Valvular heart disease in patients with hypocomplementemic urticarial vasculitis syndrome associated with Jaccoud's arthropathy.

BACKGROUND: Since 1973, more than 75 patients with hypocomplementemic urticarial vasculitis syndrome (HUVS) were reported, but valvular heart disease does not seem to have been noted in these patients. Since 1993, however, five patients with HUVS accompanied by Jaccoud's arthropathy (JA) were found to have serious valvular heart disease. METHODS: To characterize the cardiac valvulopathy of the third patient with HUVS/JA to have undergone valve replacement, this study included the use of routine and special tissue stains, as well as immunohistochemical staining. We compared gross and histologic findings of this patient's valve to those of two other patients with this complex syndrome who underwent valve replacement. Pathologic findings of these latter two patients were described in separate earlier reports. RESULTS: Histologic examination of the resected valves in all three patients showed an acute necrotizing endocarditis and fibrin deposition on the surface of valve leaflets. Beneath the surfaces of the leaflets, there was evidence of chronic inflammation, consisting of lymphocytes and histiocytes. A fibrocalcific degenerative change was also present in all three valves. Positive staining for IgG, IgA, IgM, and light-chain determinant-bearing proteins was detected primarily at the valve surface in special studies of the aortic valve of the patient described in the current report. CONCLUSION: Patients with HUVS and associated JA should be evaluated for the presence of valvular heart disease. The latter is probably a nonrheumatic, inflammatory, and degenerative process, mediated by immune complex, as well as cellular immune mechanisms.

Serologic evaluations of women exposed to breast implants.

OBJECTIVE: There continues to be uncertainty whether women with silicone breast implants experience activation of their immune system and show increased prevalence of serologic markers of connective tissue diseases. We conducted laboratory tests in a large number of women with and without breast implants, and in diabetic patients with presumed silicone exposure via insulin syringes. METHODS: Subjects were chosen from women enrolled in the run-in phase of the Women's Health Study (WHS, a randomized trial testing aspirin and vitamin E in preventing cardiovascular disease and cancer), and included 298 women without breast implants, 298 women with breast implants, and 52 diabetic patients diagnosed before age 30. Comparison groups were matched on age, race, date of blood provided to the WHS, and randomization status. We compared the proportion with abnormal results in 16 serologic tests among the 3 groups of women, stratifying by the matching factors. We also tested for monoclonal immunoglobulins by electrophoresis. RESULTS: For 14 of the 16 serologic tests, the proportions with abnormal results among the 3 groups of women were not significantly different. Of the remaining tests, C3 levels were decreased in 8 (2.7%) women without breast implants and 22 (7.4%) women with breast implants (p = 0.003). C4 levels were decreased in 31 (10.4%) women without breast implants and 48 (16.1%) women with breast implants (p = 0.03). Women without breast implants and diabetic patients did not differ significantly in the proportions having decreased C3 and C4 levels. Women with breast implants did not have higher frequency of monoclonal immunoglobulins detected by electrophoresis. CONCLUSION: We found little evidence for activation of the immune system in women with breast implants. The clinical significance of isolated reductions in C3 and C4 levels, in the absence of other abnormalities such as elevated levels of antinuclear antibody, is unknown.

Hypocomplementemic urticarial vasculitis, jaccoud's arthropathy, valvular heart disease, and reversible tracheal stenosis: a surfeit of syndromes.

We describe a patient who, during 29 years of observation, manifested polyarthralgia and polyarthritis leading to progressive deformity of the joints of hands and feet (without loss of cartilage or erosion of bone); persistent urticaria made worse by cold and accompanied by hypocomplementemia; and progressive cardiac valvular disease with mitral and aortic stenosis and regurgitation. In 1996, she developed subglottic tracheal stenosis that resolved by the end of 1997 without a change in treatment, which has consisted of low dose azathioprine, glucocorticoid, and nonsteroidal antiinflammatory drugs. Tests for cryoprecipitable protein, antineutrophil cytoplasmic antibodies, antinuclear antibody, and rheumatoid factor were negative. Skin biopsy was consistent with "leukocytoclastic vasculitis." The pathogenesis of this remarkable combination of syndromes is unknown.

Anti-heat shock protein 70 antibodies in Meniere's disease.

OBJECTIVES: To determine the prevalence of anti-heat shock protein 70 (anti-HSP70) antibodies in patients with Meniere's disease and healthy subjects and to probe the relationship between antibody status and clinical features of Meniere's disease. STUDY DESIGN: Prospective cohort study of consecutive consenting patients with Meniere's disease. METHODS: Serum samples were obtained prospectively from 134 patients with Meniere's disease and 124 blood donors. Serial samples were taken at 3-month intervals in 38 of 134 patients with Meniere's disease. Demographic data and clinical characterization of vestibular and auditory status were acquired with each sample. Serum was assayed for anti-HSP70 antibodies by Western blot using bovine renal extract, recombinant bovine HSP70, and recombinant human HSP70 antigens. RESULTS: Immunoreactivity against bovine renal extract HSP70 was found in 38% of patients with Meniere's disease, compared with 25% of blood donors (P < .04). Reactivity with recombinant antigens was not significantly different between patients with Meniere's disease and healthy control subjects. Patients with Meniere's disease who reacted with all three antigens were more likely to have simultaneously active hearing and balance symptoms (P = .03). Neither univariate nor multivariate statistical analysis established any other association between serological findings and clinical features of Meniere's disease. Tests performed on serial samples of patients with Meniere's disease also showed no association of positive or negative test results with changes in clinical course. CONCLUSIONS: Because of the high prevalence of antiHSP70 antibodies in healthy subjects and the very limited association of anti-HSP70 antibody status with clinical features or course of Meniere's disease, we conclude that, at present, the detection of anti-HSP70 antibodies by Western blotting offers little clinically useful information in Meniere's disease.

Rapid oral challenge-desensitization for patients with aspirin-related urticaria-angioedema.

BACKGROUND: Acetylsalicylic acid (ASA), commonly known as aspirin, is indicated in the treatment of coronary artery disease (CAD). Many patients are denied treatment with ASA because of a history of ASA or nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria or angioedema. OBJECTIVE: We sought to develop a safe and practical protocol to allow the administration of ASA to patients with a history of ASA- or NSAID-induced urticaria-angioedema. METHODS: Eleven subjects with a history of ASA- or NSAID-induced urticaria-angioedema were challenged-desensitized by oral protocols based on rapidly escalating doses of ASA. Most had CAD, one had a history of pulmonary embolism, and one had refractory chronic sinusitis and asthma. Starting doses ranged from 0.1 to 10 mg and were administered at intervals of 10 to 30 minutes. Dosing was individualized for each patient but followed this general sequence (in milligrams): 0.1, 0.3, 1, 3, 10, 20, 40, 81, 162, 325. RESULTS: Nine patients tolerated the procedure without adverse effects and continued taking ASA for periods ranging from 1 to 24 months, without development of urticaria or angioedema. A patient who had a history of chronic idiopathic urticaria in addition to aspirin-induced urticaria had chest tightness during the protocol. Another patient who had continuing urticaria and angioedema associated with antithyroid antibodies developed angioedema several hours after completing the protocol. CONCLUSION: In patients with historical ASA- or NSAID-induced urticaria-angioedema reactions but who did not have urticaria and angioedema independent of ASA/NSAID, rapid oral challenge-desensitization to ASA was performed safely and permitted patients with CAD and other diseases to receive treatment with ASA.

Recognition of a dominant epitope in bovine heat-shock protein 70 in inner ear disease.

OBJECTIVE: To investigate the specificity of antibodies to heat-shock protein 70 (HSP70) in patients with idiopathic, progressive, bilateral sensorineural hearing loss (IPBSNHL) and Meniere disease. STUDY DESIGN: Test immunoreactivity of patients' sera using recombinant human (rh) and bovine (rb) HSP70, as well as segments representing different regions of bovine HSP70 as antigen. METHODS: Sera were tested by Western blotting. RESULTS: Of 52 patients with IPB-SNHL, 40 sera reacted only with rbHSP70; 12 reacted with both rbHSP70 and rhHSP70. Sera from 13 patients with IPBSNHL and from 8 with Meniere disease were tested on the panel of bovine HSP70 segments. Eleven and 7 samples, respectively, reacted with amino acid segment 427-461 from the carboxy (C)-terminal region of the molecule. CONCLUSION: In IPBSNHL and Meniere disease, antibodies are directed primarily against an epitope(s) within the C-terminal region of HSP70 where diversity in sequence among different species, including possible pathogens, is greatest. These findings may provide clues to the pathogenesis or specific serodiagnosis (or both) of diseases of the inner ear.

Polyamines in human and rat milk influence intestinal cell growth in vitro.

BACKGROUND: Polyamines are required for intestinal growth and development. In this study, we examined whether milk can supply the polyamines needed for growth of IEC-6 cells, a line on non-transformed rat intestinal crypt cells. METHODS: Human, bovine, and rat milk, and cow's milk-based infant formula were studied. Human, bovine, and rat milk were defatted and sterilized by filtration. IEC-6 cells were stabilized in Dulbecco's modified Eagle's medium (DMEM) containing 0.5% fetal bovine serum, 5 mM L-glutamine, 100 U/mL penicillin and 100 microg/mL streptomycin for 24 h at 37 degrees C. Thereafter, to initiate active growth, cells were placed in fresh DMEM containing 5% FBS (plus the other ingredients) supplemented with 5% (vol/vol) milk or infant formula. In some experiments, cells were also treated with difluoromethylornithine (2.5 mM) (DFMO), an inhibitor of polyamine synthesis, or dialyzed milk plus DFMO. After 44 hours of culture, cells were pulsed with 3H-thymidine (3H-TdR) for 4 hours, harvested and the radioactivity incorporated into DNA was measured. RESULTS: Human and rat milk stimulated proliferation of IEC-6 cells (p < 0.05 compared to controls); addition of DFMO did not reverse the stimulatory effect. Bovine milk and the infant formula did not stimulate proliferation or prevent the growth inhibition induced by DFMO. After dialysis, human milk had less ability to reverse the DFMO inhibition (p < 0.05). CONCLUSIONS: These experiments suggest that both human and rat milk, but neither bovine milk nor the infant formula, contain sufficient bioactive polyamines to sustain cell growth during inhibition of polyamine synthesis.

Defining the smallest analyte concentration an immunoassay can measure.

An immunoassay's minimal detectable concentration (MDC), the smallest analyte concentration the assay can reliably measure, is one of its most important properties. Bayes' theorem is used to unify the five current mathematical MDC definitions. The unified definition has significant implications for defining positive results for screening and diagnostic tests, setting criteria for immunoassay quality control and optimal design, reliably measuring biological substances at low concentrations, and, in general, measuring small analyte concentrations with calibrated analytic methods. As an illustration, we apply the unified definition to the microparticle capture enzyme immunoassay for prostate-specific antigen (PSA) developed for the Abbott IMx automated immunoassay system. The MDC of this assay as estimated by our unifying approach is shown to be 4.1-7.1 times greater than currently reported. As a consequence, the ability of the assay to measure reliably small concentrations of PSA to detect early recurrences of prostate cancer is probably overstated.

Inhaled nitric oxide. A bronchodilator in mild asthmatics with methacholine-induced bronchospasm.

Nitric oxide (NO) reduces airway tone in the methacholine-treated guinea pig. We examined whether low levels of inhaled NO gas would relax airway smooth muscle tone in patients with mild asthma subjected to methacholine-induced bronchospasm. Thirteen adult volunteers with mild asthma inspired increasing concentrations of methacholine until their baseline forced expiratory volume in one second (FEV1, 3.29 +/- 0.17 L, mean +/- SEM) decreased by > or = 20% (2.33 +/- 0.18 L, p < 0.01). Thereafter, they sequentially inhaled 100 parts per million (ppm) NO, 40% O2; 40% O2; and 100 ppm NO, 40% O2 while spirometry was performed. Subsequent inhalation of isoproterenol returned the FEV1 levels to baseline. Inhaling 100 ppm NO increased FEV1 to 2.66 +/- 0.18 L (p < 0.01), and this increase was maintained after NO was discontinued. FEV1 did not change during the second period of NO inhalation. Similar results were observed for vital capacity, but no significant effect was noted on forced expiratory flow at 25% of vital capacity or peak expiratory flow. Subjects were then divided into a responder subgroup, which showed a mean increase in FEV1 after initial NO inhalation of 560 +/- 150 ml, and a nonresponder subgroup, which showed a mean increase in FEV1 of 129 +/- 29 ml. Our data suggest that inhalation of nitric oxide by patients with mild asthma with methacholine-induced bronchospasm results in a minor but significant relaxation of airway tone.

Serum antibodies to heat shock protein 70 in sensorineural hearing loss.

OBJECTIVE: To identify the 68-kd target of antibody in serum samples from patients with idiopathic, progressive, bilateral sensorineural hearing loss. DESIGN: To purify target protein from renal extracts using gel filtration, ion-exchange chromatography, and polyacrylamide gel electrophoresis and to transfer to nitrocellulose membranes. The purified protein was digested with trypsin, and peptide fragments were separated by high-pressure liquid chromatography. RESULTS: One fraction obtained by high-performance liquid chromatography contained a peptide of 2776 molecular weight. The sequence of a stretch of 22 amino acids within this peptide was identical to that of amino acids 424 through 445 of heat shock protein 70 (HSP70). On Western blotting, monoclonal antibody directed against HSP70 (but capable of recognizing both constitutive HSP70 [HSC70] and stress-inducible HSP70) reacted with the purified 68-kd protein. We compared the reactivity of serum samples from six patients with idiopathic, progressive, bilateral sensorineural hearing loss, as well as monoclonal antibody to HSC70, and monoclonal antibody to HSP70 with renal extract. The pattern obtained suggested that patient antibodies are preferentially directed at HSP70. CONCLUSION: The target of antibody in serum samples from patients with idiopathic, progressive, bilateral sensorineural hearing loss is HSP70.

Serum antibodies against heat shock protein 70 in Menière's disease.

Menière's syndrome of fluctuating sensorineural hearing loss, episodic vertigo, and tinnitus is the clinical presentation resulting from several different pathologic processes. The present study was designed to probe for immunologic factors in Menière's disease. It has previously been shown that the presence of circulating antibodies against a 68-kD protein detected by Western blot immunoassay of serum from patients with idiopathic, progressive, bilateral sensorineural hearing loss (IPB SNHL) is highly correlated with both activity of disease and corticosteroid responsiveness of the hearing loss. The authors recently have identified the 68-kD protein as heat shock protein 70 (HSP70). This study presents a retrospective review of results of Western blot assays in 30 patients meeting strict AAO-HNS diagnostic criteria for Menière's disease. Overall, 47% of patients had anti-HSP70 antibodies. When broken down by clinical pattern, anti-HSP70 antibodies were present in 58.8% of bilateral Menière's disease, 37.5% of contralateral delayed endolymphatic hydrops, and 33.3% of unilateral Menière's disease with IPB SNHL in the second affected ear. Detection of antibodies to HSP may serve to identify a subset of patients with Menière's disease in whom immunologic factors have a pathogenic role.

What is a clinical immunologist?

The author defines the clinical immunologist as one who applies the concepts and techniques of basic immunology to the investigation, diagnosis, and treatment of patients. The formal requirements for certification in this discipline in the United States are described, and the intellectual and technical content of training are outlined. Potential future roles of the clinical immunologist are reviewed.

Serum antibody to inner ear proteins in patients with progressive hearing loss. Correlation with disease activity and response to corticosteroid treatment.

OBJECTIVE: To test whether detection of serum antibody to a 68-kd inner ear protein distinguishes among different causes of sensorineural hearing loss, and identifies patients with active disease and those likely to respond to corticosteroid therapy. DESIGN: Serum samples were tested by Western blot using bovine inner ear extract as antigen, and results were correlated with patient information obtained by chart review. SETTING: Referral center. SUBJECTS OF STUDY: Serum samples were obtained from patients with idiopathic, progressive, bilateral sensorineural hearing loss (IPBSNHL) (n = 72) otosclerosis (n = 11), Cogan's syndrome (n = 8), patients with positive tests for antinuclear antibodies (n = 10), and normal controls (n = 53). MAIN OUTCOME MEASURE: Detection of serum antibody to a 68-kd inner ear protein. RESULTS: Serum from 42 to 72 patients with IPBSNHL reacted with a 68-kd protein constituent of inner ear extract. This reactivity was not detected in serum from 11 of 11 patients with otosclerosis, or in eight of eight with Cogan's syndrome. It was found in serum from one of 10 patients with a positive test for antinuclear antibody and in one of 53 normal controls. Antibody to the 68-kd protein was detected in serum from 89% of patients with actively progressing IPBSNHL and none of the 25 patients with inactive disease (P < .001). Patients who were antibody-positive responded to steroid treatment more frequently than did those who were antibody-negative (P < .001). CONCLUSIONS: These results indicate that the presence of circulating antibody to a 68-kd constituent of bovine inner ear extract serves as a marker for IPBSNHL and that its presence correlates with disease activity and responsiveness to corticosteroid treatment.

Vancomycin hypersensitivity: synergism with narcotics and "desensitization" by a rapid continuous intravenous protocol.

BACKGROUND: We examined the clinical spectrum of patients with persistent adverse reactions to vancomycin, assessed contributing factors, and evaluated the efficacy and safety of a rapid continuous intravenous "desensitization" protocol in these patients. METHODS: Seven patients with serious staphylococcal infections resistant to beta-lactam antibiotics whose adverse reactions to vancomycin persisted despite slowing of the vancomycin infusion and pretreatment with H1-antihistamine were studied. All seven patients underwent a rapid continuous intravenous desensitization protocol with multiple small increases in vancomycin concentration tightly regulated with a syringe pump. RESULTS: Most of the seven patients safely achieved, during the first day, a vancomycin infusion rate (VIR) sufficient, or close to sufficient, to provide the desired vancomycin dose. In three patients there appeared to be a threshold VIR beyond which adverse reactions were repeatedly elicited; these reactions abated when the VIR was slightly lowered. Narcotic administration was found to adversely affect treatment with vancomycin. After concurrent narcotic administration was discontinued in three patients, they and the other four patients successfully completed the full course of treatment with vancomycin. CONCLUSION: Patients whose adverse reactions to vancomycin did not respond to slowing of the infusion rate and additional H1-antihistamines can be safely treated with a rapid continuous intravenous desensitization protocol and discontinuance of narcotic administration.

Influence of the polyamine, spermidine, on intestinal maturation and dietary antigen uptake in the neonatal rat.

Polyamines appear to have an important role in postnatal growth of the rat intestine. In the present study, we examined the effect of spermidine on the maturation of the intestine and on its ability to exclude macromolecules. Two litters of Sprague-Dawley rat pups were assigned to one of four experimental groups. These groups received, on Days 7, 8, and 9, either (a) saline by gavage; (b) spermidine, 0.9 mg (6 mumol) by gavage; (c) cortisone acetate, 3.5 mg i.p.; or (d) saline i.p. On Day 10, animals were fed by gavage with a mixture of bovine serum albumin (BSA; 2 mg/g) and the gamma-globulin fraction of mouse antiovalbumin (anti-OVA) antiserum (1 mg/g) and were bled 4 h later. Intestinal tissues were processed for histologic examination, sucrase determination, and identification of neonatal intestinal Fc receptor (FcRn) by Western blot. Serum immunoreactive BSA (iBSA) and mouse IgG1 and IgG2a anti-OVA antibodies were estimated by enzyme-linked immunosorbent assay. Sucrase activity was elevated in cortisone- and spermidine-treated compared to control rats. iBSA and anti-OVA were significantly reduced in cortisone-treated compared to control rats but were not diminished significantly in the spermidine-treated animals. A decrease in the neonatal intestinal Fc receptor was apparent in the spermidine-fed group; cortisone produced a large reduction in FcRn. Spermidine-fed animals showed morphologic evidence of maturation, with loss of giant vacuoles in the distal intestine; cortisone did not produce significant changes in morphology.(ABSTRACT TRUNCATED AT 250 WORDS)

The urinary light-chain ladder pattern. A product of improved methodology that may complicate the recognition of Bence Jones proteinuria.

OBJECTIVE: --To describe the recently reported urinary light-chain "ladder" pattern and to indicate that this phenomenon, which may give rise to confusion with Bence Jones protein (BJP), may be observed during routine examination of 50-fold concentrated urine samples tested by high-resolution agarose gel electrophoresis and immunofixation. METHODS: --Urine samples that were usually submitted for examination for the presence of BJP were concentrated 50-fold. Concentrated urine samples were subjected to immunoelectrophoresis and agarose gel electrophoresis. Samples that failed to show a BJP on immunoelectrophoresis but which did show a faint banding pattern in the stained agarose gel were subjected to immunofixation. RESULTS--Samples of urine from 23 patients failed to show a distinct BJP. Nevertheless, these samples did show a kappa, with or without a lambda, light-chain banding pattern. The urine samples came from patients with serum M components associated with neoplasms of either plasma cells (n = 2) or lymphocytes (n = 2) or with M components of undetermined significance (n = 6). The remainder came from patients with infectious (n = 8), inflammatory (n = 4), or neoplastic (n = 1) processes. Some of these patients had no apparent renal disease, while others had variably altered renal function. CONCLUSIONS--The urinary light-chain ladder pattern was found by routine examination of 50-fold concentrated urine samples subjected to agarose gel electrophoresis and immunofixation. The pattern probably reflects the limited heterogeneity of normal human light chains. Detection in the urine samples of some patients may reflect increased synthesis, failure of resorption/degradation in the kidney, or the interference in proximal tubular function by substances producing transient tubular proteinuria. The presence of the light-chain ladder pattern in urine may prevent the detection of small amounts of BJP sharing the electrophoretic mobility of one of the normal light-chain bands.

Intestinal adaptation during lactation in the mouse. II. Altered intestinal processing of a dietary protein.

We previously demonstrated in lactating mice a six- to eightfold increase in the intestinal uptake of the dietary protein, ovalbumin (OVA), administered by gavage. In this study, we tested the possibility that alterations in intestinal morphology, transit time, reduced luminal proteolysis, and enhanced association with the intestinal surface might account for the increased uptake of the protein observed in lactating mice. We found that these animals had a significant increase in length, wet weight, and surface area of the small intestine. No change in the number of Peyer's patches was noted. Intestinal transit was assessed by gavage administration of 125I-OVA and 10 mg OVA and localization of the peak of radioactivity 15, 30, and 60 min after feeding. Although motility (distance traveled per unit time) was not different in lactating and control mice at 15 and 30 min, the fraction of the small intestine traversed by the peak of radioactivity was less in lactating mice. Digestion of 125I-OVA administered by gavage with 10 mg unlabeled OVA was examined by trichloroacetic acid precipitation and gel permeation of the resulting fragments. Lactating and control mice did not show differences in digestion of 125I-OVA by either measurement. The association of 125I-OVA with small intestinal segments, however, was enhanced in lactating mice, especially in the second and third segments of the small intestine. Thus several factors including an increase in length and surface area of the small intestine, prolonged contact of protein with the small intestinal absorptive surface, and enhanced association of the protein with the intestinal surface contribute to increased uptake.(ABSTRACT TRUNCATED AT 250 WORDS)