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1 The synthesis of several butyrophenone analogues of haloperidol is described. 2 The effects of these compounds on alpha-adrenoceptors were evaluated by examining their ability to reduce alpha 1-stimulated K+ release from rat parotid slices and to displace [3H]-phentolamine from human platelet membrane alpha 2-adrenoceptors. 3 The affinity of haloperidol and its analogues for alpha 1-receptors was found to be 1 to 2 orders of magnitude greater than that for alpha 2-adrenoceptors. These observations suggest that most of the alpha-adrenoceptor activity of butyrophenones results from their interaction with alpha 1-adrenoceptors. 4 The relatively high affinity of the butyrophenones for alpha 1-adrenoceptors suggests that they may be useful as probes in studies of alpha 1-adrenoceptors in these and other tissues.

[delta Ala2, Leu5]-enkephalin has been prepared and shown to be more active than the parent saturated enkephalin in a binding assay using rat brain membranes and [3H]dihydromorphine as a tracer. In a comparison of potencies against [3H]dihydromorphine and [3H]-[D-Ala2, D-Leu5]-enkephalin as tracers, [delta Ala2, Leu5]-enkephalin showed preference for micro opiate receptors, possibly due to the hydrophobicity of the delta Ala2 residue. A synthetic tetrapeptide enkephalin [delta Ala2]-desLeu5-enkephalin had weak activity and high selectivity for the micro receptors. O-Acylation of a serine residue in the peptide was achieved by coupling between the peptide and a carboxylic acid using DCC and a catalytic amount of 4-dimethylaminopyridine.

Assays of estrogen receptors (ER) and progesterone receptors (PgR) were performed by using the dextran-coated charcoal (DCC) method in 124 cases of invasive breast cancer. The results were correlated with clinical and pathological characteristics. There was no correlation between steroid hormone receptor contents and menopausal status, size of tumor, axillary lymph node status, or histological type. The presences of ER and PgR were significantly correlated with histological grade and its mitotic component. 78.3% of well-differentiated (Grade I) tumors were ER positive. Of this number, 61.1% were also PgR positive. In contrast, 69.0% of poorly differentiated (Grade III) tumors were ER and PgR negative. Tumors with a prominent lymphoid infiltration demonstrated a low frequency of positive ER and PgR. There was a significant inverse correlation between the degree of lymphoid infiltration and histological grade. These results suggest that the ER and PgR status of tumors may indicate a malignancy, and prognostic information can thus be obtained independently of other known factors such as size of the tumor and axillary lymph node status.

Non-emigrated Greenlanders have a low incidence of acute myocardial infarction (AMI), when compared with age- and sex adjusted death rates for ischemic heart disease in western countries. We find that Greenlanders have plasma lipid levels corresponding to favourable risk factor levels for AMI. This can be attributed to their diet, rich in n-3 polyunsaturated fat. This diet further supplies eicosapentaenoic acid which influence platelet vessel wall function in an antithrombotic direction. A high level of plasma-antithrombin-III, raising the anticoagulant activity of the blood, in combination with a genetically high activation threshold for the complement system may further contribute to the resistancy against thrombo-embolic disorders. Bleeding tendency, and susceptibility to infection disorders may be the possible draw-backs. Our data are framed into a hypothesis combining the indications of genetic predispositions and the evidence of exogenous protective factors, inflicting a coherent enhancement of nonsusceptibility to vascular ischemic catastrophies.

Daily monitoring of the plasma proteolytic enzyme systems i.e. the coagulation, the fibrinolytic and the kallikrein-kinin system in multitraumatized patients with chromogenic substrate assays disclosed significant differences in the levels of Prekallikrein, Hageman Factor, Antithrombin-III, Prothrombin in survivors (N = 9) and fatal cases (N = 6) during the first week after admission. Since chromogenic peptide substrate assays are simple, cheap and easily automated, close monitoring of critical care patients may be rewarding.

Different forms of cellular cytotoxicity that may constitute potential effector mechanisms in the spontaneous autoimmune thyroiditis (SAT) arising in Obese strain (OS) chickens have been investigated. A microcytotoxicity assay (MCA) employing 51Cr-labelled-, thyroglobulin (Tg) coated-chicken red blood cells (Tg-CRBC) was used to detect cells mediating Tg-specific direct cellular cytotoxicity (DCC). Tg-CRBC presensitized with anti-Tg autoantibody (Tg-AAB) obtained from high titer OS sera served as targets for antibody-dependent cell-mediated cytotoxicity (ADCC). Tannic acid-only treated CRBC (TA-CRBC) were used simultaneously as specificity controls for DCC and also as targets for cells eliciting spontaneous cellular cytotoxicity (SCC) to surface-modified normal cells. The results demonstrated that Tg-specific cytotoxic cells exist in the OS and thus represent an effector mechanism in SAT, in addition to the previously well-documented role of antibody. This DCC appears to be unrelated to the presence and titer of circulating Tg-AAb. It is present in highest levels in the peripheral blood of OS chickens, but in only 55% of the animals tested, indicating either a secondary importance to humoral immunity in the disease process or the possibility of different effector mechanisms prevailing in different birds. There were no overall differences in ADCC between OS and normal chickens when the two strains were considered as a whole. Chronological analysis, however, revealed very low ADCC in the peripheral blood of young OS birds, followed by a later elevation above that in the normal control chickens. Destruction of the gland by ADCC may be initiated via maternally-derived of in situ-produced anti-Tg antibody. No overall significant differences in SCC were observed between OS and normal chickens.

Graft vs. host response (GVHR)-activated donor T cells bind to stimulatory host cell-derived Ia antigens. Radioimmune cell-binding assays demonstrate that activated donor T cells acquire both host I-A and I-E alloantigens on their surface. Approximately threefold to fivefold less I-E products than I-A products are transferred. Immunoprecipitation and one-dimensional and two-dimensional gel electrophoresis analyses show that radioiodinated alpha and beta polypeptide chains of both I-A and I-E-encoded host Ia molecules may be transferred in an apparently structurally unaltered form from host cells to donor cells. Biosynthetic studies indicate that [35S]methionine-labeled activated donor T cells do not synthesize Ia antigens of the donor haplotype. Functional analyses with fluorescence-activated cell sorter sorted donor T cell subpopulations show that donor T cells that bind host I-A antigens preferentially cooperate with nonimmune host B cells. Donor T cells that do not bind detectable amounts of host I-A antigens preferentially help nonimmune donor B cells. By contrast, donor T cells that either bind or do not bind host I-A antigens display no H-2-restricted interaction and help both donor and host immune B cells. These data reveal that the Ia antigen-binding specificity of distinct functional subpopulations of alloactivated donor T cells regulates their I-region-restricted (self or allo) helper activity for nonimmune B cells but not immune B cells. Furthermore, they suggest that T cell-macrophage and T cell-B cell collaboration is mediated by a complementary anti-Ia:Ia receptor:ligand type of interaction in which the receptor of a T cell binds to the ligand of an antigen-presenting macrophage and/or B cell.

An immunofluorescent method has been developed for localizing estrogen receptors (ER) in frozen sections of human breast cancer biopsies which utilizes the biochemically well-characterized antibodies to the cytoplasmic ER of human breast cancer produced in rabbits. Frozen sections of sixteen breast cancer biopsies, in which the receptor content has been quantified using dextran-coated charcoal assay (DCC technique), were used to study the localization of ER. Two aspects of ER detection, namely "estrogen-binding" and ability to react with the homologous antibodies, have been analyzed and the results compared with those of DCC technique. Fluorescent labelled estrogen method (F.E2) of Pertschuk was utilized to detect the distribution of estrogen binding proteins and the indirect immunofluorescent (IM-AR) method using anti-receptor antibodies to assess the antigenic sites of the receptor protein. In addition to the comparison of the results of three techniques, DCC, IM-AR and F.E2, for ER detection, a procedure for processing the frozen sections, which enables the study of estrogen binding characteristic as well as the antigenic reactivity of the receptor molecules, is described.

In five families with idiopathic (hereditary) hemochromatosis, clinical and biochemical expression of the disease occurred in offspring of probands, suggesting an autosomal dominant mode of inheritance. However, HLA typing of subjects indicated that a homozygous-heterozygous mating almost certainly had occurred in four of the five families, resulting in homozygous offspring. Thus, in these families inheritance of the hemochromatosis trait was best explained in terms of an autosomal recessive or intermediate mode of inheritance. This study demonstrates the value of HLA typing in identifying homozygous-heterozygous matings in hemochromatosis families.

Transfusion-induced hemochromatosis is a potential therapeutic complication of the management of sickle cell anemia. Selective transfusion with young erythrocytes (neocytes), which theoretically have a longer life-span than do regular donor red cells, could decrease transfusion frequency and reduce iron deposition in the sickle cell patient. Using blood cell separators, a method has been devised to prepare neocyte units for transfusion. Neocyte enrichment was evaluated by reticulocyte count and mean red cell age was estimated from erythrocyte pyruvate kinase, an age-dependent enzyme. These neocyte units have an average estimated men cell age of 30 days compared to 60 days for unfractionated units. Radiochromium studies in seven splenectomized thalassemia major patients revealed an average half-life of 47.4 days for neocytes stored in the frozen state compared to an average half-life of 29.5 days for standard frozen red cells. Neocyte aliquots collected from three normal, eusplenic donors had an average estimated mean cell age of 6.5 days and an average half-life of 57.2 days when reinfused. Neocyte units cost +300 to collect and process compared to $92 for frozen red cells, but use of neocyte units could reduce by one-half the transfusion requirement in transfusion-dependent patients.

Two patients with familial antithrombin III deficiency developed deep venous thrombosis of the lower limb. The diagnosis of venous thrombosis was made by the indium labelled platelet technique which also allowed for the daily assessment of thrombus size. Each patient received treatment with Warfarin, subcutaneous heparin, and infusions of antithrombin III concentrates. The authors conclude that infusions of antithrombin III concentrates may be of value in limiting the extent of acute thrombosis in patients with a severe deficiency of this protein and may help prevent pulmonary embolism. The haemorrhagic risk of continuing modest doses of heparin with high dose ATIII therapy appears small. In addition to its value in the diagnosis of venous thrombosis the indium platelet technique may give an early indication of thrombus extension and may thus indicate the effectiveness of treatment.

Prostatic binding protein (PBP), polyamine, and DNA synthesis were examined in primary cultures of rat ventral prostate cells. Soon after aggregates of prostate cells were placed in culture, PBP synthesis fell dramatically and DNA synthetic activity in the epithelial cells increased. The amount of polyamines that were labeled with [3H] from [3H] ornithine fell transiently, but rose again at or before the peak of DNA synthesis. Individual 3H-labeled polyamines in cells and medium were dansylated and separated by thin-layer chromatography. The ratio of [3H] Spermidine plus [3H] Spermine to [3H] Putrescine in the culture medium declined as DNA synthesis increased. Ornithine decarboxylase (ODC) activity fell dramatically along with PBP synthesis even as DNA synthesis and 3H-labeled polyamines increased in the prostate-cell cultures. These results support others that suggest that high ODC activity in prostate epithelial cells is a correlate of prostate epithelial cell function rather than proliferation. However, prostate epithelial cells retain the capacity to synthesize significant levels of polyamines from ornithine (especially Putrescine) during proliferation even when ODC activity is low.