Pathological and epidemiologic study of gastric cancer in atomic bomb survivors, Hiroshima and Nagasaki, 1959-77.
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Biomedical subjects
Publications and source records attributed to Y Ochi.
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TSH-receptor antibody (TRAb) activity and LATS activity of Graves' sera were compared. All of 50 LATS-positive cases were TRAb positive, although only 63% of LATS-negative cases were TRAb positive. Binding of 125I-TSH to the TSH receptors was inhibited dose-dependently by LATS-immunoglobulin. However, no correlation between TRAb activity and LATS activity was observed. TRAb was positive in 2 LATS-positive cases even when the symptoms of hyperthyroidism were controlled by treatment (antithyroid or radioisotope). The positive TRAb was not changed in 4 Graves' disease patients whose LATS activity had disappeared following antithyroid treatment. These clinical studies show that TRAb is more sensitive than LATS and suggest that LATS may be one of a heterogenous population of antibodies to the TSH receptor in Graves' disease.
The structural characteristics of carcinoembryonic antigen (CEA) and CEA-like antigen in feces and meconium were examined using antibody raised against 2 antigens. When antibody to CEA was made, anti-alpha 1-acid glycoprotein (AG) (nonprecipitating antibody) besides the precipitating antibody for CEA was made. When antibodies against each CEA-like antigen (mol. wt. 180,000) purified from feces and meconium were tested, each antibody showed a fused precipitin line for 2 antigens. Some antibodies showed the non-precipitating antibody for AG. CEA and CEA-like antigen in feces and meconium may be composed of 2 portions (AG portion and non-AG portion). Antibody specific to these antigens may be the antibody directed to the non-AG portion.
In this report we describe the characteristics of auto-antibodies to bovine TSH (bTSH) detected in the serum of 2 females among 102 patients with Graves' disease. These patients had never been injected with bTSH. One patient had high LATS activity and high bTSH binding activity after isotope therapy. The other patient showed no detectable LATS activity. Interestingly, the antibody showed a specifically high binding activity for the labelled TSH preparation purified by receptor. The auto-antibody could be demonstrated by the double antibody method, polyethylene glycol method, and by gel-filtration. The antibody was polyclonal immunoglobulin G (IgG). Because the binding of [125I]bTSH with the patient's antibody was inhibited by pituitary extracts from mammalian species other than human, this antibody may cross-react with bovine, rat, dog, rabbit and whale TSH. Although the incidence of the antibody in Graves' disease is low and the pathological significance remains obscure, the existence of this antibody in the serum of patients may suggest that autoimmune mechanisms may involve not only the thyroid but also the pituitary in Graves' disease.
The antihypertensive effect of nifedipine (Adalat), a Ca2+-antagonistic drug, was studied in patients with mild or severe hypertension. In both short- and long-term trials, nifedipine exerted a strong hypotensive effect, more pronounced in patients with severe than in cases with mild hypertension. The results of our short-term study showed a positive correlation between the maximum fall in blood pressure induced by nifedipine and pretreatment systolic blood pressure values or the total severity index score of hypertension. In our long-term trial, we also observed a positive correlation between maximum reduction of blood pressure--induced by nifedipine--and pretreatment values. However, no correlation between reduction of blood pressure and total severity index score of hypertension could be established. Our results indicate that nifedipine could be effective in the management of severe hypertension. The hypotensive action of nifedipine, at least partly due to its Ca2+ influx blocking action, suggests that etiologically hypertension may be connected with an abnormal calcium metabolism of the cardiovascular muscle cells.
The purified CEA preparation by anti-alpha 1-acid glycoprotein (AG) chromatography shows specific binding with both auto-antibodies for CEA in cancerous patients and the monoclonal antibody for CEA. By this method CEA purification is possible. CEA preparation obtained from CEA producing cell line and CEA producing tumor grafted in nude mice contain AG antigenic determinants. Both tumors also contain free AG (Mr, 50,000). When tryptic hydrolysis of purified CEA preparation is performed, AG-like protein (Mr, 30,000) is released. The carbohydrate composition and amino acid content of both CEA and AG have a significant similarity. We postulate that CEA may be a biosynthetic precursor of AG based on differences in binding affinities between CEA with anti-CEA and with anti-AG.
Purification of radiolabeled carcinoembryonic antigen (CEA) preparations by affinity chromatography with anti-AG bound to Sepharose was attempted, since an immunological similarity between AG (alpha 1-acid glycoprotein) and a portion of CEA had been noted. When 125I-CEA was purified in this manner, the fraction which did not bind to the column showed decreased reactivity with either anti-AG or anti-CEA. The retained fraction showed enhanced reactivity with both anti-AG and anti-CEA. The yield of purified CEA increased when the CEA preparation was allowed to react with the anti-AG column overnight. Purification of CEA from tumor tissue was performed by affinity chromatography. A perchloric acid (PCA) extract from cancer tissue was mixed with antiserum against CEA to give an immune complex, and a CEA-reactive fraction obtained by PCA extraction. The CEA-reactive fraction was eluted from a Sephadex G-200 column, and final purification was by anti-AG chromatography. When purified CEA was applied to a Sephadex G-200 column with carrier protein after labeling with 125I, the eluted radioactivity was found only in the 180,000 dalton fraction. Almost all the radioactivity was precipitated from the labeled protein by either anti-AG or anti-CEA. Purification of CEA is possible by affinity chromatography with anti-AG bound to Sepharose.
We have demonstrated that 125 I-CEA (carcinoembryonic antigen) from two commercial sources (Roche and CIS RIA kit) can be precipitated by antibody to alpha 1-acid glycoprotein (AG) dose-dependently. The binding of 125 I-CEA to anti-AG can be displaced by unlabelled AG, though, there was no cross-reaction between AG and anti-CEA. The data strongly suggest that CEA has an immunological similarity to AG. The perchloric acid extract from cancerous tissue was fractionated on a Sephadex G-200 column, and the first eluted fraction (containing large amounts of CEA) was subjected to affinity chromatography using anti-AG bound to Sepharose. The bound fraction was eluted, labelled with 125 I, and then applied to a Sephadex G-200 column with carrier protein. The radioactivity was found mainly in the large molecular size eluted fraction (Fr 1). Almost all radioactivity of Fr 1 was precipitated by anti-AG and anti-CEA. This experiment also demonstrated that a large molecular weight component (Mr: 180 000) obtained from tumor was immunologically related to both CEA and AG. Based on differences in binding affinities between CEA with anti-CEA and with anti-AG we postulate that CEA may be a large molecular precursor of AG (big form of AG).
We have recently suggested that carcinoembryonic antigen (CEA) may contain alpha 1-acid glycoprotein (AG) antigenic determinant. In the present work we examined a protein with CEA-like activity in the feces of healthy subjects (NCA) for immunological cross-reactivity with AG. When the perchloric acid extract of feces was fractionated on a Sephadex G-200, two fractions (large and small molecular weight) were obtained. The large molecular weight fraction had higher CEA activity than the small one. The perchloric acid (PCA) extract of feces was subjected to affinity chromatography using anti-CEA bound to Sepharose, and the bound protein was labelled with 125I, and then fractionated on a Sephadex G-200 column. Two radioactive peaks, Peak 1 corresponding to an approximate Mr of 180 000 and Peak 2, corresponding to an approximate Mr of 60 000 were found. Both peaks showed immunoreactivity with either anti-CEA or anti-AG. This experiment suggests the presence of two kinds of CEA-reactive proteins in feces: one which may be a big protein with immunological similarity to AG and a second which appears to be a hydrolysed fragment of this protein.
An assay for detection of serum IgG binding to thyroid membrane using 125I-Protein A was examined. The test serum is incubated with purified thyroid membranes, and the IgG bound to the membrane is detected by its interaction with 125I-Protein A. Most of the bound IgG is not bound to the TSH receptor, because TSH does not induce any appreciable decrease in the binding of the IgG to thyroid membranes. Increased serum IgG binding to thyroid membrane is found in most patients with Graves' disease and Hashimoto's thyroiditis, but not in patients with thyroid cancer or simple goiter. Many sera with positive binding activity showed positive microsomal antibody. Serum IgG binding to thyroid membrane in Graves' disease correlates neither with LATS activity nor thyroglobulin antibody. This finding suggests that TSH receptor is not involved in the reaction. The assay method is useful for measuring the binding immunoglobulin for thyroid membrane that is frequently increased in autoimmune thyroid disease, and the present data provide further support to the concept that thyroid autoimmune disorders are associated with antibodies to thyroid cell surface components.
The present study evaluated the effect of sodium loading and sodium depletion on cAMP and cGMP content of rat aorta. Enhanced generation of prostacyclin (PGI2) in aorta was noticed in sodium loading and sodium-depletion. As PGI2 is potent vasoactive agent, the interaction between PGI2 generation in the aorta and cyclic nucleotide accumulation in the aorta was investigated. Sodium depletion of rats induced the elevation of both cAMP and cGMP in the aorta and of cAMP in plasma. No change in cyclic nucleotides was noticed following sodium loading. These changes in cyclic nucleotides were felt to reflect the fluctuation of vasoactive agents under various sodium metabolism conditions. These observations may indicate that PGI2 is not a major factor in the regulation of cyclic nucleotide metabolism under sodium loading and sodium depletion. The increased accumulation of cAMP and cGMP in rat aorta in sodium depletion may be due to the cumulative effects of PGI2, catecholamine and probably angiotension II which are induced by sodium depletion.
Serum thyroxine binding prealbumin (TBPA) levels in various thyroidal states were examined by radioimmunoassay (RIA). This technique is highly sensitive, accurate and reproducible. The normal mean (+/- 2SD) level of serum TBPA is 26.9 +/- 8.0 mg/dl (29.4 +/- 5.2 in men and 24.9 +/- 7.6 mg/dl in women). Serum TBPA levels in pregnant women were significantly lower than in normal females (P less than 0.05). Serum TBPA levels in patients with untreated hyperthyroidism were 12.9 +/- 4.0 mg/dl (mean +/- SD) and in patients with untreated hypothyroidism were 25.2 +/- 4.7 mg/dl (mean +/- SD). The mean TBPA concentrations in untreated hyperthyroidism were significantly lower than that for normal population (P less than 0.01), but untreated hypothyroidism was almost within normal range. The changes in TBPA levels in hyperthyroidism and hypothyroidism were similar to those in TBG levels. In untreated hyper- and hypothyroidism, restoration to euthyroidism by treatment was uniformly accompanied by a normalization of serum TBPA and TBG levels. A negative correlation between serum thyroid hormone binding protein (TBG and TBPA) and free thyroxine was observed in patients with hyperthyroidism. The coefficient of correlation between TBPA and free thyroxine was -0.80 (P less than 0.01) and between TBG and free thyroxine -0.58 (P less than 0.01). From these experiments it appears that not only TBG but also TBPA may play an important role in the regulation of the free thyroxine concentration in response to various thyroidal states.
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Serum thyroxine-binding globulin (TBG) in 169 patients with various cancers was determined by radioimmunoassay (RIA). Eleven patients showed a high serum TBG level (greater than 35 micrograms/ml). Two of them had been treated with estrogen for prostate cancer. One patient had high serum TBG with serum hepatitis. Another 8 cases had normal liver function and also normal levels serum estrogen. Thus, about 4.7% (8/169) of the cancer patients had high serum TBG and mild hyperthyroxinemia caused by unknown mechanisms. The high TBG level in these patients continued until just before death, or in some cases decreased to normal after removal of cancer tumors by operation. Cancer is occasionally associated with an increase in serum TBG. Although the mechanism is not clear, the increased TBG in the cancerous state in interesting and has significance as a tumor marker.
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A case report of a female patient with Graves' disease complicated by nephrotic syndrome with high LATS activity in urinary gamma-globulin is presented. When in the hyperthyroid state with high LATS activity in the serum, she was treated with antithyroid drugs, excess iodine, and finally radioisotopes. Mild hypothyroidism occurred transiently without any significant change in serum LATS activity. Nephrotic syndrome suddenly appeared. Urinary IgG was purified by salting out with ammonium sulfate, DEAE and protein A-Sepharose, and LATS activity in the purified urinary IgG fraction was demonstrated. The specific activity of LATS activity in urinary IgG protein was slightly lower than that of the serum. This case is the first demonstration of LATS activity in urine from a patient with hyperthyroidism and nephrotic syndrome.
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