Dilemmas of medical ethics in the Canadian Penitentiary Service. There is a unique hospital in Canada-and perhaps in the world-because it is built  outside prison walls and it exists specifically for the psychiatric treatment of prisoners. It is on the one hand a hospital and on the other a prison. Moreover it has to provide the same quality and standard of care which is expected of a hospital associated with a university. From the time the hospital was established moral dilemmas appeared which were concerned with conflicts between the medical and custodial treatment of prisoners, and also with the attitudes of those having the status of prisoner-patient. Dr Roy describes these dilemmas and attitudes, and in particular a special conference which was convened to discuss them. Not only doctors and prison officials took part in this meeting but also general practitioners, theologians, philosophers, ex-prisoners, judges, lawyers, Members of Parliament and Senators. This must have been a unique occasion and Dr Roy's description may provide the impetus to examine these prison problems in other settings.


The just provision of health care: a reply to Elizabeth Telfer. Dr Hillel Steiner in this reply to Elizabeth Telfer takes each of her arguments for different arrangements of a health service and examines them--'four positions which can be located on a linear ideological spectrum'--and adds a fifth which could have the effect of 'turning the alleged linear spectrum into a circle'. Underlying both Elizabeth Telfer's article and Dr Steiner's reply, the base is inescapably a 'political' one, but cannot be abandoned in favour of purely philosophical concepts. Whatever the attitude of mind of the reader of these two papers to the provision of a health service, the stimulus to more careful assessments of our own National Health Service and its problems can only be good.


The case for a statutory 'definition of death'. Karen Quinlan, the American girl who has lain in deep coma for many months, is still 'alive', that is to say, her heart is still beating and brain death has not occurred. However, several other cases have raised difficult issues about the time of death. Dr Skegg argues that there is a case for a legal definition of death enshrined in statutory form. He suggests that many of the objections to a statutory provision on death are misplaced, and that a statute concerning the occurrence of death could remove all doubts in the minds of both doctors and public as to whether a 'beating heart cadaver' was dead or alive for legal purposes.


Genetic polymorphism and interethnic variability of plasma paroxonase activity. A method for determining plasma paroxonase activity using an auto-analyser is described. Frequency distributions for British and Indian subjects show bimodality. A study of 40 British families confirms the presence of a genetic polymorphism with regard to plasma paroxonase activity. Two phenotypes can be defined, controlled by two alleles at one autosomal locus. The frequency of the low activity phenotype is less in the Indian population than in the British population. Malay, Chinese, and African subjects fail to show obvious bimodality.


An unusual family of benign "X" linked muscular dystrophy with cardiac involvement. A family of benign X-linked muscular dystrophy is described. Two of the 3 affected members appear quite representative of Becker's dystrophy. A third shows no pseudohypertrophy, only gross atrophy, affecting proximal and distal muscles and also shows early onset contractures and electrocardiographic abnormalities and is in these ways much more representative of the variety described by Emery and Dreifuss (1966). Two of the cases have distinctly abnormal electrocardiograms with extensive and deep Q waves and abnormal R/S ratios and VI. Both these have shown progression of electrocardiographic abnormalities during a 2-year follow-up. The family is reported to document this very unusual occurrence.


Familial essential ("benign") chorea.

Familial essential ("benign") chorea. A family is described with essential non-progressive chorea occurring in an autosomal dominant inheritance pattern over four generations. A few families with an apparently similar disorder have been reported previously. This condition is characterized by early childhood onset of chorea which is not progressive and is compatible with a long life. It is not associated with dementia, seizures, rigidity, or ataxia. It is a socially embarrassing condition and may, sometimes, be associated with behavioural problems and learning difficulties. For genetic counselling, it is important to distinguish this disorder from Huntington's disease and other hereditary disorders associated with chorea.


Haemoglobin LeporeBoston in a Turkish family. Haemoglobin Lepore was demonstrated in four members of a Turkish family. It was found in the heterozygote state and was associated with erythrocyte morphology similar to that observed in the beta thalassaemia trait. The average concentration of haemoglobin Lepore was 8.1% of the total haemoglobin. Structural analysis showed that the Lepore haemoglobin was the LeporeBoston type. This is the first reported instance of the occurrence of haemoglobin Lepore in Turkey.


Partial monosomy and partial trisomy 18 in two offspring of carrier of pericentric inversion of chromosome 18. A pericentric inversion of chromosome 18 is described in the mother of a patient with clinical diagnosis of 18q--syndrome. The propositus' chromosome complement includes the recombinant 18 with deficiency of the distal one-third of the long arm and duplication of the terminal segment of the short arm. The propositus' sister carrier the recombinant 18 with a duplication of the distal one-third of the long arm and a deficiency of the terminal segment of the short arm. The relative length of the inverted segment represents about 60% of the total chromosome 18 length. The probability of recombinant formation following the occurrence of a chiasma within the inverted segment is predicted to be high.


Structure and inheritance of some heterozygous Robertsonian translocation in man. Banding studies in 25 Robertsonian translocations showed that all could be interpreted as stable dicentrics. The mechanism for their stability is likely to be the proximity of their centromeres but centromeric suppression could also have a role. In many of these dicentric translocations, discontinuous centromeric suppression, as indicated by chromatid separation at one of the centromeric regions, was observed in C-banded preparations. A further observation of undefined relation to the first was that the ratio of the two constitutive centromeric heterochromatin (CCH) regions from the component chromosomes of the translocations was variable in the same translocation type, e.g. t(13;14). It is proposed that this ratio may influence the segregation ratio. Abnormal spermatogenesis is suggested as the likely mechanism for the difference in the proportion of aneuploid offspring in the progeny of maternal and paternal heterozygotes. Neither of the t dic(21;21)s could be interpreted as isochromosomes. It is proposed that Robertsonian fusion translocations be defined as stable, dicentric, whole-arm translocations, with both centromeres in a median position and resulting in the loss of a small acentric fragment during this formation. It is suggested that they occur at high frequency between telocentric or, as in man, certain acrocentric chromosomes because of some intrinsic property of those chromosomes not possessed by metacentric chromosomes and mediated by interphase association of centromeres.


Family study of inherited syndrome with multiple congenital deformities: symphalangism, carpal and tarsal fusion, brachydactyly, craniosynostosis, strabismus, hip osteochondritis. A syndrome of brachydactyly (absence of some middle or distal phalanges), aplastic or hypoplastic nails, symphalangism (ankylois of proximal interphalangeal joints), synostosis of some carpal and tarsal bones, craniosynostosis, and dysplastic hip joints is reported in five members of an Italian family. It may represent a previously undescribed autosomal dominant trait.


Linkage relations of locus for X-borne type of Charcot-Marie-Tooth muscular atrophy and that for Xg blood groups. The locus for the X-borne type of Charcot-Marie-Tooth muscular atrophy is not close to the Xg locus and probably not within direct measurable distance of it.


Discordance for Cornelia de Lange syndrome in twins. A male infant, the first-born of twins, with features of Cornealia de Lange syndrome is described. His normal twin was discordnat for 3 of the 14 blood loci tested. Chromosomes from the affected infant appeared normal. Though the aetiological basis for the Cornealia de Lange syndrome remains obscure, most authorities accept genetic rather than environmental causation. The present findings of discordance for Cornelia de Lange syndrome in twins support this view but do not clarify the mode of inheritance.


Gardner's syndrome and steatocystoma multiplex. Two unusual genetically determined conditions occurring in same patient. A 43-year-old man is described who had Gardner's syndrome and steatocystoma multiplex. These two unusual genetically determined conditions were associated because he had inherited the Gardner's syndrome from his father and the steatocystoma multiplex from his mother.


The influence of a diet rich in wheat fibre on the human faecal flora. The effect on the faecal flora of adding wheat fibre to a controlled diet in four healthy volunteers for a 3-week period has been observed. No change in the concentration of the bacteria in the bacterial groups counted was found, although there was a slight increase in total output associated with increased faecal weight. The predominant organisms in all subjects were non-sporing anaerobes, but the dominant species in each subject was different and was unaffected by changing the diet. Similarly, the concentration of faecal beta-glucuronidase detected in two subjects was unaltered and the concentration of clostridia able to dehydrogenate the steroid nucleus found in one subject was unaltered. It is suggested that the faecal microflora is not primarily controlled by the presence of undigested food residues in the large bowel.


Immunising potency of Leptospira interrogans serotype canicola after heat inactivation at different temperatures. The immunogenicity of Leptospira interrogans serotype canicola suspensions inactivated by various degrees of heat exposure was examined in hamsters. No differences between leptospires killed at 50 degrees C and at 98 degrees C were shown. After exposure to 121 degrees C, suspensions retained their ability to protect against lethal infections but lost their ability to prevent leptospiruria. Tests with vaccines inactivated at or below 98 degrees C showed that the doses required for complete protection varied with the interval between vaccination and challenge. Larger doses were required to prevent the development of leptospiruria than to prevent death.


Diagnosis of pregnancy in chimpanzees using the nonhuman primate pregnancy test kit. The usefulness of The Nonhuman Primate Pregnancy Test kit for diagnosis of pregnancy in chimpanzees was determined. This hemagglutination inhibition test for urinary chorionic gonadotropin accurately indicated conception by positive responses in 151 to 153 specimens collected between 20 and 133 days after the estimated day of fertilization. The rate of false positive responses did not exceed 1%.


Sensory innervation in the rim of the octopus sucker. Anatomical components of afferent innervation in the rim of the octopus sucker are described. In the sensory epithelium under the smooth cuticle two associated ciliated receptor cell-types (presumably chemosensitive) occur in clusters. A third ciliated receptor cell-type under the toothed cuticle may be a mechanoreceptor. A non-ciliated receptor cell-type of unknown function, under the toothed culticle, is characterized by a microvillus-lined apical canal containing dense granular material. The axons of the latter two receptors go directly into large nerve tracts which run through the infundibular muscle and on to the ganglion of the sucker. The axons of the first cell-types terminated on interneurons either in the base of the epithelium or below the epithelium. All the interneurons of the basal region of the epithelium migrate centripetally and develop into encapsulated interneurons. Within the epithelium, fine fibers provide collateral contact among cluster receptors. Collateral interaction among basal and encapsulated interneurons occur in the infundibular plexus. The microanatomy of the rim of the sucker suggests that chemosensory cues are funneled into the interneurons where they are concentrated into integrated signals, while other sensory input is probably sent directly to the ganglia of the sucker and/or arm.


Observations on the ultrastructure of developing myocardium of rat embryos. Timed pregnancies were obtained in Sprague-Dawley rats and early ultrastructural differentiation of myocardium of embryos of 10, 11, 12, 13, and 14 days were investigated and compared with that of newborn. Ten-day myocardium is characterized by loosely packed cells; the cytoplasm is typified by a dearth of organelles. Both thick (myosin) and thin (actin) filaments become identifiable for the first time in the 10-day myocardium where the heart is pulsating but circulation is not established. These filaments are not visible in the embryos of 9-day-old myocardium. The formation of these filaments is observed to continue throughout the period covered in this investigation. Concomitant with the appearance of the myofilaments is the synthesis of Z band material. By the eleventh day of gestation and during the subsequent days there is a rapid proliferation and differentiation of most of the organelles. The myofilaments become organized into fully formed striated fibrils. Intercalated discs appear as small wavy lines on the eleventh day and become plicated in later stages and serve as cell boundaries and points of attachment for myofilaments and fibrils. There is a perceptible change in the number and morphology of mitochondria from the tenth to eleventh day and later stages of development when the heart becomes functional. Similarly, there is a rapid proliferation and differentiation of granular endoplasmic reticulum and Golgi bodies. Large quantities of free ribosomes are dispersed in the cytoplasm of 10-day myocardium; however, in later stages there is a progressive reduction in the distribution of these particles. An intimate association of ribosomes and polysomes with the developing myofibrils is discernible. The T-system and sarcoplasmic reticulum begin to appear in 11-day myocardium. The embryonic myocardium displays intense mitotic activity throughout its development and a unique feature of embryonic myocardial cells is the simultaneous occurrence of myofilament synthesis and mitotic activity within the same cells.


Ultrastructure of the blowfly chemoreceptor sensillum (Phormia regina). The ultrastructure of a well studied insect chemosensory unit is presented in this report. Two separate lumina are present in this chemosensory unit, the trichogen and sensillar lumina. The fluid within the trichogen lumen exclusively bathes the dendritic terminals, and may be involved with the reception and/or modulation of environmental stimuli. Cytoplasmic extensions of the trichogen cell which line the trichogen lumen may be involved in the production of the cuticular sheath. The sensillar lumen is bordered by the tormogen and a sleeve cell, and is continuous with the unoccupied channel of the setal shaft. Functions for the various cellular components of the blowfly chemoreceptor sensillum are offered.


Mediation of cytotoxic immune responses against human tumor-associated antigens by allogeneic immune RNA. Allogeneic immune RNA (I-RNA), extracted from the peripheral blood lymphocytes of patients putatively cured of cancer, mediated cytotoxic immune reactions that apparently were directed specifically against human tumor-associated antigens. I-RNA was extracted from the peripheral blood lymphocytes of patients with various types of cancer. Patients selected had not been previously sensitized to HL-A or other normal transplantation antigens or to blood group antigens. Normal human peripheral blood lymphocytes were incubated with these allogeneic I-RNA preparations and tested for cytotoxicity against human target cells in vitro. Allogeneic I-RNA mediated cytotoxic immune reactions only against tumor target cells of the same histologic type as the I-RNA donor. I-RNA's extracted from peripheral blood lymphocytes of melanoma patients mediated cytotoxic immune reactions only against melanoma cells. Similarly, only I-RNA's extracted from the lymphocytes of patients with colon cancer mediated cytotoxic immune reactions against colon carcinoma cells, and only I-RNA's from the lymphocytes of breast cancer patients mediated immune reactions against breast cancer target cells. Allogeneic I-RNA extracted from peripheral blood lymphocytes of cancer patients possibly mediated specific cytotoxic immune reactions that were directed against common tumor-associated antigens shared by human tumors of similar histologic type.


Intratracheal instillation studies with 7H-dibenzo(c,g)carbazole in the Syrian hamster. The morphologic effects and the retention and distribution times of single and multiple intratracheal instillations in Syrian hamsters of 7H-dibenzo[c,g]carbazole (DBC) and benzo[a]pyrene (BP) were compared. A single instillation of DBC induced slight changes in the hamster respiratory tract; however, five treatments caused tracheobronchial epithelial proliferation, cell hyperplasia, and occasionally, squamous metaplasia. The particle size of both carcinogens was approximately the same. BP in saline remained longer in the lungs than did DBC in saline. The shortest retention time was recorded when DBC was administered in aqueous solution, whereas multiple doses of DBC in aqueous solution did not markedly affect retention time. DBC passed from the lungs to the intestinal tract and was mainly excreted in the feces.


Alteration by malignant transformation of the calcium requirements for cell proliferation in vitro. Cells from the thigh muscles of normal fetal rats proliferated rapidly and indefinitely in a medium containing adult rat "plasma" and a normal free-calcium concentration, but they could not proliferate in calcium-deficient plasma medium. As the animals grew older, the cells became increasingly less able to proliferate even in normal (high-calcium) plasma medium, though they retained the potential to proliferate in a more conventional medium containing fetal bovine serum. By contrast, neoplastic adult cells from malignant rhabdomyosarcomas (induced by Ni3S2) proliferated rapidly and indefinitely in both normal and low-calcium plasma medium


Local adoptive transfer of antitumor cellular immunity to xenogeneic animals studied with a rapid radioisotopic footpad assay. The antitumor cellular immune response to Gross virus-induced rat tumor cells in F344 rats, as measured by a sensitive radioisotopic footpad assay, was adoptively transferred to syngeneic rats and to xenogeneic irradiated BALB/c mice. Xenogeneic transfer was accomplished by the injection of a mixture of rat tumor cells and syngeneic spleen cells, peritoneal exudate cells, or blood lymphocytes from specific immune rats into the footpads of mice. Peritoneal exudate cells produced the strongest footpad reaction in xenogeneic recipients. Use of the xenogeneic adoptive transfer system in a bioassay for human antitumor immunity appeared feasible.


Adenocarcinoma of the glandular stomach following 3-methylcholanthrene, N-nitrosodiethylamine, or N-nitrosodimethylamine feeding in carcinogen-susceptible inbred Syrian. Invasive adenocarcinoma of the glandular stomach was induced in 3 BIO 87.20 inbred Syrian hamsters by the administration of 1 ppm N-nitrosodiethylamine or N-nitrosodimethylamine in the drinking water, and in 2 BIO 15.16 and 5 BIO 72.29 inbred Syrian hamsters by gavage of 3-methylcholanthrene. In contrast, many other similarly treated inbred Syrian hamster lines did not develop carcinoma of the glandular stomach. The glandular stomachs of rats and mice are resistant to polycyclic hydrocarcon carcinogenesis; however, the glandular stomachs of certain inbred Syrian hamsters develop adenocarcinoma after polycyclic hydrocarbon gavage. This work demonstrated the importance of genetic factors.


Nature of early appearing, carcinogen-induced liver lesions to iron accumulation. A technique for induction of iron accumulation in hepatocytes of rats was used to identify early carcinogen-induced lesions by their histochemical absence of iron. Foci of iron-free altered hepatocytes produced by the feeding of N-2-fluorenylacetamide (FAA) for 3 weeks were composed of cells that were replicating when surrounding iron-containing hepatocytes were not, and that responded to a mitotic stimulus when surrounding hepatocytes were inhibited or showed a delayed response. Thus these lesions represented focal hyperplastic overgrowths. The iron-free hyperplastic foci developed into hyperplastic areas that progressed with longer feeding of FAA to form hyperplastic nodules. The lack of iron was a sensitive and reliable marker for hyperplastic lesions, which also permitted their identification in the fresh state. Both early hyperplastic lesions and nodules were often resistant to the necrogenic effects of dimethylnitrosamine, as well as to the antireplicative effect of FAA. The selection of such cells resistant to the toxic effects of carcinogens may be important in the pathogenesis of liver neoplasia.


Inhibition of macromolecular binding of benzo(a)pyrene and inhibition of neoplasia by disulfiram in the mouse forestomach. Benzo[a]pyrene (BP) administered to female outbred ICR/Ha mice by oral intubation induced neoplasia in the forestomach after 30 weeks in more than 90% of treated animals. However, no tumors occurred at that site if 1% disulfiram was added to the experimental diet. This inhibition of tumor formation was paralleled by a large inhibition of macromolecular binding of [3H]BP and [14C]BP to RNA and protein in the forestomach. The inhibitory effect of specific binding was strongest in the RNA fraction isolated at 8,000 X g for 20 minutes (6 times that of the control) and weakest in the DNA fraction (no significant difference). The highest specific binding was measured in the RNA fraction isolated at 32,000 X g for 120 minutes and the lowest binding in the DNA fraction. The relative distribution of the BP binding was such that greater than 90% of the BP was bound to protein and less than 1% was bound to DNA. Of the total inhibition of BP binding to all the macromolecular species studied, that to protein constituted the largest component (95%). In contrast to the forestomach, no inhibitory effect of BP binding to DNA, RNA, or protein by disulfiram was found in the liver, which remained free of cancer under the experimental conditions employed.


Metabolism of N-nitrosohexamethyleneimine. The metabolism of [2-14C]N-nitrosohexamethyleneimine in male MRC-Wistar rats was studied and some of the major urinary metabolites were identified. The extent of total oxidation to 14CO2 was 18.1% in 24 hours and radioactivity incorporation was observed in various tissues; that in the liver was the highest. Analysis of urine after 24 hours showed that 36.7% of the radioactivity administered was excreted by this route, with a minimum of 11 products present. Hexamethyleneimine (HX), epsilon-caprolactam, epsilon-aminocaproic acid, and 6-aminocaprohydroxamic acid were the identified metabolites. Of the remaining products, two appeared to result from HX metabolism and one was a glucuronide conjugate. No parent compound was found.


Ultrastructure of a mammosomatotrophic and a nonfunctional transplantable pituitary tumor induced in rats by 2,4,6-trimethylaniline. A pituitary tumor was induced in a female inbred BUF rat on an 18-month diet containing 1.1 mmole 2,4,6-trimethylaniline/kg. In the sixth transfer, this tumor developed into two lines of transplantable tumors with different characteristics. Here these two lines were studied by light and electron microscopy; histologically, both tumors were well-differentiated pituitary carcinomas. In the ultrathin sections, the neoplastic cells were separated by a wide intercellular space and covered by numerous microvilli. In the mammosomatotrophic tumor (7315a) the neoplastic cells contained big, electron-dense, ovoid or globular secretory granules (560-1,700 nm in size) that were similar to the prolactin granules of mammotrophs. However, in these cells were also small, pale, uniform, secretory granules that were along the plasma membrane, measured 160 nm in diameter, and resembled the ACTH-containing granules of corticotrophs. The neoplastic cells in tumor line 7315i possessed secretory granules comparable to the granules of the ACTH-secreting cells. The differentiation of the ergastoplasm was abnormal. The tumor cells contained an endoplasmic reticulum similar to mammotrophs and somatotrophs but dissimilar to ACTH-secreting cells. These investigations suggested that the production of several hormones in transplantable pituitary tumors resulted from the multisecretory differentiation of one neoplastic pituitary cell.


Immunologic parameters of ultraviolet carcinogenesis. Skin tumors induced in mice by UV light are usually immunologically rejected by normal syngeneic recipents. We evaluated the immune status of primary hosts against these highly antigenic tumors immediately after surgical removal of the primary tumor. All primary hosts were susceptible to challenge with their autochthonous tumors, though most of these were rejected by untreated control mice. Primary hosts were also susceptible to challenge with isografts of antigenically dissimilar UV-induced neoplasms. The susceptibility of the primary hosts to tumor challenge was probably induced by chronic exposure to UV light, since UV-irradiated non-tumor-bearing mice were also susceptible to challenge with these tumors. Although UV-treated mice were unalbe to reject these syngeneic tumors, they could reject skin and tumor allografts. Further, UV irradiation did not interfere with the second-set rejection of syngeneic UV-induced tumors in mice that were specifically immunized before UV treatment.


Serum factor: the inhibition of phytohemagglutinin-induced blastogenesis of chronic lymphocytic leukemia lymphocytes. A serum factor (SF), isolated from acidified sera of normal donors, inhibited phytohemagglutinin (PHA) stimulation of lymphocytes isolated from patients with chronic lymphocytic leukemia (CLL),but had no effect on those from healthy donors. An SF isolated by an identical procedure from the sera of patients with CLL had essentially no inhibitory effect on DNA synthesis in normal or leukemic lymphocytes. The SF was isolated from sera or plasma by ammonium sulfate precipitation, acidification to pH  1.5, and chromatography on DEAE-cellulose. The SF was heat labile and sensitive to digestion by trypsin. Maximum inhibition was obtained when the factor was added within 24 hours after the cells were stimulated with PHA.


Induction of DNA degradation in vivo by adriamycin. The anthracycline antibiotic adriamycin (Ad) induced degradation (single-strand breaks) of cell DNA in vivo in murine L1210 leukemia cells. Measurement was made by alkaline sucrose gradient methods. Exposure of isolated DNA to Ad had little effect; the in vivo DNA strand breaks were probably due to the action of nucleases on DNA distorted by bound Ad. Toxicity of Ad to postmitotic cells such as cardiac cells could be mediated by this mechanism, since it could be demonstrated in periods substantially shorter than the cell generation time and thus could be responsible for interphase death.


Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. III. Effect of C. parvum on cyclophosphamide metabolism. Results of investigations employing [14C]cyclophosphamide (CY) demonstrated that even though total plasma radioactivity was similar in female C3HeB/FeJ mice treated either with CY alone or Corynebacterium parvum and CY, the proportion of total activity due to nonmetabolized CY was greater when C. parvum was used. These findings indicated that the antitumor effect of C. parvum may not have been entirely due to its immunopotentiating properties but may also have been related to its effect on the metabolism of CY.


Covalent binding to protein of the K-region oxide of benzo(a)pyrene formed by microsome incubation. Incubation of 20,000 X g supernatant proteins of rat liver with benzo]a]pyrene (BP) and appropriate cofactors produced metabolites of BP covalently bound at the 4,5- position to protein. After being incubated, protein samples were freed from noncovalently bound metabolites and hydrolyzed chemically or both enzymatically and chemically. All steps were performed under minimum exposure to light and air; benzene extracts were prepared during hydrolysis. Chemical hydrolysis released the K-region metabolite BP-4,5-dihydrodiol (identified by UV and mass spectra) and BP. Hydrolysis with trypsin and pronase gave products with the characteristic UV spectrum of substituted chrysene. Chemical hydrolysis of these products released BP and BP-4,5-dihydrodiol.


Light and scanning electron microscopy of exfoliated bladder epithelial cells in rats fed N-(4-(5-nitro-2-furyl)-2-thiazolyl)formamide. Urine specimens obtained periodically from weanling male F344 rats fed 0.2% N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) for 25 weeks followed by control diet for an additional 35 weeks, were examined by light microscopy (LM) and scanning electron microscopy (SEM). LM revealed red blood cells and atypical transitional cells in the urine at 25 and 43 weeks, when microinvasive transitional cell carcinoma was present. Malignant transitional cells were seen in the urine by LM at 60 weeks, when muscle invasion was present in histologic sections. However, SEM showed pleomorphic microvilli on exfoliated urothelial cells as early as 10 weeks after the beginning of FANFT administration, and the microvilli became increasingly pleomorphic as the bladder lesions progressed to muscle invasion at 60 weeks. Noninvasive tumors were present in histologic sections of rat bladders examined at the end of 10 weeks of FANFT administration. The numerous microvilli on exfoliated bladder tumor cells were in sharp contrast to the peaked microridges of normal exfoliated superficial cells.


Mediation of cytotoxic immune responses against human tumor-associated antigens by xenogeneic immune RNA. Xenogeneic immune RNA (I-RNA), extracted from the lymphoid organs of sheep or guinea pigs immunized with human tumor cells, mediated in vitro cytotoxic immune responses that were directed specifically against tumor-associated antigens of human tumor target cells. Normal human peripheral blood lymphocytes from healthy donors became markedly more cytotoxic for human tumor target cells after being incubated with I-RNA extracted from the lymphoid organs of animals that had been immunized with that particular tumor. Gastric carcinoma, malignant melanoma, and carcinoma of the breast were studied. Lymphocytes incubated with RNA from animals immunized with only complete Freund's adjuvant evidenced no increased cytotoxic activity. RNA extracted from the lymphoid organs of animals immunized with normal skin fibroblasts that were autologous to the immunizing tumor, when incubated with normal allogeneic lymphocytes, also mediated cytotoxic immune reactions against tumor target cells. These immune responses probably were directed principally against normal transplantation antigens. However, when lymphocytes that were autologous to the immunizing tumor and/or the tumor target cells were incubated with RNA from animals immunized with autologous normal fibroblasts, cytotoxicity did not increase. Only I-RNA extracted from donor animals specifically immunized with tumor cells mediated cytotoxic antitumor immune responses when incubated with autologous lymphocytes.


Mutation theory of carcinogenesis in retinoblastoma. To test Knudson's hypothesis that two successive mutations are involved in retinoblastoma, we studied the data on 899 cases. Some of the findings appeared to differ from those that might be expected if Knudson's hypothesis were correct. Certain criticisms of Knudson's methodology and model were suggested. Alternative explanations proposed were 1) the role of the sequence in which mutations occur, and 2) the possibility of three mutational events.


Comparative carcinogenicity of 5-nitrothiophenes and 5-nitrofurans in rats. We investigated the carcinogenicity of five 5-nitrothiophenes with heterocyclic substituents at the 2-position of the thiophene ring by feeding the chemicals to Sprague-Dawley rats and comparing the type and incidence of lesions with those appearing after exposure to two 5-nitrofurans. Benign and malignant mammary tumors and intestinal tract sarcomas were the most frequent lesions induced by 5-nitrothiophenes. 4-Bis(2-hydroxyethyl)amino-2-(5-nitro-2-thienyl)quinazoline caused a 100% incidence of mammary adenocarcinomas in 28 female rats at risk; it induced 3 benign and 5 malignant mammary tumors and 13 small intestine sarcomas in 20 male rats. A high incidence of similar lesions was observed in male and female rats fed the corresponding 5-nitrofuran analogue, 4-bis(2-hydroxyethyl)amino-2-(5-nitro-2-furyl)quinazoline. In marked contrast, 4 of 28 female rats receiving 4-bis(2-hydroxyethyl)amino-2-(2-thienyl)quinazoline, which lacks the nitro group at the 5-position on the thiophene ring, had solitary benign mammary tumors (P greater than 0.2). Additional 5-nitrothiophenes demonstrating significant oncogenic activity for female rats were 4-morpholino-2-(5-nitro-2-thienyl)quinazoline, 4-(2-hydroxyethylamino)-2-(5-nitro-2-thienyl)quinazoline 4-(2,3-dihydroxypropylamino)-2-(5-nitro-2-thienyl)quinazoline, and 1,2-dihydro-2-(5-nitro-2-thienyl)quinazolin-4(3H)-one. Another nitrofuran, 4,6-dimethyl-2-(5-nitro-2-furyl)-pyrimidine, provided the following types of neoplasms in 30 female rats at risk: squamous cell carcinomas of the forestomach (30), sarcomas of the intestine (21), adenocarcinomas of the kidney (2).


Incorporation of tritiated uridine into DNA of Ehrlich ascites tumor cells. Ehrlich ascites tumor cells were labeled with [5,6-3H]uridine in vivo during the exponential growth phase of the tumor in the mouse. Hydroxyapatite column chromatography of the total cell nucleic acid revealed a level of activity in the DNA approaching 50% of the incorporated activity of the RNA after 24 hours. After perchloric acid hydrolysis, the constituent bases of the DNA, separated by paper chromatography, contained more than 90% of the tritium radioactivity in the cytosine and thymine, at a ratio of approximately 2:1. Prior to digestion of the polymer, the level of label in the DNA was not sensitive to RNase, alkaline, or heat denaturation. Equilibrium density gradient centrifugation produced a single peak, coincidental for radioactivity and optical density at 260 nm. Our results indicate that tumor cells under replicative stress incorporated more than one-third of the tritium radioactivity of uridine into the DNA, whereas those at a growth plateau had less than 10% of the label in the DNA. This exogenous uridine radioactivity observed in the DNA represented neither a DNA-RNA hybrid, RNA primer pieces in DNA synthesis, nor any other RNase-sensitive species, but was apparently the consequence of amination and methylation of the tritium-labeled uracil moiety to satisfy the metabolic needs of the replicating cells for cytosine and thymine bases.


Further observations on the inhibition of tumor growth by corynebacterium parvum with cyclophosphamide. The cytotoxic macrophage was further characterized as an important effector cell in the inhibition of tumor growth. When we administered rifampin (a semisynthetic antibiotic that interferes with macrophage function but not viability) with Corynebacterium parvum and/or cyclophosphamide to tumor-bearing C3HeB/FeJ female mice, the tumor growth-inhibitory effects of the C. parvum were reduced. Moreover, when bone marrow cells from those animals were cultured, we found a marked decrease in the cytotoxicity of macrophages comprising clonies arising from colony-forming cells (CFC) in the bone marrow. Such findings supported our contentions that 1) the cytotoxic property of macrophages originates in ancestral stem cells or CFC in bone marrow, and 2) receptor sites of the CFC (or stem cells) that respond to a stimulus for self-replication probably differ from sites that when activated produce progeny with cytotoxic properties. Although the administration of rifampin resulted in macrophages virtually devoid of cytotoxic properties, both relative and absolute numbers of CFC increased.


Epithelial lesions induced by N-nitrosoheptamethyleneimine in host and transplanted rat tracheas. N-Nitrosoheptamethyleneimine (NHMI) was given by gastric intubation, at a dosage of 10 mg/kg body weight twice weekly for 5-20 weeks, to F344 rats bearing subcutaneous tracheal transplants. Groups of 5 rats were killed at 5, 10, 15, and 20 weeks, and 1 group was killed at week 33 of the experiment (13 weeks after the last NHMI dose). Sequential changes in host tracheas consisted of hyperplasia with complete loss of mucociliary epithelium, squamous metaplasia, intense mononuclear infiltration, reestablishment of mucocillary epithelium (during the course of NHMI administration) except for focal areas of hyperkeratotic squamous metaplasia or marked dystrophic changes, and finally, papillomas, polyps, and invasive squamous cell carcinomas. Lesions in tracheal transplants consisted mostly of atrophic and dystrophic changes, with only a few small foci of squamous metaplasia and no neoplastic changes.


Role of donor immunocompetent cells in allograft rejection. Allotransplantable lines of the BALB/c (H-2d) Leydig cell tumor C4092 were established in DBA/1 (H-2q) mice after maintenance in organ culture. These modified tumors had reduced immunogenicity but were recognized and rejected by previously sensitized DBA/1 mice. The addition of 3.4 X 10(3)-1 X 10(5) peritoneal exudate cells (PEC) from untreated BALB/c mice to cell suspensions of the modified tumor did not restore Immunogenicity when the cell mixture was Inoculated sc Into DBA/1 recipients. However, when equivalent numbers of PEC or spleen cells were inoculated iv into animals receiving the tumor cell suspension sc, the acceptance of the tumors was significantly reduced or prevented. This indicated that the BALB/c lymphoid cells inoculated iv stimulated the immune system of the host, which in turn recognized the tumor cell inoculum. The lack of effect of the BALB/c lymphoid cells when admixed with the tumor did not support the assumption that the loss of passenger lymphoid cells was responsible for the allotransplantability of grafts after organ culture explantation. Additional evidence was presented that supports our view that the reduced immunogenicity was associated with a phenotypic modification of the tumor cells per se.


Effect of zinc administration on the growth of L1210 and BW5147 tumors in mice. Aqueous zinc acetate injected ip prevented tumor growth in 50-70% of BDF male mice previously inoculated ip with L1210 leukemia cells. However, aqueous zinc acetate injected sc did not prevent tumor growth in AKR/J mice inoculated im with BW5147 lymphatic leukemia cells. In the latter mice, only a small but statistically significant increase in mean survival was noted.


The relationship between diet and rat fecal bacterial enzymes implicated in colon cancer. We studied the effect of diet on the activities of four enzymes found in the intestinal flora of the male F344 rat. Animals initially fed a diet with high vegetable and grain content were shifted to a diet consisting predominantly of beef. While eating the meat diet, the rats had significantly higher levels of nitroreductase, azoreductase, and beta-glucuronidase in their fecal flora when compared to levels measured during grain feeding. However, beta-glucosidase activity was significantly lower during meat feeding, which probably reflected the lack of beta-glucosidic linkages in this diet. These findings suggested that a high-beef diet, similar in composition to that consumed by humans with a relatively high risk of colon cancer, is associated with elevated levels of specific enzymes in the colon microflora. These enzymes have been implicated in the conversion of procarcinogens into carcinogens.


Dual-frequency proton spin relaxation measurements on tissues form normal and tumor-bearing mice. Measurements of pulsed nuclear magnetic resonance relaxation times T1 and T2 were made at 2.7 MHz and 15 MHz on water protons in liver, kidney, spleen, muscle, and brain tissue from normal A.SW mice, and in the same tissues and tumors from A.SW mice developing MSWBS tumors (an ascites sarcoma) following dorsal sc implantation of tumor fragments. The measurement precision obtained from improved spectrometer design made it possible to show that T1 and T2 in all tissues except brain were increased by the presence of the tumor in the animal. The responses exhibited by T1 and T2 in liver and kidney were proportional to the size of the tumor. The smaller responses shown by T1 in spleen (15 MHz) and T1 and T2 in muscle (2.7 MHz) also showed a significant correlation with tumor size. The relaxation times for tumor (T1 at 2.7 MHz, T2 at 2.7 and 15 MHz) showed a significant negative correlation with tumor size: The times decreased as tumor size increased. The results were analyzed by use of the two-phase fast exchange model and were consistent with the effects expected if tissue water content increased and tumor water content decreased as tumor size increased. The analysis indicated that the effects arose primarily through changes in b, the fraction of water bound to fast exchange sites on the protein, with important modifications from changes in the correlation times Tc and Tm;Tr controlled the frequency that must be chosen for specific diagnostic applications.


Ultrastructure of N-nitorsodibutylamine-induced tumors of the nasal cavity in the European hamster. The ultrastructural characteristics of N-nitrosodibutylamine-induced adenocarcinomas and squamous cell carcinomas in the nasal cavities of European hamsters suggested that the cells of origin for adenocarcinomas were the goblet cells of the normal epithelial lining, whereas squamous cell carcinomas seemed to originate either from squamous metaplastic epithelium or from adenomatous areas, perhaps even as a later developmental stage of adenocarcinomas.


Beta-aminoaciduria in patients with Burkitt's lymphoma. The massive amounts of beta-aminoisobutyric acid (beta-AIBA) in the urine of Burkitt's lymphoma patients were measured along with other alpha-amino acids and beta-alanine present in normal and decreased levels. The ratios of the amount of beta-AIBA to beta-alanine, in mumoles/kg urine collected in 24 hours, were elevated for all patients. The degree of elevation of beta-AIBA excretion and the ratio of the two beta-amino acids appeared to be related to the amount of tumor mass present. These analyses may have possible value in monitoring patients with Burkitt's lymphoma during their disease course.


In vivo distinction between a target cell for Friend virus (FVP) and murine hematopoietic stem cells. Busulphan (BU) treatment of DBA/2 mice with hypertransfusion (HT)-induced polycythemia resulted in an ablation of detectable hematopoietic stem cells (CFUS) in pooled marrow from the long bones. Daily injections of erythropoietin (EP) stimulated an EP-responsive population of cells in the absence of detectable CFUS. Mice treated with BU and EP and having HT-induced polycythemia were inoculated with the polycythemia-inducing strain of Friend virus (FVP) and determinations were made for the presence of tumor colony-forming units (tCFU). No change in CFUS/10(6) bone marrow cells was detected as a result of EP treatment. However, tCFU were increased more than 100-fold in HT-BU-EP-treated mice compared with saline-treated controls. The demonstration of tCFU in mice in which CFUS were not detectable indicated that this leukemogenic effect of FVP could occur in the absence of the pluripotent stem cell. Furthermore, the increased numbers of this FVP target cell in the EP-stimulated, BU-treated mice with HT-induced polycythemia supported the model licating the target for this effect in the EP-responsive cell population.


Afferent and efferent interference of cell-mediated cytotoxic reactions by heparin. Heparin influenced the induction (afferent interference) and effector (efferent interference) phases of cell-mediated cytotoxic reactions against FBL-3 cells, a syngeneic Friend virus-induced leukemia in inbred C57BL/6 mice. Heparin was cytotoxic at high concentrations (greater than or equal to 100 U/ml) and inhibitory for cell-mediated cytotoxic response at lower concentrations (less than or equal to 50 U/ml).


In vitro lymphocyte immunization to cultured human tumor cells: parameters for generation of cytotoxic lymphocytes. Conditions for optimal immunization of allogeneic lymphocytes against human tumor cells were studied. Maximal cell-mediated cytotoxic responses were generated usually with 2-4 X 10(4) tumor cells and 1 X 10(6) lymphocytes after a 5-day incubation. A further increase in the number of stimulating cells usually suppressed the immunization of lymphocytes. Viable untreated tumor cells were generally more immunogenic than were the mitomycin C-treated tumor cells. Lymphocytes (1 X )0(6)) sensitized in small volumes (0.5-1 ml) of medium were invariably transformed into cytotoxic effector cells, whereas the same number of lymphocytes sensitized in relatively larger volumes (4 ml) of medium had little or no cytotoxic activity. Occasional shaking of mixed culture during the sensitization provided better immunization than that in similar stationary culture. The replacement of culture fluids with fresh medium during incubation decreased the cytotoxicity level of sensitized cells.


Effect of BCG (Tice strain) on primary sensitization to 2,4-dinitrochlorobenzene and on established delayed hypersensitivity in human malignant melanoma. Studies of primary sensitization and delayed hypersensitivity reactions to 2,4-dintrochlorobenzene (DNCB) and recall antigens were conducted in 71 patients with melanoma who were receiving BCG (Tice strain) immunotherapy by scarification. Similar studies were conducted in 32 control patients with melanoma who did not receive BCG. No significant differences were observed, in the various clinical stages, between patients receiving and those not receiving BCG, in terms of the frequency or intensity of primary sensitization to DNCB. Furthermore, there was no significant difference in delayed hypersensitivity to recall antigens between these groups of patients. The apparent discrepancy between the clinical benefit from BCG immunotherapy and its failure to stimulate certain parameters of cellular immunity in patients with melanoma is discussed.


Relationship of age to incidence of breast cancer in young women. The rate of increase with age in the incidence of breast cancer in women was at a maximum at the lowest age that it could reasonably be estimated (in these data, 25 yr). It then declined linearly with age to about 50 years. The rate of increase with age, and its changes with age, were similar in many Western populations and in Japan. The decline with age in the rate of increase in the incidence of breast cancer was arrested at the age of 50 and replaced by rates of change that altered little with age. The premenopausal changes could be reproduced by a breast cancer precursor model with exponential decay of precursor prevalence with time. There was evidence for the existence of such a precursor.


Fluoridated drinking water and the occurrence of cancer. A recent report by the National Health Federation, a private agency, related cancer mortality patterns in the United States to fluoridation of water supplies, triggering much public health concern and some political response. To clarify the issues raised, we studied cancer mortality and incidence statistics for U.S. counties, 1950-69. No trends could be ascribed to the consumption of water that is artificially or naturally fluoridated.


Adenocarcinoma of the kidney. I. Ultrastructure of renal adenocarcinomas induced in rats by N-(4'-fluoro-4-biphenylyl)acetamide. The ultrastructure of tumors induced in kidneys of F344 rats by the carcinogen N-(4'-fluoro-4-biphenylyl)acetamide appeared similar in many aspects to that described in humans and other animal models. The neoplastic cells exhibited microvilli resembling brush border and other adaptations of the cell membrane. Tumor lobules were surrounded by basement membrane-like material, which also extended into the tumor mass between individual cells. The ultrastructure appeared to reflect a proximal tubular origin of these lesions.


Susceptibility of fetal lung to transplacental 1-ethyl-1-nitrosourea: its relation to epithelial proliferation. The relationship between the age-dependence of the number of lung adenomas produced by exposure of fetal mouse lung to 1-ethyl-1-nitrosourea (ENU) and changes in the number of epithelial cells within  the population that are in the cell cycle on different gestation days was studied. The epithelial cells lining peripheral tubules of growing lung were counted by morphometric methods, and, based on previous studies, their distribution in various phases of the cell cycle was estimated. The curve of multiplicity of adenomas was biphasic, with the maximum number in fetuses exposed on days 16 and 17 and the minimum in those exposed on day 19. The number of epithelial cells in the proliferative cycle followed a similar pattern. A linear regression curve relating the number of cells in the cell cycle to the number of adenomas produced 16 weeks after exposure to ENU showed a correlation coefficient of 0.82. The number of adenomas was more highly correlated with the number of cells in the G1 phase at carcinogen exposure than with the number of cells in either the S phase or the G2 phase and mitosis. The incidence of adenomas per 10(6) cells in cycle was greater when fetuses were exposed to ENU on day 15, and tumors induced on this day grew to a significantly larger size by 16 weeks after birth than did those induced on days 17, 18, or 19. Factors of possible significance in this age-related response may have been the high growth fraction in fetal lung epithelium on day 15, the short cell-cycle time, and the longer period available for cell proliferation between tumor initiation and birth.


Antileukemic properties of organoplatinum complexes. The antitumor activity of 46 cis-amineplatinum congeners was evaluated against L1210 leukemia in (C57BL/L X DBA/2)F1 mice. Several compounds in this series significantly prolonged the life-spans of mice with the leukemia. During the selection of the compound that yielded optimal activity [dichloro(1,2-diaminocyclohexane)platinum], the chlorides were substituted with various organic and inorganic anions. The aqueous solubility was greatly increased with retention of significant antileukemic activity. Most of the active compounds were synergistic with cyclophosphamide, and cure rates up to 80% were obtained with certain combinations.


Depressed chemotactic responses in vitro of peritoneal macrophages from tumor-bearing mice. The in vitro chemotactic responses of peritoneal macrophages from mice bearing transplantable syngeneic 3-methylcholanthrene-induced tumors in their footpads were depressed to about 50% of normal levels. This chemotactic defect to both lymphocyte- and complement-derived stimuli was evident before the appearance of palpable tumor (within 1 week of tumor injection) and persisted until the death of the animal by 6-8 weeks. Chemotactic depression was not observed with macrophages from mice treated with tissue culture medium, fetal calf serum, incomplete Freund's adjuvant, or syngeneic spleen cells.


Tumorigenic effect of 3-amino-1H-1,2,4-triazole on rat thyroid. Six groups of female outbred Wistar rats were subjected to the following treatments: 2,500 ppm 3-amino-1H-1,2,4-triazole (amitrole) administered in the drinking water (group I); partial thyroidectomy and administration of amitrole in the drinking water (group II); partial thyroidectomy plus autoimplantation of resected thyroid tissue plus administration of amitrole in the drinking water (group III); no treatment (control of group I) (group IV); partial thyroidectomy without amitrole administration (control of group II) (group V); or partial thyroidectomy plus autoimplantation of resected thyroid tissue without amitrole administration (control of group III) (group VI). Goiters developed in all rats given amitrole (groups I-III). Invasive growth of the proliferating follicular tissue through the capsule into adjacent fatty tissue and of pericapsular blood vessels was frequent in these groups (P less than 0.001); invasive lesions were more frequent in the lobectomized thyroid glands of rats (groups II and III). Seven papillary adenomas composed of atypical cells with hyperchromatic nuclei and many mitoses were found in the thyroid glands and grafts in amitrole-treated groups I-II. No invasive growth or adenomas appeared in the control rats of groups IV-VI. Cholangiofibrosis developed in 5 of 100 rats in groups I-III.


Effect of diet high in beef fat on the composition of fecal bile acids during intestinal carcinogenesis in the rat. Two groups of 20 male Sprague-Dawley rats each were given sc 8 mg azoxymethane/kg body weight and fed a normal diet or one high in beef fat. Control groups were not given azoxymethane. Fat-control animals did not excrete more total bile acids than did the normal-control group but did excrete more deoxycholic acid as the result of increased cholic acid degradation. Azoxymethane itself caused an increase in fecal bile acid concentratation but tended to reduce the level of cholic acid degradation. Fatty acid content in the feces increased in the animals on the fat diet but was not affected by azoxymethane. A fat-diet-dependent increase was apparent in total fecal neutral steroids and a carcinogen-dependent increase in cholesterol degradation. Dietary fat and bile steroids altered by gut microflora were important interrelated factors in the intestinal carcinogenic process of this animal model.


Development of teratomas from the ectoderm of mouse egg cylinders. We studied the developmental capacities of the primary ectoderm and endoderm of 6-day embryos of hybrids between strains 129/Sv-SIJ C P and A/He mice by grafting these germ layers into the testes of adult mice for 30 days. Grafts of embryonic ectoderm gave rise to teratocarcinomas composed of undifferentiated embryonal cells and derivatives of all three germ layers including respiratory and alimentary epithelium. Grafts of extraembryonic ectoderm gave rise to invasive trophoblastic giant cells. Grafts of endoderm did not develop.


Deuterium isotope effect in the microsomal metabolism of dimethylnitrosamine. The rates of N-demethylation of dimethylnitrosamine and dimethylnitrosamine-d6 by rat liver microsomes were studied by monitoring formaldehyde production. Deuterium isotope effects of 1.6 and 3.8 were found for the Michaelis constant and the maximum velocity, respectively.


Gastric cancer in Colombia. I. Cancer risk and suspect environmental agents. A case control study of patients discharged from hospitals revealed fourfold differences in geographic variation in stomach cancer risk within the Department of Narino (Colombia). Data from gastroscopic surveys of population groups, samples of water supplies, and urine and saliva in Narino also indicated a generally positive correlation among the following parameters: 1) gastric cancer risk, 2) prevalence of chronic atrophic gastritis and intestinal metaplasia, 3) nitrate content of well waters, and 4) nitrate excretion by the population. Urinary excretion reflected the ingestion of nitrates, and this implied a higher average intake of nitrates in the populations at high risk for stomach cancer. The Narino data could be construed as presumptive epidemiologic evidence for the role of nitrate availability in the etiology of stomach cancer.


Gastric cancer in Colombia. II. Case-control epidemiologic study of precursor lesions. Endoscopic surveys in the Department of Narino (Colombia) showed that natives of areas of very high risks for stomach cancer have a higher prevalence of atrophic gastritis and intestinal metaplasia than do persons born in other parts of Narino. In these surveys, diets were compared between individuals with and without evidence of these suspect precursor lesions of stomach cancer and between individuals born in the areas designated as high and low risk for stomach cancer. The composite evidence from the comparisons indicated lettuce to be negatively associated with stomach cancer and raised the possibility to a positive association for corn. The relationship of these findings to other epidemiologic evidence and the implications for applying the epidemiology of stomach cancer to the epidemiology of precursor lesions were examined.


Gastric cancer in Colombia. III. Natural history of precursor lesions. The premalignant process in the gastric mucosa was studied by gastroscopic surveys of Colombian populations, and the prevalence of superficial gastritis, chronic atrophic gastritis, and intestinal metaplasia was calculated for population samples having a very high gastric cancer risk (Nariño), very low risk (Cartagena), and intermediate risk (Cali). The prevalence of individuals with normal mucosa in successive age groups was used to estimate "depletion" curves, which were taken as indicators of the dynamics of the premalignant process in each community. Differences corresponding to the geographic variation in stomach cancer risk were found: In the high-risk areas of Nariño, around 75% of the population developed some type of gastritis by 45 years of age, whereas in the low- and intermediate-risk population of Cartagena and Cali, the proportion of such lesions did not exceed 50% at age 45 or thereafter. The effect of environmental factors in early life seemed to be important in determining the prevalence of lesions in each population.


Uterine cervical carcinoma in Connecticut, 1935-1973: evidence for two classes of invasive disease. The Connecticut Tumor Registry recorded 5,781 women with carcinoma in situ (CIS) and 7,614 with invasive cervical cancer from 1935 to 1973. True incidence rates for invasive disease were calculated. CIS rates indicated newly diagnosed cases, but true CIS incidence is unknown. Starting in 1945-49, the incidence of invasive cervical declined about 20% in Connecticut before CIS screening could have influenced the disease to that extent. Continuing declines in invasive disease rates after 1955 in Connecticut were probably attributable largely to screening. The persistent occurrence of invasive disease in screened populations and the rapid progression of cancer, with early death among some women with apparently localized disease at diagnosis, suggested that a second class of invasive cervical cancer may exist. Cancers in this class may develop and progress rapidly without a practical possibility of detection in the premalignant stage by cytologic methods. Other screening methods, e.g., metabolic, hormonal, immunologic, or virologic, may be required to control this disease.


Leukocyte migration inhibition by soluble extracts of MCF-7 tissue culture cell line derived from breast carcinoma. Studies were conducted to determine whether MCF-7, a tissue culture cell line derived from a pleural effusion of a patient with breast carcinoma, could be used as a source of tumor-associated antigen for direct leukocyte migration-inhibition (LMI) assays. Of 32 patients with breast carcinoma, 27 (84.4%) gave positive migration-inhibition results on their initial tests with a 25-mug protein/ml concentration of a 3 M KCl extract of MCF-7; 1 of 24 (4.5%) normal donors reacted with MCF-7. An  intermediate incidence of reactivity (7/16) was observed with the extract when leukocytes of patients with melanoma, lung carcinoma, and Ewing's sarcoma were used. In further specificity studies, leukocytes of patients with breast carcinoma gave a lower incidence of LMl reactivity than did those of patients with Ewing's sarcoma and lung carcinoma with KCl extracts of the appropriate histologic type of tumor. The results indicated that the MCF-7 cells possessed a tumor-associated antigen to which many patients with breast carcinoma are sensitized.


Cytotoxic effects of hyperthermia and adriamycin on Chinese hamster cells. Chinese hamster cells, exposed to simultaneous hyperthermia (43 degrees C) and adriamycin (ADM), were intially sensitized to the cytotoxic activity of ADM. If the duration of the combined treatment exceeded about 30 minutes, however, the cells became refractory to additional killing by ADM. If heat was applied before ADM exposure, the cells also could be rendered insensitive; this state persisted so that 24 hours after a 50-minute exposure to 43 degrees C, the cells still showed considerable resistance to ADM. The most reasonable explanation for the findings was that cell membrane permeability to ADM was initially increased by hyperthermia, but prolonged (greater than 30 min) heat exposure reversed this situation and inhibited additional ADM from penetrating to sensitive sites. However, the data yield no hints as to the precise mechanisms involved nor are they sufficiently precise to exclude other explanations. The results do point to precautions that must be observed if the combination of ADM and hyperthermia is to be used clinically.


Effects of murine tumors on delayed hypersensitivity to dinitrochlorobenzene. I. Description of anergy caused by transplanted tumors. In the murine model presented for tumor-associated immune suppression, normal BALB/c mice displayed significant foodpad swelling when sensitized on the flank with 2 mg dinitrochlorobenzene (DNCB) dissolved in dimethyl sulfoxide and challenged in a footpad with 0.05 mg DNCB 10 days later. This reaction in challenged footpads seemed to be a classic delayed hypersensitivity reaction, since it took 24 hours to develop and included an extensive mononuclear infiltrate. The reaction was transmissible from sensitized to normal mice by the transfer of lymphoid cells but not to serum. When sensitized 10 days after tumor inoculation, mice bearing either an allogeneic melanoma or a syngeneic lymphoma or fibrosarcoma did not demonstrate delayed hypersensitivity to DNCB.


Function of myocardial mitochondria in the adriamycin-induced cardiomyopathy of rabbits. Ultrastructural examination of the myocardia of New Zealand White rabbits showed a progressive cardiomyopathy with prominent mitochondrial lesions after 56 days of increased doses of adriamycin. During all phases of study, similar respiratory control rates and ADP:O ratios were found in myocardial mitochondria isolated from adriamycin-treated and control rabbits.


Characteristics of Gross virus-induced leukemia cell clones. I. In vivo and in vitro properties. Clones of four Gross virus-induced murine lymphoblast lines, established in culture from C3H mice, were selected for detailed study of the relationships among in vitro growth parameters, oncogenicity, and agglutination with concanavalin A. The four clones were intially divided into two groups on the basis of their in vitro growth properties. Two strains, N-811 and H-111, had low saturation densities, low cloning efficiencies, and slower doubling times; the other two strains, L-274 and L-258, had higher saturation densities, higher cloning efficiencies, and faster doubling times. The ability of the strains to produce tumors in mice correlated with their in vitro growth properties: L-274 and L-258, with their high saturation densities and high cloning efficiencies, were more tumorigenic in mice than were N-811 and H-111 cells with their lower saturation densities and lower cloning efficiencies. All strains were agglutinable with concanavalin A; however, the agglutination response did not correlate with saturation density or oncongenicity.


Characteristics of Gross virus-induced leukemia cell clones. II. Oncornavirus production. Oncornavirus production differed quantitatively among four Gross virus-induced murine leukemia clones. To determine the proportion of cells in each clone that were producing virus particles, the cells were stained by indirect immunofluorescence with antiserum to Gross antigen. All four clones had the same percentage of cells positive for the presence of Gross antigens irrespective of their ability to produce virus particles. A direct correlation was observed between the amount of RNA tumor virus attached to the plasma membrane and agglutination by concanavalin A. The leukemia strain that produced the most virus also had the greatest degree of agglutination. Oncornavirus production was indirectly related to oncogenicity of the cells in vivo: The clones that produced the most virus were the least malignant. The interaction of the host and virus-producing cells was monitored during animal passage, and virus production decreased during animal passage whereas transplantability increased.


Metabolism of the pancreatic carcinogens N-nitroso-bis(2-oxopropyl)amine and N-nitroso-bis(2-hydroxypropyl)amine in the Syrian hamster. Metabolisms of the potent pancreatic carcinogens N-nitroso-bis(2-oxopropyl)amine (BOP) and N-nitroso-bis(2-hydroxypropyl)amine (BHP) were studied in male Syrian hamsters. BHP and a new metabolite, N-nitroso-(2-hydroxypropyl)(2-oxopropyl)amine (HPOP), were detected in the urine of hamsters administered BOP and BHP. The rates of HPOP formation from BOP and BHP were determined by the measurement of blood and urine levels at various times after each compound was administered: HPOP was formed readily from BOP, but slowly from BHP. This may explain the different organotropic spectra and carcinogenic potencies of BOP and BHP.


Teratomas in the Igbos of Nigeria.

Teratomas in the Igbos of Nigeria. A study was made of the site of 86 teratomas occurring in approximately 7,500 surgical specimens received at a central laboratory serving government, mission, and private physicians working among the lgbos of Nigeria. Most teratomas [74 cases (86%] arose in the ovaries. Testicular teratoma was not seen in the series that included three testicular and 37 ovarian primary cancers. Accordingly, gonadal tumors are as uncommon in Igbo males as in other Nigroes.


Occupation and Hodgkin's disease.

Occupation and Hodgkin's disease. An incidence survey of Hodgkin's disease (HD) was conducted in the Boston Standard Metropolitan Statistical Area for 1959-73. Information on affected persons, 20 to 64 years old, was related to the 1960 and 1970 U.S. decennial censuses to evaluate the rates of HD in several occupational groups of special interest. No excess HD risk was found for two groups with high exposure to persons with the disease: Physicians had a relative risk (RR) of 1.2(0.4-2.6, 95% confidence interval) and nurses had an RR of 0.9 (0.4-1.8). Teachers, a group suggested to be at high risk due to exposure to "carriers" or contacts, had an RR of 1.1 (0.7-1.6). A high sex ratio, 1.9:1, at 35-64 years of age suggested that occupational exposures might increase disease risk. However, no difference in HD incidence was seen between employed and unemployed women in this age group. As in previous studies, woodworkers had an excess risk of HD [RR=1.6(0.9-2.6-a)], but the reason for this is obscure.


Endrocrine factors and the growth and spread of B16 melanoma. B16 melanomas grew more slowly in female than in male syngeneic C57BL/6J mice. After oophorectomy, the growth rate was similar to that in normal and castrated male mice and was not altered in pregnant mice. The growth in vitro was similar in the presence of serum from normal and castrated male and female mice.


Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines. The fate of bloodborne malignant melanoma cells selected for their enhanced ability to form lung colonies was examined to determine how specific tumor cells are arrested in certain organs during the experimental metastasis process. After murine B16 melanoma variant tumor cell lines with low (B16-F1) or high (B16-F10) survival and growth potential in vivo were admisistered by iv or intracardiac injections into syngeneic C57BL/6 mice, the quantitative distribution of [125l]5-iodo-2'-deoxyuridine (125IUDR)-labeled cells in the organs and subsequent formation of metastatic lung colonies were assessed. The initial distribution of viable tumor cells was dependent on the route of injection: Soon after iv injection, more 125IUDR-labeled B16 cells were localized in the lungs and fewer in the blood and other organs than after intracardiac injection. However, 1 day after the injection, the number of viable tumor cells in the lungs was independent of the route of injection, and at 14 days the quantity of resulting lung tumor colonies was similar. Variant line B16-F10 cells were better arrested and formed more tumors per input cell than B16-F1, regardless of the injection route. B16-F10 yielded only lung tumor colonies, whereas B16-F1 formed some extrapulmonary tumor growths. The results suggested that the ultimate fate of circulating tumor cells was not determined solely by nonspecific arrest in the capillary bed of the first organ encountered, and that in vivo selection could produce tumor line variants with organs preferences.


Immunogenetic aspects of nasopharyngeal carcinoma. IV. Increased risk in Chinese of nasopharyngeal carcinoma associated with a Chinese-related HLA profile (A2, Singapore 2). The results of this study of 110 Singapore Chinese with nasopharyngeal carcinoma (NPC) and 91 controls confirmed the association between the occurrence of HLA antigen Singapore 2 (Sin2) and NPC in the Chinese population, and indicated that their increased risk for NPC was confined to the joint occurrence of Sin 2 and A2 antigens. These findings suggested that the genotype of importance in susceptibility to NPC is the A2-Sin 2 haplotype.


Effects of tissue culture environment on growth patterns and ultrastructure of poorly differentiated human cervical carcinomas. Growth patterns and ultrastructure were compared between biopsy specimens and primary cultures of poorly differentiated carcinomas of the human uterine cervix. Though not obvious histologically, all carcinomas in vivo retained ultrastructural traits of squamous, glandular, or basal cell differentiation. Carcinomas with squamous traits grew as compact masses in vivo and formed cohesive colonies in vitro; tumors with basal and glandular traits infiltrated host tissues in a dispersed fashion, but their growth patterns in vitro were variable and unpredictable. The growth patterns of mixed carcinomas, in which squamous and glandular characteristics were evident in the same cells, generally resembled those of tumors with squamous traits. The levels of differentiation in vitro exceeded those found in vivo: Tonofilaments, desmosomes, and glycogen aggregations (squamous traits) as well as secretory vesicles, endoplasmic reticulum, and cilia (grandular traits) became more numerous and complex in culture. The direction of differentiation, expressed in vivo, usually persisted in vitro, through squamous traits appeared de novo or became more prominent when some of the tumors were explanted. The enhancement of differentiation by the culture environment indicated that the cervical carcinomas did not express their full potential to differentiate when growing in the natural host. The coexistence of squamous and glandular traits in the same cells and the capacity of tumors to shift from a glandular to a squamous differentiative pathway upon explantation support the concept that cervical carcinomas originate in bipotential cells, i.e, either reserve cells or metaplastic basal cells derived from the glandular epithelium.


Characterization of mammotrophs separated from the human pituitary gland. Human pituitary tissues from 27 patients and 7 persons post mortem were dissociated into single cell suspensions. On the average, 23% of the cells were mammotrophs. The concentration of prolactin in these suspensions averaged 3.8 ng/1,000 cells. After cell separation by velocity sedimentation at unit gravity, mammotrophs and other cell types were enriched twofold to threefold. The separated mammotrophs retained structural integrity at light and electron microscopic levels. In eight separation experiments, cells recovered from different gradient regions were assayed for intracellular prolactin levels. In cells from "normal" subjects, 8.5% of the prolactin recovered from the gradient was associated with large mammotrophs, whereas in patients with breast cancer, 28% of the hormone was associated with large mammotrophs. The number of mammotrophs recovered from this gradient region (beyond fraction 6) was doubled in breast cancer (2 expts). These mammotrophs showed areas of hypertrophied Golgi and endoplasmic reticulum. Culture of the separated cells from 1 patients with diabetes and 2 patients with breast cancer for 21 days showed that mammotrophs in the upper gradient fractions (diabetic) secreted seven times more hormone than those in the lower regions, whereas those mammotrophs from patients with breast cancer that fell to the lower gradient regions secreted 15 times more prolactin than did those in the upper regions. These data suggest that pituitaries of patients with breast cancer contain a small pool (10-20%) of hypertrophied mammotrophs that have the potential for significant secretory activity in vitro.


Geographic patterns of large bowel cancer in the United States. Age-adjusted rates of mortality from colon and rectal cancer during 1950-69 were correlated by sex and race (white and nonwhite) with demographic data for the 3,056 counties of the contiguous United States. Mortality was consistently elevated in counties with large populations, higher income and education levels, and high percentages of residents of Irish, German, or Czechoslovak descent. The urban, socioeconomic, and, ethnic factors were each linked to large bowel cancer, but they only partly explained the predominance of this tumor in the Northern United States. A survey was made of the limited data available on dietary habits by region and on alcohol sales by county, but the concomitant variation with bowel cancer mortality rates was not impressive.


Rapidly acquired cytotoxicity of lymphoid cells from ice inoculated with allogeneic spleen cells. Spleen cells from C57BL/6J or CBA mice inoculated iv with spleen cells from BALB/c mice produced a strong nonspecific cytotoxic effect on target cells (mouse L-cells). Lymph node cells from CBA or C57BL/6J mice inoculated sc with BALB/c spleen cells also destroyed L-cells. Lymph node cells from mice inoculated with syngeneic spleen cells were not cytotoxic. The cytotoxic effect was observed ion of allogeneic but not syngeneic spleen cells. This effect was considerably reduced or completely suppressed after partial or total removal of plastic-adherent cells.


Screening of cytotoxic drugs for residual bone marrow damage. Several cytotoxic drugs were tested for their ability to produce permanent residual damage to the bone marrow. A short course of the drug was given to BALB/c female mice, and the numbers of various types of bone marrow cells were determined at least two months later. Evidence of residual damage was found after administration of busulfan and 1,3-bis(chloroethyl)-1-nitrosourea, but not after administration of cyclophosphamide, 5-fluorouracil, 6-mercaptopurine, methotrexate, or vinblastine.


Carcinogenicity of N'-nitrosonornicotine in Sprague-Dawley rats. N'-Nitrosonornicotine was added to the drinking water of outbred Sprague-Dawley rats. Adenocarcinomas of the olfactory epithelium occurred in all 15 rats, squamous papillomas o- the esophagus in 1, squamous papillomas of the nonglandular stomach in 1, and a hepatacellular tumor in 1. The possible ingestion and subsequent in vivo nitrosation of nicotine and/or nornicotine could create a serious carcinogenic hazard to cigarette smokers.


Nature of 3,6-bis(5-chloro-2-piperidinyl)-2,5-piperazinedione-induced cytotoxicity in Chinese hamster ovary cells. We sutdied the effect of 3,6-bis(5-chloro-2-piperidinyl)-2,5-piperazinedione (BCP) on various parameters of the replication cycle and cell grwoth on monolayer cultures of Chinese hamster ovary cells. The results indicated that BCP had no effect on the G-S transition or the passage of cells from metaphase to G. However, BCP prolonged S- and G-phases because of its retarding effect on DNA synthetis. BCP was more toxic to S-phase cells than to G or mitotic cells. As with other alkylating agents, chromosome damage due to BCP could be seen only in cells that had undergone DNA replication after exposure to the drug.


Cell interactions between epithelial and mesenchymal components in primary sheets of fetal rat lung cells, and the effects of 3-methylcholanthrene treatment. Cell rearrangement of epithelial and mesenchymal components was analyzed in primary cell sheets derived from whole lungs from fetal rats and maintained in tissue culture for 3-175 days without being subcultured. A limited reconstruction of original lung tissue from the dissociated cells was observed in these primary cell sheets. From the initial monlayer spread, ciliated columnar epithelial coverage appeared on fibroblast sheets after appoximately 2 weeks' maintence. Cystic formation also developed within the fibroblast layers. Histotypic collagen fibril formation eventually appeared in the fibroblast layers and resulted in the development of multilayered collagenous connective tissue in vitro. Epithelial elements survived as a form of surface coverage during maintenance of the sheets and as cystic structures in the collagenous layers. Treatment with 3-methylcholanthrene induced severe proliferation of epithelial elements in the cell sheets. These proliferative changes included rapid extension of epithelial surface coverage, stratification of immature cells, and squamous cell mataplasia.


Spontaneous tumors and atypical proliferation of pancreatic acinar cells in Mastomys (Praomys) natalensis. In 17 of 90 untreated 2-year-old Mastomys (Praomys) natalensis, an acinar cell tumor was observed, and atypical acinar proliferation was noted in 30. The lesions, either neoplastic or proliferative, consisted of large polygonal cells with prominent nucleili in the enlarged hyperchromatic nuclei. The cytopalsms of these cells were polychromatic and were characterized by a central eosinophilic granular area and a peripheral basophilic fibrillar zone around an eccentric nucleus. The differntiated cells retained acinar organization with occasional fromation of small luminal spaces, but the less-differentiated cells, particularly in the anaplastic tumor nodules, lacked polarity and lost lamost completely the normal acinar architecture. Eelctron microscopy of 1 tumor nodule revealed numerous zymogen granules of various sizes and an abundance of often dilated, rought endoplasmic reticulum. No defnite ductlike structure was found within the lesions, and metastic spread was not evident in any of the organs examined. Isntead, normal pancreatic tissues of Mastomys frequently contained small foci of degenerated acini in which thin psuedoducts proliferated.


Chemotactic response of leukocytes to cord factor (trehalose-6,6'-dimycolate). Cord factor (trehalose-6,6'-dimycolate), a glycolipid extractable from myocobacteria, was chemotactic for peritoneal cells of mice at concentrations from 5 to 25 mug/ml medium, as well as for peripheral white blood cells of mice and humans. At higher concentrations, presumably only macrophages were attracted.


Cilia formation in cultures of human lung cancer cells treated with dimethyl sulfoxide. Cells from cultures of the ChaGo line of human lung cancer were examined periodically by electron microscopy for 4 years and no cilia were observed. However, when cells  were grown in medium containing 2% dimethyl sulfoxide, as many as 50% of the cells had cilia with a 9+0 microtubular pattern.


Expansion of interstitial fluid is required for full restitution of blood volume after hemorrhage. Dogs with splenectomy and intact adrenals and adrenalectomized-splenectomized dogs infused with cortisol at a physiologically increased rate restored plasma volume and protein and demonstrated early extracellular hyperosmolality. In contrast, adrenalectomized-splenectomized dogs infused with cortisol at a basal rate did not restore volume or protein after a transient initial phase and did not demonstrate extracellular hyperosmolality. From the foregoing evidence, it is postulated that the second state of restitution of blood volume following hemorrhage proceeds as follows: 1) Hemorrhage and the subsequent increase in plasma cortisol concentration lead to an increase in extracellular osmolality. An osmotic shift of intracellular fluid to the interstitium ensues. 2) The small increase in interstitial fluid volume results in a relatively large increase in interstitial hydrostatic pressure (because of the low compliance of the interstitium), thus accelerating lymphatic movement of interstitial protein to the vascular system. This movement results in a reequilibration of extracellular fluid toward the plasma. 3) The osmotically active agents mobilized by cortisol and hemorrhage do not appear to be glucose, sodium, or potassium. 4) There may be an adrenal factor other than cortisol that is necessary for full restitution of blood volume with 24 hours after hemorrhage.


The management of renal injuries.

The management of renal injuries. Of 161 traumatic renal injuries analyzed for the period 1962-1975, 154 were due to blunt trauma and seven to penetrating wounds (5 gunshot wounds and 2 stab wounds). All the latter were treated by surgical exploration. Fifty-five patients had moderate injuries and 20 had severe injuries from nonpenetrating wounds and were managed without operation except for 10 cases that required surgical intervention. Of the patients with blunt trauma, 5% required nephrectomy, which is similar to the results reported with immediate operation. The other 79 patients (51%) with nonpenetrating injuries had only a renal contusion and were treated by bedrest and early ambulation. Conservative treatment is thus recommended for the more severe renal injuries; operative intervention is reserved for specific indications. The results of this approach are equal to those achieved by early surgical repair without subjecting a significant number of patients to an unnecessary operation.


Diabetes insipidus caused by craniofacial trauma. A patient is presented with diabetes insipidus secondary to craniofacial trauma. Diabetes insipidus can occur in any patient within ten days of craniofacial trauma. Even the masked disease in the unconscious patient can be diagnosed by observation of intake and output, urinary specific gravities, and appropriate chemical studies. The disease can recur following operative reduction of facial fractures. Diabetes insipidus can be successfully treated by intramuscular Pitressin and appropriate fluid intake.


Suppressed in vitro chemotaxis of burn neutrophils. A comparison of the chemotactic response of peripheral blood neutrophils between burn patients and control individuals was performed. Beginning approximately 5 days postburn a decreased chemotactic response of neutrophils from burned patients was noted. The most severely reduced chemotaxis was noted in the burn patients who died. No evidence of a burn serum factor which inhibited the chemotactic response of control neutrophils was found in this study.


Assessment of bone viability by scintiscanning in frostbite injuries. Radionuclide bone imaging with a radiotechnetium-labeled phosphate (99mTc-methylene diphosphonate) has been employed to study the extremities injured by frostbite. The degree of accretion of the radiopharmaceutical in bone is dependent on the integrity of the vascular supply. This property has been used successfully to distinguish viable and nonviable bone.


[Para-sphincteric infiltrations (authors transl)]. The aut horsdescribe the technique and the first results of para-sphincteric anaesthetic infiltrations of the striate sphincter of the urethra in paraplegics. These infiltrations may decrease, or even cause to disappear altogether, dysuria as long as the striate sphincter is alone responsible and that the straite sphincter muscle is not the process of fibrosis. In certain special cases, this simple technique may have a durable effect which makes it possible to avoid definitive procedures such as endoscopic or surgical section.


[Reflections on ureterocystomeostomy using a tubular vesical flap]. Authors cite 25 uretero-noecystostomy cases, carried out with the Boari flap technique, as well as their respective results several time after the operation. Authors underline both advantages and disadvantages, of presently most followed technics, i.e. Boari-Küss and Boari-Gil Vernet; furthermore, their experience suggests that vesico-ureteral reflux has never caused injuries to the upper urinary tract; the event a surgeon should be particularly afraid of, is stenosis of the uretero-vesical anastomosis. In order to have an easier anastomosis in case of dilated ureters, they also propose the Boari-Küss technique. while for normal-caliber ureters Boari-Gil Vernet technic is suggested.


[The treatment of impotence of vascular origin. Revascularisation of the corpora cavernosa]. Importence in young subjects is often vascular in origin. This concept is recent. Selective arteriography shows isolated lesions of arterial occlusion. Revascularisation of the corpora cavernosa makes it possible to cure impotence of this type.


[The psoic bladder or Boari's knell. 4 cases (author's transl)]. Repairing a pelvic ureter is always an ideal when the kidney above it is still functional. But this operation imposes technical artifices when direct urtero-vesical implantation is not possible. Referring to four cases, the authors show the value of the psoic bladder and compare it with the tubulate vesical strip and vesical bipartition.


[Anterior urethral valve in a five year old boy (author's transl)]. The authors report the case of a valve of the anterior urethra in a five year old boy, which was carefully explored from a radiological, endoscopic and urodynamic standpoint. The lesion was successfully treated by transurethral resection. The features of this type of obstructive problem are discussed in the light of the case, together with the diagnostic value of urodynamic studies and endoscopic photography and, finally, the possibilities of treatment, emphasising the simplicity and effectiveness of transurethral resection.


[Hypospadias. The treatment of associated lesions and ectopic meatus (author's transl)]. A study of stenosis of the meatus, torsion, deviation of the penis, embedding and transposition is made, with emphasis on anatomical lesions and in particular the skin folds of the covering of the penis, relevant to incisions and surgical technique.


[The treatment of organic impotence by implantation of plastic prosthesis. Reflections on 50 cases (author's transl)]. The treatment of impotence by implantation of a semi-rigid silastic prosthesis is suitable only for the patient with persistent libido and who has a short or weak erection. Patients in whom libido is absent; or in whom there is absolutely no erection are not improved by operation. Use of a semi-rigid silastic prosthesis which may be introduced unto a canal formed between the tunica albuginea and the corpora cavernosa is, in our experience, the simplest and most rapid method, as well as being associated with the least complications. The semi-rigidity of the penis did not pose any problems in any of our patients and none reported any complaints by the partner.


Calcium oxalate stone disease: congenital defect of metabolism? Kidney tissue enzyme patterns from patients with calcium oxalate stone disease were compared to enzyme patterns from healthy and inflamed human kidneys. In the case of oxalate stone disease there was a significantly decreased activity of the glycolytic enzyme aldolase, resulting in a cumulation of oxaloacetate and of oxalic acid. This decrease of the aldolase activity does not completely reveal the cause of calcium oxalate stones but provides a new aspect to the disease.


A case of uric acid renal stone with hypouricemia caused by tubular reabsorptive defect of uric acid. A 60-year-old man had a uric acid stone in the kidney and laboratory findings of hypouricemia (1.1 mg. per 100 ml.) and increased uric acid clearance (43 ml. per minute per 1.73 m.2). Clearance of uric acid exceeded the endogenous creatinine clearance after administration of pyrazinamide, an inhibitor of renal tubular secretion of uric acid. It was suggested that our patient had a complete defective mechanism for uric acid reabsorption, resulting in hyperuricuria and the formation of the uric acid stone.


Use of hemiacidrin in management of infection stones. Unless all fragments are removed at the time of surgery for struvite stones a high incidence of recurrent infection and stone formation is likely. To reduce the recurrence rate of such stones the renal pelvis is irrigated postoperatively with 10 per cent hemiacidrin solution for at least 48 hours or until all fragments have been dissolved. We have managed successfully 35 patients (36 kidneys) without enxountering any complications. Included in our most recent series are 2 patients with solitary kidneys who had successful dissolution of stone fragments. Absolute contraindications to the use of hemiacidrin are infected urine, fever or flank discomfort. Although we have found hemiacidrin dissolution of renal stones to be safe and effective it is essential that the clinician be aware of the proper technique and its possible complications.


The ileal ureter in recurrent urolithiasis. An ileal segment was interposed between the renal collecting system and bladder in 4 cases. The surgical technique is outlined, with emphasis on the pyelo-infundibulocalico-ileal anastomosis and other technical aspects. The ileal ureter is recommended in selected cases of recurrent renal calculi and nephrocalcinosis with associated nephrolithiasis.


The role of hemiacidrin in the management of renal stones in spinal cord injury patients. Hemiacidrin is known solvent of renal calculi. Our report concerns its use in 5 cases as the sole medical agent for dissolving pelvic stones and in 6 others to supplement an operation and dissolve postoperative residual concretions. No serious complications were noted in either group. An accurate and safe technique for its use is described. The results of the method are presented.


Renal phlebography: an aid in the diagnosis of the absent or non-functioning kidney. There are clinical situations that may preclude the use of retrograde pyelography and renal arteriography in the differential diagnosis of the absent, dysgenetic and non-functioning kidney. At times these procedures are non-diagnostic. We present 8 cases to demonstrate the efficacy of selective renal phlebography as an aid in the diagnosis of these entities.


Solitary renal cyst, hypertension and renin. Solitary renal cysts may cause renin hypersecretion with associated hypertension by compressing surrounding tissue and by distortion of renal vessels. Selective measurements of plasma renin activity in the renal veins can predict the antihypertensive effect of decompression. An illustrative case is presented and its significance is discussed.


Angiomyolipoma: diagnosis and treatment. Four cases of renal angiomyolipoma are presented, 3 of which were diagnosed in non-tuberous sclerosis patients. In 1 case diagnosis was made preoperatively and in another case it was made intraoperatively, allowing for preservation of functioning renal parenchyma. The second successful kidney transplant in a patient with tuberous sclerosis and renal failure is reported. One cannot always differentiate renal angiomyolipomas from adenocarcinoma. However, if the classical angiographic findings of sacculated pseduo-aneurysms supplied by the interlobular and interlobar arteries are present non-operative observation or limited surgery with preservation of renal tissue is possible. Also, knowledge of the gross pathologic appearance and the syndrome of tuberous sclerosis will allow one to make a preoperative or intraoperative diagnosis with confidence.


Benign renal angiomyolipoma with regional lymph node involvement. The 2 cases reported herein involve benign renal angiomyolipomas, showing the same angiomyolipoma changes in the regional lymph nodes. It is concluded that these lymph node changes are caused by a multicentric origin of the angiomyolipoma rather than true metastasis. A plea is made not to over treat these tumors since all evidence points to the fact that they are indeed benign.


Ureteral structure and ultrastructure. Part I. The normal human ureter. Twenty-eight normal human ureters were examined under the light and electron microscope. Three uretero-trigonal units were microdissected. The ureter is a non-layered muscular tube wherein the anatomical unit is muscle bundles that contain heterogeneously oriented muscle cells. Functional continuity of muscle cells is provided through the nexus, which are clearly defined structures. A group of morphologically distinct muscle cells are identified and these may represent the ureteral pacemaker cells. The functional status of muscle cells causes certain morphologic changes and, thus, the cells fixed in contraction differ from those fixed in relaxation and in vitro testing of muscle cell contractility is feasible. The ultrastructure of the normal urothelium and the adrenergic and cholinergic components of ureteral nerves are presented briefly.


Ureteral structure and ultrastructure. Part II. Congenital ureteropelvic junction obstruction and primary obstructive megaureter. The structure and ultrastructure were studied of 48 specimens from cases of congenital ureteroplevic junction obstructions and primary obstructive megaureters. Under light microscopy a spectrum of findings occurs, extending from the nearly normal to the clearly abnormal obstructive segments. However, under electron microscopy there were consistent abnormalities: 1) excessive collagen fibers between and around the muscle cells and 2) a group of compromised muscle cells proximal to the collagenous segment. These findings are responsible for functional discontinuity via the nexus and indistensibility of the pathologic areas. The high resolution of the electron microscope allows clearer definition of these obstructions and the impact of these findings on surgical remodeling is discussed.


Phenoxybenzamine in the management of neurogenic vesical dysfunction. The clinical effect of phenoxybenzamine, an alpha blocking agent, was studied in a series of 37 patients with varying degrees of neurogenic vesical dysfunction. An over-all 78 per cent success rate was achieved, with an 86 per cent success rate in patients with reflex neurogenic bladder. Phenoxybenzamine demonstrates excellent results in patients with neurovesical dysnfunction who are unable to empty their bladders by other means. The drug demonstrated effectiveness regardless of the level of the lesion, cystometric findings or duration of neurogenic vesical disease.


Management of urinary incontinence with electronic stimulation: observations and results. The evolution in the management of urinary incontinence with electronic stimulation of the pelvic floor is reviewed. The effect of stimulation is analyzed. Our methods of candidate screening and the contraindications to treatment are discussed. Forty patients were treated for 2 to 15 months. Sixteen patients were post-prostatectomy, 4 had stress incontinence, 4 had upper motor neuron lesions, 1 was incontinent after repair of a rectovesical fistula and 15 were post-bladder exstrophy closure. The success rate in the first group was 45.4 per cent, in the second group 100 per cent, in the third group 50 per cent, in the fourth group 100 per cent and in the fifth group 27.2 per cent. In view of the method having been tried on cases resistant to other forms of treatment the results were encouraging. The most satisfying results were in the post-exstrophy group in which no response was expected.


Priapism: treatment with corpus cavernosum to dorsal vein of penis shunts. Deep and superficial dorsal vein to corpus cavernosum shunts successfully relieved priapism lasting 6 and 3 1/2 days in 2 patients. Since the procedures are anatomically sound, require a small surgical field, do not require saphenous vein mobilization and cannot result in a urethrocutaneous fistula further, clinical trials are warranted. If this brief procedure is unsuccessful in relieving priapism corpus cavernosum to saphenous vein or corpus cavernosum to corpus spongiosum shunts can be accomplished without again preparing or positioning the patient.


Forty years of transurethral prostatic resections. The 4 consecutive series of transurethral prostatic resections compared were done by the senior authors during a period of nearly 40 years: 420 cases in 1937 to 1938, 520 cases in 1940 to 1945, 480 cases in 1950 to 1955 and 270 cases in 1972 to 1973. The most notable improvements in the recent series are the fewer patients with temperatures more than 100 degrees (69 virsus 29 per cent) and the improved mortality rate (5.5 verus 0.7 per cent). In our opinion these improvements are owing to antibacterial medication, improved instruments, more skillful performance of the operation, the use of isotonic irrigating fluid and improved postoperative care.