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1. Monochloroacetate, dichloroacetate, trichloroacetate, difluoroacetate, 2-chloropropionate, 2,2′-dichloropropionate and 3-chloropropionate were inhibitors of pig heart pyruvate dehydrogenase kinase. Dichloroacetate was also shown to inhibit rat heart pyruvate dehydrogenase kinase. The inhibition was mainly non-competitive with respect to ATP. The concentration required for 50% inhibition was approx. 100μm for the three chloroacetates, difluoroacetate and 2-chloropropionate and 2,2′-dichloropropionate. Dichloroacetamide was not inhibitory. 2. Dichloroacetate had no significant effect on the activity of pyruvate dehydrogenase phosphate phosphatase when this was maximally activated by Ca2+and Mg2+. 3. Dichloroacetate did not increase the catalytic activity of purified pig heart pyruvate dehydrogenase. 4. Dichloroacetate, difluoroacetate, 2-chloropropionate and 2,2′-dichloropropionate increased the proportion of the active (dephosphorylated) form of pyruvate dehydrogenase in rat heart mitochondria with 2-oxoglutarate and malate as respiratory substrates. Similar effects of dichloroacetate were shown with kidney and fat-cell mitochondria. Glyoxylate, monochloroacetate and dichloroacetamide were inactive. 5. Dichloroacetate increased the proportion of active pyruvate dehydrogenase in the perfused rat heart, isolated rat diaphragm and rat epididymal fat-pads. Difluoroacetate and dichloroacetamide were also active in the perfused heart, but glyoxylate, monochloroacetate and trichloroacetate were inactive. 6. Injection of dichloroacetate into rats starved overnight led within 60 min to activation of pyruvate dehydrogenase in extracts from heart, psoas muscle, adipose tissue, kidney and liver. The blood concentration of lactate fell within 15 min to reach a minimum after 60 min. The blood concentration of glucose fell after 90 min and reached a minimum after 120 min. There was no significant change in plasma glycerol concentration. 7. In epididymal fatpads dichloroacetate inhibited incorporation of14C from [U-14C]glucose, [U-14C]fructose and from [U-14C]lactate into CO2 and glyceride fatty acid. 8. It is concluded that the inhibition of pyruvate dehydrogenase kinase by dichloroacetate may account for the activation of pyruvate dehydrogenase and pyruvate oxidation which it induces in isolated rat heart and diaphragm muscles, subject to certain assumptions as to the distribution of dichloroacetate across the plasma membrane and the mitochondrial membrane. 9. It is suggested that activation of pyruvate dehydrogenase by dichloroacetate could contribute to its hypoglycaemic effect by interruption of the Cori and alanine cycles. 10. It is suggested that the inhibitory effect of dichloroacetate on fatty acid synthesis in adipose tissue may involve an additional effect or effects of the compound.

Plasma CEA values and serum γ glutamyl transpeptidase activities have been compared in control subjects and 109 patients with colorectal carcinoma and 35 with non-malignant hepatic disease. CEA values alone differentiate hepatic metastases from non-malignant hepatic disease with a high degree of certainty. While CEA may be elevated with metastases, irrespective of site, γGT is elevated mainly in association with hepatic metastases. The combination of CEA and γGT is helpful in identifying hepatic metastases and in their differentiation from local recurrences or metastases to other sites.

The evolution and structure of adenomatous polyps and adenocarcinomata of the colon in NMRI mice induced by dimethylhydrazine are described. Severe toxic reactions in the liver and other organs are produced by dimethylhydrazine (DMH), but tumours are induced only in the colon and around the anus. The 100% incidence and growth characteristics of the tumours make it potentially a good model system, but investigators should take into account the widespread nonspecific cellular injury induced by this carcinogen.

1. The activity of pig heart pyruvate dehydrogenase kinase was assayed by the incorporation of [32P]phosphate from [γ-32P]ATP into the dehydrogenase complex. There was a very close correlation between this incorporation and the loss of pyruvate dehydrogenase activity with all preparations studied. 2. Nucleoside triphosphates other than ATP (at 100μm) and cyclic 3′:5′-nucleotides (at 10μm) had no significant effect on kinase activity. 3. The Km for thiamin pyrophosphate in the pyruvate dehydrogenase reaction was 0.76μm. Sodium pyrophosphate, adenylyl imidodiphosphate, ADP and GTP were competitive inhibitors against thiamin pyrophosphate in the dehydrogenase reaction. 4. The Km for ATP of the intrinsic kinase assayed in three preparations of pig heart pyruvate dehydrogenase was in the range 13.9–25.4μm. Inhibition by ADP and adenylyl imidodiphosphate was predominantly competitive, but there was nevertheless a definite non-competitive element. Thiamin pyrophosphate and sodium pyrophosphate were uncompetitive inhibitors against ATP. It is suggested that ADP and adenylyl imidodiphosphate inhibit the kinase mainly by binding to the ATP site and that the adenosine moiety may be involved in this binding. It is suggested that thiamin pyrophosphate, sodium pyrophosphate, adenylyl imidodiphosphate and ADP may inhibit the kinase by binding through pyrophosphate or imidodiphosphate moieties at some site other than the ATP site. It is not known whether this is the coenzyme-binding site in the pyruvate dehydrogenase reaction. 5. The Km for pyruvate in the pyruvate dehydrogenase reaction was 35.5μm. 2-Oxobutyrate and 3-hydroxypyruvate but not glyoxylate were also substrates; all three compounds inhibited pyruvate oxidation. 6. In preparations of pig heart pyruvate dehydrogenase free of thiamin pyrophosphate, pyruvate inhibited the kinase reaction at all concentrations in the range 25–500μm. The inhibition was uncompetitive. In the presence of thiamin pyrophosphate (endogenous or added at 2 or 10μm) the kinase activity was enhanced by low concentrations of pyruvate (25–100μm) and inhibited by a high concentration (500μm). Activation of the kinase reaction was not seen when sodium pyrophosphate was substituted for thiamin pyrophosphate. 7. Under the conditions of the kinase assay, pig heart pyruvate dehydrogenase forms 14CO2 from [1-14C]pyruvate in the presence of thiamin pyrophosphate. Previous work suggests that the products may include acetoin. Acetoin activated the kinase reaction in the presence of thiamin pyrophosphate but not with sodium pyrophosphate. It is suggested that acetoin formation may contribute to activation of the kinase reaction by low pyruvate concentrations in the presence of thiamin pyrophosphate. 8. Pyruvate effected the conversion of pyruvate dehydrogenase phosphate into pyruvate dehydrogenase in rat heart mitochondria incubated with 5mm-2-oxoglutarate and 0.5mm-l-malate as respiratory substrates. It is suggested that this effect of pyruvate is due to inhibition of the pyruvate dehydrogenase kinase reaction in the mitochondrion. 9. Pyruvate dehydrogenase kinase activity was inhibited by high concentrations of Mg2+ (15mm) and by Ca2+ (10nm–10μm) at low Mg2+ (0.15mm) but not at high Mg2+ (15mm).

Some diastereoisomeric dimethylaminobornyl acetates and their methiodides have been prepared and tested for ganglion blocking activity. Included in these compounds was an enantiomeric pair and associated quaternary salts. These optical antipodes displayed virtually no difference between their actions at the ganglion. Differences between the activities of the least and most potent diastereoisomers was limited to a factor of about five. Assays were made upon the cat superior cervical ganglion and also the guinea-pig vas deferens preparation the successful quantitative use of which is described.

There are many controversies concerning the use or abuse of methods for the prevention of adhesions, and sides are taken by men of equal renown. Favoring the advancement of the study of prevention of adhesions are men who have devoted much time to experimentation to prove or disprove certain theories. Among them are Payr, Vogel and Siderenko, and more recently Kubota, Ochsner, Warren and Trusler. On the other hand, some have abandoned all hope of finding a substance which will take nature's place, and most prominent among them are Hertzler, D. F. Jones and W. L. McClure. The subject is concrete and lends itself to experimentation.The purpose in view in all work of this type is not so much to prevent entirely the formation of all adhesions as to limit their formation to such an extent that they may not result in complications. It is not the adhesions, but

The relationship between the morphology of human erythropoietic cells and their position in interphase has been studied. In normal bone marrow, pro-normoblasts, basophilic normoblasts and early polychromatic normoblasts were present in all stages of interphase. It has been shown that a significant increase in nuclear size occurs as a cell moves through its cell cycle, in both normal and megaloblastic erythropoiesis. The relative distribution of the basophilic erythropoietic cells and the dividing polychromatic cells, in the various stages of interphase, has been determined in normal bone marrow, vitamin B12 deficiency and iron deficiency anemia. In vitamin B12 deficiency, associated with moderate or severe anemia, there was an increased proportion of cells in G2, and there were several cells with DNA contents that were between the 2c and 4c values, which were not in DNA synthesis as judged by 3H-TdR labeling. These abnormalities were most pronounced in the dividing polychromatic cell group. Similar abnormalities were not present in iron deficiency anemia, indicating that these disturbances were not produced by the presence of anemia per se. The possible relationship between these changes in the cell cycle and the ineffective erythropoiesis seen in anemia due to vitamin B12 deficiency has been discussed.

1. An assay, based on competition between adenosine 3′:5′-cyclic monophosphate (cyclic AMP) and cyclic [3H]AMP for binding to a rabbit skeletal muscle protein, has been used to measure tissue contents of cyclic AMP. The assay has a sensitivity of 0.05pmol of cyclic AMP. Cyclic GMP and cyclic CMP have 0.5%, and cyclic IMP 6.5%, of the ability of cyclic AMP to displace cyclic [3H]AMP from binding protein; AMP, ADP and ATP have no effect. 2. By using this method, the cyclic AMP content of ox pituitary slices exposed to prostaglandin was determined; release of growth hormone was measured by radioimmunoassay. 3. Release of growth hormone was increased by 45min incubation in 1μm-prostaglandin E2 in the absence of theophylline, or in 10nm-prostaglandin E2, 0.1μm-prostaglandin A1 or 1μm-prostaglandin B1 in the presence of 0.5mm-theophylline. 4. Pituitary cyclic AMP content was increased by 10min incubation in 1μm-prostaglandin E2 in the absence of theophylline, or in 0.1μm-prostaglandin E2 in the presence of 0.5mm-theophylline. 5. The maximum increase in cyclic AMP content was observed 10min, and significant changes in growth hormone release 30min, after introduction of prostaglandin E2. 6. The increase in pituitary cyclic AMP content, but not in the rate of release of growth hormone, was observed in the absence of external Ca2+. 7. The stimulation of release of growth hormone by prostaglandin was decreased by preincubation of tissue for 2h in colchicine (100μm) or cytochalasin B (10μg/ml). 8. These results support the suggestion that increased release of growth hormone after treatment with prostaglandin is the result of increased tissue cyclic AMP content, and possibly involves a microfilamentous or microtubular protein.

The current widespread interest in jogging and the frequency of ischemic heart disease in the American male population have prompted many physicians to request specific guidelines in the management of patients who wish to begin an exercise program. This communication provides such guidelines in the following areas: The type and the importance of the initial medical examination; physical fitness testing, its value and its risks; contraindications and abnormal responses to exercise; and restrictions to be placed upon the older exercising patient. With this information, physicians can better advise their patients about the hazards associated with exercise as well as the use of exercise as a therapeutic tool.

The hyphal septa of 3 chromomycosis agents, Phialophora pedrosoi, Phialophora verrucosa, and Cladosporium carrionii were investigated ultrastructurally. Single pores were observed in the septa of all 3 species. Conspicuous bodies consistent in appearance with previous descriptions of Woronin bodies were also observed. These observations suggest an ascomycetous affinity for these imperfect dematiaceous fungi.

Chemical analyses demonstrated the similar compositions of hyphal walls isolated from the chromomycosis agents Phialophora verrucosa, P. pedrosoi and Cladosporium carrionii. Unfractionated walls of each species consisted of large amounts of glucose (17-31%) and protein components (29-42%) and smaller amounts of mannose (8-14%) and glucosamine (6-8%). Alkali-soluble wall fractions consisted predominantly of glucose and mannose, while alkali-insoluble wall fractions consisted predominately of glucosamine and protein components. Chitin was identified as a wall component by release of N-acetylglucosamine during enzymatic digestions of the walls with Streptomyces griseus chitinase. The presence of chitin in the walls and alkali-insoluble residues was confirmed by X-ray powder analysis. The suggestion is made that the hyphal forms of human pathogenic fungi have wall compositions intermediate between those of euascomycetes and hemiascomycetes.

Newborn rats of one inbred strain were given an intracardiac injection of adult thoracic duct lymphocytes from another inbred strain. It was found that although there was a direct relationship between the number of small lymphocytes injected and the incidence of fatal runt disease, there was no particular relationship between the large lymphocyte content of an inoculum and its runt-inducing potentiality. Using tritiated thymidine and an autoradiographic technique, the small lymphocytes in the inoculum were labelled and found to migrate in large numbers into the cortex of the lymph nodes and into the Peyer's patches of the host animal, and in smaller numbers into the white pulp of the spleen. Within 24 hours isotope, previously present in the DNA of small lymphocytes, appeared in a number of the large pyroninophilic cells which were a characteristic feature of the spleen and lymph nodes in this early phase of runt disease. When the large lymphocytes in the inoculum were labelled they were found to migrate to the red pulp of the spleen, medulla of the lymph nodes, and the Peyer's patches and the lamina propria of the small intestine. Later some labelled small lymphocytes appeared at these sites. These findings suggest that: (1) Some small lymphocytes are immunologically competent cells, and (2) After introduction into the circulation of a newborn rat, these same small lymphocytes are the first cells to react with the antigens of the host, and in the process they become transformed into large pyroninophilic cells capable of division. The large lymphocytes seem to play little part in this initiating of an immunological response, but do give rise to some small lymphocytes.

Pulmonary function and work capacity were evaluated in nine young adult men with straight thoracic spines noted on inspection and confirmed by x-ray. Subjects with pectus excavatum or scoliosis were excluded. Only one subject had a pulmonic systolic heart murmur. In the straight back group (SB), the observed total lung capacity (TLC), percent of predicted TLC, and FEV3.0were reduced significantly (P < 0.001) over a control group. There were no significant differences between SB subjects and controls for FEV1.0,FEF0-25,FEF25-75, DL, or arterial blood gas studies. Working capacity data obtained on a level one mile run and on a treadmill showed no differences from control subjects before and after training. Despite a reduced TLC and a tendency to reduced terminal air flow, the young adult man with absent physiologic dorsal thoracic kyphosis does not have a significant decrease in working capacity and can undergo effective physiologic training.

By means of a 12-minute field test, the effect of cigarette smoking on endurance performance was measured in 419 airmen before and after six weeks of basic training. In 47 airmen, cardiopulmonary indexes also were obtained during maximal treadmill performance. Field testing showed that endurance performance was inversely related to the number of cigarettes smoked daily and the duration of smoking. The training response also was impaired significantly in the smokers. During treadmill studies, smokers had a decrease in respiratory minute volume and a lower oxygen consumption at equivalent heart rates than nonsmokers. Further statistical studies demonstrated not only the independent effect of smoking, but also the effect of prior athletic history and physical characteristics on endurance performance. The latter effects become less significant as physical training progressed.

One hundred and fifteen US Air Force male officers and airmen were evaluated on a 12-minute field performance test and on a treadmill maximal-oxygen-consumption test. The correlation of the field-test data with the laboratory-determined oxygen-consumption data was 0.897. The significance of this relationship makes it possible to estimate with considerable accuracy the maximal oxygen consumption from only the results of the 12-minute performance test. This test is readily adaptable to large groups, requires minimum equipment, and appears to be a better indicator of cardiovascular fitness than the more commonly accepted 600-yard run. Because of the high correlation with maximal oxygen consumption, it can be assumed that the 12-minute field performance test is an objective measure of physical fitness reflecting the cardiovascular status of an individual.

A difference between the United States and Austria in number of deaths from heart attacks among men 35 to 44 years of age aroused considerable interest with respect to the role of physical activity. The purpose of the present study was to evaluate the level of physical fitness of younger men, ie, 18 to 29 years of age, in the US Air Force and the Austrian Army. A marked difference in endurance performance was observed on a 12-minute field test of performance irrespective of the stage of training or the age, even though the Austrian soldiers weighed more and a comparable percentage of them smoked cigarettes. The results indicate that the 12-minute field test is a good substitute for the laboratory-determined maximal oxygen consumption if the subjects are well motivated.

Formulations are given for the coefficients λ, μ, ν defined by Hertz in terms of the solution of a transcendental equation involving elliptic integrals and used by him to describe the deformation of bodies subjected to contact stresses. Methods of approximate calculation are explained and errors in the tables prepared by Hertz are noted. For the purpose of providing a more extensive and more accurate tabulation, using an automatic digital computer, these coefficients are reformulated so that a large part of the variation is expressed by means of easily interpreted elementary formulas. The remainder of the variation is tabulated to 6 places for 100 values of the argument. Graphs of the coefficients are also provided.