Effective Treatment of Edema and Endothelial Barrier Dysfunction With Imatinib.

Oct 2012

Aman J, van Bezu J, Damanafshan A, Huveneers S, Eringa EC, Vogel SM, Groeneveld AB, Vonk Noordegraaf A, van Hinsbergh VW, van Nieuw Amerongen GP.

Source

1 Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands;

Abstract

BACKGROUND:

Tissue edema and endothelial barrier dysfunction as observed in sepsis and acute lung injury carry high morbidity and mortality, but currently lack specific therapy. In a recent case-report, we described fast resolution of pulmonary edema upon treatment with the tyrosine kinase inhibitor imatinib through an unknown mechanism. Here, we explored the effect of imatinib on endothelial barrier dysfunction and edema formation.

METHODS AND RESULTS:

We evaluated the effect of imatinib on endothelial barrier function in vitro and in vivo. In human macro- and microvascular endothelial monolayers, imatinib attenuated endothelial barrier dysfunction induced by thrombin and histamine. siRNA knock-downs of the imatinib-sensitive kinases revealed that imatinib attenuates endothelial barrier dysfunction via inhibition of Abl-Related Gene kinase (Arg/Abl2), a previously unknown mediator of endothelial barrier dysfunction. Indeed, Arg was activated by endothelial stimulation with thrombin, histamine and VEGF. Imatinib limited Arg-mediated endothelial barrier dysfunction by enhancing Rac1 activity and enforcing adhesion of endothelial cells to the extra-cellular matrix. Using mouse models of vascular leakage as proof-of-concept, we found that pretreatment with imatinib protected against VEGF-induced vascular leakage in the skin, and effectively prevented edema formation in the lungs. In a murine model of sepsis imatinib treatment (6h and 18h after induction of sepsis) attenuated vascular leakage in the kidneys and the lungs (24h after induction of sepsis).

CONCLUSIONS:

Thus, imatinib prevents endothelial barrier dysfunction and edema formation via inhibition of Arg. These findings identify imatinib as a promising approach to permeability edema, and indicate Arg as novel target for edema treatment.

AHA Journals CIRCULATION

Purinergic 2Y1 Receptor stimulation decreases cerebral edema and reactive gliosis in a Traumatic Brain Injury Model.

Oct 2012

Watts LT, Sprague S, Zheng W, Garling RJ, Jimenez D, Digicaylioglu M, Lechleiter JD.

Source

University of TExas Health Science Center at San Antonio, Department of Cellular and Structural Biology, 7703 Floyd Curl Drive, San Antonio, Texas, United States, 78229, 210-567-8186, 210-567-8152; wattsl@uthscsa.edu.

Abstract

Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults. Neuroprotective agents that may promote repair or counteract damage following injury do not currently exist. We recently reported that stimulation of the purinergic receptor subtype P2Y1R using 2-methylthioladenosine 5' diphosphate (2MeSADP) significantly reduced cytotoxic edema induced by photothrombosis (Zheng et al., 2010). Here, we tested whether P2Y1R stimulation was neuroprotective following TBI. A controlled closed head injury model was established for mice using a pneumatic impact device. Brains were harvested at 1, 3 or 7 days post-injury and assayed for morphological changes by immunocytochemistry, western blot analysis and wet/dry weight. Cerebral edema and expression of both aquaporin type 4 (AQ4) and glial fibrillary acidic protein (GFAP) were increased at all time points examined. Immunocytochemical measurements in both cortical and hippocampal slices also revealed significant neuronal swelling and reactive gliosis. Treatment of mice with 2MeSADP (100 µM) or MRS2365 (100 µM) thirty minutes after trauma significantly reduced all post-injury symptoms of TBI including edema, neuronal swelling, reactive gliosis and AQ4 expression. The neuroprotective effect was lost in IP3R2-/- mice treated with 2MeSADP. Immunocytochemical labeling of brain slices confirmed that P2Y1R expression was defined to cortical and hippocampal astrocytes, but not neurons. Taken together, the data show that stimulation of astrocytic P2Y1Rs significantly reduces brain injury following acute trauma and is mediated by the IP3-signaling pathway.

Mary Ann Liebert

Treatment of bone marrow edema syndrome with intravenous Ibandronate.

Oct 2012

Bartl C, Imhoff A, Bartl R.

Source

Department of Orthopaedic Trauma Surgery, University of Ulm, Albert-Einstein Allee 23, 89081, Ulm, Germany, christoph.bartl@uniklinik-ulm.de.

Abstract

BACKGROUND:

In this pilot study, we investigated the therapeutic efficacy of intravenous Ibandronate compared to pain medication on the outcome of bone marrow edemas (BME) of the knee and talus.

PATIENTS AND METHODS:

Fifteen patients with a painful BME of the knee and 15 patients with a BME of the ankle, confirmed on MRI, were enrolled and treated with three ambulatory infusions of each 6 mg Ibandronate (group 1). A control group (group 2) of 10 patients with a BME of the knee and 10 patients with a BME of the talus was treated with pain medication and partial weight bearing. Patients were evaluated clinically at baseline and at 1, 3, 6 and 12 months after therapy start with a visual analog pain-scale (VAS) and specific joint scores (Larson knee- and Mazur ankle-score). BMEs were assessed with MRI at baseline and after 6 months in both groups.

RESULTS:

In the knee group, the mean VAS pain score decreased from 8.5 at baseline to 1.2 at 12 months (p < 0.0001) in patients treated with Ibandronate and, respectively, from 8.1 to 4.0 in the control group (p < 0.001). In the ankle group, the mean VAS pain score decreased from 8.2 at baseline to 0.9 at 12 months (p < 0.0001) in patients treated with Ibandronate and, respectively, from 7.9 to 3.9 in the control group (p < 0.001). The mean Mazur ankle score increased from 51 to 91 points (p < 0.001) in group 1, and from 52 to 72 points in group 2 (p < 0.01). The mean Larson knee score increased from 54 to 89 points (p < 0.001) at 12 months in group 1, and from 51 to 70 points in group 2 (p < 0.01). For both joints, we observed a significant clinical improvement in the Ibandronate treatment group and in the control group, but functional results were significantly more improved in the Ibandronate treatment group. Only the Ibandronate treatment group showed a significant BME regression at the 6 months MRI follow-up.

CONCLUSIONS:

Intravenous Ibandronate therapy showed significantly better clinical results and BME regression rates on MR-imaging compared to analgesic medication in combination with partial weight bearing in the treatment of BME of the knee and talus and shortens the natural course of the disease.

Springerlink

Early bilateral cystoid macular oedema secondary to fingolimod in multiple sclerosis.

2012

Liu L, Cuthbertson F.

Source

Department of Ophthalmology, Royal United Hospital Bath, Bath BA1 3NG, UK.

Abstract

We report a case of fingolimod-associated bilateral cystoid macular oedema in a patient with multiple sclerosis (MS). A 34-year-old female, diagnosed with MS at age of 30, developed bilateral blurred vision 5 days after initiation of fingolimod. She was misdiagnosed as optic neuritis initially and fingolimod was only discontinued 3 weeks after onset of her visual symptoms when OCT showed prominent bilateral cystoid macular oedema and subretinal fluid. Although her left corrected vision returned to 6/6, she had persistently decreased right visual acuity of 6/12 after 5 months. This paper aims to raise awareness among ophthalmologists and neurologists of the importance of early recognition of macular oedema associated with fingolimod.

NIH PubMed

Management of High Altitude Pulmonary Edema in the Himalaya: A Review of 56 Cases Presenting at Pheriche Medical Aid Post

Management of High Altitude Pulmonary Edema in the Himalaya: A Review of 56 Cases Presenting at Pheriche Medical Aid Post (4240 m).

Oct 2012

Jones BE, Stokes S, McKenzie S, Nilles E, Stoddard GJ.

Source

Department of Pulmonary/Critical Care Medicine, University of Utah, Salt Lake City, UT. Electronic address: barbara.jones@hsc.utah.edu.

Abstract

OBJECTIVE: The purpose of this study was to review the patient characteristics and management of 56 cases of high altitude pulmonary edema at the Pheriche Himalayan Rescue Association Medical Aid Post, and to measure the use of medications in addition to descent and oxygen. 

METHODS: In a retrospective case series, we reviewed all patients diagnosed clinically with high altitude pulmonary edema during the 2010 Spring and Fall seasons. Nationality, altitude at onset of symptoms, physical examination findings, therapies administered, and evacuation methods were evaluated. 

RESULTS: Of all patients, 23% were Nepalese, with no difference in clinical features compared with non-Nepalese patients; 28% of all patients were also suspected of having high altitude cerebral edema. Symptoms developed in 91% of all patients at an altitude higher than the aid post (median altitude of onset of 4834 m); 83% received oxygen therapy, and 87% received nifedipine, 44% sildenafil, 32% dexamethasone, and 39% acetazolamide . Patients who were administered sildenafil, dexamethasone, or acetazolamide had presented with significantly lower initial oxygen saturations (P ≤ .05). After treatment, 93% of all patients descended; 38% descended on foot without a supply of oxygen. 

CONCLUSIONS: A significant number of patients presenting to the Pheriche medical aid post with high altitude pulmonary edema were given dexamethasone, sildenafil, or acetazolamide in addition to oxygen, nifedipine, and descent. This finding may be related to perceived severity of illness and evacuation limitations. Although no adverse effects were observed, the use of multiple medications is not supported by current evidence and should not be widely adopted without further study.

Elsevier

Clinical Applications of Cost Analysis of Diabetic Macular Edema Treatments.

Oct 2012

Smiddy WE.

Source

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. Electronic address: wsmiddy@med.miami.edu.

Abstract

OBJECTIVE:

To apply cost-benefit analyses in specific circumstances in which the results of multiple modalities of treating diabetic macular edema (DME) are similar, as a basis for considering economic ramifications in clinically relevant applications.

DESIGN:

A model of resource use, outcomes, and cost-effectiveness and utility.

PARTICIPANTS:

There were no participants.

METHODS:

Results from published clinical trials (index studies) of laser, intravitreal corticosteroids, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and vitrectomy trials were used to ascertain visual benefit and clinical protocols of patients with DME. Calculations followed from the costs of 1 year of treatment for each modality and the visual benefits as ascertained.

MAIN OUTCOME MEASURES:

Visual acuity (VA) saved, cost of therapy, cost per line saved, cost per line-year saved, and costs per quality-adjusted life years (QALYs) saved.

RESULTS:

Four specific situations were observed or analyzed: (1) Treatment results for DME causing VA loss less then twenty over two hundred. at least as much visual benefit for intravitreal triamcinolone versus laser; a subgroup analysis of pseudophakic DME eyes shows equivalent visual results with anti-VEGF treatment versus laser combined with IVTA, eyes with VA of greater then or equal to twenty over thirty two,  have been studied only by laser; and (4) less frequent use of aflibercept yields equivalent visual results as more frequent treatment. When the results are equivalent, opting for the less-expensive treatment option could yield cost savings of forty percent to eighty eight percent..

CONCLUSIONS:

Cost-effectiveness analyses can be clinically relevant and may be considered when formulating and applying treatment strategies for some subsets of patients with DME.

Elsevier

Nitric Oxide-Associated Pulmonary Edema in Children With Pulmonary Venous Hypertension.

Oct 2012

Baird JS, Havalad V, Aponte-Patel L, Ravindranath TM, October TW, Starc TJ, Smerling AJ.

Source

College of Physicians and Surgeons, Children's Hospital of New York-Presbyterian, Columbia University, 3959 Broadway, CHN 10-24, New York, NY, 10032, USA, jsb106@columbia.edu.

Abstract

Nitric oxide (NO)-associated pulmonary edema is rarely reported in children; in adults, it is often associated with left-sided heart failure. We report a case series of children with NO-associated pulmonary edema, which was defined as new multilobar alveolar infiltrates and worsening hypoxemia within 24 h of initiation or escalation of NO and radiologic or clinical improvement after NO discontinuation. We identified six patients (0.4-4 years old) with ten episodes of NO-associated pulmonary edema. Diagnoses included atrioventricular canal defect with mitral valve disease (n = 2), pulmonary atresia and major aorta-pulmonary collateral arteries (n = 2), total anomalous pulmonary venous return (n = 1), and pulmonary veno-occlusive disease (n = 1). All patients had evidence of pulmonary venous hypertension, and two had mitral valve disease resulting in clinical evidence of left-sided heart failure. Pulmonary edema improved or resolved within 24 h of discontinuing NO. At cardiac catheterization, mean left atrial pressure was <15 artery="artery" disease="disease" in="in" mitral="mitral" mmhg="mmhg" nbsp="nbsp" none="none" occlusion="occlusion" of="of" patients="patients" pressure="pressure" pulmonary="pulmonary" three="three" valve="valve" was="was" whereas="whereas" with="with">15 mmHg in two of five patients. In conclusion, we describe six young children with NO-associated pulmonary edema and pulmonary venous hypertension. Only two of these children had left-sided heart failure: Left atrial pressure as well as pulmonary artery occlusion pressure may not be helpful in identifying children at risk for NO-associated pulmonary edema.

Springerlink

Lymphoscintigraphy for differential diagnosis of peripheral edema: Diagnostic yield of different scintigraphic patterns.

Sept 2012

[Article in English, Spanish]

Infante JR, García L, Laguna P, Durán C, Rayo JI, Serrano J, Domínguez ML, Sánchez R.

Source

Servicio de Medicina Nuclear, Complejo Hospitalario Universitario de Badajoz, Badajoz, España.

Abstract

Edema of the limbs is a common reason for medical consultation, for which the lymphoscintigraphy is considered to be a reliable method for its differential diagnosis.

OBJECTIVE:

To evaluate the usefulness of radionuclide studies in the differential diagnosis of edema, and the diagnostic yield of different scintigraphic patterns.

MATERIAL AND METHODS:

A total of 61 patients, mean age 43 years, referred to our Department in the last three years for suspected lymphoedema, were considered. One patient was discarded due to lack of diagnosis, 56 had lower limbedema and 4 upper limb edema. After intradermal injection of two doses of (99m)Tc-nanocolloid, scintigraphic scans were made at 30 and 120minutes. The final diagnosis was based on imaging tests, clinical course, and response to treatment. We calculated the parameters of the diagnostic yield of four different scintigraphic patterns (presence of dermal backflow, asymmetry-alteration in inguinal/axillary nodes, presence of collateral pathways, and visualization of intermediate lymph nodes), considering them individually and jointly.

RESULTS:

The best diagnostic yield was achieved by considering dermal backflow and asymmetry in inguinal/axillary nodes (accuracy 88.9%, specificity 96.4%, PPV 95.5%). Evaluation of intermediate lymph nodes and presence of collateral pathways contributed little to the diagnostic yield, showing poor sensitivity and high false positive rates.

CONCLUSION:

The lymphoscintigraphy had high diagnostic yield, allowing early treatment of lymphœdema. The dermal backflow and asymmetry in inguinal/axillary nodes had the greatest diagnostic accuracy. Evaluation of intermediate lymph nodes and visualization of collateral pathways contributed little to improving the diagnosis.

PubMed