The effect of human leukocyte antigen disparity on cyclosporine neurotoxicity after allogeneic bone marrow transplantation

PURPOSE: We examined the relationship between human leukocyte antigen (HLA) matching and the development of cyclosporine (CyA) neurotoxicity in patients undergoing allogeneic bone marrow transplantation, and determined the frequency and imaging characteristics of CyA neurotoxicity in these patients. METHODS: Records of 87 patients who underwent allogeneic bone marrow transplantation were reviewed. Eight patients who presented with visual disturbance and/or seizures and had MR imaging within 24 hours were identified. Transplant donor relatedness was examined, and patients' imaging studies were reviewed. Clinical parameters, including blood pressure, CyA, creatinine, and magnesium levels, and the presence of graft-versus-host disease were reviewed. RESULTS: CyA neurotoxicity was seen more frequently in HLA-mismatched and unrelated donor transplants. The frequency of CyA neurotoxicity was 4% for patients with a 5/6 or 6/6 HLA match, 13% for matched unrelated donor transplants, and 50% for haplotypic 3/6 or 4/6 transplants. Patients with matched unrelated donor transplants and haplotypic transplants presented earlier in the posttransplant time course and had decreased survival time relative to patients with HLA-matched transplants. Imaging abnormalities most commonly affected the occipital lobes and the posterior cerebral hemispheres; both cortical and white matter involvement was identifiable as T1 hypointense and T2 hyperintense signal with associated gyral swelling and sulcal effacement on the initial MR studies. Hypodensity in the affected areas was noted on CT scans. Contrast enhancement was seen in HLA-mismatched and unrelated transplants only. Follow-up imaging showed interval decreases in subcortical edema; however, residual signal abnormality, primarily affecting the cortex, was present in all cases and seen best on proton density-weighted MR images. CONCLUSION: The frequency of severe CyA neurotoxicity increases with increasing HLA disparity, suggesting that immune factors may play a role. CyA neurotoxicity appears to represent a spectrum of disease processes. Disruption of the blood-brain barrier as well as hypoxic or vasculitic cortical injury resulting in MR-detectable cortical signal abnormalities may occur in severe cases.     

IgE-mediated food allergy diagnosis: Current status and new perspectives

In June 2005, the work of the EU Integrated Project EuroPrevall was started. EuroPrevall is the largest research project on food allergy ever performed in Europe. Major aims of the project are to generate for the first time reliable data on the prevalence of food allergies across Europe and on the natural course of food allergy development in infants. Improvement of in vitro diagnosis of food allergies is another important aim of the project. The present review summarizes current knowledge about the clinical presentation of food allergy and critically reviews available diagnostic tools at the beginning of the project period. A major problem in diagnosis is a relatively poor 'clinical specificity', i. e. both positive skin tests and in vitro tests for specific IgE are frequent in sensitized subjects without food allergy symptoms. So far, no in vitro test reliably predicts clinical food allergy. EuroPrevall aims at improving the predictive value of such tests by proceeding from diagnosis based on allergen extracts to purified allergen molecules, taking into account the affinity of the IgE-allergen interaction, and evaluating the potential of biological in vitro tests such as histamine release tests or basophil activation tests including assays performed with permanently growing cell lines.     

Immunogenetic analysis of the heavy chain variable regions of IgE from patients allergic to peanuts

Although the histologic examination of routine tissues, such as hernia sacs and intervertebral disks, has shown a low incidence of detecting clinically significant unsuspected disease, the cost-effectiveness of histologic examination has not been determined. By using a theoretical model that assumed variable costs and gains in life expectancy secondary to detecting clinically significant disease, a threshold incidence of disease detection at which histologic examination is cost-effective was determined. By using the University of lowa (Iowa City) cost of examination (approximately $25), at least 1 of every 2,000 examinations would have to show clinically significant disease for histologic examination to be cost-effective. This threshold incidence decreases as production costs decrease or life-year values increase. Before definitive policy conclusions can be made, additional studies are needed to better define the trade-off between cost and the value of information and the incidence of detecting clinically significant disease.     

Relation of granulomas to lymphatic vessels in Crohn's disease

AIMS: To examine the relation between granulomas and lymphatic vessels in Crohn's disease. METHODS: Formalin fixed, paraffin wax embedded sections were selected from surgical resection specimens from 10 cases diagnosed as Crohn's disease. The block that showed the most granulomas was selected from each case. Sections 5 microns thick were immunostained with antibodies directed against the endothelial markers factor VIII related antigen and Ulex europaeus lectin, and against the vascular wall components collagen IV and laminin. Granulomas were counted on each slide in the serosa, muscularis propria, submucosa, and mucosa. In each area granulomas were classified according to their relation to lymphatic or blood vessels. RESULTS: Overall, an average of 46.1% of granulomas (range 15.3-90.4%) was related to lymphatic vessels, with the majority of these being adjacent to the vessel, rather than in the lumen or distorting the wall. A smaller percentage (10.1%, range 2.4-25.8%) was related to blood vessels. CONCLUSIONS: A significant proportion of granulomas in Crohn's disease is associated with lymphatic vessels. Blood vessel involvement may be a secondary phenomenon, rather than the primary event.     

An evaluation of the sensitivity of subjects with peanut allergy to very low doses of peanut protein: a randomized, double-blind, placebo-controlled food challenge study

PURPOSE: To find out if the physical instability of a lyophilized dosage form is related to molecular mobility below the glass transition temperature. Further, to explore if the stability data generated at temperatures below the glass transition temperature can be used to predict the stability of a lyophilized solid under recommended storage conditions. METHODS: The temperature dependence of relaxation time constant, tau, was obtained for sucrose and trehalose formulations of the monoclonal antibody (5 mg protein/vial) from enthalpy relaxation studies using differential scanning calorimetry. The non-exponentiality parameter, beta, in the relaxation behavior was also obtained using dielectric relaxation spectroscopy. RESULTS: For both sucrose and trehalose formulations, the variation in tau with temperature could be fitted Vogel-Tammann-Fulcher (VTF) equation. The two formulations exhibited difference sensitivities to temperature. Sucrose formulation was more fragile and exhibited a stronger non-Arrhenius behavior compared to trehalose formulation below glass transition. Both formulations exhibited < 2% aggregation at t/tau values < 10, where t is the time of storage. CONCLUSIONS: Since the relaxation times for sucrose and trehalose formulations at 5 degrees C are on the order of 10(8) and 10(6) hrs, it is likely that both formulations would undergo very little (< 2%) aggregation in a practical time scale under refrigerated conditions.