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Incubation of the carcinogenic arylhydroxamic acids N-hydroxy-N-2-fluorenylacetamide or N-hydroxy-N-4-biphenylacetamide and tRNA with 105,000 times g supernatants of homogenates of human small intestine, liver, or colon led to formation of arylamine-substituted nucleic acid adducts. These data indicated that enzymes of human tissues could activate arylhydroxamic acids by N leads to O acyl transfer. The unstable N-acetoxyarylamines formed by these enzymes reacted spontaneously with the tRNA to give covalently linked adducts with the nucleic acid.

Foreign-body (FB) tumorigenesis was induced in female CBH/H and CBA/H-T6 mice and their hybrids by sc implantation of about 0.2-mm thick, large (660-720 mm2) or small (210-400 mm2) pieces of glass, smooth-surfaced plastic, or roughened plastic (rigid unplasticized vinyl chloride vinyl acetate copolymer). The tumorigenic process was analyzed in the various implantation groups by the evaluation of tumor incidences and latencies, and by the determination of 1) frequency of originator ("parent") cells, 2) appearance of preneoplastic cells in FB-reactive capsule tissue, 3) expansion of preneoplastic cell clones throughout the tissue capsule, and 4) pace of cellular preneoplastic maturation in terms of time remaining until neoplastic autonomy. Established methods included transfer of preneoplastic FB-reactive tissue capsules to recipient animals (hybrids of CBA/H and CBA/Br or C57BL/10ScSn). Specific preneoplastic events or stages of FB tumorigenesis were affected differently, depending on the size, material, and surface properties of implants.

Phytohemagglutinin (PHA) inhibited the growth of mouse leukemia lymphoblasts L5178Y in culture. RNA synthesis was repressed significantly within the first hour, and the rates of DNA and protein synthesis were significantly decreased within the second hour; maximum inhibition occurred after 24 hours. The ability of the cells to form colonies in soft agar was limited to a greater extent at much lower PHA concentrations. The cells lost their tumorigenicity in syngeneic DBA/2 mice after 4 hours of PHA treatment, when the viability was not appreciably decreased. The cultures of a PHA-resistant strain derived from a resistant colony cloned from the PHA-containing soft agar plate showed increased resistance toward PHA. A fourfold increase in PHA concentration was needed for the same rate of inhibition of the original cell line to be attained.

The effects of two types of research cigarettes, which differed in their total smoke delivery and condensate, on the bronchial epithelium of Syrian hamsters were examined electronmicroscopically. The animals were exposed once a day for 5 days each week for 1 year to the total smoke of the cigarettes. Two groups and a control group were killed 1 day after the last exposure, and one group 12 months after the last exposure. The bronchial epithelia of all smoke-exposed animals were hyperplastic, and their ultrastructure showed invaginations, tilt of nuclear axes, an increase in the number and size of lysosomes and multivesiculated bodies, and increased numbers of enlarged intramitochondrial granules. Squamous metaplasia, rarely found, was present at the stage of filamentous bundle formation. The induced alterations were independent of the type of cigarette used. One year after smoking was terminated, the alterations had neither reversed nor advanced, as compared to those occurring 1 day after the last smoke exposure.

Female Sprague-Dawley rats were continuously exposed to equilibrium levels of tritiated water (HTO) during pregnancy. The tritium activities were 1, 10, 50, and 100 muCi HTO/ml body water which provided cumulative, whole-body radiation doses of approximately 6.6, 66, 330, and 660 rads. Administration of the radioisotope was terminated at parturition. Throughout their life-spans and at autopsy, the dams showed an increased incidence of mammary fibroadenomas at exposure to 330 and 660 rads. Although the data for the incidence of malignant mammary neoplasms were consistent with a linear dose response, the small numbers of tumors preclude specific definition of the dose-response curve. Postexposure life-spans for dams chronically exposed to 66, 330, and 660 rads during pregnancy were reduced by 14, 24, and 22%, respectively. Accelerated aging was also demonstrated in these rats: The mean age for mammary fibroadenoma onset decreased with an increasing dose of radiation.

Epithelioid cells from the livers of normal and genetically impaired (Gunn) rats were established in long-term cultures in vitro. These cells grew as flat, epithelioid cobble-stone-type monolayers and showed a diploid karyotype. They secreted rat serum albumin and proteins into their growth media and contained aryl hydrocarbon hydroxylase. Such cells were transformed by treatment with methylazoxymethanol acetate; they then exhibited an irregular, piling growth pattern, acquired the ability to grow in soft agar, and thereafter grew as tumors in hamsters given cortisone and in nude mice. These malignant spindle-cell tumors were reestablished in culture and still secreted serum albumin. The transformed cells became highly multinucleate when exposed to cytochalasin B and thus behaved like tumor cells. This behavior was not shown by the original cells. Cells transformed by benzo[a]pyrene failed to grow in soft agar culture or as tumor in animals. Cells were not affected by diethylnitrosamine.

A single injection of Myleran reduced the pluripotent hematopoietic stem cell, i.e., colony forming unit(s) (CFU), and the erythropoietin-responsive cell (ERC) in polycythemic mice to around 0.5% that of the controls. Repeated injections of erythropoietin (EP) restored ERC populations, whereas the CFU remained at very low levels. This selective action of Myleran and EP in polycythemic mice seemed to be a good approach for the study of oncogenic action of Friend virus on target cells. When the CFU and ERC compartments were decreased, practically no response to the virus was obtained. When there was an appreciable ERC population present with decreased CFU, leukemogenesis still occurred (as judged by the increased spleen weight). This result was in proportion to the dose of EP, i.e., stimulation of the ERC or closely related cells.

A transplantable, pregnancy-dependent, mouse mammary tumor line (TPDMT-4) showed a pregnancy-dependent growth in DDD breeders. The tumors grew during pregnancy, regressed rapidly after parturition, and reached ascending peaks in subsequent pregnancies. Growth without regression occurred in animals with pituitary isografts (PI), but not after the hosts were ovariectomized. The effects of ovariectomy was negated by sc injections of both 17beta-estradiol (E) and progesterone (P), but single injections of E or P did not abolish the effect of the ovariectomy. The tumors also grew in virgins given sc implants of E and P or deoxycorticosterone acetate (DCA) pellets. Adrenalectomy had no influence on the tumor growth in PI-bearing animals, but DCA injections stimulated secretion production by both tumor cells and normal mammary cells. The hormonal conditions that produced tumor growth caused in the host mammary glands the full lobulo-alveolar development seen in mid- to late-pregnant animals. In the hosts without tumor growth, the mammary glands had small clusters of acini at most. The tumors were classified as type A morphologically. Our results suggest that the growth of TPDMT-4, like that of normal mammary glands, is controlled by prolactin, E, and P.

The growth and metastasis of sc transplanted Lewis lung carcinoma were inhibited in C57BL/6J mice by treatment with pyran copolymer. The mean volume of the tumors of pyran-treated animals was 15% that of the saline-treated controls at day 33 post transplantation. Thereafter, the carcinomas gradually increased in volume. Pulmonary metastasis was first observed histologically at day 28 after pyran treatment, compared to day 15 after saline administration. All saline-treated animals died by day 48, whereas 70% of those given pyran remained alive. Tumor necrosis was much more extensive in the lesions of pyran-treated mice. Although neutrophils and monocytes, but few lymphocytes, infiltrated the subcutaneous connective tissue above the neoplasms of animals receiving saline, few leukocytes were present in other connective tissue sites around the tumor. In contrast, treatment with pyran was characterized by a shift at an early interval from a predominance of neutrophils to a predominance of histiocytes and some lymphocytes in the connective tissue above and around the subcutaneous tumor. These cells were often closely associated with degenerate-appearing tumor cells. Additionally, activated macrophages removed from the peritoneal cavity of pyran-treated, tumor-bearing mice exhibited nonspecific cytotoxicity for tumor cells in vitro.

The metabolism of benzo[a]pyrene (BP) by liver microsomes in female A/HeJ mice fed a control diet or a diet containing butylated hydroxyanisole (BHA) was studied. Aryl hydrocarbon hydroxylase activity (AHH) was not changed by BHA feeding. However, the measurement of other parameters demonstrated that BHA feeding altered the microsomal system metabolizing BP. Incubation of BP and calf thymus DNA with liver microsomes from BHA-fed mice showed about half the binding of BP metabolites to DNA as compared to that of controls. The AHH activity of mice fed BHA was much more sensitive to in vitro inhibition by alpha-naphthoflavone than that of controls. The amount of cytochrome P450 was increased per unit weight of microsomal protein and liver in mice fed BHA. The ethyl isocyanide binding spectra were measured to see if alterations of cytochrome P450 might be produced by BHA feeding. The maximum at 430 nm was the same in control and BHA-fed mice. However, the maximum at 455 nm was lower in BHA-fed mice than in controls, which indicated that BHA had caused some changes. The data showed that BHA feeding resulted in altered properties of liver microsomes, including a decrease in BP metabolite binding to DNA.

Sera collected from mice rejecting an allogeneic tumor and showing arming activity for normal splenocytes increased target-cell lysis by immune cells when low (less than or equal to 25:1) attacker:target-cell ratios (A:T) were used but inhibited cytotoxicity at higher (100:1) A:T. The importance of this methodologic variable in studies of serum activity on cellular cytotoxicity is emphasized and the possible mechanisms are discussed.

Mammary carcinomas were found at autopsy 98--100 days after irradiation in 12 of 14 (86%) multiparous Fischer female rats which had been adrenalectomized and given grafts of secretory pituitary tumor strain MtT-F4 soon after exposure to gamma-rays or fission neutrons. A single carcinoma was found in 1 of 10 unirradiated, MtT-bearing, adrenalectomized animals. When adrenalectomy was not done, no tumors were found in 8 unirradiated or in 13 irradiated MtT-bearing rats rats. In view of the well-established finding that Cortisol is essential for milk production, we suggested as a working hypothesis that, in the presence of high titers of mammotropic hormone and adrenal corticoids, differentiation of a given cell for milk secretion reduced that cell's proliferative potential. When such differentiation was precluded by adrenocorticoid deficiency, more irradiation-altered mammary epithelial cells retained their high proliferative potential and contributed to carcinoma formation.

The incidence of neoplastic disease was determined by a mail survey of 2,872 young adults given X-ray treatments in infancy and of their 5,005 nonirradiated siblings. Newly diagnosed benign and malignant neoplasms appeared more frequently in the irradiated subjects than in their siblings or the age- and sex-matched general population of upstate New York. Only thyroid neoplasms occurred in sufficient numbers to permit statistical analysis for the effects on incidence of sex, age, and dose, and of being in a high-risk group (sub-group C). Thyroid cancers developed earlier in life than did benign neoplasms, especially in boys; benign goiters occurred after smaller doses, predominantly in females. Females had a greater risk of developing thyroid cancer than males--2,3 times for females of all ages and 5 times for young adults. Except for young adult females, there was no definite age effect. The risk of cancer (but not of benign goiter) was proportional to the thyroid dose, with a linear risk coefficient of 2.5/year/million people exposed to 1 rad for the entire irradiated population and 4.0 for subgroup C. The high risk of thyroid cancer in subgroup C may be the result of the high percentage of Jews, who had a 3.4-fold greater risk than non-Jews. Young adult Jewish females had a 17-fold increased risk. An incidental observation was an apparent increased incidence of asthma and rare diseases with abnormal immunologic features in the irradiated population.

Lower incidence rates of cancer for all anatomic sites combined were found in male and female Spanish-surnamed residents of Los Angeles County when compared to other whites. These Mexican-Americans were at lower risk for cancer of the buccal cavity, colon, rectum, larynx, lung, breast, bladder, prostate, and testis, and were at higher risk for cancer of the stomach, gallbladder, liver, and cervix. Immigrant Mexican-Americans had incidence rates most divergent from other whites, whereas indigenous Mexican-Americans had rates between the other two groups. The cancer pattern in Mexican-Americans was generally similar to that in American Indians. These data were most consistent with environmental variations in cause.

During 1960-69, 321 reported deaths among Alaskan natives (Eskimos, Indians, and Aleuts) were attributed to cancer. This number is not significantly different from the cancer mortality of U.S. Caucasians during this period, but is significantly higher than that of U.S. Indians. The mortality of Alaskan natives from cancers of the nasopharynx, esophagus, kidneys, and salivary glands was significantly increased. Among Alaskan Caucasians, only nasopharyngeal cancer was in excess in both sexes. Deficits in mortality among Alaskan Caucasians for cancers of other sites may be attributable, at least in part, to selection factors associated with the migration of healthy workers into the State.

The antigenic surface pattern of a continuous cell line (HT29) derived from a human primary carcinoma of the colon was studied by the immunofluorescence technique. Monovalent and polyvalent immune sera were used. The cells of this long-term culture kept the ability to synthesize the three principal colon tumor antigens: carcinoembryonic and nonspecific cross-reacting antigens, and the membrane-associated tissular autoantigen. On the HT29 cells, which still carry the original blood group of the tumor donor, no receptors for human Ig's were detected.

Peritoneal macrophages from C3Hf/Bu mice treated with killed Corynebacterium granulosum bacteria were tested for their effect on in vitro growth of syngeneic fibrosarcoma cells, tumorigenic mouse L-P59 cells, human malignant melanoma cells, allogeneic fibroblasts, erythrocytes, and epithelial kidney cells. Only the cell cultures having neoplastic properties were destroyed by stimulated macrophages; the rate of tumor cell destruction was greater as the ratio of effector to target cells was increased. Neither irradiation nor trypsinization of macrophage monolayers altered the cytotoxicity of stimulated macrophages. The results indicated that C. granulosum activated macrophages to destroy tumor cells in an immunologically nonspecific manner but had no cytotoxic effect on normal allogeneic cells.

Lewis lung adenocarcinoma growth was retarded by the oral administration of delta9-tetrahydrocannabinol (delta9-THC), delta8-tetrahydrocannabinol (delta8-THC), and cannabinol (CBN), but not cannabidiol (CBD). Animals treated for 10 consecutive days with delta9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth. Mice treated for 20 consecutive days with delta8-THC and CBN had reduced primary tumor size. CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days. Delta9-THC, delta8-THC, and CBN increased the mean survival time (36% at 100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg, respectively), whereas CBD did not. Delta9-THC administered orally daily until death in doses of 50, 100, or 200 mg/kg did not increase the life-spans of (C57BL/6 times DBA/2)F1 (BDF1) mice hosting the L1210 murine leukemia. However, delta9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly by 71% at 200 mg/kg as compared to 90.2% for actinomycin D. Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta9-THC and delta8-THC showed a dose-dependent (10(-4)-10(-7)) inhibition (80-20%, respectively) of tritiated thymidine and 14C-uridine uptake into these cells. CBD was active only in high concentrations (10(-4)).

Spleen cells from untreated young male and female C57BL/6 and C58 mice and of male C3H/He mice showed cytotoxic activity in vitro against BALB/c X-radiation-induced leukemia RL male 1 cells by 51Cr-releasing lymphocyte-mediated cytoxicity (LMC) tests, but old mice of these strains lacked LMC activity. In contrast, spleen cells from male and female AKR, BALB/c, and DBA/2 mice, and from female C3H/He mice had no appreciable LMC activity. The proportion of active cells in spleens from young (C57BL/6 times BALB/c)F1 or reciprocal hybrid mice was higher in females than in males. The specificity of the LMC reaction of RL male 1 cells, determined by LMC inhibition assays, was somewhat different from that of previously reported serologic X.1 tests. Thus the antigen detected by LMC has been tentatively designated X.1'. The main effector cells in this system were uncharacterized cells not adherent to glass surfaces or nylon-wool columns. These findings in RL male 1 leukemia extend the evidence for the presence of naturally occurring LMC. With the single unexplained exception of strain C3H/He, the LMC activity against RL male 1 cells, exhibited by untreated mice of various strains, corresponded with a previous classification of mouse strains immunologically as X.1 responders or as X.1 nonresponders according to their ability to reject X.1-positive leukemia cells.

Treatment of a transplantable leukemia in AKR mice with both amphotericin B and 1,3-Bis(2-chloroethyl)-1-nitrosourea cured a significant percentage of animals with advanced disease. Some long-term survivors developed paralysis, and they invariably demonstrated central nervous system (CNS) leukemia. Some of these animals had a systemic relapse of their leukemia, and the CNS appeared to act as a focus for systemic dissemination. The occurrence patterns and histopathologic features of the CNS leukemia in the long-term survivors were strikingly similar to those observed in humans with acute lymphoblastic leukemia.

C57BL/6J mice inoculated sc with 50 mg of a transplantable Leydig cell tumor (M5480) demonstrated a reproducible pattern of slow tumor growth up to day 10 followed by rapid growth at the rate of approximately 0.5 g per day through day 27. The mean survival time of tumor-bearing mice was 33 days, when tumor weight accounted for more than 25% of total body weight. The rapid increase in weight occurring around day 10 resulted largely from a 20-fold increase in the quantity of extravasated blood inside the tumor, which in turn promoted a 50% reduction in host hematocrit. Sustained enlargement of M5480 during the third and fourth weeks of growth was supported by proliferation of tumor cells. Apart from blood-filled cavities, over 90% of the tumor consisted of neoplastic Leydig cells exhibiting generalized cytoplasmic features usually associated with mitotic activity. An activated macrophage was the next most abundant cell type, accounting for 2-3% of the nucleated cell mass. The remaining 3% was occupied by vascular elements, leukocytes, and giant cells. Depending on the age of the tumor, varying proportions of the cell population showed signs of anoxic degeneration. Degenerate cells were minimal at day 14, accounting for less than 4% of the total population, and maximal beyond day 21, when they occupied more than 50% of the cell mass.

Lung adenomas were induced in strain A mice by chronic treatment with N-nitroso compounds (given in drinking water) and with amines or ureas in food plus NaNO2 in drinking water. We studied the effects of varying the concentrations of three N-nitroso compounds and NaNO2 concentration in the morpholine plus NaNO2 and methylurea plus NaNO2 systems. Sodium ascorbate (NaASC) at the highest level tested (11.5 or 23 g/kg food) gave 89-98% inhibition of adenoma induction by the NaNO2 plus piperazine, morpholine, and methylurea systems. In 7 groups, NaASC produced increases of 15-59% in adenoma induction by nitrosomorpholine (NM) and mononitrosopiperazine (MNP), possibly because the mice consumed more of the nitrosamine solution. Adenoma induction by morpholine plus NaNO2 was strongly inhibited by gallic acid, moderately inhibited by caffeine, and unaffected by thiocyanate (all added to the food). Gallic acid inhibited or had no effect on the action of NM and MNP. We discussed the proposal that NaASC (or perhaps gallic acid) be administered with readily nitrosatable drugs.

Gerbils (Meriones unguiculatus), given N-methyl-N-nitrosourea iv once weekly for 15 weeks at doses related to the mean lethal dose, developed tumors of the species-specific midventral sebaceous gland. These neoplasms were more frequent in males than females and were histologically classified as sebaceous adenomas or carcinomas of varying differentiation.

B16 melanoma tumors and cultures are composed of cells with different melanin contents and replicative activities. The hypothesis was tested in vitro that these various cells constituted a population in the process of differentiation and maturation. Early cultures were predominantly composed of small, amelanotic cells with high replicative activity. Older cultures contained mostly larger and heavily melanotic cells with little or no replicative activity. Replicative activity, as measured by the uptake of tritiated thymidine, was inversely proportional to cell size and melanin content. Colony-forming ability was impaired if the original cells were melanotic. Tumorigenicity was unaffected except in very old (9-day) cultures. Our results support the concept that malignant melanocytes undergo a sequence of developmental changes which eventuates in the production of mature cells characterized by enlargement, elevated melanin content, and reduced replicative and colony-forming capacity.

Melanin granules were isolated from the Cloudman S91 mouse melanoma and from Amphiuma liver in highly purified form, as judged by electron microscopy and the lack of a mitochondrial enzyme marker. The granules from both tissues contained small amounts of DNA (less than or equal to 1% of the cell content) that was distinguished from nuclear DNA by the broadness of its buoyant density band in cesium chloride, by its sedimentation rate, and by a two-phased melting curve. The melanosome DNA could not be distinguished from nuclear and mitochondrial DNA by the amount of tritiated thymidine incorporated. The results are discussed and the suggestion made that the melanin DNA may provide the information that led to the production of the granules.

Development of resistance to actinomycin D, daunomycin, or vincristine in Chinese hamster cells growing in vitro resulted in reversion to or retention of normal phenotypes in comparison to spontaneously transformed drug-sensitive parent populations. Sublines resistant or cross-resistant to actinomycin D showed reduced uptake of antibiotic in proportion to degree of resistance. The cells with acquired resistance were either weakly tumorigenic or nontumorigenic when tested in the cheek pouches of weanling Syrian hamsters treated with cortisone. In contrast, parent cells and several amethopterin (methotrexate)-resistant sublines produced many tumors. Antibiotic- and Vinca-alkaloid-resistant cell lines showed oriented growth patterns often associated with the behavior of normal cells in culture; antibiotic-sensitive, tumorigenic lines had morphologic characteristics of malignant cells. The altered cell membrane properties that accompanied development of resistance or cross-resistance to actinomycin D appeared to account also for the lower oncogenic potential and greater cell adhesiveness of resistant cells relative to their malignant counterparts.

Female Syrian hamsters were given a single sc dose of 45 mg diethylnitrosamine (DEN)/kg body weight on 1 of the 15 days of pregnancy. In the offspring of females treated on 1 of the first 11 days of pregnancy, no respiratory tract tumors were found. The offspring of mothers given DEN on 1 of the last 4 days (12-15) of pregnancy developed respiratory tract neoplasms at a rate of up to 95%. A lower incidence of tumors in other organs seemed independent of the day of DEN treatment.

Since the route of administration of BCG may have an important function in immunotherapy, we investigated intralymphatic administration to direct BCG to the lymph nodes. Multiple injections of high doses of BCG were administered to 6 rhesus monkeys via the dorsal lymphatics of the lower limb. A suppurative lymphadenitis was observed along the lower limb and in the inguinal area in 5 of the 6 monkeys. However, many of the complications reported with other routes of administration were not observed. Granulomatous reactions and histiocytic responses developed in lymph nodes on the injected sides of the pelvis and distant nodes as well as in the liver. The intralymphatic route is the method by which high doses of nonspecific immunostimulants were delivered to regional lymph nodes. The efficacy of this approach remains to be established in tumor-bearing animals and humans.

Three oxygenated N-nitrosopiperidines--nitroso-3-piperidinol, nitroso-4-piperidinol, and nitroso-4-piperidone--were prepared and given in drinking water at equivalent molar doses to Sprague-Dawley rats. All were potent carcinogens, 100% of the rats developed tumors in all treatment groups. Nitroso-3-piperidinol resembled nitrosopiperidine in inducing a high incidence of tumors of the nasal cavity and upper alimentary tract, and a few liver tumors. Nitroso-4-piperidinol and nitroso-4-piperidone caused a high incidence of tumors of the nasal cavity but very few tumors of the upper alimentary tract. After treatment with the 4-substituted compounds, a high incidence of liver tumors was observed in females but not in males.

Immediate and delayed effects of nitrogen mustard (HN2) (0.1 mg/kg/day for 4 days) on the growth and cell proliferation patterns of the 3-methylcholanthrene-induced autogenous rat sarcoma were studied. Tumor cells were labeled continuously with 0.5 muCi tritiated thymidine/g for 24 hours. The labeling index fell from 36.4 to 14.0% and the mitotic index from 0.88 to 0.67% after two treatments with HN2. At that time, tumor growth stopped and remained arrested during HN2 administration. After four injections of HN2, the labeling index was reduced further to 0.73% and the mitotic index to 0.36%. After the drug was withdrawn, tumor growth resumed at the pretreatment rate, even though the labeling index on day 3 was only 15.5% (or 40% of the control). The percent labeled mitosis curves and DNA contents, before and 4 days after HN2 was given, were similar. It was concluded that a subpopulation of cells of predominantly short intermitotic times caused tumor growth before and after drug treatment.

A murine anaplastic sarcoma and an in vitro cell line established from it were studied by the TG banding technique. The neoplasm originated in a BALB/c mouse inoculated with human tumor cells. Microchromatin bodies were found in 100% of the karyotypes in the original tumor and in the 120 in vitro passages. A long marker chromosome, also observed in all metaphases, was interpreted as a translocation in tandem of a No. 16 chromosome into a No. 1; this involved loss of the centromeric part of chromosome No. 1.

Components of mycobacterial cell wall(s) (CW) attached to oil droplets were evaluated for their ability 1) to inhibit the growth of line-10 tumor transplants in the skin of syngeneic guinea pigs when inoculated together with 10(6) tumor cells (suppression experiments) and 2) to regress established 7-day-old intradermal tumors and eradicate microscopic lymph node metastases upon injection into the tumors (regression experiments). CW and cell-wall skeleton (CWS) preparations from Mycobacterium phlei, a fast-growing saprophyte of group IV of the atypical mycobacteria, suppressed tumor growth in essentially all animals when 37.5-mug doses were administered; at a dose of 300 mug, they cured 50-60% of the animals in regression tests. The addition of 300 mug of a purified trehalose mycolate, isolated from M. tuberculosis strain Aoyama B, to 300 mug M. phlei CW or CWS preparations significantly increased their tumor regressive potency to provide cure rates to about 90%. Because M. phlei can be propagated more readily, it can be used advantageously in place of BCG to prepare stable, non-living immunologic adjuvants of defined composition and consistently high potency to meet the need for standards with minimal residual malignant disease.

Lethality of Candida albicans was monitored in (C57BL times DBA/2)F1 mice bearing the transplanted Lewis lung carcinoma and in sham-operated controls inoculated with Hanks' balanced salt solution. The lethal response to C. albicans infection was significantly delayed in animals inoculated with the microorganism 6-16 days after transplantation of the Lewis lung carcinoma. Maximal increases in survival times were observed when C. albicans was inoculated 8-12 days following tumor transplantation. Therefore, a delay in the lethal response to C. albicans in this untreated model murine tumor system could be elicited through implantation of the Lewis lung carcinoma; preliminary studies with some other model murine tumors and with cell-free filtrates indicated that this phenomenon is not restricted to the Lewis lung carcinoma.

Gastroduodenoscopy with biopsy was performed in nine patients within 5 days after major thermal injury. Biopsies were evaluated by special histochemical techniques to visualize and differentiate cellular mucosubstances. Acute gastroduodenal lesions were encountered early and frequently in 78% of adult burn patients. The early occurrence, morphology, and histology of these lesions suggest that alterations in gastric mucosal blood flow may play an important etiologic role. A decreased production of gastric mucus does not appear to be an etiologic factor since acute gastric mucosal disease was encountered in most patients despite normal quantities of cellular mucosubstances.

A unique previously unreported injury is described, namely the avulsion of the posterior cruciate ligament from its femoral attachment, as an isolated injury. The mechanism of injury, i.e., hyperextension, is also unique although it is one that is commonly experienced by riders attempting to start their motorcycles.

The surgical management of 75 consecutive blunt liver injuries seen at the Albany Medical Center between 1969 and 1973 is reviewed and analyzed. The most common associated injury was right lower rib fractures which were found in one out of three patients. The spleen was the intra-abdominal organ most commonly injured (one out of four patients). The symptoms and signs of blunt liver injury may be misleading, since in one out of five cases there was no clinical evidence of intra-abdominal injury. The findings of fractured ribs on the right side associated with hypotension and a positive peritoneal tap demand immediate abdominal exploration. In patients with large amounts of disrupted hepatic tissue, a wedge resection was preferred over either simple debridement or hepatic lobectomy. A simple technique for limited hepatic resection provided fast, safe control of massive hemorrhage. The overall mortality was 33.3%. In six patients death was ascribed directly to the liver injury. The results of the present study suggest that death from liver injury per se can generally be prevented by prompt adequate surgical control of hemorrhage. When mortality occurs in these patients it is a result of injury to other organ systems.

The management of eleven patients with major venous and associated liver injuries has been summarized. Aggressive resuscitation includes early operative intervention. Repair of venous injury can be effected if hemorrhage is contained and stepwise exposure instituted. The critical steps in management include: 1) thoraco-abdominal exposure; 2) intermittent occlusion of the porta hepatis; 3) total liver mobilization; 4) judicious use of cava-hepatic bypass.

A 22-week training program for EMT-A technicians, developed at the University of Connecticut Health Center, has been described. The program is coordinated by a trauma surgeon and a security officer, and teaching is carried out by faculty, residents, emergency-room nurses, experienced rescue-team members, EMT firemen, and the like. Lectures and videotaped practical problems are used. High levels of teaching and cooperation between the university health center and the community were maintained.

Two large series of civilian-incurred (212) and combat-incurred (228) tibial shaft fractures are compared. Closed tibial fractures were treated by closed manipulation and weight bearing ambulation in a long leg plaster cast. Open injuries following wound exploration and debridement were treated similarly with wound closure. Combat-incurred tibial shaft fractures responded similarly to civilian-incurred injuries. Allowing an open fracture to heal with exposed bone at the fracture site resulted in an average time to removal of external immobilization only two weeks greater than for the uncomplicated tibial fracture. Whether weight bearing ambulation was instituted immediately (24-48 hr) or early (3-4 wk) did not shorten the time to removal of external immobilization. The infection rate in 289 open tibial fractures (228 combat-incurred and 61 civilian-incurred) was 3.8%, and all infections occurred in the open penetrating injuries.

Analyses of 67 cases again emphasized that the following factors are critical in management: 1) early cerebral arteriography, followed by definitive surgery if indicated; 2) immediate pulmonary assessment with normalization of respiratory performance; 3) constant vigilance for associated injuries and appreciation of known medical diseases; 4) consideration of the use of ventricular pressure monitoring and drainage in suitable cases.

Penetrating injuries of the thoracic and abdominal aorta are controlled and repaired successfully with increasing frequency. Penetration of the suprarenal abdominal aorta has been associated with a high mortality rate because of difficult exposure and associated injuries. Between January 1969 and July 1973, 28 patients have undergone operative treatment for traumatic injury to the suprarenal aorta and other associated thoraco-abdominal injuries with 10 long-term survivors. Eight survivors sustained their injuries during the last 3 years, when a medial mobilization of the viscera was the preferred approach. Dacron prosthetic material was employed in seven patients, and in two there was ligation of the celiac axis. With satisfactory exposure, control of exsanguinating hemorrhage, and utilization of available vascular reconstructive techniques, successful management of this relatively inaccessible intra-abdominal lesion can be accomplished in an increasing number of patients.

1) In major vein trauma, an attempt should be made to repair the vein. 2) Whenever possible, lateral suture seems to be the ideal type of repair. However, excellent results can be obtained with end-to-end anastomosis. 3) When the damaged segment of the vein is too long to permit end-to-end approximation, a vein interposition graft (and if necessary, a composite tube) appropriate to the width of the injured vein and length of the gap should be employed. Use of synthetic grafts should be avoided. 4) Although the importance of a distal temporary A-V fistula is still disputed, the present authors have adopted this method in the graft repair of the femoral vein in the groin. Better results were obtained in the cases in which the fistula functioned than in those in which it became occluded.

Bullet emboli from peripheral wounds occur with sufficient frequency that they must be considered in every case of missile injury not accompanied by an exit wound. A case is presented which demonstrated a venous migration of such a bullet from the axillary vein into the femoral vein through the heart, presumably by gravity.

A case of successful removal of a catheter foreign body retained in the right atrium for 6 months is presented. The hooked catheter approach was used to retrieve the catheter from the right atrium. Due to the hook configuration of the retrievers, the catheter had to be surgically excised from the common femoral vein. Subsequently a system was developed and used successfully in other cases which eliminates the need for performance of a further surgical procedure to remove successfully the catheter or retrieval device.

A comparative study of the in vitro reaction kinetics of the virion RNA polymerase of influenza A strains WS and WSN was conducted to establish phenotypic differences for enzyme activity that might be exchanged as genetic markers among recombinants of these viruses. Characteristically, the RNA polymerase activity of WS virus showed an initial rate of synthesis about two- to threefold higher than that of WSN when assayed at 32 C. The two strains were also distinguishable by comparing the transcription rates of each strain at 32 and 37 C. The initial rate of WS was invariably higher at 37 than at 32 C, whereas the opposite was found with WSN. When a series of recombinants obtained from mixed infections with the WS and WSN viruses were examined for virion transcriptase activity, it was found that the two polymerase related markers behaved as properties which segregated independently of each other and of additional nonselective markers that were scored. Seven temperature-sensitive mutants of WSN virus representing distinct recombination-complementation groups were found to show a diminished transcriptase activity as compared to wild-type virus, and one of these clones (ts 24) was largely deficient for this function. None of these mutants appeared to possess a heat-liable virion polymerase.

Cleavage of adenovirus-associated virus type 2 (AAV2) DNA linear duplex monomers with the restriction endonuclease R-EcoRI yielded three fragments, A, B, and C, having approximate mol wt of 1.6 X 10(6), 1.1 X 10(6), and 1.3 X 10(5), respectively. Radioactive labeling the 5' termini of AAV DNA before cleavage with R-EcoRI showed that A and B were terminal fragments and C was internal. Separation of the complementary strands of fragments A and B showed that A contained the 5' terminus of the minus strand and the 3' terminus of the plus strand, and conversely for fragment B. The physical map of the AAV R-EcoRI fragments can thus be unambiguously determined and is drawn with B at the left-hand and A at the right-hand end. On this map, transcription of stable AAV mRNA from the minus strand proceeds from left to right, beginning in fragment B and terminating in fragment A. The asymmetry in distribution of thymidine between the AAV DNA plus and minus strands is preferentially located in fragment A, which represents the right-hand half of the duplex molecule. These experiments enable preparative separation of all four single-strand termini of AAV DNA and provide a basis for orientation of fragment maps derived by cleavage with other restriction enzymes.

The glycoproteins of Semliki Forest virus, grown in chicken embryo cells, were labeled with radioactive sugars. The data indicate a high mannose content of the nonstructural precursor glycoprotein NSP 63. This protein can also be readily labeled with 2-deoxy-D-glucose. The envelope glycoproteins E1 and E2 are relatively rich in galactose, glucosamine, and fucose. Glycosylation can be impaired by 2-deoxy-D-glucose or D-glucosamine or by omission of sugars in the culture medium. Under these conditions characteristic changes in the electrophoretic profile of the viral polypeptides are observed: in the regions of glycoproteins NSP 97, NSP 63, and E1 and E2 new protein peaks can be detected. These polypeptides seem to be aberrant forms of the glycoproteins. When compared with the normal molecules they have lower molecular weights and contain less carbohydrates, especially mannose. Pulse-chase experiments indicate that the altered glycoproteins are degraded very slowly if at all. If, however, impairment is caused by omission of sugars in the culture medium, the radioactivity is chased after addition of glucose from the region between NSP 63 and E1 + E2 into the E1 + E2 peak. This suggests a completion of the carbohydrate chains under these conditions.

Replicative form DNA of bacteriophage f1 was found to be sensitive in vitro to restriction by endonuclease R-EcoRII if the DNA was isolated from an Escherichia coli strain deficient in cytosine methylase activity. A similar observation was previously made with DNA from the closely related bacteriophage fd (S. Schlagman, S. Hattman, M. S. May, and L. Berger, submitted for publication). The two DNA fragments produced by the endo R-EcoRII digestion of f1 DNA were localized on the f1 cleavage map and their genetic content was determined. The polypeptides synthesized in a "coupled" transcription-translation system under the direction of each RII fragment were examined. The results of such experiments allow the ordering of genes V and VII and indicate the location of a RNA promotor for gene VIII.

We investigated the protein composition of the lipid-containing bacteriophage phi 6. We also studied the synthesis of phage-specific proteins in the host bacterium Pseudomonas phaseolicola HB10Y. The virion was found to contain 10 proteins of the following molecular weights: P1, 93,000; P2, 88,000; P3, 84,000; P4, 36,800; P5, 24,000; P6, 21,000; P7, 19,900; P8, 10,500; P9, 8,700; and P10, less than 6,000. Proteins P3, P9, and P10 were completely extracted from the virion with 1% Triton X-100. Protein P6 was partially extracted. Proteins P8 and P9 were purified by column chromatography. The amino acid composition of P9 was determined and was found to lack methionine. Labeling of viral proteins with [35S]methionine in infected cells indicated that proteins P5, P9, P10, and P11 lacked methionine. Treatment of host cells with UV light before infection allowed the synthesis of P1, P2, P4, and P7; however, the extent of viral protein synthesis fell off exponentially with increasing delay time between irradiation and infection. Treatment of host cells with rifampin during infection allowed preferential synthesis of viral proteins, but the extent of synthesis also fell off exponentially with increasing delay time between the addition of rifampin and the addition of radioactive amino acids. All of the virion proteins were seen in gels prepared from rifampin-treated infected cells. In addition, two proteins, P11 and P12, were observed; their molecular weights were 25,200 and 20,100, respectively. Proteins P1, P2, P4, and P7 were synthesized early, whereas the rest began to increase at 45 min post-infection.

We have found by negative staining electron microscopy that when similar concentrations of adenovirus and reovirus (viruses of about the same diameter, 75 to 80 nm, and density, 1.34 to 1.36 g/cm3) were incubated with a carbon support film containing microtubules, 72% of adenovirus on the grid, but only 32% (equivalent to random association) of reovirus, were associated with microtubules. Similar concentrations of both larger and smaller particles, such as polystyrene latex spheres and coliphage f2, also exhibited a low degree of interaction, viz., 17 to 37%, with microtubules. Moreover, 90% of microtubule-associated adenovirus binds to within +/- 4 nm of the edge of microtubules, but lower fractions (again equivalent to a random association) of the other particles bind to the edge of the microtubules. The mechanism behind this phenomenon, which we denote as "edge binding," is presently obscure; however, it provides us with a second, albeit empirical, method to distinguish between the microtubular association of adenovirus and other particles. We found that edge binding of adenovirus also occurred when adenovirus was initially placed on the carbon support film and then incubated with microtubules and when adenovirus and microtubules were mixed prior to placement on the support. In contrast, reovirus or the other particles prepared by similar techniques exhibited a random amount of edge binding. The binding of adenovirus appears to involve the hexon capsomers of the virion since (i) high resolution electron micrographs showed that the edge of the virus was in contact with the edge of the microtubules, and (ii) adenovirions briefly treated with formamide to remove pentons and fibers bind as efficiently as intact virions. Core structures, which were obtained by further formamide degradation of the virion, do not associate with microtubules. These observations support the hypothesis of Dales and Chardonnet (1973) that the transport of adenovirions within infected cells is mediated by interaction with microtubules.

A physical map of the adeno-associated virus type 2 genome has been constructed on the basis of the five fragments produced by the restriction endonucleases HindII + III from Hemophilus influenzae. There are three endo R-HindII cleavage sites and one endo R-HindIII site. Evidence has been obtained to support the existence of two nucleotide sequence permutations in adeno-associated virus DNA, the start points of which have been estimated to be separated by 1% of the genome. The three cleavage fragments produced by endo R-Eco RI have been ordered and oriented with respect to the endo R-HindII + III cleavage map.

Actinophage MSP2 is infectious for Streptomyces venezuelae S13. Based upon electron microscopy of coliphage T4 mixed with MSP2, MSP2 had a head about 48 +/- 2 nm wide and 87 +/- 5 nm long. DNA from polyoma virus and from coliphages T4 and T7 served as reference markers in estimating the molecular weight of MSP2 DNA from sedimentation in sucrose gradients. Denatured MSP2 DNA was estimated to be about 17 x 10(6) and double-stranded MSP2 DNA was about (36 +/- 1.6) x 10(6) in molecular weight.

We herein describe 44 new cases of leukoplakia of the renal pelvis, bladder and urethra. Leukoplakia is uncommon. It occurs twice as often in the bladder as in the pelvis and ureter and it is associated with and perhaps caused by chronic infection. Carcinoma is present in 10 to 20 per cent of the cases at diagnosis. We believe that leukoplakia is not simple squamous metaplasia but a step further down the line--a process that evolved through squamous metaplasia and perhaps could result in cancer. We think leukoplakia is potentially pre-malignant and it should be treated as a low grade and low stage tumor since no satisfactory treatment exists.

While an operation is rarely indicated for a small intrarenal calculi their presence can result in the loss of an individual's career in selected occupations. Because of this problem in military aviators the technique of intrarenal manipulation of these calculi with vascular catheters and guide wires was devised. With this method 2 young fliers were freed of calculi and allowed to resume their chosen career. Additional experience with the procedure is indicated to further delineate its limitations and applications.

A solitary renal caliceal calculus may require surgical management when it becomes symptomatic or is the contributing factor in urinary tract infection. Segmental nephrotomy is an effective approach to remove a solitary calculus accurately with minimal loss of parenchyma. Calirrhaphy may be accomplished simultaneously.

Indications for an operation on renal artery aneurysms include patients 1) with a rupture or an impending rupture, 2) with a possibility of pregnancy, 3) with hypertension and renin differentials suggesting remediable disease and 4) with functional or symptomatic impairment traceable to the aneurysm proper. If the aneurysm is calcified some temporization may be justified, although this observation alone should be only of secondary importance. The size of the aneurysm is likewise generally of secondary value. Of course, the patient's picture and expectancy need balancing in the decision. Conservative management in other situations is acceptable, particularly for the elderly.

Spontaneous rupture of the kidney involves either the collecting system or parenchyma, the latter being associated with a subcapsular or perirenal hematoma. A review was made of 78 cases of spontaneous parenchymal rupture with perirenal hematoma, including 4 of our own. One of these cases is the first description of spontaneous rupture of the kidney secondary to renal vein thrombosis. The patients are usually in the fourth decade of life and present with an acute onset of flank pain, a tender mass and commonly symptoms and signs of shock. Hematuria is often present and generally urography reveals a mass, distorted collecting system and/or non-visualization of the kidney. Tumors are the most common cause followed by vascular diseases, infection, nephritis and blood dyscrasias. Nephrectomy when possible should be performed expeditiously since conservative therapy is uniformly unsuccessful.

The fact that approximately 95 per cent of asymptomatic renal masses are benign is a compelling reason for the streamlined diagnostic approach which is described herein. Within the confines of these guidelines for the study of renal masses, when proceeding from simple to complex methods of evaluation, one should always consider the age of the patient, the status of the cardiovascular system, the radiologic appearance of the mass on drip infusion nephrotomography and the results of renal echography as qualifying determinants and then propose the logical sequence of individualized studies under the best possible circumstances.

Before a ureteral operation is undertaken for dilated, non-refluxing ureters it is essential to determine whether obstruction is present, since an operation is unnecessary and can be hazardous if there is no obstruction or infection. Obstruction is most accurately diagnosed by perfusing the upper tract at a known flow rate and measuring the resulting pressure. This test was performed on 5 patients in whom there was doubt as to the presence of obstruction from the radiographic evidence. In 4 of the 5 patients low pressure was found, the obstruction was excluded and an operation was avoided. In the fifth patient the obstruction was confirmed and relieved. The pressure flow test is useful in the diagnosis or exclusion of obstruction in the upper urinary tract.

In order to diagnose and treat patients with micturitional disturbances it is necessary to obtain as much information as possible about the function of the lower urinary tract in each case. We studied 70 female patients with micturitional disturbances by monitoring pulse, respiration, intrinsic bladder pressure, urine flow rate and volume, and detrusor and sphincter electromyograms during a 2 to 4-hour period. As earlier investigators have shown, there are 2 types of detrusor electromyograms: low frequency and high frequency activity. The low frequency activity is random in nature and has definite patterns in disturbed bladder function. It is a useful diagnostic parameter and, when considered with the results of the sphincter electromyograms and pressure recordings, it provides much diagnostic information in this group of patients. The high frequency activity is similar to that of striated muscle.

Open surgical drainage is not necessary in all patients with bladder rupture. Two patients with an extraperitoneal rupture and 1 with an intraperitoneal rupture were successfully managed with urethral catheter drainage only. Our rationale and specific criteria for this treatment are presented. We believe that in selected patients urethral catheter drainage is a safe, simple and effective method of treating the ruptured bladder.

Patients with bladder tumors underwent a course of topical bladder instillation of 20 mg. mitomycin C in 20 ml. sterilized distilled water 3 times weekly for a total of 20 procedures. In 22 of the 50 patients (44 per cent) the tumors disappeared completely, while in 16 patients (32 per cent) there was partial disappearance and in 12 patients (24 per cent) there was no affect. Therefore, the total effective rate was 76 per cent. We concluded from our studies that mitomycin C topical therapy could be applied to low stage and low grade bladder tumors less than 1 cm. in diameter, without regard to the number of tumors. We now use mitomycin C topical therapy in all cases of bladder tumors. Local bladder reaction was noted in 3 cases but a complete course of therapy was accomplished in each case--in 2 cases without interruption of treatment and in 1 case by delaying treatment for 1 week. Abnormal values of hematocrit, white blood cells and platelets in blood were not observed during therapy.

Specimens obtained after scraping the bladder mucosa were found to be of excellent quality because of the large cell harvest and the minimal inflammatory exudate. In addition, tumor recurrence could be predicted in a significant number of cases with this technique.

Abnormal tryptophan metabolism in patients with bladder carcinoma has been reported to have an extremely high correlation with future tumor recurrences. The methods for determination of these urinary metabolites have not been applicable for routine clinical use in the past. A new method is described using thin layer chromatography followed by fluorescent scanning with the SD 3000 spectrodensitometer. The range of recovery for the 6 tryptophan metabolites was from 96.9 to 106.7 per cent. In our study 31 per cent of the male and 50 per cent of the female bladder cancer patients had 2 or more abnormal tryptophan metabolites.

Urinary carcinoembryonic antigen-like activity was increased (more than 1.5 ng. per ml.) in 61 per cent of patients with transitional cell carcinoma of the bladder. The frequency of abnormal carcinoembryonic antigen values correlated with the extent and the grade of the tumor. However, urinary tract infection can produce abnormal carcinoembryonic antigen values in non-cancer patients. The use of urinary carcinoembryonic antigen measurement and urine cytologic examination for diagnosis of transitional cell carcinoma gave a better diagnostic yield than did use of either test alone. In transitional cell carcinoma patients with abnormal preoperative urinary carcinoembryonic antigen values, postoperative urinary carcinoembryonic antigen values were useful for determining completeness of tumor resection. However, with total cystectomy and creation of an ileal conduit or ureterosigmoidostomy, urinary carcinoembryonic antigen values increased markedly postoperatively. Serum carcinoembryonic antigen values were of little value in the diagnosis of transitional cell carcinoma.

A review was made of 111 spinal cord injury patients who underwent bladder rehabilitation. The essential mode of treatment was intermittent catheterization. About 91 per cent of the patients were free of the catheter after 3 to 168 days of intermittent catheterization. Acute patients given an initial dosage of 30 to 40 mg. bethanechol chloride 3 times daily for 2 to 3 weeks recovered reflex activity in almost half the period (average of 32 days compared to 79 days). Modified sphincterotomy at the bladder neck was performed in 10 patients. This procedure improved the results to 98 per cent catheter-free reflex bladder status in the group of patients.

Intermittent catheterization was used as a method to achieve reflex voiding and a catheter-free status in 111 chronic spinal cord injury patients. Of this group 70 patients achieved reflex (automatic) voiding within 90 days, or a mean of 19 days. Five patients required transurethral incision of the external urethral sphincter after achievement of automatic voiding because of elevated residual urine. Chronic urinary tract infection persisted in 16 per cent of the patients after completion of the program. No sequelae occurred because of the coexistent urinary tract infection. An 18-month followup disclosed stability in renal function and appearance of pyelograms. Urethral, scrotal and bladder complications secondary to chronic indwelling urethral catheters have been eliminated in these patients. Patient endorsement and enthusiasm have been spectacular and have overwhelmingly contributed to an ongoing, successful program.

The mechanism of infertility after high retroperitoneal lymphadenectomy was studied in 36 patients. In 35 patients infertility occurred because of unavoidable seminal vesicular and ductus deferential sympathetic denervation, with consequent aspermia. Potency and orgasm were unchanged in all patients and there was no evidence of retrograde ejaculation. The findings suggest that sympatholytic drugs be studied for possible application as reversible male contraceptives.

Patients with bilateral aplasia of the vas deferens have been considered sterile. In 2 such patients a segment of great saphenous vein, anastomosed to the globus major, was used to accept and store spermatozoa. Aspirations of the venous cap of the patient B at 1 and 4 months revealed numerous sperm with normal morphology and poor motility. At re-exploration of patient A, 4 months after the original venoepididymal procedure, the venous cap was found to be obliterated by scar tissue yet the epididymal tubules remained dilated. A 12-inch segment of the epididymal tubule was compressed between glass slides to obtain sperm in this patient. However, attempted insemination with this sperm was unsuccessful. Our results with the venous cap are disappointing.

The primary objective of our study was to obtain pure cultures of prostatic epithelium. The phenomena of encapsulation by epithelial cells and hypocellularity in stroma occurred when explants of human prostatic tissue were maintained in suspension cultures. Hypocellularity progressed with time and was more pronounced in encapsulated explants. When encapsulated explants were allowed to attach to the substrate they formed an outgrowth of epithelial cells in a monolayer. The significance of these findings is in the use of the described changes in isolating and establishing epithelial cultures of human prostatic epithelium. These cultures are required for studies on the biology of prostatic epithelium and the etiology and treatment of prostatic neoplasia.

In a continuing search for karyotypic changes characterizing various human cancers we have examined in detail with Q and G banding techniques the chromosomal constitution of a metastatic cancer of the prostate. The results obtained with these techniques present not only what is to our knowledge the first description of the chromosome constitution in cancer of the prostate but also the first observation of an isochromosome 17 marker in a cancerous state other than a blood disease. Only further studies on the precise identification of individual chromosomes in other cancers will reveal the significance of this marker in human cancer.

The usefulness of prophylactic diuretic therapy with furosemide was investigated in 6 patients with stages III and IV prostatic cancer who were undergoing diethylstilbestrol therapy. A significant increase was noted in sodium and water excretion, whereas outputs of chloride and potassium, and serum electrolyte concentrations, blood volume, blood pressure and body weight remained unchanged. The results demonstrate the value of diuretics in preventing fluid retention whenever large doses of estrogen are to be used in the treatment of prostatic cancer.

The effects of age, histological grade and clinical extension of carcinoma of the prostate are analyzed in a series of 213 patients with stage C carcinomas treated by total perineal prostatectomy. Survival data and the incidence of local recurrence, distant metastases and deaths from cancer of the prostate are the parameters used for comparison with 132 stage B patients, 70 patients with seminal vesicle invasion and data from the literature. Long-term survivors in the young age group and some long-term survivors with high grade lesions are good arguments for the possible curability of early stage C carcinoma of the prostate by total prostatectomy. Correct surgical staging of these tumors by previous pelvic lymphadenectomy is mandatory.

The add-on ileal loop is a procedure designed to create sufficient ileal conduit length to allow for stomal revision or relocation. We report 3 cases in which the operation was used with satisfactory results and describe the technique. The procedure is simple to perform and has the advantage of leaving a satisfactory functioning ureteroileal anastomosis intact.

A 2 to 16-year followup of 96 ileal conduit urinary diversions in children is discussed. To assess the effect of time on renal function and structure we divided the patients into recent and remote operative groups. Patients with a longer followup (average 11.3 years) had a significantly greater incidence of pyelographic deterioration, particularly from preoperative normal status, compared to patients in the short followup group (average 4.5 years). Preoperative pyelonephritis was associated with a small but significant percentage of patients who progressed to poor renal function. Three potentially preventable and correctable late complications--stomal stenosis, excessive conduit length and ureteroileal obstruction--were associated with significant long-term deterioration in either renal function or pyelographic appearance. By using ileal conduit urinary diversion in children we attempt to provide a lifelong solution to urologic and social problems. The pyelographic deterioration rates would suggest that the solution is not perfect. Alternative forms of treatment need similar assessment for comparison. Patients who have ileal conduit urinary diversion need vigilant lifelong followup with accurate assessment of renal function, infection and pyelographic status to prevent or arrest renal deterioration.

A study of the long-term results of ileal conduit urinary diversion for non-malignant disease in 90 children has shown that there were 75 survivors after 10 to 16 years. Stomal stenosis and ureteroileal or other intrinsic obstructions requiring ileal loop revisions occurred frequently and as late as 13 years postoperatively. Of 144 renal units 76 per cent improved or remained stable and 69.3 per cent of normal kidneys remained normal after more than a decade of urinary diversion. In order to obtain these results close lifetime followup and aggressive loop revisions have been required. Urine cultures were consistently negative in 70.5 per cent of all patients. Good results were obtained in terms of preservation of renal function in all categories. Creatinine clearance remained in the normal range after 10 years if the excretory urogram remained normal. Ileal conduit urinary diversion remains a major surgical undertaking but it also remains the standard of urinary diversion against which all other methods must be judged. The results in terms of renal preservation are impressive but so too are the significant number of long-term complications. Any other method of diversion (such as the sigmoid conduit) that can improve upon these results will be welcomed. All children with ileal conduit urinary diversion for reasons other than a neurogenic bladder must be considered candidates for urinary reconstruction.

Gross, painless hematuria as the only symptom in a 53-year-old male diabetic necessitated partial nephrectomy and was then found to have been caused by atheromatous embolism associated with recent infarction of the renal parenchyma. This case appears to be the first one reported in which the diagnosis of renal atheromatous embolization had been established intravitam. A similar episode of hematuria occurred a year postoperatively and another renal infarction, likely caused by atheromatous embolization, was demonstrable with tomographic and angiographic techniques.

The low incidence of embryonal rhabdomyosarcoma prevents any one person or institution from presenting any meaningful data in the form of effective treatment based on clinical experience. We realize that this is an antidotal case but the stakes are high when treating any malignancy of the young. Therefore, we advocate early and aggressive therapy using all modalities of treatments, and cite this case which initially seemed hopeless but to date has all the hallmarks of a cure.

In evaluation of cardiac function by the non-invasive method, the possibility of separation of cardiac muscle performance from cardiac pump performance was studied. Among the non-invasive values, SV/ET, SV/(AO/EO), Pd/ICT, Pd/PEP, 1/ICT2, ET/PEP, and ET/ICT were considered as parameters for myocardial contractility. This research especially focused on Pd/ICT and ET/PEP. In auricular fibrillation it was possible to draw Starling-like curves and 3 dimensional coordinates to estimate a Vmax-like value. However this method could not be used in sinus rhythm. Whereas, in hypertension with abnormal afterload and uremia with abnormal preload, myocardial contractility was expressed by Pd/ICT under the influence of almost pure preload and ET/PEP under the influence of both preload and afterload. Therefore Pd/ICT was corrected with preload (AO/EO) and (Pd/ICT)/(AO/EO) may be used as the index for myocardial contractility.

Statistical analysis of the realtion between blood pressure and renal function in 421 patients with CGN, referred to the Second Internal Medicine at Nihon University Hospital, and in 253 Hypertensive patients with CGN by questionaires sent to 29 Medical Universities were investigated. The relationship between survival rate and blood pressure of 84 patients with CGN in Surugadai Nihon University Hospital was also examined. These data show that antihypertensive therapy for CGN with hypertension has an important effect on prognosis. Propranolol was given to 10 hypertensive patients with CGN and hypotensive effect on renal function was observed. Our experience suggests that propranolol may be useful for treating a high renin component in the hypertension with non renal failure, and renal function does not become worse. But in renal failure, propranolol therapy must be used carefully because of inducement to cardiac failure.

The difference of the prognosis between essential and renal hypertension (chronic glomerulonephritis) was examined by compairing the survival rate of the patients, and the effect of lability of blood pressure and the effect of the response to hypotensive drugs on the prognosis of the two types of hypertension was observed. The prognosis of renal hypertensives was remarkedly worse when it was compaired with the prognosis of essential hypertensives. More then 80% of the latter was still alive after ten years, while the mortality rate of the former after 5 years was only 20%. Each factor of severity (diastolic pressure, optic fundi, cardiac, cerebrovascular and renal complication) in non severe patients (group O-II) did not differently affect the survival rate of both hypertensives. Diverse prognosis was observed in severe patients (group III-IV), depending on each factor of severity. In renal hypertension the survival rate was extremely low when the patients had high diastolic pressure, severe cardiac and cerebrovascular complication. It was not so low in the patients with severe ophthalmoscopic change. The prognosis of essential hypertension was poor in the order of severe cerebrovascular complication, renal complication and cardiac complication. The survival rate of the patients with high diastolic pressure or severe ophthalmoscopic change was considerably high. The patients with both renal and essential hypertension showed greater survival rate when the blood pressure was much more reduced by bed rest or antihypertensive drugs during the first hospitalization.

Incidence of hypertension in chronic glomerulonephritis and its influence on the clinical course of the disease were studied using statistic technique, especially that of Markovian process. 1. Incidence of hypertension in a total of 283 cases was 15.2%, while in the patients of which renal function reduced to approximately one half of the normal was about 50%. 2. The average of blood pressure in this disease tends to elevate with the decrease in 15 minute value of PSP excretion test and with the increasing serum creatinine level, although the variations are large. 3. After a fall of renal function to approximately one-third of the normal, the rate of clinical course is markedly rapid. 4. The prognosis of the progressive type of chronic glomerulonephritis is obviously affected to be shorten by the presence of hypertension. 5. According to the results obtained by the Markovian approach, survival years of the patients with wide range of renal function can be predicted with relative accuracy.

The plasma renin activity in both peripheral venous blood and the renal vein of the involved kidney showed high values. Angiotensin infusion elevated the urine volume and angiotensin excretion on the intact side, and the difference in urine volume and angiotensin excretion between the two sides was accentuated after angiotensin infusion. These findings are useful for the diagnosis of the stenotic side in renovascular hypertension. No difference in the prognosis of extirpation of the involved kidney and of vascular reconstruction of the stenotic artery was found for the treatment of renovascular hypertension. However, autotransplantation of the involved kidney was found to be more useful, since it allowed improvement of renal circulation, suppression of thrombosis formation, and the maintenance of kidney tissue.

Since the discovery of cephalothin in 1962, many semi-synthetic cephalosporins have appeared. To choose the most suitable drug for the clinical treatment of infections, the characteristics of these antibiotics must be sufficiently understood. When cephalosporins which are or will be commercially available are divided into two categories, one consists of cephaloridine, cefazolin and cephalexin which are comparatively stable in the living body; and the other cephalothin, cephaloglycin, cephapirin and cephacetrile which are metabolized into desacetyl compounds with low antibacterial activity. In this study, the author compared the absorption, excretion and some other properties of cefazolin and cephalothin, (widely used clinically), and cephapirin (still under study in Japan).

When the antibacterial substances of cephalothin and cephapirin in the serum and urine after intramuscular injection were separated and assayed, desacetyl metabolities of both drugs were detected. These tendencies were especially apparent in the tissue concentrations. When both the drugs were given intravenously to healthy volunteers, the amounts of their desacetyl metabolites were not greater in man than in rats.

Mode of left ventricular contraction was studied by cine left ventriculography in 22 cases with mitral valve diseases and 7 control cases. In rheumatic mitral valve diseases, local hypokinesis of the left ventricular wall and poor contraction of the mitral annulus were observed frequently, at various location and to various extent. Transient asynergic motion of local wall was also seen either during systole or during diastole. Local hypokinesis was seen even in normal-sized left ventricles, and was associated with decreased cardiac pump performance, when its localization was extensive. Severe mitral regurgitation of rheumatic nature was always associated with poor contraction of the mitral annulus, although the reverse was not true.

A total of 14 cases of papillary muscle dysfunction have been observed in Ehlers Danlos syndrome. Five patients had clinically identifiable syndrome of prolapsing mitral leaflets. This form of rare interesting cardiovascular abnormality in Ehlers Danlos syndrome is discussed. The relevant literature is reviewed.

The systematic nonlinearity exhibited in a comparison of 2 commonly used electrocardiographic lead-systems, when the net QRS axis-angle from one system is plotted against the other, is quantitatively analyzed. A family of nonlinear correlation curves is implemented using the ratio of 2 correction factors, fc/fo, as a parameter. Such curves, replacing linear regression lines, provide a more realistic representation of the actual problem of this type. Between the Frank and the 12-lead systems, the value of fc/fo is found to be 0.53 for the frontal plane from a sample of 1,000 subjects. The combination of correction factors, fc=1.155 and fo=2.18, is a possibility among countless others to make up the same fc/fo of 0.53. Appreciable improvement in axis correlation is demonstrated after the data are corrected by such factors.

Arterial pressure, cardiac output, and total peripheral resistance were compared between spontaneously hypertensive rats (SHR) and normotensive control rats (NCR) at 4, 7, and 12 months of age. The rats were anesthetized with pentobarbital sodium, thoracotomized and kept under positive pressure respiration. Cardiac output was measured with an electromagnetic flowmeter probe placed at the ascending aorta. On all the age groups, arterial pressure and total peripheral resistance were significantly higher in SHR than in NCR, while cardiac output per body weight was not different. However, the significant differences in pressure and resistance at each age disappeared after ganglion blockade with hexamethonium bromide. Total peripheral resistance was not higher in SHR than in NCR even after cardiac output, which had once been diminished by blockade, was restored to the pre-blockade level by dextran infusion. Phenoxybenzamine, an alpha adrenergic receptor blocker, also equalized arterial pressure and total peripheral resistance between SHR and NCR, both aged about 10 months, without decrease in cardiac output. It is concluded that, in both young and old SHR's, the hypertensive state is maintained by an increase in total peripheral resistance ascribable to sympathetic activity.

The effect of electrical stimulation of the efferent cardiac sympathetic nerves on activity of afferent cardiac fibers in the sympathetic nerves and coronary hemodynamics of anesthetized dogs has been examined. During partial constriction of the coronary artery, a brief stimulation of the efferent cardiac sympathetic nerves resulted in sustained excitation of the afferent fibers and a sustained decrease in blood flow of the constricted artery which were associated with systolic bulge of the left ventricle and elevation of the ST segment of electrocardiogram. These changes were not produced without constriction. Pretreatment with phentolamine suppressed excitation of the afferent fibers, development of systolic bulge and elevation of the ST segment. Also, the decrease in coronary blood flow induced by stimulation was replaced by an increase after the administration of the agent. Propranolol suppressed excitation of the fibers, systolic bulge and elevation of the ST segment, but could not eliminate the decrease in blood flow. The results indicate that sympathetic stimulation caused a decrease in coronary blood flow through excitation of the alpha-adrenergic receptors while increasing cardiac work load and energy requirements through excitation of the beta-adrenergic receptors, leading to more severe myocardial ischemia and excitation of the afferent fibers.

Hemodynamic effects of dopamine were studied on 30 open-chest dogs with experimental myocardial infarction. These dogs were divided into 3 groups. Three different doses of intravenous dopamine, 5, 10, and 20 mug/Kg/min, were administered for 30 min. Heart rate and myocardial contractility were increased dose-dependently. Total peripheral vascular resistance was reduced with 5 or 10 mug/Kg/min of dopamine. With 20 mug/Kg/min of dopamine, it became the lowest 5 min after the initiation of infusion but increased above the control value 20 min after the start of administration. Renal vascular resistance was decreased with 5 mug/Kg/min of dopamine but increased with 20 mug/Kg/min. These results suggested that this drug would be useful for treatment of shock state.

Two cases of hypertensive pulmonary vascular disease with Raynaud's phenomenon are reported. One is a 32-year-old housewife of primary pulmonary hypertension with some immunological disorders and the other is a 28-year-old female of systemic lupus erythematosus. It may be considered that some immunological process could play a role in the etiology of some cases of primary pulmonary hypertension and the relationship of pathogenesis between these 2 cases was discussed.

Clinical and experimental studies were carried out in order to evaluate the role of myocardial dysfunction in the genesis of circulatory congestion associated with renal failure. Among the patients with chronic renal failure, those with circulatory congestion had greater blood volume and higher venous pressure while lower cardiac index and stroke work index than those without circulatory congestion. After peritoneal dialysis, although blood volume and venous pressure decreased in both groups, cardiac index increased in the former while it decreased in the latter group. In 15 dogs, acute renal failure was produced by ligating both ureters. As uremia developed, blood volume and left ventricular end-diastolic pressure increased with or without an increase in cardiac index. The depression of ventricular function curve was evident in all the dogs. The peritoneal dialysis performed at this stage resulted in a prompt recovery of left ventricular end-diastolic pressure with minimum change in cardiac index. The measurement of dp/dt/IIT also indicated a depression of myocardial contractility at uremic stage and its recovery after dialysis. We conclude that impairment of myocardial function is implicated in the development of circulatory congestion in renal failure.

The effect of vagal stimulation on activity of afferent sympathetic nerve fibers from the dog's left ventricle has been examined. During partial constriction of the coronary artery, a brief electrical stimulation of the cervical vagus nerves resulted in a decrease in blood flow of the constricted artery, systolic bulge of the left ventricle, elevation of the ST segment of electrocardiogram and excitation of the afferent nerve fibers, which continued for up to 15 min. These changes were not produced without coronary artery constriction. Intravenous injection of phentolamine eliminated the decrease in blood flow, and suppressed systolic bulge, elevation of the ST segment and excitation of afferent fibers. Propranolol could not eliminate the decrease in blood flow while suppressed the other changes. Atropine eliminated all of these changes. The results indicate participation of adrenergic alpha-receptors in sustained decrease of coronary blood flow and excitation of afferent cardiac sympathetic nerve fibers which can be produced by a brief vagal excitation.

Although the recordings of the His potential have been shown to be very useful in the study of cardiac conduction and rhythm disturbances, there remain some problems regarding the clinical His bundle electrogram. Some of the studies were performed to solve in the perfused dog hearts and in situ dog hearts, and consequently the following results were obtained. In some experiments, recording of the His potential could not be achieved even in the perfused hearts in spite of the preserved A-V conduction, suggesting that, as experienced sometimes in the clinical cases, inability to record the His potential might not be due to the technical failure or the anatomical abnormalities of the His bundle. On the other hand, real "splitting of H" occurred in association with the increase in the duration and decrease in the amplitude of the His potential after the ligation of the anterior septal artery. In addition, the true Mobitz II type A-H block, and Wenckebach type intra-Hisian and H-V block could be produced experimentally.

Acute responses of blood pressure and turnover of norepinephrine in the brain to intracisternally injected guanethidine were studied in rats. Systolic blood pressure in guanethidine-treated rats showed a dose-relating rise for over 9 hrs, while norepinephrine contents in cortex-cerebellum, brain stem and heart were not affected. The endogenous norepinephrine in brain samples, however, did not decrease against alpha-methyl-p-tyrosine to result in regression coefficients significantly different from those in the saline-treated group whereas norepinephrine in heart was reduced similarly in the 2 groups, indicating a slowered turnover of norepinephrine selectively in the brain. The results may indicate that the retarded norepinephrine turnover in the brain is causatively related with an acute elevation in blood pressure.

Short-term, repeated myocardial ischemia was produced in 20 opened-chest anesthetized dogs by left anterior descending (LAD) branch occlusion. Left ventricular pressure (LVP) and its dP/dt were recorded by Satham SF-1 transducer, and isometric local force (F) was measured by a Walton-Brodie strain gauge arch sewn onto LV free wall. In all experiments, within a few beats after LAD occlusion, peak negative dP/dt started to diminish its amplitude, reaching a nadir after 20-30 sec (63 +/- 5% of control, 9 dogs). It recovered to 83 +/- 3% of control level in 45 sec and remained essentially unchanged thereafter. This change preceded those of LVP and max dP/dt, which showed only minor falls. In 6 dogs, changes by occluding root of LAD were compared with those by its branch occlusion. The greater the extent of ischemia, the more marked and prolonged were the changes. While F in the ischemic center (Fc) rapidly lost its contractile activity following LAD occlusion, F in marginal zone between infarcted and non-infarcted region (Fm) showed variable extent and different time-course of its diminution. Thus, it was concluded that the change in peak negative dP/dt following LAD occlusion was one of the sensitive signs of early ischemic changes, and was attributed at least in part to characteristic changes in contractile activity of myocardium surrounding the ischemic injury.

A 14-year-old boy, admitted with intractable chest pain, was found to have an enlarged heart and calcification in the apical region, with electrocardiographic features of massive inferolateral myocardial infarction. Left ventricular angiography revealed a large left ventricular aneurysm. He died following resection of the aneurysm and post mortem examination showed changes of a non-specific chronic myocarditis. A vasculitis involving small coronary arterioles was also found in the vicinity of the aneurysm, and the possibility of a rheumatic vasculitis was suggested by a transient episode of an erythema marginatum-like eruption. It is concluded that the association of infarction pattern on the electrocardiogram together with calcification of the heart in children is highly suggestive of a ventricular aneurysm secondary to a myocarditis or a vasculitis involving small, intramyocardial branches of the coronary arteries.

The Romano-Ward syndrome is very rare as hereditary disease. Only 5 families have been reported in Japan before the present report. The patient, a 15-year-old female, had been treated for epilepsy due to syncopal attacks. Electrocardiography revealed occurrence of an augmented and labile U wave and prolongation of the Q-T interval, with recordings of frequent multifocal extrasystoles and transient ventricular fibrillation. Also noticed was sinus bradycardia. Clinical examinations presented no results coinciding with those specific ECG findings. It was inferred through surveys of her family tree that the present case had an autosomal dominant trait, heterozygously affected through the male line. Severe arrhythmias detected on her ECGs were suppressed by oral administration of 30 mg/day propranolol. Judging from the fact, propranolol may be the first to be administered among a variety of anti-arrhythmic agents in the Romano-Ward syndrome.

An electrocardiogram (ECG) of bilateral bundle branch block (BBBB) which may be attributable to a mixture of 2 : 1 and 3 : 1 atrioventricular (A-V) block is described. The irregularity of QRS complexes with left bundle branch block (LBBB) pattern during 2 : 1 A-V block may be ascribable to "Wenckebach periods", which might be due either to A-V nodal or His bundle or bundle branch delay. However, it was impossible to distinguish between them precisely because appropriate His bundle studies were not performed during the active arrhythmic phase. Although the exact mechanism involved were not established with certainty, different rates of recovery in conduction in the bundle branches in association with a marked prolongation of the refractoriness would seem to be the unique feature of this complex arrhythmia. An ECG tracing of BBBB indicating high grade second degree (2 : 1 and 3 : 1) A-V block, in which "spontaneous" occurrence of "Wenckebach periods" with 2 consecutive blocked P waves can be observed during 2 : 1 A-V block, has never been reported previously as far as can be ascertained from published records.