Guinea-pig milk-protein synthesis. Isolation and characterization of messenger ribonucleic acids from lactating mammary gland and identification of caseins and pre-alpha-lactalbumin as translation products in heterologous cell-free systems. 1. The major milk proteins synthesized by the lactating mammary gland of the guinea pig were identified and designated as caseins A, B and C and alpha-lactalbumin, with estimated mol.wts. of 28000, 25500, 20500 and 14500 respectively. 2. Antisera to the total casein fraction and to alpha-lactalbumin were prepared from rabbits. The milk proteins were also iodinated with either 131I or 125I. 3. A poly(A)-rich RNA fraction was isolated from lactating guinea-pig mammary glands. Isolation was by affinity chromatography on oligo(dT)-cellulose. 4. Examination of this RNA fraction by electrophoresis on polyacrylamide gels containing formamide indicated three major species 1, 2 and 3, with estimated wol.wts. of 5.4 X 10(5) and 3.3 X 10(5), and the apparent absence of rRNA species. 5. The poly(A)-rich RNA stimulated protein synthesis in heterologous cell-free systems based on wheat germ, Krebs II ascites-tumour cells, and the latter supplemented with an initiation factor-3 fraction from rabbit reticulocyte ribosomes. 6. Between 80 and 90% of the protein synthesis directed by the mRNA was for milk proteins. 7. Analysis of the proteins immunoprecipitated by the alpha-lactalbumin antiserum showed in the wheat-germ system that the product was a protein with a molecular weight greater than that of alpha-lactalbumin, whereas in the ascites-tumour-cell systems both this protein and alpha-lactalbumin were found. When the larger protein was treated with CNBr and the resulting peptides were examined, it was shown that the extra peptide was at the N-terminus. This and other evidence is adduced for the initial translation product of alpha-lactalbumin being a precursor with an addition of about ten amino acids at the N-terminus. 8. Similar analysis of the casein immlnospecific proteins produced under the direction of mRNA indicated that the products had a molecular weight that was apparently a littel smaller than that of the caseins synthesized in vivo. This was not consistent with higher-molecular weight casein precursors. 9. Possible explanations for the results obtained are discussed, especially in terms of the physiological significance of the pre-alpha-lactalbumin as a secretory protein.


Metabolism of methionine and biosynthesis of caffeine in the tea plant (Camellia sinensis L.). 1. Caffeine biosynthesis was studied by following the incorporation of 14C into the products of L-[Me-14C]methionine metabolism in tea shoot tips. 2. After administration of a 'pulse' of L-[Me-14C]methionine, almost all of the L-[Me-14C]methionine supplied disappeared within 1 h, and 14C-labelled caffeine synthesis increased throughout the experimental periods, whereas the radioactivities of an unknown compound and theobromine were highest at 3 h after the uptake of L-[Me-14C]methionine, followed by a steady decrease. There was also slight incorporation of the label into 7-methylxanthine, serine, glutamate and aspartate, disappearing by 36 h after the absorption of L-[Me-14C]methionine. 3. The radioactivities of nucleic acids derived from L-[Me-14C]methionine increased rapidly during the first 12 h incubation period and then decreased steadily. Sedimentation analysis of nucleic acids by sucrose-gradient centrifugation showed that methylation of nucleic acids in tea shoot tips occurred mainly in the tRNA fraction. The main product among the methylated bases in tea shoot tips was identified as 1-methyladenine. 4. The results indicated that the purine ring in caffeine is derived from the purine nucleotides in the nucleotide pool rather than in nucleic acids. A metabolic scheme to show the production of caffeine and related methylxanthines from the nucleotides in tea plants is discussed.


Effects of calcium-antagonistic drugs on the stimulation by carbamoylcholine and histamine of phosphatidylinositol turnover in longitudinal smooth muscle of guinea-pig ileum. A number of drugs classed as calcium antagonists, spasmolytics, non-specific receptor antagonists or receptor antagonists with multiple sites of action were tested to determine whether they prevent the stimulation of phosphatidylinositol turnover caused in various tissues by the activation of receptors which increase cell-surface Ca2+ permeability. The experiments were done with fragments of longitudinal smooth muscle from guinea-pig ileum; these were incubated in vitro with 32Pi and either 100 muM-carbamoylcholine or 100 muM-histamine, in the presence of antagonistic drugs at concentrations at least sufficient to cause complete blockade of smooth-muscle contraction. The phosphatidylinositol response to carbamoylcholine was not changed by cinchocaine, papaverine, nifedipine, dibenamine, amethocaine, cinnarizine, lidoflazine, methoxyverapamil, prenylamine or two antimuscarinic alkane-bis-ammonium compounds, and the response to histamine was unaffected by the first four drugs. In contrast, phenoxybenzamine prevented the increase in phosphatidylinositol labelling caused by either carbamoylcholine or histamine. The insensitivity of the phosphatidylinositol response to most of the drugs provides further experimental support for the conclusion that the receptor-stimulated phosphatidylinositol breakdown which initiates the increase in phosphatidylinositol turnover is not caused by an increase in intracellular Ca2+. The simplest interpretation of the available information appears to be that phosphatidylinositol breakdown plays a role in the coupling between the receptor-agonist interaction and the opening of cell-surface Ca2+ gates [Michell, R. H. (1975) Biochim. Biophys. Acta 415, 81-147]. If this is correct, then phenoxybenzamine must exert its inhibitory effects on phosphatidylinositol breakdown early in this sequence of events, but the drugs must act at a stage later than phosphatidylinositol breakdown. The unexpected difference in the effects of dibenamine and phenoxybenzamine, which are chemically very similar, may provide a useful experimental tool with which to explore the way in which activated receptors provoke the opening of cell-surface Ca2+ gates.


Synthesis and turnover of cerebrosides and phosphatidylserine of myelin and microsomal fractions of adult and developing rat brain. The synthesis and turnover of cerebrosides and phospholipids was followed in microsomal and myelin fractions of developing and adult rat brains after an intracerebral injection of [U-14C]serine. The kinetics of incorporation of radioactivity into microsomal and myelin cerebrosides indicate the possibility of a precursor-product relationship between cerebrosides of these membranes. The specific radioactivity of myelin cerebrosides was corrected for the deposition of newly formed cerebrosides in myelin. Multiphasic curves were obtained for the decline in specific radioactivity of myelin and microsomal cerebrosides, suggesting different cerebroside pools in these membranes. The half-life of the fast turning-over pool of cerebrosides of myelin was 7 and 22 days for the developing and adult rat brain respectively. The half-life of the slowly turning-over pool of myelin cerebrosides was about 145 days for both groups of animals. The half-life of the rapidly turning-over microsomal cerebrosides was calculated to be 20 and 40 h for the developing and adult animals respectively. The half-life of the intermediate and slowly turning-over microsomal cerebrosides was 11 and 60 days respectively, for both groups of animals. The amount of incorporation of radioactivity into microsomal cerebrosides from L-serine was greatly decreased in the adult animals, and greater amounts of the precursor were directed towards the synthesis of phosphatidylserine. In the developing animals, considerable amounts of cerebrosides were synthesized from L-serine, besides phosphatidylserine. The time-course of incorporation indicated that a precursor-product relationship exists between microsomal and myelin phosphatidylserine. The half-life of microsomal phosphatidylserine was calculated to be about 8 h for the fast turning-over pool in both groups of animals.


Effect of ornithine and lactate on urea synthesis in isolated hepatocytes. 1. In hepatocytes isolated from 24 h-starved rats, urea production from ammonia was stimulated by addition of lactate, in both the presence and the absence of ornithine. The relationship of lactate concentration to the rate of urea synthesis was hyperbolic. 2. Other glucose precursors also stimulated urea production to varying degrees, but none more than lactate. Added oleate and butyrate did not stimulate urea synthesis. 3. Citrulline accumulation was largely dependent on ornithine concentration. As ornithine was increased from 0 to 40 mM, the rate of citrulline accumulation increased hyperbolically, and was half-maximal when ornithine was 8-12 mM. 4. The rate of citrulline accumulation was independent of the presence of lactate, but with pyruvate the rate increased. 5. The rate of urea production continued to increase as ornithine was varied from 0 to 40 mM. 6. It was concluded that intermediates provided by both ornithine and lactate are limiting for urea production from ammonia in isolated liver cells. It was suggested that the stimulatory effect of lactate lies in increased availability of cytosolic aspartate for condensation with citrulline.


Uridine diphosphate xylosyltransferase activity in cartilage from manganese-deficient chicks. The glycosaminoglycan content of cartilage is decreased in manganese deficiency in the chick (perosis). The activity of xylosyltransferase, the first enzyme in the biosynthetic pathway of sulphated glycosaminoglycans, was studied in the epiphysial cartilage of 4-week-old chicks which had been maintained since hatching on a manganese-deficient diet. Enzymic activity was measured by the incorporation of [14C]xylose from UDP-[14C]xylose into trichloroacetic acid precipitates. Optimal conditions for the xylosyltransferase assay were established and shown to be the same for both control and manganese-deficient cartilage. Assay of the enzyme by using an exogenous xylose acceptor showed no difference in xylosyltransferase activity between control and manganese-deficient tissue. Further, the extent of xylose incorporation was greater in manganese-deficient than in control cartilage preparations, suggesting an increase in xylose-acceptor sites on the endogenous acceptor protein in the deficient cartilage. 35S turnover in the manganese-deficient cartilage was also increased. The data suggest that the decreased glycosaminoglycan content in manganese-deficient cartilage is due to decreased xylosylation of the acceptor protein plus increased degradation of glycosaminoglycan.


Developmental aspects of glutathione S-transferase B (ligandin) in rat liver. The postnatal development in male Sprague-Dawley rats of hepatic glutathione S-transferase B (ligandin) in relation to the other glutathione S-transferases is described. The concentration of glutathione S-transferase B in 1-day-old male rats is about one-fifth of that in adult animals. The enzyme reaches adult concentrations 4-5 weeks later. When assessed by substrate specificity or immunologically, the proportion of transferase B relative to the other glutathione S-transferases is high during the first week after birth. At this age, 67.5% of the transferase activity towards 1-chloro-2,4-dinitrobenzene is immunoprecipitable by anti-(transferase B), compared with about 50% in adults and older pups. Between the second and the fifth postnatal week, the fraction of transferase B increases in parallel fashion with the other transferases in hepatic cytosol. Neither L-thyroxine nor cortisol induce a precocious increase in glutathione S-transferase activity. Phenobarbital did induce transferase activity towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene in both pups and adults. The extent of induction by phenobarbital was a function of basal activity during development such that the percentage stimulation remained constant from 5 days postnatally to adulthood.


Subcellular localization of oestrogen-induced uterine peroxidase. The distribution of oestrogen-induced peroxidase in the resuspended 8000g pellet of rat uterine homogenates was examined by centrifugation in a sucrose density gradient. Within 10h of treatment with oestradiol, peroxidase activity was found in a region devoid of catalase or urate oxidase (peroxisomal markers) which did not overlap the fractions containing succinate dehydrogenase (mitochondrial marker) or acid phosphatase (lysosomal marker). The induced uterine enzyme was localized in reticular membrane-bound vesicles with isopycnic density of 1.28g/ml from which it could be released by treatment with detergent.


A new approach to assessing collagen turnover by using a micro-assay. A highly efficient and rapid turnover of collagen in rat periodontal tissues. Measurement of [3H]proline incorporation into newly synthesized and mature collagen in connective tissues was used to compare rates and efficiency of collagen turnover. The approach minimizes label-recycling problems. By using a micro-assay to determine hydroxyproline specific radioactivities, a highly efficient and rapid collagen turnover in rat periodontal tissues was demonstrated.


The synthesis and hydrolysis of long-chain fatty acyl-coenzyme A thioesters by soluble and microsomal fractions from the brain of the developing rat. 1. The specific activities of long-chain fatty acid-CoA ligase (EC6.2.1.3) and of long-chain fatty acyl-CoA hydrolase (EC3.1.2.2) were measured in soluble and microsomal fractions from rat brain. 2. In the presence of either palmitic acid or stearic acid, the specific activity of the ligase increased during development; the specific activity of this enzyme with arachidic acid or behenic acid was considerably lower. 3. The specific activities of palmitoyl-CoA hydrolase and of stearoyl-CoA hydrolase in the microsomal fraction decreased markedly (75%) between 6 and 20 days after birth; by contrast, the corresponding specific activities in the soluble fraction showed no decline. 4. Stearoyl-CoA hydrolase in the microsomal fraction is inhibited (99%) by bovine serum albumin; this is in contrast with the microsomal fatty acid-chain-elongation system, which is stimulated 3.9-fold by albumin. Inhibition of stearoyl-CoA hydrolase does not stimulate stearoyl-CoA chain elongation. Therefore it does not appear likely that the decline in the specific activity of hydrolase during myelogenesis is responsible for the increased rate of fatty acid chain elongation. 5. It is suggested that the decline in specific activity of the microsomal hydrolase and to a lesser extent the increase in the specific activity of the ligase is directly related to the increased demand for long-chain acyl-CoA esters during myelogenesis as substrates in the biosynthesis of myelin lipids.


The selective isolation of the uterine oestradiol-receptor complex by binding to oligo(dT)-cellulose. The mediation of an essential activator in the transformation of cytosol receptor. The [3H]oestradiol-receptor complex was selectively isolated from rat uterus cytosol by column chromatography on oligo(dT)-cellulose. Optimal conditions are described for the binding of the complex to oligo(dT)-cellulose, which is shown to be similar to its binding to DNA-cellulose. The cytosol complex has an apparent mol. wt. of 50,000-60,000 in high salt concentrations, as determined by Sephadex G-100 chromatography. This corresponds to the 4S cytoplasmic oestradiol receptor. In binding to oligo(dT)-cellulose the receptor is transformed into a form with an apparent mol.wt. of 100,000-120,000, corresponding to the 5S nuclear receptor complex. This transformation mimics the conversion in vivo of the cytoplasmic oestradiol receptor into the nuclear form. The binding of the complex to oligo(dT)-cellulose as a 5S nuclear form is unequivocally demonstrated to require the mediation of an activating present in the cytosol. The requirement for an activating factor is discussed in relation to reports that nuclear binding of the oestradiol-receptor complex is not dictated solely by the availability of the cytoplasmic oestradiol receptor.


Insulin regulation of amino acid transport in mesenchymal cells from avian and mammalian tissues. Insulin regulation of amino acid transport across the cell membrane was studied in a variety of mesenchymal cell directly isolated from avian and mammalian tissues or collected from confluent cultures. Transport activity of the principal systems of mediation in the presence and absence of insulin was evaluated by measuring the uptake of representative amino acids under conditions approaching initial entry rates. Insulin enhanced the transport rate of substrate amino acids from the A system(alpha-aminoisobutyric acid, L-proline, glycine, L-alanine and L-serine) in fibroblasts and osteoblasts from chick-embryo tissues, in mesenchymal cells (fibroblasts and smooth muscle cells) from immature rat uterus, in thymic lymphocytes from young rats and in chick-embryo fibroblasts from confluent secondary cultures. In these tissues, the uptake of amino acid substrates of transport systems L and Ly+ (L-leucine, L-phenylalanine, L-lysine) was not affected by the presence of the hormone. No insulin control of amino acid transport was detected in chick-embryo chondroblasts and rat peritoneal macrophages. These observations identify the occurrence of hormonal regulatory patterns of amino acid transport for different mesenchymal cells types and indicate that these properties emerge early during cell differentiation.


A new method for the assay of tissue. S-adenosylhomocysteine and S-adenosylmethione. Effect of pyridoxine deficiency on the metabolism of S-adenosylhomocysteine, S-adenosylmethionine and polyamines in rat liver. The hepatic synthesis and accumulation of S-adenosylhomocysteine, S-adenosylmethionine and polyamines were studied in normal and vitamin B-6-deficient male albino rats. A method involving a single chromatography on a phosphocellulose column was developed for the determination of S-adenosylhomocysteine and S-adenosylmethionine from tissue samples. Feeding the rat with pyridoxine-deficient diet for 3 or 6 weeks resulted in a four- to five-fold increase in the concentration of S-adenosylhomocysteine, whereas that of S-adenosylmethionine was only slighly elevated. The concentration of putrescine was decreased to half, that of spermidine was somewhat decreased and that of spermine remained fairly constant. The activities of L-ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, L-methionine adenosyltransferase and S-adenosyl-L-homocysteine hydrolase were moderately increased. S-Adenosylmethionine decarboxylase showed no requirement for pyridoxal 5'-phosphate. The major effect of pyridoxine deficiency of S-adenosylmethionine metabolism seems to be a block in the utilization of S-adenosylhomocysteine, resulting in the accumulation of this metabolite to a concentration that may inhibit biological methylation reactions.


The role of free serum tryptophan in the biphasic effect of acute ethanol administration on the concentrations of rat brain tryptophan, 5-hydroxytryptamine and 5-hydroxyindol-3-ylacetic acid. 1. Acute administration of ethanol exerts a biphasic effect on the concentrations of rat brain tryptophan, 5-hydroxytryptamine and 5-hydroxyindol-3-ylacetic acid. Both effects are associated with corresponding changes in the availability of circulating free tryptophan. 2. The initial increases in the above concentrations are prevented by ergotamine, are unaltered by allopurinol and are potentiated by theophylline, whereas the later decreases are prevented by both ergotamine and allopurinol. 3. It is suggested that the initial enhancement by ethanol of brain tryptophan metabolism is caused by catecholamine-mediated lipolysis followed by displacement of protein-bound serum tryptophan, whereas the activation of liver tryptophaan pyrrolase, which is produced by the same  mechanism, leads to the later decreases in the brain concentrations of tryptophan and its metabolites. 4. The initial effects of ethanol can be reproduced by an equicaloric dose of sucrose, and a comparison of the two treatments alone could therefore be misleading. 5. The effects of ethanol on liver and brain tryptophan metabolism have also been examined in mice, and a comparison of the results with those previously reported suggests that the ethanol effects are strain-dependent.


Regeneration of renal proximal tubules after mercuric chloride injury is accompanied by increased binding of aminoacyl-transfer ribonucleic acid. Homogenates of rat kidney cortex obtained 1,3 or 14 days after a single injection of HgCl2 were used to prepare the post-microsomal pH5 supernatant fraction. The activity of this fraction for peptide synthesis from [14C]phenylalanyl-tRNA was significantly increased at 1 and 3 days, at which time the proximal tubules are regenerating [Cuppage & Tate (1967) Am. J. Pathol. 51, 405-429]. This increased activity could not be attributed to a decreased inhibitory activity, but was due to an increased aminoacyl-tRNA binding, i.e. elongation-factor-1 activity, in the supernatant fraction.


Lectins as membrane components of mitochondria from Ricinus communis. 1. Mitochondria were isolated from developing endosperm of Ricinus communis and were fractionated into outer membrane and inner membrane. The relative purity of the two membrane fractions was determined by marker enzymes. The fractions were also examined by negative-stain electron microscopy. 2. Membrane fractions were sequentially extracted in the following way. (a) Suspension in 0.5M-potassium phosphate, pH7.1; (b)suspension in 0.1M-EDTA (disodium salt)/0.05M-potassium phosphate, pH7.1; (c) sonication in 0.05M-potassium phosphate, pH7.1;(d)sonication in aq. Triton X-100 (0.1%). The membranes were pelleted by centrifugation at 100 000g for 15 min, between each step. Agglutination activity in the extracts was investigated by using trypsin-treated rabbit erythrocytes. 3. The addition of lactose to inner mitochondrial membrane resulted in the solubilization of part of the lectin activity, indicating that the protein was attached to the membrane via its carbohydrate-binding site. Pretreatment of the membranes with lactose before tha usual extraction procedure showed that lactose could extract lectins that normally required more harsh treatment of the membrane for solubilization. 4. Lectins extracted from inner membranes were purified by affinity chromatography on agarose gel. Polyacrylamide-gel electrophoresis of purified samples in sodium dodecyl sulphate indicated that at least part of the lectin present in inner mitochondrial membrane was identical with the R. communis agglutinin of mol.wt. 120 000.


Investigation of the relationship between cell-surface calcium-ion gating and phosphatidylinositol turnover by comparison of the effects of elevated extracellular potassium ion concentration on ileium smooth muscle and pancreas. Incubation of fragments of guinea-pig ileum smooth muscle in the presence of an elevated extracellular K+ concentration, which causes an increase in cell-surface Ca2+ permeability and thus leads to contraction, caused a marked increase in phosphatidylinositol turnover, as assessed by incorporation of 32Pi. This response was not diminished by atropine or propylbenzilycholine mustard, two muscarinic cholinergic antagonists, and was therefore not caused by the release of endogenous acetylcholine within the tissue. In contrast, exposure of guinea-pig pancreas fragments to high extracellular [K+], which does not increase cell-surface Ca2+ permeability or evoke secretion, did not cause an increase in phosphatidylinositol turnover, even though such an increase was triggered by carbamoylcholine, which is a secretagogue. These observations are consistent with a suggested function for phosphatidylinositol breakdown in the mechanisms of cell-surface Ca2+ gates.


Phospholipid requirement for dimethylnitrosamine demethylation by hamster hepatic microsomal cytochrome P-450 enzyme system. Extraction with butan-1-ol of freeze-dried microsomal fractions from livers of 3-methyl-cholarthrene-pre-treated hamsters removed about 90% of the total lipid content, but the lipid remaining proved sufficient for the cytochrome P-450 enzyme system to retain about 15-40% of its original catalytic activity for dimethylnitrosamine demethylation. Addition of butan-1-ol-extracted total phospholipid or phosphatidylcholine could not restore any activity, whereas the addition of the synthetic phospholipid dilauroyl phosphatidylcholine was able to restore almost complete activity. Synthetic dipalmitoyl or distearoyl phosphatidylcholine was ineffective in restoring the activity in this reconstituted system.


The degradation of semisynthetic tritiated insulin by perfused mouse livers. Semisynthetic [3H]insulin was stored under various conditions for up to 180 days and the stability of the insulin under these conditions was assessed. A sample that had been stored for 180 days was repurified and shown to be degraded at the same rate as native insulin by perfused mouse livers, even at low physiological concentrations. After perfusion, intact insulin could be separated from degradation products, and the radioactivity associated with the insulin fraction could be used to determine the percentage degradation. The initial rate of degradation of insulin was a linear function of concentration over the range 360pM-1.9nM.


Cell proliferation in the atherosclerotic plaques of cholesterol-fed rabbits. Part 3. Histological and radioautographic observations on glucocorticoids-treated rabbits. Tritiated thymidine radioautography was employed to study the effect of cortisol and other glucocorticoids on cellular proliferation in the aorta and pulmonary artery of rabbits with cholesterol atherosclerosis. Labelled cell counts showed that glucocorticoids, even after one day and at a relatively low dose, decrease sharply the deoxyribonucleic acid synthesis in the intimal plaques. The hormonal influence on [3H]thymidine uptake seems to be a dose-dependent process. The relative potency of these steroids in inhibiting DNA synthesis in the plaques parallels closely their anti-inflammatory effectiveness. Conversely mineralocorticoids, including aldosterone and deoxycorticosterone, increase the rate of DNA synthesis in the plaques. It is concluded that the antiatherogenic effect of glucocorticoids on cholesterol-fed rabbits may be due, at least partly, to the inhibitory effect of these steroids on the DNA synthesis of the cellular components of the intimal plaques.


Influence of glycosaminoglycan content of mass transfer behavior of porcine artery wall. Part 1. Diffusive transport of 45Ca2+ and 3HHO. The diffusion coefficients of Ca2+ and H2O in in vitro porcine arterial tissue were determined to provide a measure of vascular permeability. The effect of anatomical location and diet on the magnitude of that permeability was evaluated. The diffusion coefficient of calcium was found to vary focally and, in addition, pulmonary artery was much more permeable than thoracic aorta. Four months feeding of a high lipid diet did not affect diffusive transport.


Influence of glycosaminoglycan content on mass transfer behavior of porcine artery wall. Part 2. Differences in mass transfer rates related to variations in glycosaminoglycan content. It has been suggested that the glycosaminoglycans (GAG) influence atherogenesis by regulating the permeability of the arterial wall. For this reason, a study has been made of the diffusive transport of Ca2+ and water across the in vitro porcine artery wall, where particular attention was focused on the influence of GAG content and distribution within the wall on the transport properties. The radioisotop-s 45Ca and 3HHO were used to measure the tracer-diffusion flux in a stirred, two chamber diffusion cell. GAG were isolated, fractionated using a cetyl pyridinium chloride-cellulose column procedure, and assayed using a colorimetric carbazole reaction for uronic acid. The biochemical analyses showed that the pulmonary artery contains significantly more hyaluronic acid and dermatan sulfate than found in two locations in the thoracic aorta. In addition, a significant regression  was found for the diffusion coefficient of 45Ca2+ (99% level) and 3HHO (95% level) versus specific GAG fractions. The regression indicated an increase in permeability with increase in the ratio of sulfated: nonsulfated GAG.


A comparative study of human tissue and post-heparin plasma triglyceride lipases. Human post-heparin plasma contains at least two different triglyceride lipases (TGL). The plasma lipolytic activity has been attributed to extra-hepatic and hepatic origin. Both post-heparin triglyceride lipases were partially purified and characterized. With heparin-Sepharose 4 B affinity chromatography it was possible to partially purify human adipose tissue lipoprotein lipase (LPL) as well as a lipase from human liver. The effects of NaCl, pre-heparin plasma, pH and temperature on these two tissue lipases and plasma lipases were studied in parallel. Antibodies were produced against plasma hepatic triglyceride lipase (plasma H-TGL) that did not cross react with LPL. TGL activity of human liver was completely inhibited by antibodies against plasma H-TGL. From these results it appears that human post-heparin plasma contains two triglyceride lipase activities which originate from liver and extra-hepatic tissues such as adipose tissue.


Effects of clofibrate treatment on arginine-induced insulin secretion in endogenous hypertriglyceridemia. Arginine-induced insulin secretion was evaluated in 13 patients with endogenous hypertriglyceridemia (Fredrickson's Type IV) before and after a two-month period of Clofibrate therapy. Clofibrate reduced triglyceride, cholesterol and FFA levels by 68, 28 and 15% respectively and provoked a significant reduction in arginine-induced insulin secretion without modifying glucose response. Arginine-induced insulin secretion was also studied in 11 normal subjects during saline and intralipid infusions. Glucose and insulin basal values, and glucose and insulin response to arginine infusion were not influenced by Intralipid infusion in these controls. These results confirm that clofibrate reduces insulin secretion thereby contributing to decreased serum triglyceride levels.


Lipid metabolism in cultured aortic smooth muscle cells and comparison with other cell types. Part 2. Reversibility of lipid accumulation caused by hyperlipemic serum. The lipid compositions of cultured rabbit aortic smooth muscle cells and skin fibroblasts were determined for cells grown in media containing either normolipemic or hyperlipemic sera. Both cell types accumulated cholesteryl esters and triglycerides after treatment with hyperlipemic serum. Within 4 days of returning cells that had accumulated these neutral lipids to medium containing a low percentage of normolipemic serum, their concentrations in both cell types had returned to levels similar to those found in cells cultured in standard growth medium. Thus the accumulation of cholesteryl esters and triglycerides in smooth muscle cells, as in fibroblasts, may be completely reversed in vitro.


Effects of methyl prednisolone and colchicine on the development of aortic atherosclerosis in swine. The effect of methyl prednisolone and colchicine on the development of both the early proliferative and advanced atherosclerotic lesion in swine aorta was studied. In order to accelerate the development of atherosclerosis, the abdominal aortic endothelium was partially denuded by a balloon before the animals were placed on either a moderate or severe hypercholesterolemic diet. Neither drug in either dietary group inhibited the development of atherosclerosis. Swine receiving methyl prednisolone and severe hypercholesterolemic diet actually had a significantly greater number of the advanced necrotic lesions and more arterial calcification than the group receiving the atherogenic diet alone. In addition, the thoracic aorta of swine receiving the moderate hypercholesterolemic diet and methyl prednisolone showed larger amounts of lipid than did the non-drug fed control group. In swine receiving the moderate hypercholesterolemic diet, methyl prednisolone significantly raised serum cholesterol levels. Colchicine only slightly worsened the atherosclerosis in swine aorta and had no effect on serum cholesterol levels.


Consideration of atherosclerotic plaques as benign neoplasms. The monoclonal nature of atherosclerotic plaques, as well as their altered cell size, proliferation rate and function have led to the hypothesis that plaque tissue is analogous to benign tumors. To test this hypothesis, we have studied rates of DNA release by histologically-normal human arterial wall tissue and by early atherosclerotic plaques during incubation in a maintenance medium. No DNA was detected in media conditioned by normal arterial tissue after a 24 h incubation period, but plaque tissue (like benign tumors) released 10-100 ng DNA/ml during this period. These data offer additional support for the thesis that atherosclerotic plaques are similar to benign tumors.


The synthesis of lipids from [1-14C]acetate by human venous endothelium in tissue culture. Endothelial cells from human umbilical cords were harvested, using a trypsin technique, grown in tissue culture and lipid synthesis studied using [1-14C]acetate as a precursor. Radiosubstrate was incorporated into fatty acids, mono-, di- and triglycerides, cholesterol esters and phospholipids. Radioactivity was also present in the culture medium in the mono-and diglyceride fractions and in the phospholipids running with the solvent front.


Influence of Etofibrate on plasma fibrinogen and plasminogen concentrations in patients with different forms of primary hyperlipoproteinemia. The effect of Etofibrate, a chemical compound of the two antihyperlipidemic agents Clofibrate and nicotinic acid, on elevated plasma fibrinogen and plasminogen concentrations was investigated in a 6 months' survey in 25 patients with different types of primary hyperlipidemia. A consistent reduction of fibrinogen levels to normal occurred after 6 months' therapy, whereas the effect on plasminogen concentrations was weaker and not significant. The fibrinogen-lowering effect of Etofibrate was not related to the pretreatment levels but nearly equal in all cases. The possible consequences on the hemostatic system are discussed. On account of the low daily dosage, apart from a slight flush, no side-effects were noted.


ABO blood group and cardiovacular disease: the Framingham study. Following determination of ABO blood type at the sixth biennial examination, the Framingham Heart Study cohort was followed for the occurrence of cardiovascular events for a period of 10 years. A significant association was found between blood type and intermittent claudication, with blood group O showing the lowest rates. Slight but non-significant excesses for certain other CHD events were also found in non-O individuals. Serum cholesterol showed marginally significant but consistent elevations in non-O subjects but the increased risk in non-O individuals was found to occur independently of the known intermittent claudication risk factors. Since the observed relationship between blood type and intermittent claudication occurs independently of the usual atherosclerotic risk factors, blood type, possibily through an effect on clotting, should be considered in the pathogenesis of intermittent claudication.


Influence of oxygen tension of the metabolism of vascular smooth muscle: demonstration of a Pasteur effect. The influence of variations of oxygen tension on the metabolism of bovine mesenteric arteries was studied in vitro. Glucose uptake, lactate production, glycogen content, adenosine triphosphate (ATP), creatine phosphate (CrP) and incorporation of [14C]leucine into protein were determined. The mesenteric arteries were suspended in Krebs-Henseleit bicarbonate buffer which was aerated with a gas mixture containing 5% CO2,O-95% O2 and N2 to 100%. Reduction of the O2 concentration of the gas phase from 95-20% resulted in little metabolic change. A further reduction from 20-0% O2 increased the lactate production 4-fold, indicating a marked Pasteur effect. At 0% O2 the glucose uptake was moderately increased and the glycogen content was decreased. The tissue level of CrP was reduced at a low oxygen tension and at 0% O2 the ATP content was also lowered. The incorporation of leucine into proteins was reduced at 0% O2.


[Influence of urban air pollution on DDT blood levels in children]. The blood levels of DDT in two groups of girls from two districts of São Paulo (Brasil) were the same. Both groups were equal in age and nutrition. The difference in air pollution showed no influence on the blood levels of DDT.


[Perforation of the esophagus. Diagnosis and treatment. Analysis of 20 cases]. The experience on perforation of the esophagus at the Hospital Infantil de México is reviewed. Between 1961 and 1975, 20 cases were attended. The most frequent perforation is the iatrogenic subsequent to dilatations or to esophagoscopy. Esophageal perforation is the most serious of the digestive tube perforations and must be considered as a real medicosurgical emergency. The clinical picture is analyzed and the necessity to take chest x-rays and esophagogram as urgent measures is emphasized at the slightest clinical doubt. The different treatment methods are mentioned and it is stressed that the best results are obtained with an urgent thoracotomy, closure of the perforation, full canalization and antibiotic therapy at high doses. According to the literature referred and to the results obtained from the present study, mortality is higher in cases where treatment is delayed. The clinical and radiological pictures are described together with the therapeutic behavior in spontaneous perforation in the newborn. The theories to explain this etiology are set forth. At present, mortality is still high; therefore, in order to bring down this high percentage, it is concluded that an early diagnosis together with an agressive surgical treatment are necessary.


[Ectopic ureter in Gartner's duct. Report of a clinical case]. Presentation is made of a clinical case of paradojical urinary incontinence due to ectopic ureter in Gartner's duct. Diagnosis was made almost entirely from the patient's history, the child voids normally but she was always damp. Embryological, radiological and pathophysiological considerations are made; the patient showed sudden and positive continence after heminephrectomy.


[Cervical cryptothyroidism. Report of 2 cases]. Two cases of abnormality in the normal embrionary migration of the thyroid gland are reported with hyoid and sublingual location. Both cases where misdiagnosed and operated as thyroglossal cysts. The methods of treatment are reviewed and emphasis is placed on the convenience to make gammagraphic studies in patients with a mid-line cervical mass.


[Latin American pediatrics confronting challenge]. The problems related with health of the mother and child in Latin America are discussed. Due to the fact that the infant mortality rate is still high in many countries, the establishment of rural and peripheral health centers attended by pediatricians, obstetricians and trained nurses are advised; when professional staff is not available, paramedical personnel with a short training on preventive medicine, nutrition and health education may be used. Hospital facilities must be available for more complicated medical services.


[Syndrome of the 1st and 2nd branchial arches. Report of 3 cases]. Three newborn babies were studied in our hospital with the following associated unilateral deformities: macrostomia, hemignathia and anomalies of the external ear. The main symptom was the inability for suction causing some weight loss. These cases could be logically named "syndrome of the first and second branchial arches" because of their common origin. We discuss the pathogenesis and the differences with other diseases including those of hereditary origin. The initial management is discussed.


[Duodenal ulcers in children].

[Duodenal ulcers in children]. This paper includes a report of five cases of peptic ulcer in infancy. Emphasis is made between clinical symptoms and signs with adult's disease, and the great difficulty in its diagnosis, during childhood. Pertinent literature is reviewed.


[Fatal toxoplasmosis in children].

[Fatal toxoplasmosis in children]. Fatal cases of toxoplasmosis seen at the Hospital Infantil de México between 1943 and 1973, together with postmortem studies are reviewed. There were five postmortem studies where it was possible to identify toxoplasma in histologic lesions. Clinical manifestations were grouped in pictures; thus, the infectious picture, the intracranial hypertensive, the neurological and the meningeal pictures were made up. In all five cases of this small group, toxoplasma was identified within and without parasitized cells and was found specially abundant in the central nervous system. Considering the early initiation of neurological manifestations and the intensity of encephalic lesions, it may be assumed that all five cases of prenatal toxoplasmosis. The reason why an infection so usually light in the mother is able to cause a disease so severe in the fetus seems to have an explanation on the fact that toxoplasma increases in virulence when reaching the product as second-step infection. In all five cases, the intensity of the lesions agrees with the severeness of the clinical picture and with the early manifestations following birth. The parasite was identified in the brain in all cases and in some of them, in the liver and lungs.


[Immunopathological prediction index of frequent relapses in children with lipoid nephrosis]. Forty-four renal biopsies were performed in the same number of selected patients with the diagnosis of lipoid nephrosis. Immunopathologic studies were carried out in all the biopsies. Positive immunofluorescence to immunoglobulins, complement/or fibrin was found in 21 cases (48%). A correlation was found between immunopathological findings and the number of patients with frequent relapses. More number of patients with frequent relapses were found in the group with positive immunofluorescence (p less than 0.01) than in those with negative results. No explanation was found for this situation; however it is suggested that the glomerular detection of immune proteins with lipoid nephrosis could be a useful parameter to predict frequent relapses in children with lipoid nephrosis.


[Diagnostic orientation of principal surgical entities in the newborn infant and generalities on their management]. The present article describes the main surgical pathology of the newborn, which often requires immediate management. The author(s) mention the essential points of diagnosis and treatment. The principal objective in the article is to emphasize the importance of this surgical pathology in pediatric and general practice.


[Goldenhar's syndrome].

[Goldenhar's syndrome]. We are presenting five cases of Goldenhar's syndrome studied at the Clinical Genetics Unit of the Hospital Infantil of México. We do not know exactly the type of inheritance of this congenital malforamtion; in one of our cases, it seems to be related to advanced paternal age. We can consider the possibility of autosomal dominant neomutation.


[Thoracic complications of liver abcess in children]. The study included 58 cases of liver abscess draining into the thorax, seen at the Hospital Infantil de Mexico from January, 1963 to December, 1973. These 58 complicated cases represent 16.2% from a total of 358 patients with liver abscess seen through the same period of time. The clinical picture, period of evolution, methods of diagnosis, treatment and results are analyzed finding that out of 50 cases draining into pleura or lungs, 44 were admitted with this complication already present, the same as 5 out of the 8 cases to pericardium. From the 58 cases, 24 died and 34 recovered. An early diagnosis of uncomplicated amebic liver abscess and adequate treatment constitute the basis to prevent the high morbilethality subsequent to complications.


[Shigellosis related with the cause of death in children]. From a series of 4,147 postmortem studies, there were 2,280 cases of infectious processes as responsibility of death out of which, 647 corresponded to the digestive tract. Within the group of digestive tract infections, 283 were of bacterial nature and within this last group, there were 43 cases of shigellosis. Included in the fatal cases of shigellosis is the description of their description by ages and sexes; the types of enteropathogenic germs identified in the course of disease and at postmortem studies are mentioned and special reference is made to the type and localization of lesions within the digestive tract. Also, the type and localization of extraintestinal lesions, directly or indirectly related with shigellosis are described. Pathological processes considered as immediate cause of death are pointed out and from the group is extraintestinal infections, the germ identified in each as responsible of death is mentioned. Finally, a brief outline is made of the clinicopathological correlation.


[Study of visual acuity disorders in school children]. The results of an analysis of 475 ophthalmologic examinations in children between eight and nine years old with an electric "Titmus" apparatus, are presented. The main object of the present communication was the detection of early alterations in visual acuteness. The alterations were: Distant visual acuteness: 57; distant lateral phoria 70.1%; distant vertical phoria: 47.3%; color perception (just males) 15.5%. These results stress the importance of the procedure in detecting alterations of visual acuteness in children.


[Longitudinal study of patients with febrile convulsive crises]. This longitudinal study included 113 patients seen through a period of 8 years with febrile convulsive crises, especially of the tonoclonic type, with predominance in males and with average age at the onset of the disease of 6 months. Infectious respiratory processes were considered as the main cause of fever and the drug given most often was sodium diphenylhydantoin. The value of EEG in febrile convulsive crises was confirmed since the first graphic traces were abnormal in 95% of cases and that generalized paroxysmal or focal alterations were considered suggestive of epilepsy and or organic damage. The most common grapho-element was of slow wave of high voltage. Alterations in the E.E.G. persisted and was more abnormal in 23% of the cases including specific tracings in 37%. These findings are similar to those reported in other studies carried out in children with febrile convulsions.


[Osteogenesis imperfecta].

[Osteogenesis imperfecta]. Our clinical files on osteogenesis imperfecta are brought up-to-date reviewing a total of 33,555 cases admitted between 4/XII/48 and 31/VIII/76. From these, 5 clinical cases were found. The extreme rareness of this regional pathology in our Cátedra y Sericio de Pediatría, which is the largest concentration center in Paraguay had led us to make this publication. From our casuistics, we may single out a three-month-old infant which would be a case of congenital osteogenesis imperfecta. The remaining 4 would correspond to cases of late osteogenesis imperfecta. Generalized osteoporosis was present in 3 patients and all of them showed blue sclera the same as fractures of femur. Fractures of radius, tibia and fibula were seen in 2 cases. The humerus was fractured in one patient and the ulna in another one. Three patients were under one year old, another one was on his second year and the last one was a school ager. An audiologic examination was normal in the nine-year-old patient. In the other 4 cases, it was not possible to carry out such test.


[Description of health problems affecting the maternal and child groups]. This article is a brief description related to maternal and child health problems in Mexico, with an introduction of Latin-American scope of the problem. The author mentions also the up-to-date systems for the analysis of these health problems, like the indicators based on life-level instead of infant mortality or maternal mortality and others; however the author chooses to use the traditional indicators in his article.


[Juvenile rheumatoid arthritis, Report of 12 cases]. This report includes 12 cases of juvenile rheumatoid arthritis seen through a period of 4 years of Unidad de Pediatría del Hospital General de México, S.S.A. An analysis is made on the etiology, prevalence, clinical symptoms, laboratory findings, radiology and treatment. The youngest patient was 3 years old and the oldest 14. Three groups were formed on the basis of the mode of onset; 4 patients were included in the systemic group, 7 in de polyarthritis and one in the monoarticular. All patients showed arthralgias and flogosis with joint disability in one or more joints; eleven patients developed joint deformity; 4 patients had fever and rheumatoid rash was detected during the course of the disease. Subcutaneous nodules were detected in one patient. Radiological abnormalities, compatible with juvenile rheumatoid arthritis, were found in all patients. Laboratory findings are discussed and a clinical correlation is made in order to emphasize the differences with adult disease. The principles of general treatment are analyzed including, medical, phychologic and rehabilitation programs. Pertinent literature is reviewed.


Anatomical study of truncus arteriousus communis with embryological and surgical considerations. Twelve specimens of truncus arteriosus communis have been studied anatomically, with special reference to the conal anatomy and to the associated cardiac anomalies which can create additional problems if surgical repair is planned. A wide spectrum of conal morphology has been observed, suggesting that differential conal absorption is a developmental characteristic of truncus arteriousus as well as of transposition complexes. The invariable absence of septation of the ventricular infundibula and semilunar valves, in spite of the variable anatomy of the free wall of the conus, indicates that all types of truncus arteriosus, ontogenetically, should be considered as a single undivided conotruncus. Various types of ventircular septal defect were found: (a) ventricular septal defect with absent crista, in which no remnants of conal septum are present; (b) supracristal ventricular septal defect, in which vestigial conal septum is seen in front of the membranous septum; (c) bulloventricular foramen, associated with univentricular origin of the truncus from the right ventricle. Frequent associated anomalies are underdevelopment of the aortic arch, truncal valve malformations, and obstructive ventricular septal defect. The AV conduction system studied in one case showed an arrangement similar to Fallot's tetralogy with the His bundle and the left bundle-branch in a safe position behind the posteroinferior rim of the defect. The postoperative fate of the frequently abnormal truncal valve and the theoretical indications for total repair for Type IV truncus are also discussed.


Double outlet right ventricle. Study of 27 cases. Out of 1610 children's hearts with congenital malformations there were 27 specimens showing double outlet right ventricle. Cases with dextrocardia, situs inversus, or l-venticular loop were excluded. Anatomical examination was performed with particular reference to the infundibular region, the great vessels, and the ventricular septum. The commonest associated malformations were ventricular septal defect and pulmonary stenosis. Aortic stenosis was the predominant finding in those cases dying in the neonatal period. An aortic conus was associated with pulmonary stenosis, ventricular septal defect, and d-transposition, a pulmonary conus with ventricular septal defect and a double conus with stenosis of either great vessel. The anterior vessel always had a muscular conus and the posterior vessel was commonly stenotic.


Pregnancy in patients after valve replacement. This report is based on information obtained from a questionnaire sent to major cardiac centres in the United Kingdom. This produced details of 39 pregnancies in 34 patients after valve replacement. The 39 pregnancies gave rise to 30 healthy babies. The small size of the series probably reflects both the increasing rarity of young women with rheumatic heart disease in this country and the cautious attitude of their cardiologists. This makes it likely that these women represented the best end of the spectrum of cardiac function after valve replacement. Twenty-four pregnancies in 20 women who were not given anticoagulants producted 23 healthy babies and 1 spontaneous abortion. This group comprised 6 patients with free aortic homografts, 1 patient with a fascia lata mitral valve, 1 with a Beall tricuspid prosthesis, 1 with a combined mitral homograft and Starr Edwards aortic prosthesis, and 1 with mitral and aortic frame-mounted fascia lata valves. There were no maternal deaths or thromboembolic complications in this group which included 5 patients who were in atrial fibrillation. Fifteen pregnancies in 14 women who received anticoagulants gave rise to 7 healthy babies. The fetal losses were one stillbirth, one intrauterine death at 34 weeks, and 3 spontaneous abortions; one surviving child has hydrocephalus as a result of blood clot and there were 2 maternal deaths. This group included 13 patients with Starr Edwards valves, 11 mitral and 2 aortic. A patient with a Hammersmith mitral valve was the only one to have been treated with heparin and her valve thrombosed. One patient with a mounted mitral homograft had a cerebral embolus. Nine of these patients were in atrial fibrillation. In 3 additional patients the valve replacement was carried out during pregnancy. Two of the patients survived operation. In one of these who was treated with warfarin the pregnancy well, but there is an increased fetal wastage in patients pregnancy gave rise to a congenitally malformed baby who died in the neonatal period. The baby born to the mother who did not receive anticoagulants has a hare-lip and talipes. Women with artificial valves can tolerate the haemodynamic load of pregnancy well, but there is an increased fetal wastage in patients taking oral anticoagulants. This is probably largely attributable to fetal haemorrhage but there is also a risk of malformation caused by a teratogenic effect of warfarin. Experience gained in non-pregnant patients suggests that withholding anticoagulatns in pregnant patients with prosthetic valves would usually be undersirable but warfarin should be avoided. The advantages of biological valves were apparent in this series.


Malfunction of Björk-Shiley valve prosthesis in tricuspid position. Eight months after triple valve replacement with Björk-Shiley tilting disc valves a patient developed symptoms and signs suggesting malfunction of the prosthesis in the tricuspid position. This was confirmed by echocardiography and angiocardiography, and at operation thedisc of the prosthesis was found to be stuck half-open by fibrin and clot. A further 11 patients with the same tupe of prosthesis in the triscupid position were then studied by phonocardiography and echocardiography. In one of these the prosthesis was found to be stuck and this was confirmed by angiocardiography and surgery. These 2 cases are reported in detail and the findings in the other 10 are discussed. The implications of this high incidence of malfunction of the Björk-Shiley prosthesis in the tricuspid position are considered. Echocardiography appears to be essential in the follow-up of such patients.


Intraoperative left ventricular perforation with false aneurysm formation. Two cases of perforation of the left ventricle during mitral valve replacement are described. In the first case there was perforation at the site of papillary muscle excision and this was recognized and successfully treated. However, a true ventricular aneurysm developed at the repair site. One month after operation rupture of the left ventricle occurred at a second and separate site on the posterior aspect of the atrioventricular ring. This resulted in a false aneurysm which produced a pansystolic murmur mimicking mitral regurgitation. Both the true and the false aneurysm were successfully repaired. In the second case perforation occurred on the posterior aspect of the atrioventricular ring and was successfully repaired. However, a false ventricular aneurysm developed and ruptured into the left atrium producing severe, but silent, mitral regurgitation. This was recognized and successfully repaired. The implications of these cases are discussed.


Short left coronary artery trunk as a risk factor in the development of coronary atherosclerosis. Pathological study. The relation between the length of the main left coronary artery and the degree of atherosclerosis in its branches was studied by postmortem examination in 204 subjects aged 20 to 90 years. The findings suggest that in cases with a short main left coronary artery the atherosclerotic lesions in the anterior descending and circumflex branches appear earlier, progress faster at higher levels of severity, and lead more frequently to myocardial infarction, than in cases with a long left coronary artery trunk. In cases over the age of 50 years, where disease is expected to have developed, it was shown that the degree of atherosclerosis in the left anterior descending and circumflex branches was inversely related to the length of the main left coronary artery. The correlation coefficients were -0-527 and -0-428, respectively, and in either case a test for zero correlations was significant (P less than 0-001). The possible changes in the haemodynamic and mechanical conditions associated with the variations of the anatomical pattern of the coronary arteries and their influence in the development of atherosclerosis are discussed. It is suggested that the length of the main left coronary artery is a congenital anatomical and possibly hereditary factor influencing  the rate of development of atherosclerosis in the branches of the main left coronary artery.


Frequency of arrhythmias and other cardiac abnormalities in fulminant hepatic failure. In a series of 106 patients with fulminant hepatic failure and grade 4 encephalopathy, cardiac arrhythmias and other abnormalities occurred in 92 per cent. The most common was sinus tachycardia (75%) and this was the only abnormality in 22 per cent of the patients. Sudden cardiac arrest occurred in 25 per cent, various ectopic beats in 20 per cent, and heart block or bradycardia in 18 per cent. Other electrocardiographic abnormalities, mostly of the T wave and ST segment, were found in 31 per cent. Cardiac and respiratory arrests were usually unrelated to each other and both frequently occurred without warning. Only 7 out of 71 patients with arrhythmias other than sinus tachycardia survived, compared with 15 out of 31 patients without them (P less than 0-005). During the latter part of the series when an arrhythmia computer was used to monitor 38 patients, it was shown that significantly lower arterial oxygen levels occurred in those with arrhythmias, other than sinus tachycardia, than in those without. They were also found to be more acidotic and hyperkalaemic, and a higher number required dialysis and ventilation. Macroscopical cardiac abnormalities including scattered petechial haemorrhages, small pericardial effusions, and fatty, pale, and flabby ventricles, were found at necropsy in 64 per cent of the patients examined. Combinations of these macroscopical abnormalities occurred, particularly in the paracetamol overdose group. Another necropsy finding of possible significance in the pathogenesis of arrhythmias was cerebral oedema, present in 48 per cent of the patients examined, and often associated with coning of the brain stem. However, 7 of the 16 patients who suffered asystolic cardiac arrests had no macroscopical abnormality of either heart or brain. In the management of patients with fulminant hepatic failure continuous cardiac monitoring is essential. Correction of the biochemical and coagulation defects may decrease the frequency of arrhythmias but studies of the mechanism and control of cerebral oedema and its relation to cardiovascular function are urgently needed.


Discriminant function analysis of factors related to myocardial infarction in male patients on antihypertensive therapy. Records of 367 male patients who began attending the Dunedin Hospital Hypertension Clinic between 1959 and 1969 were coded up to the end of 1972. Of these patients, 60 had their first myocardial infarction, or sudden cardiac death without previous evidence of myocardial infarction, while they were attending the clinic. This infarct group was compared with a control group of 120 which was chosen from the remaining patients so that the two groups would be comparable with regard to their age and year of first attendance. A stepwise discriminant function analysis showed that the basal systolic and diastolic pressures measured when patients started attending the clinic were the variables with the most significant difference. Further analysis showed that inclusion of the average casual standing systolic pressure when patients were receiving antihypertensive therapy improved the discrimination between the groups. The average casual standing diastolic pressure during antihypertensive therapy also improved the discrimination, but, curiously enough, with a negative sign in the discriminant function. Quetelet's index of obesity similarly improved the discrimination, obese subjects having less risk of infarction or sudden death. Serum cholesterol, however, was not related to prognosis.


Coronary angiography Review of 1500 consecutive cases. Fifteen hundred coronary angiograms have been performed by the staff of Harefield Hospital since 1970. Only 2 deaths have occurred in the last 1000 consecutive cases though there were 5 in the first 500 cases. This drop in the mortality is ascribed to careful attention to detail and better training of the operators. It is concluded that the Fudkin's method of coronary angiography in trained hands is a safe method of investigation but that because of the very serious potential dangers it is unjustifiable for new units to start unless there is a fully experienced investigator in charge.


Echocardiographic diagnosis of large fungal verruca attached to mitral valve. In a patient with endocarditis due to Candida tropicalis echocardiograms from mitral valve vegetations were found to mimic the typical pattern of a left atrial myxoma. A mass was shown occupying the mitral orifice posterior to the anterior mitral leaflet; densities also appeared in the left atrium. Though these echocardiographic findings were consistent with the diagnosis of a left atrial myxoma, there were other distinctive differential diagnostic features. Other diagnostic possibilities must, therefore, be considered in the interpretation of echocardiograms which suggest left atrial tumour.


Left ventricle to pulmonary artery conduit in treatment of transposition of great arteries, restrictive ventricular septal defect, and acquired pulmonary atresia. Progressive cyanosis after banding of the pulmonary artery in infancy occurred in a child with transposition of the great arteries and a ventricular septal defect, and a Blalock-Taussig shunt operation had to be performed. At the time of correction a segment of pulmonary artery between the left ventricle and the band was found to be completely occluded so that continuity between the left ventricle and the pulmonary artery could not be restored. A Rastelli type of operation was not feasible as the ventricular septal defect was sited low in the muscular septum. Therefore, in addition to Mustard's operation, a Dacron conduit was inserted from the left ventricle to the main pulmonary artery to relieve the obstruction. Postoperative cardiac catheterization with angiocardiography indicated a satisfactory haemodynamic result. The patient remains well 11 months after the operation. This operation, a left ventricle to pulmonary artery conduit, may be used as an alternative procedure in patients with transposition of the great arteries, intact interventricular septum, and obstruction to the left ventricular outflow, if the obstruction cannot be adequately relieved.


Reversion to sinus rhythm 11 years after surgically induced heart block. A patient is presented in whom the heart reverted spontaneously to sinus rhythm 11 years after surgical closure of a ventricular septal defect complicated by complete heart block. It seems unlikely that regeneration of fibres in the bundle of His, if these had indeed been destroyed, could account for the restoration of sinus rhythm after so long an interval.


Left ventricular function in chronic renal failure. Left ventricular function was studied in 14 patients with end-stage chronic renal failure using non-invasive methods (echocardiography and systolic time intervals). Patients were divided into 3 groups. Group 1 consisted of 5 patients who were normotensive at the time of study and group 2 of 7 patients who were hypertensive when studied. Group 3 consisted of 2 patients: one was receiving propranolol and the other, studied 302 days after renal transplantation, was receiving digitalis for recurrent episodes of cardiac failure. All except the patient receiving propranolol had normal left ventricular function in systole with normal measurements of fractional fibre shortening (% delta S, EF) and normal measurements relating to the velocity of ventricular contraction (mean Vcf, mean velocity of posterior wall motion). Stroke volume and cardiac output were normal in some patients but were increased in patients with fluid overload. Early diastolic compliance of the left ventricle seemed to be normal except in the patient with recurrent cardiac failure. The study provided no evidence for the existence of a specific uraemic cardiomyopathy.


Haemodynamic adaptation at rest and during exercise to long-term antihypertensive treatment with combination of beta-receptor blocking and vasodilator agent. Systemic and pulmonary haemodynamics were studied at rest in the supine and upright position, and during exercise in the sitting position at 75 and 150 Watt, in 13 hypertensive men aged 50-8 +/- 8-7 years before and after 13 months treatment with oral oxprenolol (120 to 160 mg t.i.d.) supplemented by oral hydrallazine (50 to 75 mg t.i.d.) during the last 6 months. Pressures were recorded by means of catheters inserted percutaneously into the pulmonary and brachial artery; cardiac output was determined according to Fick. Treatment resulted in a significant reduction of systemic systolic, diastolic, and mean pressures at rest in the supine position and during exercise, and of systolic pressures in the upright posture. Pulmonary systolic and mean pressures increased slightly at rest in the supine position and during exercise, and no changes occurred at rest in the upright position. The left ventricular filling pressure was unchanged at rest both in the supine and upright position; it increased slightly during exercise. The haemodynamic changes by which systemic pressure was reduced were those typical of beta-adrenergic blockade: reduction of cardiac output resulting from a decrease of both heart rate and stroke volume, while the total systemic vascular resistance was unchanged at rest in the supine position but increased in the upright posture and during exercise. The A-V O2 difference increased remarkably. This long-term observation again suggests that the acute haemodynamic effects of an antihypertensive regimen can be modified during long-term application. It did not give evidence of a readjustment of the vascular resistance occurring, at least not in the upright position and during exercise, as has been suggested for long-term beta-adrenergic blockade.


Electrophysiological effects of mexiletine in man. The electrophysiological effects of intravenous mexiletine in a dose of 200 to 250 mg given over 5 minutes, followed by continuous infusion of 60 to 90 mg per hour, were studied in 5 patients with normal conduction and in 20 patients with a variety of disturbances of impulse formation and conduction, by means of His bundle electrography, atrial pacing, and the extrastimulus method. In all but 2 patients the plasma level was above the lower therapeutic limit. Mexiletine had no consistent effects on sinus frequency and atrial refractoriness. The sinoatrial recovery time changed inconsistently in both directions; however, of the 5 patients in whom an increase was evident, 3 had sinus node dysfunction. In most patients mexiletine increased the AV nodal conduction time at paced atrial rates and shifted the Wenckebach point to a lower atrial rate. The effective refractory period of the AV node was not consistently influenced, while the functional refractory period increased in 12 out of 14 patients. The HV intervals increased by a mean of 11 ms in 8 patients and were unchanged in 17. Both the relative and effective refractory period of the His-Purkinje system increased after mexiletine. Non-cardiac side effects occurred in 7 out of 25 patients, and cardiac side effects, including one serious, in 2. The results indicate that mexiletine shares some electrophysiological properties with procainamide and quinidine, when given to patients with conduction defects, and that the drug should not be used in patients with pre-existing impairment of impulse formation or conduction. It has additional effects on AV nodal conduction which may be of value in the treatment of re-entrant tachycardias involving the AV node.


Angiographic abnormalities associated with alterations in regional myocardial blood flow in coronary artery disease. To evaluate the association between alterations in myocardial blood flow and angiographic findings, myocardial blood flow was compared in 26 patients with asymergy, 15 patients with a similar extent of coronary artery disease but without asynergy, and 10 patients without coronary artery disease or obvious myocardial or valvular disease. Myocardial blood flow was measured at rest with an Anger camera and PDP-11/20 computer after the intracoronary injection of 133xenon. In comparison with the normal subjects, whole heart blood flow was significantly reduced in patients with asynergy. In addition, myocardial blood flow in regions of anteroapical asynergy was reduced (85-7 +/- 7-0 ml/min per 100 g3 in controls to 65-4 +/- 4-5, P less than 0-05) and a similar reduction was noted in regions of posterolateral asymergy (91-5 +/- 8-8 in controls to 66-8 +/- 5-0, P less than 0-05). In general, regional myocardial blood flow was reduced distal to left anterior descending or left circumflex stenosis of less than 50 per cent, with a trend toward further reduction distal to less than 75 per cent stenosis. In these same patients, the presence of anteroapical or posterolateral asynergy resulted in a similar trend to even greater reduction of flow. The effect of collaterals was variable: 7 of 8 patients without asynergy but with less than 75 per cent left anterior descending stenosis and collateral circulation to the lower left anterior descending quadrant had minimally reduced flows. However, in the 17 patients with anteroapical asynergy, regional myocardial blood flow was very similar in the 9 patients with collaterals compared with the 8 patients without them. This study suggests that the degree of coronary artery stenosis and presence of asynergy are both important in evaluating alterations in myocardial blood flow in coronary artery disease, while the role of collaterals remains uncertain.


Longitudinal study of heart size in older people. Transverse cardiac diameter and transverse thoracic diameter were measured in a longitudinal study of older men and women at the original examination and after five years. The cardiothoracic ratio overestimated 5-year changes in heart size, because of significant decreases with age in transverse thoracic diameter. A regression equation to predict transverse cardiac diameter from age and weight had been previously computed from the data obtained at the initial examination. This was a satisfactory predictor of recorded 5-year changes except in women of 70 years and over at entry to the study in whom the predicted change was significantly larger than the recorded change. This had resulted from the death during the 5 years of women in that age group with larger transverse cardiac diameters.


Histopathology of conducting system in left anterior hemiblock. In 8 cases of left anterior hemiblock, combined with right bundle-branch block in 7, serial sections of the conducting system of the heart were examined histologically. In all cases there were pathological changes in the left bundle-branch but the anterior part of it was predominantly affected in only 2 cases. Acute changes were found in 6 cases of early myocardial infarction, and fibrosis in 2 cases of chronic heart disease. Reversible lesions may have a pathogenetic role in acute hemiblocks. The right bundle-branch was disrupted by fibrosis in 6 of the 7 cases with right bundle-branch block, and minor changes in the AV node were observed in 1. The widespread damage to the left bundle-branch in the majority of the present cases does not seem to be consistent with the limited clinicopathological correlation implied by the terms anterior fascicular block or hemiblock. Other cardiac lesions within the left bundle-branch and outside it may contribute to this electrocardiographic pattern.


Histopathological findings in two cases of torsade de pointes with conduction disturbances. Histological studies were made of the conducting system and the myocardium in two cases of torsade de pointes with complex disturbances of impulse conduction and formation. A fairly similar clinicopathological pattern was seen, consisting of an unusual association of non-interruptive, widespread damage to the conducting system with the intermittent and variable electrocardiographic disorders. The inherent desynchronization of cardiac action and the bilateral, uneven, and partial disruptions of the bundle-branches have been tentatively correlated, pathophysiologically, with the re-entry circuit, or mechanism, which is held to be responsible for the cyclic fluctuation of QRS axis, peculiar to torsade de pointes.


Non-invasive assessment of left ventricular function after correction of severe aortic regurgitation. Twenty patients were studied with simultaneous left ventricular cavity echocardiograms and apex cardiograms during the first two weeks after correction of severe aortic regurgitation. Endocardial echoes and apex cardiograms were digitized, so that left ventricular dimensions, their rates of change, and echo dimension-apex cardiogram relations could be studied. After aortic valve replacement, there was an early reduction in end-diastolic dimension, within 2 days, from 7-0 +/- 0-8 cm to 5-7 +/- 1-0 cm (P less than 0-001), while peak normalized shortening rate (peak Vcf) dropped from 1-9 +/- 0-6 to 1-4 +/- 0-6 S-1 (P less than 0-01), and remained unchanged for the remainder of the study. Immediately after operation, striking abnormalities of isovolumic contraction and, to a lesser extent, of early relaxation, could be seen, which regressed over 4 to 7 days, except in 2 patients who developed a low output state. These changes in left ventricular dimension, Vcf, and isovolumic contraction could not have been described by an single "measure" of left ventricular function.


Heart rate--left ventricular ejection time relations. Variations during postural change and cardiovascular challenges. Regression equations for heart rate (HR)--ejection time (LVET) relations provide the appropriate factors for predicting or correcting left ventricular ejection time at any HR. We investigated HR-LVET regressions under different conditions common to both physiological and clinical studies of LVET which had been selected because of predictably different physiological responses. Ten normal subjects were studied during both supine and sitting rest and during isometric handgrip (IHG) in both supine and sitting postures and 10 during head-up tilt. Unexpectedly, as compared with pre-exercise rest on a bicycle ergometer, the slope for the resting state on a chair was slightly flatter, and LVET values were uniformly higher throughout the range of HRs measured. Differences among HR-LVET slopes and intercepts appeared to reflect the established behaviour of stroke volume and ejection rate under the conditions studied. Differences observed among intercepts, especially in supine vs. upright postures, are substantial and require that the appropriate intercept be applied in predicting LVET at a given HR. differences among slopes, while not statistically significant, may, under practical conditions, lead to unacceptable error if the appropriate slope factor is not used in correcting LVET for HR.


Plasma zinc in acute myocardial infarction. Diagnostic and prognostic implications. Zinc is a metal component of many important enzymes, and its availability controls the rate of synthesis of nucleic acids and protein. Serum zinc levels have been shown to fall after acute tissue injury, including myocardial infarction. The purpose of this clinical study was to examine the value of plasma zinc measurements in a coronary care unit. Studies were made in 188 patients: 88 with unequivocal myocardial infarction, 52 controls, and 48 in a borderline group. Patients with myocardial infarction showed a fall in plasma zinc within the first three days, whereas patients in the other two groups did not. The difference in the mean minimum zinc levels between the groups with and without infarction was highly significant. In patients with myocardial infarction there was good correlation between the minimum plasma zinc level and the peal value of plasma enzymes, and also with some clinical estimators of prognosis. A fall in plasma zinc is a reliable diagnostic test for acute myocardial infarction, and the extent of the fall has prognostic implications.


Chronic His bundle block. Clinical, electrocardiographic, electrophysiological, and follow-up studies on 16 patients. This report describes 16 patients with block within the His bundle seen over a period of 55 months. Ten were women and 6 men, with an average age of 76 years, range, 42 to 98 years. All patients had His bundle recordings showing split His bundle potentials (H and H) (13 patients) or narrow QRS with block distal to the His bundle potential (3 patients). Of the 16 patients, 10 had complete heart block, 4 second degree AV block (2 patients with Mobitz type II, and 2 with 2:1), and 2 first degree AV block. Ten patients had a narrow QRS in the conducted beats or escape rhythms. Intravenous atropine (1 to 2 mg) had a variable effect on AV conduction and the rate of the escape rhythm. Twelve patients have had a permanent pacemaker implanted. During the follow-up period, 10 patients died 1 to 31 months from the time of initial examination. The remaining 6 patients (5 with pacemaker) are alive 3 to 58 months later.


Monophasic action potentials of right atrium and electrophysiological properties of AV conducting system in patients with hypothyroidism. In 12 patients with manifest hypothyroidism right atrial monophasic action potentials showed a significant prolongation in comparison with data from normal or euthyroid patients. Atrial effective refractory periods were also significantly prolonged. After thyroid treatment the monophasic action potential duration and the effective refractory period of the right atrium were within normal ranges. In 6 hypothyroid patients studies of AV conduction with the aid of His bundle electrography and atrial pacing showed a supraHisian conduction delay which was manifest in one case and latent in another two. InfraHisian conduction delay was encountered in 2 cases.


Fatal outcome arising from use of a sutureless "corkscrew" epicardial pacing electrode inserted into apex of left ventricle. A 59-year-old man is described in whom the insertion of an epicardial sutureless "corkscrew" electrode resulted in fatal ventricular perforation. Fatal myocardial perforation can occur with this electrode and the apex of the left ventricle should never be used as the site of insertion. Necropsy also showed that the transvenous right ventricular electrode, inserted one year previously, had penetrated a tricuspid leaflet. This could have accounted for the ensuing pacing failure.


Pseudo second degree atrioventricular block with bradycardia. Successful treatment with quinidine. Pseudo second degree atrioventricular block resulting from blocked His premature beats was successfully treated with quinidine. The diagnosis was proved by His bundle electrogam which showed both blocked and conducted His premature beats. The blocked His prematures produced second degree atrioventricular block by making the atrioventricular junction refractory. Quinidine abolished both conducted and blocked His extrasystoles. There has been no recurrence of arrhythmia during a one-year follow-up.


Macrophage electrophoretic mobility (MEM) with myelin basic protein. Lymphocytes from a total of 161 subjects, including normal controls and patients with malignant and non-malignant conditions, have been investigated for their response to myelin basic protein, using the macrophage electrophoretic mobility (MEM) test. It has been confirmed that there was a high level of association between clinically evident cancer and a positive response. Lymphocytes from 24/25 patients with non-malignant inflammatory and ischaemic diseases also gave positive responses. In 46 patients with breast lumps studied before mastectomy or biopsy, the test was positive in 15/19 cases which proved to be malignant and in 5/27 which proved benign on histological examination. In its present form the test is not sufficiently reliable for the diagnosis of early cancer. Our results suggest that tissue necrosis in malignant and non-malignant conditions may be one of the factors resulting in sensitization to antigenic determinants present in preparations of myelin basic protein. Despite its technical difficulties, the test may provide a means of examing some aspects of immune recall not readily revealed by other test systems.


Stimulation of autologous blood lymphocytes by malignant lymphoma cells and homogenates. The blastogenic response to autologous blood lymphocytes to whole-cell suspensions and to homogenates obtained from malignant lymphoma tissue has been investigated. Spleens were obtained from patients in whom laparotomy was performed for staging of malignant lymphoma. Cell suspensions prepared from tumour nodules were treated with mitomycin C and allowed to react with separated autologous blood lymphocytes for 6 days. Lymphocyte stimulation was measured by liquid scintillation counting after exposure to 3H-TdR. Cultures were also prepared in which autologous lymphocytes were treated with spleen tumour homogenate. Control experiments used spleens from staging procedures in which no tumour deposits were present, and normal spleens removed incidentally during other operations. In the controls, the uptake of TdR was never more than twice that of unstimulated lymphocytes. Greater degrees of lymphocyte stimulation were seen in 6 out of 14 patients, using whole tumour cells, and in 7 out of 16 patients, using tumour homogenates. The results indicate an antigenic difference between tumour and host cells, and suggest that lymphocytes can react to a tumour-associated antigen.


Inhibition of K cell function by human breast cancer sera. Sera from breast cancer patients and from female controls were tested for inhibition of lysis of antibody-coated target cells by human leukocytes (K cells). Sera from 39% of breast cancer patients, but from only 8% of controls, inhibited lysis by more than 30%. This inhibition was unrelated to the stage of the disease, the patient's age or whether the patient was pre- or post-operative. Inhibition was apparently not due to anti-HLA antibodies and did not correlate with the IgG level or anti-complementary activity of the serum. On fractionation by gel-filtration, inhibitory activity was found in fractions of higher molecular weight than IgG. As no IgG could be detected in these fractions, inhibition is probably not due to immune complexes containing IgG antibody. The inhibitory factor may well contribute to the immunosuppressed status of a proportion of breast cancer patients.


Prognostic value of peripheral lymphocyte count in hormone therapy of advanced breast cancer. Peripheral lymphocyte counts were performed on 41 patients with advanced breast cancer, before starting treatment with oestrogens or androgens. Patients were seen at monthly intervals, and the response to treatment was independently assessed, using the criteria of the British Breast Group. In the patients treated with oestrogens and androgens, the successful responders were found to have significantly higher pre-treatment peripheral lymphocyte counts than the intermediate responders and failures. It is suggested that pre-treatment peripheral lymphocyte counts may have a prognostic value in assessing potential response to hormone therapy in patients with breast cancer.


Rat sarcoma model supports both "soil seed" and "mechanical" theories of metastatic spread. Following injection into the portal venous or vena caval systems, tumour cells are held up almost exclusively in the liver or lung respectively, and subsequent outgrowth of tumour only occurs in these organs. Following systemic arterial injection, cells are distributed, and subsequently grow, in a variety of organs. However, the adrenal gland supports tumour growth from much fewer cells than the lung, and this is partly due to the fact the rate of tumour cell loss in the initial 48 h is very high in the latter compared to the former organ.


Selective promoting activity of phorbol myristate acetate in experimental skin carcinogenesis. Experiments were undertaken to study the effect of promotion treatment on epidermal tumour induction pattern in precancerous mouse skin. Swiss albino mice were given a single s.c. injection of 0-5 mg 20-methylcholanthrene in the right scapular region. Six weeks later, 1-83 nmol of phorbol myristate acetate (PMA) was applied biweekly on the reactive skin. Histopathology of the induced tumours showed early appearance of squamous cell carcinomas and rhabdomyosarcomas. Fibrosarcoma, the most common tumour type induced on MCA injection alone, was absent. Trichoepithelioma, a benign tumour, was induced in PMA-treated mice. This gives new evidence of the selective action of PMA, enhancing the induction of epithelial and muscle tumours, with concurrent inhibition of fibroblastic tumours.


Sex dependence of human intracranial gliomata. The age and sex distribution of 1223 cases of intracranial gliomata, diagnosed in the geographical area covered by the Mersey Regional Cancer Registry over the period 1961-70, are analysed. In children and adults, the intracranial gliomata predominates in males, the tumour incidence figures indicating a ratio of 3 : 2. For young adults, the tumour incidence increases with age and is approximately the same in males and females. It is not until the age group 45-49 years is reached that the tumour incidence in males is higher. The peak tumour incidence occurs at the same age in both sexes (60-64 years) and thereafter incidence declines with age. These results are compared with previously published human data, and with the findings of experimental studies in the rat. Factors including naturally occurring changes in the hormone levels are discussed, in an attempt to explain the observed age-related sex differences.


Isoprenaline-induced changes in regional myocardial perfusion in the pathogenesis of myocardial necrosis. Isoprenaline in a single dose induces impairment in perfusion of the subendocardial myocardium of the rat left ventricle. This defect in perfusion persists for up to 150 min and corresponds in distribution to the myocardial necrosis produced by similar doses of isoprenaline. It is mediated by the beta-receptors as it is prevented by beta-blockade with propranolol. It is considered that isoprenaline-induced myocardial necrosis represents myocardial infarction.


Experimental canine distemper infection as a means of demonstrating latent effects of subacute lead intoxication. Observations on the response of the body to experimental infection with distemper virus in dogs previously dosed subacutely with lead have demonstrated a latent effect of lead on several body systems. Effects which indicated a relationship to earlier treatment with lead included evidence for stimulation of haemoglobin synthesis, changes to red blood cells resulting in increased destruction, increased vulnerability of the parenchymatous cells of the liver to damage, reduction in the weight of the skeleton and thyroid, an increase in weight of the thymus and brain and histopathological changes in the thymus.


Comparative effects of cortisone, dianabol and enovid on isoprenaline-induced myocardial infarction in arteriosclerotic vs nonarteriosclerotic rats. Male and female nonarteriosclerotic (virgin) and arteriosclerotic (breeder) Sprague-Dawley rats were subjected to acute myocardial infarction with isoprenaline. When myocardial necrosis was most intense, animals were given cortisone (high and low doses), Dianabol, or Enovid. Animals receiving large doses of cortisone manifested the best survival rate during the early stages of myocardial infarction. Although their serum enzyme levels were least elevated and their hearts showed tha least amount of damage, these animals had undergone the most intense body weight loss and began to die suddenly during the later stages of the experiment. These animals also manifested hyperlipidaemia, hyperglycaemia, septicaemia, severe disuse atrophy of their adrenal glands, and reduced Cmpd. B production. Animals treated with low doses of cortisone or with the anabolic and androgenic steroid, Dianabol, manifested none of the myocardial pretective effects of the larger dose of cortisone. These animals displayed a high incidence of left ventricular aneurysm formation concomitant with extensive cartilaginous metaplasia within the aneurysmal sites. Treatment with the contraceptive drug, Enovid, caused body weight loss, hyperlipidaemia, hyperglycaemia, gonadal atrophy and reduction of Cmpd. B production. Although the high dose of cortisone exercised definite salutary effects during early myocardial infarction, chronic treatment led to adrenal disuse atrophy and hypoadrenocorticism associated with sudden death during the later stages of myocardial repair. These findings indicate that proper adjustment of the dose and chronicity of corticosteroids used for treating the crisis of acute myocardial infarction must be made in order to provide effective protection against untoward pathophysiological conditions, acceleration of myocardial repair, but without suppression of adrenal function.


Colchicine inhibition of the first phase of amyloid synthesis in experimental animals. Colchicine was found to inhibit the first phase of casein-induced synthesis of murine amyloid. When mice were treated with colchicine during the first 7 days of an amyloid induction regimen or when colchicine was given to the donor mice in a transfer model, the amyloidogenic stimulus of casein was blocked completely. Amyloid synthesis was however, not interrupted by the administration of colchicine during the last 7 days of the casein regimen nor by colchicine treatment of recipient mice in a transfer model.


The role of prostaglandins in chemically induced inflammation. Dye leakage in rats, produced by intracutaneous injections of irritants into the abdominal skin, was quantitated using the Evans blue technique of Harada et al. (1971). In control rats and in rats pretreated with indomethacin (an inhibitor of prostaglandin synthesis) concentration-response lines were obtained for 5-hydroxytryptamine, histamine, bradykinin and prostaglandin E1, bradykinin in the presence of prostaglandin E1 (10-6 M), adenosine-5'-triphosphate, compound 48/80, capsaicin and silver nitrate. In rats pretreated with indomethacin the dye leakage responses to histamine, prostaglandin E1, adenosine-5'-triphosphate and silver nitrate were significantly reduced, but no significant changes were observed in the responses to the other irritants. It is suggested that part of the action of histamine, adenosine-5'-triphosphate and prostagland in E1 is produced indirectly by releaseor stimulation of the synthesis of prostaglandins or their precursors. These results might have important implications in the understanding of the inflammatory response.


Skin reaction and antibody responses in guinea-pigs sensitized to human leukaemia cells or their nuclei in combination with Bacillus Calmette-Guérin. Guinea-pigs sensitized by subcutaneous injection of chronic lymphatic leukaemia (CLL) cells combined with Bacillus Calmette-Guérin (BCG) displayed good skin reacitons 24 and 48 h after challenge with CLL cells. Equally good responses were also demonstrated using nuclei from the leukaemic cells in combination with BCG. These reactions were significantly greater than those produced in the same manner but without BCG. Sera form the animals were examined for the presence of antibodies against CLL cells by cytotoxicity and immunofluorescence techniques. Only samples from guinea-pigs innoculated with CLL cells were found to contain significant antibodies. Histological examination showed that whereas leukaemic cells persisted at the sensitizing injection site leukaemic cell nuclei could not be visualized. It is suggested that because leukaemic cell nuclei in combination with BCG are able to induce good skin reactivity without provoking a vigorous humoral antibody response they may have possible advantages over leukaemic cells when used for immunotherapy.


The action of the benzopyrones on an experimental model of lymphoedema: a contribution to their mode of action. A number of preparations containing benzopyrones are used clinically as a therapy for lymphoedema; however, their exact mode of action is not well known. This work presents evidence which indicates that, as in the treatment of thermally induced oedemas, the benzopyrones work by enhancing the lysis of the accumulated proteins. This is evidenced by reduced levels of total protein in the extracellular compartment of the skin, while peptides and amino acids were increased in the serum at 6 and 12 h respectively after the drug's administration. Failure to observe very marked increases in peptides and amino acids at other times in the serum and skin was attributed to the rapid incorporation of these into the large number of maturing phagocytes which enter the lymphoedematous tissues. Likewise, protease activity levels were not elevated as expected. This possibly was the consequence of a number of factors including serum deactivation, inhibition of release and membrane stabilization.


Thrombosis induced in vivo in the mesenteric artery of rats. An electron microscopic study of the initial phases. Local thrombosis was initiated in vivo by applying a weak electric current to the mesenteric artery of rats. The thrombi adhered to areas of arterial wall exhibiting endothelial cell loss and muscle cell damage. They showed no tendency to sustained growth and contained large amounts of vaguely fibrillary substance that enmeshed platelet aggregates and infiltrated the denuded subendothelial layer. The subsequent local administration of dilute ADP led to brisk platelet aggregation and rapid increase in size of the thrombi. The large thrombotic masses disappeared as soon as the administration of ADP was stopped, leaving behind small remnants which, like the initial thrombi, were predominantly composed of enmeshing substance and could be stimulated to renewed growth by resuming the administration of ADP. It appears that the enmeshing substance plays a major role in the stability and cohesion of early thrombi which do not yet contain fibrin. It conceivably is made up of fibrin monomers.


Decreased vascular reactions to permeability factors in experimental diabetes. Light and electron microscopic studies showed that blood vessels of the cremaster muscle of alloxan-diabetic rats under the local influence of histamine or serotonin presented less labelling by colloidal carbon, previously injected i.v., than vessels of normal rats. The hyporeactive state of these vessels was promptly reversed to normal conditions by the administration of insulin. Insulin also potentiated leakage of carbon particles in the vessels of normal animals. These findings add new evidence that insulin might be involved in vascular events following injury and that decreased levels of the hormone, as occurring in diabetes, might result in decreased inflammatory reactions.


The cell cycle in psoriasis: a reappraisal. The current belief that the clinical manifestations of psoriasis (excessive scaling) are due to a twelve-fold speeding up or shortening of the cell division cycle time of the germinative cells in psoriatic epidermis (from 457 to 37-5 h) is shown to be incorrect. A new concept is introduced--that the germinative layer in human epidermis is composed of not one, but three separate and distinct populations of epidermal cells. First, there are cycling cells which are actively moving through the cell cycle. Then there are two categories of non-cycling cells (blocked in the G1 or the G2 periods of the cell cycle) which are capable of moving into the proliferative pool upon specific stimulation. Thus, increased epidermal cell proliferation in active lesions of psoriasis would be brought about mainly by a recruitment or a relase of the two categories of non-cycling cells. The idea that germinative epidermal cells are primarily non-cycling, leads to the suggestion of focusing attention on non-cycling cells (rather than on cycling cells) for the control and treatment of psoriasis. It might be worthwhile considering treating psoriatic patients during periods of clinical remission--with factors to keep the germinative cells in the non-cycling state--rather than during psoriatic flare up--with cancer chemotherapy drugs.