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TSRI Scientific Report 1998-1999

Bylund/SRL/NEW Scripps Reference Laboratory

David J. Bylund, M.D.

The Scripps Reference Laboratory (SRL), located at 11107 Roselle Street in San Diego, California, is a division of TSRI. Its core mission is to support TSRI's biomedical research through validation and verification of new, medically useful laboratory assays. Most new assays are based on innovative research discoveries made at TSRI or elsewhere. Data and clinical samples from new assays performed for U.S. clients are made available to TSRI investigators in support of the investigators' applied research work.

Several new assays were introduced in 1998--1999. An antiproteinase 3 enzyme-linked immunosorbent assay (ELISA) used in the diagnosis of idiopathic necrotizing vasculitis, especially Wegener's granulomatosis, was added to our autoimmune test menu. Autoantibodies against ß2-glycoprotein I and ribosomal P detected by ELISAs were also added to our autoimmune test menu. Autoantibodies to ß2-glycoprotein I occur in patients with antiphospholipid syndrome. Autoantibodies with high specificity for ribosomal P occur in patients with systemic lupus erythematosus and occasionally in patients with this disease who have neuropsychiatric disorders.

Two new molecular genetics assays introduced in our laboratory were the prothrombin G20210A gene mutation assay and the methylenetetrahydrofolate reductase C677T gene polymorphism assay. The prothrombin mutation and the reductase polymorphism are positive risk factors for thrombosis. These 2 assays were developed with John Griffin, Department of Molecular and Experimental Medicine.

We are currently working with Thomas Kunicki, Department of Molecular and Experimental Medicine, on a molecular assay to detect 2 polymorphisms in the gene for the a2 subunit of the platelet integrin a2ß1. Two allelic polymorphisms in the gene for a2 are associated with an increase in the density of a2ß1 on the platelet surface and thus may increase the risk factors for thrombosis.

Identification by DNA sequence analysis of mutations in the gene that encodes the gp91 phox subunit of the cytochrome b558 component of NADPH oxidase will soon be added to our list of tests. Patients with chronic granulomatous disease and carriers of the gene for the disease have mutations in this X-linked gene. This assay will be used in conjunction with our dihydrorhodamine 123 functional flow cytometric assay for chronic granulomatous disease that measures the ability of a patient's stimulated granulocytes to produce reactive oxygen intermediates. These assays were developed under the direction of John Curnutte, Department of Molecular and Experimental Medicine. Also with Dr. Curnutte, we plan to offer a flow cytometry assay that measures the relative quantity of CD18 on the surface of peripheral granulocytes. This assay will be used for diagnosis of leukocyte adhesion deficiency type 1.

Jerry Ware, Department of Molecular and Experimental Medicine, is assisting David Carney, SRL staff scientist, with validation of an assay to help diagnose the hemophilia A carrier state. This assay is based on the principle of detecting restriction fragment length polymorphisms in families with a known hemophilia A proband.

Several new coagulation assays are being developed under the guidance of Zaverio Ruggeri, Department of Molecular and Experimental Medicine, and Dr. Ware. Two ELISA-based tests that measure binding of factor VIII and platelet membrane glycoprotein Iba to von Willebrand factor will be used to detect patients with type 2N and type 2b variants, respectively, of von Willebrand disease. We are also working on ELISAs for antibodies to heparin--platelet factor 4 and for heparin-induced serotonin release by platelets that will be used for diagnosis of heparin-induced thrombocytopenia.

SRL has assembled a set of certain specialized medical assays in the areas of diagnostic immunopathology, coagulation and thrombosis, and molecular pathology. We continue to face the many challenges of working in an industry characterized by highly competitive economics, excess capacity, and consolidation and regionalization of laboratory services. Government and other third-party health care regulations continue to encourage a rather parsimonious approach to use of medical laboratory tests and motivate the entire laboratory industry to proactively address medical usefulness, cost containment, and managed care/capitation issues.

SRL remains committed to its role as a close partner with SmithKline Beecham Clinical Laboratories, Inc., in the United States and as a reference laboratory for Special Reference Laboratories, our affiliate based in Tokyo, Japan.



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