Biomedical subjects
Publications and source records attributed to E Alpert.
The prenatal diagnosis of neural tube defects is now possible in about 90 per cent of cases by assaying the amniotic fluid for alpha fetoprotein. The accuracy of beta-trace protein assays on amniotic fluid samples from defective fetuses was compared to alpha-fetoprotein studies. At present, alpha-fetoprotein studies provide more reliable results.
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A quantitative immunoenzymatic assay has been developed for alpha-fetoprotein which is sensitive and specific. Seventy-eight percent of United States hepatoma patients have detectable serum alpha-fetoprotein elevations over 50 ng/ml, whereas only 2 of 93 other gastrointestinal tumors were positive. Thirteen percent of patients with acute viral hepatitis, 44% of patients with massive hepatic necrosis, and 23% of patients with chronic active hepatitis had measurable serum alpha-fetoprotein concentrations. However, patients with non-viral acute or chronic liver disease were largely alpha-fetoprotein negative and alpha-fetoprotein was undetectable on multiple postoperative samples from 6 patients after hepatic lobectomy in the rapidly regenerating phase. Therefore, alpha-fetoprotein elevations in nonmalignant liver diseases are not due solely to hepatic regeneration but appear to be related to viral injury. The immunoenzymatic assay does not require purified antigen or radioisotope equipment and can detect and quantitate clinically significant alpha-fetoprotein levels greater than 50 ng/ml.
Carcinoembryonic antigen (CEA) preparations, from various sources were compared by radioimmunoassay. The preparations studied included four CEA standards (CEA-Roch, CEA-Montreal, CEA-City of Hope, and CEA-British) and CEA from serum and liver metastases of a patient with cancer of the colon who had an extremely high concentration of serum CEA (more than 26,000 ng/ml). The data indicate that the CEA-Roche standard differs significantly from the other three CEA standards tested, and that the serum CEA from the patient was antigenically different from currently available CEA standards as well as from the CEA obtained from the patient's own liver metastases. These antigenic differences were reflected in radioimmunoassay inhibition curves that were different and that were not affected by perchloric acid extraction of CEA. Because of the antigenic variation in the serum CEA, markedly different CEA concentrations (varying by three orders of magnitude) were measurable by two different antisera (Roche and Montreal). All the various CEA standards and samples cochromatographed on columns of Sepharose-6B, despite the large antigenic variation. We postulate that CEA consists of a family of "isoantigens" with multiple antigenic determinants. We identified a serum CEA isoantigen that was different from the currently available standards. Consequently, we believe that results of radioimmunoassays currently used for CEA measurement may not represent absolute concentrations of serum "CEA", but may reflect the binding affinity of different isoantigens to a particular polyvalent CEA antiserum.
Ferritins from human liver, spleen, heart, pancreas and kidney were compared by electrophoresis and isoelectric focusing in polyacrylamide gels, by immunodiffusion against antisera to homologous and heterologous ferritin, and in some cases by their cyanogen bromide peptides. All ferritins appeared to consist of a single species on gel electrophoresis with the exception of heart ferritin which separated into two major components. Small differences in electrophoretic mobility were found in all tissue ferritins. By contrast, all tissue ferritins were found to consist of multiple forms when analysed by gel electrofocusing. At least five isoferritins were found in most tissues, several of which were common to most tissues. At least two were common to all tissues. Those ferritins which were most easily distinguishable electrophoretically, e.g. spleen and heart ferritin, showed the greatest differences on gel electrofocusing. The ferritin profile was characteristic of each organ and was reproducible both within individuals and between individual tissues. There were striking differences in the iron content of the various isoferritins within a tissue. Further, the iron content of isoferritins common to more than one tissue varied with the tissue of origin. Some isoferritins in several organs and all of the isoferritins in pancreas appeared to contain little, if any, iron. All five tissue ferritins contained antigenic determinants in common with liver ferritin. However, an additional antigenic determinant was found in liver ferritin which was not detectable in the ferritins from the other organs.
Peripheral lymphocytes from patients with hepatitis-B surface antigen (HBsAg)-positive and -negative acute hepatitis (AH), chronic active hepatitis (CAH), chronic persistent hepatitis (CPH), and normal controls were tested for in vitro cytotoxicity and blast transformation. Cytotoxicity was measured by chrominum (21Cr) release into the medium from 51Cr-labeled Chang liver cells after incubation for 6 h with peripheral lymphocytes at a lymphocyte target cell ratio of 200:1. Concomitant 72-h incubation studies were performed to assess thymus cell-dependent (T) lymphocyte function as measured by conccanavalin A (Con A)- stimulated incorporation of tritiated thymidine (blast transformation) and by cytotoxicity. It was found that (a) lymphocytes from patients with AH are cytotoxic to Chang liver cells compared to controls (P less than 0.001); (b) lymphocytes from patients with acute and chronic hepatitis are less cytotoxic when incubated with autologous and homologous HB2Ag-positive and -negative AH, CAH, and CPH are as cytotoxic as normal controls when stimulated with a nonspecific mitogen such as Con A; and (d) lymphocytes from patients with CAH while on prednisone therapy showed marked depression of cytotoxicity when stimulated with Con A. Thus these studies show that patients with AH have circulating T lymphocytes which are capable of causing the destruction of Chang liver cells. There is no defect in T-cell function as measured by Con A-stimulated cytotoxicity. There is a serum factor (s) in patients with acute and chronic hepatitis which inhibits spontaneous and induced lymphocyte cytotoxicity and blast transformation. Finally, prednisone treatment appears to inhibit lymphocyte cytotoxicity in patients with CAH.
Circulating immune complexes were identified in cryoproteins isolated from serial samples of serum from six patients with acute viral hepatitis with and without arthritic symptoms. Cryoprecipitates were analyzed for the presence of hepatitis-B surface antigen (HBsAg) and hepatitis-B surface antibody (anti-HBs) by hemagglutination inhibition and hemagglutination. Complement components were detected by counter electrophoresis, and immunoglobulins were detected by gel diffusion. HBsAg, IgG, and IgM were identified in cryoprecipitates from all hepatitis patients, but were higher in concentration in patients with arthritis. Only cryoprecipitates from hepatitis patients with arthritis contained IgA and complement components C3, C4, and C5 as well as IgG and IgM, which disappear with resolution of the arthritis. The subtypes of IgG in these cryoprecipitates were predominantly the complement-fixing IgG1 and IgG3, HBsAg and anti-HBs were concentrated several-fold in the cryoprecipitates when compared to the serum concentration. Sequential studies in two patients demonstrated that the initial appearance of anti-HBs in the cryoprotein complex was associated with the detection in the complex of IgM suggesting a primary immune response to HBsAg. The C3 activator fragment (C3A) of the properdin complex was found in fresh serum obtained from three hepatitis patients with arthritis and not in uncomplicated hepatitis. The cryoprecipitable immune complexes from patients with arthritis converted C3PA in fresh normal sera to C3A in vitro whereas cryoprotein isolated from patients with uncomplicated hepatitis had no such effect. Thus, the transient appearance of circulating complement-fixing immune complexes in patients with the arthritis of acute hepatitis is associated with activation of both classical and alternate complement pathways and suggests that they play an important role in the pathogenesis of these serum sickness-like extrahepatic symptoms.
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Circulating immune complexes were identified in cryoproteins isolated from serial serum samples from 6 to 10 patients with chronic active hepatitis (CAH) with frank arthritis and arthralgias. These immune complexes were not detectable in patients with uncomplicated CAH. Only cryoprecipitates from CAH patients with frank arthritis contained IgG, IgM, IgA, and complement components C3, C4, and C5. Hepatitis B surface antigen was concentrated several-fold in the cryoprotein immune complexes as compared with the serum concentration. The C3 activator fragment of the properdin complex was found in fresh serum in all patients with arthritis but was undetectable in patients with arthralagias and uncomplicated CAH. Thus, the presence of circulating complement-fixing immune complexes in patients with alternate complement pathways, and suggests that they play an important role in the pathogenesis of the arthritis.
Ferritin was purified from normal, fetal, and malignant liver tissue. Ferritin purified from hepatoma tissue migrated slightly faster than normal human liver ferritin in polyacrylamide gel electrophoresis. Hepatoma and fetal liver ferritin contained an acidic components in gel and liquid isoelectric focusing not found in normal liver ferritin. We have called it a carcinofetal isoferritin. The subunit compositions of ferritins purified from human liver cell carcinoma and normal liver were then compared. Both ferritin consisted of a subunit species with an identical molecular weight of approximately 18,500. A single subunit of similar molecular weight was also demonstrable after dissociation of 8 M urea and by gel filtration in urea. Two subunits were demonstrable in normal liver ferritin by means of acrylamide electrophoresis in 8 M urea in acid pH. The same two subunits were also demonstrable in ferritin isolated from human liver cell carcinoma. However, a third subunit, intermediate in charge between the two normal liver subunits, was demonstrable in different amounts in ferritins from two hepatomas. Ferritins from normal and malignant livers were immunologically indistinguishable. The tumor-specific acidic isoferritin was isolated and antisera were prepared. The isolated acidic isoferritin was found to be immunologically identical to normal liver isoferritins. It is concluded that the multiple isoferritins of the human liver ferritin consist of two subunits, which are identical in molecular weight but which differ in net charge. Ferritin, isolated from two human liver carcinoma tissues, was composed of the same two subunits and a third unique subunit. Different amounts of these subunits may account for the several normal isoferritins and a unique tumor-specific acid isoferritin found in hepatoma.
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