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In a patient with autosomal dominant polycystic kidney disease, liver and kidney cysts were found by biopsy at the age of 8 months. Computed tomography at the age of 16 years confirmed the presence of liver and kidney cysts and also revealed pancreatic cysts. Such early onset of liver cysts in a patient with autosomal dominant polycystic kidney disease has not been reported previously.

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The toxic effects of protein A (Prosorba, IMRE Corporation, Seattle, WA) treatments given as part of an on-line plasmapheresis or off-line procedure were determined in a Phase I Study. Patients were randomized and treated 12 times either once per week or three times per week with a Prosorba column containing 50 or 200 mg protein A. Treated plasma volumes varied from 150 ml off-line to 2000 ml on-line. Seven patients having advanced metastatic breast adenocarcinoma patients were evaluated. All had advanced progressive disease that was resistant to chemotherapy and/or radiation therapy. Greater than 50% regression of measurable tumor volume occurred in four of seven patients; an additional patient responded with 33.5% regression. Two patients with only bony metastases demonstrated stable disease for a 60-day period. Side effects resulting from protein A treatments included transient fever, chills, rigors, and infrequently nausea, vomiting, diarrhea, episodic hyper and/or hypotension, bronchospasm, venospasm, headache, joint and tumor pain. Mild to moderate reactions were seen in all patients regardless of clinical response, but abated spontaneously or were controlled with pretreatment and/or post treatment with antipyretics and/or antihistaminics. The side effects decreased notably during the course of the week with the more intense reaction occurring during the first treatment of the week. Side effects occurred regardless of column size or volume of plasma treated. In the course of 12 treatments, anemia requiring transfusion developed in two of seven patients. Significant tumor regression was obtained in this group of patients with advanced disease. In light of the mild to moderate side effects and tumor regression in five of seven of the patients treated, protein A treatment merits further evaluation to determine the effectiveness of this treatment in breast adenocarcinoma.

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The clinical value of a scaled-down prototype of an extracorporeal plasma ultrafiltration system for the treatment of acute serum sickness in rabbits was examined. The system uses two filters: the primary separates red cells from plasma, and the secondary filter excludes high molecular weight proteins from plasma. In vitro and in vivo experiments showed that the secondary filters rejected substantially more IgM (80-90%) than IgG (10-30%) or albumin (10%) and totally rejected immune complexes (IC) prepared in vitro. Two groups of rabbits were submitted to either sham filtration with the primary filter only (n = 5), receiving back the remixed components of their blood, or to the complete ultrafiltration protocol (n = 7), with removal of high molecular weight proteins and IC. Several parameters were studied longitudinally, such as circulating IC, which appeared to rise more slowly in animals whose blood was ultrafiltered, and total proteinuria, which appeared to remain at lower levels in the same animals. Histologic examination of the kidneys, collected after killing, showed evidence of glomerular IC deposition in three of five sham-treated animals (a similar frequency to that observed in a separate group of five rabbits with acute serum sickness), while one of six treated animals had evidence of glomerular deposition of IC. These observations are tentative because of the small number of animals in each group, but are encouraging. Further studies with larger groups of animals are needed to determine whether the observed effects are reproducible and to better characterize the factors directly related to the removal of circulating IC.

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Studies of etiopathogenic mechanisms of bronchoconstriction in byssinosis indicate the possible involvement of histamine, 5-HT, platelet-activating factor, and metabolites of arachidonic acid as mediators of bronchoconstriction. These substances might be released by a variety of lung and/or recruited cells to induce construction of respiratory airways characteristic of the acute byssinotic reaction. It certainly seems possible that cotton dust induces acute bronchoconstriction by more than one mechanism and that a number of factors, both endogenous and exogenous, influence the increased bronchomotor response to cotton dust inhalation in any given textile worker.

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New Zealand White rabbits were acutely bronchochallenged for 5 min to ascertain airway responsiveness with six potential byssinogenic agents and mediators: 0.1 g/mL cotton dust extract (CDE), 0.1 g/mL cotton bract extract (CBE), 1 mg/mL endotoxin, 1 mg/mL n-formyl methionyl peptide (n-fMet), 10 mg/mL 5-hydroxytryptamine (5-HT), and 1 mg/mL prostaglandin F2 alpha (PGF2 alpha). Methacholine (MC), 10 mg/mL, was used as a control bronchoconstrictor. Clinically objective criteria were established using increases in resistance values compared to those obtained with saline controls. Animals were classified as: mild responders (Mi) = 125-149%; moderate responders (Mo) = 150-199%; or severe responders (S) = greater than 200%. Three of five (2Mo, 1S) rabbits showed increased pulmonary resistance to CDE bronchochallenge, 3/5 (1Mi, 1Mo, 1S) to CBE, 1/5 (Mo) to purified endotoxin, 4/5 (1Mo, 3S) to n-fMet, 3/5 (1Mi, 1Mo, 1S) to 5-HT, and 2/5 (1Mo, 1S) to PGF2 alpha. All five rabbits (1Mo, 4S) responded to MC bronchochallenge. Rabbits responded minimally to saline, the common solvent of all test agents; however, when challenged with methacholine, a known bronchoconstrictor, rabbits showed significant overt symptoms of acute respiratory distress with immediate and substantial increases in resistance over saline controls. CDE, CBE, and n-fMet inhalation challenge resulted in a majority or all animals showing increased resistance. 5-HT contained in CDE and CBE, exhibited similar resistance increases; however, endotoxin, also found in cotton dust, showed little airway reactivity. The rabbit is useful for characterizing changes in pulmonary function parameters seen in the acute byssinotic reaction. This study has demonstrated that bronchochallenge in the rabbit with potential byssinogenic agents (CDE, CBE, endotoxin, and n-fMet) and mediators (5-HT and PGF2 alpha) result in measurable changes in airway function, particularly increased resistance. Since bronchoconstriction is the major clinical manifestation of the acute byssinotic reaction in man and animals, it is likely that bronchoconstriction observed in cotton mill workers may be in part or totally the result of inherent dust constrictor substances or secondarily released mediators.

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Systemic lupus erythematosus (SLE) is a multisystem disorder accompanied by a diverse spectrum of serum autoantibodies. Antibodies to double stranded DNA (dsDNA) are considered to be the most specific marker for this disease. In this study the results obtained from three different assays for dsDNA are compared: an indirect fluorescence antibody assay (IFA), a radioimmunoassay (RIA) and, an enzyme-linked immunosorbent assay (ELISA), on 57 SLE sera and 28 Sera from other disorders. Correlation of these anti-DNA results are made with C3, C4, and antinuclear antibody (ANA) titers. Our results show the IFA assay is the most sensitive and the least specific of the three tests. The RIA was found to be the most specific and was approximately as sensitive as the ELISA. We also found significant inverse correlations between anti-dsDNA levels and circulating complement levels among SLE sera for all three assays. ANA titers were significantly correlated with all anti-dsDNA assays as well. However, these anti-dsDNA assays show only modest differences explainable by numerous mechanisms. Hence, a clearly superior anti-dsDNA method does not emerge from our study.

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The cationic ultrastructural tracer polyethyleneimine (PEI: pI approximately equal to 11.0), binds electrophysically to uniformly spaced discrete electron-dense anionic sites present in the laminae rarae of the rat glomerular basement membrane (GBM), mesangial reflections of the GBM, Bowman's capsule, and tubular basement membranes when administered intravenously. Computer-assisted morphometric analysis of glomerular anionic sites reveals that the maximum concentration of stainable lamina rara externa (lre) sites (21/10,000 A GBM) occurs 60 minutes after PEI injection with a site-site interspacing of 460 A. Lamina rara interna (lri) sites similarly demonstrate a maximum concentration (20/10,000 A GBM) at 60 minutes with a periodicity of 497 A. The concentration and distribution of anionic sites within the lri was irregular in pattern and markedly decreased in number, while the lre possesses an electrical field that is highly regular at all time intervals analyzed (15, 30, 60, 120, 180, 240, and 300 minutes). Immersion and perfusion of renal tissue with PEI reveals additional heavy staining of the epithelial and endothelial cell sialoprotein coatings. PEI appears to bind to glomerular anionic sites reversibly: ie, between 60 and 180 minutes the concentration of stained sites decreases. At 300 minutes, the interspacing once again approaches the 60-minute concentration. This suggests a dynamic turnover or dissociation followed by a reassociation of glomerular negatively charged PEI binding sites. In contrast, morphometric analysis of anionic sites stained with lysozyme and protamine sulfate reveals interspacings of 642 A and 585 A, respectively; in addition, these tracers produce major glomerular ultrastructural alterations and induce transient proteinuria. PEI does not induce proteinuria in rats, nor does it produce glomerular morphologic alterations when ten times the tracer dosage is administered intravenously. These findings indicate that the choice of ultrastructural charge tracer, the method of administering the tracer, and the time selected for analysis of tissue after administration of tracer significantly influences results. Morphometric analysis of the distribution of glomerular anionic sites in nonproteinuric rats provides a method of evaluating quantitative alterations of the glomerular charge barrier in renal disease models.

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In two separate studies (labeled A and B), concentrations of IgC, IgM, IgA, C3, and C4 were determined in the sera of byssinotic and non-byssinotic cotton mill workers. In study A, sera were collected on Monday morning and Monday afternoon and Friday afternoon in order to ascertain if the waning byssinotic response from Monday to Friday correlates with changes in serum immunoglobulin and complement concentrations. In study B, sera was collected on Monday morning and afternoon and was performed primarily to evaluate history of atopy and smoking as complicating factors in byssinosis. In study A, the concentrations of all immunoproteins were found to decrease from Monday morning to to Friday afternoon in all textile workers, and in study B only C3 concentration decreased morning to afternoon. There was, however, no difference between the immunoprotein changes for byssinotic workers when compared to non-byssinotic workers in either study. Due to the fact that hypersensitivity pneumonitis causes a decrease in immunoprotein concentrations in affected workers while no decreases are noticed in normal workers, our data do not support an immune complex etiology for byssinosis. In addition, decreased serum C3 concentrations observed in this study could be caused by complement activation; however, there was no difference in complement levels between byssinotic and non-byssinotic textile workers. Therefore, these data neither support nor eliminate the involvement of antibody-independent complement activation in the pathogenesis of byssinosis.

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A wide variety of tests for the detection of circulating immune complexes (IC) has been proposed by different authors, but there is very little to no information concerning the performance of IC screening assays in samples known to contain in vivo-formed IC. The purpose of our investigation was to compare the behavior of a non-specific assay, the PEG-IgG screening test for IC, with an antigen-specific assay in serum samples sequentially obtained from rabbits to which we induced acute serum sickness. Five animals were used in the study; we were able to detect an increase of IC constituted by the heterologous antigen (human serum albumin) and corresponding antibodies in all, and in 4 animals the results of the PEG-IgG assay closely correlated with the results of the antigen-specific assay (rho values between 0.975 and 1.00). The 4 animals in which IC showed a definite peak by both assays developed proteinuria and IC deposits at the glomerular level, while the animal that failed to develop IC detectable by the PEG-IgG test remained normal throughout the study. These results demonstrate the ability of the PEG-IgG test to detect in vivo-formed IC and suggest that the IC detected by this test have pathogenic potential.

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Extracts of cotton dust and bract induced in vitro release of arachidonic acid metabolite thromboxane A2 (TxA2), a potent bronchoconstricting agent, from human platelets. TxA2 release, determined by radioimmunoassay of the stabile metabolite TxB2, was both time- and dose-dependent. Cotton green bract extract was significantly more potent in releasing TxA2 from human platelets than cotton dust extract or cotton brown bract (field-dried bract) extract, while brown bract extract was least active, which suggests that the etiological agent(s) is of plant origin and not microbial in nature. TxA2 release was shown to be enzyme-dependent by inhibition of the reaction by indomethacin (cyclooxygenase inhibitor) and 7-(1-imidazolyl) heptanoic acid (thromboxane synthetase inhibitor). This study is the first to show in vitro platelet TxA2 release by cotton extracts and may provide an explanation for increased concentrations of TxB2, a metabolite of TxA2, in the bronchoalveolar spaces of rabbits exposed to aerosolized cotton dust extract. Platelet aggregation and production of TxA2 may prove to be an important mechanism in the pathogenesis of bronchoconstriction in byssinosis.

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Fifty-five unrelated whites with disorders in the scleroderma spectrum who had both antinuclear antibodies and Raynaud's phenomenon (RP) were studied. Of the 22 patients with anticentromere antibody (ACA), three had diffuse scleroderma; 16 had the complete or incomplete syndrome of calcinosis, RP, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST syndrome); and three had RP only. Thirty-three patients with other nuclear patterns all had systemic scleroderma (28 diffuse scleroderma, five CREST syndrome). Patients with ACA had less organ system involvement, and lower frequencies of anemia and elevation of sedimentation rate than ACA-negative patients, but these differences were not statistically significant. They also had fewer manifestations of CREST syndrome. All 55 patients were studied for the Gm and Km allotypic markers. No association was found between Gm or Km allotypic markers and scleroderma or between the allotypic markers and the presence of ACA.

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Three skin biopsies (proximal nailfold, extensor forearm and buttock) and serum samples were studied by direct and indirect immunofluorescence, immunodiffusion and radioimmunoassay techniques in 6 patients with dermatomyositis. A variety of serologic and immunopathologic abnormalities was observed in the patients. Three of 6 patients had antinuclear antibodies (ANA) of a speckled pattern mixed with a peculiar dot pattern. Epidermal intercellular deposits of immunoglobulins were seen in the nailfold biopsies of 2 patients; one of them also had IgG deposits in the cytoplasm of epidermal cells. Forearm and buttock biopsies were negative.

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The distribution of fibronectin (FN) was studied in skin biopsies of 13 patients with scleroderma (SD), 7 patients with dermatomyositis (D), and 10 normal controls (NC) by direct immunofluorescence. In normal tissues, continuous or segmental linear staining of the dermal-epidermal junction (DEJ) was seen. Papillary, subpapillary dermis, and papillary capillary loops showed a reticular pattern of deposition with fibronectin. Scleroderma patients revealed similar staining in the dermis and DEJ. The reticular distribution of FN appeared to stain more intensely in the dermis than in controls, especially in deeper layers. The amount of FN in walls of blood vessels from SD patients was markedly increased; all dermal vessels stained with FN and revealed considerably thicker walls and larger lumens. FN distribution in DM patients was similar to that seen in SD with an increased amount of FN staining in capillary walls.

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Serum IgE concentrations were determined by the paper radioimmunosorbent test in 56 patients with psoriasis and 50 normal controls, and by the paper enzyme-immunosorbent test in 32 of these patients and 50 controls. Elevated IgE levels were found in 26 (46%) of 56 patients with psoriasis and in 1 normal control (2%). The mean value (208 U/ml) in 56 patients was significantly higher than in normal controls (31 U/ml). Thirteen of 19 patients (68%) with extensive involvement (greater than 20% body surface) had an increased IgE level; the mean value (365 U/ml) was 4 times greater than in 17 patients with limited lesions (89 U/ml) and 12 times higher than in 50 normal controls (31 U/ml). No correlation was found between serum IgE levels and the presence of psoriatic arthritis. Both paper radioimmunosorbent and paper enzyme-immunosorbent testing produced similar results.

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New Zealand White rabbits were exposed intratracheally to aerosolized cotton dust extract (CDE) for 5 minutes of tidal breathing and lavaged 15 minutes 1, 4, and 6 hours after exposure. Bronchoalveolar lavage cells were counted, and the number of macrophages and polymorphonuclear leukocytes (PMNs) was determined. Cell recruitment, which began 1 hour after exposure to CDE and plateaued at 6 hours, consisted of both mononuclear cells and PMNs. Lavage fluid was analyzed for concentrations of prostaglandin F2 alpha (PGF2 alpha), prostaglandin E1 and E2 (PGE), thromboxane B2 (TxB2), and 5-hydroxytryptamine (5-HT). PGF2 alpha, PGE, TxB2, and 5-HT were maximally increased in the lavage 4 hours after exposure to CDE. This is the first study to demonstrate the in vivo release of arachidonic acid metabolites and 5-HT in the lung in response to CDE inhalation. This study also demonstrates that maximum mediator release occurs at 4 hours after exposure to aerosolized CDE. These findings strongly suggest that arachidonic acid metabolites are available to mediate either totally or partially the pathogenic mechanism(s) of bronchoconstriction seen in the acute byssinotic reaction of man.

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Immunofluorescence (IF) data from three different biopsy sites (nailfold, forearm, buttock) were studied in 18 patients with scleroderma (SD, systemic sclerosis) and the results compared with those obtained from 10 normal controls (NC) and 7 patients with systemic lupus erythematosus (SLE). Immunoglobulin (Ig) deposits were detected by direct IF technique at the dermo-epidermal junction (DEJ) in 8/14 nailfolds, 6/15 forearms and in none of the buttock specimens of SD patients. Epidermal nuclear staining was present in 6/14 nailfolds, and in 6/15 forearms and buttocks. The most prominent finding was the observation of multiple Ig deposits in the cuticle of 9/14 patients with SD. NC group was negative in all sites for epidermal nuclear staining and the only DEJ deposit occurred in the forearm of one subject. In conclusion, this study demonstrates that Ig deposits in SD, both at the DEJ and in the epidermal nuclei, occur more often than previously reported and are especially frequent in the nailfold & cuticle area.

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Epidermal nuclear deposits of immunoglobulins (Ig) were studied by direct immunofluorescence in three groups of patients: ten scleroderma (SD, systemic sclerosis), seven dermatomyositis (DM) and seven systemic lupus erythematosus (SLE). Each patient had skin biopsies taken from three different sites (nailfold, forearm, buttock) on the same day that a serum sample was also obtained. Epidermal nuclear deposits were observed in nine of twenty-four patients (five SD, two DM, two SLE). A high serum ANA titre correlated significantly with the presence of epidermal nuclear Ig deposits. The nucleolar epidermal nuclear pattern was limited to the SD group, four of ten patients showing this pattern. Two of nine patients with positive results in the nailfold and forearm had negative findings in the buttock, supporting the view that deposition of Ig in the epidermal nuclei occurs in vivo.

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Antinuclear antibody and in vivo capillary patterns were studied in 33 patients with Raynaud's phenomenon only and in 68 patients with scleroderma spectrum disorders; the results were correlated with clinical and laboratory findings. In addition, antinuclear antibody results in the groups with Raynaud's phenomenon only and scleroderma spectrum disorders were compared with those found in 70 patients with systemic lupus erythematosus (SLE). Distinct antinuclear antibody profiles were observed in the three diagnostic groups. Comparison of patients with anticentromere antibodies with others in the group with scleroderma spectrum disorders demonstrated that anticentromere antibody-positive patients tended to have a milder disease: less skin and visceral involvement, less frequent presence of hypertension, anemia, and elevated sedimentation rate. These differences did not, however, reach statistical significance. Comparison of patients with scleroderma spectrum disorders according to in vivo capillary patterns revealed that those with an "active" pattern had significantly more extensive skin involvement than those with a "slow" pattern. Visceral involvement tended to be greater in all organ systems in the group with an "active" pattern and reached statistical significance for muscle and kidney. Hypertension was also significantly more frequent in the group with an "active" pattern than in the group with a "slow" one. The latter was positively correlated with the presence of anticentromere antibody.

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Forty-one patients with various forms of systemic sclerosis (scleroderma) and positive antinuclear antibodies of nucleolar (ten patients), speckled (eleven patients), or centromere pattern (twenty patients) were selected for study of immune complexes by the radioisotope labeled Clq binding and the radioisotope labeled protein A binding methods. The presence of immune complexes was found by the Clq binding assay in sixteen patients (39%) and by a protein A binding assay in eight patients (20%). Overall, 46% of patients (19/41) had immune complexes. A lower incidence of organ involvement and fewer positive results in the screening of serum immune complexes were observed in patients with centromere antibody (35%) than in patients with nucleolar (60%) or speckled pattern (55%). Patients with immune complexes had higher frequencies of kidney, heart, and muscle involvement and digital ulceration than did patients with no detectable immune complexes, but the differences were not statistically significant. Diffuse skin involvement was not related to the presence of immune complexes.

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