Vascular Permeability In Patients Research Articles

PLCβ2 Promotes VEGF-Induced Vascular Permeability.

Regulation of vascular permeability is critical to maintaining tissue metabolic homeostasis. VEGF (vascular endothelial growth factor) is a key stimulus of vascular permeability in acute and chronic diseases including ischemia reperfusion injury, sepsis, and cancer. Identification of novel regulators of vascular permeability would allow for the development of effective targeted therapeutics for patients with unmet medical need. In vitro and in vivo models of VEGFA-induced vascular permeability, pathological permeability, quantitation of intracellular calcium release and cell entry, and phosphatidylinositol 4,5-bisphosphate levels were evaluated with and without modulation of PLC (phospholipase C) β2. Global knock-out of PLCβ2 in mice resulted in blockade of VEGFA-induced vascular permeability in vivo and transendothelial permeability in primary lung endothelial cells. Further work in an immortalized human microvascular cell line modulated with stable knockdown of PLCβ2 recapitulated the observations in the mouse model and primary cell assays. Additionally, loss of PLCβ2 limited both intracellular release and extracellular entry of calcium following VEGF stimulation as well as reduced basal and VEGFA-stimulated levels of phosphatidylinositol 4,5-bisphosphate compared to control cells. Finally, loss of PLCβ2 in both a hyperoxia-induced lung permeability model and a cardiac ischemia:reperfusion model resulted in improved animal outcomes when compared with wild-type controls. The results implicate PLCβ2 as a key positive regulator of VEGF-induced vascular permeability through regulation of both calcium flux and phosphatidylinositol 4,5-bisphosphate levels at the cellular level. Targeting of PLCβ2 in a therapeutic setting may provide a novel approach to regulating vascular permeability in patients.

Vascular permeability in patients with portal hypertension before and after surgery

The issue of the passage of protein substances through the walls of blood capillaries is controversial.

The Endothelial Glycocalyx: A Fundamental Determinant of Vascular Permeability in Sepsis.

Sepsis is a significant cause of morbidity and mortality. Children with sepsis often have alterations in microcirculation and vascular permeability. Our objective is current evidence regarding the role of the endothelial glycocalyx as a determinant of capillary leakage in these patients. We reviewed PubMed, EMBASE, and Google scholar using MeSH terms "glycocalyx", "fluids", "syndecan", "endothelium", "vascular permeability", "edema", "sepsis", "septic shock", "children". Articles in all languages were included. We include all studies in animals and humans related to glycocalyx and vascular permeability. Studies in children and adults, as well as animal studies, were included. One of the fundamental components of the endothelial barrier structure is the glycocalyx. It is a variable thickness layer distributed throughout the whole body, which fulfills a very important function for life: the regulation of blood vessel permeability to water and solutes, favoring vascular protection, modulation, and hemostasis. In the last few years, there has been a special interest in glycocalyx disorders and their relationship to increased vascular permeability, especially in patients with sepsis in whom the alterations that occur in the glycocalyx are unknown when they are subjected to different water resuscitation strategies, vasopressors, etc. This review describes the structural and functional characteristics of the glycocalyx, alterations in patients with sepsis, with regard to its importance in vascular permeability conservation and the possible impact of strategies to prevent and/or treat the injury of this fundamental structure. The endothelial glycocalyx is a fundamental component of the endothelium and an important determinant of the mechanotransduction and vascular permeability in patients with sepsis. Studies are needed to evaluate the role of the different types of solutions used in fluid bolus, vasoactive support, and other interventions described in pediatric sepsis on microcirculation, particularly on endothelial integrity and the glycocalyx.

Mechanism of heparin-binding protein increasing vascular permeability in early burn

To investigate the effect of heparin-binding protein (HBP) on the damage of vascular permeability in early burn. (1) Clinical research: 12 patients with severe burns admitted to Suzhou Hospital of Nanjing Medical University from January 1st to August 30th in 2019 were enrolled. Eight patients with severe trauma admitted to the same hospital during the same period were also enrolled as controls to explain the specificity of burn injury. Whole blood samples were obtained within 0.5 hour after admission. The white blood cell count (WBC), absolute value and ratio of neutrophils, and serum HBP levels were measured. Serum samples of 12 patients with severe burn were collected within 9 days after admission, and enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of metabolism products of glycocalyx including syndecan-1 and hyaluronic acid (HA). The correlation between HBP and neutrophils ratio, syndecan-1 and HA were analyzed by linear correlation. (2) Basic research: a 30% total body surface area (TBSA) III degree angle burn model of Sprague-Dawley (SD) rat aged 6-8 weeks was prepared. In low molecular weight heparin (LMWH) intervention group (n = 5), 200 U/kg LMWH was injected subcutaneously immediately and every 2 hours after injury for 4 times in total; the burn group (n = 5) was given the same amount of normal saline. No intervention was given to the normal control group (n = 5). The peripheral venous blood was collected at 0, 2, 4, and 8 hours after injury, and the serum levels of HBP, syndecan-1 and HA were measured; the injury of glycocalyx on pulmonary vascular endothelial cells was observed under transmission electron microscope. (1) Clinical research results: the WBC, neutrophils absolute value and ratio, and HBP levels were increased in 12 patients with severe burn and 8 patients with severe trauma. There was no significant difference in the WBC, absolute value and ratio of neutrophils between severe burn and severe trauma patients [WBC (×109/L): 14.5±6.1 vs. 10.8±3.6, the absolute value of neutrophils (×109/L): 12.0±5.9 vs. 9.0±4.0, the ratio of neutrophils: 0.81±0.10 vs. 0.79±0.14, all P > 0.05], but the HBP levels in the burn patients were significantly higher than those in the trauma patients (μg/L: 192.92±61.73 vs. 51.17±23.05, P < 0.01). Twelve patients with severe burns had a sharp increase in serum syndecan-1 and HA levels after burns, which continued to maintain high levels and peaked at the 9th day [syndecan-1 (μg/L): 16.02±0.39, HA (μg/L): 106.83±4.90]. The analysis showed that HBP was positively correlated with neutrophils ratio, syndecan-1 and HA in severe burn patients at the 1st day after admission (r values were 0.805, 0.732 and 0.900, respectively, all P < 0.01). It indicated that the sharp increase of neutrophils after the burn released a lot of HBP, and the glycocalyx of the vascular endothelium was severely damaged. (2) Basic research results: the levels of serum HBP, syndecan-1 and HA in the burn group were increased sharply as compared with the normal control group, and continued to increase with time, reaching a peak at 8 hours after burn. In the LMWH intervention group, the serum levels of HBP, syndecan-1 and HA were significantly lower than those in the burn group, and the difference was still statistically significant after 8 hours [HBP (μg/L): 6.47±0.25 vs. 12.48±0.08, syndecan-1 (μg/L): 19.06±1.48 vs. 25.92±3.34, HA (μg/L): 35.76±2.10 vs. 54.91±2.64, all P < 0.01]. The results of transmission electron microscopy showed that in the normal control group, the glycocalyx pulmonary vascular endothelial cells was continuous, evenly distributed and dense. The glycocalyx on pulmonary vascular endothelial cells of rats were significantly damaged and shed 2 hours after burn in the burn group, and no glycocalyx was observed at 8 hours. In the LMWH intervention group, the glycocalyx on pulmonary vascular endothelial cells was damaged and the phenomenon of shedding was significantly relieved, and the glycocalyx could be observed 8 hours after the injury. The massive exudation of body fluids and the significant increase of vascular permeability in patients in early burns may be related to the destruction of the glycocalyx on endothelial cells by HBP released from increased neutrophils.

The fate of large-diameter Dacron® vascular grafts in surgical practice: Are we really satisfied?

[1] Murabito JM, PencinaMJ, NamBH, et al. Sibling cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults. JAMA Dec 28 2005;294(24):3117–23. [2] SailamV, Karalis DG, Agarwal A, et al. Prevalence of emerging cardiovascular risk factors in younger individuals with a family history of premature coronary heart disease and low Framingham risk score. Clin Cardiol Nov 2008;31(11):542–5. [3] Nieuwdorp M, Meuwese MC, Mooij HL, et al. Measuring endothelial glycocalyx dimensions in humans: a potential novel tool to monitor vascular vulnerability. J Appl Physiol Mar 2008;104(3):845–52. [4] Vlahu CA, Lemkes BA, Struijk DG, et al. Damage of the endothelial glycocalyx in dialysis patients. J Am Soc Nephrol Nov 2012;23(11):1900–8. [5] VanTeeffelen JW, Constantinescu AA, Brands J, et al. Bradykininand sodium nitroprusside-induced increases in capillary tube haematocrit in mouse cremaster muscle are associated with impaired glycocalyx barrier properties. J Physiol Jul 1 2008;586(13):3207–18. [6] Meuwese MC, Mooij HL, Nieuwdorp M, et al. Partial recovery of the endothelial glycocalyx upon rosuvastatin therapy in patients with heterozygous familial hypercholesterolemia. J Lipid Res Jan 2009;50(1):148–53. [7] Broekhuizen LN, Lemkes BA, Mooij HL, et al. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia Dec 2010;53(12):2646–55. [8] Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation Aug 6 2002;106(6):653–8. [9] Schindler TH, Cadenas J, Facta AD, et al. Improvement in coronaryendothelial function is independently associated with a slowed progression of coronary artery calcification in type 2 diabetes mellitus. Eur Heart J Dec 2009;30(24):3064–73. [10] Dekker LH, SnijderMB, BeukersMH, et al. A prospective cohort study of dietary patterns of non-western migrants in the Netherlands in relation to risk factors for cardiovascular diseases: HELIUS-Dietary Patterns. BMC Public Health 2011;11:441.

A phase I trial and pharmacokinetic study of trebananib (AMG386) in children with recurrent or refractory solid tumors: A Children’s Oncology Group Phase 1 Consortium report.

2538 Background: Trebananib is a first-in-class peptibody (peptide-Fc fusion protein) that selectively inhibits Angiopoietin 1 and Angiopoietin 2 to inhibit interaction with the Tie2 receptor tyrosine kinase and prevent angiogenesis by a VEGF independent mechanism. A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of trebananib. Methods: Trebananib was administered as a weekly 30 - 60 minute IV infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. PK sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks of therapy. Results: Fifteen eligible patients (14 evaluable for toxicity) with a median age of 14 yrs (range, 3 to 20) and diagnoses of neuroblastoma (n=4), rhabdomyosarcoma (n=3), Ewing sarcoma (n=3), osteosarcoma (n=2), other soft tissue sarcoma (n=2), or nasopharyngeal carcinoma (n=1) have been enrolled. There were no DLTs observed at either the 10 mg/kg (n=6 pts) or 15 mg/kg (n=3 pts) dose. 1/6 pts receiving 30 mg/kg/dose developed DLT (venous thrombosis at a central line site). Non-dose limiting grade 3 or 4 toxicities included lymphopenia (n=2) hypertension (n=1), and neutropenia (n=1). Response in evaluable patients after eight weeks of therapy included stable disease (n=6 pts) and progressive disease (n=7 pts). PK were linear over the 3 dose levels, with t1/2 and Clpvalues of 69±18 h and 1.6±0.5 ml/h/kg, respectively. Conclusions: Trebananib is well tolerated in pediatric patients with recurrent or refractory solid tumors with recommended Phase 2 dose of 30 mg/kg. Correlative biology studies will be presented. Further study is planned to evaluate tolerability and changes in vascular permeability in patients with primary CNS tumors. Clinical trial information: NCT01538095.

Sudden Infant Death in an 8-Month-Old Baby With Dengue Virus Infection

Sudden infant death due to dengue virus infection is very rare. An 8-month-old male infant was found unresponsive during a nap in his nursery school. We emphasize the usefulness of dengue viral antigens as a postmortem diagnostic technique to demonstrate the presence of virus in human tissue specimens by immunohistochemistry and Western blotting.

Pulmonary vascular permeability in patients with burn sepsis

Djanelidze Research Institute of Emergency Medicine, Department of Anaesthesiology and Intensive Care, Saint-Petersburg, Russian Federation

S74 Increased plasma levels of syndecan-1 and sFlt-1 during cardiopulmonary bypass surgery: associations with sRAGE

<h3>Introduction and Objectives</h3> Endothelial barrier dysfunction contributes to the systemic inflammatory response syndrome (SIRS) for which cardiac surgery necessitating cardiopulmonary bypass (snCPB) is a human model. A growing body of evidence suggests that the receptor for advanced glycation end products (RAGE) is also implicated in the pathogenesis of SIRS. While RAGE activation, in vitro, is known to decrease barrier function of cultured endothelial cells, the role of RAGE in regulating vascular permeability in patients undergoing snCPB is unknown. We hypothesised that plasma levels of markers of endothelial barrier dysfunction, syndecan-1, an endothelial glycocalyx component; and sFlt-1, a soluble form of the vascular endothelial cell growth factor (VEGF) receptor-1, will increase during snCPB and levels relate to patient outcome. <h3>Methods</h3> ELISA measurements/western blotting was used to determine syndecan-1 and sFlt-1 levels in pre-, intra- and post-snCPB plasma samples; for comparison, glypican-1, another glycocalyx component and Robo4, an endothelial barrier stabilising protein, were also measured. Clinical indices: age, nature of operation, CPB time, ischaemic time, intensive care unit (ICU)/ hospital length of stay (LOS) were collected from electronic databases. <h3>Results</h3> Syndecan-1 was significantly higher during CPB (77.17±39.72 ng/ml) compared with pre-snCPB levels (35.26±25.81 ng/ml, n=14, p&lt;0.01). Plasma levels of sFLt-1 were significantly (p&lt;0.001) higher during (10 000 pg/ml±3601, n=10) and post-snCPB (4282±3271 pg/ml) compared with preoperative levels (69.68±35.22 pg/ml). Preoperative plasma syndecan-1 correlated positively with ICU LOS (r²=0.486, p=0.006); whereas, intraoperative sFlt-1 correlated negatively with ICU LOS (r²=0.406, p=0.048). Intraoperative syndecan-1 levels positively associated with ischaemic time (r²=0.383, p=0.018) and plasma sRAGE levels (r²=389, p=0.040); postoperative syndecan-1 levels correlated with sRAGE (r²=0.790, p=0.0003). Glypican-1 and Robo4 were also detected in snCPB plasma samples. <h3>Conclusion</h3> Plasma levels of syndecan-1 and sFlt-1 were highest during snCPB. A positive association between preoperative syndecan-1 and ICU LOS is consistent with a relationship between endothelial barrier dysfunction and outcome. By contrast, higher intraoperative sFlt-1 correlating with shorter ICU LOS implied a protective role of sFlt-1. Associations between syndecan-1 and sRAGE suggest a link between RAGE and endothelial barrier dysfunction that merits further investigation; as do the novel findings that glypican-1 and Robo4 were detected in plasma of patients undergoing snCPB.

Impact of cardiac arrest duration on extravascular lung water and pulmonary vascular permeability in patients with postcardiac arrest syndrome: a prospective observational study

Pulmonary dysfunction after cardiac arrest is a common phenomenon. Evidence appears to support the usefulness of quanti-tative assessment of pulmonary dysfunction using extravascular lung water (EVLW) and the pulmonary vascular permeability index (PVPI). We hypothesized that the duration of cardiac arrest (CPA TIME) would impact the pulmonary dysfunction in patients with postcardiac arrest syndrome. The aim of the present study was to investigate the lung dysfunction quantitatively using EVLW and PVPI in successfully resuscitated patients after cardiac arrest (CPA).

Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus

Aims/hypothesisEndothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties.MethodsMale participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TERalb) and hyaluronan catabolism were assessed as measures of vascular permeability.ResultsBoth sublingual dimensions (0.64 [0.57–0.75] μm vs 0.78 [0.71–0.85] μm, p < 0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88–6.59] μm vs 8.89 [4.74–11.84] μm, p < 0.05) were reduced in the type 2 diabetes group compared with the controls whereas TERalb was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p < 0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p < 0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83–0.99] μm and to 5.88 [5.33–6.26] μm, respectively, p < 0.05). In line, a trend towards TERalb normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p < 0.05) were observed in the diabetes group.Conclusion/interpretationType 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk.Trial registration www.trialregister.nl NTR780/http://isrctn.org ISRCTN82695186FundingAn unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037)

Pigment epithelium-derived factor and vascular endothelial growth factor in branch retinal vein occlusion with macular edema

We investigated whether pigment epithelium-derived factor (PEDF) or vascular endothelial growth factor (VEGF) influence macular edema in patients with branch retinal vein occlusion (BRVO). This investigation aimed to clarify the influence of PEDF in the vitreous fluid on retinal vascular permeability in patients with macular edema secondary to BRVO. The findings were expected to be useful for the treatment of macular edema in BRVO patients. This was a retrospective cross-sectional comparative case series. Thirty-three BRVO patients with macular edema and 24 control patients with nonischemic ocular diseases were enrolled. Retinal ischemia was evaluated by measuring the area of capillary nonperfusion on fluorescein angiography with Scion Image software. Macular edema was examined by optical coherence tomography. Vitreous fluid samples were obtained via pars plana vitrectomy, and the VEGF and PEDF levels were determined by enzyme-linked immunosorbent assay. The vitreous level of VEGF was significantly higher in BRVO patients than controls (P < 0.001). The vitreous PEDF level was significantly lower in BRVO patients than controls (P = 0.026). In BRVO patients, vitreous levels of PEDF and VEGF showed a significant negative correlation with each other (P < 0.001). Additionally, the vitreous VEGF level had a significant positive correlation (P < 0.001) and the vitreous PEDF level had a significant negative correlation (P < 0.001) with the nonperfused retinal area in BRVO patients. Furthermore, vitreous levels of VEGF and PEDF showed significant positive (P = 0.001) and negative (P = 0.014) correlations, respectively, with macular edema in BRVO patients. VEGF and PEDF may inversely influence retinal vascular permeability in patients with ischemic BRVO and macular edema. However, prospective validation will be needed to confirm these observations.

A prospective pilot study of the effect of neutrophil elastase on the pulmonary vascular permeability in patients with pneumonia

Some cases of pneumonia may lead to hypoxemia with acute respiratory failure, acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which may require intensive management. Neutrophil elastase is thought to be one of the causes of ALI/ARDS, because it raises the pulmonary capillary permeability, lyses of pulmonary connective tissue proteins, and produces leukocyte chemotactic factors. However, a causal relationship between the plasma neutrophil elastase level and changes in the pulmonary capillary permeability has not been established in patients with pneumonia, one of the most serious diseases underlying ALI/ARDS. Therefore, the objective of this study was to determine whether an increase in plasma neutrophil elastase is related to elevation of the pulmonary capillary permeability in patients with pneumonia.

Vitreous Levels of Interleukin-6 and Vascular Endothelial Growth Factor in Macular Edema with Central Retinal Vein Occlusion

To investigate whether interleukin (IL)-6 or vascular endothelial growth factor (VEGF) influences macular edema in patients with central retinal vein occlusion (CRVO). Retrospective case-control study. Twenty-seven patients who had macular edema with CRVO and 16 patients with nonischemic ocular diseases (control group). Retinal ischemia was evaluated by measuring the area of capillary nonperfusion using fluorescein angiography and the public domain Scion Image program, and macular edema was examined by optical coherence tomography. Vitreous fluid samples were obtained at pars plana vitrectomy. VEGF and IL-6 levels in vitreous fluid and plasma were determined with enzyme-linked immunosorbent assay kits. Vitreous fluid levels of IL-6 and VEGF. The vitreous fluid levels of VEGF (median: 435 pg/ml) and IL-6 (median: 51.2 pg/ml) were significantly higher in the patients with CRVO than in the control group (median: 62.4 pg/ml and 1.07 pg/ml, respectively; P = 0.0046 and P<0.0001, respectively). The vitreous fluid level of VEGF was significantly correlated with that of IL-6 (P = 0.0029). Vitreous fluid levels of both VEGF and IL-6 were significantly higher in patients with CRVO who had retinal ischemia than in those without ischemia (P<0.0001 and P = 0.0003, respectively). Vitreous fluid levels of VEGF and IL-6 were also significantly correlated with the severity of macular edema (P = 0.0014 and P = 0.0047, respectively). Both IL-6 and VEGF were elevated in the vitreous fluid of patients with ischemic CRVO and macular edema. VEGF may increase vascular permeability in patients with macular edema and CRVO, whereas IL-6 may also contribute by acting together with or via VEGF. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

A randomized open-label phase I study to assess the effect of vandetanib on vascular permeability in patients with advanced colorectal cancer and liver metastases

4113 Background: Vandetanib is a once-daily oral inhibitor of VEGFR-2, VEGFR-3, EGFR and RET tyrosine kinases. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to assess the effects of vandetanib on tumor perfusion and vascular permeability in patients with advanced colorectal cancer (CRC) and liver metastases. Methods: Eligible patients received vandetanib 100 or 300 mg/day. DCE-MRI (iAUC60 and Ktrans) was used to quantify the primary endpoints of tumor perfusion and vascular permeability. An exploratory assessment of tumor oxygenation was performed using MRI/T2*. All MRI parameters were measured at baseline (twice) and on days 2, 8, 29 and 57. Secondary assessments were pharmacokinetics (PK), safety and tolerability, and a preliminary evaluation of efficacy. Results: Twenty-two patients received vandetanib (n=10, 100 mg; n=12, 300 mg). Baseline measurements of iAUC60 and Ktrans were reproducible, with low intrapatient coefficients of variation (11% and 24%, respectively). Changes from baseline in iAUC60 or Ktrans were not significant in either cohort, with no difference between cohorts (Table). There was a significant increase in T2* at 300 mg compared to 100 mg. Changes in iAUC60 and Ktrans did not appear to correlate with any PK parameter. Both doses of vandetanib were generally well tolerated; the most common toxicities were rash, fatigue, diarrhea, dysphonia and hypertension (majority CTC grade 1 or 2). RECIST evaluation showed no objective tumor responses, with stable disease ≥8 weeks in five patients receiving vandetanib 300 mg. Conclusions: In this study of patients with CRC, vandetanib (100 or 300 mg) did not reduce tumor vascular perfusion and permeability as measured by DCE-MRI. The T2* increase at 300 mg is attributed to increased tumor necrosis. Vandetanib continues to be investigated in CRC and a range of other tumor types, including Phase III evaluation in NSCLC and medullary thyroid cancer. Change from baseline in MRI parameters Parameter Mean % change from baseline (95% CI) P-value (300 mg vs 100 mg) Vandetanib 100 mg Vandetanib 300 mg iAUC60 -3.4 (-13.6, 8.1) -4.6 (-13.4, 5.0) 0.429 Ktrans 4.6 (-22.4, 17.4) 2.7 (-18.4, 16.2) 0.558 T2* -2.2 (-7.1, 2.9) 7.3 (3.1, 11.7) 0.006 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology AstraZeneca

Acute Pancreatitis: Bench to the Bedside

Acute Pancreatitis: Bench to the Bedside

Microalbuminuria, Blood Pressure Load, and Systemic Vascular Permeability in Primary Hypertension

Microalbuminuria, a powerful predictor of cardiovascular events, is thought to reflect widespread subclinical vascular abnormalities. To explore the pathogenesis of increased urinary albumin excretion in primary hypertension we evaluated systemic capillary permeability and ambulatory blood pressure (BP) measurement in two groups of matched untreated patients with (n = 11) and without (n = 29) microalbuminuria. Albuminuria was measured as the mean of albumin-to-creatinine ratio (ACR) in three nonconsecutive first morning urine samples. Systemic capillary permeability was evaluated by transcapillary escape rate of albumin (TERalb) (ie, the 1-h decline rate of intravenous (125)I-albumin). Twenty-four-hour ambulatory BP, renal hemodynamics, and hormones of the renin-angiotensin-aldosterone system (RAAS) were also assessed. Patients with microalbuminuria showed greater body mass index (BMI) (P < .04), higher 24-h systolic and diastolic BP levels (P = .02), and higher capillary permeability to albumin (P < .02) as compared to normoalbuminurics. Renal hemodynamics and RAAS hormones were similar in the two groups. Univariate analysis showed that urinary ACR was related to ambulatory pressure components (P < .02), TERalb (r = 0.31, P < .05), smoking habits (r = 0.36, P = .02), and left ventricular mass index (LVMI) (r = 0.57, P < .001) among the whole study group. Logistic regression analysis showed that each 1% increment in TERalb or 10 mm Hg increase in systolic BP entailed an almost three times higher risk of having microalbuminuria. Microalbuminuria is associated with greater systemic BP load and increased vascular permeability in patients with primary hypertension.

Hydroxyethylrutosides. A review of its pharmacology, and therapeutic efficacy in venous insufficiency and related disorders.

Hydroxyethylrutosides is a standardised mixture of semisynthetic flavonoids, mainly mono-, di-, tri-, and tetrahydroxyethylrutosides, which acts primarily on the microvascular endothelium to reduce hyperpermeability and oedema. In patients with chronic venous insufficiency or diabetes, hydroxyethylrutosides improves microvascular perfusion and microcirculation, and reduces erythrocyte aggregation. The preparation also has a possible protective effect on the vascular endothelium. In short to medium term placebo-controlled studies (up to 6 months) hydroxyethylrutosides therapy improved signs and symptoms of chronic venous insufficiency, including venous insufficiency associated with pregnancy and lymphoedema, and was well tolerated. However, the long term effects of hydroxyethylrutosides administration have yet to be demonstrated. The preparation also alleviated symptoms in patients with severe haemorrhoids, although there were no corresponding objective improvements. Hydroxyethylrutosides administration has been associated with reductions in retinal vascular permeability in patients with diabetic retinopathy but has no apparent effect on signs of retinal haemorrhage, although a reduction in oedema and haemorrhage has been reported in other patients receiving oral hydroxyethylrutosides in the acute phase of central retinal vein occlusion. There are only limited effective pharmacological treatment options for patients with chronic venous insufficiency or lymphoedema, and hydroxyethylrutosides clearly improves signs and symptoms of these disorders. While its role in diabetic retinopathy and haemorrhoids requires some clarification, hydroxyethylrutosides therapy shows promise as a useful additional option for the management of oedema and other symptoms of chronic venous insufficiency.

Lung vascular permeability in patients with acute pancreatitis.

Acute pancreatitis may be complicated by acute lung injury associated with increased lung vascular permeability to plasma protein. The pulmonary accumulation of the plasma protein transferrin, radiolabelled in vivo with indium-113m, was monitored using a portable probe radiation detector in sixteen patients with acute pancreatitis. Plasma protein accumulation (PPA) indices were within normal limits (less than 0.5 X 10(-3)min-1) in all survivors (n = 10) and elevated in all but one of the non-survivors. All non-survivors had severe acute pancreatitis as judged by standard criteria. Thus increased lung vascular permeability was not a constant feature of uncomplicated acute pancreatitis and was only observed in patients with multisystem failure accompanied by clinically evident acute lung injury.

Proceedings of the British Institute of Radiology. Radionuclide investigations of the lung. Joint meeting with The Institute of Physical Sciences in Medicine Radionuclide Topic Group. London, February 11, 1987. Abstracts.

Radionuclide investigations of the lungPublished Online:29 May 2014https://doi.org/10.1259/0007-1285-60-718-1044SectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail AboutAbstractRespiratory complications are associated with a high proportion of the deaths from acute pancreatitis. These acute lung injuries may be associated with increased vascular permeability and may result in patients developing the adult respiratory distress syndrome. Lung vascular permeability in patients with acute pancreatitis has been investigated and the results have been related to the clinical findings.Lung permeability studies were undertaken on 16 patients with acute pancreatitis, confirmed by serum amylase levels of greater than 1000 IU/1: 10 patients had mild and six had severe transferrin radiolabelled with 113Inm was monitored over a 2 h period using a probe radiation detector, as described previously (Basran et al, 1985). Previous article Next article FiguresReferencesRelatedDetails Volume 60, Issue 718October 1987Pages: 947-B70 © The British Institute of Radiology History Published onlineMay 29,2014 Metrics Download PDF