Palliative treatment of obstructing esophagogastric malignancy by endoscopic positioning of a plastic prosthesis. Two hundred patients with obstructing esophagogastric malignancy were treated with positioning of a plastic prosthesis. With the aid of a small caliber fiberendoscope and a pusher tube, the prosthesis was positioned under continuous visual control, using only local anesthesia. Seventy-seven patients had esophageal carcinoma, 25 had pulmonary carcinoma obstructing the esophagus, and 98 had gastric carcinoma. Of the latter, 21 had extensive stomach involvement and 8 had local tumor recurrence after esophagojejunostomy. A bronchoesophageal fistula was present in 17 patients. Complications were bleeding (3), perforation (16) with only one death, and obstruction either due to food impaction (13), tumor overgrowth (17), or reflux esophagitis (5); the latter two conditions were corrected by changing the tube in all cases. Tube migration occurred frequently, but could be prevented by adapting the shape of the prosthesis. The procedure was performed as ultimate palliation in patients unfit for surgical insertion and had a low mortality rate of 2%. In general, there was marked improvement in the quality of life.


Cell differentiation in human gastric gland as revealed by nuclear binding of tritiated actinomycin. The nuclear binding of H3 actinomycin, which is closely linked to the differentiation phenomenon, was studied in human normal gastric mucosa. Actinomycin binding decreases in cells which differentiate and becomes very low in fully differentiated cells. In the gastric pits, there is a decreasing gradient of labelling from the deeper stem cells to the well-differentiated superficial cells. This indicates that migration and renewal of the surface epithelium occurs following a 'pipe-line' system. All the undifferentiated stem cells are labelled. Where the parietal cells are concerned all degrees of labelling are observed at various levels with a decreasing proportion of labelling from the surface to the bottom of the gland. With mucous cells and chief cells in the upper part of the gland a great number of poorly labelled mucous neck cells is observed. In the middle and lower part of the gland there is a new growth of heavily labelled cells. This means that in the normal human stomach chief cells probably do not originate from mucous cells.


The histomorphology of the elastic tissue system in the skin of the human hand. This study compares the effectiveness of the Verhoeff and Puchtler-Sweat resorcin fuschin methods of staining the elastic tissue of palmar and dorsal skin specimens of the human hand. The resorcin stain demonstrates the "oxytalan" fibres of the elastic tissue system in the dermal papillary layer of the palmar skin. Oxytalan fibres are not generally demonstrated by the Verhoeff method and are not demonstrated in the dorsal skin specimens. These studies substantiate the existence of a system of elastic tissue fibres in the skin of the hand. The inter-relationship of the elastic and collagenous fibres appears to complement each of their functions; namely, in anchoring the dermo-epidermal junction, absorbing the stresses of stretch and compressive forces and return the tissues to their original state of tension, and providing protection to the dermal appendages in addition to lending a gradient mobility transmitted through the dermis to the subcutaneous layer to give suppleness and mobility to the skin.


Hemocyanins in spiders, VII. Immunological comparison of the subunits of Eurypelma californicum hemocyanin. The isolated subunites of Eurypelma californicum hemocyanin were studied by aid of antibodies raised against whole, dissociated hemocyanin. The proportion of impurities was found to be low in almost all subunits. There was no cross reaction between the individual chains, and the total number of antigenically different subunits was found to be seven, confirming results obtained by different methods. If an artificial mixture prepared from purified subunits is compared to whole, dissociated hemocyanin, an overall very similar pattern is obtained but differences appear which are due to specific interaction.--The dimeric subunit 4D was shown to be a heterodimer (asymmetric dimer) composed of chains b and c4.


Preparative electrophoresis of human lymphocytes. II. Use of non-immunoglobulin bearing lymphocytes obtained by electrophoretic levitation for the elicitation of a rabbit anti-human "T-cell" serum. By intradermal injection (in Freund's complete adjuvant) of rabbits with only a few million human T-lymphocytes, obtained by preparative electrophoresis, an anti-human "T-cell" serum can be obtained. Although the antiserum is best used in a fairly concentrated form, its anti-human "T-cell" specificity (by immunofluorescence and E-rosetting) appears excellent, without the need to resort to absorption with various unwanted antigens. There may however, also be other specificities in the antiserum, as it also reacts with human granulocytes.


[Animal experimental studies on the volume expanding effect of hydroxyethyl starch 40000 in the dog acute hemorrhagic shock]. After acute hemorrhagic shock in dogs the hemodynamics of hydroxyethyl starch (MW: 40,000) are studied. The experiment shows that this plasma expander has a good efficiency for 3 to 4 hours. The indications of application of this colloidal solution are discussed.


Characterization of the antigenic determinants of cholera toxin subunits. The antigenic specificity of purified preparations of A subunit, B subunit, alpha chain, and gamma chain of cholera toxin was studied by double immunodiffusion and radioimmunoassay with antisera produced in rabbits and mice. Rabbits immunized with A subunit produced serum antibodies which were capable of binding radiolabeled A subunit, alpha chain, and B subunit. Rabbits immunized with alpha chain produced serum antibodies that would bind radiolabeled alpha chain and A subunit. Rabbits immunized with the B subunit produced serum antibodies monospecific for the B subunit. The gamma chain did not elicit measurable antibodies in rabbits or mice as evidenced by radioimmunoassay or double immunodiffusion. A sensitive competitive radioimmunoassay was developed in which the B subunit could inhibit binding of radiolabeled A subunit and alpha chain with either antisera prepared against A subunit or alpha chain. Neither the A subunit nor the alpha chain could inhibit binding of B subunit with the antiserum prepared against B subunit. In addition, selected elution fractions obtained during A- and B-subunit purification were used to immunize groups of mice. Mice responded to immunization with the elution fractions of A subunit by producing anti-A-subunit and anti-B-subunit serum antibody responses, whereas mice immunized with elution fractions of B subunit produced only antibodies specific for the B subunit. An equimolar amount of the two resulting protein peaks was used to immunize two groups of rabbits. Rabbits immunized with A subunit, produced a serum anti-B subunit response equal to that of rabbits immunized with the B subunit. Rabbits immunized with equimolar concentrations of A and B subunits were observed to be equally protected against intestinal loop challenge with Vibrio cholerae Inaba V86. The A subunit, not the B subunit, was biologically active when tested by the S49 mouse lymphosarcoma cell test. These studies provide additional evidence supporting the hypothesis that the A subunit, specifically of alpha chain, of cholera toxin contains antigenic determinants in common with the B subunit.


The indirect rat mast cell degranulation test reconsidered. The indirect rat mast cell degranulation test for the detection of human reaginic antibodies was reinvestigated. When the mast cells were incubated with human reaginic serum at concentrations exceeding approximately 3%, a massive, non-specific histamine release occurred, irrespective of the presence or absence of allergen. At tolerated serum concentrations (below 3%), the allergen concentration did not influence the release process. We conclude that the indirect rat mast cell test is not applicable as an alternative test system for the study of immediate hypersensitivity in humans.


Complement profiles in monkeys subjected to aggregate (immune complex) anaphylaxis, and following injection of soluble and particulate polysaccharides. Complement profiles were established in four groups of Macaca irus monkeys: (I) Aggregate (immune complex) anaphylaxis was induced following immunization, with ovalbumin. Upon challenge, systemic arterial pressure decreased from 115 to 50 mm Hg (mean values) in 10 min. The complement profiles revealed decreases in: C1q to less than 10% of initial value within 5 min; C4 proportional to hypotension; C3 slowly to 60% at 24 h; C5, C6, C7, C8 and factor B to about 80% of initial value in 5--30 min. Conversion products of C3 and factor B were detected on the day of anaphylaxis. In conclusion, mainly the classical and to a lesser extent the alternative pathway, were activated. Following injection of (II) native B 512 dextran, (III) biodegradable starch microspheres, and (IV) saline, no significant changes of complement profiles were seen. Conversion products of C3 and factor B were, however, demonstrable in groups II and III without appearance of clinical signs.


Analysis of the expression of H-2 and H-2-linked antigens on mammary tumor cells. The products of the recently discovered H-2L locus were expressed on BALB/c mammary tumor cells and behaved as histocompatibility antigens, in contrast to the products of H-2 linked loci (Qa-loci) that did not influence the acceptance or rejection of tumor transplants.


Establishment, characterization and virus expression of cell lines derived from radiation- and virus-induced lymphomas of C57BL/Ka mice. Permanent cell lines have been established in vitro from lymphoid tumors induced in C57BH/Ka mice by fractionated X-irradiation or by inoculation of the radiation leukemia virus (RadOV). The cultured cells are lymphoblastic, replicate rapidly in vitro, and are tumorigenic in vivo. The cell surface markers Thy 1, Ly 1, Ly 2,3 and GIX are expressed by the lymphoid tumor cells in the mouse and persist in the corresponding cell lines; expression of the H-2 and TL antigens is greatly reduced during in vitro passage, but is restored on in vivo transplantation. The cell lines derived from RadLV-induced tumors (BL/VL lines) produce a virus population (RadLV/LTC) with the thymotropic and leukemogenic attributes of RadLV. Those derived from radiation-induced, virus-negative lymphomas (BL/RL lines) are initially devoid of MuLV expression, but frequently become spontaneous virus producers during in vitro cultivation.


Characterization of a type-C virus produced by co-cultures of human leukemic bone-marrow and fetal canine thymus cells. The putative human helper virus SKA-21/A204V, isolated by Nooter et al. in 1977 from human leukemic bone-marrow cells following co-culture with normal fetal canine thymus cells, Cf2th, has been characterized with respect to its major viral core protein, reverse transcriptase, and nucleic acid sequences. The results of these analyses show that this virus is not distinguishable from the woolly monkey type-C virus, SSAV-1, by the techniques employed.


The differentiation of clonal rat yolk sac tumor cell lines cultivated with dibutyryl-cyclic 3', 5'-adenosine monophosphate. Five rat yolk sac tumor cell lines were cloned from a yolk sac tumor line which originally arose following fetectomy. The doubling time of each of the cloned tumor lines was about 50 h. All of the cloned tumor cell lines synthesized and secreted AFP and albumin but there was a gradual decrease in the synthesis of these proteins during serial passage. The cells formed clusters which looked like vitelline ducts or the parietal yolk sac and they also had basement membranes which closely resembled Reichert's membrane. When the cloned cell lines were cultivated in the presence of 1 mM dibutyryl cyclic-AMP, myotube-like and neuron-like cells appeared. Acetylcholine esterase and creatine phosphokinase activity were present when myotube-like cells were present whereas acetylcholine esterase activity predominated when neuron-like cells were present.


Demonstration of chicken fetal antigen (CFA) on normal splenic lymphocytes, Marek's disease lymphoblastoid cell lines and other neoplasms. Chicken fetal antigen (CFA) was detected on normal splenic lymphocytes and a direct relationship was observed between the percentage of CFA-positive cells and the age of the donor. The fetal antigen was also detected on lymphoblastoid tumor cells and cell lines induced by known avian oncogenic viruses (Marek's disease virus and avian leukosis virus), and on spontaneously occurring adenocarcinoma cells. The fetal antigen appears to be distinct from Marek's disease tumor-associated surface antigen.


Identification of a Mycobacterium leprae specific protein antigen(s) and its possible application for the serodiagnosis of leprosy. Acetone-killed Mycobacterium leprae separated from infected armadillo liver tissue without the use of proteases were treated with 0.2 M lithium acetate, 20 mM EDTA, pH 8.8 solution, and the concentrated antigen extract was analyzed by Ouchterlony immunodiffusion. The antigen extract gave a single immunoprecipitate when reacted with pooled lepromatous leprosy (LL) patients sera made highly specific for M. leprae by adsorption. Apparently identical precipitates were produced by reacting the antigen extract with sera of each of 15 treated LL patients, 5 of 7 patients with tuberculoid leprosy, and 3 of 4 M. leprae infected armadillos. Serum from 1 of 16 persons immunized with BCG and from none of 15 patients with chlamydial urethritis or brucellosis reacted with the antigen. Identically prepared extracts of M. smegmatis, M. phlei, M. vaccae, M. duvali and M. diernhoferi gave no immunoprecipitates with sera from LL patients or infected armadillos. Preliminary characterization indicates the antigen is protein since antigenicity was destroyed by pronase and/or heat treatment. The relative specificity of the protein antigen for M. leprae and the presence of antibody to this antigen in patients with leprosy suggest a possible role for this antigen in the serodiagnosis of leprosy.


Pyridine extractability of acid-fastness from Mycobacterium leprae. Various mycobacteria were tested for their ability to retain acid-fastness after treatment with pyridine: a) Mycobacterium leprae separated from organs of 20 experimentally infected armadillos (which were sacrificed); b) M. leprae separated from a biopsy of a lepromatous patient; c) direct smears of lepromatous tissues from armadillos; d) eighteen cultivable mycobacteria obtained from the American Type Culture Collection (ATCC); E) cultivatable mycobacteria separated from the lymph nodes of a wild-caught armadillo and also the same organism grown in culture and Skinsnes' alleged M. leprae culture. A loss of acid-fastness was observed microscopically from M. leprae separated from experimentally infected armadillo tissues, M. leprae separated from a lepromatous patient biopsy, and M. leprae found in direct smears prepared from infected armadillo tissues. The eighteen cultivatable mycobacteria from ATCC, cultivatable mycobacteria separated from the tissue of a wild-caught armadillo (and also grown in culture) and Skinsnes' alleged M. leprae culture retained their acid-fastness. Testing of pyridine extractability of acid-fastness combined with those of D-DOPA oxidase testing proved to be extremely reliable in our laboratory in differentiating M. leprae from other mycobacteria.


Tobacco leaf mesophyll peroxidase. Isolation, purification and some properties. Two isoperoxidases, P1 and P2, were isolated from tobacco mesophyll leaves by the combined methods of ammonium sulphate precipitation, PAGE and DEAE-cellulose column chromatography. The pH otpima for P1 and P2 were 7.0 and 7.5 respectively. The values of Km for H2O2 were 1.82 and 0.87 mM for P1 and P2. Results from this investigationsuggest that these isoperoxidases differ in their electrophoretic, catalytic and physical properties.


On the mechanism of Verhoeff's elastica stain: a convenient stain for myelin sheaths. Verhoeff (1908) recommended an iron-hematein formula containing Lugol's solution for demonstration of elastic tissue; sections are differentiated until desired staining patterns are obtained. Verhoeff's stain colored a variety of tissue structures and showed higher substantivity for myelin sheaths than for elastin. Addition of HCL or omission of Lugol's solution decreased or abolished coloration of pseudo-elastica and thus enhanced selectivity for elastin. Substitution of Fe++ for Fe+++ abolished dye binding by elastin. A review of chemical data indicated interaction of components of Lugol's solution with the dye. Hematein and Fe+++ form a variety of cationic, anionic and non-ionic chelates; the ratio of these compounds changes with time. Dye binding apparently occurs mainly via van der Waals forces and hydrogen bonds. Verhoeff's elastica stain is definitely not specific for elastin and is inferior to orcein and resorcin-fuchsin because of the required differentiation with its inherent bias to produce patterns which conform to expectations. However, Verhoeff's elastica stain is far superior to other metal-hematein technics for myelin sheaths. The combined Verhoeff-picro-Sirius Red F3BA stain can be performed in 30 min and does not require differentiation. It is therefore suggested to reclassify Verhoeff's elastica stain as a method for myelin sheaths.


A structure in the wall of the internal carotid artery in the rat. A structure has been found consistently in the wall of the internal carotid artery of the rat as it passes through the carotid canal. It consists of modified smooth muscle cells arranged longitudinally which exhibit abundant pinocytosis and are located close to endothelial cells, with which they make contact. These cells do not appear to be innervated. The closeness of this structure to the arterial lumen, into which it may actually protrude, suggests that it may be sensitive to vaso-active substances in arterial blood. If so, it is well place to affect cerebral blood flow.


Purification and characterization of multiple species (isolectins) of a slime mold lectin implicated in intercellular adhesion. An improved purification procedure for the carbohydrate-binding proteins (lectins) of cohesive Polysphondylium pallidum cells has been devised. The procedure uses extraction of cells with lactose-containing buffer followed by ammonium sulfate precipitation and affinity chromatography of the redissolved precipitate on a column of acid-treated Sepharose 6B. All hemagglutination activity is adsorbed to the column and recoveries are about 70% of the activity of the starting cell lysate. Sodium dodecyl sulfate-gel electrophoresis of the protein obtained with this procedure resolved three subunits with molecular weights of 26,500 (A), 26,000 (B), and 25,000 (C). Three species are resolved by isoelectric focusing with apparent pI values of 6.4 (I), 7.3 (II), and 7.5 (III) which contain Subunits A, B, and C in the following ratios: I, B:C at 2:1; II, A:B at 2:1, and III, A:B at 1:2. All three isoforms agglutinate rabbit and human type O erythrocytes and are thus isolectins. Isoforms II and III are separated from Isoform I by galactose-gradient elution of the Sepharose 6B column. Isoforms II and III aggregate extensively (nonamers and multiples thereof), but reduction with 2-mercaptoethanol reverses this process yielding a single species of Mr = 73,000 (trimer). Isoform I exists as trimers and hexamers and reduction has no effect on this distribution. Amino acid compositions and tryptic peptide maps of S-[14C]carboxymethyl-isolectins indicate that Subunits A and B are very similar and may represent the same peptide chain, while Subunit C is a peptide quite distinct from A and B.


Purification of a new high activity form of glucose-6-phosphate dehydrogenase from rat liver and the effect of enzyme inactivation on its immunochemical reactivity. A new form of cytoplasmic glucose-6-phosphate dehydrogenase (E.C.1.1.1.49) was purified from rat liver by protamine sulfate precipitation, ammonium sulfate fractionation, ion exchange chromatography with diethylaminoethyl cellulose, and affinity chromatography with Cibacron blue agarose and NADP agarose. This form of the enzyme has a specific activity of over 600 units/mg of protein and gives essentially a single band by polyacrylamide gel electrophoresis. The form of the enzyme isolated by this purification method is 3 times more active than the form purified from liver by previously reported procedures. The relative mass of this pure glucose-6-phosphate dehydrogenase enzyme was determined by disc gel electrophoresis to be 269,000. This high activity glucose-6-phosphate dehydrogenase enzyme, after inactivation by reaction with palmityl-CoA, was no longer precipitated by specific rabbit and goat antisera to this purified enzyme. Thus, the possibility still exists that starved fat-refed animals contain glucose-6-phosphate dehydrogenase (G6PD) enzyme protein in an inactivated form no longer detectable by either enzyme activity or immunoprecipitation.


Simplification and spin-spin analysis of the side chain proton magnetic resonance spectrum of the decapeptide gramicidin S using difference scalar decoupling and biosynthesis of specifically deuterated analogs. Biosynthesis of specifically deuterated molecules and difference scalar decoupling permitted an analysis of all C alpha-C beta spin systems of gramicidin S. Proof is presented that proton magnetic resonance spectra obtained by difference scalar decoupling yield not only spectral assignments and simplification but also accurate chemicals shifts and scalar coupling constants. The variations in (3J alpha beta) and in proton chemical shifts at temperatures over the range of -54 degrees -+66 degrees C are consistent with the internal rotation around the C alpha-C beta bonds of Val1, Orn2, Leu3, and Phe4 residues discovered using carbon 13 spectroscopy. The value (3J alpha beta) = 1.5 Hz for the proline residue is consistent with there being only one C alpha-C beta conformer. This is supported by the small temperature dependence of (3J alpha beta). However, it cannot be rigorously excluded that oscillation between a major and a minor C alpha-C beta conformation occurs for proline.


Multiple solution conformations and internal rotations of the decapeptide gramicidin S. The conformations of every C alpha H-C beta H2 moiety of the peptide gramicidin S are reported. Internal rotation occurs, but distinct preferences for one side chain rotamer, greater than 80%, are found for the D-phenylalanine and ornithine residues. Leucine and valine exhibit more extensive averaging while proline is shown to be at least 90% in the Ramachandran B conformation. The data are consistent with the coexistence of many tertiary conformations of gramicidin S; the statistical weights of the twelve major tertiary conformations consistent with the rotamer populations are reported. The relative statistical weights of the tertiary conformers depend upon temperature and solvent. A comparison of the conclusions from this publication and conformations derived by energy minimization procedures is made. Partial agreement was found, but the calculations have not yet predicted the wealth of coexisting tertiary conformations nor accounted for the subtle effects of solvent. It is proposed that a more complete picture of the conformational dynamics of gramicidin S and other peptides will result from calculations which use as a basis the extensive data reported here.


The inhibition by xanthine phosphodiesterase inhibitors of the induction of alkaline phosphatase activity in HeLa cells: relationship of enzyme activity to cyclic AMP concentrations. The three xanthine derivatives, caffeine, theophylline and 3-isobutyl-1-methyl-xanthine (IBMX) produced dose-dependent increases in cyclic AMP concentrations in HeLa cells after long term treatment. Only IBMX produced increases over the first 60 minutes, with a peak of approximately 5-fold control values five to 10 minutes after the addition of the drug. About four hours after the addition of either 0.67 or 1.0 mM IBMX there was a second peak in the concentration of cyclic AMP which was at least as large and usually larger than the peak observed at five to ten minutes. Neither caffeine nor theophylline increased cyclic AMP concentrations above control values until one hour after addition of the compounds, and there was no indication of a peak in the concentration at four hours. Between 24 and 72 hours, all three compounds produced elevations in cyclic AMP levels that were steadily maintained. At any given concentration, the order of potency was IBMX greater than theophylline greater than caffeine. If the xanthine derivatives were removed from the medium after 24 hours of treatment, the cyclic AMP concentrations fell to control levels within one hour. Treatment with 5-iodo-2'-deoxyuridine (IdUrd) or hydrocortisone alone did not change the levels of cyclic AMP, nor did the presence of these inducers of alkaline phosphatase activity alter the effects of the xanthine derivations on cyclic AMP concentrations. The data showed a significant correlation between the magnitude of the increase in cycli AMP concentrations over the period from 24 to 72 hours and the degree of inhibition by the xanthine derivatives of the induction of alkaline phosphatase activity.


Radioimmunoassay system using a serovar-specific lipopolysaccharide antigen of Leptospira. The serovar-specific main (TM) antigen of Leptospira interrogans serovar kremastos strain Kyoto was labeled with sodium boro[3H]hydride after 1 h of oxidation with periodate. When 50 ng of the labeled compound was employed, 50% of the compound was bound to the antibodies contained in 7.5 x 10(-2) nl of anti-kremastos Kyoto serum. Under this condition, only 9 ng of the homologous TM antigen was required for 50% inhibition of serovar kremastos Kyoto 3H-TM antigen-anti-kremastos Kyoto serum binding, whereas 5,000 times as much TM antigen of serovar hebdomadis, which belongs to the same Hebdomadis serogroup as serovar kremastos, was required for the same inhibition. The TM antigens from serovars pomona, icterohaemorrhagiae, and copenhageni, which belong to different serogroups, showed no inhibition in an amount of up to 3 x 10(3), 2 x 10(5), and 2 x 10(5) ng, respectively. In the inhibition study using the serovar hebdomadis TM antigen, inhibition values slightly fluctuated due to the antigen's insolubility. When the TM antigens were solubilized with 0.1% sodium taurodeoxycholate, the fluctuation in inhibition values was minimized, and the cross-reactivity of the serovar hebdomadis TM antigen with anti-kremastos Kyoto serum was diminished, while the inhibitory activity of the serovar kremastos Kyoto TM antigen was enhanced.


New method for estimating digestion of Paracoccidioides brasiliensis by phagocytic cells in vitro. We describe a method by which phagocytosis and digestion of Paracoccidioides brasiliensis yeast cells by polymorphonuclear leukocytes or other phagocytic cells may be estimated. Suspensions of P. brasiliensis in its yeastlike phase were sonicated, counted, and incubated with known numbers of peripheral blood polymorphonuclear leukocytes. At given intervals, cytocentrifuge droplets were stained by a variation of Papanicolaou's method. Stained preparations were examined with phase-contrast optics. Digested organisms showed total or partial disappearance of protoplasm. Green-stained cell walls resisted digestion. The proportion of digested cells as a function of time was estimated.


Regional topography within noradrenergic locus coeruleus as revealed by retrograde transport of horseradish peroxidase. A hitherto unsuspected degree of regional topographic organization in the noradrenergic nucleus, locus coeruleus, was revealed by the use of retrograde transport of horseradish peroxidase (HRP) from terminal areas receiving noradrenergic innervation. HRP was injected into hippocampus, hypothalamus, thalamus, caudate-putamen, septum, amygdala-piriform cortex, cerebellum and cortex. Successful transport was obtained from all areas, including the caudate-putamen and cerebral cortex. The pattern of HRP positive cells in the ipsilateral locus coeruleus was markedly different depending on the location of the HRP injection. Thus, hippocampal injections labeled cells in the dorsal locus coeruleus but not at all in the ventral tip. Injections of HRP into caudate-putamen or cerebellum labeled the ventral tip along with the rest of the dorsal portion. HRP injections into the septum labeled cells only in the dorsal half of the dorsal locus coeruleus. There thus exists a three tier division of locus coeruleus into the ventral one third, dorsal one third and intermediate one third. A further division was seen in the anterior-posterior plane with HRP injections into the thalamus labeling the posterior pole of locus very intensely but with little transport to more anterior levels; conversely HRP injection into the hypothalamus resulted in intense labeling only in the anterior pole of locus coeruleus. Amygdala-piriform cortex HRP injections revealed a further pattern with very intensely reactive cells scattered sparsely throughout the nucleus. Cortical HRP injections yielded weaker labeling also in occasional, scattered cells. All HRP transport to locus coeruleus was shown to be noradrenergic by degeneration with 6-hydroxydopamine and due to terminal, rather than fiber of passage, uptake by control injection into the dorsal NA bundle. It is concluded that the locus coeruleus is not an homogenous nucleus with respect to the origin of the noradrenergic projections to sundry forebrain, spinal and cerebellar areas but is comprised of distinct subdivisions of noradrenergic neurons.


Nutritional deficiencies and nutritional support therapy in geriatric cancer patients. Nutritional deficits and their correction were studied in 45 cancer patients (age range, 60--86 years) who were undergoing various modalities of cancer therapy. Their nutritional status was maintained with a variety of commercially available special diets, and serum albumin concentrations were sequentially determined in order to gauge the efficacy of the nutritional support. Serum albumin levels were preserved when nutritional support was employed in surgical therapy. However, patients undergoing palliative chemotherapy or radiotherapy responded only to adequate levels of the standard hospital diet with or without supplements of special enteral diets. In the survivors, albumin levels were maintained; in the nonsurvivors, albumin levels decreased. This group of older patients tolerated nutritional support therapy, especially when it was carefully monitored. Satisfactory nutritional therapy can be achieved by use of appropriate enteral formulas. The method lends itself to adequate management in the outpatient or nursing-home situation during certain phases of cancer.


Human T cell differentiation antigens and correlation of their expression with various markers of T cell maturation. Two sets of differentiation antigens are demonstrated on human T cells by using 11 heterologous anti-human antisera raised against various normal and malignant T cells. The two antigenic determinants from the first set of differentiation antigens are expressed only on thymus cells and on T lymphoblasts, whereas the two antigenic determinants from the second set are expressed on blood T cells, Sezary cells, T.CLL cells, and thymus cells. Four T cell phenotypes are thus defined; two phenotypes are expressed only by T lymphoblasts, whereas the other two phenotypes are expressed both by normal and malignant T cells. Moreover, a clear-cut relationship exists between the four T cell antigenic phenotypes and two other markers of T cell differentiation: terminal deoxynucleotidyl transferase and peanut agglutinin. Two phenotypes are linked with the presence of TdT, one phenotype is linked with the affinity for PNA, and the fourth phenotype is correlated with the absence of both markers.


Avian antigen-binding cells. I. Characterization of antigen-binding T cells from bursectiomized chickens by autoradiography. Antigen-binding cells (ABC) from spleens of HGG-immunized, bursectomized agammaglobulinemic (Bx) chickens were detected by direct autoradiography with 125I-HGG and by sandwich autoradiography with HGG plus 125I-goat-anti-HGG. The specificity of antigen binding was demonstrated by 1) inhibition of binding of 125I-HGG by preincubation with unlabeled HGG and 2) a specific increase in ABC after immunization. The ABC from Bx chickens were not B cells, as shown by the virtual absence of immunoglobulin-bearing cells in this population and by the lack of inhibition of antigen binding by anti-immunoglobulin sera. The ABC were not macrophages and did not bind HGG via Fc receptors because their frequency was unchanged after passage over nylon wool or incubation with antigen-antibody complexes. The temperature dependence and azide stabilization of the ABC were characteristic of antigen-binding T cells. Therefore, T cells capable of binding soluble antigen were demonstrated in Bx chicken spleen, which is free of contamination by B cells and passively adsorbed antibody.


Avian antigen-binding cells. II. Enrichment of antigen-binding B and T cells. Antigen-binding B and T cells from chicken spleens were selected on plates of antigen-derived gelatin. Hapten-specific B cells from DNP-immune normal chicken spleens were selected on DNP-gelatin. As much as 165-fold functional enrichment of precursors of anti-DNP antibody-producing cells, as measured in an adoptive transfer system, was achieved. However, the enrichment of DNP-binding cells assessed by rosette formation and autoradiography was no more than 25-fold. HGG-specific T cells from bursectomized agammaglobulinemic chickens immunized with deaggregated HGG were selected on HGG-gelatin. In the fraction adherent to HGG-gelatin, at least a 20-fold enrichment of suppressors of the antibody response to TNP-HGG, as measured by adoptive transfer, was accomplished. In contrast, no more than 6-fold enrichment of HGG-binding cells was detected by autoradiography. Antigen-specific depletion and enrichment of suppressor T cells and of HGG-binding cells occurred in parallel, suggesting that suppressor cells can bind soluble antigen and can be isolated on antigen coupled to a solid support.


Functional differentiation of T cell precursors. I. Parameters of carrier-specific tolerance in murine helper T cell precursors. Irradiated mice reconstituted with bone marrow from sheep gamma-globulin- (SGG) tolerant syngeneic donors display reduced IgG responsiveness to challenge with trinitrophenylated (TNP)-SGG compared with recipients of normal marrow. This effect is SGG-specific and is due neither to suppressor T cells nor to antigen carryover. "Helper T cell precursor tolerance" can be induced with as little as 40 micrograms tolerogen (SGG). Unlike mature helper T cells, these precursors show both a rapid induction and rapid waning patterns, suggesting a high rate of turnover. Our results imply that marrow helper T cell precursors bear antigen-specific receptors and that the T cell repertoire must be at least partially generated before residence in the thymus.


Effect of cyclophosphamide on suppressor cell activity in mice unresponsive to EAE. Protection against experimental allergic encephalomyelitis (EAE) was induced in susceptible mice of (SJL/J X BALB/c)F1 hybrid, by injection of either mouse spinal cord homogenate, the small mouse basic protein, or Cop 1 in incomplete Freund's adjuvant, before EAE induction. It was demonstrated that the unresponsiveness induced by the three antigens is mediated by suppressor T cells residing in the spleen cell population and can be adoptively transferred to normal syngeneic recipients. Low dose of cyclophosphamide (20 mg/kg) administered 2 days before the encephalitogenic challenge abrogated the unresponsiveness to EAE and reverted the protected mice sensitive to disease induction. Cyclophosphamide was also active on adoptively transferred unresponsiveness, thus donors that had been treated with cyclophosphamide were unable to further transfer unresponsiveness to EAE. These results indicate the elimination by cyclophosphamide of suppressor cells that interfere with the effector mechanisms leading to EAE.


B lymphocyte determinants in immunoglobulin A nephropathy. Because of our prior demonstration of a strong association betwen a specific B lymphocyte determinant and the occurrence of chronic membranoproliferative glomerulonephritis and the demonstration by others of the frequent concurrence of an IgA deposit disease, anaphylactoid purpura nephritis,with HLA-BW35, we conducted an investigation of the association among Minnesota Caucasians of the HLA markers BW35, DW1 and B lymphocyte determinants identified by three alloantisera with IgA nephropathy and the syndrome of recurrent macroscopic hematuria. The highly significant association between HLA-BW35, DW1, and B cell antigens identified by alloantisera L, B, and F, present in 50 normal Minnesota Caucasians, was not observed in 18 Minnesota patients with IgA nephropathy. The frequency of HLA-DW1 was the same among controls and patients, whereas the relative risk of developing IgA nephropathy was demonstrated to be increased 4- to 5-fold in the presence of the B cell antigens identified by alloantisera L and B. These sera appear to identify determinants on B lymphocytes associated with the disease state and possibly not intimately related to the HLA-D region. These findings emphasize the possible informativeness of defining B cell alloantisera on disease panels.


Selective effects of anti-Ia serum and complement treatment upon polyclonal B lymphocyte responses to dextran sulfate and lipopolysaccharide. Subpopulations of B lymphocytes have been shown to vary in their expression of Ia alloantigens and polyclonal responsiveness to thymic independent antigens. We have demonstrated that the polyclonal B cell antibody response to dextran sulfate is less sensitive to removal of Ia-positive cells than is the response to LPS. This is a consistent finding whether alloantibody and complement (C) pretreatment is directed toward cells bearing Ia antigens coded for by the entire I region or by the I-A or I-E subregions. Heterogeneity appears to exist within the dextran sulfate-sensitive population in that using high antibody; cell ratios during antibody and C-mediated cell selection results in an inhibition of the proliferative but not the antibody response. This result may indicate a differential expression of Ia antigens on dextran sulfate-sensitive B cells that respond by proliferation versus those cells that produce antibody. Alternatively, proliferative responses to dextran sulfate may be more dependent upon Ia-positive accessory cells than is the polyclonal antibody response.


Inhibition of specific immune responses by feeding protein antigens. IV. Evidence for tolerance and specific active suppression of cell-mediated immune responses to ovalbumin. We studied the effect of a single intragastric administration of ovalbumin (OVA) on the subsequent development of OVA-specific cell-mediated immune (CMI) responses in BDF1 mice. In animals fed OVA 7 days before subcutaneous sensitization with OVA-CFA, we observed a concomitant dose-dependent decrease in both the humoral and CMI responses specific for OVA. The CMI tolerance was found to be antigen-specific when assayed in vivo by ear swelling or in vitro by an antigen-induced T cell proliferation assay because OVA-fed mice responded normally to sensitization with horse gamma-globulin. It was also shown that either spleen or lymph node cells, but not serum, from OVA-fed donors transferred suppression to normal recipients. The transfer was mediated by antigen-specific suppressor T cells (Ts) that appeared to inhibit the induction phase (afferent limb) of the CMI response, since the Ts were only effective when transferred before or shortly after the onset of sensitization.


Mechanisms of C-type viral leukemogenesis. I. Correlation of in vitro lymphocyte blastogenesis to viremia and leukemia. Various inbred strains of mice respond immunologically to genetically transmitted ecotropic C-type viruses. Part of this response is T cell blastogenesis with type specificity for the viral envelope glycoprotein gp71. Of those nonviremic, nonleukemic strains, and F1 crosses examined, in which virus expression occurs early in life, gp71-specific blastogenic T cells were detected within the first 2 months of age and temporally preceded the development of a humoral immune response. However, in the viremic, highly leukemic strain of AKR mice, gp71-specific T cell blastogenesis in vitro was readily detectable throughout the preleukemic phase, the first 5 months of age. In appropriate F1 crosses and backcrosses, the persistent in vitro blastogenic response segregated with viremia and leukemia. These data suggest that in vivo T cell stimulation by endogenous viral gp71, caused by viremia, may contribute to virus-induced leukemogenesis in mice.


FC receptor for IgM: factors influencing detection on human T lymphocytes. This paper is concerned with technical standardization in detecting Fc-IgM receptors on human T lymphocytes. We have investigated a number of factors of critical importance in obtaining easily reproducible and reliable estimates of the numbers of TM cells among human peripheral T lymphocytes. A point of major importance is optimal coating of erythrocytes by IgM molecules. For this condition to be met, particular attention is required when erythrocytes from animals other than the one used for obtaining antiserum are used to prepare EA-IgM. Determination of the agglutinating titer of IgM preparation is useful in determing optimal sensitizing dilutions. Full expression of Fc receptors is favoured when human cord serum is added to the medium. The influence of incubation period of EA-lymphocytes mixtures on TM counts has also been investigated.


A radioimmune assay for human cupro-zinc superoxide dismutase and its application to erythrocytes. A competition radioimmunoassay for human superoxide dismutase (SOD-1) is described. Radioiodinated SOD-1 is incubated with unlabeled competitor and limiting antibody, then immune complexes are isolated using Staphylococcus aureus. The assay is sensitive (detecting 5 ng enzyme) and reproducible. Average values for SOD-1 in lysates of erythrocytes from normal individuals is 854 +/- 100 ng/mg hemoglobin and that of patients with trisomy-21 is 1313 +/- 110 ng/mg hemoglobin.


The genetics of an expanded secretor system. The genetics of salivary secretion of ABH blood group substance was investigated. Eight secretor phenotypes were determined by Sephadex G-100 chromatography. Presence or absence of three different fractions were shown to be controlled by three different secretor gene loci. These loci are called Sec1, Sec2 and Sec3. Sec1 controls expression of the traditional secretor status. Sec2 and Sec3 are linked, but distinct, loci controlling the expression of low molecular weight ABH substance in human saliva. A dominant mode of inheritance for the Sec2 and Sec3 systems is described.


Absence of four H-2d antigenic specificites in an H-2d sarcoma. MCG4 is a BALB/c sarcoma induced as a solid tumour with 0.2 mgs of methylcholantrene. The primary tumour was serially transplanted subcutaneously in syngeneic mice. The ascites form obtained was sued to study the expression of H-2 antigeneic specificities in a postlabelling radioassay. MCG4 did not express H-2D.4 (private specificity of H-2d haplotypes) as well as H-2.3, H-2.8 and H-2.13 (public specificities). In addition it expressed H-2.5 (a public specificity not present in H-2d cells). These results were confirmed by quantitative absorption analysis using MCG4 and positive-negative normal lymphoid cells for a particular specificity. Results are discussed with regard to the control of expression of H-2 antigens by regulatory genes.


Interganglionic axonal transport of neural peptides within the nervous system of Aplysia. Neurons of the circumesophageal ganglia of Aplysia synthesize 1--2000 dalton peptides and subject them to axonal transport in large quantities in the pleuro-visceral connective and pedal nerves. Most of the protein transported in the connective nerves accumulates in the abdominal ganglion, although some passes out its peripheral nerves. Autoradiography revealed no evidence for terminations of the transporting axons in possible neurohemal areas of this ganglion. It is suggested that these data reflect the existence of a pathway mediating the "directed delivery" of neural peptides in this nervous system.


Secretion of axonally transported neural peptides from the nervous system of Aplysia. The possibility that proteins reaching the abdominal ganglion of Aplysia by axonal transport from the circumesophageal ganglia might be subject to secretion in that structure was examined. Transported labeled protein was found to be released from the abdominal ganglion; such release was enhanced by exposure to a high K+ medium and by electrical stimulation of the transporting axons. Stimulation of release was inhibited by lowering the Ca2+/Mg2+ ratio of the medium. The released material is predominantly of 1--2000 daltons in molecular weight and appears to have been derived from a group of transported peptides of about the same size. The possibility is raised that these data may reflect the existence of a peptidergic second-order neurosecretory pathway in this nervous system.


Batrachotoxin inhibits axonal transport without affecting membrane potential in single neurons of Aplysia californica. Intrasomatic injection of 0.25 ng of batrachotoxin (BTX) caused no depolarization of giant cerebral neurons (GCN) of Aplysia californica within 4 hr at 23 degrees C. The amplitude of action potential and the input resistance were slightly and reversibly decreased. The same dose of BTX caused a 68% inhibition of fast axonal transport.


On the kinetics and maximal capacity of the system for rapid axonal transport in mammalian neurones. 1. Rabbit peroneal nerves were incubated in vitro in two-compartment chambers. Step-gradients of temperature were established so that the proximal part of each nerve was slightly warmer than the distal part. After incubation, the distribution of dopamine-beta-hydroxylase (DBH) activity along the nerves was examined as an indication of the behaviour of rapid transport in adrenergic axons. 2. With temperature gradients of 5 and 8 degrees C, transport velocity in the proximal regions was expected from previous work to be, respectively, 1.5 and 2 times faster than in the distal regions. Exposing nerves to these gradients induced a significant increment in the concentration of DBH activity, beginning at the boundary between regions. This increment was up to 50% of the normal activity and it propagated distally at the velocity expected for transport at the local temperature. 3. A temperature gradient of 13 degrees C was expected to produce a threefold difference in transport velocity between proximal and distal regions. This gradient produced a slightly larger increment of DBH activity propagating distally, again at the expected velocity. However there was also a disproportionate accumulation of enzyme activity at the boundary between regions. Further increases in the temperature gradient did not enhance the size of the propagating increment but only the rate at which enzyme accumulated at the temperature boundary. 4. It was concluded that adrenergic nerves can transport between two and three times as much material per unit time as they normally do. The ability to increase the flux of material appeared to depend on increases in the concentration of material in motion. There was no indication that such increases led to significant changes in the velocity of transport.


Use of color microfiche cards in teaching preclinical prosthodontics. Color microfiche afford a low-cost method for providing students with a complete series of color illustrations depicting procedures to be performed in their preclinical laboratory exercises.


Figural symbolism in Chinese ideographs. Hebrew-speaking subjects were presented with 42 pairs of Chinese characters designating antonymic concepts and were required to match them with their corresponding Hebrew words. Correct translation was significant and was related to foreign language study and academic experience. Highest success was found for the activity domain of the semantic differential and for attributes judged to afford a diagrammatic representation. Examination of the character-referent relationships suggested that translation success was due to principles of figural symbolism rather than to pictographic representation of the attributes in question. The results are seen as suggestive of the effects of figural symbolization on the invention and/or evolution of natural scripts and are discussed in terms of the manner in which the graphic medium has been fashioned to convey abstract concepts.


BLEDTA: tumor localization by a bleomycin analogue containing a metal-chelating group. Two different Co(III) complexes of the antitumor antibiotic bleomycin have been prepared, and their in vivo distribution in mice has been investigated. The more thermodynamically stable of the Co(III)-bleomycin complexes has been modified by reaction with the bifunctional chelating agent 1-(p-bromoacetamidophenyl)ethylenedinitrilotetraacetic acid, to give a bleomycin derivative (BLEDTA) containing a powerful metal-chelating group. BLEDTA was radiolabeled with 111In(III) and its in vivo distribution in mice was examined. The potential of 111In-labeled BLEDTA as a tumor-visualizing agent was also investigated in humans with biopsy-proven cancers, predominantly (70%) squamous carcinoma of the head and neck. All of the 29 patients studied had at least one clinically proven site of the disease visualized with 111In-BLEDTA. These clinical results are significantly better than results we obtained in a comparable group of patients using directly labeled 111In-bleomycin and are similar to those reported by Nouel for 57Co-bleomycin [GANN Monogr. Cancer Res., 19, 301 (1976)].


Modification of medical student perceptions of the cancer experience. Social, cultural, economic, psychological, and interpersonal dimensions of cancer and cancer patient management were addressed by a diverse group of faculty in an elective course conducted for a small number of students in their second, third, and fourth years of medical school. The covert, symbolic attitudes which students held toward this disease were inferred from their scores on the Beck Hopelessness Scale and the Brief Symptom Inventory (BSI) prior to and at the conclusion of the course. At the outset of the course the degree of hopelessness attributed to cancer patients by students was projected in excess of the amount cancer patients actually experience. Test results from an additional 50 medical students identified these bleak perceptions as typical of second-through fourth-year medical students. Significant attitudinal shifts, new insights into cancer patient management, and generally improved interactional skills resulted from the course.


Proteolytic degradation of human erythrocyte band 3 by membrane-associated protease activity. Antisera directed against the cytoplasmic portion of human erythrocyte Band 3 were used to follow the degradation of the band 3 molecule. Small amounts of Band 3 were degraded when well-washed red cell membrane ghosts were incubated in the cold; this process was greatly accelerated by incubating ghosts were incubated in the cold; this process was greatly accelerated by incubating ghosts at 37 degrees C. Band 3 labeled with pyridoxal-phosphate was digested at comparable rates. Band 3 digestion also took place when alkali-extracted ghost membranes were incubated at 37 degrees for prolonged periods. These results suggest that human erythrocytes contain tightly bound, membrane-associated proteolytic activity.


Asymmetry of the gramicidin channel in bilayers of asymmetric lipid composition: I. Single channel conductance. Gramacidin-doped asymmetric bilayers made by the Montal-Mueller method exhibited an asymmetric current-voltage relationship. The asymmetric conductance was shown to be the product of two components, a rectifying single-channel conductance and an asymmetric voltage dependence of the reaction which leads to the conducting channel. The single-channel conductance was asymmetric in both asymmetric bilayers made of charged lipids and asymmetric bilayers made only of neutral lipids. The single-channel asymmetry decreased with increasing ion concentration. From the comparison of the single-channel conductance in symmetric and asymmetric bilayers and the dependence of the asymmetry on the solution ion concentrations, it was concluded that (1) the rate of ion entry into the channel is dependent on the lipid composition of the membrane and is asymmetric in asymmetric bilayers; (2) the entry step is rate determining at low ion concentrations; and (3) at higher ion concentrations the rate-determining step is the translocation across the main barrier in the membrane; and this translocation appears insensitive to lipid asymmetry.


Asymmetry of the gramicidin channel in bilayers of asymmetric lipid composition: II. Voltage dependence of dimerization. The asymmetric current-voltage relationship of gramicidin-doped asymmetric bilayers made by the Montal-Mueller technique was investigated in current relaxation experiments. It was shown that, in addition to the contribution of the asymmetric single channel conductance to the asymmetry of the steady-state current-voltage relationship, there is an asymmetric voltage dependence of the step which leads to the formation of the conducting channel. This asymmetric voltage dependence could be simulated in a model assuming a membrane-internal electrical potential drop or an equivalent potential, called asymmetry potential, which could be compensated by externally applying an offset potential. Significant asymmetry potentials were found in asymmetric bilayers made of charged lipids or only of neutral lipids. The asymmetry potential was dependent on the salt composition in the aqueous phase. The factors responsible for the asymmetry potential do not appear to be of electrostatic origin. Several lines of evidence suggest that the dimerization step which leads to the conducting ion channel may be a complex series of reactions which are influenced by one or more membrane structural properties not yet characterized, in addition to the effects of the externally applied electric field.


An historical account of the development and applications of the negative staining technique to the electron microscopy of viruses. A brief historical account of the development and applications of the negative staining techniques to the study of the structure of viruses and their components as observed in the electron microscope is presented. Although the basic method of surrounding or embedding specimens in opaque dyes was used in light microscopy dating from about 1884, the equivalent preparative techniques applied to electron microscopy were comparatively recent. The combination of experiments on a sophisticated bacterial virus and the installation of a high resolution electron microscope in the Cavendish Laboratory, Cambridge, during 1954, subsequently led to the analysis of several important morphological features of animal, plant and bacterial viruses. The implications of the results from these early experiments on viruses and recent developments in negative staining methods for high resolution image analysis of electron micrographs are also discussed.


Biological X-ray microanalysis.

Biological X-ray microanalysis. By means of X-ray microanalysis it is now practical to detect approximately 10(-19) g of an element in a static-probe analysis within an ultrathin section, with analytical spatial resolution in the range 20--30 nm. The main difficulties for biological microanalysis are connected not with sensitivity but with specimen preparation and beam damage. Careful cryopreparation, beginning with the quench-freezing of a small block of tissue, is essential even for determining the storage sites, or sites of binding in vivo, of physiologically active elements. In frozen-dried or frozen-hydrated sections of quench-frozen tissue, it is now possible to measure local mass fractions of diffusible as well as of bound elements.


[Assay of "pregnancy alpha 2 glycoprotein" in the serum of prostatic cancer patients and changes during estrogen therapy]. Preliminary results are presented after measuring Pregnancy alpha 2 glycoprotein (P.A.G.) in a series of healthy males and those with cancer of the prostate, some of whom were being treated with oestrogens. Serum P.A.G. levels were measured in 21 patients with cancer of the prostate to observe any changes occurring during treatment with oestrogens. There was no significant difference between the P.A.G levels in healthy males and those with untreated prostatic cancer. Treatment however causes increased P.A.G. levels with wide individual variations. There is no apparent relationship between P.A.G. levels and the tumor stage, or efficacy of treatment. A relationship does exist however between the curves of serum P.A.G. levels in pregnant women and patients with prostatic cancer treated with oestrogens. Until proved otherwise, these measurements are of no practical value in patients with prostatic cancer, and future confirmation of these results by the study of a larger number of cases would be of value only in that they avoid other teams from repeating the same investigations.


Long-term antithyroid treatment in hyperthyroidism. The major drawback to treatment of hyperthyroidism with antithyroid compounds is the reported low rate of remission. Eighty patients have been given long-term (at least one year; average, 4.4 years; range, one to 14 years) continuous treatment with a remission rate of 76% and an average follow-up of 7.8 years (one to 21 years). The prognostic test of suppressed uptake by the thyroid of less than 20% was about 75% accurate in predicting continuing remission when treatment was stopped. Of those in remission, 14 (23%) were treated for one year, 35 (57%) for one to five years, and 12 (20%) for more than five years. Mild reactions occurred in five (6%), hypothyroidism in two (3%). An antithyroid drug is safe and effective therapy for hyperthyroidism.


Neo-enactin, a new antifungal antibiotic potentiating polyene antifungal antibiotics. II. Taxonomic studies of the producing microorganism and simultaneous production of bleomycin group and streptothricin-like antibiotics. A new antifungal antibiotic, named neo-enactin, was produced mainly in the mycelia of strain H 829-MY 10. Strain H 829-MY 10 was identified as a Streptoverticillium, determined to be nonchromogenic, and fits in the white color-series. Although Streptoverticillium olivoreticuli is known to be chromogenic, strain H 829-MY 10 is most related to that species. Thus, strain H 829-MY 10 is named as Streptoverticillium olivoreticuli subsp. neoenacticus. Besides neo-enactin, two bleomycin-group antibiotics and two streptothricin-like antibiotics were simultaneously produced by strain H 829-MY 10.


[Clinical application of NK 631, a new derivative of bleomycin (author's transl)]. It is impossible to accurately evaluate NK 631 as an anticancer agent from the findings only in the 7 cases; hence, the following is no more than the author's impression about the drug. However, NK 631 appeared to exert a similar anticancer effect to the currently available bleomycin. In other words, the drug will completely cure or greatly improve the early cases of squamous cell carcinoma, and bring about a transient regression in the advanced cases. The response of malignant lymphoma to this drug varied from case to case; in any event, it is impossible to anticipate a complete cure in this malignancy by single NK 631 therapy but by multiple combination chemotherapy, e.g., BEMP therapy. The adverse reactions to NK 631 that were observed included pulmonary fibrosis, though only in 1 case; hence, no conclusive opinion should be given herein about it pulmonary toxicity in comparison with the pulmonary toxicity of bleomycin. It remains a theme of the future statistic studies in a large number of cases. The other adverse reactions were anorexia and mild alopecia in some of the cases, which were similar to those to bleomycin. Pigmentation also occurred in one of the cases, but the author was impressed that this reaction was less likely to occur with NK 631.


[Clinical effects of NK 631 (pepleomycin) against malignant tumors of the head and neck (author's transl)]. 1. The antitumor effect of pepleomycin observed in 11 cases of malignant tumors of the head and neck was compared with that of bleomycin in similar cases, and the former appeared slightly preferable. 2. The adverse reactions to the 2 drugs were similar to each other; however, those to pepleomycin were milder. 3. Only few cases exhibiting such severe pulmonary fibrosis as emphasized in the published data have been encountered in bleomycin treatment in the authors' department. However, with reference to the measurements of PaO2 in the pepleomycin-treated cases, this may be said to be an anticancer drug which is easier to use clinically. 4. Adverse reactions to pepleomycin, e.g., alopecia, malaise, and others, were less frequent and less severe than those to bleomycin. 5. It was studied by the auditory acuity test in 10 cases (excluding 1 dropout) whether any auditory acuity disorder would occur after pepleomycin treatment: No changes in auditory acuity were observed in any of the cases.


[New methods for the automatic detection and differentiation of extrasystoles]. Two new methods for automatic detection of extrasystoles are proposed: according to the area described by T wave and changes in the projection of the cardiac EMF vector on different ECG leads when the localization of the excitation focus is changed. Telemetry at an ultrashort distance and a device preventing the recording of extrasystoles when patients move increase the authenticity of the findings in automatic detection of extrasystoles.


Methods of training deaf children to comprehend the passive voice. Four variations of programmed filmstrips were shown to deaf children to improve comprehension of the passive voice. The design included two training strategies that treated the passive voice either as a unitary structure or as a contrast to the active voice. Within strategies two orders of training were compared for the various types of passive sentences: (nonreversible, reversible, agent-deleted) and (agent-deleted, nonreversible, reversible). Six filmstrips were constructed for the two strategies and three types of passive. Evaluation tests were administered before, immediately after, and three months following training. Forty deaf children were selected from two age ranges, 9 to 12 and 13 to 16 years. Within age groups 10 subjects served under each of the four strategy-order conditions. Evaluation tests consisted of a multiple choice picture-sentence matching test and a performance test in which subjects acted out six passive sentences using toys. Performance test scores increased significantly after training and surpassed pretraining after three months. Highest scores were achieved on nonreversible passives followed by reversible and agent-deleted passives. Reversal of agent and object was the most frequent error. Strategy and order differences were not significant.


Age-dependent variability of ribosomal RNA-gene activity in man as determined from frequencies of silver staining nucleolus organizing regions on metaphase chromosomes of lymphocytes and fibroblasts. Frequencies of silver staining nucleolus organizing regions (NORs) have been determined in lymphocytes and fibroblasts from very young and from aged persons. Since silver staining of NORs is associated with activity of ribosomal RNA-genes, we used this approach to investigate a possible inactivation of these genes during aging. Our lymphocyte data are based on a study per age-group of 220 metaphases from 10 subjects. Although in both age-groups modal numbers of silver staining chromosomes per metaphase had similar ranges over the subjects, the frequency of metaphases containing the maximal number of staining chromosomes was in the old age-group (80--89 years) significantly lower than in the young age-group (less than 1 year old). In fibroblasts, of which 75 metaphases from 4 subjects were included per age-group, differences were more pronounced. Modal numbers of silver staining chromosomes were for the aged persons (69--83 years) lower than for the young children (less than 1 year old). Highly significant differences were observed between both groups in frequency of metaphases containing the maximal number of positively reacting acrocentric chromosomes and, more in general, in frequencies of silver staining D- and G-group chromosomes, the lower frequencies being found in the old age-group. We propose the term NOR-junctions as distinct from satellite associations for arrangements of acrocentric chromosomes which after silver staining are visibly connected at their NORs. The number of acrocentric chromosomes involved in lymphocyte NOR-junctions of aged people was significantly higher than the number of joined acrocentrics in young children. The frequency of these NOR-junctions themselves, irrespective of the number of chromsomes involved, was higher for aged persons than for young children, although this difference appeared to be statistically not significantly higher than in fibroblasts. Also based on qualitative observations from our study we discuss tcehnical and biological problems of our approach to study cell aging in vivo by means of silver staining of NORs. We conclude that in man, reflected by the difference in frequencies of silver staining NORs between young and aged persons, a rather extensive loss of ribosomal RNA-gene activity may occur during aging.


Dapsone and severe hypoalbuminaemia. A report of two cases. Severe hypoalbuminaemia developed in two patients on long-term dapsone treatment for dermatitis herpetiformis. The patients had been treated with dapsone for 3 and 11 years before the syndrome developed and both recovered completely when dapsone was withdrawn. Albumin-turnover studies revealed a great increase in intravascular albumin catabolism and a modest decrease in synthesis.


Does the nephrotic syndrome increase the risk of cardiovascular disease? Cardiovascular mortality and morbidity were assessed, after a mean follow-up period of 5 years, in an unselected series of 159 adults presenting with the nephrotic syndrome between 1972 and 1975. 60% of the deaths were attributed to terminal renal failure, and the incidence of deaths from ischaemic heart-disease (IHD) was not significantly above normal. The proportion of patients experiencing angina and intermittent claudication and the prevalence of ischaemic electrocardiographic changes did not differ significantly from those of a London control population. At follow-up, hypertension was significantly more common (p less than 0.001) in male nephrotic patients than in controls. Earlier reports of a greatly increased incidence of IHD in unselected patients with the nephrotic syndrome were not confirmed. Routine treatment of hyperlipidaemia in the nephrotic syndrome is not, therefore, recommended.


Hypertriglyceridaemia associated with an abnormal triglyceride-rich lipoprotein carrying excess apolipoprotein C-III-2. Two men aged 48 and 35 years with severe hypertriglyceridaemia, glucose intolerance, and a secondary anaemia had more apolipoprotein C-III-2 and less apo C-III-1 on their triglyceride-rich lipoproteins (d less than 1.006) than did types IV or V lipaemic controls. Although the patients' abnormal lipoproteins seemed to produce normal activation of lipoprotein lipase, they did not serve as an efficient substrate for purified lipoprotein lipase. Adipose tissue of case 1 had considerable lipoprotein-lipase activity and the hypertriglyceridaemia responded to dietary therapy (carbohydrate 180 g, fat 80 g, protein 60 g per day, and no alcohol). The haemolytic anaemia improved, but the patient remained glucose intolerant. The abnormal content of apo C-III-2 on the triglyceride-rich lipoproteins, rendering them resistant to clearance by lipoprotein lipase, is believed to have contributed to the patients' severe hypertriglyceridaemia.


Cimetidine in bleeding peptic ulcer.

Cimetidine in bleeding peptic ulcer. The effect of cimetidine on the risk of further bleeding shortly after acute gastrointestinal haemorrhage from peptic ulcer was investigated in a double-blind randomised trial. 34 patients were given cimetidine and 32 placebo, the two groups being matched for age, sex, and severity of haemorrhage. Further bleeding within a week of admission was detected clinically in 8 patients on cimetidine and 15 on placebo. Cimetidine had no effect on bleeding from duodenal ulcer, but only 2 of 14 patients with gastric ulcer treated with cimetidine bled again, compared with 10 of 19 patients on placebo. Cimetidine, therefore, may help to prevent haemorrhage from gastric ulcer but not duodenal ulcer.


The nature of remission in acute myeloblastic leukaemia. 15 patients with acute myeloblastic leukaemia (AML) in remission were given immunotherapy and 17 similar patients were given immunotherapy plus chemotherapy with the drugs used to induce remission. Median remission length was 245 days for both groups and median survival was 465 days for patients given chemoimmunotherapy and 476 days for patients given only immunotherapy. The failure of remission chemotherapy in AML cannot be attributed to induced resistance because the same drugs induced a second remission in 60% of the patients. From laboratory studies with human AML cells it is suggested that in AML the residual leukaemic cells mature after induction chemotherapy and are then refractory to further drug treatment. Relapse occurs when the leukaemic population proliferates and the environment permits dedifferentiation into frank blast cells.


Safety of postabortion sterilisation compared with interval sterilisation. A controlled study. 406 women--about one-fifth of those requesting an induced abortion and sterilisation over a thirty-three-month period--volunteered to be allocated randomly to either a concurrent induced-abortion/sterilisation group or a group which was sterilised six weeks after abortion. The abortion-attributable and sterilisation-attributable complication rates of 3.8% and 5.2%, respectively, for the concurrent group did not differ significantly from the 6.7% and 6.9% rates for the interval group. The estimated 2%-10% of women who would have changed their minds must be set against the 4% of women who became pregnant again before being sterilised. Efforts should be made to identify women likely to regret sterilisation.


Increased tendency to spontaneous in-vitro lymphocyte transformation in clinically active multiple sclerosis. Lymphocytes from 8 of 10 patients with clinically active multiple sclerosis (MS) but from only 3 of 18 patients with quiescent MS and 4 of 20 healthy donors transformed spontaneously on in-vitro culture. The transformed cells from all donors had the characteristics of B lymphocytes (surface and intracytoplasmic immunoglobulin and complement receptors) and carried antigens of Epstein-Barr virus. It is suggested that these results are further evidence that immunoregulation in active MS is abnormal.


Post-menopausal oestrogens protect against fractures of hip and distal radius. A case-control study. To assess the efficacy of oestrogens in preventing the common major limb fractures of postmenopausal women, retrospective case-control research was used for a new purpose--to explore beneficial rather than adverse effect of treatment. Postmenopausal women admitted with fractures of the hip or distal radius and matched women admitted to the orthopaedic service for other reasons were surveyed. The "risk" of the non-oestrogen users, was estimated by inverting the customary odds ratio to calculate protection in terms of numbers of (exposed controls x non-exposed cases) divided by (exposed cases x non-exposed controls). Medical-record data for oestrogen usage in 157 matched case-control pairs gave an odds ratio for "protection" of 1.5 (10 x 150 divided by 7 x 147). If "exposure" was defined as starting oestrogens within 5 years of the menopause, this ratio rose to 2.6 (10x153 divided by 4x147). With oestrogen usage ascertained from standardised interviews of 80 case-control pairs, the ratio was 3.0 (20x72 divided by 8x60) (p=0.01), and rose to 3.8 (16x75 divided by 5x64) (p=0.01) for oestrogen "exposure" that began within five years of menopause. When lateral chest X-rays were blindly reviewed, the prevalence of oesteoporosis was 32% in the fracture cases and 15% in controls (p less than 0.01). The results add epidemiological evidence for the belief that exogenous oestrogens protect against postmenopausal osteoporosis.


Relation of myocardial metal concentrations to water hardness and death-rates from ischaemic heart disease. Samples of normal heart muscle from an area with soft drinking-water (Burnley) contained significantly more magnesium and potassium than samples from an area with hard drinking-water (Hull). Females from the soft-water area had significantly more iron and copper. Males from the soft-water area had significantly less manganese and slightly less water in the heart muscle. Males in the soft water areas had significantly lower magnesium/potassium ratios, and both sexes had significantly higher potassium/sodium ratios, than those in hard water areas. The relationship between potassium/sodium ratio and death rates from arteriosclerotic disease suggests that the optimum potassium/sodium ratio is 2.8--3.0, and deviations in both directions are associated with increases in the death-rate from ischaemic heart-disease.


Colonic motility in proctalgia fugax.

Colonic motility in proctalgia fugax. Intraluminal pressure recordings were obtained from the rectum and sigmoid colon in two patients experiencing attacks of proctalgia fugax. In each patient the pain appeared to result from contractions of the sigmoid colon, and not from spasm of the levator ani, rectal wall muscle, or anal sphincters, all of which have previously been suggested as the source of such pain. Proctalgia fugax therefore appears, at least in some patients, to be an unusual variant of the irritable bowel syndrome, in which pain is referred from the sigmoid colon to the rectum.


Acute graft-versus-host disease in recipients of bone-marrow transplants from identical twin donors. Three patients with acute leukaemia received bone-marrow from identical twin donors after pre-transplant preparation with cyclophosphamide, cytosine arabinoside, and total body irradiation. Later clinical and microscopic changes in all three patients suggested cutaneous acute graft-versus host disease. In two of the recipients thrombolytic thrombocytopenia developed during the seventh week after transplantation, and platelet half-life was reduced to 9 h in one recipient (normal 3--4 days). It is suggested that acute graft-versus-host disease in bone-marrow recipients sometimes may result from an imbalance between autoreactive lymphocytes and lymphocytes which suppress their effect and not always from genetically determined histocompatibility differences between donor and recipient.


Pre-eclampsia--a state of mother-fetus immune imbalance. Serial lymphocyte counts and function tests were done during and after pre-eclamptic pregnancies, and in the offspring. Compared with normal pregnancies, pre-eclamptic pregnancies were associated with lower B-lymphocyte counts in the fathers; lower T-lymphocyte count, lower B-lymphocyte count, and impaired T-lymphocyte function in mothers; a low response in mixed lymphocyte culture (MLC) tests between the mother and father; and an increased B-cell count in the children. Follow-up of one pre-eclamptic woman throughout pregnancy showed important immune changes at the beginning of the second trimester. These findings suggest that pre-eclampsia is caused by a combination of maternal and paternal hyporesponsiveness together with fetal hyperresponsiveness.


Bottle feeding as a risk factor for cholera in infants. To determine risk factors for cholera in infants, a retrospective matched-pair study of 42 cases and their controls was undertaken during an outbreak of El Tor cholera in Bahrain in the autumn of 1978. The highest attack-rate of cholera (125/10 000) occurred in infants in the 6--11 month age-group, which corresponds to the weaning age in this community. Significantly more cases than controls were principally bottle fed (greater than 50% milk intake by bottle) than principally breast fed during the week before onset of illness (p=0.004). Analysis of various patterns of breast and bottle feeding did not determine whether the protection afforded by breast feeding was a negative effect (due to the lack of exposure to contaminated bottle feedings for breast fed infants) or a positive effect (due to protective functions of constituents of human breast milk). Cholera infection (with or without symptoms) among mothers of either case or control infants was uncommon (case mothers 3, control mothers 5), and mean serum vibriocidal and antitoxic antibody levels were similar for the two groups of mothers. These observations suggest that maternal infection did not affect the relative risk of infants having symptomatic cholera.


Bacteriological criteria for feeding raw breast-milk to babies on neonatal units. Aerobic cultures of 207 samples of drip breast-milk from seventy mothers in hospital showed that 6 (3%) were sterile and 170 (82%) contained only the commensal organisms coagulase-negative staphylococci and Streptococcus viridans. 25 (15%) grew potential pathogens--Staphylococcus aureus in 13 (6%); enterobacteria in 15 (7%); and group-B streptococci in 3 (2%). It is proposed that milk with commensals in any numbers may be considered for use unheated but not milk containing any potential pathogens.


Perinatal mortality: effectiveness of selective interventions. Selective interventions for areas with high perinatal mortality-rates have been proposed. Measuring the effectiveness of intervention requires prior calculation of spontaneous regression towards the mean. A method is described and applied.


Alcohol-induced brain damage and liver damage in young males. 37 alcoholic males under the age of 35 were examined clinically, by psychometric tests, by computerised tomography (CT scans), and by liver biopsy. Factors other than alcoholism that might have caused brain damage were excluded. The prevalence of brain damage in this group was far greater than that of severe liver damage: 59% were intellectually impaired and 49% had cerebral atrophy on CT scan, whereas only 19% had cirrhosis. There was no significant correlations between the degree of liver damage and the degree of intellectual impairment (p greater than 0-05), nor between the degree of intellectual impairment and the presence of cerebral atrophy. The CT scan is an inadequate measure of functional brain damage, psychometric testing is preferable. Other neurological complications of alcoholism were not impressive. Disabling intellectual impairment may be the earliest complication of chronic alcoholism and may arise early in the alcoholic career.


Prophylactic peroperative intravenous metronidazole in elective colorectal surgery. In a prospective double-blind randomised trial 83 patients undergoing elective colorectal surgery were given either preoperative intravenous metronidazole or intravenous normal saline. No other antimicrobials were given. Bowel preparation was the same for both groups. Deep post-operative wound sepsis occurred in 6 of 44 (13-6%) patients on metronidazole but in 20 of 39 (51-2%) control untreated patients. Anaerobes were responsible for all cases of deep sepsis in the metronidazole group (in 5 of the 6 cases aerobes were also isolated), and for 16 of the 20 cases of deep sepsis in the control group (all with aerobes). Superficial infection in the metronidazole group was caused by aerobes. Anastomotic leakage occurred in 5 of the 6 patients who developed deep sepsis on metronidazole and in 10 of 20 patients on placebo. Peroperative intravenous metronidazole dramatically reduced postoperative sepsis but failed to prevent infection in the presence of anastomotic breakdown.


Suppression of pancreatic endocrine tumour secretion by long-acting somatostatin analogue. A new long-acting octapeptide analogue of somatostatin, Des AA1,2,4,5,12,13 D Try8 somatostatin, has been tested in 8 patients with pancreatic endocrine tumours. The analogue given subcutaneously suppressed the tumour-derived hormones in patients with insulinomas, glucagonomas, and gastrinomas for up to 24 h. The prolonged action appeared to be the result of slow release from the injection site. No side-effects were observed. Studies of long-term administration of this new peptide are now warranted.


Prostacyclin overproduction in Bartter's syndrome. Urinary excretion of 6-keto-prostaglandin F1alpha and thromboxane B2, the major metabolites of prostacyclin and of thromboxane A2, respectively, was measured by specific radioimmunoassays in five female patients with Bartter's syndrome and in five normal female controls. The patients with Bartter's syndrome excreted about four times as much 6-keto-PGF1alpha as the controls; their excretion of thromboxane B2 was no different from that of the controls. These data suggest that overproduction of prostacyclin mediates both the hyper-reninaemia and the hyporesponsiveness of blood-pressure to pressor agents in Bartter's syndrome.


A physiological role for calcitonin: protection of the maternal skeleton. Plasma-calcitonin levels, measured with an established and reliable extraction radioimmunoassay technique, were significantly higher throughout normal pregnancy and lactation than in normal non-pregnant women, and were not immediately influenced by the acute stimulation of breast-feeding. Thus, more calcitonin circulates at times of physiologically increased calcium need. It is suggested that an important function of calcitonin is the protection of the healthy maternal skeleton from excessive resorption by opposing the resorptive action of 1,25-dihydroxycholecalciferol on bone.


Strong association between idiopathic membranous nephropathy and HLA-DRW3. HLA A, B, and DR antigens were determined in a homogeneous group of patients with idiopathic membranous nephropathy. The frequency of HLA-DRW3 was significantly higher in the patients than in a control population. The frequencies of HLA B8 and B18, which are in linkage disequilibrium with DRW3, were also increased.


Hyperammonaemia, plasma aminoacid imbalance, and blood-brain aminoacid transport: a unified theory of portal-systemic encephalopathy. It is proposed that hyperammonaemia in liver cirrhosis or after portacaval shunt contributes to plasma neutral aminoacid imbalance and to increased activity of the blood-brain neutral amino-acid transport system. Plasma neutral aminoacid concentrations are deranged, partly, but not completely, because ammonia stimulates glucagon secretion; a high rate of gluconeogenesis and hyperinsulinaemia follow. Brain uptake of neutral aminoacids rises because ammonia stimulates brain-glutamine synthesis, which results in rapid exchange of brain glutamine for plasma neutral aminoacids. Hyperammonaemia therefore contributes to encephalopathy indirectly, by raising the brain concentration of neutral aminoacids which after neurotransmitter metabolism, rather than directly, by toxic effects on neuronal metabolism.


Dietary cholesterol, fat, and fibre, and colon-cancer mortality. An analysis of international data. It has been suggested that high fat, high cholesterol, and low fibre intakes play a role in the causation of colon cancer, but since they are highly intercorrelated, it is difficult to determine which (if any) variable is truly related to colon cancer. Food disappearance data for 1954--65 and mortality data for 1967--73 from 20 industrialised countries were used to assess which variables are independently related to colon cancer. Simple correlation analysis indicated that intake of total fat, saturated fat, monounsaturated fat, cholesterol, and fibres are each highly correlated with mortality-rate for colon cancer. The partial correlation of dietary cholesterol with colon cancer remains highly significant when fat or fibre is controlled. However, the partial correlations of fat or of fibre iwth colon cancer are no longer significant when cholesterol is controlled. Cross-classification showed a highly signficant main effect for cholesterol, but nor for fat or fibre. The findings support the possibility of a causal relationship between cholesterol intake and colon cancer.


Psychological response to breast cancer: effect on outcome. A prospective, multidisciplinary, 5-year study of 69 consecutive female patients with early (T0,1N0,1M0) breast cancer was conducted. Patients' psychological responses to the diagnosis of cancer were assessed 3 months postoperatively. These responses were related to outcome 5 years after operation. Recurrence-free survival was significantly common among patients who had initially reacted to cancer by denial or who had a fighting spirit than among patients who had responded with stoic acceptance or feelings of helplessness and hopelessness.


Diarrhoeal mortality in two Bangladeshi villages with and without community-based oral rehydration therapy. To combat dehydration from diarrhoea in Shamlapur, a village of 7021 people, multiple community-based points were set up by trained volunteers for the distribution of glucose-electrolyte oral rehydration salt (ORS) packets. The comparable adjoining village, Bordil, with a population of 3888, obtained its supply of ORS from Shamlapur. Surveilance for 2 years showed that although diarrhoeal attack-rates were equal, consumption of ORS after diarrhoea was 80% in Shamlapur and 38% in Bordil. There were 8 deaths in Shamlapur caused by diarrhoea and 23 in Bordil, showing an overall case fatality-rate of 0.5% and 2.4%, respectively, and a diarrhoeal mortality-rate per 1000 population of 0.6 and 2.9, respectively. The observation indicated that although it may not be possible to reduce diarrhoeal attack-rates, easy availability of rehydration solution and its early use after village-based training may save many lives, particularly those of children.


Role of endothelium in sequestration of lipoprotein and firbrinogen in aortic lesions, thrombi, and graft pseudo-intimas. In the soft, gelatinous thickenings that appear to be the precursors of fibrous plaques, concentrations of plasma low-density lipoproteins (LP) and fibrinogen were three to four times higher than that in normal intima, but their concentrations of fibrin was not significantly higher. By contrast, in 60% of cholesterol-rich areas from more advanced plaques, fibrin (mean concentration 22.7 mg/100 mg lipid-extracted dry weight) was ten times higher than normal, and this was associated with a twelve-fold increase in a bound LP fraction that was released by incubation with fibrinolytic enzymes. The origin of this fibrin is uncertain, and to test similarity of fibrin in the lesion with that of mural thrombus free and bound LP, fibrinogen, and cholesterol were measured in thrombi and pseudo-intimas from prosthesis grafts. In the pseudo-intimas and the thrombi that were not covered with endothelium the concentrations of all these substances were very low, but in thrombi covered with endothelium the concentrations of free and bound LP were similar to those in intimal lesions. Thus, endothelialisation appears to promote accumulation of LP in mural thrombi.


Lymphocyte alteration by procainamide: relation to drug-induced lupus erythematosus syndrome. Sera from 11 (65%) of 17 patients with newly diagnosed procainamide-induced lupus contained cold-reactive lymphocytotoxic antibodies to normal human lymphocytes in titres of 1/2 to 1/128. In contrast, only 3 of 15 patients on long-term procainamide therapy without lupus and 3 of 65 normal men had serum lymphocytotoxic antibodies, none at a titre higher than 1/2. Antibody levels in the lupus patients declined quickly after procainamide was stopped, in parallel with their clinical improvement. Procainamide (3.75 x 10(-3) mol/l) suppressed by more than 80% in-vitro phytohaemagglutinin-induced 3H-thymidine incorporation by normal human blood lymphocytes. At 3.75 x 10(-4) mol/l, procainamide enhanced the mitogenic response to 160 +/- 20% of normal. Thus procainamide may interact with the lymphocyte membrane, possibly producing a lupus syndrome directly, by altering lymphocyte function, or indirectly, by generating autoantibodies reactive with normal membrane structures.


Iron absorption and loading in beta-thalassaemia intermedia. Iron absorption and rates of iron accumulation were analysed in a group of patients with beta-thalassaemia intermedia. Iron absorption was strikingly increased and there was a progressive iron loading with increasing age. Balance studies indicated that by the time many of these patients reach the third or fourth decades their total iron loads may be of a similar magnitude to those of transfusion-dependent beta-thalassaemia homozygotes. If these patients are to be protected from cardiac, hepatic, and endocrine complications of iron overload in middle life it will be necessary to reduce gastrontestinal iron absorption, starting from early childhood.


Maternal blocking factors in human pregnancy are found in plasma not serum. Pregnancy plasma and sera were evaluated for differential blocking effects in mixed lymphocyte culture reactions. Autologous pregnancy plasma, but not serum was found to contain a specific allogeneic inhibitor for paternal lymphocytes.


Extracorporeal immunoadsorption: initial experience in human systemic lupus erythematosus. Extracorporeal immunoadsorption and filtration was used in treatment of a 29-year-old woman with severe lupus nephritis. For the previous 35 days single-stranded DNA (ssDNA) antibody and immune-complex levels had been continuously raised with only partial improvement on prednisone therapy. Levels of immune complexes and ssDNA antibodies were substantially reduced by extracorporeal plasma filtration and adsorption of DNA collodion charcoal. There were no major clinical complications. After perfusion, the reduction of ssDNA binding and immune complexes in serum was sustained, serum C'3 became normal, and serum creatinine and proteinuria improved. 28 days after perfusion, subendothelial glomerular deposits were much reduced compared with those in a pre-perfusion biopsy specimen. Selective immunoadsorption is a promising new approach to persistent lupus nephritis refractory to drug therapy alone.


The nature of piecemeal necrosis in chronic active hepatitis. On the basis of histological studies, it is proposed that the type of liver-cell death in piecemeal necrosis is apoptosis. The characteristic inconspicuousness of apoptosis explains why the mode of hepatocyte elimination in piecemeal necrosis has hitherto remained obscure. Cell-mediated immune attack induces apoptosis, not classical necrosis, and the occurrence of apoptosis in piecemeal necrosis links the observed morphological changes in chronic active hepatitis with the other evidence for an autoimmune pathogenesis. It is significant that apoptosis does not evoke inflammation or fibroplasia. In attempting to elucidate the cause of the fibrosis that accompanies progression to cirrhosis in chronic hepatitis, it may thus be more relevant to study the effect on fibroblasts of substances liberated during lymphocyte-hepatocyte interactions than the death of the hepatocytes.


Effect of alprenolol on mortality among patients with definite or suspected acute myocardial infarction. Preliminary results. A double-blind study of alprenolol versus placebo was done in patients with definite or suspected myocardial infarction to show the effect of the drug on mortality-rate after a year of treatment in patients aged less than or equal to 65 and to study the tolerance of the drug by patients greater than 65 years of age. The dose given was 5--10 mg intravenously, followed by 200 mg twice a day, orally. Patients in whom beta-blockade was contraindicated were excluded. All deaths, side-effects, and dropouts were recorded. Of the 480 patients in the study, 238 patients received alprenolol and 242 placebo. During the year of follow-up 108 patients dropped out from the study. Mortality was not reduced in patients greater than 65 years of age. In those less than or equal to 65 years alprenolol significantly reduced mortality-rate (20% mortality in placebo group vs 9% in treated group). There was also a significant reduction in mortality-rate among those with definite infarction (28% in the placebo vs 15% in the treated group).


Effect of atenolol on recovery of the electrocardiographic signs of myocardial infarction. The most notable changes in the 35-lead precordial electrocardiogram in 22 subjects in the first 6--12 months after acute myocardial infarction were a reduction in the amplitude of Q waves and a significant increase in the amplitude of the R waves. Patients who, in a random trial, had been given 100 mg atenolol daily from admission showed a significantly greater recovery in R-wave amplitude and decrease in Q waves than patients given placebo. It is concluded that atenolol improves the recovery of the electrocardiographic signs of myocardial infarction.


Long-term continuous subcutaneous insulin infusion in diabetics at home. 6 insulin-requiring diabetics were treated at home with continuous, long-term, dual-rate subcutaneous insulin infusion (CSII) by means of a portable syringe pump. The duration of infusion was 48--111 days. Patients were initially stabilised on CSII in hospital and then allowed home, where capillary-blood glucose control was monitored by the patients with glucose-oxidase reagent strips. Patients diluted and changed their own insulin for the pump, adjusting the dose according to the control achieved. Mean (+/- SD) blood-glucose values ranged from 4.8 +/- 1.6 to 7.5 +/- 1.6 mmol/l. In 1 longstanding diabetic insulin requirements fell from 92 U/day to about 35 U/day on CSII. 2 newly diagnosed juvenile-onset diabetics were also infused: in 1 patient requirements fell to zero after 48 days and in the other the dose fell to 14 J/day after 51 days of CSII. No cannula-site infection or significant palpable lipodystrophy was experienced. Patients treated with "open-loop" systems have little or no insulin reserve: potential loss of control--for example, during intercurrent illness-demands careful metabolic monitoring and prompt correction.


Cerebral blood-flow and viscosity in relative polycythaemia. Cerebral blood flow (CBF), red-cell mass, and plasma volume were measured in 39 patients with venous haematocrit values in the range 0.47--0.58. Patients with true polycythaemia were thus excluded. The 39 patients studied fell into two groups--those with a measured red-cell mass in the high-normal range and those with normal red-cell-mass values but reduced plasma-volume values (the relative-polycythaemia, low-plasma-volume group). The mean CBF was low in both the high-normal red-cell-mass (HNRCM) group (45.8 ml/100 g/min) and low-plasma-volume (LPV) group (48.8 ml/100 g/min). The haematocrit in the HNRCM group was 0.504 and in the LPV group 0.513. In a control group of subjects with a mean haematocrit of 0.421 CBF was 68.6 ml/100 g/min. Venesection was associated with a significant rise in CBF in both groups of patients--to 59.7 ml/100 g/min in the HNRCM group and 65.0 ml/100 g/min in the LPV group. Whole-blood viscosity fell significantly in both groups. Both groups demonstrated significant inverse relationships between CBF and haematocrit and between CBF and blood viscosity.


Response of intestinal mucosa to gluten challenge in autistic subjects. Eight autistic patients with steatorrhoea, hypocalciuria, and alleged behavioural improvements on gluten restriction, were fed ordinary diets plus 20 g gluten/day for 4 weeks. None of the patients had any significant change in body-weight or bowel habit as a result of gluten challenge, nor were any histological abnormalities detected on jejunal biopsy. The data suggest that the steatorrhoea and hypocalciuria seen in some autistic subjects cannot be accounted for by the presence of coeliac disease. Furthermore, these patients should not be confined to gluten-free diets, unless rigorous behavioural studies demonstrate a statistically significant improvement in behaviour as a result of the diet, or deterioration during challenge.


Urinary immunoreactive trypsin excretion: a non-invasive screening test for pancreatic cancer. The ratio of renal clearance of immunoreactive trypsin relative to renal clearance of creatinine was measured in 71 subjects including 27 controls and patients with cancer of pancreas, chronic pancreatitis, and acute pancreatitis. The upper limit of the control range was 4.1 x 10(-5) (mean + 2SD). 6 of 9 patients (67%) with acute pancreatitis had raised values. All 18 patients with chronic pancreatitis had values within the control range. In contrast, all 17 patients with carcinoma of pancreas had raised clearance ratios. The test may therefore prove valuable in distinguishing between chronic pancreatitis and cancer of pancreas.


Dopamine disorder in duodenal ulceration. Cysteamine-induced duodenal ulcers in rats were prevented by the dopamine agonists bromocriptine, lergotrile, and apomorphine, whereas both the severity of duodenal ulcers and the mortality among cysteamine-treated rats were raised by the dopamine receptor antagonist, haloperiodol. Bromocriptine and lergotrile greatly reduced gastric-acid output in cysteamine-treated rats. A review of the literature shows a high incidence of duodenal ulcers in patients with Parkinson's disease (associated with dopamine deficiency) and a low occurrence in schizophrenics (associated with dopamine excess and/or hyperactivity). Thus, changes in peripheral and/or central dopamine concentrations and/or receptor activity may have a role in the pathogenesis of duodenal ulceration.