In an across study analysis of five multicenter, placebo-controlled trials of the synthetic surfactant, Exosurf Neonatal in infants weighing at least 700 gm, the incidence of clinical pulmonary hemorrhage was 1.9% in treated infants and 1.0% in control infants. To investigate whether a similar increase was also present histologically at postmortem examination, a blinded retrospective review of all autopsy reports from infants dying during these live trials was conducted. Pulmonary hemorrhage was present in 55% of 159 infants undergoing autopsy; the incidence was not different in infants treated with surfactant or air placebo. Birth weight was inversely related to the incidence of pulmonary hemorrhage in both groups. Pulmonary pathologic findings significantly associated with pulmonary hemorrhage included pulmonary interstitial emphysema and necrotizing laryngotracheitis in both groups. In the surfactant group, patent ductus arteriosus, intraventricular hemorrhage, and pneumothorax were significantly more frequent among those who developed pulmonary hemorrhage. In contrast to clinical diagnosis, pathologic diagnosis of pulmonary hemorrhage at autopsy was not more common in infants treated with Exosurf Neonatal.

In an across study analysis of five multicenter, placebo-controlled trials of the synthetic surfactant, Exosurf Neonatal in infants weighing at least 700 gm, the incidence of clinical pulmonary hemorrhage was 1.9% in treated infants and 1.0% in control infants. To investigate whether a similar increase was also present histologically at postmortem examination, a blinded retrospective review of all autopsy reports from infants dying during these five trials was conducted. Pulmonary hemorrhage was present in 55% of 159 infants undergoing autopsy; the incidence was not different in infants treated with surfactant or air placebo. Birth weight was inversely related to the incidence of pulmonary hemorrhage in both groups. Pulmonary pathologic findings significantly associated with pulmonary hemorrhage included pulmonary interstitial emphysema and necrotizing laryngotracheitis in both groups. In the surfactant group, patent ductus arteriosus, intraventricular hemorrhage, and pneumothorax were significantly more frequent among those who developed pulmonary hemorrhage. In contrast to clinical diagnosis, pathologic diagnosis of pulmonary hemorrhage at autopsy was not more common in infants treated with Exosurf Neonatal.

The use of animals for the screening of chemotherapeutic agents effective against cancer is not always satisfactory. In addition to the problems of cost, space, and care, the results obtained by animal screening do not always parallel those obtained by the clinical use of the agents. With the advent of more refined in vitro technics which can be applied directly to the patient's own tumor tissue, additional information may permit a more critical evaluation of the laboratory findings. The critical index of sensitivity probably lies in the combined evaluation of biochemical analysis and observed morphological damage. From this investigation it would appear that tissue culture of human tumors may serve as a valuable adjunctive method for the screening of chemicals in order to find drugs valuable in the treatment of cancer in man and to serve as a method in the selection of the most effective therapeutic agent for a given tumor in a given patient.

The plasma half-life (T 1/2) of two drugs has been measured to investigate whether liver disease impairs drug metabolism in man. The T1/2 of phenylbutazone, a drug hydroxylated by a microsomal enzyme system and isoniazid (I.N.A.H.) a drug metabolised by a non-microsomal acetylase may be prolonged in patients with acute or chronic liver disease compared with healthy individuals. Pretreatment with a variety of drugs known to induce microsomal enzymes shortens the T1/2 of phenylbutazone but not of isoniazid. Pretreated volunteers had a comparable phenylbutazone T1/2 whether they had liver disease or not. Some previous investigators may have failed to demonstrate that liver disease impairs drug metabolism in man because the importance of other drug treatment and its influence on the microsomal enzymes was not appreciated. When assessing the effect of a drug in both healthy individuals and those with liver disease note must be taken of the method by which the drug is metabolised and of any previous therapy that could affect it.

Les auteurs ont étudié le comportement in vitro de 607 échantillons de tumeurs humaines, réparties en 5 grands groupes histologiques. Ils ont établi, pour ces tumeurs, le pourcentage relatif de croissance (pourcentage de cultures positives), le temps de survie, l'activité mitotique et le degré d'incorporation de nucléosides tritiés.

The urinary excretion of amines was investigated in 20 normal children by means of two-dimensional paper chromatography, following preliminary separation of amines from other urinary constituents by the use of a cation exchange resin. Normal children were found to excrete the following 19 amines: tryptamine, serotonin, bufotenin, kynuramine, histamine, βN-acetylhistamine, p-tyramine, m-tyramine, p-hydroxybenzylamine, octopamine, synephrine, 3-methoxytyramine, 3-methoxy-4-hydroxybenzylamine, normetanephrine, metanephrine, ethanolamine, ethylamine,βhydroxy-propylamine, and pyrrolidine. Of these, kynuramine, p-hydroxybenzylamine, 3-methoxy-4-hydroxybenzylamine, and β-hydroxypropylamine have not been previously reported as constituents of human urine. The methods used were not stisfactory for the detection of methylamine, dimethylamine, piperidine, norepinephrine, epinephrine, and dopamine, but the presence of these six amines in urine has been reported by others. An additional 24 unidentified compounds, probably amines, were found in most or all of the urines studied, and some of them appeared to be present in relatively large amounts. Other unidentified bases were encountered in a few urines. The effects of monoamine oxidase blockade on the urinary excretion of amines have been described, as well as the effects of exclusion of plant foods from the diet, and antibiotic restriction of intestinal flora. Figures are presented for the approximate range of daily excretion of 12 amines. It is suggested that study of the excretion of amines in the urine of children who are mentally defective or mentally ill, and comparison with the pattern of urinary amines in normal children, may provide clues to the mechanisms of certain forms of cerebral dysfunction.

CancerVolume 15, Issue 2 p. 284-293 ArticleFree Access Further investigation of the relation between the clinical and tissue culture response to chemotherapeutic agents on human cancer Jane C. Wright M.D., Jane C. Wright M.D. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this authorJewel P. Cobb PH.D., Jewel P. Cobb PH.D. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this authorStephen L. Gumport M.D., Stephen L. Gumport M.D. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this authorDavid Safadi M.D., David Safadi M.D. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this authorDorothy G. Walker M.A., Dorothy G. Walker M.A. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this authorFrederick M. Golomb M.D., Frederick M. Golomb M.D. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this author Jane C. Wright M.D., Jane C. Wright M.D. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this authorJewel P. Cobb PH.D., Jewel P. Cobb PH.D. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this authorStephen L. Gumport M.D., Stephen L. Gumport M.D. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this authorDavid Safadi M.D., David Safadi M.D. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this authorDorothy G. Walker M.A., Dorothy G. Walker M.A. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this authorFrederick M. Golomb M.D., Frederick M. Golomb M.D. Department of Surgery, New York Medical Center, 550 First Ave., New York 16, N.Y.Search for more papers by this author First published: March/April 1962 https://doi.org/10.1002/1097-0142(196203/04)15:2<284::AID-CNCR2820150212>3.0.CO;2-ICitations: 38AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References 1. Antikajian, G., Wright, L. T., Plummer, J. I., and Weintraub, S.: Effect of triethylene melamine, aureomycin, and some 4-amino derivatives of folic acid on tissues in vitro. J. Nat. Cancer Inst. 12: 269– 274, 1951. 2. Cobb, J. P.: Tissue culture observations of effects of chemotherapeutic agents on human tumors. Tr. New York Acad. Sc. 17: 237– 249, 1955. 3. Cobb, J. P.: Comparative cytological effects of several alkylating agents on human normal and neoplastic cells in tissue culture. Ann. New York Acad. Sc. 84: 513– 542, 1960. 4. Cobb, J. P., and Walker, D. G.: Effect of actinomy-cin D on tissue cultures of normal and neoplastic cells. J. Nat. Cancer Inst. 21: 263– 278, 1958. 5. Cobb, J. P., and Walker, D. G.: Studies on human melanoma cells in tissue culture; I, growth characteristics and cytology. Cancer Res. 20: 858– 867, 1960. 6. Cobb, J. P., Walker, D. G., and Wright, J. C.: Observations on action of triethylene thiophosphora-mide within individual cells. Acta Unio internat. contra cancrum 16: 567– 583, 1960. 7. Cobb, J. P., and Wright, J. C.: Studies on cranio-pharyngioma in tissue culture; I, growth characteristics and alterations produced following exposure to 2 radiomimetic agents. J. Neuropath. & Exper. Neurol. 18: 563– 568, 1959. 8. Golomb, F. M.: Selection of drugs for perfusion. In Cancer Chemotherapy Reports, No. 10. Bethesda, Md. Cancer Chemotherapy National Service Center. 1960; pp. 53– 55. 9. Gumport, S. L., Golomb, F. M., and Wright, J. C.: Summary of results obtained with CB 1348. Ann. New York Acad. Sc. 68: 1024– 1034, 1958. 10. Gumport, S. L., Wright, J. C., and Golomb, F. M.: Treatment of advanced malignant melanoma with triethylene thiophosphoramide (Thio-TEPA or TSPA). Ann. Surg. 147: 232– 238, 1958. 11. Hu, F.: Cytological studies of human pigment cells in tissue culture. In M. Gordon, Ed.: Pigment Cell Biology; Proceedings of the Fourth Conference on the Biology of Normal and Atypical Pigment Cell Growth. New York, N.Y. Academic Press Inc., Publishers. 1959; pp. 147– 158. 12. Reiman, M. S., Stern, I. R., Ford, M. Z., and Hoster, H. A.: Studies in Hodgkin's syndrome; XI, influence of normal serum and Hodgkin's serum on cellular growth and morphology in tissue culture. Cancer Res. 10: 467– 473, 1950. 13. Wright, J. C., Cobb, J. P., Gumport, S. L., Golomb, F. M., and Safadi, D.: Investigation of relation between clinical and tissue-culture response to chemotherapeutic agents on human cancer. New England J. Med. 257: 1207– 1211, 1957. 14. Wright, J. C., Golomb, F. M., and Gumport, S. L.: Summary of results with triethylene thiophosphoramide. Ann. New York Acad. Sc. 68: 937– 966, 1958. 15. Wright, J. C., Gumport, S. L., and Golomb, F. M.: Dihydro E-73; drug with antitumor effects in man; preliminary clinical report. In Cancer Chemotherapy Reports, No. 8. Bethesda, Md. Cancer Chemotherapy National Service Center. 1960; pp. 7– 17. 16. Wright, J. C., Gumport, S. L., and Golomb, F. M.: Remissions produced with use of Methotrexate in patients with mycosis fungoides. In Cancer Chemotherapy Reports, No. 9. Bethesda, Md. Cancer Chemotherapy National Service Center. 1960; pp. 11– 20. 17. Wright, J. C., Plummer, J. I., Coidan, R. S., and Wright, L. T.: In vivo and in vitro effects of chemotherapeutic agents on human neoplastic diseases; preliminary report on comparison of effects of chemotherapeutic agents on human tumors in tissue culture and effects of each such agent in patient from whom tissue culture was taken. Harlem Hosp. Bull. 6: 58– 63, 1953. 18. Zubrod, G.: In Jones, R. Jr., Chairman: Use of alkylating agents and future of these agents. [Panel disc.] In B. H. Morrison, Ed.: Conference on Experimental Clinical Cancer Chemotherapy. National Cancer Institute Monograph No. 3. Washington, D.C. U. S. Government Printing Office. 1960; pp. 136– 140. Citing Literature Volume15, Issue2March/April 1962Pages 284-293 ReferencesRelatedInformation

THE mechanism by which mental defect is produced in phenylketonuria is unknown. No correlation has been found in patients having this disorder between the degree of mental defect and blood-levels of phenylalanine or phenylpyruvate, or urinary excretion of phenylalanine, phenyllactate, phenylpyruvate or o-hydroxyphenylacetate1. The possible implication of biologically active amines has been examined in several papers. Mitoma et al. 2 administered o-tyrosine and m-tyrosine to experimental animals and observed conversion to the corresponding amines in brain, with attendant central nervous system stimulation and convulsions. Association of the mental defect in phenylketonuria with an excessive production of o-tyramine was suggested. It also seems possible that overproduction of phenylethylamine may be responsible for the disturbance in cerebral metabolism. Jepson et al. 3 have recently shown that administration of a monoamine oxidase inhibitor to phenylketonuric individuals results in an increase much greater than normal in the urinary excretion of phenylethylamine, but not of o-tyramine. The mental defect in phenylketonuria may also be due to an underproduction of amines vital to normal brain function. Pare et al. 4 have reported low serum serotonin-levels and decreased urinary excretion of 5-hydroxyindoleacetic acid in phenylketonuria. They suggest that one or more aromatic acid metabolites of phenylalanine inhibit 5-hydroxytryptophan de-carboxylase, the enzyme responsible for the production of serotonin.

SUMMARY Fifty-four tissues of human melanomas from 33 patients with primary or meta static lesions were cultivated in vitro using several chemically defined media supple mented with horse, calf, or human serum. Forty-two or 77.8 per cent developed out growths in vitro. All cultures exhibited radial outgrowths, and cells migrated as independent units. The dendritic melanocyte resembled a nerve cell in its initial emigration in vitro. The melanocyte was found in various stages of differentiation ranging from the un differentiated uni- or bipolar form, in cultures of anaplastic melanomas, to the dif ferentiated dendritic form in cultures of more heavily pigmented melanomas. The dendritic form was observed in most pigmented cultures regardless of primary or metastatic site. Melanin formation in vitro coincided with the aggregation and dif ferentiation of the melanocytes which increased with age of the cultures. Prior treatment in vivo appeared to influence subsequent successful growth in vitro, as indicated by 95.8 per cent successful tissue culture growth in melanomas from un treated patients and only 70.3 per cent successful growth from patients who had re ceived prior radiation or chemotherapy or both. This paper describes the cellular morphology and behavior of 54 human melanomas in tissue culture. The sites of removal, gross and micro scopic appearance of the lesions, and in vivo ther apy prior to biopsy were recorded and related to growth characteristics in vitro.1

VARIOUS studies have suggested that the excretion of β-amino-isobutyric acid in human urine is under genetic control1–4. This amino-acid is derived from the metabolism of thymine via dihydrothymine and β-ureido-isobutyric acid5. Variation in excretion of β-amino-isobutyric acid may be controlled by a single gene pair, with high excretors being homozygous for a single recessive gene and low excretors being either heterozygous or homozygous for the dominant allele6. It also has been suggested that low and high excretors may differ in their metabolism of β-amino-isobutyric acid7. An increased incidence of high excretors has been found in certain ethnic groups, notably the Athabascan and Apache Indians of North America, the Black Caribs of British Honduras, and the Chinese and Japanese4,6,8. High excretors of β-amino-isobutyric acid are relatively uncommon in populations of Caucasian origin1,2,3.

Administration of the English borders during the reign of Queen Elizabeth, by C. A. Coulomb 687 Alger, G. W., The old law and the new order 685 Aliens in China, The status, by V. K. Wellington Koo, rev. by P. J. Treat.. 298 Aliens in the United States, Exclusion and expulsion of, by C. L. Bouvis, rev. by James Brown Scott 310 Allin, C. D., rev. of Lucas, Lord Durham's report on the affairs of British North America 156 rev. of Stuart-Linton, The problem of empire governance 317 Alsace-Lorraine et l'Empire Allemand, by Robert Baldy, rev. by W. B. Hunting 512 American city government, by Charles A. Beard, rev. by R. G. Gettell.. 319 American Mediterranean, by Stephen Bonsai, rev. by Paul S. Reinsch... . 304 American occupation of the Philippines, by James H. Blount, rev. by O. G. Jones 308 American syndicalism, by J. G. Brooks 287 Andrews, C. M., rev. of Beer, The old colonial system, 1660-1754 509 Annulment of legislation by the Supreme Court, by Horace A. Davis . . . . 541 Argentine, Le Gouvernement reprlsentatif F6d6ral dans la R6publique, by J. N. Matienzo 484 Armaments and arbitration, by A. T. Mahan, rev. by A. H. Snow 318 Asile accord6 aux vaissaux de guerre des belligerants dans les ports neutres, by Joseph Levy-Bouillier 291 Authority of Vattel, by C. G. Penwick 395