Influence of  a chronic environmental stress on the incidence of methylcholanthrene-induced tumors. The influence of a chronic environmental stress, living in a 2 degrees environment, on the incidence of methylcholanthrene-induced tumors in albino female Simonsen rats, a Sprague-Dawley-derived strain, was studied. The results indicated that the metabolic rate was double for rats kept at 2 degrees, compared with those kept at 25 degrees. Exposure to 2 degrees for life, with no other treatment, reduced median life expectancy to 560 days compared with 686 days for rats kept at 25 degrees. Transfer to a 2 degrees environment after 250 days at 25 degrees reduced the incidence of spontaneous tumors, while transfer to 25 degrees after 250 days at 2 degrees increased the incidence of tumors compared to that for rats always kept at 25 degrees. Exposure to an environmental temperature of 2 degrees immediately following a carcinogenic stimulus (3-methylcholanthrene, 2 mg s.c.) significantly reduced the incidence of tumors compared to that in rats kept at 25 degrees but did not change tumor induction time. The reduced tumor incidence may have resulted from inhibition of the carcinogenic transformation by chronic stress. The survival time of rats with 3-methylcholanthrene induced tumors was not significantly less in a 2 degrees environment than it was at 25 degrees.


Mechanism of tumor cell resistance to lysis by syngeneic lymphocytes. B16 melanoma variant lines, which resisted lysis by syngeneic lymphocytes, were selected in vitro by repeated exposure of the tumor cells to purified cytotoxic lymphocytes. The resistance of the tumor cells to lysis mediated by syngeneic lymphocytes was not accompanied by a loss or masking of major histocompatibility antigens. Neither the lymphocyte-susceptible B16 (F10) nor the lymphocyte-resistant B16 (F10Lr) cells grew in allogeneic recipients, and both were destroyed in vitro by allogeneic lymphocytes. The resistance to lysis by syngeneic lymphocytes was not accompanied by loss or masking of receptors for macrophage recognition and destruction. F10Lr cells did not protect F10 cells from lymphocyte-mediated lysis in cocultivation experiments. Immunization of syngeneic mice in vivo with B16-F10 cells successfully protected mice against challenge with B16-F10 cells. However, mice immunized with B16-F10Lr cells were not protected against challenge with B16-F10 cells. B16-F10Lr cells were not immunogenic when tested under this condition. Light, scanning, and transmission electron microscopic studies of tumor cell-lymphocyte interaction suggested that the resistance of B16-F10Lr cells to destruction by syngeneic lymphocytes in vitro was due to the masking or absence of tumor-specific antigen(s) present on the lymphocyte-susceptible F10 cells.


Ultrastructural comparison between cultured and tumor cells of human malignant melanoma. Tumor cells from 28 human malignant melanomas were compared by electron microscopy with cultured cells of 17 established human melanoma cell lines derived from the same types of tumors. Both tumor and cultured cells were classified into five types according to their different fine-structural characteristics. There was a correlation between the cell types observed in the tumor fragments and in the cell lines. This evidence suggests that cultured human melanoma cells retained in vitro the characteristics of the melanoma cells in vivo, from which they were derived.


Disposition of 5-fluorouracil after intravenous bolus doses of a commercial formulation to cancer patients. A high-pressure liquid chromatographic method that is used to determine the pharmacokinetic disposition of 5-fluorouracil from the plasma compartment is presented. The method requires only 0.5 ml of plasma for each determination and is sensitive to 0.1 mg of drug per liter. Novel methodology with the use of an ion-specific electrode technique for the determination of urinary excretion kinetics of 5-fluorouracil and its metabolites is also presented. This study demonstrated a much greater variability for the disposition of 5-fluorouracil by cancer patients than has been reported previously. The apparent volume of distribution for this drug varied more than 37-fold. Its plasma half-life varied more than 19-fold, and its urinary excretion half-life varied almost 400-fold. These data are compatible with the hypothesis that this variation could account, at least in part, for the variable therapeutic and toxic response to 5-fluorouracil. The methodology presented in this study is sufficiently simple and sensitive to allow assessment of this hypothesis by investigating cancer patients who receive therapeutic doses of 5-fluorouracil.


Method for quantitating tumor cell removal and tumor cell-invasive capacity in experimental metastases. An improved method is presented for analyzing the decay of i.v.-injected labeled tumor cells in the lung. A simple compartment analysis yields quantitative values for (a) the rate at which tumor cells are lost or cleared from the lung, and (b) the "invasion" rate at which tumor cells colonize the interstitial space. Statistical methods are outlined for testing the significance of the contribution of each rate to the overall shape of the decay curve and for testing whether or not a given rate is altered significantly during an experiment. The usefulness of the method is demonstrated in analysis of experiments involving perturbations of the host or of the injected tumor cells.


Variants of a human colon adenocarcinoma cell line which differ in morphology and carcinoembryonic antigen production. A variant, HCT-8R, of the colon adenocarcinoma cell line HCT-8 was located and cloned. The variant and parent cell line were characterized with respect to morphology, growth characteristics, karyotype, production of Cea, and ability to form tumors in nude mice. The variant cells differed from the parent cells in morphology, marker chromosomes, and ability to form colonies in soft agar and produced more carcinoembryonic antigen. The two cell strains were equally oncogenic in nude mice, although HCT-8R cells produced poorly differentiated tumors while HCT-8 cells produced tumors with both differentiated and poorly differentiated areas. Thus, in nude mice, no correlation was observed between carcinoembryonic antigen production by cells and their oncogenicity.


Heterotransplantation of a human prostatic adenocarcinoma cell line in nude mice. Nude mice of NIH/Swiss background were utilized for the heterotransplantation of a tissue culture cell line derived from a human prostate adenocarcinoma metastatic to the brain. These cells, which had been grown in vitro for 13 passages, formed solid tumors when injected s.c. into nude mice. The cell line DU 145 has been passaged 60 times in vitro over a period of 18 months. Tumors removed from the mice were serially transplanted to additional mice and reestablished in vitro. Light-microscopic analysis of the tumor grown in nude mice revealed a strong similarity to the patient's metastatic tumor. The ultrastructure of the tumor cells propagated in nude mice was compared to that of the original human tumor cells and to the tissue culture cells, both before and after passage in nude mouse. No major differences were detected. Karyotypic analysis of the tumor cells grown in vitro before mouse passage, grown in nude mouse, and grown in vitro after mouse passage indicated chromosomal identity and consistent marker chromosomes: three large acrocentric chromosomes and metacentric minute chromosomes.


Cellular and serum involvement in protection against Friend leukemia virus. Treatment of mice with the immunomodulator pyran copolymer inhibited leukemogenesis produced by Friend leukemia virus (FLV) complex, as evidenced by inhibition of the spleen focus-forming virus and lymphatic leukemia virus, as well as by a significant decrease in splenomegaly. In this report we present data suggesting that the protective effect of pyran is mediated by macrophages. Protection was conferred on normal recipient mice when peritoneal exudate cells from pyran-treated mice were transferred to recipient mice infected 24 hr later with FLV. Animals receiving pyran-activated peritoneal cells had a significant reduction of splenomegaly and of titers of spleen focus-forming virus and lymphatic leukemia virus than did control animals. In contrast, when glycogen-elicited peritoneal exudate cells were transferred, the mice were not protected. Pyran-activated peritoneal cells, but not normal peritoneal cells, also inhibited FLV growth in vitro. Serum from pyran-treated, but not glycogen-treated, mice also transferred resistance to FLV-infected mice.


Clinical significance of fucose level in glycoprotein fraction of serum in patients with malignant tumors. Serum fucose content in the glycoprotein fraction was determined in various patients with malignant and benign diseases. The results showed that, in contrast to benign diseases, malignant diseases were characterized by an increased fucose content in the glycoprotein fraction. However, no significant difference was noted in the fucose levels in the mucoprotein fraction. The increased fucose level in glycoprotein in malignant diseases was parallel to the increment in total fucose content in serum, which suggests that the increased levels in total fucose in malignant diseases, reported previously, are primarily due to the increase in fucose-containing glycoprotein.


Isozymes of acid phosphatase in normal and cancerous human prostatic tissue. The supernatants of the homogenates from normal and cancerous human prostatic tissue run on polyacrylamide gel electrophoresis have 2 major electrophoretic bands when stained for prostatic acid phosphatase. The ratios of the electrophoretically distinguishable isoenzymes differ in normal and cancerous tissues. Similar distinctions between isoenzymes in normal and cancerous prostates are observed following column chromatographic separation or isoelectric focusing. The faster electrophoretic band can be separated by diethylaminoethyl cellulose column chromatography or by isoelectric focusing into at least five fractions with different electrophoretic mobilities. We could not find any differences in normal and cancerous tissues among these subfractions of the faster-moving electrophoretic band. Analysis by gel electrophoresis does not show association between these fractions after chromatographic or isoelectric separation of the prostatic acid phosphatase fractions. Quantitative, but no qualitative, differences in prostatic acid phosphatase isozymes occur in normal versus cancerous prostates.


Modification of benzo(a)pyrene metabolism with microsomes by addition of uridine 5'-diphosphoglucuronic acid. The metabolism of benzo(a)pyrene (BaP) by rat liver microsomes was examined in the presence and absence of uridine 5'-diphosphoglucuronic acid (UDPGA). BaP metabolites were separated by high-pressure liquid chromatography. The normal chromatographic patterns of the metabolities were altered by the addition of UDPGA. At concentrations of UDPGA at which the elutions of dihydrodiol components were unchanged, phenol and quinone elution profiles were selectively decreased. The decreased activities of microsomal mixed-function oxidases by UDPGA were also observed with the use of the aryl hydrocarbon hydroxylase assay. The decrease may not be due to inhibition of those enzymes, but rather to formation of glucuronide conjugates with oxygenated BaP metabolites. These results suggest that glucuronidation may be important in the detoxification of BaP.


Comparison of the tumor-initiating activities of benzo(a)pyrene arene oxides and diol-epoxides. The ability of arene oxides, and diol epoxides of benzo(a)pyrene to initiate skin tumors in mice was determined by using a two-stage system of tumorigenesis. (+/-)-7beta,8alpha-Dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was a more effective tumor initiator than was (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene when applied topically to CD-1 mice and then followed by twice-weekly applications of the promotor 12-O-tetradecanoylphorbol-13-acetate. (+/-)-7beta,8alpha-Dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was approximately 20 to 30% as active as benzo(a)pyrene was as a tumor initiator. (+/-)-7beta,8alpha-Dihydroxy-7beta,8beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, benzo(a)pyrene, 9,10-oxide, and benzo(a)pyrene 11, 12-oxide, possessed about 1, 2, and 10%, respectively, of the tumor-initiating activity of benzo(a)pyrene.


Immune RNA-mediated transfer of tumor antigen responsiveness to unresponsive peritoneal exudate cells from tumor-bearing animals. Peritoneal exudate cells (PEC) from mice inoculated 5 to 7 days previously with 1 X 10(6) MOPC-315 plasmacytoma cells exhibit in vitro migration-inhibitory factor reactivity to soluble tumor-associated antigens. By 10 to 14 days of tumor growth, PEC from MOPC-315-bearing mice did not elicit migration-inhibitory factor when stimulated with MOPC-315 tumor-associated antigens but were still capable of migration-inhibitory factor production when stimulated with nontumor antigens. RNA-rich extracts prepared from 5- and 6-day postgrafting tumor bearers were capable of transferring tumor antigen reactivity to both normal PEC and PEC from unresponsive MOPC-315-bearing mice. On the other hand, RNA from unresponsive tumor bearers was incapable of transferring tumor antigen reactivity to normal mouse cells.


Immunomorphological features of prognostic significance in Dukes' Class B colorectal carcinoma. Histological slides of primary tumors and regional lymph nodes from 134 unselected patients operated on for colorectal carcinoma of Dukes' Class B were assessed semiquantitatively for the presence of perivascular lymphocyte cuffing in the muscular layers and pericolic/subserosal fat immediately subjacent to the tumors and for paracortical hyperplasia in the regional lymph nodes. These two immunomorphological features related significantly to each other (p less than 0.05), and their combined presence related signifcantly to favorable disease-free interval (p = 0.02) and to survival (p = 0.04), making possible the identification of a subgroup of approximately one-third of Dukes' B class patients with an estimated better than 85% chance for 5-year recurrence-free survival.


Effect of high-fat diet on colon carcinogenesis in F344 rats treated with 1,2-dimethylhydrazine, methylazoxymethanol acetate, or methylnitrosourea. Male inbred F344 weanling rats were fed semipurified diets containing 20 or 5% beef fats. At 7 weeks of age, all animals except controls were given 1,2-dimethylhydrazine [DMH (150 mg/kg body weight s.c.; one dose)], methylazoxymethanol acetate [MAM acetate (35 mg/kg body weight i.p.; one dose)], or methylnitrosourea (2.5 mg/rat/week intrarectally; two doses), and autopsied 35 weeks later. No major differences were observed in the frequency (number of rats with tumor) of DMH- or MAM acetate-induced duodenal, ear duct, and kidney tumors between the rats fed diets containing 20 or 5% fat. However, the animals fed the diet containing 20% fat had slight although not statistically significant influence on the incidence of adenomas and adenocarcinomas in the colon.


Embryogeneic cell type, organ site sequence specificity in human cancers. An extensive series of cross-hybridization studies were carried out with the DNA-RNA molecular hybridization technique. Molecular 70 S [3H]DNA probes synthesized from human central nervous system, gastrointestinal, pulmonary, and prostatic carcinomas were hybridized to cytoplasmic RNA's isolated from cancers of virtually all organ sites of the human body. Results indicated sequence homology between cancers of the same organ or cell type but not with cancers of different cell types. Thus cell types based on embryological origins determine the organ site specificity of the involved sequences. The designation of 70 S [3H]DNA denotes those [3H]DNA's that were copied off the template 70 S RNA, as distinguished from total [3H]DNA product, which includes all DNA's synthesized. It does not necessarily follow nor is it to be inferred that the 70 S [3H] DNA thus designated contains the full complement of the sequences found in the 70 S RNA template.


Combined gas chromatography-chemical ionization mass spectrometry of sphingolipids. I. Glucosyl sphingosine, ceramides and cerebrosides of the spleen in Gaucher's disease. Trimethylsilylated glucosyl sphingosine, ceramides and glucocerebrosides were analysed by combined gas chromatography (GC)-chemical ionization (CI) mass spectrometry. Isobutane, methane and ammonia were used as reactant gasses for chemical ionization. Essentially the same fragment ions were detected in the spectra with the different reactant gases. Purified glucocerebrosides isolated from the spleen of a patient with Gaucher's disease were clearly separated into their 8 molecular species by gas chromatography. Three other minor components were detected by spectrometry, and these 11 molecular species of glucocerbrosides from the spleen of the patient with Gaucher's disease have been analysed. The ceramides obtained by periodate oxidation and then alkaline reduction of the glucocerebrosides were also separated into 11 molecular species by GC-CI mass spectrometry. Molecular weight could be determined using the major fragment ion of m/e (M+-90) in the spectra of ceramides and cerebrosides. The chemical ionization method is useful for structural analysis and determination of the molecular species of sphingoglycolipids.


The interaction of 1-anilino-8-naphthalenesulfonate with thyroid lipids and membranes: a nuclear magnetic resonance study. The proton magnetic resonance (PMR) spectra of thyroid cell membranes and their total lipid extracts, in the presence of 1-anilino-8-naphthalenesulfonate (ANS), have been studied. The addition of ANS causes an shifting of the head group PMR signal, a splitting of the signal into two components and an increase in total spectral intensity. The data suggest that ANS interacts with phospholipid in the membrane as it does in total lipid vesicles. Evidence is also presented for the removal of lipids from the membrane, by ANS, and the subsequent formation of micelles. The membrane results are compared with our earlier work on the interaction of ANS with egg phosphatidylcholine (P.C.) vesicles and the results are used in explaining the inhibition of iodide transport in isolated thyroid slices.


Proton conduction in phosphatidylethanolamine. The dc conductivity of polycrystalline phosphatidylethanolamine (PE) was measured in the temperature range 60-120 degrees C. Since no conclusive evidence had so far been obtained for the presence of proteon conduction in this phospholipid, hydrogen gas was shown in the present experiment to evolve during the electrolysis in its premelted state between 91 and 124 degrees C. In this temperature range molecules assume rotation around the molecular axes and proton conduction of the Grotthus type takes place possibly along two chains of intermolecular hydrogen bonds running in parallel. Zwitter-ions behave cooperatively as proton donors and acceptors in transferring proton from molecule and molecule via the hydrogen bond networks. This efficient push-pull way of proton transferring seems to account for the fact that no polarization was observed in the dc conduction experiments. The amount of devolved gas appears to be not exactly in accordance with Faraday's law and discussions are made on possible causes for this slight deviation.


Cerebroside analogues from 3-phenylserines. Cerebroside analogues were synthesized from DL-threo-and DL-erythro-3-phenylserines by the following sequence of reactions: esterification, N-acylation, reduction with sodium bis (2-methoxyethoxy)-aluminum hydride (SMEAH), and condensation with acetobromoglucose followed by deacetylation. Mass spectrometry disclosed that the glycosidic bond was formed at the primary hydroxyl group.


Heterogeneity of the hypoxic state in perfused rat heart. Tissue oxygen gradients were examined in the saline-perfused rat heart by NADH fluorescence photography. In high flow hypoxia, where the coronary flow was maintained and the arterial oxygen tension was gradually reduced, oxygen extraction was virtually complete before oxygen consumption was significantly diminished. Inadequate oxygen delivery resulted in a well defined pattern of anoxic zones. The anoxic zones were several hundred microns in width, an order of magnitude greater than intercapillary distances. In low flow hypoxia (ischemia), where the arterial oxygen tension remained at its control value and the coronary flow was diminished, anoxic zones also developed, following the same pattern as in high flow hypoxia. However, in ischemia, the anoxic areas developed while the effluent oxygen tesion was significantly greater than zero. Whereas respiratory acidosis between pH 7.3 and 6.9 resulted in vasodilation, below PH 6.8 there was a marked increase in vascular resistance. Anoxic zones appeared despite only a slight change in effluent oxygen tension from the control. In high flow hypoxia, ischemia, and acidosis-induced ischemia, the anoxic zones disappeared when control perfusion conditions were restored. The data demonstrate that tissue oxygen gradients are very steep in the hypoxic state, so that ischemia and hypoxia result in discrete heterogeneous areas of anoxic tissue bounded by sharp areas where the oxygen supply is sufficient to maintain normal mitochondrial oxidative function. In these states in which oxygen delivery is less than oxygen demand, coronary perfusion appears to be regulated at the level of the arterioles rather than the capillaries.


Relationship between acetylstrophanthidin-induced aftercontractions and the strength of contraction of canine ventricular myocardium. Contractile activity was recorded from isolated canine ventricular muscle exposed to acetylstrophanthidin (AS), 0.5 to 2 X 10(-7) g/ml. Development of the positive inotropic effect of AS was accompanied by the appearance of aftercontractions (AC) coupled to the driven responses. The amplitudes of AC increased with the number of preceding beats. Test beats occurring during the ascending limb of AC were potentiated and the potentiation increased with the amplitude of the AC. Beats falling during the descending limb decreased in strength as the amplitude of the AC increased. As eliminated the frequency dependence of restitution. However, staircase phenomena persisted and were then found to be dependent on the phase relationship of each beat to underlying AC. These findings suggest an important role for AC in the inotropic actions of digitalis and in determining strengh-interval relationships of ventricular muscle treated with digitalis.


Differential effects of digoxin at comparable concentrations in tissues of fetal and adult sheep. Electrocardiogram (ECG) electrodes and carotid arterial and superior vena caval (SVC) catheters were placed in eight nonpregnant ewes and 11 fetuses (109-129 days gestation) to measure heart rate, arterial presssure, P-R interval, left ventricular pre-ejection period (PEP), and left ventricular ejection time (LVET), before and after digoxin infusion into the SVC. After the ewes were killed, the steady state concentration of digoxin in plasma was related to the concentration in midbrain and left ventricular free wall. Although concentrations of digoxin in tissue differed between fetuses and ewes, tissue-plasma ratios were similar; the myocardial-plasma ratio was 87 for fetuses and 90 for ewes and the midbrain-plasma ratios were 6.4 and 5.3, respectively. In spite of these similarities, physiological and toxic effects differed at comparable plasma concentrations. Reduction in PEP/LVET ratio was greater in ewes than fetuses, and P-R interval prolongation was linearly related to digoxin concentration in fetuses but uncommon at plasma concentrations below 2 ng/ml in ewes. Arrhythmias occurred in six ewes, but in only one fetus, even though the mean steady state concentration of digoxin in plasma was 4.5 ng/ml in the fetuses and 2.3 ng/ml in the ewes. Atropine had little effect on digoxin-induced P-R interrval prolongation, and isoproterenol produced no tachyarrhythmias in the fetuses. Age-related differences in inotropic and arrhythmogenic effects of digoxin exist exist and are related to differences in drug response rather than drug kinetics; this provides experimental support for the different dosage responses.


Electrophysiological responses of cardiac muscle to isoproterenol covalently linked to glass beads. We investigated the effects of isoproterenol aryl glass beads on the electrical properties of cardiac muscle and related these to our previous results concerning biochemical and contractile effects (Ingebretsen et al., Circ, Rs., 40: 474-484, 1977). Beads (10-15) were placed near one end to guinea pig papillary muscles mounted horizontally in a bath perfused with Krebs-Henseleit solution at 30 degrees C and stimulated at 0.2 Hz. The beads produced increased tension and elevation and slight lengthening of the plateau potential when [k+]o = 3.8 mM. After depolarization to a resting potential of -49 mV with [K+]o = 22 mM, isoproterenol beads restored contraction to a comparable extent as occurred with 10(-8) M soluble drug. During field stimulation, action potentials were initiated at the site of bead application and spread decrementally. When beads were placed distal to the site of point stimulation, virtually no excitation could be obtained from cells in the vicinity of the beads. When they were placed close to the stimulating electrode, the beads increased excitability and typical slow action potentials spread to the other end of the muscle. These potentials had the characteristics associated with the slow inward Ca2+ current. The slow channel blocker, D-600, blocked responses to isoproterenol beads. Tetrodotoxin caused responses similar to those obtained with K+ depolarization. The beads probably act by stimulating only a small fraction of the papillary muscle catecholamine receptors. Spread of action potentials from these sites and propagated tension depend on Ca2+ influx, but the nature of an intermediate messenger involved in the propagation of contractions is unknown.


Absence of a lateral border zone of intermediate creatine phosphokinase depletion surrounding a central infarct 24 hours after acute coronary occlusion in the dog. Myocardial creatine phosphokinase (CPK) activity was measured as an indicator of cell viability 24 hours after ligation of the left anterior sescending coronary artery (LAD) in normal myocardium, the entire region supplied by the LAD, and individual samples from the border and center of the infarct. Tissue supplied by the LAD and delineated by dye was carefully dissected from normal tissue along the stained border, CPK activity in the ischemic myocardium was calculated by assuming normal CPK activity in the ischemic myocardium was calculated by assuming normal CPK activity in normal myocardium interdigitating with ischemic tissue at the border. Normal tissue was marked prior to occlusion with microspheres injected into the left atrium, whereas the distal portion of the LAD was perfused separately with unlabeled blood from a reservoir. With this correction, the CPK activity in the ischemic tissue from the lateral border of the infarct was essentially the same as in samples from the center, whereas that in the normal tissue immediately adjacent to the stained border was equal to values in remote normal myocardium. Thus, CPK depletion throughout the entire ischemic myocardium was nearly equal to CPK depletion in the center of the infarct. The uncorrected intermediate CPK levels in the individual samples from the border of the stained region correlated with the amount of normal tissue contaminating these samples. However, differences in CPK depletion across the heart wall resulted in the most depletion in the subendocardium and the least in the epicardium. Further more, coronary collateral blood flow measured 10 minutes after occlusion correlated well with the subsequent extent of CPK depletion.


Altered performance of rat cardiac muscle follows changes in mechanical stress during relaxation. We compared two sets of loading conditions for their effect on the mechanical performance of isolated rat trabecular muscle: (1) loading which approximated that of the intact ventricle; (2) nonphysiological afterloaded isotonic contractions. Improved performance, manifested by increased shortening and rate of shortening at constant load, was seen when lengthening occurred at light loads, as in the intact heart. In contrast, lengthening occurring at the same load against with shortening had taken place was followed by diminished performance. Viscous elements in series with the muscle could not account for this phenomenon. The results suggest the presence of an autoregulatory response of myocardium to mechanical stress during relaxation.


Behavior of cardiac receptors with nonmyelinated vagal afferents during spontaneous respiration in cats. Activity from left atrial and left ventricular receptors with nonmyelinated vagal afferents (mean conduction velocity, 1.2 m/sec) was recorded in 13 closed-chest spontaneously breathing cats anesthetized with alpha-chloralose. The anatomic position of each receptor was determined by probing the opened heart at the conclusion of the experiment. Three of eight left atrial receptors and four of five left ventricular receptors were silent under resting conditions. The mean discharge frequency under resting conditons for the six receptors displaying spontaneous activity was 1.0 +/- 0.15 impulse/sec. Thus cardiac receptors with vagal nonmyelinated afferent have a low resting discharge in spontaneously breathing cats. The frequency and pattern of discharge of atrial but not of ventricular receptors was altered during spontaneous respiration. The atrial receptors discharged with cardiac rhythmicity during end inspiration and early expiration when transmural pressure was greatest and were silent for the remainder of the respiratory cycle. Whe respiration was augmented by CO2 breathing or blood volume was increased, the rate of discharge was a linear function of atrial transmural pressure. Eleven ventricular receptors with nonmyelinated afferents (mean conduction velocity, 1.0 m/sec) were exposed to graded volume expansion and phenylephrine infusion in eight open-chest and three spontaneously breathing cats. Raising left ventricular end-diastolic pressure alone increased the frequency of discharge, and a concomitant increase in systolic pressure caused a further increase in firing.


The course of passive elasticity of myocardial tissue following experimental infarction in rabbits and its relation to mechanical dysfunction. Given the substantial reserve of normal myocardium, its inability to sustain life in the presence of 30-50% necrosis of the left ventricle (LV) seems a paradox. It is known that dyskinesia of the infarcted area probably plays a dominant role in initiating failure after an infarction. To study this problem, a well defined experimental infarction was produced by cryogenic means in 58 rabbits, and the animals  were allowed to recover. Groups of rabbits were killed 4 hours and 1,2,5, or 10 days following infarction. As quickly as possible (within 4 minutes) a sample specimen from the infarcted area was removed from the LV and subjected to a force-elongation test while being bathed in Ringer solution at 37 degrees C equilibrated with 95% O2-5% CO2. The data were interpreted assuming an exponential stress-strain law with constants K and C. Mean values of K of 10.6 +/- 0.94 (SEM) were found for the noninfarcted control group, whereas, rather surprisingly, no significant trend in K over 10 days was found in the infarcted group. Mean values of K +/- SEM for the postinfarction groups were as follows: 4 hours, 9.51 +/- 0.63; 1 day 10.54 +/- 1.13; 2 days, 13.15 +/- 2.28; 5 days, 11.59 +/- 1.36; and over 10 days, 12.93 +/-1.02. The functional implications were estimated with a simple model of the shortening required of the viable muscle during the isovolumic phase. It was found that contractile reserve fell rapidly with increasing infarct size, reaching zero for a 60% infarct when K = 10. With K greater than 100, there was no appreciable reduction in reserve. With a constant infarct size, variation in reserve with the afterload-preload ration was found to be logarithmic.


A theoretical model of regionally ischemic myocardium. The isometric tension development of a one-dimensional regionally ischemic muscle was analyzed theoretically. The model consist of a one-dimensional normal segment in series with a one-dimensional ischemic segment. Each segment is modeled as a three-element muscle. The inputs to the various elements, except the contractile element in ischemic segment, were obtained from published data for cat papillary muscles. To be consistent with segment length measurements on ischemic canine hearts, it was assumed that the ischemic contractile element contracted normally at the beginning of contraction and then at some tension, TM, fell behind in its rate of tension development compared to the contractile element in the normal segment. Rate of tension development of various lengths of the ischemic segment and strengths of the ischemic contractile element. At the tension, TM, the ischemic segment begins undergoing paradoxical expansion and, simultaneously, as a result of the expansion. the time derivative of the tension produced by the regionally ischemic muscle exhibits a sudden decrease.


Bronchial reactivity to inhaled histamine: a method and clinical survey. An easy and safe dose-response histamine-inhalation test is described, to measure the level of non-specific bronchial reactivity. The test was performed in 307 subject. Non-specific bronchial reactivity was increased in 3% of presumed normal subjects, in 100% of active asthmatics and in 69% of asymptomatic asthmatics with previous symptoms only at times of exposure to clinically relevant allergens. It was also increased in 47% of patients with cough and no other chest symptoms, in 40% of patients with rhinitis and vague chest symptoms not by themselves diagnostic of asthma, and in 22% of patients with rhinitis and no chest symptoms. The patients with asthma were studied when their asthma was well controlled and when their minimum drug requirements had been established. The mean level of bronchial reactivity increased with increasing minimum drug requirements. The level of bronchial reactivity also showed a strong negative correlation with the forced expiratory volume in 1 sec (FEV1). Atopic subjects, with or without asthma, showed a significant positive correlation between the level of bronchial reactivity and atopic status as indicated by the number of positive allergy skin tests.


Eosinophilic leucocytes in nasal allergy--movement of enzymes. The changes in peroxidase of the granules of eosinophils were examined in cells in the nasal mucous membranes of persons allergic to house dust. There was a slight leakage of peroxidase from eosinophil granules immediately after placing an antigen-treated disc (house dust, Torii, 2560 microgram/disc) on the nasal mucous membrane. Leakage of peroxidase from the eosinophil granules into the cytoplasm, and extracellular release from some eosinophils, was greater 20 min after provocation, than at 30 sec. There were two forms of peroxidase release from the plasma membrane. In one, the granule membrane fused with the plasma membrane and the peroxidase was released from the cell through destruction of the two fused membranes. This was considered to be active secretion. In the other form, the plasma membrane was damaged by peroxidase released from the granules into the cytoplasm. This was considered to be passive release following degeneration of the cell.


A method for the simultaneous determination of serum and cell-bound IgE. A method for determining the amount of total IgE bound to leucocytes has been devised by measuring that released on incubating various cell number dilutions in acetate buffer pH 4-0. A linear relationship between IgE released and cell number was obtained over a limited concentration range. The method seemed to work satisfactorily with 50 ml of whole blood for those subjects with very high serum levels of total IgE. However, with subjects having a slightly elevated or normal serum IgE level it may be necessary to use twice the amount of blood.


Tetracycline asthma--a case report.

Tetracycline asthma--a case report. A mechanic working in the antibiotic capsuling section of a pharmaceutical company developed asthmatic attacks 1 year after starting work. His occupation involved exposure to a variety of chemical agents including tetracycline. He developed immediate weal and flare reaction to the intradermal test and an immediate (type 1) asthmatic response to intradermal, inhalation and oral challenge tests with tetracycline. On leaving the tetracycline plant he became symptom free.


[Laurell electroimmunodiffusion. Concerns and limits of various technics for the study of immunoaffinity chromatographic eluants]. Monodimensional and bidimensional electroimmunodifusion techniques were applied to the study of immunochromatography eluates. They were obtained with human sera as samples, and rabbit anti human sera alpha1AGP antibodies coupled to CNBr Sepharose 4B packed in a chromatography column. By monodimensional electroimmunodiffusion alpha1AGP could be quantitated. By tandem bidimensional immunoelectrophoresis the eluate purity could be shown, as well as its identity to alpha1AGP. Besides, this last technique was used to the critical study of elution conditions, and to put forward the influence of some parameters (such as pH ionic strength) on alpha1AGP denaturation and its transformation into a protein which is still antigenic but has lost a part of its electrophoretic mobility at pH 8.6. This phenomenon could explain the alpha1AGP loss observed after column elution. The precautions in the interpretation, the interest and the sensitiveness of the electroimmunodiffusion techniques are exposed.


Toxicity from tea ingestion in an infant: a computer simulation analysis. A seven-week-old infant presented with tonic posturing and nervous irritability after concentrated tea ingestion. The tea was analyzed and found to contain caffeine, a methylxanthine central nervous system stimulant. With the aid of a computer, projected blood levels were calculated over a thirty-hour time period and comared to the infant's clinical status. It is recommended that beverages containing xanthines be given to infants and small children with caution.


A study of the salivary glycoprotein in cystic fibrosis patients and controls: fucose incorporation and protein pattern. The incorporation of fucose to glycoprotein acceptors prepared from the saliva of Cystic Fibrosis (CF) patients was compared with the incorporation into acceptors from controls. The CF acceptor glycoprotein incorporated significantly more fucose in the presence of either patients' or control plasma. The fucosyl transferase activity in the patients' plasma was not significantly different from controls. Fucosidase activity was similar also for both groups. The protein bands of the acceptor glycoproteins from the patients' saliva differed from those of the control in number and electrophoretic mobility. On the basis of these studies of fucose incorporation we propose that glycoprotein in the salivary secretion of CF patients are qualitatively different from normal.


A simple cost control format in clinical laboratories. Laboratory scientists must be able to demonstrate their proficiency not just in the analysis of specimens but also financial management. The cost information in real dollar term is the only way to measure the productivity of a laboratory. We have demonstrated a simple procedure in tabulating the income and expenditure of our laboratories. In our hand, we have found the information to be useful and timely for various decisions and plannings.


Rapid enzymic micromethod for the quantitative determination of L(+)alanine in blood and urine. A micromethod for the quantitative determination of L-alanine in blood and urine is described. No interference of D-alanine, D-cysteine, L-proline, L-glutamine, L-valine, L-histidine or glycine in concentrations up to 5 mmol/l was found. Using this method fasting blood levels of L-alanine in children were determined. Defects in gluconeogenesis can be easily established by measuring with this method the in vivo L-alanine metabolism in an oral, or intravenous L-alanine loading test.


Ectopic production of a salivary type amylase by adenocarcinoma cells: demonstration by a culture technique. Characterization of an elevated amylase activity in ascitic fluid obtained from a patient with carcinomatous peritonitis is described; ninety-one percent of the increased amylase activity in the fluid was of salivary type and the remainder of pancreatic type, when studied by ion-exchange chromatography. Culture of ascitic cells successfully demonstrated morphologically characterized tumor cells surviving for at least 31 days. During that period, significant amylase activities were detected in the culture media, and the isozyme pattern was a single band whose electrophoretic mobility corresponded to salivary amylase. The data obtained indicate that the ascites amylase of salivary type was produced ectopically by the tumor cells.


Monoamine oxidase activity in cultured human skin fibroblasts. Skin fibroblast cultures were prepared from 21 men, and found to contain types A and B activity of monoamine oxidase, with a possible slight predominance of type A, as evaluated by substrate preferences and differential inhibition by clorgyline and deprenyl. Three women had similar activities. There was a close correlation of activities with different substrates, but there was no quantitative correlation between fibroblast and blood platelet enzyme (type B) activities. The fibroblasts also contained catechol-O-methyltransferase activity exceeding, but poorly correlated with, that in erythrocytes. Fibroblasts may be advantageous in studies of monoamine oxidase in man by providing both types of enzyme as found, for example, in the central nervous system, and by providing a means of removing many in vivo chemical influences from the cells in culture. Nevertheless, great caution must be exercised in generalizing results of this "model" to other tissues, since activities of both enzymes correlated poorly with those in blood cells of the same individuals.


A rapid and simple fibrinogen determination. A fast and simple fibrinogen determination is presented, based on the ammonium sulfate precipitation of fibrinogen. The nature of the precipitated material is investigated by means of immunoelectrophoresis. A comparison is made with a paper electrophoretic method, and a method based on the clotting properties of fibrinogen. The linearity, the within-run precision and normal values, obtained by this method are given. An advantage over other well-known methods is the use of a serum blank instead of a plasma blank without reagent. In this way all interfering substances are detected immediately and simple subtraction of blank readings from sample readings gives true fibrinogen values. The clinical application with respect to the acute phase of inflammation is discussed.


Comparison of serum IgE determination by conventional radioimmunoassay (RIST) and by a modified (sandwich) technique (PRIST). It has been reported that the sandwich technique (PRIST) is a more accurate method for determining serum IgE levels than the conventional radioimmunoassay (RIST), especially for low IgE levels. By using half the volumes prescribed for RIST and by introducing a 3-h preincubation step at room temperature, IgE values in the range of 30-4000 I.U./ml could accurately be established. It is concluded that the proposed modification may replace the conventional RIST for routine purposes, because it offers comparable accuracy, is more exonomical, and provides better results in the low IgE range. Discordant results between RIST and PRIST cannot be correctly interpreted, because interfering serum factors may cause either exaggerated IgE values with RIST, or falsely low values with PRIST.


[Evolution of serum and erythrocyte magnesium levels in burn patients (author's transl)]. The study of the evolution of serum and erythrocyte magnesium in burn patients shows there exists, immediately after the thermic aggression, a reduction in the concentration of this cation. The hypomagnesemia is generally moderate and short; return to values considered normal is usually registered from the third day. Variations of the serum level are similar to those induced after a surgical operation. The hypothesis according to which there could exist a link between hypomagnesemia and a number of neuropsychiatric manifestations met simultaneously in the same patient cannot be excluded.


The urinary excretion of the nucleosides pseudouridine and 1-methylinosine during normal menstrual cycle. The excretion levels of the nucleosides pseudouridine and 1-methylinosine were determined by gas-liquid chromatography in 24-h urine specimens from young women during normal menstrual cycle. These nucleosides are derived primarily from transfer RNA and their excretion reflects the turnover of tRNA. The excretion levels were found to be essentially unaltered by the cycle and the average excretion values with standard deviations were 0.70 +/- 0.078 and 0.051 +/- 0.011 mg/kg/24 h for pseudouridine and 1-methylinosine, respectively.


Differential spectrophotometry for the determination of serum methemalbumin. A method for the direct determination of methemalbumin in serum by means of difference scanning spectrophotometry is described. The advantages of this quantification technique resides in the ability to obviate unequal background characteristics such as turbidity in one treated sample portion, the avoidance of subtractive measurement on the sides of steep spectra, and a qualitative observation simultaneously derived from the single difference scan. A measure of the stability of the prepared standards is described along with a minimized use of sample and reagent volumes if the latter is desired.


Hypoxanthine-guanine phosphoribosyltransferase: a simple spectrophotometric assay. A simple spectrophotometric assay is described based on the conversion of hypoxanthine to inosine monophosphate and precipitation of both the reaction product and protein with lanthanum phosphate. The extent of conversion is determined by the fall in absorbance of hypoxanthine at 249 nm. The assay is suitable for screening red cell lysates for hypoxanthine-guanine phosphoribosyltransferase deficiency.


Activities of bone and liver alkaline phosphatases in serum in health and disease. A heat-inactivation method for determining absolute activities of liver and bone alkaline phosphatases in serum has been applied extensively in routine diagnosis. Values for each isoenzyme in healthy individuals of different ages are reported together with results obtained in various diseases. Data from normal subjects show that bone alkaline phosphatase contributes about half the total alkaline phosphatase activity in adults. Liver phosphatase shows a slight increase with age. The method is also able to detect reliably the presence of carcinoplacental isoenzymes.


Determination of creatine kinase isoenzyme MB (CK-MB): comparison of methods and clinical evaluation. An ion-exchange chromatography method based on the method of Mercer is advocated for the routine determination of serum CK-MB. This method has some prominent advantages over other methods with which it is compared, and which include electrophoresis and an immunological technique. This method proves to be reliable and highly reproducible, while it allows a rather large number of samples to be analyzed within a relatively short period of time. Some parameters of the release pattern of CK-MB after acute myocardial infarction are characterized: normal values, time of first rise, time of peak value and rate-constant of inactivation. The clinical significance of serum CK-MB determination is evaluated.


The conversion of D-xylose into D-threitol in patients without liver disease and in patients with portal liver cirrhosis. An oral D-xylose tolerance test was carried out on 12 patients with portal liver cirrhosis, on 7 patients with active fatty liver disease and on 29 subjects without liver diseases. D-Xylose and D-threitol were measured by means of gas-liquid chromatography. Fifteen percent of the D-xylose dose excreted in urine within five hours was recovered as D-threitol. The proportion of D-threitol was greater when the collection was extended to 24 h. The D-threitol excretion was markedly diminished in cirrhotic patients, suggesting that a substantial proportion of the D-xylose-D-threitol conversion occurs in the liver. No decrease was detected in patients with fatty liver disease. No significant change in D-xylose excretion was observed in liver cirrhosis or in fatty liver disease. D-Threitol can be regarded as the main end product of D-xylose metabolism in man. The role of the glucuronate pathway in the D-xylose-D-threitol conversion is discussed.


Induction of the thyroxine (T4) to triiodothyronine (T3) converting enzyme in rat liver by thyroid hormones and analogs. In thyroidectomized, unsubstituted rats the T4 to T3 converting activity of liver homogenate is reduced to about 30% of that in unoperated control animals. The enzyme activity can be reinduced dose-dependently with T4. To achieve a normal activity, high, non-physiological plasma T4 concentrations are needed. Plasma T3 levels are much better correlated to the T4 to T3 converting activity. Pure T3 proved to be a more potent enzyme inducer than T4. No difference could be detected between L- and D-T3. Tyrosine, diiodotyrosine, 3,3'-diiodothyronine and 3,3',5'-T3 (reverse-T3) showed no inductive effect for the enzyme. These results demonstrate that the T4 to T3 converting enzyme is specific and shows regulatory properties.


Carboxyhaemoglobin. Spectrophotometric determination tested and calibrated using a new reference method for measuring carbon monoxide in blood. The spectrophotometric determination of HbCO at lambda = 562 and 540 nm in the system HbCO/HbO2 was reinvestigated using a new reference method for measuring CO in blood. This reference method is based on the conversion of CO from HbCO into CO2 which is determined by titration. Plotting the absorbance ratio A562/A540 against the titrimetrically determined HbCO fractions of 46 blood samples demonstrated a linear relationship up to 90% HbCO and yielded more accurate values for the constants in the equation for calculating the HbCO fraction from A562/A540. The standard deviation of the differences between the spectrophotometric and the titrimetric method was 1.2% HbCO. It is shown that the influence of other haemoglobin derivatives and other possible sources of error is either negligible or can be prevented by simple precautions.


The effect of insulin on lung metabolism in the rat. A new model has been established for the perfused in situ rat lung. During perfusion with glucose at 4 mmol/l, physiological concentrations of insulin (50 mu/l) caused an initial 1.5 fold increase in lactate production; the increase being sustained at 30% for the 4 h of perfusion. The observation that the lung responds to physiological concentrations of insulin could have important implications with respect to whole body carbohydrate metabolism.


Increased prolactin and thyrotrophin secretion following oral metoclopramide: dose-response relationships. Four normal men received 1, 5, 10 and 20 mg doses of oral metoclopramide, a dopamine receptor antagonist, or placebo to determine the effect of this drug on anterior pituitary hormone secretion. Increases in serum prolactin (PRL) occurred even after the 1 mg tablet (P less than 0.01) while maximal responses were observed 60 min after ingestion of the 20 mg tablet (mean 27.8 ng/ml; range 25.6-30.3 ng/ml). Serum PRL levels peaked 60-90 min after ingestion of any dose of metoclopramide and values remained significantly elevated (P less than 0.05) for up to 8h after the tablet. Increases in serum thyrotrophin (TSH) also occurred after the 10 and 20 mg doses of metoclopramide. Peak responses were seen at 120-180 min, with significant elevation (P less than 0.05) persisting from 60 to 240 min after ingestion. No consistent changes in serum FSH, LH or GH were observed and no side-effects were reported. It was concluded that metoclopramide elevated serum PRL and TSH. The threshold dose of metoclopramide required for these effects was different for the two hormones; their peak responses occurred at different times and the duration of the elevation was dissimilar, suggesting a mechanism other than the release of hypothalamic thyrotrophin-releasing hormone (TRH).


Hormonal and metabolic responses to glucagon in diabetes mellitus. The metabolic and hormonal responses to glucagon (1 mg, subcutaneous) were studied in twelve diabetic and twelve non-diabetic subjects. Diabetics showed a GH response, which although commencing slightly earlier, did not otherwise differ from that of the controls. There was the expected diminished insulin response to glucagon among the patients on oral agents. The GH response to glucagon in the diabetics began before there was any significant fall in blood glucose (BG). The hyperglycaemic response in the diabetics peaked later, was greater in amplitude and was more prolonged. In this group both pyruvate and lactate changes were delayed and diminished in amplitude. The diabetics showed a biphasic response of both acetoacetate and 3-hydroxybutyrate to glucagon; a small transient significant rise in the first 2 h followed by a second rise after 3h. In contrast the controls showed a significant fall in these metabolites during the initial 2 h, before a rise after 3 h. The significance of these hormonal and metabolic responses is discussed.


The behaviour of thyroid hormones in an infant with untreated neonatal thyrotoxicosis. The clinical course from birth and serial measurements of serum T3, T4 and TSH in an infant with untreated neonatal thyrotoxicosis are reported. The thyroid hormone levels fell exponentially with time at rates very much slower than those previously reported for the maternally-transmitted thyroid stimulating antibody generally thought to cause the disorder. Steady physiological levels of thyroid hormones were achieved after 110 days (serum T3 = 3.4 NMOL/L, T4 = 118 nmol/l). TSH first rose to a measurable level after about 90 days.


Effect of pimozide on levodopa-induced growth hormone release in man. Serum growth hormone (GH) behaviour after levodopa administration was measured in twelve healthy subjects both in basal conditions and after a 4 day course of pimozide (4 mg daily), a specific blocker of dopamine (DA) receptors. In addition, fasting plasma GH was measured on the first, second and third day of treatment. No significant difference was found between GH response to levodopa in basal conditions and after pimozide; moreover, fasting GH was uninfluenced by pimozide.


Time course of physiological hyperprolactinaemia during two years lactation. In Central Africa, mothers on nursing for 2 years are hyperprolactinaemic during the first 15-18 post-partum months; serum prolactin levels are some three times higher than in non-pregnant and non-lactating women.


Coexisting primary empty sella syndrome and acromegally. The 'empty' sells syndrome is now a more frequent diagnosis due to the increased use of pneumoencephalography in the evaluation of the enlarged pituitary fossa. This syndrome has also been classified into a 'primary' form in which there has been no prior pituitary irradiation or surgery, and a 'secondary' form in which the empty sella is found after such procedures. Most patients with the primary empty sella syndrome are found to have normal pituitary function while about 30% have varying degrees of hypopituitarism (Neelon et al., 1973). It is not widely appreciated, however, that the primary empty sella may harbour a pituitary tumour with resultant acromegaly. In this report we describe two such patients who presented with active acromegaly. This entity of pituitary tumour in a primary empty sella merits careful consideration since the coexistence of these two findings may influence the therapeutic approach that might otherwise be appropriate for the pituitary tumour.


Mydriasis and heredity.

Mydriasis and heredity. Routine ophthalmoscopy and fundoscopy of 673 individuals revealed 42 whose irides failed to dilate to a clinically useful degree within 25 to 30 min after the administration of drops of 1% mydracil. These individuals occurred with different frequency among the Aymara, Mestizo, and non-Aymara groups which made up the sample of examinees. The phenomenon was most common among the Aymara, less common among the Mestizos, and least common among the non-Aymara. Distribution of affected individuals within the three groups suggests that the trait is inherited.


Hereditary cholinesterase deficiency: a report of a family with two rare genotypes. Cholinesterase deficiency was detected in a young girl following an episode of postanesthesia apnea. Subsequently, plasma and serum cholinesterase levels and dibucaine numbers were determined on blood samples from 56 members of her extended family. Including the proband, three individuals were identified with severe cholinesterase deficiency and 12 were found to have mild abnormalities. The occurrence of two genetic variants regulating cholinesterase production, the "silent" gene and the atypical enzyme, is postulated to account for the unusual pattern of inheritance in this family. Screening family members of confirmed cases is essential to prevent the potentially fatal consequences of this hereditary disorder.


Major karyotypic abnormality in a child born to a woman with untreated malignant melanoma. The karyotype of a 7-month-old child had 46 chromosomes, including five abnormal chromosomes in cultured lymphocytes. G-banding indicated the presence of reciprocal translocation products between chromosomes 1 and 7 and between chromosomes 4 and 15. A probable third translocation involved the same chromosome 4p arm and 12q. All metaphases showed these changes. C-band markers and the presence of reciprocal exchange products indicated that the chromosome changes occurred in the zygote or a post-zygotic cell of the child. The mother developed malignant melanoma while carrying the child but did not receive therapy before its birth. The suggestion is made that an undetected common agent was involved in the aetiology of the mother's tumour and the clastogenic change to the child's chromosomes.


Bloom's syndrome. V. Surveillance for cancer in affected families. The Bloom's Syndrome Registry comprises the 71 individuals in whom this rare genetic disorder has been recognized between the time it was described in 1954 and the end of 1976. The major objective of the Registry is surveillance for cancer in both affected homozygotes and heterozygotes. Of the 61 homozygotes known to have had Bloom's syndrome before cancer was diagnosed and for whom follow-up has been possible, one in nine has developed cancer. Thirteen cancers have been diagnosed, in 12 individuals. The mean age in 1976 of the living individuals with the syndrome was 16.4 years. The mean age at the time cancer was diagnosed was 20 years. Cancers have been of multiple types and have affected various sites.


On the classification of the acrocephalosyndactyly syndromes. This report describes a family in which two different types of acrocephalosyndactyly (ACS) were clinically identified. The proband presented with the classic stigmata of Pfeiffer syndrome, while her cousin was considered to be a typical case of Apert syndrome. Seven other family members also have unusually shaped heads and the facial appearance reminiscent of Crouzon disease. From the observations made in this family and from previous reports in the literature, we feel there is substantial reason to re-evaluate the ACS classification and to consider that the Apert and Pfeiffer types of ACS may be one and the same.


Immune complexes in ulcerative colitis and Crohn's disease. Sera from 156 patients with ulcerative colitis and Crohn's disease were tested for the presence of immune complexes, by the detection of anti-complementary activity and 125I-labelled Clq precipitation. Using aggregated IgG, a comparison between the two tests indicated that the anti-complementary test was most sensitive to aggregates of 11S in size, while the 125I-labelled Clq test detected aggregates over 20S in size. Excess anti-complementary activity was common in patients with active bowel disease, and in those with extra-intestinal manifestations, particularly acute arthritis, ankylosing spondylitis and liver disease. Large complexes were only common in patients with liver disease. Immune complexes in the gut mucosa may play a role in the pathogenesis of these diseases, and the deposition of circulatory immune complexes may explain at least some of the extra-intestinal manifestations.


Increased EA-rosette formation by lymphocytes from patients with rheumatoid arthritis. A modified method for estimating erythrocyte-antibody (EA) rosette formation of human peripheral blood lymphocytes (PBL) reveals consistent differences between rheumatoid arthritis (RA) patients tested and healthy control subjects. Using this method we find an average of 27 +/- 0-8% (standard error of mean) of PBL from 120 RA patients forming EA rosettes in contrast to only 6 +/- 0-6% of PBL from ninety-five healthy controls, and 7 +/- 0-9% from eighteen patients with systemic lupus erythematosus (SLE). This difference is not due to monocytes forming EA rosettes or to T-cell sheep red blood cell (SRBC) binding. The concentration of antibody used in our assay appears to highlight the RA-control  differences--suggesting a possible qualitative difference in EA-binding capacity. We find no correlation between EA binding and disease duration or rheumatoid factor titre. The assay is susceptible to technical variation, and the effects of antibody concentration, lymphocyte to SRBC ratio, method of blood collection and lymphocyte-separation procedure have all been evaluated.


Immunoglobulin levels in Iraq.

Immunoglobulin levels in Iraq. In a study of immunoglobulin levels in 192 apparently healthy individuals in Iraq, regional differences occur in IgE and IgG. The main levels of IgG, IgM and IgA tend to be low, and of IgE clearly elevated. It is suggested that this pattern may be explained by the presence of intestinal parasites which stimulate IgE production. The genetic differences that exist between the regional populations, and the occurrence of associations of immunoglobulin level with several polymorphic systems, suggests the possibility of a genetic element in the regional immunoglobulin differences.


Lymphocyte-stimulation tests and patch tests to carbamazepine hypersensitivity. Seven cases of severe hypersensitivity to carbamazepine (Tegretol) were described in patients with epilepsy or trigeminal neuralgia. Clinical manifestations consisted of fever, rash, facial oedema, lymphadenopathy, impaired liver function, eosinophilia and atypical lymphocytes in the peripheral blood. Lymphocyte-stimulation tests with carbamazepine in vitro showed positive results in all cases; patch tests with carbamazepine were positive in six cases. In two cases the lymphocyte-stimulation tests with carbamazepine were found to be negative during, and shortly after, the illness. However, when the tests were repeated several months later, they turned out to be positive. Lymphocyte reactivity to PPD and PHA in vitro was also impaired during the acute phase of the disease. Thus false-negative lymphocyte-stimulation tests may be found in the first months following such a hypersensitivity reaction, probably due to impaired lymphocyte reactivity. As carbamazepine is a potent drug and is often prescribed for long periods together with other anticonvulsants, it seems important to prove that the allergic reaction is caused by carbamazepine. If the lymphocyte-stimulation test in vitro or the patch test with carbamazepine is found to be negative during or shortly after the illness, they should be repeated several months later.


The effects of azathioprine and levamisole on rosette-forming cells of healthy subjects and cancer patients. The in vitro effects of azathioprine and levamisole on the capacity of peripheral lymphocytes to form rosettes with sheep erythrocytes were studied in fifteen healthy subjects and forty-one cancer patients. Azathioprine significantly inhibited rosette formation of T lymphocytes in healthy subjects and cancer patients in remission. In contrast, azathioprine could not inhibit rosette formation of T lymphocytes in cancer patients with advanced disease. Patients with advanced tumour had also fewer rosette-forming cells (RFC) than healthy subjects. Levamisole, an anti-anergic chemotherapeutic agent, restored azathioprine-inhibited RFC in healthy subjects and in fifteen out of twenty-two cancer patients. Levamisole alone significantly enhanced low RFC in cancer patients.


Mechanisms of protective immunity in experimental cutaneous leishmaniasis of the guinea-pig. III. Inhibition of leishmanial lesion in the guinea-pig by delayed hypersensitivity reaction to unrelated antigens. The purpose of this investigation was to determine whether prior induction of a non-specific delayed reaction at a site of leishmanial infection could modify the course of infection. Groups of animals were made hypersensitive to either DNCB or BCG and a delayed reaction was elicited by corresponding antigen in one or both ears when an infective dose of L. enriettii was inoculated. With various experimental designs the following results were obtained: (a) induction of delayed reaction by DNCB or BCG inhibited the development of leishmanial lesions; (a) the protection was effective only when delayed reaction occurred at the site of infection; (c) to be effective, the reaction had to be continuously present at the site of infection for at least 3--4 weeks; (d) lesions developed normally, in the absence of delayed reaction, in DNCB-tolerant animals treated with DNCB; (E) a protective delayed reaction did not completely eliminate the parasites from the host tissues, since metastatic lesions appeared later at ectopic areas; (f) the suppressed development of a lesion did not confer resistance to reinfection dose of the parasite. It is concluded that cell-mediated immunity plays an important role in healing leishmanial lesions in the guinea-pig and that the final effector mechanism may be sought in the non-specific microbicidal capacity of activated macrophages. The relevance of leishmania-specific delayed reaction in the course of the disease is discussed.


Comparative study of plasma dopamine-beta-hydroxylase activities in noradrenaline-secreting and adrenaline-secreting phaeochromocytomae. 1. Circulating dopamine-beta-hydroxylase activities were measured in two hypertensive patients, with a phaeochromocytoma tumour. Tumours were found to differ by their secretory properties, one secreting noradrenaline, the other adrenaline. After removal of the tumour, the plasma dopamine-beta-hydroxylase activities in both patients gradually decreased to reach a stable value in correlation with urinary, excreted catecholamine levels. The only difference was the rate of the plasma enzyme activity decrease. 2. Thus, it appeared that some phaeochromocytomae are able to secrete dopamine-beta-hydroxylase in addition to catecholamines. Therefore, dopamine-beta-hydroxylase activity measurements may be of interest: (1) in determining secretory properties of phaeochromocytoma tumours, and (2) in following the evolution during the postoperative period.


Pharmacokinetics of methyldopa. Plasma levels following single intravenous, oral and multiple oral dosage in normotensive and hypertensive subjects. 1. The pharmacokinetics of methyldopa after oral and intravenous administration was studied in hypertensive and normotensive patients. After intravenous administration methyldopa plasma concentrations decayed according to a two-compartment open model. 2. For intravenous administration the overall elimination constant Ke1 was 0.56 +/- 0.03 h-1, the volume of distribution of the central compartment 0.29 +/- 0.80 1 kg-1 and the plasma clearance rate 11.2 +/- 0.6 1 h-1. 3. Plasma half-times during the beta-phase of the methyldopa plasma decay curve following intravenous and oral administration were 2.8 +/- 1.3 and 2.1 +/- 0.7 h, respectively. 4. Maximal plasma levels in hypertensive out-patients show great variation and range from 0 to 1.9 microgram ml-1. 5. No relationships were found between maximal methyldopa plasma levels in patients under treatment and control of hypertension.


Cardiac arrest temperature: the effect of ethyl alcohol and carbon dioxide on rats, guinea-pigs and isolated rat hearts. 1. Previous clinical and experimental reports have suggested that the systemic administration of ethyl alcohol permits lower body temperatures before the onset of hypothermic cardiac arrest. 2. In the investigations described here, the effect of ethyl alcohol on the temperature at which cardiac arrest occurred in rats, guinea-pigs and isolated rat hearts was studied. Comparison was also made of the difference between pulmonary ventilation with air and with 5% carbon dioxide in oxygen. 3. The results demonstrated that both the administration of ethyl alcohol and ventilation with 5% carbogen reduced the cardiac arrest temperature of rats. Ethyl alcohol did not influence the cardiac arrest temperature of guinea-pigs nor of isolated rat hearts.


The effect of tricyclic antidepressant drugs on the isolated perfused guinea-pig heart. 1. The effects of tricyclic antidepressants were studied on the isolated perfused guinea-pig heart simultaneously recording myocardial contractile force and cardiac electrogram. 2. Tricyclic antidepressants in a concentration 4 X 10(-5) mol/1 decreased cardiac contractile force and increased cardiac conduction time. 3. Doxepin had significantly greater negative inotropic effect than nortriptyline, protriptyline, desipramine, amitriptyline and imipramine (P less than 0.01). 4. There was no significant difference in the increase in P-R interval (P less than 0.5) and QRS width (P greater than 0.95) between the tricyclic antidepressants. 5. The isolated perfused guinea-pig heart can be used as a toxicological model for testing and treating cardiac arrhythmias induced by tricyclic antidepressants.


G-band patterns of the Siberian snow sheep (Ovis nivicola) and their relationship to chromosomal evolution in sheep. G-band patterns of the Siberian snow sheep, Ovis nivicola alleni, 2n=52, were compared with the patterns reported in 2n=54 wild Asiatic mouflon and 2n=54 North American sheep and those in domestic sheep with 2n=54, 53, and 52. The three largest pairs of biarmed autosomes displayed indistinguishable, presumably homologous, G-banding patterns in all types of sheep. The banding and morphology of the fourth pair of biarmed autosomes in O.nivicola differed from those of the three translocation variants described in domestic sheep. Wild sheep with 2n=54 may have evolved monophyletically from an ancestral 2n=58-56-54 population or polyphyletically by a series of independent, nonrandom fusions. In contrast, the fouth pair of biarmed autosomes in O.nivicola and in 2n=52 domestic sheep variants may have resulted from random fusions of different chromosomes.


Population kinetics of chromosomally abnormal human fibroblast subpopulations. The proportion of cells with clonally derived chromosome rearrangements has been recorded at different passage levels in 16 lines of human fibroblast cultures derived from adults. All abnormal clone populations regonized at the lowest passge levels showed a stable or declining frequency relative to the normal cells, although 2 out of the 21 clones detected did show a transient increase. Only 2 clones were found at higher passage levels that were not previously identified at low passge. The observed selection against cells with rearrangements may reflect a general property of chromosome organization which ensures that cytogenetic abnormalities do not normally accumulate in rapidly dividing tissues.


Operator-assisted semi-automatic karyotyping of banded metaphases. Computerized chromosome analyses have resulted in up to 25% erroneous classifications, whereas a cytogenetically trained laboratory technician has an error rate of less than 0.1% in the preparation of a karyotype. In the project reported here, computerized classification is eliminated, and instead, the other steps of the analysis leading to the final karyotype are automated. In the instrument is a projection microscope, modified to project the image on paper before the operator. The slide is scanned on a motor-driven scanning table, in search of a suitable metaphase. The operator stops the scanning motor when a suitable metaphase comes into view. The individual chromosomes of the metaphase are then framed, using a view finder, and are identified, after which the chromosome number is entered on a kayboard. The instrument automatically ensures that, for each data entry, the framed chromosome is photographed in such a manner that the chromosome is placed in the proper location with the correct orientation in the karyotype. When all chromosomes have been identified, and the data have been keyed in, a photograph of the finished karyotype is presented. Marking the metaphase chromosomes on the paper, chromosomes are counted within 20 s. With conventional methods, a total chromosome analysis takes 3-6 h, but the above-described device requires 20-30 min.


Flow-cytogenetics: sources of DNA content variation among euploid individuals. We have studied possible sources of resting human lymphocyte DNA content variation among euploid males and females as determined by flow-microfluorometry. A major source of variation arises from instrumental instability, most notably flow-rate changes. This variation can be detected and minimized by the use of chicken erythrocytes as an internal standard. A second source of variation arises from differences in rates of lymphocyte stain uptake. The lowest coefficients of variation (0.3%) among individuals of like sex, and optimal distinction between sexes, were achieved after exposing lymphocyte samples for 24 h to the hypotonic staining solution. Four males and females with either low or high relative DNA contents within their respective sexes showed correspondingly divergent values upon repeat venipuncture. Some of the observed interindividual DNA content variation might therefore reflect truly genetic differences. For two male samples with repeatedly divergent DNA content values, preliminary C-banding of conventional metaphases suggest corresponding differences in constitutive heterochromatin.


Prospective evaluation for pneumonectomy using the 99mtechnetium quantitative perfusion lung scan. We evaluated 33 high-risk patients before pneumonectomy, all of whom had a forced expiratory volume in one second (FEV1) of less than 2.0 L before surgery. A quantitative perfusion lung scan was used to assess the right-left distribution of blood flow. A predicted postoperative FEV1 was calculated from the information on the lung scan and the preoperative FEV1. If this calculated value exceeded 800 ml, the patient was physiologically cleared for surgery up to and including a pneumonectomy. Surgery was otherwise believed to be contraindicated in the absence of studies using balloon occlusion. Perioperative mortality (less than or equal to 30 days after surgery) was found to be 15 percent (5/33). In surgery of this magnitude, we find this to be an acceptable percentage of mortality and have continued to use these simple physiologic criteria to determine whether a patient can tolerate pneumonectomy.


Ventricular tachyarrhythmias following surgery for myocardial revascularization. A follow-up study. Of 1,599 patients who underwent surgery for direct myocardial revascularization in 1973 at Cleveland Clinic Hospital, 19 patients (1.2 percent) developed primary ventricular fibrillation or ventricular tachycardia during the immediate postoperative period. Occurrence of postoperative ventricular tachyarrhythmias could not be predicted by assessment of preoperative symptoms or by evaluation of the extent of coronary artery disease and left ventricular function. There was no increase in early or late mortality or morbidity (including postoperative myocardial infarction) among patients who developed postoperative primary ventricular tachyarrhythmias.


Systemic air embolism following penetrating trauma to the lung. Systemic air embolism following penetrating injuries of the lung has not been widely recognized clinically. Experimental studies designed to reproduce the phenomenon in dogs have been at variance, although none has taken into consideration the often high intrabronchial pressures created during resuscitative efforts in such patients. Twelve patients with systemic air embolism following penetrating traumatic injuries to the lung have been seen at our hospital. Ventilatory pressures created during resuscitative thoracotomy in traumatized patients were monitored and found to be as high as 100 mm Hg. Penetrating injuries of the lung were created in mongrel dogs, and the animals were ventilated with pressures reaching 90 mm Hg. All dogs unequivocally developed systemic air embolism, with air visualized in the coronary arteries. It would appear that systemic air embolism following penetrating injury to the lung may result when increased intrabronchial pressure, such as found during manual ventilatory assistance, forces air through traumatic bronchovenous fistulae into the systemic circulation.


Echocardiographic features of second degree atrioventricular block. Echocardiographic studies demonstrated abnormalities of motion of the pulmonary valve, the aortic root and valve, the mitral and tricuspid valves, the left ventricle, and the left atrium in two patients with second-degree atrioventricular block. During Wenckebach 3:2 atrioventricular conduction, ventricular beats exhibited alternately long and short periods of systolic opening of the pulmonary and aortic valves and alternately large and small left ventricular stroke volumes. During 4:3 and 3:2 Wenckebach atrioventricular conduction, the left ventricular stroke volume was directly proportional to the preceding end-diastolic volume. During 2:1 atrioventricular conduction, the blocked atrial contractions may produce movements of the left atrial wall, thereby revealing the true atrial rate when the blocked P waves are obscured in the electrocardiogram by their superimposition on preceding T waves.


Echocardiographic manifestations of ruptured aortic valvular leaflets in the absence of valvular vegetations. The diagnosis of ruptured (perforated or torn) aortic valvular leaflets due to various causes has been made primarily at surgery or postmortem examination. Although angiocardiographic studies readily reveal aortic regurgitation, they rarely establish the presence of a ruptured aortic cusp as the cause of the aortic leak. Recent echocardiographic experience has brought to our attention seven patients with ruptured aortic valvular leaflets in whom the absenc of valvular vegetations was confirmed at surgery in six and at autopsy in one. The echocardiogram of the aortic root in these subjects revealed little or no increment in the diameter of the aortic root. In systole the usual box-like configuration of the leaflets, similar to that observed in normal subjects, was seen; however, in diastole the normal thin midaortic linear echoes were replaced by a thick band of echoes which often revealed high-frequency oscillations. In addition, high-frequency fibrations of the anterior mitral leaflet in diastole and increased systolic excursion of the interventricular septum and left ventricular posterior wall were observed.


The effect of tumor size and location on diagnosis by fiberoptic bronchoscopy. Evaluation of data from fiberoptic bronchoscopic procedures revealed that for peripheral bronchogenic carcinomas, the diagnostic yield was influenced by the size of the lesion and its distance from the hilum. Failure to diagnose visible carcinomas was related to inability to obtain deep specimens for biopsy. Biopsy, brushing, and washing were complementary procedures in diagnosing bronchogenic carcinomas.


Range of frontal plane QRS axes. Electrocardiograms of subjects in a multiphasic screening program. The range of mean QRS axes in the frontal plane was determined in electrocardiograms of subjects examined in a program of periodic health screening. Fifty-three of 5,163 individuals had a mean frontal QRS axis between -30 degrees and -60 degrees. Fourteen individuals had an axis between +110 degrees and +133 degrees. These findings suggest that individuals with no history of heart disease may manifest a considerable range of frontal plane QRS axes often to a degree previously considered abnormal. The axes were calculated by the use of leads 1 and 3. Other leads, or the use of the method of Grant, would give different results. Comparison of series of patients can be made only if these variables are understood.


Investigations of black bronchoalveolar human lavage fluid. The removal by bronchoalveolar lavage (two occasions) of 10(11) black macrophages containing crystals of aluminum silicate, large amounts of amorphous carbon, and oxidized lipids was followed by considerable improvement in gas exchange in a patient. Sixty-eight percent of these pulmonary macrophages were viable and normal, as judged by chemotatctic and phagocytic activity. Except for cigarettes, no source for the previously mentioned ingested foreign substances was found. These observations suggest that removal by lavage of nonviable macrophages laden with foreign bodies from distal portions of the lungs of pulmonary patients may be therapeutically useful.


Intermittent left anterior hemiblock during treadmill exercise test. Correlation with coronary arteriogram. Two patients in whom left anterior hemiblock occurred during a treadmill exercise test were found at cardiac catheterization to have significant obstruction of the proximal portion of the left anterior descending coronary artery. After successful myocardial revascularization in one of these patients, a disturbance in conduction no longer appeared during treadmill testing. To our knowledge, this association has not been previously reported, and this finding may be a useful clinical marker for significant obstructive disease of the proximal portion of the left anterior descending coronary artery.


Pseudocoarctation and mid-arch aortic coarctation. A 21-year-old woman was found to have a mid-arch aortic coarctation in combination with pseudocoarctation. The angiographic disgnosis was established by left atrial injection after transseptal puncture.


Interstitial pneumonitis complicating rheumatoid arthritis. Sustained remission with azathioprine therapy. A patient with classic rheumatoid arthritis developed biopsy-proven diffuse interstitial pulmonary fibrosis and ventilatory insufficiency which appeared to be irreversible. The administration of azathioprine coincided with significant immediate improvement in pulmonary function and clinical status. During five years of continuous azathioprine therapy, progressive improvement in lung function has been accompanied by marked deterioration of the rheumatoid joint disease, suggesting that the pulmonary and joint lesions of rheumatoid disease may not be mediated by the same pathways.


Rate-dependent variation in the duration of the QRS complex with left anterior fascicular block. The case of a 67-year-old man with combined ischemic and valvular heart disease is presented. Electrocardiographic abnormalities included left anterior fascicular block with a variable duration of the QRS complex. The width of the QRS complex was dependent on the length of the cycle, being broader with short than with long preceding R-R intervals. This is interpreted as a tachycardia-dependent focal block coexisting with a fixed delay in fascicular conduction.


Idiopathic atrial flutter, high grade atrioventricular block and sino-atrial dysrhythmia in a young man. Effects of exercise testing. A 25-year-old man with idopathic atrial flutter and high grade atrioventricular (AV) block is described. Postcardioversion, sino-atrial (SA) and AV nodal dysrhythmias occurred. Treadmill exercise during atrial flutter increased AV conduction to 2:1, and normalized SA and AV nodal function following cardioversion. A neurogenic basis for these arrhythmias is hypothesized.


Right heart failure secondary to compression of the right pulmonary artery by a syphilitic aortic aneurysm. A 68-year-old man presented with right heart failure due to compression of the right pulmonary artery by a syphilitic aneurysm of the ascending aorta. The diagnosis was made by cardiac catheterization and angiography and it was proven by autopsy. This complication is unusual and supports the experimental evidence that unilateral pulmonary obstruction may be responsible for the development of pulmonary hypertension.


Pericardial tamponade secondary to sudden steroid withdrawal in chronic rheumatoid arthritis. A patient with chronic rheumatoid arthritis was admitted to the hospital with cervical fracture. Two weeks after acute steroid withdrawal, she was noted to have pleural effusion, and signs and symptoms of acute pericardial tamponade. An open partial pericardiectomy and drainage relieved the symptoms. The sequence of events suggests that rapid steroid withdrawal might have precipitated rapid accumulation of pleural and pericardial fluid.


Pulmonary nodules and rheumatoid factor in the absence of arthritis. Bilateral pulmonary parenchymal nodules were detected in a 41-year-old woman in 1964. These lesions gradually enlarged over a ten-year period. In 1974, the diagnosis of rheumatoid pulmonary disease was based on her clinical course, the presence of rheumatoid factor in the serum, interpretation of a biopsy of a cutaneous nodule, and review of a lung biopsy performed in 1964. The patient never developed arthritis.


Normal single coronary artery and myocardial infarction. A single left coronary artery was found in an asymptomatic 21-year-old man who initially had electrocardiographic and vectorcardiographic evidence of anterolateral myocardial infarction. The single left coronary artery, which supplied the distribution of both the left and right coronary arteries, was free of disease at catheterization. There has been no previous association of a normal single left coronary artery and anterior myocardial infarction. Patients with the finding of a single coronary artery should be watched closely, as this may represent a potentially fatal condition.


Splenic echinococcal cyst burrowing into left pleural space. We describe a rare case of hydatid cyst in the spleen which communicated to the left pleural cavity. The patient presented with respiratory distress, characterized by nonproductive cough and dyspnea. The difficulties in diagnosis, using standard laboratory and radiologic techniques, were overcome by the use of ultrasound examination diagnosing both the cysts and the supra-diaphragmatic extension.


Tobramycin serum levels and tissue content in children. Tobramycin serum levels as well as muscle and fat tissue content have been determined for 8 h in hourly intervals using an agar diffusion method following a single intramuscular injection of 2.5 mg/kg body weight to 29 children. In addition two specimens of spleen and one testis could be assayed for tobramycin content in these children. Tissue fluid was obtained by use of a Colworth Stomacher Nr.80. At 1 1/2 hours mean peak concentrations in serum were found to be 4.32 microgram/ml, in muscle 0.93 microgram/g and in fat 1.16 microgram/g, from thereon declining to lower values. At 8 h tissue content fell below the smallest detectable amount of 0.01 microgram/g tobramycin. At any time tobramycin content in fat (on average 24% of the corresponding serum level) was significantly higher than in muscle (17% of the serum level), whereas tobramycin content in spleen never exceeded that in muscle as well as in fat. Thus blood supply of the tissue does not seem to the main factor determining tobramycin content in various tissues.


[Hepato-biliary sequence-scintigraphy in pre- and postoperative upper abdominal diagnosis. Studies on 200 patients using the radiopharmacon 99mTechnetium-Solcoscint-Hepatobida]. Hepato-biliary dynamic studies with 99mTc-Solcoscint-Hepatobida are suggested in the pre- and postoperative investigation of patients with possible surgical disease of the biliary tract. The equipment used for the studies was a gamma camera. The diagnostic criteria used were those of blood retention, liver, gall bladder, and biliary tree visualisation. Results from findings in 200 patients are presented to demonstrate the ability of the technique; especially to disclose evidence indicating intra- or extrahepatic causes of cholestasis.


[Use of a new method for the determination of the duodeno- and jejunogastral reflux after gastric surgery]. The use of hepato-biliary sequential scintigraphy with 99mTechnetium as a new method to demonstrate duodenogastric or jejunogastric reflux is described. In contrast to other techniques, the benefit of minimal stress for patients, routine practice, and combined measurement of fasting and postprandial reflux is pointed out. First clinical studies in postoperative patients are presented and it is accentuated, that this technique has a special field of application in gastric surgery.


[Dissecting arterial disease of the renal vessels as a cause of hypertension]. With modern specific diagnostic studies like isotope renography, angiotensin-infusion-test, peripheral venous renin assay, comparative assays of the renin activity in the individual renal veins, and angiography the renal and renovascular causes for hypertension become more and more significant. When it has been shown that the hypertension is caused by a constriction of the renal arteries, instant operative therapy is indicated. The rare case of a dissectioning arteriopathy of the renal arterial wall causing hypertonia is described.


[Surgical interventions in patients with pacemakers]. The increasing rate of pacemaker patient operations is due to the rising number of pacemaker carriers. Preoperative recognition of cardiac dysrhythmia is frequent, so that pacemaker implantation prior to operation is essential for the achievement of the operability. The corresponding control of pacemaker function and the appropriate checking of security precautions permit feasible preoperative preparations as well as operations similar to those in non-pacemaker carriers. Our observations are in agreement with others in the literature that a pacemaker does not increase the operation risk. On the contrary, it often makes operability achievable. A continuous and safe patient control through the new ECG-apparatus is possible, even with use of high frequency surgical instruments.


Validation of the Watson-Thomas rules for MMPI diagnosis. The Watson-Thomas rules for MMPI diagnosis of organic versus functional disorder were applied to the profiles of five groups of 14 male veteran patients, one neurologic and four psychiatric. The psychiatric groups were married schizophrenics, unmarried schizophrenics, alcoholics, and mixed functional diagnosis. Rule 4 was found to discriminate among the groups most reliably. In the psychiatric samples, married schizophrenics were not successfully categorized by any of the Rules.


Spinal arterio-venous malformations simulating multiple sclerosis: importance of early diagnosis. Two cases of spinal arteriovenous malformation (AVM) in young patients are presented. Symptoms were compatible with the spinal form of multiple sclerosis in both cases. The lesions were not diagnosed on initial evaluation. Subsequently they were found by myelography and arteriography, the one eight months and the other nine years after the first symptoms. The contrasting clinical courses of the two patients suggest that: (a) the diagnosis of multiple sclerosis where symptoms and signs are restricted to the spinal cord should be made only after a thorough investigation which includes myelography, to rule out the presence of a surgically correctible lesion such as an AVM; (b) myelography should be carried out in both the supine and prone positions as an AVM may be completely missed by routine prone myelography views; (c) early surgery of the resectable AVM may prevent a progressive deterioration of neurological function, making early diagnosis particularly important.


Effect of ionic strength on charcoal adsorption assays of receptor-estradiol complexes. The effect of increasing ionic strength on the efficacy of the charcoal adsorption assay for estrogen receptors has been examined. Cytosol prepared from immature rat uteri was exposed to variable concentrations of KCl and the saturable or "specific" binding of [3H]estradiol was measured by charcoal and hydroxylapatite adsorption, gel filtration, and/or density gradient centrifugation using excess diethylstilbestrol to correct for non-saturable or "non-specific" binding. As the concentration of KCl was increased, the number of estradiol binding sites as measured via charcoal adsorption decreased in proportion to the conversion of receptor from a low salt (8S) to a high salt (4S) complex. This "stripping" of [3H]estradiol from the 4S receptor species was both time- and charcoal concentration-dependent. It is concluded that the charcoal adsorption procedure quantitatively assesses the binding of [3H]estradiol to low salt, 8S receptor species but is not the assay of choice for salt-extracted or salt-treated receptors in view of the potential for artifactually low estimates of receptor number. Low values for receptor number under high salt conditions may result from exposure of the binding site of the estrogen receptor to charcoal.


Anti-estrogenic compounds increase prolactin and growth hormone synthesis in clonal strains of rat pituitary cells. Established clonal strains of rat pituitary cells, GH-cells, responded prior to 1974 to 10(-11) to 10(-8)M 17beta-estradiol by increasing prolactin synthesis 2-fold and decreasing the production of growth hormone to between 20 and 70% of control values. In experiments in 1975-76, these effects of estradiol were no longer statistically significant. Unexpectedly, the estrogen antagonists enclomiphene, CI-628, tamoxifen, and Lilly 88751 caused increases in both prolactin and growth hormone synthesis at concentrations of about 10(-7) to 10(-6)M after one week of treatment. These increases were prevented by 10(-8)M 17beta-estradiol. Prolactin synthesis remained elevated for at least 11 days after removal of enclomiphene from the culture medium but, in the presence of estradiol, synthesis approached control levels by 11 days. In GH-cells, compounds which are estrogen antagonists in other systems mimic the previously observed effect of estradiol on prolactin synthesis, but have an effect opposite to that of estradiol on growth hormone, namely stimulation of its synthesis.


The regulation of 24,25-dihydroxyvitamin D3 production in cultures of monkey kidney cells. Primary kidney cell cultures from normal rhesus monkeys were used to study the regulation of 24,25-dihydroxyvitamin D3 production. Kidney cells were grown to confluency in the modified National Cancer Institute Medium NCTC 135 with 2% fetal calf serum and then maintained in a serum-free medium (2% bovine serum albumin) for five additional days prior to a study of regulation. Morphologically, 80% of the cultured cells were epithelial in nautre. These cells produced 24,25-dihydroxy-[3H]vitamin D3 from 25-hydroxy-[3H]-vitamin D3. The identity of the 24,25-dihydroxy-[3H]vitamin D3 was established by Sephadex LH-20 chromatography, by co-chromatography with authentic 24,25-dihydroxyvitamin D3 on high pressure liquid columns, and by periodate sensitivity. Bovine parathyroid hormone at a level of 3 U/ml or human 1-34 parathyroid hormone at 0.05 U/ml for five days suppressed 24,25-dihydroxyvitamin D3 production. Nonradioactive 1,25-dihydroxyvitamin D3 (13 pmol/ml) added once every two days for eight days led to a 2-fold increase in production of 24,25-dihydroxyvitamin D3. Exposure of renal cells to 3 mM instead of 1 mM calcium led to a marked increase in 24,25-dihydroxyvitamin D3 production. These results suggest that renal cell cultures may be an important new approach to a study of regulation of the vitamin D renal hydroxylases.


The interaction of the photoperiod and testosterone in regulating serum gonadotropin levels in castrated male hamsters. Castrated adult male golden hamsters maintained on either a stimulatory (LD 14:10) or a nonstimulatory (LD 6:18 ) light cycle for 10 weeks following surgery were implanted sc with empty or testosterone-filled Silastic capsules of various lengths. Capsules which maintained circulating androgen levels between 0.5 and 1.7 ng/ml reduced serum levels of LH and FSH in castrated animals exposed to LD 6:18 but not in animals maintained on LD 14:10. When serum androgen levels were maintained at about 3 ng/ml, serum gonadotropin levels were reduced 30--35-fold in nonphotostimulated hamsters but only 2--3-fold in photostimulated animals. Maintenance of serum androgen levels at 14--17 ng/ml induced a maximum decrease in serum LH and FSH in animals exposed to either photoperiod. These results indicate that exposure to short days for 10 weeks renders the hypothalamic-hypophyseal axis of the castrate hamster extremely sensitive to the negative feedback effect of testosterone. This alteration in steroid feedback sensitivity may be one way in which the photoperiod acts to alter neuroendocrine-gonadal activity in seasonally breeding animals.