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Chromium (III) has recently been shown to be an essential trace mineral in rats, being required for normal function of insulin in controlling glucose metabolism. Chromium is transported in the body bound to transferrin, where it binds competitively with iron. Hemochromatosis is an iron storage disease in humans characterized by highly saturated transferrin levels and sometimes by diabetes. We postulated that the diabetes may be due to exclusion of chromium by iron at metabolic binding sites. 51Cr(III) was administered i.v. to 5 normal males, 6 patients with hemochromatosis prior to therapeutic removal of iron, and 5 patients with varying levels of iron loading. The retention of 51Cr was measured with a whole-body counter for 8 mo and blood levels were measured for 40--80 days. Analysis of the whole-body retention curves revealed 3 exponential components with T1/2s of .56 days, 12.7 days, and 192 days; the blood curves had 4 components with T1/2s of 13 min; 6.3 hr, 1.9 days, and 8.3 days. The T1/2s were not significantly different between the normals and patients. The coefficients of these components however, were significantly lower for the long T1/2 components in the iron-loaded patients, demonstrating reduced retention of 51Cr as postulated. Whether this reduced retention of chromium is causally related to diabetes in hemochromatosis and whether abnormal chromium metabolism is involved in endogenous diabetes, thus, becomes an important question for future study.

Cytoplasmic receptors for 5 alpha-dihydrotestosterone (3H-DHT) were determined in normal and hypertrophic human prostate using the slightly modified DCC method we previously standardized for 17beta-estradiol-receptor. Incubations were always performed at 0 degree C for 1 hr. Discrimination between 3H-DHT binding to cytoplasmic receptor and to Sex Hormone Binding Globulin (SHBG) was achieved on the basis of binding affinity, thermolability and pattern of specificity by various steroid hormones. In particular, 5 beta-DHT did not bind to cytoplasmic receptor, while it did to SHBG.

A method for determining cytoplasmic progesterone receptor was standardized in normal human endometrium comparing two different tracers, 3H-progesterone (3H-P) and 3H-medroxyprogesterone acetate (3H-MAP), a synthetic progestin which does not bind to Corticosteroid Binding Globulin (CBG). Receptor assays were performed as previously reported for 17beta-estradiol receptor, with slight modifications: incubation lasted 1 hr at 0 degree C, followed by 5 min DCC exposure under the same conditions. When 3H-P was employed as tracer, blanks performed with cold MAP gave similar results as using cortisol in incubation tubes and progesterone and cortisol in blanks. 3H-MAP was a good tracer for progesterone receptor because it neither bound to CBG nor to androgen or cortisol receptors; it had very high affinity and specificity for P-R; it was not metabolized by cytosol at 0 degree C and, finally, it detected receptor amounts quite comparable to those obtained using 3H-P.

The effect of L-asparaginase (L-asp) therapy on circulating antithrombin-III (AT-III) was monitored in three patients with acute lymphoblastic leukemia. Serial determination for AT-III by both a functional assay and an immunologic assay demonstrated a rapid decrease in serum AT-III levels, followed by a protracted recovery beyond the period of L-asp exposure. One of the three patients developed a reversible venous thrombosis of the arm. The mechanism of the L-asparaginase effect may be related to peripheral degradation of AT-III or to inhibition of production.

By using an indirect immunofluorescence technique, the presence of host cell derived H-2K, H-2D, and Ia alloantigens on donor cells recovered from recipient spleens after a graft-versus-host response (GVHR) was demonstrated. Mapping studies indicated that only host K, D, and I-A region gene products could be identified on the donor cells. Host I-E/C- and I-J-subregion products were not absorbed by donor cells. Treatment of activated donor cells with anti-Ly sera plus C' revealed that donor cells carrying host Ia antigens have a Ly-1+,2-,3- phenotype, whereas donor cells carrying H-2K and H-2D host antigens have a Ly-1-,2+,3+ phenotype. A GVHR that resulted from only an I-region incompatibility was suppressed by the injection of recipient mice with an anti-Ia antiserum directed against self Ia antigens. The degree of suppression was proportional to the amount of anti-Ia antiserum administered.

18 patients suffering from idiopathic hemochromatosis were studied. Plasma testosterone was stimulated by HCG. Basal plasma LH and FSH were significantly lower for the male group compared to healthy men. Lack of reponse of plasma LH and FSH after IV LHRH (100 microgram) was observed in 10 cases; among the patients with a normal response there were a postmenopausal woman, a 47 XXY syndrome, and the two youngest patients. Repeated infusions of LHRH (200 microgram/day x 5 d) did not increase LH in 8 out of 9 cases. Repeated plasma LH determination for 4 hours showed no pulsatile pattern in 6/7 patients. Plasma LH-RH measured in 7 cases was not elevated. The conclusion is that hypogonadism in hemochromatosis, when present, is related to a gonadotropin secretion defect, presumably of pituitary origin.

(1) Brief introduction to iron metabolism and the biochemistry of ferritin. (2) Early studies of circulating ferritin. (3) Methods for measuring serum ferritin concentrations -- immunoradiometric, radioimmuno- and enzyme-linked immuno assays based on liver or spleen ferritin -- an evaluation of these techniques. (4) Serum ferritin concentrations in normal subjects -- definition of normality -- relationship between storage iron and serum ferritin concentrations -- changes during development from birth to old age -- iron deficiency -- variability of serum ferritin concentration -- evaluation of use of ferritin assay for assessment of storage iron levels. (5) Serum ferritin concentrations in disease -- hemochromatosis -- secondary iron overload -- liver damage -- infection and chronic disease -- cancer. (6) Assay of serum ferritin with antibodies to ferritins other than liver or spleen -- ferritinemia and cancer. (7) Properties of serum ferritin -- molecular weight -- iron content -- isoelectric focusing patterns -- carbohydrate content -- immunological properties. (8) Physiology of circulating ferritin -- release of ferritin from tissues -- origin of circulating ferritin -- clearance from the plasma -- iron and protein turnover. (9) Summary -- factors influencing serum ferritin concentrations and clinical use of ferritin estimations.

A Hungarian family with four heterozygotes for Hb Lepore Washington is described. One, a 43-year-old male, had high levels of serum iron, saturated iron-binding capacity, and ferritin, and normal levels of folic acid and vitamin B12. Liver biopsy showed slight cirrhosis and marked iron deposition in parenchymal cells and in cells of the reticuloendothelial system. Heavy iron deposition was also found in the bone marrow. The patient is not an alcoholic and has no disease that requires blood transfusion. The hemochromatosis thus seems to be of idiopathic nature.

The presence of H-2 gene products on mixed leukocyte reaction (MLR) supressor factor was investigated by passage of MLR-suppressor factor (SF) over solid immunoadsorbents prepared with various anti-H-2 subregion sera. Antisera with specificity for all or certain I subregion determinants removed or significantly reduced suppressor activity; adsorption was not consistent with K or D region specificity. The single I subregion specificity common to all adsorbing preparations was I-C. Serologic differentiation of I-C products of k and d haplotypes expressed on MLR-SF was established with antisera prepared in I-Cd/I-Ck disparate strain combinations. These sera define allelic T cell restricted Lad determinants encoded by I-C genes. MLR-SF prepared from (BALB/c X CBA)F1 mice and exposed to the I-Cd and I-Ck specific adsorbents demonstrated d and k haplotype specific adsorption respectively. F1 suppressor activity adsorbed on an anti-I-Cd column was eluted by glycine-HCl buffer and suppressed only BALB/c (H-2d) responses. B10.A suppressor activity was removed by anti-I-Cd sera, but was unaffected by anti-I-Ck sera, indicating that B10.A suppressor activity is encoded by an I-C subregion derived from the d haplotype. Antisera with anti-I-Jk specificity did not remove suppressor activity of various H-2k factors. Finally, adsorption with antisera directed against H-2-associated determinants of the allogeneic cell used to stimulate suppressor factor generation demonstrated that sensitizing alloantigens are not components of MLR suppressor factor. Thus among the major histocompatibility complex (MHC)-controlled suppressor factors, MLR suppressor factor is uniquely determined by the I-C subregion.