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Biomedical subjects

D Amundson

Publications and source records attributed to D Amundson.

13 recordsLinked to original sources

A computerized medical incident reporting system for errors in the intensive care unit: initial evaluation of interrater agreement.

Errors resulting in adverse events in the medical care system are ubiquitous and underreported. Critical incident techniques that have been used to reduce errors in aviation have recently been applied to evaluate adverse events in the critical care arena. We report an evaluation of interrater agreement on responses to questions concerning adverse event reporting using a computer-based medical incident reporting system (MIRS). Thirty-four intensive care unit staff volunteers reviewed five fabricated test cases containing iatrogenic factors, then completed an incident report for each case using the MIRS. Interrater agreement was significant for all five cases (p < 0.01). The time required to complete a report decreased significantly from the first case to the last (p < 0.01). Overall, the MIRS was perceived as a relatively quick (< 6 minutes) and comprehensive reporting tool. The results indicate that health care providers report adverse events similarly, suggesting that the MIRS would be a useful tool in the reduction of errors (as a process improvement program) and to facilitate the continuing process of health care improvement.

Analysis of Variance↗

Gonadal hormones influence the immune response to PLP 139-151 and the clinical course of relapsing experimental autoimmune encephalomyelitis.

Females have an increased incidence of multiple sclerosis (2:1). This gender dimorphism can be studied effectively using a murine model of relapsing experimental autoimmune encephalomyelitis (R-EAE). We demonstrated previously that male SJL mice immunized with proteolipid protein (PLP) peptide 139-151 developed an initial episode of paralysis, but failed to relapse. In the present study, clinical EAE relapses were induced by orchidectomy. Relapses in castrated mice were accompanied by an influx of activated CD4+, Th1 cells into the CNS which were absent in sham mice. Our data suggests an important regulatory role for androgens on the immune response to PLP 139-151 and the clinical course of R-EAE.

Animals↗

Anti-enolase-alpha autoantibodies in cancer-associated retinopathy: epitope mapping and cytotoxicity on retinal cells.

Patients with cancer-associated retinopathy syndrome (CAR), a progressive blinding disease related to retinal degeneration and systemic tumor outside the eye, develop autoantibodies against alpha-enolase. A small percentage of healthy subjects without evident tumor or visual symptoms also possess autoantibody against enolase. In these studies we examined the fine specificity of anti-enolase antibodies derived from patients with CAR and healthy individuals, using synthetic peptides covering the entire sequence of human alpha-enolase. Epitope mapping revealed that three binding regions of enolase within the residues 31-38 (FRAAVPSG), 176-183 (ANFREAMR), and 421-428 (AKFAGRNF) were common for all autoantibodies tested. However, pathogenic sera recognized an additional unique region, the sequence 56-63 (RYMGKGVS). There were also differences in in vitro cytotoxic activities on E1A.NR3 retinal cells and cell-death promoting activities between anti-enolase antibodies of healthy and CAR affected individuals. These studies showed that anti-enolase antibodies from patients with CAR were able to induce apoptotic cell death in E1A.NR3 retinal cells and provided a potential mechanism for retinal degeneration in humans.

Animals↗

Similar pattern of MCP-1 expression in spinal cords and eyes of Lewis rats with experimental autoimmune encephalomyelitis associated anterior uveitis.

Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC chemokine family responsible for the recruitment of T cells that have been found during inflammation of the spinal cord in experimental autoimmune encephalomyelitis (EAE) in Lewis rats immunized with myelin basic protein (MBP). Lewis rats injected with MBP also developed anterior uveitis (AU), which coincided with the onset of EAE. In the present studies, we examined the expression and distribution of MCP-1 in the eye and spinal cord during disease and compared it to the expression of Th1 cell type cytokines. Initially, MCP-1 expression was detected at the preclinical phase in the iris/ciliary body and lumbar spinal cord and increased during the course of EAE/AU. Mononuclear infiltrating cells and endothelial cells and astrocytes of the CNS could be identified as a source of MCP-1 by in situ hybridization. Kinetics of expression of Th1 characteristic cytokines such as IL-2 and IFNgamma was in agreement with the expression of MCP-1 chemokine. Moreover, induction of the gene expression of MCP-1 seemed to occur earlier than that of MIP-2, and it correlated with increasing disease severity. MCP-1 seems to contribute to the initial recruitment of inflammatory cells into both the tissues of the eye and CNS over the course of disease.

Animals↗

Epitope recognition of recoverin in cancer associated retinopathy: evidence for calcium-dependent conformational epitopes.

Recoverin, a photoreceptor-specific calcium-binding protein, is a target for antibodies in human cancer-associated retinopathy. We have studied the binding properties of antirecoverin human autoantibodies and rat monoclonal antibodies (MAbs). The majority of antibodies to recoverin, both in human disease and in animals immunized with recoverin, are directed against the same major immunodominant region, the sequence within the residue 64-70 in proximity to the calcium-binding domain EF-hand 2. The immunodominant epitopes consist of linear and conformational components. Our data demonstrate that the reactivity of autoantibodies was dependent on conformational changes induced by the binding of calcium to recoverin. Some patients' antibodies could be detected by immunocytochemical methods and enzyme linked immunosorbent assay (ELISA); however, their binding was abolished on Western blots; their epitopes were sensitive to SDS treatment. Immunization of Lewis rat with purified recoverin induces antibodies with properties strikingly similar to human autoantibodies. Comparison between the monoclonal antibodies (MAbs) and native autoantibodies showed that the calcium-induced changes in conformation were critical for specificities of the antibody generated. The recoverin region within the sequence 61-82 is a key region for antibody binding; it also contains a major T-cell epitope, and it is highly uveitogenic in Lewis rats.

Amino Acid Sequence↗

Myelin basic protein specific T-helper cells induce experimental anterior uveitis.

Immunopathological changes in the eyes were examined in Lewis rats after active and passive induction of experimental autoimmune encephalomyelitis (EAE) with myelin basic proteins (MBP) at various stages of EAE. The onset of anterior uveitis (AU) coincided with hind limb paralysis, but uveitis persisted after clinical signs of EAE had subsided. A mild form of uveitis was characteristic for the majority of rats. The changes within the iris and ciliary body consisted of an accumulation of inflammatory cells lining the anterior surface of iris, the trabecular meshwork, and, in some cases, within the ciliary body and the aqueous humor. A similar histopathological picture was observed when rats were injected with the secondary encephalitogenic determinant for Lewis rats, MBP peptide 87-99. Flow cytometry analysis of T cells from the anterior segment of the inflamed eyes after immunization with MBP revealed the presence of CD4+ cells exclusively expressing V beta 8.2 and OX-40 markers. Our data suggest that MBP are encephalitogenic and uveitogenic in Lewis rats and that the V beta 8.2-positive T cells in the eye represent encephalitogenic T cells. Many of those T cells were distributed in the iris and the anterior chamber. These findings indicate that these MBP-specific T cells may play a critical role in EAE as well as in AU.

Animals↗

Recoverin, a photoreceptor-specific calcium-binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy.

Recoverin is a member of the EF-hand family of calcium-binding proteins involved in the transduction of light by vertebrate photoreceptors. Recoverin also was identified as an autoantigen in the degenerative disease of the retina known as cancer-associated retinopathy (CAR), a paraneoplastic syndrome whereby immunological events lead to the degeneration of photoreceptors in some individuals with cancer. In this study, we demonstrate that recoverin is expressed in the lung tumor of a CAR patient but not in similar tumors obtained from individuals without the associated retinopathy. Recoverin was identified intially by Western blot analysis of the CAR patient's biopsy tissue by using anti-recoverin antibodies generated against different regions of the recoverin molecule. In addition, cultured cells from the biopsy tissue expressed recoverin, as demonstrated by reverse transcription-PCR using RNA extracted from the cells. The immunodominant region of recoverin also was determined in this study by a solid-phase immunoassay employing overlapping heptapeptides encompassing the entire recoverin sequence. Two linear stretches of amino acids (residues 64-70, Lys-Ala-Tyr-Ala-Gln-His-Val; and 48-52, Gln-Phe-Gln-Ser-Ile) made up the major determinants. One of the same regions of the recoverin molecule (residues 64-70) also was uniquely immunopathogenic, causing photoreceptor degeneration upon immunization of Lewis rats with the corresponding peptide. These data demonstrate that the neural antigen recoverin more than likely is responsible for the immunological events associated with vision loss in some patients with cancer. These data also establish CAR as one of the few autoimmune-mediated diseases for which the specific self-antigen is known.

Amino Acid Sequence↗

Phenytoin hypersensitivity with pulmonary involvement in a hemophiliac patient with human immunodeficiency virus infection.

Acquired immunodeficiency syndrome (AIDS), with its attendant sequelae of opportunistic infections and aggressive lymphatic malignancies, continues to dominate the world's medical literature. Pneumocystis carinii pneumonia (PCP) remains as the most commonly encountered infection in AIDS and an early cause of morbidity and mortality. Current therapy for PCP revolves around the administration of either pentamidine isoethionate or trimethoprim-sulfamethoxazole; however, the major AIDS centers report a high incidence of adverse drug reactions to these drugs. We describe an association with human immunodeficiency virus (HIV) infection in a hemophiliac with multiple drug-related hypersensitivity reactions, which include constitutional, dermatologic, and pulmonary manifestations. This observance is intriguing and suggests that the presence of HIV infection may predispose a patient treated with a multitude of drugs and medications to a higher incidence of adverse reactions.

Acquired Immunodeficiency Syndrome↗

Familiar hyperkalaemic acidosis.

We evaluated a 26-year-old man with hyperkalaemic acidosis, apparently inherited as an autosomal dominant trait. Type II pseudohypoaldosteronism was suggested by normal aldosterone production and renal sodium conservation. The cause of acidosis in this syndrome is unknown. Both urinary ammonium excretion and bicarbonate threshold were low during hyperkalaemia. After correcting the hyperkalaemia ammonium excretion was normal, but bicarbonate threshold remained low. Maximum bicarbonate reabsorption, urine to blood pCO2 gradients, and minimum urine pH were normal. These findings suggest that hyperkalaemia might contribute to the acidosis by limiting urinary buffer, but that the primary defect is reduced mineralocorticoid effect on hydrogen ion secretion. When the poorly reabsorbed anion, sulphate, was infused, hydrogen ion and potassium secretion were normal. When the relatively reabsorbable anion, chloride, was infused, potassium secretion was decreased. These findings suggest that the attenuated mineralocorticoid effect on hydrogen ion secretion is due to increased reabsorptive avidity for chloride in the distal nephron. To determine if this defect caused resistance to mineralocorticoid we increased mineralocorticoid by dietary sodium restriction and later administered desoxycorticosterone and fludrocortisone. Both endogenous and exogenous mineralocorticoid caused increased net acid excretion and corrected the acidosis, indicating no resistance to mineralocorticoid. Hydrochlorothiazide 50 mg daily promptly corrected the acidosis and the hyperkalaemia by increased urinary potassium excretion. We conclude that the acidosis of type II pseudohypoaldosteronism is due in part to attenuation of the voltage-dependent moiety of mineralocorticoid-driven acidification caused by enhanced distal chloride reabsorption. Suppression of ammoniagenesis by hyperkalaemia exaggerates the acidosis. The acidosis and hyperkalemia are corrected by hydrochlorothiazide.

Acid-Base Equilibrium↗