Markers Of Endothelial Cell Damage Research Articles

The impact of fluid status and decremental PEEP strategy on cardiac function and lung and kidney damage in mild-moderate experimental acute respiratory distress syndrome

BackgroundWe evaluated the effects of abrupt versus gradual PEEP decrease, combined with standard versus high-volume fluid administration, on cardiac function, as well as lung and kidney damage in an established model of mild-moderate acute respiratory distress syndrome (ARDS).MethodsWistar rats received endotoxin intratracheally. After 24 h, they were treated with Ringer’s lactate at standard (10 mL/kg/h) or high (30 mL/kg/h) dose. For 30 min, all animals were mechanically ventilated with tidal volume = 6 mL/kg and PEEP = 9 cmH2O (to keep alveoli open), then randomized to undergo abrupt or gradual (0.2 cmH2O/min for 30 min) PEEP decrease from 9 to 3 cmH2O. Animals were then further ventilated for 10 min at PEEP = 3 cmH2O, euthanized, and their lungs and kidneys removed for molecular biology analysis.ResultsAt the end of the experiment, left and right ventricular end-diastolic areas were greater in animals treated with high compared to standard fluid administration, regardless of PEEP decrease rate. However, pulmonary arterial pressure, indicated by the pulmonary acceleration time (PAT)/pulmonary ejection time (PET) ratio, was higher in abrupt compared to gradual PEEP decrease, independent of fluid status. Animals treated with high fluids and abrupt PEEP decrease exhibited greater diffuse alveolar damage and higher expression of interleukin-6 (a pro-inflammatory marker) and vascular endothelial growth factor (a marker of endothelial cell damage) compared to the other groups. The combination of standard fluid administration and gradual PEEP decrease increased zonula occludens-1 expression, suggesting epithelial cell preservation. Expression of club cell-16 protein, an alveolar epithelial cell damage marker, was higher in abrupt compared to gradual PEEP decrease groups, regardless of fluid status. Acute kidney injury score and gene expression of kidney injury molecule-1 were higher in the high versus standard fluid administration groups, regardless of PEEP decrease rate.ConclusionIn the ARDS model used herein, decreasing PEEP abruptly increased pulmonary arterial hypertension, independent of fluid status. The combination of abrupt PEEP decrease and high fluid administration led to greater lung and kidney damage. This information adds to the growing body of evidence that supports gradual transitioning of ventilatory patterns and warrants directing additional investigative effort into vascular and deflation issues that impact lung protection.

ACE2 and Proinflammatory Signaling by S1 Protein of SARS‐Cov‐2 in Human Endothelial Cells

IntroductionCOVID‐19 is primarily a respiratory disease associated with cardiovascular risk. SARS‐CoV‐2, the virus causing COVID‐19, uses ACE2, an important enzyme in the cardiovascular system that regulates the conversion of Ang II (deleterious/pro‐hypertensive) to Ang 1‐7 (protective/anti‐hypertensive), as a receptor for host cell entry and infection. Considering the relationship between the viral S1‐protein and the host's ACE2, it is unclear whether this interaction is merely a mechanism of infection or whether it also contributes to cardiovascular damage associated with COVID‐19. We hypothesisedthat SARS‐Cov‐2‐ACE2 interaction induces activation of vascular cell inflammatory responses that are influenced by ACE2 dependent and/or independent enzymatic Ang‐(1‐7) production.MethodsHuman microvascular endothelial cells (MEC) were used and stimulated with SARS‐CoV‐2 recombinant S1 protein (rS1p) (0.66 μg/mL) at 10/30 min (acute) and 5/24h (chronic). Activation of pro‐inflammatory signaling pathways (immunoblotting, real‐time PCR), microparticle (MP) generation (NanoSight), and cytokine production (ELISA) were assessed. In some experiments, cells were pre‐incubated with an ACE2 activator (DIZE – 190 nM) and inhibitor (MLN‐4760 – 440 pM).ResultsrS1P increased NFκB activation (Control ©=0.99±0.06 vs. 1.38±0.19 AU; p<0.05) and MP formation (C=1.01±0.17 vs. 2.06±0.21, x109/mL; p<0.05), a marker of endothelial cell damage. mRA expression of IL‐1β (C=1.07±0.13 vs. 50.04±4.63 2^‐ddCT), IL6 (C=1.15±0.0.19 vs. 13.52±2 2^‐ddCT), TNFα (C=1.12±0.16 vs. 20.29±2.15 2^‐ddCT), VCAM‐1 (C=1.21±0.24 vs. 13.39±1.57 2^‐ddCT) and MCP‐1 (C=1.02±0.06 vs. 7.01±2.16 2^‐ddCT) was increased by rS1p (p<0.05). This was associated with an increased production of IL6 (C=22.77±3.27 vs. 1221±18.33 pg/mL) and MCP‐1 (C=876.9±33.47 vs. 1110±13.33 pg/mL, (p<0.05). rS1p did not change gene levels of TGFβ, galectin‐3 or ACE2. While DIZE did not influence rS1p pro‐inflammatory markers; MLN‐4760 potentiated rS1p‐induced increase in IL‐1β gene levels (rS1p=27.59±5.05 vs. MLN=62.11±11.17 2^‐ddCT) and blocked rS1p effects on MCP‐1 (rS1p=5.08±0.47 vs. MLN=2.43±0.6 2^‐ddCT) and VCAM‐1 (rS1p=72.82±13.76 vs. MLN=20.74±4.53 2^‐ddCT). ACE2 inhibition did not interfere with rS1p‐induced increase in IL6 or TNFα mRNA expression. Analysis of MP content revealed the expression of ACE2 short form (60 kDa) and flotillin‐1, suggesting that ACE2 localizes in membrane microdomains.ConclusionsOur data demonstrate that in human endotheial cells rS1P induces a pro‐inflammatory response and stimulates generation of ACE2‐containing microparticles. These findings suggest that the spike protein 1 of SARS‐CoV‐2 has a direct injurious effect on the endothelium that may contribute to endotheliitis in COVID‐19. Whether these processes are associated with viral infection await clarification.

Effect of Coagulation Factor Concentrates on Markers of Endothelial Cell Damage in Experimental Hemorrhagic Shock.

Plasma-based resuscitation showed protective effects on the endothelial glycocalyx compared with crystalloid resuscitation. There is paucity of data regarding the effect of coagulation factor concentrates (CFC) on the glycocalyx in hemorrhagic shock (HS). We hypothesized that colloid-based resuscitation supplemented with CFCs offers a therapeutic value to treat endothelial damage following HS. Eighty-four rats were subjected to pressure-controlled (mean arterial pressure (MAP) 30-35 mm Hg) and lab-guided (targeted cutoff: lactate >2.2. mmol/L and base deficit > 5.5 mmol/L) HS. Animals were resuscitated with fresh frozen plasma (FFP), human albumin (HA) or Ringer's lactate (RL) and RL or HA supplemented with fibrinogen concentrate (FC) or prothrombin complex concentrate (PCC). Serum epinephrine and the following markers of endothelial damage were assessed at baseline and at the end-of-observation (120 min after shock was terminated): syndecan-1, heparan sulfate, and soluble vascular endothelial growth factor receptor 1 (sVEGFR 1). Resuscitation with FFP had no effect on sVEGFR1 compared with crystalloid-based resuscitation (FFP: 19.3 ng/mL vs. RL: 15.9 ng/mL; RL+FC: 19.7 ng/mL; RL+PCC: 18.9 ng/mL; n.s.). At the end-of-observation, syndecan-1 was similar among all groups. Interestingly, HA+FC treated animals displayed the highest syndecan-1 concentration (12.07 ng/mL). Resuscitation with FFP restored heparan sulfate back to baseline (baseline: 36 ng/mL vs. end-of-observation: 36 ng/mL). The current study revealed that plasma-based resuscitation normalized circulating heparan sulfate but not syndecan-1. Co-administration of CFC had no further effect on glycocalyx shedding suggesting a lack of its therapeutic potential. VExperimental in vivo study.

Intravital imaging of a pulmonary endothelial surface layer in a murine sepsis model

Direct intravital imaging of an endothelial surface layer (ESL) in pulmonary microcirculation could be a valuable approach to investigate the role of a vascular endothelial barrier in various pathological conditions. Despite its importance as a marker of endothelial cell damage and impairment of the vascular system, in vivo visualization of ESL has remained a challenging technical issue. In this work, we implemented a pulmonary microcirculation imaging system integrated to a custom-design video-rate laser scanning confocal microscopy platform. Using the system, a real-time cellular-level microscopic imaging of the lung was successfully performed, which facilitated a clear identification of individual flowing erythrocytes in pulmonary capillaries. Subcellular level pulmonary ESL was identified in vivo by fluorescence angiography using a dextran conjugated fluorophore to label blood plasma and the red blood cell (RBC) exclusion imaging analysis. Degradation of ESL width was directly evaluated in a murine sepsis model in vivo, suggesting an impairment of pulmonary vascular endothelium and endothelial barrier dysfunction.

OZONE THERAPY IN DIABETES AND ITS COMPLICATIONS

OZONE THERAPY IN DIABETES AND ITS COMPLICATIONS

The effect of pre-operative methylprednisolone on early endothelial damage after total knee arthroplasty: a randomised, double-blind, placebo-controlled trial.

We wished to evaluate whether inhibition of the systemic inflammatory response by a single pre-operative dose of methylprednisolone reduced markers of early endothelial damage after fast-track total knee arthroplasty. We randomly allocated 70 patients undergoing elective unilateral total knee arthroplasty (1:1) to receive either pre-operative intravenous methylprednisolone 125 mg (methylprednisolone group) or isotonic saline (control group). All procedures were performed under spinal anaesthesia without a tourniquet, using a standardised multimodal analgesic regime. The outcomes included changes in Syndecan-1 concentrations, a marker of glycocalyx degradation, markers of endothelial cell damage and activation (plasma soluble thrombomodulin and sE-Selectin), and permeability by vascular endothelial growth factor, as well as C-reactive protein concentrations. Blood samples were collected at baseline and 2 h, 6 h and 24 h after surgery, with complete sampling from 63 patients for analyses. Methylprednisolone significantly reduced markers of endothelial damage at 24 h following surgery compared with saline (methylprednisolone group vs. control group, adjusted means (SEM)) expressed by circulating Syndecan-1: 11.6 (1.0) ng.ml-1 vs. 13.4 (1.1) ng.ml-1 p = 0.046; soluble thrombomodulin: 5.1 (0.1) ng.ml-1 vs. 5.7 (0.2) ng.ml-1 , p = 0.009; sE-Selectin: 64.8 (1.8) ng.ml-1 vs. 75.7 (1.9) ng.ml-1 , p = 0.001, and vascular endothelial growth factor: 35.3 (2.7) ng.ml-1 vs. 58.5 (2.8) ng.ml-1 , p < 0.001. The effect of the intervention increased with time for soluble thrombomodulin, sE-Selectin and vascular endothelial growth factor, and was more pronounced in patients with high baseline values. Finally, methylprednisolone reduced the C-reactive protein response 24 h postoperatively; 31.1 (1.1) mg.l-1 vs. 68.4 (1.1) mg.l-1 , p < 0.001. Pre-operative administration of methylprednisolone 125 mg reduced circulating markers of endothelial activation and damage, as well as the systemic inflammatory response (C-reactive protein) early after fast-track total knee arthroplasty. These findings may have a positive effect on surgical outcome, but require studies in major surgery.

Hemoglobin as a response marker of endothelial cell damage in elderly nonoverweight non-anemic subjects.

Title Hemoglobin as a response marker of endothelial cell damage in elderly nonoverweight non-anemic subjects. Author(s) Kadota, Koichiro; Shimizu, Yuji; Nakazato, Mio; Noguchi, Yuko; Koyamatsu, Jun; Yamanashi, Hirotomo; Nagayoshi, Mako; Murase, Kunihiko; Arima, Kazuhiko; Maeda, Takahiro Citation Acta medica Nagasakiensia, 60(3), pp.103-108; 2016 Issue Date 2016-04 URL http://hdl.handle.net/10069/36572 Right NAOSITE: Nagasaki University's Academic Output SITE

AB1056 Aortic calcification on lumbar spine radiographs: Is it important?

BackgroundVascular calcification is a marker of endothelial cell damage and is associated with cardiovascular morbidity. Calcification of the abdominal aorta (AA) is occasionally noted as an incidental finding on lumbar...

Radiation as an independent risk factor for atherosclerosis

Radiation as an independent risk factor for atherosclerosis

Kinetics of Thrombin Generation in Patients with Multiple Myeloma.

Thalidomide has emerged as a promising treatment for multiple myeloma (MM). Thrombosis is the most serious complication of thalidomide therapy, essentially when it is combined with dexamethasone. The pathogenesis of thrombosis in MM patients (pts) treated with thalidomide is not clear and probably of multi factorial origin. We used the Thrombin Generation test (TGT) and measured the plasma levels of soluble thrombomodulin (sTM) to better clarify the MM-related and thalidomide-related thrombogenicity. TGT was performed in citrated frozen platelet poor plasma (PPP). Blood was obtained from 26 MM pts, Salmon and Durie stage II and III, 62.5 years old (42–77), 9 males and 17 females, 10 treated with thalidomide (100–200mg/d orally) and dexamethasone (40mg/d for 4 days) (TD group) and 16 receiving no treatment (MM group). 13 healthy volunteers formed the control group. Thrombin Generation (TG) was initiated by adding the PPP reagent (Thrombogram-Thrombinoscope®) and the triggering solution (CaCl2 and fluorogenic substrate). We analyzed the endogenous thrombin potential (ETP), the Cmax and the velocity index of TG. The plasma levels of sTM in PPP were measured by a specific ELISA (Diagnostica Stago, France). In the MM group we observed an increase of the ETP, though not significant compared to the controls. The Cmax was almost equal to the control group value, while the velocity index of TG was statistically lower in the MM group compared to controls. In the TD group, a statistically significant increase of ETP was observed as compared to the control group. The Cmax was higher, compared to controls, though not significantly, whereas the velocity index of TG was almost equal to the control group value. There was no significant difference in the TG parameters between MM and TD groups. sTM in the control group was 45±14ng/ml. Both groups of pts had significantly increased sTM plasma levels as compared to the control but the difference between the two groups did not reach significance. Results are shown in Table 1. In patients with MM coexists an increase of sTM, a marker of endothelial cell damage, together with an increased TG capacity. The addition of thalidomide treatment is associated with a slight but not significant increase of ETP and Cmax. The co-existence of endothelial cell damage with increased TG capacity could be associated to the increased thrombotic risk in MM patients treated with thalidomide. This hypothesis will be controlled in a prospective study.Table 1:Thrombogram parameters and sTM plasma levels of studied pts.ControlMM groupTD groupETP (nM×min)1399±2971651±4781747±448*Cmax (nM)366±54342±52402±99Velocity Index (nM/min)198±45160±19*184±65STM (ng/ml)45±1484±42*73±30** Results significantly different between the MM and TD groups and the control group (p<0.05 vs the control group)

Therapeutic efficacy of ozone in patients with diabetic foot

Oxidative stress is suggested to have an important role in the development of complications in diabetes. Because ozone therapy can activate the antioxidant system, influencing the level of glycemia and some markers of endothelial cell damage, the aim of this study was to investigate the therapeutic efficacy of ozone in the treatment of patients with type 2 diabetes and diabetic feet and to compare ozone with antibiotic therapy. A randomized controlled clinical trial was performed with 101 patients divided into two groups: one ( n = 52) treated with ozone (local and rectal insufflation of the gas) and the other ( n = 49) treated with topical and systemic antibiotics. The efficacy of the treatments was evaluated by comparing the glycemic index, the area and perimeter of the lesions and biochemical markers of oxidative stress and endothelial damage in both groups after 20 days of treatment. Ozone treatment improved glycemic control, prevented oxidative stress, normalized levels of organic peroxides, and activated superoxide dismutase. The pharmacodynamic effect of ozone in the treatment of patients with neuroinfectious diabetic foot can be ascribed to the possibility of it being a superoxide scavenger. Superoxide is considered a link between the four metabolic routes associated with diabetes pathology and its complications. Furthermore, the healing of the lesions improved, resulting in fewer amputations than in control group. There were no side effects. These results show that medical ozone treatment could be an alternative therapy in the treatment of diabetes and its complications.

Absence of hypercoagulability in acute Kawasaki disease

Kawasaki disease (KD) is a systemic vasculitis syndrome with the striking feature of cardiovascular involvement. Endothelial cell (EC) damage has been suggested to predispose individuals to the development of coronary vascular disorders. When EC are perturbed, prethrombotic complications ensue. The purpose of this study was to examine the clinical relevance of EC activation and hypercoagulability in the pathogenesis of KD and to determine if plasma levels of these markers are correlated with the development of coronary aneurysms. EC function and coagulation status were assessed in 52 patients with acute KD, 20 febrile control subjects, and 20 healthy control subjects. Biological markers of EC and hypercoagulability were measured and included thrombomodulin, tissue factor, tissue factor pathway inhibitor, von Willebrand factor (vWF), coagulation factor VII (FVII), activated factor VII, prothrombin fragment 1 + 2 (F1 + 2), and D-dimer. Transient dilatation of coronary arteries was the most common complication (55.8%), and coronary aneurysm was noted in five patients (9.6%). Levels of vWF, FVII, F1 + 2 and D-dimer were higher in acute KD patients compared with healthy controls but not febrile controls. Markers of EC and hypercoagulability were not different between patients with cardiac complications and those without cardiac complications. Biological and immunological assays did not demonstrate the prethrombotic state in acute KD. Our results suggest that hypercoagulability does not occur during the acute stage of KD. Markers of EC damage and hypercoagulability are not predictive of coronary aneurysms in KD.

Short-term high-dose folic acid does not alter markers of endothelial cell damage in patients with coronary heart disease

Background and objective: Endothelial dysfunction is an early, pre-clinical manifestation of coronary heart disease and is associated with increased plasma levels of von Willebrand factor (vWF), soluble E-selectin, and thrombomodulin, markers of endothelial cell damage/activation and reduced nitric oxide bioavailability. Homocysteine is associated with an increased risk of cardiovascular disease and mortality. High-dose folic acid treatment lowers plasma homocysteine by 25% and improves nitric oxide bioavailability; however, the effects on other indices of endothelial cell activation/damage has not been examined in patients with coronary heart disease and normal renal function. Design and methods: In a randomised, double-blind, cross-over study in 50 patients with coronary heart disease and normal serum creatinine, folic acid (5 mg/daily) was administered for 6 weeks and blood was analysed for von Willebrand factor, soluble E-selectin, and thrombomodulin. Endothelial nitric oxide bioavailability was assessed by flow-mediated dilatation. Results: Plasma folate levels increased (9.1±3.4 vs. 310±235 μg/l; p<0.001) and nitric oxide bioavailability improved (47±35 vs. 110±43 μm; p<0.001) following active treatment. However, markers of endothelial cell injury were not significantly influenced (von Willebrand factor 118±33 vs. 119±34%; E-selectin 52±17 vs. 51±16 μg/l; thrombomodulin 3.94±1.81 vs. 3.94±1.51 μg/l; p=NS comparing post-placebo with post-folate). No correlation was observed between improvement in flow-mediated dilatation and change in endothelial marker proteins. Interepretation and conclusion: These data suggest that endothelial markers are not useful surrogates of endothelial nitric oxide bioavailability in coronary heart disease and may be a less sensitive marker of endothelial function than nitric oxide.

Diverse Substrate Recognition Mechanisms for Rhomboids Thrombomodulin Is Cleaved by Mammalian Rhomboids

Diverse Substrate Recognition Mechanisms for Rhomboids Thrombomodulin Is Cleaved by Mammalian Rhomboids

Fasting homocysteine levels in adults with type 1 diabetes and retinopathy

Background and methods: Whether hyperhomocysteinemia is associated with diabetic retinopathy is still being debated. We measured homocysteine and thrombomodulin, a marker of endothelial cell damage, in patients with type 1 diabetes mellitus and retinopathy ( n=25) and in a well-matched group of diabetic patients without retinopathy ( n=23). All patients had normal serum creatinine and no macroalbuminuria. Results: Fasting homocysteine levels were higher in the group with retinopathy than in the group without retinopathy (8.75±1.9 vs. 7.69±1.6 μmol/l, P<0.05). Microalbuminuria was more prevalent in the group with diabetic retinopathy and it correlated with homocysteine levels in this group ( p<0.05). Microalbuminuria was the most powerful independent determinant of homocysteine levels in multiple regression analysis in the group with retinopathy ( p<0.01). Thrombomodulin levels were not different in the two groups (36.6±9.7 vs. 34.9±11.1, p>0.1) and there was no correlation between homocysteine and thrombomodulin levels in either group. Conclusions: The slight rise in homocysteine levels in patients with diabetic retinopathy was possibly caused by the early nephropathy as indicted by microalbuminuria. This small rise in homocysteine levels was not associated with endothelial dysfunction, as measured by serum thrombomodulin levels.

Increased plasma thrombin-activatable fibrinolysis inhibitor levels in normotensive type 2 diabetic patients with microalbuminuria.

Hypofibrinolysis is a common finding in patients with diabetes mellitus and a risk factor for diabetic nephropathy. Recently, a new potent inhibitor of fibrinolysis, the thrombin-activatable fibrinolysis inhibitor (TAFI), has been isolated from human plasma. The possibility that TAFI also participates in the mechanism of hypofibrinolysis has not been appraised in diabetic patients with microalbuminuria. In the present study, we investigated the plasma levels of TAFI and its relation to urinary albumin excretion in normotensive diabetic patients with normo- and microalbuminuria. Thirty-nine normotensive nonobese type 2 diabetic patients (27 with normoalbuminuria, 12 with microalbuminuria) and 20 age-matched normal subjects were enrolled in this study. The plasma level of thrombin-antithrombin complex was significantly increased (22.1 +/- 2.6 vs. 8.3 +/- 1.0 nmol/liter; P < 0.05), whereas the D-dimer/thrombin-antithrombin complex ratio was significantly decreased (15.7 +/- 1.4 vs. 26.5 +/- 2.2; P < 0.05), showing the occurrence of hypercoagulability and hypofibrinolysis in diabetic patients. The plasma level of TAFI in diabetic patients was significantly elevated, compared with normal subjects (147.4 +/- 11.6 vs. 99.5 +/- 4.9%; P < 0.05). The plasma level of TAFI in diabetic patients with microalbuminuria was significantly higher than the level in diabetic patients with normoalbuminuria (194.1 +/- 24.5 vs. 128.8 +/- 12.3%; P < 0.02) or normal subjects (194.1 +/- 24.5 vs. 99.5 +/- 4.9%; P < 0.005). Univariate analysis showed that the plasma TAFI levels are significantly and proportionally correlated with urinary albumin excretion rate (r = 0.58; P < 0.005) and with plasma soluble thrombomodulin level, a marker of endothelial cell damage, in all diabetic patients (r = 0.42; P < 0.01). These data suggest that increased plasma level of TAFI may be involved in the mechanism of vascular endothelial damage in patients with type 2 diabetes mellitus.

Thiamine reverses hyperglycemia-induced dysfunction in cultured endothelial cells

Background. High levels of glucose have previously been shown to inhibit endothelial cell migration and increase secretion of the von Willebrand factor (vWF), a marker of endothelial cell damage. This study investigates whether thiamine, an important coenzyme in intracellular glucose metabolism, improves endothelial cell migration and decreases von Willebrand factor secretion under hyperglycemic conditions. Methods. Bovine aortic endothelial cells (BAECs) were grown under physiological glucose (5.5 mmol/L) and hyperglycemic (13.8 mmol/L and 27.7 mmol/L) conditions with or without thiamine (200 μmol/L) supplementation. Endothelial cell migration was investigated in monolayers of BAECs that were wounded by scraping. The distance of migration, the number of migrating cells, and the surface area covered by the migrating cells were measured. Secretion of vWF by BAECs under physiological glucose and high glucose conditions with or without thiamine (200 μmol/L) supplementation was studied with enzyme-linked immunosorbent assay. Results. Under hyperglycemic conditions, there was a significant decrease in the number of endothelial cells and an increase in the secretion of vWF (P <.001). Thiamine treatment limited this inhibitory effect of elevated glucose levels on BAECs. Glucose (27.7 mmol/L) significantly decreased the migration distance of BAECs into the wounded area to 4.0 ± 1.4 cm, as compared with 6.2 ± 0.3 cm in the control. Thiamine supplementation restored the migration distance by BAECs (6.94 ± 0.7 cm) and the wound surface area covered (47.7 ± 5.6 cm2)(P <.001). Conclusions. Hyperglycemia activates BAECs and promotes secretion of vWF, a marker of endothelial cell damage. Thiamine inhibits this endothelial cell activation and the effects of hyperglycemia on endothelial cell migration. This beneficial effect of thiamine limiting endothelial cell dysfunction is possibly through the diversion of glucose flux from anaerobic to aerobic pathways. The data from this study lead to the speculation that thiamine intake may mitigate or delay vascular complications of diabetes. (Surgery 2001;130:851-8.)

Ozone treatment reduces markers of oxidative and endothelial damage in an experimental diabetes model in rats

Ozone has been used as a therapeutical agent and beneficial effects have been observed. However so far only a few biochemical and pharmacodynamic mechanisms have been elucidated. We demonstrate that controlled ozone administration may promote an oxidative preconditioning or adaptation to oxidative stress, preventing the damage induced by reactive oxygen species (ROS). Taking into account that diabetes is a disorder associated with oxidative stress, we postulate that ozone treatment in our experimental conditions might protect antioxidant systems and maintain, at a physiological level, other markers of endothelial cell damage associated with diabetic complications. Five groups of rats were classified as follows: (1) control group treated only with physiological saline solution; (2) positive control group using streptozotocin (STZ) as a diabetes inductor; (3) ozone group, receiving 10 treatments (1.1 mg kg−1), one per day after STZ-induced diabetes; (4) oxygen group (26 mg kg−1), one per day, as in group 3 but using oxygen only; (5) control ozone group, as group 3, but without STZ. The ozone treatment improved glycemic control and prevented oxidative stress, the increase of aldose reductase, fructolysine content and advanced oxidation protein products. Nitrite and nitrate levels were maintained without changes with regard to non-diabetic control. The results of this study show that repeated administration of ozone in non-toxic doses might play a role in the control of diabetes and its complications.

Circulating intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and plasma thrombomodulin levels in glioblastoma patients

Cellular adhesion molecules have been implicated in tumor progression and metastasis. Serum samples from 22 patients with glioblastoma (GBM), before surgery, and 19 sex and age matched healthy controls were analyzed for circulating levels of ICAM-1 and VCAM-1. At the same time also soluble plasma thrombomodulin, a marker of endothelial cell damage and activation, was detected. Soluble ICAM-1 and VCAM-1 levels were comparable in glioblastoma patients and healthy controls, while plasma thrombomodulin (TM) was significantly increased in cancer patients. There was no correlation between thrombomodulin levels and the presence of an intratumoral hemorrhage detected by CT scan, while entity of post-contrast enhacemement at CT correlated with higher TM levels. Further study with serial sampling of GBM patients and correlation with enhancement at CT will allow to ascertain the value of serum TM as a marker of disease recurrence or angiogenesis in those tumors.

Octreotide (somatostatin analog) treatment reduces endothelial cell dysfunction in patients with diabetes mellitus

Octreotide is a long-acting somatostatin analog that has been shown to have various effects in diabetes. This study was performed to evaluate whether octreotide affects the vascular complications of diabetes mellitus. Albuminuria and serum thrombomodulin were used as markers of vascular and renal dysfunction. We studied the effect of octreotide in 27 patients with insulin-dependent diabetes mellitus (IDDM). They received 200 μg octreotide per day over a period of 6 months. As a marker of endothelial cell damage, we measured the serum thrombomodulin level. We also measured urinary albumin excretion, hemoglobin A 1C (HbA 1C), insulin-like growth factor-1 (IGF-1), and other parameters. IGF-1 decreased from 123 ng/mL before treatment to 114 ng/mL after 6 months of octreotide treatment ( P = .009), while no significant change was observed in the unblinded control group (from 103 ng/mL to 102 ng/mL after 6 months of treatment). Urinary albumin excretion in patients with macroalbuminuria declined from 1,124 mg/L before octreotide treatment to 556 mg/L after 6 months of treatment ( P < .05), whereas no change was observed in the control group. There was also a reduction of the plasma thrombomodulin level from 61.8 ng/mL to 46.1 ng/mL ( P < .07) after 6 months of treatment. Furthermore, HbA 1c decreased from 8.75% ± 1.27% to 8.12% ± 1.23% ( P < .07) after octreotide treatment.