Traditional criteria as predictors of minority student success in medical school. There have been many reports stating that the traditional criteria of the Medical College Admission Test (MCAT) and undergraduate grade-point average (GPA) have little, if any, value in predicting success in the preclinical years of medical school among students from underrepresented (racial and ethnic) minority groups. In contrast to previous articles this report emphasizes that traditional criteria and the quality of the undergraduate college attended are of some statistical value in predicting success in the preclinical years of medical school among accepted students from under represented minority groups. Of these criteria, the one with the greatest predictive value is the selectivity of the undergraduate college attended.


An attempt to predict graduation from medical school. Although there is less attrition from medical school now than in prior years, 500 or more students can be expected to withdraw from American medical schools during each academic year. Continuing study of the problem is, therefore, warranted. Personality inventory, cognitive, and application data, all gathered at the time of admission, were examined for 1,014 graduates and 57 dropouts; separate analyses were conducted for the 17 who departed for academic reasons and the 40 whose attrition was attributable to other causes. Correlational analyses were also conducted in which graduates, nonacademic dropouts, and academic dropouts were scaled in a 4-3-1 continuum. The best predictor of this graduation versus dropout hierarchy was given by a six-variable combination, including scores on the Quantitative ability subtest of the Medical College Admission Test and premedical grades for the last two terms, with positive weightings; personality inventory scales for status potential, socialization, and communality, also with positive weightings; and a personality scale for conformist achievement drive, weighted negatively.


Student evaluations of professors: are they of value? Recent studies of the validity of student ratings of teaching leave much to be desired. Five of these studies are evaluated on the basis of adequacy of design, validity, and generalizability; and one of the studies is used as a model for further inquiry in this area. It is then argued that student evaluations of teaching can provide useful information relevant to the improvement of instruction. However, in order to use such evaluations, improved methods of data collection and analysis are needed. A primary improvement would be in the area of generalizability. A plan for expanding the use of student evaluations from personal utility to general applicability is outlined.


Continuity of care in a university-based practice. Effects of changes in a pediatric practice--expansion of the number of pediatricians and incorporation into a university hospital setting--on continuity of care and utilization were examined by means of a longitudinal study of a sample of 63 families. Continuity of care was measured by the following index: the number of visits with own physician divided by the total number of pediatric visits per year. Although continuity of well-child visits remained unchanged at the university setting, the continuity of sick visits declined markedly. An increased use of doctor visits for illness care was observed; its relationship with the decline in continuity is analyzed and discussed. While continuity is inherent in a small partnership practice, it is not so in a larger medical organization, particularly when involvement in patient care is part time. In such an organization, deliberate arrangements that enable patients with acute needs to receive care from their own doctors are needed.


The progression and evaluation of hetatologic and serum biochemical values in the chimpanzee. Summary statistics of various hematologic and serum biochemical measures are presented for a colony of 74 chimpanzees (Pan troglodytes). Covariance analysis of longitudinal values revealed a progression of some measures with maturity. Equations for evaluating these measures as they relate to the health of individual colony members and new additions to the colony were formulated. From these equations, confidence bounds (95%), which can be regarded as normative ranges, were established for each of the measures. The literature on hematologic and serum biochemical values in the chimpanzee, especially as they pertain to the evaluation and progression of values, is reviewed.


Cation effects on volume and water permeability in the halophilic algae Dunaliella parva. Rates of change of cell volume were measured in suspensions of the halophilic green algae Dunaliella parva subjected to changes in cation composition and concentration of the outside medium. Measurements were made with a particle size analyzer and results were checked by direct microphotography. For any one salt solution, changes in cell volume with concentration were consistent with the Boyle-Van't Hoff model of an osmometer. Nonosmotic volume comprised 60-80% of total cell volume and was sensitive to the nature of the cation, increasing in the order Cs less than K less than Na less than Ca less than Mg. Kinetics of volume change in response to changes in outside salt concentration are best described by two kinetic coefficients differing by one order of magnitude and dependent on the nature of the outside cation (decreasing in order Cs greater than K greater than Na greater than Mg) as well as on direction of water flow.


Axonal surface charges: evidence for phosphate structure. The effect of different extracellular alkaline-earth cations (Ca2+, Mg2+, Sr2+, Ba2+) upon the threshold membrane potential for spike initiation in crayfish axon has been studied by means of intracellular microelectrodes. This was done at the following extracellular concentrations of the divalent uranyl ion (UO2/2+): 1.0 X 10(-6) M, 3.0 X 10(-6) M, and 9.0 X 10(-6) M. At each concentration employed, extensive neutralization of axonal surface charges by UO2/2+ was evidenced by the fact that equal concentrations (50 mM) of alkaline-earth cations did not have the same effect on the threshold potential. The selectivity sequences observed at the different uranyl-ion concentrations were: 1.0 X 10(-6) M UO2/2+, Ca2+ greater than Mg2+ greater than Sr2+ greater than Ba2+; 3.0 X 10(-6) M UO2/2+, Ca2+ greater than Mg2+ greater than Ba2+ larger than or equal to Sr2+; 9.0 X 10(-6) M UO2/2+, Ca2+ approximately Ba2+ greater than Sr2+ greater than Mg2+. These selectivity sequences are in accord with the equilibrium selectivity theory for alkaline-earth cations. At each of the concentrations used, uranyl ion did not have any detectable effect on the actual shape of the action potential itself. It is concluded that many (if not most) of the surface acidic groups in the region of the sodium gates represent phosphate groups of membrane phospholipids, but that the m gates themselves are probably protein-aceous in structure.


Ionic fluxes in isolated epithelial cells of the abdominal skin of the frog Leptodactylus ocellatus. Unidirectional ion fluxes are measured in cells isolated by a trypsination-dissection method from the epithelium of the frog Leptodactylus ocellatus. Potassium seems to be contained in a single cellular compartment. The influx of potassium is 0.0068 mumole min-1 mg-1 of dry weight and is carried by a ouabain-sensitive pump. Sodium seems to be contained in two cellular compartments, one of which does not exchange its Na within the experimental period. The possibility that these compartments reflect the existence of different types of cells is not discarded. 49% of the rate constant for the Na efflux is ouabain-sensitive and 23% is ethacrynic-sensitive. Under control conditions the permeability to potassium (PK), sodium (PNa) and chloride (PC1) are 7.6 X 10(-5), 2.6 X 10(-5) and 2.8 X 10(-5) liters/min mg, respectively. The value of PNa is much higher than predicted by current electrical models of the epithelium. The discrepancy might offer some insight into the nature of the "inner facing barrier" of the skin.


Sodium-calcium exchange and calcium-calcium exchange in internally dialyzed squid giant axons. The influx and efflux of calcium (as 45Ca) and influx of sodium (as 24Na) were studied in internally dialyzed squid giant axons. The axons were poisoned with cyanide and ATP was omitted from the dialysis fluid. The internal ionized Ca2+ concentration ([Ca2+]i) was controlled with Ca-EGTA buffers. With [Ca2+]i greater than 0.5 muM, 45Ca efflux was largely dependent upon external Na and Ca. The Nao-dependent Ca efflux into Ca-free media appeared to saturate as [Ca2+]i was increased to 160 muM; the half-saturation concentration was about 8 muM Ca2+. In two experiments 24Na influx was measured; when [Ca2+]i was decreased from 160 muM to less than 0.5 muM, Na influx declined by about 5 pmoles/cm2 sec. The Nao-dependent Ca efflux averaged 1.6 pmoles/cm2 sec in axons with a [Ca2+]i of 160 muM, and was negligible in axons with a [Ca2+]i of less than 0.5 muM. Taken together, the Na influx and Ca efflux data may indicate that the fluxes are coupled with a stoichiometry of about 3 Na+-to-1 Ca2+. Ca efflux into Na-free media required the presence of both Ca and an alkali metal ion (but not Cs) in the external medium. Ca influx from Li-containing media was greatly reduced when [Ca2+]i was decreased from 160 to 0.23 muM, or when external Li was replaced by choline. These data provide evidence for a Ca-Ca exchange mechanism which is activated by certain alkali metal ions. The observations are consistent with a mobile carrier mechanism which can exchange Ca2+ ions from the axoplasm for either 3 Na+ ions, or one Ca2+ and an alkali metal ion (but not Cs) from the external medium. This mechanism may utilize energy from the Na electrochemical gradient to help extrude Ca against an electrochemical gradient.


Comparison of some permeability properties of rat liver slices, liver cells in suspension, and in vivo-produced aggregates of dispersed liver cells. It has been reported earlier that when rat liver is dispersed to a single cell  suspension, the parenchymal cells lose the ability to take up pyrimidine bases but acquire the ability to take up RNAase and macromolecular nucleic acids. It is now shown that these changes are largely reversed on intraperitoneal reaggregation of the parenchymal cells and that, in these respects, the aggregates behave more like the organized tissue than like the dispersed cells.


Effect of cell concentration on the uptake of amino acids by rat liver parenchymal cells in suspension. The accumulation of several amino acids in the acid-soluble fraction and their incorporation into protein in rat liver parenchymal cell suspensions, has been shown to depend on the concentration of cells in the incubation medium; the uptake, both in the acid-soluble and the acid-insoluble fractions, decreased as the cell concentration increased from 0.03 X 10(6) cells/ml upwards, reaching a plateau at high cell concentrations (3-5 X 10(6) cells/ml). The uptake values at high cell concentrations were the same as those obtained in liver slices in which a similar effect was not observed. Evidence is presented which suggests that this phenomenon is mediated by a material released from the cells in suspension, which is inhibitory to enhancement of the uptake of amino acids by these cells over and above the value obtained in normal, adult liver slices.


The post-natal development of holocrine epidermal specializations in gekkonid lizards. The abdominal escutcheon, and certain aspects of pre-anal organ morphology, have been studied in Sphaerodactylus spp. and Gekko vittatus respectively. These epidermal modifications are male characteristics. The sphaerodactyline escutcheon becomes larger by the peripheral addition of specialized scales with increasing size of the individuals: this relationship is much more clearcut in S. cinereus than in the notatus species group (sensu Shreves, '68), and the possible reasons for this are discussed. The number of pre-anal organs varies between populations of G. vittatus, but within populations remains constant throughout life. Individual organs increase steadily in size throughout life. These data are discussed with reference to current interpretations of gekkonid gland evolution, and of factors controlling epidermal cell proliferation and differentiation.


Morphology of lymphoid organs in a cichlid teleost, Tilapia mossambica (Peters). In Tilapia mossambica organized lymphoid tissues are present in the thymus, head-kidney and spleen, whereas they are lacking in pericardial tissue, liver, mesonephros, intestine and rectum. No lymphoid tissue was observed in the chondrocranium and cartilaginous viscerocranium of young adults. The thymus in Tilapia is encapsulated by thin strands of collagen fibers and consists of outer, middle and inner zones. While middle and inner zones are comparable to the thymic cortex and medulla of higher vertebrates, the homology of the outer zone is not clear. At the anterior end of the thymus, a loose aggregation of lymphocytes without a definite boundary has been observed. The head-kidney is characterized by the presence of lymphoid follicles, a subcapsular sinus, a hilus-like area and lymphatic vessels. The spleen is grossly divisible into white pulp and red pulp; the white pulp contains only a reticular area without definite lymphoid centers and the latter contains predominantly erythrocytes. Morphological changes in the lymphoid organs associated with immune response have been discussed.


The microscopic anatomy of epidermal glands in two species of gekkonine lizards, with some observations on testicular activity. The gross and microscopic anatomy of epidermal glands has been studied in laboratory maintained tokays (Gekko gecko), and house geckos (Hemidactylus bowringii) captured from the wild throughout the year. Annual testicular activity in the house gecko has also been studied. While no significant differences in glandular development at various times have been observed in G. gecko, there are clear-cut annual cycles in H. bowringii. The evolution of epidermal glands in gekkonid lizards is reviewed; the cellular dynamics of beta-glands are compared with those of unspecialized epidermis; the possibility that gekkonine epidermal glands respond to quantitative variation in circulating testosterone titers is discussed.


An ultrastructural study of adhesive junctions in reaggregates of unincubated chick embryos. Cell suspensions obtained by the dissociation of unincubated chick embryo blastoderms were allowed to reaggregate on a gyratory shaker for 24-48 hours. The reaggregates which form during this period consist of an inner phase of tightly packed cohesive cells surrounded by an external phase of loosely packed cells. This sorted out arrangement achieves its definitive form between 24 and 48 hours of rotation culture. It was determined that the external phase consists of primitive ectoderm and that the internal phase consists of primitive endoderm. Both 24- and 48-hour reaggregates were examined in the electron microscope and observations were directed to areas of close membrane apposition between cells. In 48-hour reaggregates, primitive endoderm cells were joined by many specialized junctions (desmosomes). The formation of desmosomes in reaggregates of dissociated unincubated chick embryo cells was correlated with the sorting out process.


Development of the head skeleton and pectoral girdle in Esox. A consideration of head development in two species of Esox, lucius and americanus (ssp. vermiculatus) representing the two subgenera Esox and Kenozoa respectively, focused on the significance of the variations of the latero-sensory canal system, its associated bones, and other skeletal elements. In living forms only aspects of "regression" or specialization can be studied. Canals tend to be reduced to pit lines first at their termini but can be broken in their course. Pit lines range from nearly canals to surface structures, or even fail to develop. The number of neuromasts varies. Canal bones develop from two centers: neuromast related and deeper membranous centers which may have no relationship to neuromasts. Tooth-bearing and non-canal-related dermal bones have only membranous (original) centers. The number of neuromasts associated with a bone usually does not affect its development or form. In the case of the circumorbital bones, the extrascapulars, and the nasal, a one to one relationship has developed by regression--towards the development of the latero-sensory component only. The idea that reductions in bone number are commonly traceable to fusion is rejected although examples of fusion are know. Most bones that disappear are simply lost (no blastema or other evidence of their presence seen in development). The relationship between dermal bone and chondral bone is examined and there is evidence of the former giving rise to the latter. The ontogenic order of appearances shows a feeding (functional) correlation.


Organization of the teleostean nucleus rotundus. The nucleus rotundus of 21 species of teleosts was studied by a modified Bodian and the Golgi method to clarify the histological organization, with special reference to the cell lamination and the glomerular formation. The common components of the nucleus in all species are as follows: a thick fiber bundle which comes from the commissura horizontalis and enters the nucleus from the dorsal surface, many small cells, large cells, glomeruli, and a surrounding fibrous capsule. The nuclei of all species studied are classified into three types mainly on the distribution of the small cells, and to a lesser degree on the location of the large cells and the glomeruli. The first type of nucleus has small cells, large cells and glomeruli throughout its extent. In the second type of nucleus, many small cells form a peripheral cell layer, while the large cells and glomeruli are found all over the nucleus. The third type of nucleus is clearly laminated. It is composed of four layers arranged concentrically around a central fiber net in the following order: a glomerular layer, a fibrous layer, a small-cell layer, and a peripheral fibrous capsule. In some species, the large cells are located in the fibrous capsule, and all glomeruli contain a star-like structure, which corresponds to the tips of the large cell dendrites.


Sex steroids and epidermal glands in two species of gekkonine lizards. In vivo and in vitro experiments on the endocrine relationships of epidermal glands in the tokay Gekko gecko, and the common house gecko Hemidactylus bowringii are reported. The results show that certain aspects of beta-gland differentiation involve a synergistic action between androgens and those hormones responsible for controlling the normal shedding cycle, while other aspects are solely under androgenic control. Pre-anal organ activity appears to be solely under androgenic control.


The structure and evolution of parvalbumins. I. Amino acid compositional studies of parvalbumins from four perciform species. 1. Parvalbumins were isolated from the white muscle of Cynoscion regalis, Leiostomus xanthurus, and Menticirrhus americanus of the Sciaenidae and Pomatomus saltatrix of the Pomatomidae. 2. Menticirrhus contains three isoparvalbumins. The other species contain two isoparvalbumins which are designated "fast" and "slow" in accord with their electrophoretic mobilities. Measurements of the denatured molecular weights show the "slow" isoparvalbumins have slightly larger apparent molecular weights, but all apparent molecular weights are in the range 10,400-14,000. 3. Amino acid compositional studies indicate that the fast and slow isoparvalbumins in these fish represent two distinct evolutionary lineages which appear to be evolving at different rates.


Triple helices formed by polyuridylic acid with some adenosine derivatives. We have prepared a variety of derivatives of adenosine which, at neutral pH's, carry protonated amine functions. These derivatives form stable helical structures with polyuridylic acid, but the melting points are not substantially higher than those of helical complexes formed by adenosine derivatives lacking cationic groups.


Intrinsic asymmetry of oligomer transitions and biomolecular evolution. Structural transitions in oligomeric proteins due to ligand binding are important in biomolecular regulatory processes. The transitions may occur on the secondary, tertiary or quarternary structure levels. Detailed consideration of the time sequence of ligand binding to the oligomer shows that there is an intrinsic dynamic asymmetry in all oligomer transitions, even if the initial and the final state are completely symmetric. This asymmetry has important bearing on the evolution and the divergence of the primary structure (amino acid sequence) of oligomeric proteins. It may explain (at least in part) the occurrence of oligomeric proteins with similar but not identical protomers. Certain specific groups of oligomers are shown to be under greater evolutionary pressure for protomer structure divergence. The dynamic asymmetry of oligomer transitions also results in higher complexity in reaction kinetics. Some implications on ribosome structural evolution are discussed.


Optimal design of feedback control by inhibition: dynamic considerations. The local stability of unbranched biosynthetic pathways is examined by mathematical analysis and computer simulation using a novel nonlinear formalism that appears to accurately describe biochemical systems.  Four factors affecting the stability are examined: strength of feedback inhibition, equalization of the values among the corresponding kinetic parameters for the reactions of the pathway, pathway length, and alternative patterns of feedback interactions. The strength of inhibition and the pattern of feedback interactions are important determinants of steady-state behavior.  The simple pattern of end-product inhibition in unbranched pathways may have evolved because it optimizes the steady-state behavior and is temporally most responsive to change.  Stability in these simple systems is achieved by shortening pathway length either physically or, in the case of necessarily long pathways, kinetically by a wide devergence in the values of the corresponding kinetic parameters for the reactions of the pathway.  These conclusions are discussed in the light of available experimental evidence.


Ultraviolet-gas phase and -photocatalytic synthesis from CO and NH3. The major photoproduct obtained on irradiation of gaseous NH3 and CO mixtures is ammonium cyanate; lesser amounts of urea, biurea, biuret semi-carbazide, formamide and cyanide were observed.  The formation of the major gas phase photolysis product may be rationalized by the following reaction sequence: (see article).  Urea is probably formed from NH4NCO in a thermal reaction while formamide may result from the disproportionation of NH2CO.  Photocatalytic syntheses of 14C-urea, -formamide, and -formadehyde are effected by irradiation of 14CO and NH3 in the presence of Vycor, silica gel, or volcanic ash shale surfaces.  These syntheses are catalyzed by ultraviolet wavelengths longer than those absorbed by the gaseous reactants.  The syntheses are also effected when the surface material is first irradiated in the presence of CO followed by a dark incubation with NH3.  Apparently, the initiating step is a light dependent formation of a reactive form of CO on the surface.  A discussion is given on the possible contribution of these reactions to the abiotic synthesis of organic nitrogen compounds on Mars, on the primitive Earth and in interstellar space.


Simultaneous existence of different enviroments in aqueous clay systems and its possible role in prebiotic synthesis. The formation of packets of parallel oriented platelets and separating distances of several angstrom units in montmorillonite-water systems produces an intrinsic inhomogeneity with respect to the proton donating power of internal and external zones.  Stable packets can be induced by both inorganic and organic molecules or ions, in suspensions or in drying-out systems.  The coexistence of zones with different proton donating power was demonstrated by the pH-sensitive color reaction of benzidine, where stable packets of montmorillonite platelets were formed by the use of either paraquat or diquat.  The close proximity of the two types of zones, which can be of the order of several angstroms, produces the conditions which were defined by Katchalsky as essential for the polymerization of amino acids.  Since these enviromental conditions are quite common in nature, both at present and in prebiotic times, it is proposed that the inhomogeneity of clay-water systems with respect to proton donating power should be taken into account in both theoretical and experimental efforts to demonstrate the catalytic activity of clays in prebiotic synthesis.


Comments of Holmquist's theory for paleogenetics:  the effect of multiple hits on nucleotide differences between homologous DNA's. The notion of the probability of back mutation is introduced and the method of probability generating functions is used in order to simplify and unify the Holmquist's (1972) investigation of the effect of multiple hits on nucleotide differences between homologous DNAs.  We obtain explicit expressions for the distribution of the number of hit nucleotide sites, the number of altered sites, and the number of differences between two homologous DNAs, as functions of the total number of hits.  For the case where the hit rate is a known function of time, we derive a formula for extending these results as functions of time.


Photoradiation therapy. II. Cure of animal tumors with hematoporphyrin and light. Exposure of mouse and rat tumors of various types to more than 600 nm light 24 or 48 hours after an injection of hematoporphyrin resulted in a substantial number of long-term cures. Since hematoporphyrin is preferentially retained in tumor tissue, selective tumor destruction could be obtained. Light penetration studies and the high efficiency of this technique indicated its applicability even to certain deep-seated human tumors.


Carcinogenic action of quinoxaline 1,4-dioxide in rats. Quinoxaline 1,4-dioxide was fed to 400 rats at levels of 10 mg or 1 mg/kg body weight for 18 months. It produced a high incidence of nasal and liver tumors only in the group fed 10 mg/kg. Of diverse histologies, the nasal tumors included anaplastic carcinomas, adenocarcinomas, squamous cell carcinomas, neuroepitheliomas, basal cell carcinomas, and a single fibrosarcoma. The nasal epithelium not involved in the neoplastic process showed dysplasia and hyperplasia.


Sequential development of ethylnitrosourea-induced neurinomas: morphology, biochemistry, and transplantability. Sequential evaluations were made of the morphology and biochemistry of trigeminal nerves from control and ethylnitrosourea (ENU)-exposed rats from 1 day to 6 months of age. Distinct increases in cellularity were evident as early as 20 days after exposure to ENU. Corresponding increases in N-acetyl-beta-glucosaminidase and beta-glucuronidase were detected at the same time. Transplantation studies were performed with grossly normal trigeminal nerves from 32-, 63-, and 91-day-old control and ENU-exposed rats. One of eight nerves from the 32-day-old ENU-exposed donors developed into neurinomas at the site of transplantation. No tumors developed from nerves of controls. These results indicate that the early increases in cellularity and acid hydrolase activities represent neoplastic rather than preneoplastic changes.


Low-fiber intake as an etiologic factor in cancer of the colon. A case-control dietary study of 198 patients with cancer of the colon and two matched control groups demonstrated a significantly lower fiber consumption frequency among the cancer patients. This difference was not confined to a few items. Of the 73 items on the fiber list, 61 were eaten less often by the cancer patient than by a neighborhood control, and 57 were consumed less frequently than by a surgical control. These findings support the hypothesis that low-residue foods play an etiologic role in colon carcinogenesis. A mechanism related to the possible potential carcinogenic properties of degraded biliary compounds may be implicated.


Carcinogenic and cocarcinogenic effects of inhaled synthetic smog and ferric oxide particles. The carcinogenic and cocarcinogenic activity of synthetic smog, ferric oxide (Fe2O3) dust, and a mixture of the two air contaminants was determined in a long-term inhalation study with Syrian hamsters. Inhaled Fe2O3 particles definitely enhanced diethylnitrosamine tumorigenicity in the peripheral lung. Synthetic smog did not. When tested at a concentration of 40 ppm methane equivalents or 40 mg/m3, respectively, neither air pollutant by itself appeared carcinogenic. Fe2O3 caused pulmonary fibrosis and synthetic smog caused alveolar bronchiolization in many of the exposed animals.


Early morphologic alterations in mouse skin after topical application of 3-methylcholanthrene and its metabolites. The effects of topical administration of 3-methylcholanthrene (MCA) or its metabolites on BALB/cKi mice were reported on inflammatory skin reactions, the alterations in epidermal thickness, the number of nucleated cells, pyknotic nuclei and/or nuclear fragments, and mitotic figures in the interfollicular epidermis (IFE). In the two-stage carcinogenesis system, MCA, the powerful complete carcinogen, induced an ordered sequence of cell changes strikingly similar to those caused by tumor-promoting agents such as the phorbol esters. These changes were absent after application of the "K-region" oxide of MCA. Other MCA metabolites also failed to induce notable inflammation, epidermal hyperplasia, and/or hypertrophy. Several MCA derivatives, however, caused a thinning of IFE paralleled by an increase in the relative number of pyknotic nuclei and a decrease in the total number of epithelial cells. The inhibitor of polycyclic hydrocarbon metabolism alpha-naphthoflavone did not prevent MCA-mediated skin reactions but, under suitable conditions, apparently potentiated the hyperplastic effects of MCA. The findings indicate that important events in the promotion phase of MCA-mediated skin carcinogenesis might be associated with the parent compound rather than with one of its metabolites.


Spontaneous adenocarcinomas of the ventral prostate of aged A X C rats. Spontaneous adenocarcinomas of the ventral prostate were present in 7 of 41 aged (34- to 37-month-old), virgin, untreated male A X C rats. The only consistent gross evidence of possible neoplastic involvement was intraprostate hemorrhage. The principally intraglandular neoplasms were composed of markedly anaplastic epithelial cells which retained a moderate propensity to form glandular patterns. The nuclei of the neoplastic cells were pleomorphic, vesiculated, enlarged, and hyperchromatic. Mitotic figures were frequent. Interglandular connective tissue was invaded in one rat; however, metastases were not demonstrated.


Relationship of tumor immunogenicity to concentration of the oncogen. Tumors were induced sc in (BALB/c x DBA/2)F1 female mice by various concentrations of 3-methylcholanthrene (MCA) in paraffin pellets. There was an inverse relationship between MCA concentration and tumor latency (interval between MCA implantation and detection of gross tumor). The tumors were transplanted into syngeneic recipients, and material from this first transplant generation was used to immunize a series of syngeneic mice; any resulting growth was excised. Nonimmunized mice were controls. Immunized and control mice were irradiated and given an sc inoculation of a near-threshold number of tumor cells. Tumor growth from that inoculation was measured weekly in both groups and the antigenicity ratio (mean tumor size in controls/mean tumor size in immunized mice) was calculated. In a series of tumors with similar latencies, the only ones with high antigenicity ratios were those resulting from the high MCA concentration. The results suggested that tumors induced by low levels of oncogen may be good models of spontaneous neoplasia, strengthened the hypothesis that "spontaneous' tumors may actually result from low levels of oncogen, and indicated that neoplastic transformation and the development of immunogenicity are, at least in chemically induced tumors, independent changes that may be produced in the same cell when the concentration of oncogen is sufficient.


Adriamycin-induced cardiac damage in the mouse: a small-animal model of cardiotoxicity. After one dose of adriamycin, a subacute cardiomyopathy was observed in the mouse by both light and electron microscopy. The microscopic alterations were characterized by single-cell necrosis and mitochondrial degeneration. These lesions were similar to those seen in man and shortly preceded fatal toxicity.


Cage for continuous intravascular infusion of isotopes and drugs in small animals. A cage for continuous intra-arterial or intravenous infusion is described. Major features are: a) The animal is free to move during infusion, b) loss of the infused solution is avoided, c) cleaning and decontamination are simple, and d) infusion can continue for weeks.


Increased immunogenicity of two lymphoma lines after drug treatment of athymic (nude) mice. Highly immunogenic sublines of L1210 and LSTRA lymphomas were obtained from athymic (nude) mice treated with 4(5)-(3,3-dimethyl-1-triazeno)imidazole-5(4)carboxamide (DIC) in vivo. Conventional mice, compatible with the parent tumor, rejected the DIC-treated sublines and were relatively resistant to a subsequent challenge with the parent lines. The DIC-treated sublines were not rejected by athymic mice, which indicated that the transplantation resistance to these tumors in conventional mice was thymus-cell dependent. In addition, there was marginal or no increase of tumor-cell immunogenicity when the parent lines were passaged in nude mice without DIC treatment. This indicated that the DIC-dependent immunogenic changes in DIC-treated leukemic conventional mice could not be ascribed merely to protection by naturally occurring antigenic clones that resulted from DIC-induced immunodepression.


Low-dose chemotherapy as a prelude to intensive treatment of spontaneous leukemia-lymphoma in AKR mice. Groups of AKR mice bearing spontaneous leukemia-lymphoma were treated with five different combinations of chemotherapy or chemoradiotherapy. Each treatment combination was given in two sequences--high dose first and low dose last, or low dose first and high dose last--administered over 6-7 days. When the initial treatment was a high dose of chemotherapy, radiotherapy, or chemoradiotherapy, mortality in the first 24 hours exceeded 40%, and at least 70% of the mice in each group were dead within 2 weeks. When low-dose chemotherapy was given first, mortality in the first 24 hours was minimal but, most significantly, no deaths occurred in the 24 hours after subsequent high-dose treatment. In the most successful group (100 mg cyclophosphamide/kg on day 0, and 250 mg cyclophosphamide/kg and 400 R total-body X-irradiation on day 7), the median survival time increased significantly as compared with the median survival time among mice given the same regimen in reverse sequence (p less than 0.001) or among untreated control mice (p less than 0.01). With this regimen, survival 60 days after the last treatment was 47%. No mouse survived 30 days when the sequence of treatments was reversed. From these results, we conclude that chemotherapeutic and chemoradiotherapeutic regimens for AKR spontaneous leukemia-lymphoma should be designed so that low, minimally lethal doses precede higher doses.


Radioiodinated antibody to carcinoembryonic antigen: binding to normal and cancerous human colon in vitro. Samples of tumor and normal mucosa from 32 patients with adenocarcinoma of the colorectum were examined for their capacity to bind radioiodinated antibody to carcinoembryonic antigen (anti-CEA) lgG. Twenty-three (72%) of the tumors bound significantly more antibody than the respective normal mucosa. The results indicate that radiolabeled anti-CEA may be useful in the in vivo localization of CEA-producing tumors and metastases in man, and may have application in vitro as a diagnostic marker of precancerous change in colorectal biopsies from patients at risk of developing colorectal cancer.


Hormone-independent in vitro erythroid colony formation by bone marrow cells from Rauscher virus-infected mice. Bone marrow cells from BALB/c mice infected with Rauscher erythroblastosis virus produced five to twenty-five times more erythroid colonies in vitro in the absence of erythropoietin (EP) as compared to normal cells. A good correlation existed between the state of the disease and the number of hormone-independent erythroid colony-forming cells (CFU-E). A significant number of hormone-independent CFU-E was found as early as 3 days after infection. A linear relationship existed between the number of cells plated and the number of erythroid colonies formed in vitro. Addition of EP did not enhance colony formation, even at low cell concentrations. Feeder layer experiments demonstrated that EP-independent colony formation was not due to the production of endogenous EP. Repeated injections of phenylhydrazine into normal mice did not lead to the loss of EP responsiveness in vitro; this indicated that the hormone independency induced by the virus was not due to continuous erythropoietic stimulation in vivo. Besides hormone independency, the CFU-E from infected mice required less serum in the culture medium. Normal erythroid colonies regressed after 4 days of culture, but EP-independent colonies from infected mice persisted for more than 2 weeks. These three phenomena may be regarded as indicative for a physiologic transformation.


Activation of carcinogenic arylhydroxamic acids by human tissues. 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 tumorigenesis induced by glass and smooth and rough plastic. Comparative study of preneoplastic events. 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.


Inhibitory effects of phytohemagglutinin on growth of leukemia lymphoblasts L5178Y in vitro and in vivo. 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.


Effects of cigarette smoke on the bronchial epithelium of Syrian hamsters: ultrastructural studies. 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.


Neoplastic and life-span effects of chronic exposure to tritium. I. Effects on adult rats exposed during pregnancy. 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.


Properties and malignant transformation of established rat liver parenchymal cells in culture. 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.


Target cell of the polycythemia-inducing Friend virus: studies with myleran. 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.


Response of a pregnancy-dependent mouse mammary tumor to hormones. 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.


Histopathology of the host response to Lewis lung carcinoma: modulation by pyran. 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 attacker: target-cell ratio and serum effects on in vitro cell-mediated immunity. 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.


Alterations in microsomal metabolism of benzo[a]pyrene in mice fed butylated hydroxyanisole. 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.


Mammary carcinogenesis-enhancing effect of adrenalectomy in irradiated rats with pituitary tumor MtT-F4. 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.


Neoplasms in persons treated with x-rays in infancy: fourth survey in 20 years. 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.


Cancer incidence in the Mexican-American. 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.


Cancer mortality among Alaskan natives, 1960-69. 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.


Immunohistology of the antigenic pattern of a continuous cell line from a human colon tumor. 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.


In vitro destruction of tumor cells by macrophages from mice treated with Corynebacterium granulosum. 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.


Antineoplastic activity of cannabinoids. 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)).


Natural occurrence of lymphocytes showing cytotoxic activity to BALB/c radiation-induced leukemia RL male 1 cells. 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.


A murine model for central nervous system leukemia and its possible relevance to human leukemia. 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.


Growth and composition of a transplantable murine Leydig cell tumor. 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.


Induction of mouse lung adenomas by amines or ureas plus nitrite and by N-nitroso compounds: effect of ascorbate, gallic acid, thiocyanate, and caffeine. 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.


Specific carcinogenic effect of N-methyl-N-nitrosourea on the midventral sebaceous gland of the gerbil (Meriones unguiculatus). 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.


Spontaneous maturation and differentiation of B16 melanoma cells in culture. 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.


Association of DNA with melanin granules. 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.


Membrane-mediated drug resistance and phenotypic reversion to normal growth behavior of Chinese hamster cells. 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.


Transplacental effects of diethylnitrosamine in Syrian hamsters as related to different days of administration during pregnancy. 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.


Intralymphatic injection of BCG into rhesus monkeys. 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.


Tumorigenesis by oxygenated nitrosopiperidines in rats. 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.


Growth and regrowth of an autogenous rat sarcoma: effects of nitrogen mustard. 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.


Minute chromatin bodies in a murine in vitro cell line. 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.


A possible improvement in the resolution of proton spin relaxation for the study of cancer at low frequency. Available results indicate that the water proton spin-lattice relaxation time resolution, defined as [T1(tumorous) -T1(healthy)]/T1(tumorous), may increase if relaxation time is measured at 2 rather than at 30 MHz.


Immunotherapy of cancer: tumor suppression and regression by cell walls of Mycobacterium phlei attached to oil droplets. 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.


Delayed lethal response to Candida albicans infection in mice bearing the Lewis lung carcinoma. 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.


Histochemical study of gastric mucosubstances after thermal injury: correlation with endoscopic evidence of acute gastroduodenal disease. 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.


Avulsion of the posterior cruciate ligament from its femoral attachment: an isolated ligamentous injury. 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.


Blunt liver trauma: an analysis of 75 treated patients. 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.


Massive venous injuries associated with penetrating wounds of the liver. 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.


Emergency medical technician (EMT-A) training in a medical school environment. 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.


Programmed management of severe head injuries revisited. 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.


The tibial shaft fracture.

The tibial shaft fracture. 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.


Management of penetrating injuries of the suprarenal aorta. 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.


Reconstructive surgery in major vein injuries in the extremities. 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.


Trans-thoracic venous bullet embolism.

Trans-thoracic venous bullet embolism. 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.


Avulsion of the triceps tendon.

Avulsion of the triceps tendon. Two cases of the rare injury of avulsion of the triceps tendon are presented. The difficulties in clinical diagnosis and proper evaluation of the roentgenographic findings whenever present are discussed and the treatment is outlined.


Guidewire deflector system removal of catheter foreign body retained in the right heart for six months. 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.


Virion-associated transcriptase activity of influenza recombinant and mutant strains. 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.


Physical map and strand polarity of specific fragments of adenovirus-associated virus DNA produced by endonuclease R-EcoRI. 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.


Effect of impaired glycosylation on the biosynthesis of Semliki forest virus glycoproteins. 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.


Endonuclease R-EcoRII restriction of bacteriophage f1 DNA in vitro: ordering of genes V and VII, location of an RNA promotor for gene VIII. 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.


Proteins of bacteriophage phi6.

Proteins of bacteriophage phi6. 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.


Adenovirus binds to rat brain microtubules in vitro. 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.


Study of the fine structure of adeno-associated virus DNA with bacterial restriction endonucleases. 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.


Molecular weight of DNA from actinophage MSP2. 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.


Leukoplakia of the urinary tract: a review. 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.


Selective caliceal catheterization for stone manipulation. 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.


The surgical management of the symptomatic solitary caliceal calculus. 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 surgery on renal artery aneurysms. 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 with perirenal hematoma. 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.


Tuberous sclerosis: emphasis on the angiographic findings. Two cases of angiomyolipoma of the kidney are reported. Specific emphasis is placed on the angiographic findings that distinguish this disease from malignant and polycystic renal disease.


Why every renal mass is not always a surgical lesion, the need for an orderly, logical, diagnostic approach. 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.


Ureteral pressure flow studies in difficult diagnostic problems. 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.


Electromyography of the detrusor muscle. 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.


Non-operative treatment of the ruptured bladder. 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.


Mitomycin C bladder instillation therapy for bladder tumors. 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.


The value of mechanical cell harvesting in diagnosis and prognosis of bladder tumor recurrence. 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.


A new method for determination of urinary tryptophan metabolites in bladder carcinoma. 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.