transplant and left lung edema formation was not significantly different between Normothermic and SNLF post-transplant (P = .09). Proinflammatory cytokines were significantly greater during SNLF-ESLP (tumor necrosis factor alpha, P < .05). ConclusionsProlonged normothermic (38°C) NPV-ESLP is superior to 10, 20, and 32°C perfusion. Normothermic ESLP of porcine lungs results in superior graft function and reduced inflammation versus SNLF-ESLP.

Mesh-like External Suture Splint: A Way to Improve Results and Reduce Postoperative Complications after High-definition Liposculpture.

High-definition liposculpture with variable degrees of muscular definition allows both patients and surgeons to broaden the procedure to fit almost any individual preferences; however, skin laxity and those secondary cases still represent a big challenge for the surgeon to achieve optimal outcomes. We are reporting our experience with a new suture-splint procedure to reduce edema, avoid skin laxity, and increase muscular definition after liposculpture. We enrolled patients undergoing HDL with any risk factor that could compromise aesthetic outcomes. Tumescent technique with VASER fat emulsification and power-assisted liposuction were used to complete HDL. We performed a continuous suture over the midline and other areas of muscular definition right before patients awakened from anesthesia. Real-time ultrasound imaging was performed to ensure the safety of the procedure. A total of 52 consecutive patients were treated with MesHD in our study. Only two patients voluntarily dropped off from postoperative analysis due to geographical limitations. Postoperative edema was referred by only one patient after surgery. No major complications were reported. Three patients complained of stabbing pain over one of the stitches, which resolved completely after suture removal. All patients were satisfied with postoperative results. Mesh suture-splint at body areas with high risk of adverse effects after body contouring surgery may be an effective procedure to improve recovery by decreasing edema formation, enhancingmuscular definition, decreasing risk of fibrosis, and avoiding skin laxity postoperative appearance.

Protective effects of E-CG-01 (3,4-lacto cycloastragenol) against bleomycin-induced lung fibrosis in C57BL/6 mice

Idiopathic pulmonary fibrosis is an aging-related, chronic lung disease, with unclear pathogenesis and no effective treatment. One of the triggering factors in cell aging is oxidative stress and it is known to have a role in idiopathic pulmonary fibrosis. In this paper, the protective effect of the E-CG-01 (3,4-lacto-cycloastragenol) molecule in terms of its antioxidant properties was evaluated in the bleomycin induced mice lung fibrosis model. Bleomycin sulfate was administered as a single dose (2.5 U/kg body weight) intratracheally to induce lung fibrosis. E-CG-01 was administered intraperitoneally in three different doses (2 mg/kg/day, 6 mg/kg/day, and 10 mg/kg/day) for 14 days, starting three days before the bleomycin administration. Fibrosis was examined by Hematoxylin-Eosin, Masson Trichrome, and immunohistochemical staining for TGF-beta1, Type I collagen Ki-67, and gama-H2AX markers. Activity analysis of catalase and Superoxide dismutase enzymes, measurement of total oxidant, total glutathione, and Malondialdehyde levels. In histological analysis, it was determined that all three different doses of the molecule provided a prophylactic effect against the progression of fibrosis compared to the bleomycin control group. However, it was observed that only the molecule applied in the high dose decreased the total oxidant stress level. Lung weight ratio increased in the BLM group but significantly reduced with high-dose E-CG-01. E-CG-01 at all doses reduced collagen deposition, TGF-β expression, and Ki-67 expression compared to the BLM group. Intermediate and high doses of E-CG-01 also significantly reduced alveolar wall thickness and edema formation. These findings suggest that E-CG-01 has potential therapeutic effects in mitigating lung fibrosis through its antioxidant properties.

Bradykinin 2 Receptors Mediate Long-Term Neurocognitive Deficits After Experimental Traumatic Brain Injury.

The kallikrein-kinin system is one of the first inflammatory pathways to be activated following traumatic brain injury (TBI) and has been shown to exacerbate brain edema formation in the acute phase through activation of bradykinin 2 receptors (B2R). However, the influence of B2R on chronic post-traumatic damage and outcome is unclear. In the current study, we assessed long-term effects of B2R-knockout (KO) after experimental TBI. B2R KO mice (heterozygous, homozygous) and wild-type (WT) littermates (n = 10/group) were subjected to controlled cortical impact (CCI) TBI. Lesion size was evaluated by magnetic resonance imaging up to 90 days after CCI. Motor and memory function were regularly assessed by Neurological Severity Score, Beam Walk, and Barnes maze test. Ninety days after TBI, brains were harvested for immunohistochemical analysis. There was no difference in cortical lesion size between B2R-deficient and WT animals 3 months after injury; however, hippocampal damage was reduced in B2R KO mice (p = 0.03). Protection of hippocampal tissue was accompanied by a significant improvement of learning and memory function 3 months after TBI (p = 0.02 WT vs. KO), whereas motor function was not influenced. Scar formation and astrogliosis were unaffected, but B2R deficiency led to a gene-dose-dependent attenuation of microglial activation and a reduction of CD45+ cells 3 months after TBI in cortex (p = 0.0003) and hippocampus (p < 0.0001). These results suggest that chronic hippocampal neurodegeneration and subsequent cognitive impairment are mediated by prolonged neuroinflammation and B2R. Inhibition of B2R may therefore represent a novel strategy to reduce long-term neurocognitive deficits after TBI.

Porcine lungs perfused with three different flows using the 8-h open-atrium cellular ex vivo lung perfusion technique.

The number of lung transplantations is limited due to the shortage of donor lungs fulfilling the standard criteria. The ex vivo lung perfusion (EVLP) technique provides the ability of re-evaluating and potentially improving and treating marginal donor lungs. Accordingly, the technique has emerged as an essential tool to increase the much-needed donor lung pool. One of the major EVLP protocols, the Lund protocol, characterized by high pulmonary artery flow (100% of cardiac output [CO]), an open atrium, and a cellular perfusate, has demonstrated encouraging short-EVLP duration results. However, the potential of the longer EVLP duration of the protocol is yet to be investigated, a duration which is considered necessary to rescue more marginal donor lungs in future. This study aimed to achieve stable 8-h EVLP using an open-atrium cellular model with three different pulmonary artery flows in addition to determining the most optimal flow in terms of best lung performance, including lung electrolytes and least lung edema formation, perfusate and tissue inflammation, and histopathological changes, using the porcine model. EVLP was performed using a flow of either 40% (n = 6), 80% (n = 6), or 100% (n = 6) of CO. No flow rate demonstrated stable 8-h EVLP. Stable 2-h EVLP was observed in all three groups. Insignificant deterioration was observed in dynamic compliance, peak airway pressure, and oxygenation between the groups. Pulmonary vascular resistance increased significantly in the 40% group (p < .05). Electrolytes demonstrated an insignificant worsening trend with longer EVLP. Interleukin-8 (IL-8) in perfusate and tissue, wet-to-dry weight ratio, and histopathological changes after EVLP were insignificantly time dependent between the groups. This study demonstrated that stable 8-h EVLP was not feasible in an open-atrium cellular model regardless of the flow of 40%, 80%, or 100% of CO. No flow was superior in terms of lung performance, lung electrolytes changes, least lung edema formation, minimal IL-8 expression in perfusate and tissue, and histopathological changes.

Aquaporin-4 deletion leads to reduced infarct volume and increased peri-infarct astrocyte reactivity in a mouse model of cortical stroke.

Aquaporin-4 (AQP4) is the main water channel in brain and is enriched in perivascular astrocyte processes abutting brain microvessels. There is a rich literature on the role of AQP4 in experimental stroke. While its role in oedema formation following middle cerebral artery occlusion (MCAO) has been studied extensively, its specific impact on infarct volume remains unclear. This study investigated the effects of total and partial AQP4 deletion on infarct volume in mice subjected to distal medial cerebral artery (dMCAO) occlusion. Compared to MCAO, this model induces smaller infarcts confined to neocortex, and less oedema. We show that AQP4 deletion significantly reduced infarct volume as assessed 1week after dMCAO, suggesting that the role of AQP4 in stroke goes beyond its effect on oedema formation and dissolution. The reduction in infarct volume was associated with increased astrocyte reactivity in the peri-infarct areas. No significant differences were observed in the number of microglia among the genotypes. These findings provide new insights in the role of AQP4 in ischaemic injury indicating that AQP4 affects both infarct volume and astrocyte reactivity in the peri-infarct zone. KEY POINTS: Aquaporin-4 (AQP4) is the main water channel in brain and is enriched in perivascular astrocyte processes abutting microvessels. A rich literature exists on the role of AQP4 in oedema formation following middle cerebral artery occlusion (MCAO). We investigated the effects of total and partial AQP4 deletion on infarct volume in mice subjected to distal medial cerebral artery occlusion (dMCAO), a model inducing smaller infarcts confined to neocortex and less oedema compared to MCAO. AQP4 deletion significantly reduced infarct volume 1week after dMCAO, suggesting a broader role for AQP4 in stroke beyond oedema formation. The reduction in infarct volume was associated with increased astrocyte reactivity in the peri-infarct areas, while no significant differences were observed in the number of microglia among the genotypes. These findings provide new insights into the role of AQP4 in stroke, indicating that AQP4 affects both infarct volume and astrocyte reactivity in the peri-infarct zone.

Comprehensive Evaluation of the BeShape One Device: Assessing Thermal Safety in Noninvasive Body Contouring Using Advanced Techniques.

This study aims to assess the thermal safety profile of the BeShape One Device, a noninvasive, high-intensity, non-focused ultrasound device designed for reducing waist circumference. This device possesses several features that distinguish it from other commercial ultrasound-based fat reduction devices. The study focuses on evaluating temperature-related physiological changes through thermal safety analysis and histopathology in a swine model. The study utilized three types of applicators-active, demo, and modified-to comprehensively assess the device's impact on various skin layers. Five female Large White X Landrace swine were involved in the study, and the BeShape One Device was applied to designated treatment sites using a specific treatment protocol. The assessment included clinical observations, skin reaction evaluations, gross pathology, histopathological analyses, and advanced temperature measurement techniques, including needle thermocouples, thermal cameras, COMSOL modeling, and CEM43 analysis. Clinical observations indicated the animals' overall well-being throughout the study. Skin reactions, including erythema, edema, bruising, and crust formation, were temporary and resolved over time. Gross pathology revealed no treatment-related pathologies, except for a discoloration related to a tattoo procedure. Histopathological analyses at 30 and 90 days posttreatment demonstrated an absence of heat-related lesions in skin layers. Needle thermocouples and thermal camera measurements supported the device's ability to maintain consistent thermal homogeneity. COMSOL modeling and CEM43 analysis predicted no thermal damage to the skin, confirming the safety of the BeShape One Device. Under the experimental conditions, the BeShape One Device demonstrated a favorable safety profile. Clinically and histopathologically, no adverse effects were observed. The device's ability to achieve thermal homogeneity in skin layers was validated through advanced temperature measurement techniques. COMSOL modeling and CEM43 analysis further supported the conclusion that the device is safe, making it a promising option for noninvasive body contouring procedures.

Evaluation of the Effect of Botulinum Toxin A on the Lymphatic Endothelial Cells.

Botulinum toxin A (BoTA) is a neurotoxin formed by Clostridium botulinum, with a broad medical application spectrum. While the primary effect of BoTA is on the muscles, the effects of BoTA in other systems including the blood vasculature have already been examined, revealing unexpected actions. However, no studies exist to the best of our knowledge regarding the potential effects of BoTA on the lymphatic vascular system, possessing a critical role in health and disease. Isolated human lymphatic endothelial cells (LECs) were cultured in dedicated in vitro culture systems. The analysis including imaging and cell culture approaches as well as molecular biology techniques is performed to examine the LEC alterations occurring upon exposure to different concentrations of BoTA. Human LECs were cultured and expanded on collagen-coated petri dishes using endothelial basal medium and the commercial product Botox from Allergan as used for all our experiments. Harvested cells were used in various in vitro functional tests to assess the morphologic and functional properties of the BoTA-treated LECs. Gene expression analysis was performed to assess the most important lymphatic system-related genes and pathways. Concentrations of 1, 5 or 10 U of BoTA did not demonstrate a significant effect regarding the proliferation and migration capacity of the LECs versus untreated controls. Interestingly, even the smallest BoTA dose was found to significantly decrease the cord-like-structure formation capacity of the seeded LECs. Gene expression analysis was used to underpin possible molecular alterations, suggesting no significant effect of BoTA in the modification of gene expression versus the starvation medium control. LECs appear largely unaffected to BoTA treatment, with an isolated effect on the cord-like-structure formation capacity. Further work needs to assess the effect of BoTA on the smooth-muscle-cell-covered collecting lymphatic vessels and the possible aesthetic implications of such an effect, due to edema formation. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Amiloride versus furosemide for the treatment of edema in patients with nephrotic syndrome: A pilot study (AMILOR).

In rodent models of nephrotic syndrome (NS), edema formation was prevented by blockade of the epithelial sodium channel ENaC with amiloride. However, apart from case reports, there is no evidence favoring ENaC blockade in patients with NS. The monocentric randomized controlled AMILOR study investigated the antiedematous effect of amiloride (starting dose 5 mg/day, max. 15 mg/day) in comparison to standard therapy with the loop diuretic furosemide (40 mg/day, max. 120 mg/day) over 16 days. Overhydration (OH) was measured by bioimpedance spectroscopy (BCM, Fresenius). Depending on the OH response, diuretic dose was adjusted on days 2, 5, 8 and 12, and if necessary, hydrochlorothiazide (HCT) was added from d8 (12.5 mg/day, max. 25 mg/day). The primary endpoint was the decrease in OH on d8. The study was terminated prematurely due to insufficient recruitment and a low statistical power due to a low actual effect size. Median baseline OH was +26.4 (interquartile range 15.5-35.1)% extracellular water (ECW) in the amiloride arm and + 27.9 (24.1-29.4)% ECW in the furosemide arm and decreased by 1.95 (0.80-6.40) and 5.15 (0.90-8.30)% ECW after 8 days, respectively, and by 10.10 (1.30-14.40) and 7.40 (2.80-10.10)% ECW after 16 days, respectively. OH decrease on d8 and d16 was not significantly different between both arms. The AMILOR study is the first randomized controlled pilot study suggesting a similar antiedematous effect as furosemide. Further studies are required to better define the role of amiloride in NS (EudraCT 2019-002607-18).

Two-component regulatory system TCS08 of a serotype 4 strain in pneumococcal pneumonia pathogenesis

ObjectivesStreptococcus pneumoniae, a human respiratory pathogen, causes diseases with severe morbidity and mortality rates worldwide. The two-component regulatory system (TCS) is an important signaling pathway that enables regulation of gene expression in response to environmental cues, thereby allowing an organism to adapt to a variety of host niches. Here we examined the contribution of pneumococcal TCS08 to bacterial colonization, the development of pneumonia, and pulmonary dysfunction. MethodsWe employed an hk08 knockout mutant (Δhk08) with a background of the TIGR4 wild-type (WT) strain to verify whether TCS08 is associated with bacterial colonization and the development of pneumonia in a murine infection model. To clarify the association of hk08 inactivation-induced phenotypic changes with their virulence, we examined pneumococcal capsule production, colony morphology, and surface-displayed protein profiles. ResultsPneumococcal TCS08 was involved in bacterial colonization in the respiratory tract. Interruption of the signaling pathway of TCS08 by hk08 inactivation impaired mouse survival and increased the bacterial burden within the respiratory tract. Furthermore, a histopathological examination revealed massive inflammatory cell infiltration, edema formation, and diffuse alveolar damage in the lung tissues of mice infected with Δhk08 versus the WT or complemented strain. Interestingly, virulence-associated phenotype changes, including capsule production, increased chain length, and surface-displayed protein profile, were observed in the Δhk08 strain. ConclusionsThe present findings indicate that TCS08 contributes to pneumococcal colonization and pulmonary dysfunction by assisting adaptation to the respiratory tract milieu, leading to the development of pneumonia.

The role of oxidative stress and neuroinflammatory mediators in the pathogenesis of high-altitude cerebral edema in rats

High-altitude environments present extreme conditions characterized by low barometric pressure and oxygen deficiency, which can disrupt brain functioning and cause edema formation. The objective of the present study is to investigate several biomolecule expressions and their role in the development of High Altitude Cerebral Edema in a rat model. Specifically, the study focuses on analyzing the changes in total arginase, nitric oxide, and lipid peroxidation (MDA) levels in the brain following acute hypobaric hypoxic exposure (7620 m, SO2=8.1 %, for 24 h) along with the histopathological assessment. The histological examination revealed increased TNF-α activity, and an elevated number of mast cells in the brain, mainly in the hippocampus and cerebral cortex. The research findings demonstrated that acute hypobaric hypoxic causes increased levels of apoptotic cells, shrinkage, and swelling of neurons, accompanied by the formation of protein aggregation in the brain parenchyma. Additionally, the level of nitric oxide and MDA was found to have increased (p<0.0001), however, the level of arginase decreased indicating active lipid peroxidation and redox imbalance in the brain. This study provides insights into the pathogenesis of HACE by evaluating some biomolecules that play a pivotal role in the inflammatory response and the redox landscape in the brain. The findings could have significant implications for understanding the neuronal dysfunction and the pathological mechanisms underlying HACE development.

Biophysical properties of alveolar surfactant in drever dogs with hunting associated pulmonary edema

BackgroundA syndrome of acute non-cardiogenic pulmonary edema associated with hunting is prevalent in the drever breed, but etiology of this syndrome is currently unknown. Alveolar surfactant has a critical role in preventing alveolar collapse and edema formation. The aim of this study was to investigate, whether the predisposition to hunting associated pulmonary edema in drever dogs is associated with impaired biophysical properties of alveolar surfactant. Seven privately owned drever dogs with recurrent hunting associated pulmonary edema and seven healthy control dogs of other breeds were included in the study. All affected dogs underwent thorough clinical examinations including echocardiography, laryngeal evaluation, bronchoscopy, and bronchoalveolar lavage (BAL) as well as head, neck and thoracic computed tomography imaging to rule out other cardiorespiratory diseases potentially causing the clinical signs. Alveolar surfactant was isolated from frozen, cell-free supernatants of BAL fluid and biophysical analysis of the samples was completed using a constrained sessile drop surfactometer. Statistical comparisons over consecutive compression expansion cycles were performed using repeated measures ANOVA and comparisons of single values between groups were analyzed using T-test.ResultsThere were no significant differences between groups in any of the biophysical outcomes of surfactant analysis. The critical function of surfactant, reducing the surface tension to low values upon compression, was similar between healthy dogs and affected drevers.ConclusionsThe etiology of hunting associated pulmonary edema in drever dogs is not due to an underlying surfactant dysfunction.

Biological effects of corticosteroids on pneumococcal pneumonia in Mice—translational significance

BackgroundStreptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia and the acute respiratory distress syndrome (ARDS). Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, COVID-19, and ARDS, but the mechanisms of this benefit remain unclear. The primary objective of this study was to investigate the effects of corticosteroids on the pulmonary biology of pneumococcal pneumonia in a mouse model. A secondary objective was to identify shared transcriptomic features of pneumococcal pneumonia and steroid treatment in the mouse model and clinical samples.MethodsWe carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify the mechanisms of lung injury in Streptococcus pneumoniae with and without adjunctive steroid therapy. We also studied lower respiratory tract gene expression from a cohort of 15 mechanically ventilated patients (10 with Streptococcus pneumoniae and 5 controls) to compare with the transcriptional studies in the mice.ResultsIn mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathologic lung injury score, and (5) hypoxemia but did not increase bacterial burden. Transcriptomic analyses identified effects of steroid therapy in mice that were also observed in the clinical samples.ConclusionsIn combination with appropriate antibiotic therapy in mice, treatment of pneumococcal pneumonia with steroid therapy reduced hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The transcriptional studies in patients suggest that the mouse model replicates some of the features of pneumonia in patients with Streptococcus pneumoniae and steroid treatment. Overall, these studies provide evidence for the mechanisms that may explain the beneficial effects of glucocorticoid therapy in patients with community acquired pneumonia from Streptococcus Pneumoniae.

IMPACT OF TREATMENT OF DIABETIC MACULAR EDEMA ON VISUAL IMPAIRMENT IN PEOPLE WITH TYPE 2 DIABETES MELLITUS: A COMPREHENSIVE SYSTEMATIC REVIEW AND METAAANALYSIST STUDY

Background: Diabetic retinopathy (DR) and diabetic macular edema (DME) are among the most significant and disabling chronic complications of diabetes mellitus. DME is an important cause of severe vision loss in type 2 diabetes. Hyperpermeability of retinal blood vessels and subsequent formation of edema and hard exudates are the key clinical features. Method: This systematic review and meta-analysis, conducted following PRISMA guidelines and employing the PICO format, aim to explore about impact of treatment of diabetic macular edema on visual impairment in people with type 2 diabetes mellitus, focusing on treatment, complications, and prognosis. Inclusion criteria encompass diverse study designs (RCTs, observational, quasi-experimental, and case-control studies) investigating impact of treatment of diabetic macular edema on visual impairment in people with type 2 diabetes mellitus among treatment, complications, and prognosis, while exclusion criteria filter out studies lacking relevance to impact of treatment of diabetic macular edema on visual impairment in people with type 2 diabetes mellitus. Result: After conducting three levels of screening, the results of our search in Pubmed get 6 articles, whereas the results of our search on SageJournal get 42 articles, on Lancet 21, and on Scient direct get 60 articles. Records remove before screening are 91, so we get 78 articles for screening. After we screened based on record exclude, we compiled a total of 10 papers. We included four research that met the criteria. Conclusion: There is a particularly robust response to anti-VEGF therapy in both groups when glycemic control is optimized, highlighting the critical importance of communication between the physicians managing the DME and those managing systemic diabetes control. Improving our understanding of the factors that contribute to anti-VEGF response for DME therapy may help to enhance DME treatment outcomes, particularly through the concerted coordinated efforts of the treating retina specialist and the endocrinologist or primary care physician.

Early Celecoxib Use in Spontaneous Intracerebral Hemorrhage is Associated with Reduced Mortality.

Hemorrhagic strokes constitute 10-15% of all strokes and have the worst mortality and morbidity of all subtypes. Mortality and morbidity of spontaneous intracerebral hemorrhage (sICH) are often secondary to the effects of inflammation, brain edema, and swelling. Studies have shown that celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, reduces perihematomal edema formation and inflammation. This study aimed to examine the impact of celecoxib on sICH outcomes. TriNetX, a multi-institutional research database, was retrospectively queried to identify patients with sICH. Outcomes in patients who received celecoxib within 5days (cohort 1) were analyzed and compared to those in patients who did not receive celecoxib (cohort 2). The primary end point was mortality within 1year of sICH. Secondary end points included ventilator dependence, tracheostomy, percutaneous endoscopic gastrostomy tube placement, craniotomy, deep venous thrombosis, pulmonary embolism, ischemic stroke, transient ischemia attack, myocardial infarction, and seizures. Further analysis was performed to assess these outcomes for patients treated with ibuprofen, a nonselective COX inhibitor. After propensity score matching, 833 patients were identified in each cohort based on celecoxib use. Mortality at 1year was significantly reduced in patients with sICH receiving celecoxib compared to those who did not (13.33% vs. 17.77%; p = 0.0124). Risks of ventilator dependence, tracheostomy, percutaneous endoscopic gastrostomy tube placement, craniotomy, deep venous thrombosis, pulmonary embolism, ischemic stroke, transient ischemia attack, myocardial infarction, and seizures were not significantly increased in patients who received celecoxib within 5days of sICH compared to those who did not receive celecoxib. There was no significant difference in mortality between patients based on ibuprofen administration. There exists a growing interest in using COX-2 as a potential target strategy for neuroprotection in patients with sICH, with some evidence of a mortality benefit in small cohort studies. This study shows that early celecoxib use is associated with decreased mortality in patients with sICH.

Effects of Photon versus Carbon-Ion Irradiation in the Rat Cervical Spinal Cord - a Serial T2 and Diffusion-weighted Magnetic Resonance Imaging Study.

Carbon-ion irradiation is increasingly used at the skull base and spine near the radiation-sensitive spinal cord. To better characterize the invivo radiation response of the cervical spinal cord, radiogenic changes in the high-dose area were measured in rats using magnetic resonance imaging (MRI) diffusion measurements in comparison to conventional photon irradiations. In this longitudinal MRI study, we examined the gray matter (GM) of the cervical spinal cord in 16 female Sprague-Dawley rats after high-dose photon (n = 8) or carbon-ion (12C) irradiation (n = 8) and in 6 sham-exposed rats until myelopathy occurred. The differences in the diffusion pattern of the GM of the cervical spinal cord were examined until the endpoint of the study, occurrence of paresis grade II of both forelimbs was reached. In both radiation techniques, the same order of the occurrence of MR-morphological pathologies was observed - from edema formation to a blood spinal cord barrier (BSCB) disruption to paresis grade II of both forelimbs. However, carbon-ion irradiation showed a significant increase of the mean apparent diffusion coefficient (ADC; P = 0.031) with development of a BSCB disruption in the GM. Animals with paresis grade II as a late radiation response had a highly significant increase in mean ADC (P = 0.0001) after carbon-ion irradiation. At this time, a tendency was observed for higher mean ADC values in the GM after 12C irradiation as compared to photon irradiation (P = 0.059). These findings demonstrated that carbon-ion irradiation leads to greater structural damage to the GM of the rat cervical spinal cord than photon irradiation due to its higher linear energy transfer (LET) value.

Brain‐Targeted 9‐Phenanthrol‐Loaded Lipid Nanoparticle Prevents Brain Edema after Cerebral Ischemia‐Reperfusion Injury by Inhibiting the Trpm4 Channel in Mice

AbstractBrain edema robustly increases mortality and hinders functional recovery after acute ischemic stroke. However, there are currently no effective therapies available for treating or preventing it. The unchecked opening of the transient receptor potential M4 (TRPM4) channel results in an excessive influx of Na+ and water, which contributes significantly to the formation of brain edema after ischemic stroke. 9‐phenanthrol (9‐Phe), a potent TRPM4 inhibitor, has limited clinical applicability due to its potential cytotoxicity and poor solubility. A brain‐targeting T7 (HAIYPRH)‐modified lipid nanoparticle (LNP) encapsulated 9‐Phe (9‐Phe@T7‐LNP) is designed and synthesized to improve the physicochemical properties and pharmacokinetic properties of 9‐Phe for treating brain edema in vivo. These results demonstrated that 9‐Phe@T7‐LNP can penetrate the intact blood‐brain barrier (BBB) in normal mice and target the brain parenchyma. Moreover, 9‐Phe@T7‐LNP effectively reduced infarct volume and brain edema, prevented neuronal loss and BBB disruption, improved survival, and facilitated neurological function recovery after transient middle cerebral artery occlusion in mice. Additionally, 9‐Phe@T7‐LNP scavenged oxygen‐free radicals and prevented neuronal apoptosis in cultured neurons subjected to oxygen and glucose deprivation/reperfusion. In summary, these findings showed that 9‐Phe@T7‐LNP holds strong potential as a promising targeted therapy for brain edema after stroke, providing superior pharmacological neuroprotection against brain edema.

Glymphatic System Impairment Contributes to the Formation of Brain Edema After Ischemic Stroke.

Blood-brain barrier damage has traditionally been considered to determine the occurrence and development of poststroke brain edema, a devastating and life-threatening complication. However, no treatment strategy targeting blood-brain barrier damage has been proven clinically effective in ameliorating brain edema. In mice with stroke models induced by transient middle cerebral artery occlusion (MCAO), the changes in glymphatic system (GS) function impairment were detected by ex vivo fluorescence imaging, 2-photon in vivo imaging, and magnetic resonance imaging within 1 week after MCAO, and the effects of GS impairment and recovery on the formation and resolution of brain edema were evaluated. In addition, in patients with ischemic stroke within 1 week after onset, changes in GS function and brain edema were also observed by magnetic resonance imaging. We found that the extravasation of protein-rich fluids into the brain was not temporally correlated with edema formation after MCAO in mice, as brain edema reabsorption preceded blood-brain barrier closure. Strikingly, the time course of edema progression matched well with the GS dysfunction after MCAO. Pharmacological enhancement of the GS function significantly alleviated brain edema developed on day 2 after MCAO, accompanied by less deposition of Aβ (amyloid-β) and better cognitive function. Conversely, functional suppression of the GS delayed the absorption of brain edema on day 7 after MCAO. Moreover, patients with ischemic stroke revealed a consistent trend of GS dysfunction after reperfusion as MCAO mice, which was correlated with the severity of brain edema and functional outcomes. GS is a key contributor to the formation of brain edema after ischemic stroke, and targeting the GS may be a promising strategy for treating brain edema in ischemic stroke. URL: https://www.chictr.org.cn/showproj.html?proj=162857; Unique identifier: NFEC-2019-189.

Liposomal Nanocarriers of Preassembled Glycocalyx Restore Venular Permeability in Sepsis: Assessed Quantitatively with a Novel Microchamber System

Background: The endothelial glycocalyx (EG), covering the luminal side of endothelial cells, regulates vascular permeability and senses wall shear stress. In sepsis, EG undergoes degradation leading to increased permeability and edema formation. We hypothesized that restoring EG integrity using liposomal nanocarriers of preassembled glycocalyx (LNPG) will restore normal venular permeability in a lipopolysaccharide (LPS)-induced sepsis model of mice. Methods: To test this hypothesis, we designed a unique perfusion microchamber in which the vascular permeability of isolated and cannulated mice mesenteric venules could be assessed by measuring the concentration of Evans blue dye (EBD) by fluorescent spectroscopy in microliter-samples of extravascular solution (ES). Results: Histamine-induced time- and dose-dependent increases in EBD in the ES could be measured, confirming the sensitivity of the microchamber system. Notably, the histamine-induced increase in permeability was significantly attenuated by histamine receptor (H1) antagonist, triprolidine hydrochloride. Subsequently, mice were treated with LPS, or LPS + LNPG. Compared to control mice, venules from LPS-treated mice showed a significant increased permeability, which was significantly reduced by LNPG administration. Moreover, in the presence of wall shear stress, intraluminal administration of LNPG significantly reduced the permeability in isolated venules from LPS-treated mice. Conclusion: Our newly developed microchamber system can quantitatively measure the permeability of isolated venules. LPS-induced sepsis increases permeability of venules that is attenuated by in vivo LNPG administration, which is also reestablished endothelial vasomotor responses to shear stress. Thus, LNPG presents a promising therapeutic potential for restoring EG function and thereby mitigating the increased permeability in sepsis. Support: National Institute of Health [grant number: HL144528, Dong Sun] and the Uehara Memorial Foundation [grant number: 202241049, Shinya Ishiko) and Hungarian Academy of Sciences Post-Covid 2021-34 (AK) and MIT of Hungary, National Research, Development, and Innovation Fund, OTKA K 132596 (AK). 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.