Preparation and template activities of polynucleotides containing O2- and O4-alkyluridine.

O2-Ethyl-UDP and O4-methyl-UDP have been prepared and copolymerized in various proportions with UDP or CDP, using polynucleotide phosphorylase. The copolymers were used as templates for DNA-dependent RNA polymerases in the presence of Mn2+. Both of the O-alkylated uridines caused a similar misincorporations. When copolymerized with U they led to incorporation of CMP and GMP into the poly(A). No AMP or UMP incorporation seemed to be caused by the introduction of O-alkyluridines into either poly(U) or poly(C). The mispairing of O2- and O4-alkyluridine to behave like C or G represents mutagenic events. O2 alkylation of U or T is, in contrast to O4 alkylation, a relatively frequent result of treatment of double-stranded nucleic acids with N-nitroso alkylating agents. In single-stranded nucleic acids both O2 and O4 alkylations of U and T occur to similar extents. Thus, the observed mutagenic effects of O2 and O4 alkylation of U may be involved in the high carcinogenicity of these alkylating agents.


Kinetics of biphasic reconstitution of tobacco mosaic virus in vitro.

The kinetics of the in vitro reconstitution of tobacco mosaic virus from its RNA and protein were studied by measuring the increase in turbidity, the development of ribonuclease-resistant infectivity, the emcapsidation of the terminal ends of the RNA, and the growth of rod length. The results showed that the reconstitution reaction consists of two processes in which the direction, timing, and rate of assembly are different. Rapid elongation of particles toward the 5' end of the RNA proceeds in the first 5-7 min to give intermediate particles of 260 nm in length in which only the 5' terminus of the RNA is encapsidated. The subsequent process requires 30-50 min, is accompanied by a slow increase in turbidity, and gives rise to rods of the full length, 300 nm. The 3' terminus becomes RNase resistant by this process with concomitant development of ribonuclease-resistant infectivity, showing that the 3'-distal portion of the RNA is encapsidated in the direction of 5' to 3'. The rate of rod elongation by the second process is less than 1/10 of that by the first process.


Amino acid sequence of the beta chain of human fibrinogen: homology with the gamma chain.

The beta chain of human fibrinogen is composed of 452 +/- 5 amino acid residues, 14 of which are methionines. Consistent with these findings we have isolated and characterized 15 fragments after cyanogen bromide digestion of carboxymethylated beta chains. The arrangement of several of these peptides was deduced on the basis of overlapping peptides isolated from the fragments D and E produced by the plasmic digestion of fibrinogen and/or from a tryptic digest of citraconylated beta chains. Most of the other cyanogen bromide fragments can be aligned by homology with the alpha and/or gamma chains from human fibrinogen, although the positioning of a few of the smallest peptides is still ambiguous. The homology of the beta chain with the gamma chain is especially strong in certain regions of the domain that includes fragment D.


Identification of the principal aflatoxin B1-DNA adduct formed in vivo in rat liver.

The products of in vivo covalent binding of activated aflatoxin B1 (AFB1) to DNA have been investigated in rats. The principal covalent product formed in liver DNA of rats treated with AFB1 has been identified as 2,3-dihydro-2-(N7-guanyl)-3-hydroxy-aflatoxin B1. This compound was isolated from the liver DNA of rats dosed with AFB1 (2.0 mg/kg) in sufficient quantity for characterization by physicochemical techniques, including field-desorption mass spectrometry. This information together with results of chemical methylation of the compound proved that the major adduct formed between DNA and AFB1 in vivo is identical to that produced in vitro when AFB1 is incubated with DNA in the presence of a rat liver microsomal activating system. Quantitative studies of formation of this compound revealed a dose-dependent relationship between the level of its occurence in liver DNA and AFB1 doses over the range 0.125-1.0 mg/kg.


Synthesis of phage M13 coat protein and its assembly into membranes in vitro.

The coat protein (gene 8 product) of coliphage M1O is an integral protein of the host cell membrane at all stages of virus infection. This protein, when made in a cell-free reaction, has been shown by others to have an additional NH2-terminal peptide region and is referred to as "procoat." It is initially not membrane-bound but, upon exposure to Escherichia coli membrane vesicles or to liposomes prepared from E. coli lipids, it assembles into the bilayer in an integral fashion. Much of this protein is shown to be exposed on the inner surface of the liposome. We suggest that refolding of procoat as it encounters the bilayer is sufficient to transport large segments of the peptide chain through the apolar hydrocarbon core.


"Two out of three": an alternative method for codon reading.

An alternative method for codon reading, whereby only the first two codon nucleotides are recognized by the anticodon, is discussed and the experimental evidence for this "two of three" reading method is reviewed. Misreading of codons by the "two out of three" method could pose a significant threat to the fidelity of protein synthesis unless the genetic code is organized in such a way as to prevent this method from being used when it might compromise translational fidelity. Inspection of the genetic code shows that it is arranged in such a way that the "two out of three" reading method can be used without translational errors.


mRNA-dependent synthesis of a glycosylated subunit of human chorionic gonadotropin in cell-free extracts derived from ascites tumor cells.

Protein synthesized in ascites cell-free extracts in response to first trimester placental mRNA was immunoprecipitated with antisera directed against the alpha subunit of human chorionic gonadotropin. The immunoprecipitable proteins were resolved on sodium dodecyl sulfate/polyacrylamide slab gels. In membrane-depleted extracts placental mRNA directed the synthesis of the "preprotein" form of the alpha subunit. However, when membranes were added to the cell-free extracts a protein migrating more slowly than pre-alpha subunit was observed. This protein was specifically adsorbed to a concanavalin A column, and its migration on sodium dodecyl sulfate gels was enhanced after treatment with alpha-mannosidase (EC 3.2.1.24) or endo-beta-N-acetylglucosaminidase C(II) or H. Similar results were obtained when mRNA was translated in lysates derived from first trimester placenta instead of in ascites cell extracts. Kinetic studies of the glycosylation reaction revealed that sugar attachment can occur just prior to release of the protein. These data show that the apoprotein of the alpha subunit can be glycosylated in vitro. The data also suggest that the glycosylated protein contains a sugar core consisting of di-N-acetylchitobiose and at least four mannose residues, some of which are alpha-linked. In addition, it appears that this carbohydrate unit is present in homologous placental membranes as well as in the ascites tumor membranes.


Mechanism of action of the cro protein of bacteriophage lambda.

The mechanism of action of cro protein was probed by measuring its ability to protect DNA against methylation by dimethyl sulfate and its effect on transcription in vitro. The cro protein binds to the same three sites in the right operator (OR) of bacteriophage lambda DNA as does the lambda repressor. Dimethyl sulfate protection experiments reveal major groove contacts for both proteins, and cro protein protects from methylation a subset of those purines protected by lambda repressor. These experiments also show that the relative affinity of these two proteins for the three operator sites is different: whereas lambda repressor binds with an affinity OR1 greater than OR2 greater than OR3, the order for cro protein is OR3 greater than (OR1, OR2). As predicted by these results, cro protein, like the lambda repressor, blocks in vitro transcription of cI and cro from the two divergent promoters that overlap OR. Also as predicted, transcription of cI is turned off at lower cro protein concentrations than is transcription of cro, whereas the opposite order of repression is obtained with lambda repressor. These results describe the molecular mechanism of cro protein action and show that two regulatory proteins can bind to the same three adjacent sites in DNA with markedly different consequences.


Primary induction of vitellogenin mRNA in the rooster by 17beta-estradiol.

We have studied the kinetics of vitellogenin mRNA accumulation in rooster liver after a primary injection of 17beta-estradiol. The levels of vitellogenin mRNA have been determined both by hybridization of total cellular RNA to vitellogenin cDNA and by translation of vitellogenin mRNA in a wheat germ cell-free system. The results obtained by both methods of analysis are in good agreement and indicate that vitellogenin mRNA is present in the liver of normal roosters at a level of 0-5 molecules per liver cell and increases in amount during the 3 days following injection of estrogen, reaching a level of almost 6000 molecules per cell at the peak of the response. The level of vitellogenin mRNA declined exponentially during the next 14 days with a half-life of 29 hr, reaching a level of less than 10 molecules per cell at 17 days after injection of the hormone. The levels of vitellogenin mRNA after stimulation with estrogen have been correlated with the in vivo rate of synthesis of the vitellogenin polypeptide. The results indicate that the rate of vitellogenin synthesis is closely correlated with the level of vitellogenin mRNA. On the basis of these findings, we conclude that vitellogenin mRNA does not exist in the liver in an untranslated form after withdrawal from estrogen.


Fluorescent light-induced chromosome damage and its prevention in mouse cells in culture.

Twenty-hour-exposure to fluorescent light produces chromatid breaks in a line of adult mouse lung cells grown in Dulbecco-Vogt medium supplemented with fetal bovine serum. The light-induced damage appears to be enhanced by increasing the concentration of oxygen in the gas phase of the culture. The effective wavelength(s) of light is in the visible range between 400 and 450 nm andis probably the mercury emission peak at 405 or 436 nm. Addition of catalase or glutathione with ascorbic acid to the culture medium reduced the number of chromatid breaks to a level not significantly different from that in the shielded cultures. It thus appears that the production of H2O2 in the culture medium or in the cell is responsible for the chromatid breaks. Most of the chromosomal abnormalities observed in long-term culture of mouse cells may result from exposure of cells or medium to fluorescent room lights in the presence of atmospheric oxygen. These genetic abnormalities can be minimized by shielding cells and medium from light, lowering the PO2 of the medium, and including reducing agents such as glutathione and ascorbic acid in the medium formulation.


Production of autoinhibitory factors by mouse lymphoma cells in vitro and its relationship to thiol dependence.

Five different kinds of mouse lymphoma cells conditioned culture medium so that it became inhibitory to thiol-dependent cells but not to thiol-independent cells. Conditioning was rapid and appeared to be complete in 1-3 hr. The inhibitory effects could be reversed by concentrations of 2-mercaptoethanol higher than those usually required for growth promotion. Inhibitory factors were concentrated by ultrafiltration and chromatography on Sephadex G-10 which showed their apparent molecular weights to be 300-600. The factors were stable at 100 degrees and to proteases but were inactivated (after reduction) by iodoacetamide, indicating that they may be thiols or disulfides.


Physical, morphological, and biochemical alterations in the membrane of AKR mouse cells after interferon treatment.

Interferon treatment of AKR,C- cells was followed by the establishment of an antiviral state and apparently concomitant morphological, physical, and biochemical alterations of the cell plasma membrane. The density of the plasma membrane was significant altered, and the concentration of some plasma membrane glycoproteins and the number of intramembranous particles observed in freeze-fracture electron micrographs were increased. A parallel increase in the concentration of intramembranous particles and the resistance to viral infection during interferon treatment as well as their parallel decrease upon removal of interferon suggests a relationship between the particle density and the establishment of the antiviral state.


Density-dependent regulation of growth of BSC-1 cells in cell culture: growth inhibitors formed by the cells.

Inhibitors formed by a monkey epithelial cell line, BSC-1, play an important role in limiting growth at high cell densities. At least three inhibitors are formed: lactic acid, ammonia, and an unidentified inhibitor that may be an unstable protein. The unidentified inhibitor is destroyed by shaking the conditioned medium, by bubbling gas through the medium, or by heating or storing the medium in the absence of cells. The concentrations of lactic acid and ammonia that accumulate in conditioned medium inhibit growth when added to fresh medium. These results, together with earlier studies, indicate that density-dependent regulation of growth of BSC-1 cells results from the combined effects of (a) inhibitors formed by the cells, (b) decreased availability of receptor sites for serum growth factors as the cells become crowded, and (c) limiting concentrations of low molecular weight nutrients in the medium. In contrast, density-dependent regulation of growth in 3T3 mouse embryo fibroblasts results almost entirely from inactivation of serum factors.


Calcium-dependent regulator protein: localization in mitotic apparatus of eukaryotic cells.

Calcium-dependent regulator protein is a low molecular weight (17,000), thermostable, calcium binding protein which is structurally homologous to skeletal muscle troponin C. This protein is present in all nonmuscle cells and has been shown to decorate stress fibers in interphase cells by indirect immunofluorescence. Using this procedure we have investigated the distribution of the protein during mitosis of eukaryotic cells. As the cells enter prophase, the distinct cytoplasmic localization disappears commensurate with the dissolution of the cytoskeleton. The regulator protein seems to be randomly distributed throughout the prophase cell, including the region around the condensed chromosomes. However, at prometaphase, it is localized in association with the half-spindles of the mitotic apparatus. Through metaphase and most of anaphase, the protein remains localized between the chromosomes and the poles of the spindle. During late anaphase the protein is also found in the interzone region but rapidly condenses into two small regions, one on each side of the midbody that separates the daughter cells. The regulator protein is not localized in the cleavage furrow during telophase, whereas actin is demonstrable in this region. Indeed, placement of the protein during mitosis is distinct from both that of actin and that of tubulin. The localization of calcium-dependent regulator protein during mitosis suggests that it may mediate the calcium effects on the mitotic apparatus and thus play a role in chromosome movement.


Conjugation of poly-L-lysine to albumin and horseradish peroxidase: a novel method of enhancing the cellular uptake of proteins.

The carbodiimide-catalyzed conjugation of a 6700 molecular weight fragment of poly-L-lysine to radiolabeled human serum albumin or to horseradish peroxidase enhances the membrane transport of each protein into cultured mouse fibroblasts approximately 11- and 200-fold, respectively. At least 50% of the peroxidase activity remained after conjugation. Trypsinization and carbamylation of the two conjugates demonstrates that the enhancement of their cellular uptake is related to their poly-L-lysine content. Simple addition to the medium of comparable amounts of free poly-L-lysine has no effect on the transport of either native protein. Addition of poly-L-ornithine (molecular weight 200,000) at 3-30 microgram/ml, a condition known to cause enhancement of 125I-labeled human serum albumin uptake by mouse sarcoma cells, has no visible effect on the cellular uptake of native horseradish peroxidase. The intracellular localization of the enzyme-poly-L-lysine conjugate can be demonstrated cytochemically by either light or transmission electron microscopy. A concentration of conjugate that increases the uptake more than 200-fold does not cause any detectable morphological change suggestive of cell toxicity. Furthermore, because poly-L-lysine is an excellent substrate for intracellular proteolytic enzymes, it can be expected to be broken down and reutilized in the cell.


A cell-free assay measuring repair DNA synthesis in human fibroblasts.

Osmotic disruption of confluent cultured human fibroblasts that have been irradiated or exposed to chemical carcinogens allows the specific measurement of repair DNA synthesis using dTTP as a precursor. Fibroblasts similarly prepared from various xeroderma pigmentosum cell lines show the deficiencies of UV-induced DNA synthesis predicted from in vivo studies, while giving normal responses to methyl methanesulfonate. A pyrimidine-dimer-specific enzyme, T4 endonuclease V, stimulated the rate of UV-induced repair synthesis with normal and xeroderma pigmentosum cell lines. This system should prove useful for identifying agents that induce DNA repair, and cells that respond abnormally to such induction. It should also be applicable to an in vitro complementation assay with repair-defective cells and proteins obtained from repair-proficient cells. Finally, by using actively growing fibroblasts and thymidine in the system, DNA replication can be measured and studied in vitro.


Founder effect and number of private polymorphisms observed in Amerindian tribes.

In studies extending over the past dozen years, we have observed eight examples of "private" genetic polymorphisms in 12 Amerindian tribes surveyed for electrophoretic variants of an average of 25 proteins. Each of these is presumed to trace to a single mutation. In a preceding communication [Thompson, E.A. & Neel, J.V. (1978) Proc. Natl. Acad. Sci. USA 75, 1442-1445] the statistical theory was developed for estimating the likelihood of such a founder effect in a tribal population of this type. In this paper that theory is applied to the distribution defined by these eight variants. It is demonstrated that on the assumption that the phenotypes in question are selectively neutral, such findings are most compatible with a mutation rate of 7 X 10(-6)/locus per generation. This figure applies only to variants that can be detected by the electrophoretic technique.


Electrophoretic shift mutants in Chinese hamster ovary cells: evidence for genetic diploidy.

Electrophoretic shift mutants induced in Chinese hamster ovary (CHO) cells indicate that these cells not extensively functionally hemizygotic. Therefore, effective haploidy is unsatisfactory as a general theory to explain the frequency of recessive mutants in this cell line. CHO cells were screened for electrophoretic shift variants of enzymes coded by approximately 40 genetic loci. Clones isolated after exposure to ultraviolet radiation were examined by starch gel and Cellogel electrophoresis. Shift variants were recovered for enzymes representing 11 different loci. Variant clones were subcloned to demonstrate the heritability of the variations Mutants at nine loci produced multiple-banded patterns consistent with the patterns expected of genes at loci represented twice (diploid). Chromosome localization of these diploid loci in other mammalian species where they have been mapped, suggests that they represent a random sample of CHO genes. Chromosome analysis of mutant subclones indicated that the variation did not take place in tetraploid cells. The data indicate that the quasi-diploid CHO cells appear only as functionally hemizygous as would be expected of a slightly hypodiploid cell line derived from an organism in which the haploid number is 11.


Change of gene frequencies by natural selection under population number regulation.

By incorporating a population number regulating mechanism into the formulation of genic selection involving a pair of alleles (A1 and A2) with respective frequencies x and I-x, it is shown that the change of x in one generation is given by deltax = sx(1-x)/W, in which W is the mean absolute selective value (in Wright's sense). It is also shown that, in the process in which advantageous allele (say A1) increases from a low frequency to a high frequency, quasi-equilibrium is rapidly attained where deltaW approximately 0. In this state we have W approximately 1 + (s2/c)x(1-x) in the case of logarithmic population number regulation, and W approximately 1 + s2x(1-x)/(cN) in the case of logistic regulation. In these expressions, s is the selective advantage of A1 over A2, and c is a coefficient relating to the total population number regulation. It is pointed out that the approximation formula deltax = sx(1-x) is valid under wider circumstances than usually suggested by the conventional treatment of genic selection.


Antigens of human trophoblasts: a working hypothesis for their role in normal and abnormal pregnancies.

This report describes the preparation and characterization of antisera to human trophoblast membranes. Rabbit antisera were raised to trophoblast microvilli prepared by differential ultracentrifugation. Antibodies to serum proteins were removed by solid-phase immunoabsorption with normal human serum, and indirect immunofluorescence experiments with cryostat sections of human placentas showed that the absorbed anti-trophoblast sera reacted with trophoblasts as well as with stromal cells and endothelium of chorionic villi. The antisera also produced membrane fluorescence when studied on viable lymphocytes and certain human cell lines. These anti-trophoblast sera were also lymphocytotoxic, and this reaction was abolished by prior absorption of the antisera with leukocytes. The leukocyte-absorbed anti-trophoblast sera retained their ability to react with trophoblasts and certain human cell lines, but no longer reacted with lymphocytes or placental stromal cells and endothelium. Two categories of trophoblast membrane antigens are thus defined: one present on trophoblasts and certain human cells lines (tentatively designated TA(1)), and the other on trophoblasts and lymphocytes, villous fibroblasts, and endothelium (tentatively designated TA(2)). A working hypothesis is proposed stating that normal pregnancy involves the generation of anti-TA(2) subsequent to blastocyst implantation and entrance of trophoblasts into the maternal circulation. This involves a mechanism similar to allogeneic cell stimulation and results in antibodies that block either the recognition or cytotoxicity of TA(1). Failure to mount this response allows TA(1) recognition and trophoblast immunopathology. Experimental and clinical studies in support of this working hypothesis, particularly involving abortion and toxemia, are cited from published reports.


Duality of hepatitis B e antigen in serum of persons infected with hepatitis B virus: evidence for the nonidentity of e antigen with immunoglobulins.

Hepatitis B e antigen (HBeAg) is detected in the serum of some persons infected with hepatitis B virus. Owing to a close correlation of HBeAg and hepatitis B virus in the serum, it has been used as a practical indicator of infectivity. Two entities of HBeAg activity physicochemically different from each other were demonstrated in the serum of persons infected with hepatitis B virus. One was associated with a molecule that precipitated in 1.33 M ammonium sulfate solution, was larger than IgG, and had an electrophoretic mobility in the beta- to gamma-globulin regions and an isoelectric point of approximately pH 5.7. In contrast, the other HBeAg activity was associated with a molecule that was soluble in 1.33 M ammonium sulfate solution, was smaller than IgG, and had an electrophoretic mobility in the alpha-globulin region and an isoelectric point at pH 4.8. In spite of their marked physicochemical differences, a line of antigenic identity was clearly observed for them when they were tested against antibody to HBeAg by a them when they were tested against antibody to HBeAg by a double immunodiffusion method. The HBeAg activity associated with the large molecule was completely removed by an affinity column of anti-IgG, whereas the activity of the small molecule was not. These results indicate that, in the serum, HBeAg exists as a molecule smaller than IgG and also in association with IgG.


Regulation by membrane sialic acid of beta1H-dependent decay-dissociation of amplification C3 convertase of the alternative complement pathway.

Sheep erythrocytes in their native state did not activate the alternative complement pathway, as measured by lysis in dilutions of normal human serum containing [ethylenebis(oxyethylenenitrilo)] tetraacetic acid but acquired this capacity after membrane sialic acid residues had been removed (by sialidase) or modified (by NaIO(4)). Activation of the alternative pathway by sheep erythrocytes required removal or modification of at least 40% of the membrane sialic acid to reach threshold, and it increased proportionately when larger amounts of sialic acid had been affected. Studies with isolated proteins of the alternative pathway demonstrated that the altered erythrocyte membranes resembled natural activators in protecting bound C3b from inactivation by C3b inactivator and beta1H and protecting bound amplification C3 convertase (C3b,Bb) from decay-dissociation by beta1H. A 1% decrease in intact sialic acid was associated with a 1% decrease in beta1H activity in decay-dissociation of membrane bound C3b,Bb. Because removal of the C8 and C9 carbon atoms from the polyhydroxylated side chain of sialic acid by oxidation with NaIO(4) was functionally equivalent to removal of the entire sialic acid moiety, secondary effects of the latter reaction, such as diminution of the negative charge of the membrane or exposure of penultimate galactose residues, were not considered to be responsible for the altered activity of beta1H. These studies suggest that facilitation, by membrane sialic acid residues, of the interaction between bound C3b and beta1H is essential to prevent the particle from effectively activating the alternative pathway.


Biochemical mechanisms of glucose-6-phosphate dehydrogenase deficiency.

A solid-phase radioimmunoassay for human glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate: NADP+ 1-oxidoreductase; EC 1.1.1.49) was developed that allowed the specific activity of this enzyme protein to be measured in lysates from whole erythrocyte populations, in lysates from erythrocytes of different ages, and in purified samples. The enzyme was highly purified from erythrocytes of single donors by a simple procedure of affinity chromatography with insolubilized adenosine 2',5'-bisphosphate. These techniques were used in an attempt to elucidate the molecular mechanisms leading to deficiency of glucose-6-phosphate dehydrogenase activity in two genetic variants of the enzyme, i.e., the Mediterranean and the Seattle-like variants. The results indicate that the lowered activity of erythrocytes containing the Mediterranean variant of glucose-6-phosphate dehydrogenase is related to an enhanced rate of degradation of a catalytically defective protein synthesized at a nearly normal rate. Synthesis of a normally functioning protein and an increased breakdown of it are involved in the Seattle-like variant of the enzyme.


Xeroderma pigmentosum neurological abnormalities correlate with colony-forming ability after ultraviolet radiation.

Xeroderma pigmentosum is an autosomal recessive disease in which DNA repair processes are defective. All xeroderma pigmentosum patients develop premature aging of sun-exposed skin, and some develop neurological abnormalities due to premature death of nerve cells. Sensitivity to ultraviolet radiation of 24 xeroderma pigmentosum fibroblast strains was studied in vitro by measuring each strain's ability to divide and form colonies after irradiation. The most sensitive strains were derived from patients who had an early onset of neurological abnormalities; less sensitive strains were from patients with a later onset; and the most resistant strains were from patients without neurological abnormalities. The UV sensitivities of strains from each member of a sibling pair with xeroderma pigmentosum were identical, indicating that UV sensitivity of xeroderma pigmentosum strains is determined by the patient's inherited DNA repair defect. The results suggest that effective DNA repair is required to maintain the functional integrity of the human nervous system by preventing premature death of neurons.


Role of surface in surface-dependent activation of Hageman factor (blood coagulation factor XII).

The mechanism by which negatively charged substances such as celite, kaolin, or ellagic acid contribute to the surface-dependent activation of Hageman factor (Factor XII) was studied. Kinetic studies of the proteolytic activation of (125)I-labeled human Hageman factor by human plasma kallikrein, plasma, activated Factor XI, and trypsin were performed in the presence and absence of high molecular weight kininogen and surface materials such as celite, kaolin, or ellagic acid. The results showed that surface-bound Hageman factor was 500 times more susceptible than soluble Hageman factor to proteolytic activation by kallikrein in the presence of high molecular weight kininogen. Surface binding of Hageman factor enhanced its cleavage by plasmin, activated Factor XI, and trypsin by 100-fold, 30-fold, and 5-fold, respectively. On a molar basis, trypsin was twice as potent as kallikrein in the cleavage of the surface-bound Hageman factor, while plasmin and activated Factor XI were an order of magnitude less potent than kallikrein. Kallikrein even at concentrations as low as 0.5 nM (i.e., 1/1000th of the concentration of prekallikrein in plasma) was very potent in the limited proteolysis of the surface-bound Hageman factor. These results suggest that substances classically known as "activating surfaces" promote the activation of Hageman factor indirectly by altering its structure such that it is much more susceptible to proteolytic activation by other plasma or cellular proteases.


Adrenergic differentiation of cells of the cholinergic ciliary and Remak ganglia in avian embryo after in vivo transplantation.

We have previously shown that the neural crest is regionalized early into "adrenergic" and "cholinergic" areas from which arise, respectively, the sympathetic and parasympathetic ganglioblasts of the autonomic nervous system. This regionalization does not correspond, however, to an irreversible determination of the neural crest cells since, under certain experimental conditions, cholinergic cells can arise from the adrenergic region of the crest and vice versa. The phenotypic expression of the presumptive ganglion cells appears to be responsive to the environmental conditions they encounter during and/or after their migration. In the present study we show that the developmental behavior of parasympathetic ganglion cells which have stopped migrating and at least some of which have started to differentiate into cholinergic neurons can be profoundly modified if they are transplanted into a younger embryo at the trunk neural crest level. The crest level. The grafted ganglion cells start migrating and stop in the same sites as the host neural crest cells. Their further differentiation depends on their localization. When situated in the adrenergic ganglia and in the suprarenal gland they synthesize catehcolamines, whereas they differentiate into nonfluorescent, silver-staining ganglion cells if they migrate in the gut wall. Thus, the differentiation of autonomic neurons is dependent on tissue interactions even after the neural crest cells have grouped to form ganglionic structures in which biochemical differentiation is already in progress.


Nerve extract induces increase and redistribution of acetylcholine receptors on cloned muscle cells.

The effect of rat spinal cord explants and cell-free nerve extract on acetylcholine receptor site density and distribution was studied using (125)I- and rhodamine-labeled alpha-bungarotoxin on L(6), a cloned rat muscle cell line. Control L(6) myotubes have a low and uniform distribution of acetylcholine receptors (20 +/- 3 sites per mum(2) in the present study). The addition of spinal cord explants caused an increase in average receptor site density of about 6 times on myotubes within 2 mm of the explant, while a smaller increase of 3 times was observed at distances greater than 5 mm. The formation of high-density patches of receptors was also stimulated. These observations suggested that a diffusible substance originating from the explant was responsible for these changes. Cell-free homogenates of the central nervous system were prepared and found to produce the same effects. The effect of the homogenate was not strongly dependent on the age of the fetus from which the tissue was isolated, and fetal liver had little or no effect. The active component(s) appears to be a protein(s) with a molecular weight of about 100,000. Because the nerve homogenates make the L(6) cells resemble primary muscle cultures, we suggest that a common factor is responsible for regulating the acetylcholine receptor in the two types of muscle culture. The normally acetylcholine receptor-poor L(6) cells may provide a more sensitive assay for these factors than do primary muscle cultures.


Evolutionary adaptation of membranes to temperature.

The "fluidity" of brain synaptosomal membrane preparations of arctic and hot-springs fish species, two temperature water fish species acclimated to different seasonal temperatures, and two mammals was estimated using the fluorescence polarization technique. At all measurement temperatures, the fluidity decreased in the order: arctic sculpin, 5 degrees-acclimated goldfish, 25 degrees-acclimated goldfish, desert pupfish, and rat. This correlated with increasing adaptation or body (i.e., cellular) temperatures of 0 degrees, 5 degrees, 25 degrees, 34 degrees, and 37 degrees and suggested a partial compensation of membrane fluidity for environmental temperature that occurs over the evolutionary time period as well as during laboratory (seasonal) acclimation. Evolutionary adaptation of relatively stenothermal species to constant thermal environments resulted in a more complete compensation than laboratory (seasonal) acclimation. Each compensation is accompanied by differences in the saturation of membrane phosphoglycerides. At increased cellular temperatures the proportion of saturated fatty acids increased and the unsaturation index decreased; the correlation between these indices and the measured expression of membrane dynamic structure was highly significant. It is concluded that the homeoviscous compensation of synaptic membrane function is an important component of temperature adaptation.


The law of perceptual stability: abastract foundations.

Confronted with an object of perception, an individual will spontaneously try to identify unambiguously and consistently all its parts; except in rare instances of "illusory phenomena," he will immediately succeed. This elementary fact is formalized in a law of visual perception. It is used to define sets of stable states for a sensory mode of a biological system. As characterized, stable states are to perception as quantum states are to atomic structure: they represent natural states of physical systems. They are shown to be observable and to have an exact mathematical representation.A class of bounded open subsets of a two-dimensional Euclidean space, whose boundaries are piecewise compact analytic arcs, is used to construct a nontrivial mathematical model for stable states. The finitely many components of this mathematical model of a stable state (image) are mapped onto an object of perception (icon) by perceptual judgments. These judgments, which include the judgment of stability, have an exact interpretation in this model. They unify and make precise such traditional notions of psychology as "Gestalt," "figureground," and "(visual) boundary."Postulates for a general theory of perception are given. They are used to establish a formal relationship between biological and subjective studies of sensory phenomena and so provide a framework in which subjective studies can be used to analyze (their associated) biological processes. In applying these methods to cases, all icons are divided into two classes (the static and dynamic cases). The static case is treated.


The effect of chronic parathyroid extract on tooth eruption and dental tissues in osteopetrotic mice.

The grey lethal mouse is an osteopetrotic mutant in which there is diffuse sclerosis of the entire skeleton and the teeth remain trapped in the jaws. The condition was treated with daily subcutaneous injections of PTE beginning at birth. PTE induced molar tooth eruption in some mutants and improved root formation (without eruption) in others. However, the zone of predentine in the crown of the tooth remained abnormally wide and dentinogenesis remained irregular.  Resorption of alveolar bone was adequate to permit complete tooth eruption in some animals and increased root formation in others.


Partial and full mouth recording of gingivitis scores.

Sixty-six dental students, randomly assigned to one of three examiners, were scored initially for gingivitis using the Columbia gingival index (GI). After four weekly prophylaxes, gingival scores for all teeth were recorded at day 0. Following prophylaxes, all subjects were randomly assigned one of three mouthwash formulations. Gingival scores were taken on the full mouth after three weeks and again after six weeks. Pearson product moment correlation coefficients (r) were obtained for the gingivitis index from six selected teeth (partial score) with the full mouth score, usually based on 24 to 28 teeth. GI scores obtained from partial recording on the six selected teeth correlated very well with scores obtained from full mouth examinations. A special study was set up to obtain independent GI readings for the six target teeth and for the full mouth. GI scores obtained by independent examinations of the six selected teeth also correlated well with the full mouth scores, although not as well as when the partial scores were derived from the full mouth scores. Partial scores should only be compared with partial scores obtained from evaluating the same teeth and not with full mouth scores, in clinical trials or epidemiologic surveys.


Plasma levels of lignocaine after peri-oral injections of two different concentrations.

Volunteer subjects received 50 mg of lignocaine solution as a maxillary infiltration injection, one one occasion as 1% solution and on another as 5% solution. The plasma levels of lignocaine were measured over a two-hour period and similar concentrations were achieved from both solutions, although the larger volumes of the more dilute solution gave slightly higher results, probably reaching toxic levels in one case. The injection of the higher concentration did not produce particularly high plasma levels of lignocaine.


[Pain in the maxillofacial area: diagnosis and treatment].

Based on characteristic case-reports the mostly occurring patterns of maxillo-facial pain are discussed. A description is given of pain in case of pulpitis, dento-alveolar abcess, dry socket, deep local periodonitis, temporomandibular joint arthrosis, dehiscence of the mandibular canal, maxillary sinusitis, malignant neoplasm. Trigeminal neuralgia, atypical facial neuralgia and psychogenic pains are discussed. The article concludes with a survey of the most important symptoms of these pain-syndromes in order to facilitate a correct diagnosis.


[Megaloblastic vitamin B 12 deficiency anemia with erythroleukemic blood picture].

Report on a case of severe megaloblastic anemia in a vegetarian, associated with marked erythroleukemic blood findings probably caused by infections (bronchopneumonia, asthmatic bronchitis, urinary tract infection) and severe heart failure. Successful treatment of the above mentioned complications resulted in almost complete disappearance of pathologic cells from the blood even before vitamin B12 treatment was started. With this therapy complete recovery was achieved and the signs suspect for erythroleukemia in blood and bone marrow disappeared definitively. The case also fulfilled all the criteria of pernicious anemia (Schilling's test and determination of intrinsic factor were not done).


[Temporomandibular joint, statistical study (comparative sagittal tomography) of the relationship between the surfaces of the glenoid cavity and the condyle and condylar displacement during maximal opening].

266 sagittal tomographs corresponding to the left and right temporo-mandibular joints of 133 patients were divided into 7 groups according to the absence or presence of functional disturbances or of organic lesions. The statistical analysis of the values obtained from a "triangular study" of the surface of the glenoid fossa and of the mandibular condyle showed the following: - the average surface area of the glenoid fossa does not significantly differ from one to the other of the 7 groups examined - the average surface of the mandibular condyle did not significantly vary between groups - in no group studied, except the F/P group (function disturbances/small displacement), was there any relationship between the surface of the glenoid fossa and that of the condyle. It can, however, be stated that the relationship between the surface of the glenoid fossa and the mandibular condyle would seem to play a role in the degree of displacement of the condyle during full opening of the mouth.


[Principles of the TNM system].

The principle of the TNM system consists of the exclusive description of the anatomical spreading of cancerous diseases. We distinguish between clinical and postsurgical classification. Clinical classification is applied in principle before the decision for therapy. This pretherapeutical status is the foundation for the interdisciplinary treatment planning, prognosis and recording of results. The postsurgical classification is mainly used in visceral localizations. According to the most important stages of the disease, further classifications may be used, like the surgical-evaluative and the autopsy classification. Such different classifications are necessary because the preciseness of the prognosis depends upon the accuracy of the description of tumor extension. It is therefore important to supplement the tumor formula by a factor C (C for Certainty). This factor indicates by what diagnostic means the TNM categories of the mentioned formula were determined. The C-factor categories are defined and described in their principal use. Finally there are some fundamental observations to the problem of the revision of the TNM classification.


[Comparative study on 4.cephalometric measurements for the demonstration of the sagittal intermaxillary relation with special reference to Swiss health insurance criteria].

For 4 cephalometric criteria (the angles ANB and AB-OCC and the distances AFH-BFH and "Wits"), which all are measured to show the relation between the maxilla and the mandible (i.e. the A- and B-points), average values, standard errors, standard deviations and errors of the method were determined in a sample of 298 schoolchildren of Zurich, who were selected on the basis of their date of birth only. It could be demonstrated that the angle ANB is dependent on both the angle SNA and NA to Frankfort horizontal, and that this dependence is linear. The angle AB to occlusal plane however seems to be independent of the relation between the A-point and the Nasion. Both ANB and AB-OCC could be determined with the same accuracy.


McArdle's disease--what limit to the age of onset?

A patient with McArdle's disease is reported in whome proximal muscle weakness began in the 7th decade. Other unusual features included the absence of muscle cramps at any stage, asymmetrical wasting of the shoulder girdle muscles and calf hypertrophy. Muscle biopsy revealed a vacuolar myopathy, absent phosphorylase staining and qualitatively low glycogen content.


Pathology of choroidal melanomas. Unusual aspects confusing the clinical diagnosis.

A number of morphological changes may occur in a choroidal melanoma or in the structures above it which may make the clinical diagnosis of the tumour difficult, even if modern diagnostic methods are used.


Conjunctival melanocytic lesions. Natural history.

Conjunctival melanocytes are like those of the skin and benign and malignant lesions composed of conjuctival melanocytes act much like those of skin. Conjunctival naevi are common and usually benign. Conjunctival melanomas are rare and arise de novo, from pre-existing junctional naevi or from intraepithelial melanomas either superficial spreading melanoma (SSM) or Hutchinson's freckle (HF). It is important to utilize the newer data about skin melanomas in any consideration of the diagnosis and prognosis of melanotic conjunctival lesions. Until more information is gathered we cannot provide an accurate assessment of the natural history of malignant conjunctival melanomas.


Immunological mechanisms in choroidal melanoma.

There are now several experimental immunological assays which may occasionally be useful as additional diagnostic tests for choroidal melanoma. These tests may also be helpful as a guide to prognosis. In patients who have a poor prognosis, immunotherapy may prolong survival after enucleation.


Lymphocytic infiltration in choroidal melanoma and its prognostic significance.

Lymphocytic and plasmacytic infiltration surrounding a malignant tumour probably represents an immunological response of the host directed against the neoplasm. Lymphocytic infiltration has a favourable effect on the prognosis in a number of human tunours, including cutaneous melanoma. The present study includes 326 consecutive cases of cholroidal melanoma which were examined for cellular infiltration. These data were then correlated with other histological parameters and with prognosis. An intense cellular infiltration was found in fifteen tumours (4.6 per cent) and a moderate infiltration in forty (12.3 per cent). Tumours with cellular infiltration were significantly larger and more vascularized than the remaining tumours, which may relate to the accessibility of the immune system to the tumour. There was a higher percentage of poorly differentiated tumours among those with cellular infiltration. However, it does not appear that cellular infiltration favourably influences the prognosis of choroidal melanoma, as 5-year survival rates did not correlate with the degree of cellular infiltration demonstrated by the primary tumour. Although choroidal melanomas are capable of inciting an immune response, this response is apparently ineffective in preventing metastastic spread.


Modern methods in the diagnosis of uveal melanomas.

Many of the difficulties in diagnosing choroidal melanomas which confronted clinicians in the past have now been eliminated. This is due to greater clinical awareness of melanomas and pseudomelanomas, as well as the use of indirect ophthalmoscopy and other ancillary tests. With further investigation, other diagnostic techniques may be developed for clinical use.


Radiation therapy of choroidal melanoma.

During the past 8 years, 32 patients with melanoma of the choroid have been treated with cobalt-60 ophthalmic applicators. Excluding three patients lost to follow-up, 24 patients who have now been observed for at least 3 years after treatment form the subject of this study. Each application but two delivered 8,500 to 10,000 rads to the tumour apex. A second application was performed in large tumours showing a poor response to the initial plaque treatment. The factors affecting results include age of the patient, tumour size, total dose delivered, and dose rate. Three out of seventeen patients with tumour diameters greater than 12 mm died of their disease with pulmonary and/or liver metastasis. Three eyes required enucleation and no residual tumour was found in two specimens. Three patients, average age 76 years, died from causes other than melanoma. An 83 per cent relative survival, excluding the three patients lost to follow-up, compares favourably with enucleation. The low incidence of metastasis after radiotherapy suggests augmentation and/or continuation of the host's immune response. Low energy radiation using Iodine-125, with its unusual protective characteristics is ideal for treatment of choroidal melanoma.


Regulation of growth hormone secretion during normal conditions and in patients with acromegaly.

A present considered concept of growth hormone secretion is that the hormone is tonically inhibited by the hypothalamic tetradecapeptide somatostatin. The episodic fashion of GH secretion with 6-8 GH peaks per 24 hours and its modulation by light and sleep are probably governed by factors other than somatostain, one possibly being melatonin. Evidence for a GH-releasing factor also exists, causing a basal release pattern of GH in moderate hourly peaks. The regulotary peptides in their turn, and possibly the GH producing cell itself, are influenced by dopaminergic or noradrenergic neurons. GH secretion is also modulated in a not yet elucidated relation to serotonin activity. Furthermore, GH induced somatomedin may constitute a negative feed-back on the pituitary and/or hypothalamic level. In acromegaly and gigantism, conditions characterized by chronic hypersecretion of GH, the GH producing cells are less differentiated as indicated by their response with GH release to unphysiological stimuli as well as their cessation of GH release to stimuli that normally act as releasors of GH.


Experiences with bromocriptine treatment in acromegaly--a preliminary report.

Seven acromegalic patients were treated with 20 mg bromocriptine daily for 3--8 weeks. Four responded with reduction but not normalization of plasma growth hormone (GH) whereas three showed no response. In all patients with subjective symptoms of joint stiffness, sweating and headache improvement occurred, but this was independent of GH response. Hyperacidity and/or obstipation occurred in five patients. These side effects were slight and transitory in four but severe in one. Prolactin levels were normal in all patients before treatment and became unmeasurable during bromocriptine.


Effect of the dopamine agonist bromocriptine on blood pressure, catecholamines and renin activity in acromegalics at rest, following exercise and during insulin induced hypoglycemia.

Seven acromegalic patients were given bromocriptine, starting with 1.25 mg/day, then gradually increased to 20 mg daily, which dosage was continued for 3--9 weeks. Treatment with bromocriptine resulted in a significant fall of systolic and diastolic blood pressure in supine and upright position accompanied by a marked reduction in plasma and urinary noradrenaline but without effect on adrenaline. Plasma renin activity fell during institution of bromocriptine and remained significantly lower during prolonged treatment. Urinary aldosterone showed no significant changes during medication. The plasma noradrenaline response to physical exercise was reduced by bromocriptine treatment, whereas the adrenaline response was unaltered. The plasma catecholamine response to hypoglycemia was not statistically different during bromocriptine as compared to before medication.


Comparison of the use of inorganic and organic bases in the Zimmermann reaction for 17-oxosteroids.

A comparison has been made between inorganic and organic bases proposed for use in the Zimmermann reaction for 17-oxosteroids. The use of inorganic base in pyridine solution is preferred for large scale liquid chromatography because of its high sensitivity and its better wetting characteristics. Several of the organic bases tested have desirable characteristics when used for total group assays and may be preferred by some for such assays.


The specificity of multi-column liquid chromatography of neutral urinary steroids as evaluated by comparison with parallel gas chromatography and mass spectrometry.

The use of gas chromatography/mass spectrometry is advocated as the best currently available methodology for the validation of a routine assay for steroid analysis. This is documented by comparative studies by gas chromatography/mass spectrometry and spectrophotometry of peak material obtained in routine assays by multi-column liquid chromatographic techniques.


Quality control measures in the assay of common urinary steroids as applied to a multi-column chromatographic procedure.

Quality control measures in the assay of common urinary steroids include stringent controls not only with details of the procedure but also, through a steady monitoring of the output, with the use of "blind" duplicates, the application of estimates of duplicate variability, comparison of the sum of individual steroids chromatographically estimated with independent total group assays and the use of internal standards in the procedure.


Excretion of common neutral steroids in healthy subjects as estimated by multi-column chromatography.

Excretion data for common neutral urinary steroids from a total of 330 healthy subjects from different parts of the world and of different sex and age are given. The estimations, which have been performed by multi-column liquid chromatography, include 24 h excretion values for both common 17-oxosteroids and the common metabolites of cortisol, including the cortolones and the cortols. Comparisons are made with values from the world literature and with isotope experiments.


Comparison between total group assays for urinary 17-oxosteroids and 17-oxogenic steroids and estimates of individual urinary steroids.

A comparison between a group assay for total 17-oxosteroids in urine and the summed values for individual 17-oxosteroids shows a high correlation between these sets of values. Similarly, a group assay for 17-oxogenic steroids was found to correlate highly with the sum of individual corticosteroids.


Multi-column chromatography and the use of isotopes in the study of steroid metabolism.

Multi-column liquid chromatography is demonstrated to be a technique well suited for isotope experiments involving administration of labelled cortisol. It has potential for secretion rate determinations, for dynamic studies of cortisol metabolism and for work with stable isotopes.


Multi-column chromatography of urinary steriods and adrenocortical dysfunction.

The potential of the multi-column assay for urinary neutral steroids in work with samples from patients with adrenocortical pathology is demonstrated through analyses performed on urine samples from Cushing and congenital adrenal hyperplasia cases, after modification of the routine methodology to include the quantitation of additional steroids of particular importance for pathological samples.


Multi-column chromatography of urinary 17-ox osteroids as their 2,4-dinitrophenylhdrazones.

The use of 2,4-dinitrophenylhydrazones in the multi-column chromatography of 17-oxosteroids from urinary extracts has been possible on mixed columns of alumina and silica gel. Preliminary results indicate agreement with values obtained using the Zimmermann reaction. The hydrazones have the advantage of color stability, when compared with the Zimmermann reaction, and the analysis is simpler and cheaper to perform.


The multicuvette general analytical system for combined multi-column chromatography and high capacity single substance and group analyses and its application to steroid analyses.

A description is given of the development of a general analytical system for both single and group analyses and for analyses of profiles of compounds after multi-column liquid/liquid and liquid/solid chromatography. Common for both branches of the system is a computerized quantitation system built around a multi-compartmented cuvette. The system is compared with other high capacity systems for biochemical analyses. Special attention is given to the application of the system to the analysis of urinary steroids, both individual and as groups, with a comparison with similar methology using other techniques.


General methodology for the estimation of common neutral urinary steroids by multi-columin liquid chromatography.

A method is described for the estimation of common neutral urinary steroids by multi-column liquid chromatography. Hydrolysis is performed in two steps: enzymatically, using beta-glucuronidase, followed by solvolysis. Initial short column chromatography separates the neutral steroids into three fractions according to polarity: 17-oxosteroids, corticosteriods less polar than cortolones, and cortolones and cortols. The cortolone, cortol fraction is oxidized and the different steroid groups are chromatographed on capillary aluminum oxide and silica gel columns. A computerized, spectrophotometric system is used for the quantitation procedure.


The hydrolysis of conjugated neutral steroids in urine.

Complete hydrolysis of known conjugates of neutral steroids in urine requires a combination of solvolysis and enzymatic hydrolysis. Procedures are established for optimal yield in the enzymatic part of the hydrolysis using different preparations of beta-glucuronidase. The effect of temperature and the use of conjugate extraction in the hydrolytic procedure is explored. It is stressed that relatively high concentrations of enzyme are necessary to insure full hydrolysis of a few conjugates that are particularly difficult to split by enzymatic hydrolysis.


Intermittent mandatory ventilation. A method to expand clinical applications.

The described modification of the Cameco URS-701 ventilator increases the frequency possibilities from zero to 40, without interfering with the ventilator pattern of each cycle and satisfies the required conditions for a classical IMV-system. Moreover it can provide longer periods of controlled ventilation alternating with periods of spontaneous respiration. This adaptation, mainly consisting of the introduction of a timer in the electrical circuit of the machine, provides us with a safe IMV system on our Engstrom 150 type ventilator and leads to a broader concept of IMV.


Report of an incident during the use of the Servo-ventilator 900 in paediatric anesthesia.

The authors report the occurrence of an incident during the use of the Servo-ventilator 900 for paediatric anesthesia; it consisted in self-oscillation of the gas column contained in the patient respiratory circuit. After having analysed the incident and outlined the various ways of avoiding it, attention is drawn to the importance of the total circuit volume of the respirator. The respiratory circuit chosen for ventilating children, has a compliance of 1.3 ml/cm H2O.


Circumvallate placenta and intrauterine growth retardation.

A study has been made of a prospectively selected material of circumvallate placentae; the latter being defined as an elevated edge of more than 50% of the circumference. The material consists of 447 placentae from liveborn singleton infants, where 287 were from exemplary pregnancies, and 160 from births with a gestational age (GA) of less than 266 days and/or a birth weight of less than 2750 g. The material was prospectively randomized. It was divided into clinical groups according to the GA and under-weight. Nineteen circumvallate placentae were found. Among these were more multigravidae and more with pre-gestational menstrual irregularity than expected. The number of antepartum haemorrhages was as expected. There were more premature infants, premature under-weight infants and under-weight infants than expected. Nine of the 20 premature under-weight infants in the material had circumvallate placenta. In relation to a previously published basic material, it was found that the birth weight, and placental content of RNA and DNA were significantly reduced. It is concluded that placentae with more than 50% circumvallation are associated with prematurity and under-weight, as well as a placenta with fewer cells than normal. The genesis of the anomaly is discussed.


The relationship between some disorders of the umbilical cord and intrauterine growth retardation.

Some disorders of the umbilical cord--Single umbilical artery, oedema of the cord, battledore insertion and velamentous insertion--have been examined in a prospectively randomized material. The material consists of 447 placentae from liveborn, singleton infants, where 287 were from exemplary pregnancies, and 160 from births with a gestational age of less than 266 days and/or a birth weight of less than 2750 g. The placentae were examined macroscopically and microscopically, and the total amount of protein, RNA, and DNA were determined in a randomized sample. Single umbilical artery was found to coincide with circumvallate placenta, suggesting a common fault in the placentation. Oedema of the umbilical cord was found to have no significance for the infant, but their placentae were significantly heavier, without signs of generalized oedema. The birth weight and placental weight were slightly and equally reduced in battledore insertion of the cord. The RNA/DNA ratio was increased, indicating tissue stress. This anomaly contrasted to the placentae, in which the cords were inserted velamentously. These had significantly reduced birth weights, and the weights of the placentae were slightly reduced. The incidences of complications during labour and congenital anomalies were increased.


Infarctions and intervillous thrombosis in placenta, and their association with intrauterine growth retardation.

The number of infarctions and intervillous thromboses have been determined in a randomized, optimal obstetric material, consisting of 301 placentae. All the placentae were examined without knowledge of the pregnancies, deliveries or infants. They were examined macroscopically and histologically. The total content of protein, RNA and DNA were determined in a randomized sample of the 301 placentae. Fifty-two placentae had small infarctions, and the corresponding birth weights, placental weights and placental DNA were of the same magnitude as in the remainder of the material. There was the same frequency of infarctions among the placentae with intervillous thrombosis. There were 11 with intervillous thrombosis, and they had a significant reduction in infant birth weight and in placental content of DNA. A significant part of these (6) had asphyxia at birth. In neither of the groups was there proliferation of Langhans cells as a sign of longer lasting anoxia. The extent of villous fibrosis in the groups was the same as in the remainder of the material. It is concluded, that no evidence was found to support a theory that infarctions and intervillous thromboses have the same pathogenesis.


The significance of different forms of placentitis.

A blind histological examination of placentae, with regard to placentitis, was carried out of 2 prospective, selected materials. The first consisted of 283 placentae, which were selected with regard to optimal obstetric outcome. The second consisted of 160 placentae, randomized from all premature and low birth weight infants in the local area. Placentitis was sub-divided into: funisitis, chorionitis, villitis and hypercellular villi. Funisitis was found in premature infants only. Villitis resulted in the birth of significantly smaller infants and placentae, and must therefore, in contrast to funisitis and chorionitis, be considered chronic. Hypercellular villi are found to have no importance. Funisitis, chorionitis and villitis could possibly be explained by an infection in 10 of a total of 15 cases of placentitis.


Stress/strain behavior of dental amalgams.

The stress/strain behavior at different strain rates and the creep rate of dental amalgams were evaluated and compared to the microstructure. The results indicate that substantial differences exist both in strength and strain at fracture. The strain at fracture for high strain rates was associated with the nature of the particle-matrix interface, in that amalgams with an interpenetrating interface exhibited some ductility, while amalgams with an abrupt interface exhibited practically no plastic deformation at fracture. The correlation between creep and slow compressive strength was verified and it was suggested that grain boundary sliding was the deformation mechanism in both cases.


A method for evaluation of initial tissue response to biomaterials.

In the present paper an implantation technique is described whereby the effect of the surgical operation is eliminated and initial tissue reactions to materials may be studied. A teflon body was implanted intramuscularly in rabbits. After six weeks the overlaying tissue was excised and the implant removed. An intact, nonepithelialized tissue surface was exposed, which due to the shape of the implant showed three indentations. Materials were placed in the indentations for 15 minutes and the tissue reaction was registered by enzyme histochemical methods. Silicate cement, zinc phosphate cement and a 4% phenol solution caused an inhibition in the dehydrogenase enzyme activity in the tissue subjacent to the indentations. The severity of the tissue reaction, indicated by the width of the inhibition zone, varied among the test materials. Silicate cement caused the widest inhibition zone and the phenol solution the narrowest one. These results correlate well with previous tissue compatibility studies and indicate that the method is applicable for in vivo screening of initial tissue response to biomaterials.


Remaining methacrylate groups in composite restorative materials.

The quantity of the remaining unreacted methacrylate groups in polymerized composite materials has been determined. Six proprietary composites were investigated by infrared multiple internal reflection spectroscopy. Infrared reflectance measurements were made before polymerization and repeated after the composites were subjected to polymerization at 37 degrees C for 24 hours. The quantities of remaining unreacted methacrylate groups were determined and the data expressed as percentages of the total amount of methacrylate groups in the unpolymerized materials. The specimens were specially prepared to ensure that the surface properties simulated the bulk properties of the polymerized composites. The quantities of remaining methacrylate groups in the six composites determined by this surface measuring technique ranged from 25 to 48%. The results demonstrate that commercially available composite materials exhibit different degrees of conversion 24 hours after the start of polymerization. These differences can be correlated to the different monomer compositions of the composite restorative resins.


Oral hygiene, periodontal health and need for periodontal treatment among institutionalized mentally subnormal persons in Norway.

Oral hygiene, periodontal health and periodontal treatment needs were studied in the dentulous patients (n = 328) of a sample selected to be representative of all institutionalized mentally subnormal persons in Norway aged 5--45. The average oral hygiene and periodontal health was poor except for patients in a few institutions where the nurses were trained to clean teeth regularly. Increased age, epilepsy, Down's syndrome and a high degree of mental deficiency were all elements that apparently contributed to impairment of periodontal health and to increased treatment requirements. The preventive programs used in some institutions seemed to be effective. Still better results, however, could probably be obtained by the use of dental hygienists.


Heavy trace elements in ancient Norwegian teeth.

The present work was undertaken in order to determine the content of lead, cadmium, copper and zinc in 26 teeth retrieved from burial-grounds in various parts of Norway, dated from A.D. 200 up to 1850. The analyses were made by differential pulse stripping voltammetry on hydrochloric acid digests of the teeth. High levels of lead were found in teeth dated from ca A.D. 1500 from Gimsøy Kloster and Tønsberg. Teeth originating from A.D. 200 showed a high content of Cd, Cu and Zn.


Smouldering acute myelogenous leukemia.

Among 195 patients with variants of acute myelogenous leukemia (AML), a minimum of 11 met our criteria of smouldering AML: patients with less than 30% of blast cells plus promyelocytes in the bone marrow at the time of diagnosis who were observed without specific antileukemic therapy for a period of at least 6 months without entering a fulminant stage of the disease. These patients were older than other patients with AML, they had initially relatively few infections, bled rarely, and did not enter the fullblown clinical picture typical of acute leukemia until the last months of life. For these 11 patients the median survival time was 29 months from the time of diagnosis. Patients with smouldering leukemia shall be observed carefully and not be given specific antileukemic therapy, at least not before they flare into a blast crisis. Transfusions, antibiotics and a small dose of prednisone should be given when necessary.


Development of a histiocytic medullary reticulosis-like syndrome during the course of acute lymphocytic leukemia.

A 54 year old woman presented with acute lymphocytic leukemia. Following an initial response to chemotherapy with vincristine and prednisone, progressive pancytopenia developed coincident with intense bone marrow infiltration by abnormal histiocytes. At autopsy two months later, no evidence of leukemia was found, but the bone marrow was replaced by abnormal histiocytes showing active erythrophagocytosis, consistent with histiocytic medullary reticulosis. Detailed morphologic, ultrastructural and histochemical studies performed throughout the course of the patient's illness served to confirm the transition from leukemia to histiocytosis. Four similar cases of acute lymphocytic leukemia terminating in histiocytic medullary reticulosis have been reported. This association may represent a distinct clinicopathologic syndrome.


Surgical-orthodontic correction of vertical maxillary excess.

Superior repositioning of the maxilla via maxillary ostectomy has proved to be useful method of treating patients with vertical maxillary excess. It is indicated primarily in patients with lip incompetence, excessive exposure of maxillary anterior teeth, long lower facial height, contour-deficient chin, and either Class I or Class II malocclusion. We have used this procedure as routine treatment for vertical maxillary excess over the past 5 years. Timing of the surgery is not so important in non-open-bite patients, and the procedure can be done with equal success before any orthodontic intervention, during orthodontic treatment, and following all orthodontic procedures. Timing is primarily dependent upon the orthodontist's desires. Since the surgery can produce a much simpler orthodontic problem, thus reducing treatment time and allowing a better over-all result, we recommend that it be done as early in treatment as possible. Clinically, the over-all improvement in facial appearance and the predictability and stability of the results have made this a most versatile and effective procedure when carried out with good planning, proper execution and attention to detail.


An epidemiologic survey of malocclusions among American Negroes and American Hispanics.

The malocclusions of thirty-six Negro and fifty-six Puerto Rican orthodontic patients from a specific area were surveyed. The population was divided according to sex, age, and skeletal classification. The total Negro malocclusion sample was compared to available Negro norms for both Downs and Steiner analyses. The total Hispanic malocclusion group was compared to available Negro and Caucasian norms for the same analyses. Ranges, means, and standard deviations were developed for each measurement recorded. The comparative frequency of individual skeletal classifications was found to be remarkably similar in both groups, and the percentage of open-bites was greater in both groups than in the general population. The need to expand available material to include a Puerto Rican group is noted.


Improving orthodontic results in cases with maxillary incisors missing.

This article has aimed at providing information on how to improve clinical orthodontic results in cases in which maxillary central and lateral incisors are missing. Different sections deal with (1) treatment approach and mechanics, (2) details in finishing, (3) modifications of clinical tooth crowns by special procedures (grinding, composite "corners," gingivectomy), (4) functional considerations and root resorption, and (5) retention.


The role of the occlusal "simulator" in orthodontic treatment prior to surgical osteotomy.

The application of occlusal geometry in skeletal Class III cases, as related to the surgical relocation of one or both dental arches, is described. It has been established when and why it is helpful to relate the dental arches to each other before surgery, and an orthodontic method utilizing a simulator for jaw relocation is illustrated. The effectiveness of the method is clearly demonstrated through a clinically treated case.


Osteogenesis and chondrogenesis in transplants of Dunn and Ridgway osteosarcoma cell cultures.

Dunn osteosarcomas synthesize 2 times more alkaline phosphatase than do Ridgeway osteosarcomas, 3 times more than do HeLa cells, and 4 to 5 times more than do rat or mouse fibroblast cell cultures. Implants of killed freeze-dried Dunn cell cultures into the thigh muscles are resorbed and replaced by normal cartilage, bone, and bone marrow tissue, while implants of freeze-dried Ridgeway cells are resorbed and replaced by fibrous tissue only. Outgrowths of normal muscle septum connective tissue cells onto the stroma of Ridgeway tumors differentiate into fibrous tissue. Cultures of either tumor on a substratum of bone matrix stroma prepared from normal bone proliferate, assume a spherical shape, and perpetuate the transformed osteoblast-like cell without forming attachments or adapting to the contour of the substratum. Outgrwoths of muscle mesenchymal cells on the Dunn tumor stroma differentiate into cartilage. Dunn osteosarcoma cell cultures proliferate on the inside and produce deposits of normal bone (not tumorous bone) on the outside of diffusion chambers. Killed freeze-dried cell cultures produce transfilter deposits of normal bone and bone marrow, but the quantity is significantly lower. On a substratum of cellulose acetate, outgrowths of muscle connective tissue will differentiate into cartilage when cell-free Dunn stroma is present under the organ culture grid. Tumorigenesis and normal cartilage and bone morphodifferentiation are antithetic, but tumor cells transfer a bone morphogen similar to the bone morphogenetic protein (BMP) of normal bone matrix. BMP recruits  mesenchymal cells to proliferate and differentiate into cartilage and bone.


[A simple universally applicable I.M.V. system (author's transl)].

A simple I.M.V.-system is described based on the AMBU-E-valve applied to pressure-cycled ventilators (e.g. Bird Mark VII).


The effect of storage on the activity of adrenaline in local anaesthetic solutions: an evaluation using bioassay and fluorometric techniques.

The adrenaline content of local anaesthetic solutions has been assessed using a bioassay system and a fluorometric assay method. It was found that exposure of the solutions to daylight for a period of six months greatly reduced their adrenaline content, whereas storage of the same solutions under refrigeration or in the dark reduced the decrease in catecholamine content. Solutions containing adrenaline which were shown in the clinical situation to give inadequate anaesthesia were also tested. The analysis revealed a decline of catecholamine content in each solution.


Vitamin status of patients with oral lichen planus.

Correction of proven vitamin deficiencies in patients with oral lichen planus resulted in both clinical and subjective improvement in the majority treated but did not produce complete remission of the lesions. The common finding of low levels of vitamins B1 and B6 in both the lichen planus group and in healthy controls suggests that this is a reflection of dietary habits of the local community not generally appreciated.


The influence of the refractory investment on the development of porosity in cast structures.

Four series of standard tensile specimens were produced by casting into moulds composed of silica bonded, gypsum bonded, and phosphate bonded refractories. Two nickel base alloys were employed, one a standard dental casting alloy and the other a specially formulated ductile material. Subsequently, all specimens were subjected to mechanical testing, and radiographic and metallographic evaluation, in conjunction with porosity determinations, in order to ascertain how the nature of the refractory investment influences the structural quality of the castings produced.


Spectral fluorescence of direct anterior restorative materials.

The fluorescent characteristics of silicate cements, acrylic resins, and composite resins and all anterior restorative materials have been compared with the natural teeth when specimens were submitted to ultra-violet radiation. The effect of glazes on composite resins and of discolouration from ultra-violet radiation on composites and acrylic resins is to reduce the amount of fluorescence of the former and to change the quality of the fluorescence.


Scanning electron microscopy of human dental pellicle and initial plaque formation in vivo.

Small, specially prepared gold alloy discs were recessed into the right and left posterior surfaces of duplicate maxillary dentures. At selected time intervals, a disc was removed from each side of the denture and prepared for examination with a scanning electron microscope (SEM). A thin, peeling film of pellicle was seen on the discs removed after two hours and projections designated "hemispherical globules" formed on the pellicle within the next seven hours.


Viral hepatitis: a review of clinical, laboratory and research aspects.

The nature and the diagnosis and prognosis of the two forms of viral hepatitis is discussed. The possibility of transmission of these diseases during dental treatment to other patients or to dentists or their staff is considered and measures to reduce this risk are suggested.


Postoperative infection in arterial surgery: a review of the incidence and distribution in 386 patients.

The clinical records of 386 patients undergoing surgery for peripheral arterial disease during the period 1958 to 1974 were examined for patterns of wound infection. The incidence of infection in arterial reconstructive procedures was 7.4%, of which infections 2.2% were major. A high incidence of minor wound infection was found not to be of significance with regard to patient morbidity. The greater risk of wound infection occurring when there was an ischaemic skin lesion present distally in the limb was confirmed. An incision in the groin was not clearly identified as a significant factor in the development of wound infection. The prophylactic use of antibiotics has not resulted in a lower incidence of infection, when compared with those results reported from centres where antibiotic prophylaxis has not been routine. Analysis by year has demonstrated a lower incidence of infection in the more recent years 1969 to 1974.


Intermittent non-sterile catheterization of children suffering from spina bifida: an alternative to urinary diversion.

Ten children suffering from spina bifida with recurrent urinary tract infections and incontinence have been treated by intermittent non-sterile catheterization both at home and at school. Six have shown improvement in both infection rate and incontinence. Two have undergone urinary diversion, and two have had an equivocal result.


Aspects of surgical treatment for malignant melanoma: the place of biopsy and wide excision.

Biopsy of melanoma is discussed in respect of the operator, the adequacy of biopsy, and the time delay till wide excision; statistics are taken from a series of 509 patients with this disease who had their definitive surgery and review at the Peter MacCallum Clinic between 1954 and 1973. Wide excision is described in respect of its origins and its proponents, and discussion draws on appropriate material from the series.


A long-term review of digital replantation.

An analysis of the first 130 cases of digital revascularization and replantation performed at St Vincent's Hospital, Melbourne, during the period 1970-1977, confirms the long-term functional value of these procedures provided that strict indications for replantation are adhered to. Patient satisfaction has been almost universal, and objective testing shows that the most satisfying aspect of the procedure is the quality of sensory return. Flexor tendon function and the range of joint movement, however, are universally poor, and all patients complain of sensitivity to cold. The thumb has been by far the most satisfactory digit to replant, and avulsion injuries gave the poorest results, from the point of view of both survival and long-term function.


The traumatic pseudolipoma.

A contour deformity, clinically reminiscent of a large lipoma, can develop after a severe shearing-type injury to the upper thigh, hip, or sacrum, particularly in young women. As the injury is rarely dealt with in the first weeks, it usually presents after a deep scar has contracted. At this stage active surgical intervention seriously increases the aesthetic problem. Conservative treatment with massage, pressure, and possibly injection of steroids is more effective. To the best of our knowledge, this condition has not previously been described.


Albumin-containing plasma volume expanders.

Human albumin-containing solutions have been used as plasma volume expanders and in the management of severe hypoproteinaemia for over 30 years; Modern indications for their use are described in some detail. These include the management of shock, burns, adult respiratory distress syndrome, and priming of the cardiopulmonary bypass pump. Reactions to albumin infusions are rare. Recent reports of hypotension following rapid infusion of SPPS and PPF are under active pharmacological study.


Intraabdominal desmoid causing death in a young man with Gardner's syndrome.

The case is reported of a 22-year-old man with Gardner's syndrome who died as a consequence of unremitting spread of an intraabdominal desmoid four and a half years after colectomy for polyposis, and two and a half years after clinical presentation of the desmoid tumour.


Leiomyosarcoma of the duodenum: a report of three cases.

Three cases of leiomyosarcoma of the duodenum are reported in this paper. The first patient demonstrated the development of a leiomyosarcoma from a leiomyoma, and also posed diagnostic problems as a Pólya gastrectomy had previously been performed. The second patient presented with acute pancreatitis--a hitherto unreported complication of this condition. The third patient showed that even though the primary tumour was unresectable, the patient remained well for more than a year after diagnosis.


Double pathology in acute cholecystitis.

Three cases are described in which there was concurrent development of acute cholecystitis and a second acute abdominal illness. Acute cholecystitis occurred in patients with acute appendicitis, small bowell obstruction, and acute colonic diverticulitis. Experience with three such cases over the course of eight years by a single surgeon suggests a possible aetiological link between the two diseases. It is suggested that, under some circumstances, exploration of an acute abdomen may need to be more than cursory.


Restoration of grasp and pinch in a burnt hand by pollicization of an island flap taken from the same finger.

A unique opportunity to reconstruct a deformed hand by designing two neurovascular island flaps from a damaged index finger has been presented. One flap, a composite carrying the index tip, was used basically as in pollicization, while the second flap was used to reconstruct the web space. An excellent functional result was achieved.


An overview of plastic surgery.

In addition to many technical refinements during the past decade, plastic surgery has made particular advances through the use of microsurgery, in the control of burn wound infection, by the use of implantable silicones, in the correction of craniofacial deformities and through the development of axial-pattern and other specialized flaps.


The effect of colloid concentration on the functional characteristics of isolated perfused rat liver.

The volume of bile produced by isolated perfused rat liver was dependent on the concentration of bovine serum albumin (BSA) in the perfusate, the lowest volumes being obtained with Krebs Ringer bicarbonate (KRB alone and with 70 g/l. BSA in KRB. Increasing amounts were produced as the concentration of BSA was reduced from 70 g/l. to 8.5 g/l. The concentration of bile salts in the bile decreased rapidly during the first hour, but much more slowly thereafter. The highest concentration observed during the first hour was with KRB alone and the lowest with 20 g/l. BSA; subsequently, the highest concentrations were obtained with 70 g/l. BSA and the lowest with 20 g/l. BSA. Urea synthesis was lowest with KRB alone, but increased as the concentration of BSA increased; however, values obtained with 8.5, 20, and 40 g/l. were fairly close together. With KRB alone there was a rapid release of potassium during the first hour, but thereafter the rate of release was similar to that found when BSA was present. The lowest concentrations of potassium were obtained with 20 and 40 g/l. BSA. With KRB alone, GOT was released from the start of perfusion of 300 units per minute. With BSA present, GOT release was delayed 4 hours, and thereafter the rate was dependent on the concentration of BSA, being lowest with 20 and 40 g/l. (200 units per min), higher with 8.5 g/l. (350 units per min) and highest with 70 g/l. (400 units per min).


In-vitro studies of gallstone dissolution: the effect of added heparin in bile salt solutions.

The dissolving effect of four bile salt solutions (sodium cholate, sodium taurocholate, sodium deoxycholate and sodium chenodeoxycholate) upon gallstones was tested in an in-vitro preparation, using 226 stones from 38 patients. The effect of each solution was measured by recording weight loss in the gallstone at the end of a ten-day period of immersion in the bile salt solution. Sodium deoxycholate and sodium chenodeoxycholate produced the greatest average weight loss in the groups of stones tested with pure bile salt solutions, but the addition of heparin to solutions of sodium cholate and sodium deoxycholate produced a significant increase in weight loss in these solutions. This effect of heparin in the presence of bile salts, in comparison with the failure of heparinized saline to induce weight loss in gallstones, is discussed. Sodium chenodeoxycholate cannot be recommended for clinical use on the grounds of its toxicity, and in view of the possible toxicity of sodium deoxycholate it is concluded that a combination of sodium cholate with heparin is the optimum solution for the dissolution of retained intraduct calculi in vivo.


Resistance of Heidbrink-type expiratory valves.

The minimum resistance of expiratory Heidbrink-type value has been assessed by determining the pressure decrease across the values at a flow rate of 30 litre min--1. The average resistance of 70 valves currently in clinical use was 318 Pa at that flow rate and about 44% had resistances greater than the limit of 294 Pa previously suggested. The resistances obtained in new valves were either similar or fractionally greater. Valves being introduced as parts of scavenging systems appeared, on the whole, to have lower resistances.


Anaesthesia for laryngoscopy: a technique using the Nuffield Anaesthetic Ventilator.

An inflation catheter technique has been devised for providing general anaesthesia during laryngoscopy using the control module of the Nuffield Anaesthetic Ventilator driven by 50% nitrous oxide in oxygen. The system is simple and reliable in use and ensures adequate pulmonary ventilation.


Erythropoietin dependent erythropoiesis during the erythroblastic phase of juvenile chronic granulocytic leukaemia.

A child aged 3 1/2 years with typical juvenile chronic granulocytic leukaemia whose course terminated in an erythroblastic phase is described. Both in-vivo transfusion studies and in-vitro bone marrow culture studies indicate that red cell production remains erythropoietin dependent in this situation. The relationship of erythropoietin to the reversion to fetal haematopoiesis which characterizes juvenile chronic granulocytic leukaemia is discussed.


Cytogentics of fibroblastic colonies in Ph1-positive chronic myelogenous leukemia.

The cytogenetic status of bone marrow stromal elements obtained from six patients with Ph1-positive chronic myelogenous leukemia (CML), two in blast crisis, was studied in vitro utilizing the potential of marrow to form surface-adherent colonies morphologically compatible with mesenchymal elements. We demonstrated the absence of both the marker chromosome and other chromosomal abnormalities in all the fibroblastic colonies studied, indicating that the progenitors of such colonies (plaque-forming units in culture, PFU-C) are not closely related to hematopoietic elements including macrophages. This supports previous reports suggesting that the stromal elements in myelofibrosis associated with CML are not derived from the primary Ph1-positive malignant clone but represent a stromal reactive component of benign or independent malignant potential.


Evidence for distinct lymphocytic and monocytic populations in a patient with terminal transferase--positive acute leukemia.

Two distinct cell populations with lymphoblastic and monocytic characteristics were separated and characterized by multiple cell markers in a patient with terminal transferase-positive acute acute leukemia. The clinical course and sequential cell marker studies were consistent with the interpretation of a defect at the level of a common stem cell giving rise to a terminal transferase--positive lymphoblastic cell population at diagnosis and, following initial therapy, a terminal transferase--negative monocytic population.


Clonal evolution in atypical chronic granulocytic leukemia: a non-Philadelphia translocation.

Hemopoietic cells in chronic granulocytic leukemia (CGL) frequently contain a chromosome translocation involving chromosome 22 and another autosome, usually number 9. The translocated chromosome 22 is known as the Philadelphia (Ph) chromosome. The appearance of a second Ph chromosome is the most common cytogenetic abnormality in CGL signaling the blastic phase. For 6 yr we serially studied a man with atypical CGL whose marrow cells were marked by a translocation from chromosome 18 to chromosome 11 [46XY,t(11;18)(q23;q12)]. Three months prior to blast transformation there appeared an extra copy of the marker chromosome 18: 47XY,t(11;18)(q23;q12),+(18p11 leads to 18q12). This man presents a new cytogenetic pattern of clonal evolution in CGL. The pattern is analogous to that of the Ph chromosome and is characterized by a balanced chromosomal rearrangement and the subsequent acquisition of an extra copy of the small translocation chromosome immediately prior to blast transformation.


Cap formation on lymphocytes from patients with leukemic diseases induced by four different lectins.

When ficoll purified peripheral blood lymphocytes were treated with fluorescein conjugated lectins from lentils (LCH), castor beans (RCA) and phaseolus coccineus beans (L-and E-PHA) for 15 min and the percentages of the cap forming cells were examined, the values of leukemic lymphocytes were reduced compared to the values obtained with normal lymphocytes. The reduction was more than half in patients with acute and chronic myelogenous leukemia and immunoblastoma, it was only one quarter in patients with chronic lymphocytic leukemia, Hodgkin's disease and lymphosarcoma. The lowest number of cap forming cells was found in lymphoblasts of established lymphoblastoid cell lines. The four different lectins showed nearly the same capacity in the induction of caps. After successive binding, the different lectins showed cocapping on the lymphocyte surface.


The effect of diphenidol on ouabain cardiotoxicity in the cat.

The capacity of diphenidol to influence ouabain-induced cardiotoxicity was studied in anaesthetized cats with and without spinal cord transection. 2 Diphenidol pretreatment increased the lethal dose of ouabain in both intact cats and cats in which the spinal cords had been transected. Diphenidol pretreatment increased the myocardial content of ouabain associated with death in the intact animals, but failed to influence the lethal ventricular concentration in cats with transected spinal cords. 3 The failure of diphenidol to influence tissue thresholds for toxicity in the spinal cat and the equivalence of tissue ouabain requirements for death in spinal cats and diphenidol-treated intact animals, suggest a neural mechanism for the protective effect in intact animals. 4 Ouabain administration prolonged atrio-ventricular conduction time in all animals and diphenidol attenuated this effect. Thus, the influence of both drugs on antrioventricular conduction may not be entirely mediated by central neurones.


On the initiation of the swing phase of locomotion in chronic spinal cats.

In chronic spinal cats walking with the hind legs on a treadmill, one limb can be stopped by holding the paw while the other limb continues to walk. If the held limb is slowly brought backwards at one point the limb flexes and continues walking. It was found that the hip position at which the leg lifts off during such reaction is very close to the hip angle at the initiation of swing during locomotion. Similar findings were obtained by extending only the femur. The hand-held limb tends to initiate lift-off during the midstance or the midswing of the contralateral limb step cycle. It is concluded that hip position and the contralateral step cycle phase are two important factors determining the initiation of swing in one leg.


A fatal myeloproliferative syndrome in a family with thrombocytopenia and platelet dysfunction.

Three siblings with a lifelong history of a bleeding disorder and thrombocytopenia died from a myeloproliferative disease. In 2, the terminal event resembled juvenile chronic myelogenous leukemia, and in the third, the diagnosis was acute monocytic leukemia. A family study revealed that the mother and 5 other siblings had a variety of hematologic abnormalities. These included chronic thrombocytopenia, abnormal platelet function, elevated concentrations of HgbF or serum vitamin B12, and low leukocyte alkaline phosphatase (LAP) scores either singly or in combination. At the time of study, none had evidence of malignancy. Members of this family have a myeloproliferative disorder that has the potential for terminating in nonlymphocytic leukemia, a combination of events which appears not to have been reported previously.


Malignant histiocytosis occurring in patients with acute lymphocytic leukemia.

Five cases of malignant histiocytosis (MH) in patients being treated for acute lymphocytic leukemia (ALL) have been previously reported. Two additional cases are described here, all known cases are reviewed, and the phenomenon is discussed. The most tenable explanation for this phenomenon appears to be that ALL and MH may have been interrelated in these patients with both diseases originating from a common stem cell.


Formation of 1-beta-D-arabinofuranosylcytosine diphosphate choline in cultured human leukemic RPMI 6410 cells.

When incubated with 1-beta-D-arabinofuranosylcytosine (ara-C), RPMI 6410 cells formed a hitherto unrecognized ara-C metabolite, 1-beta-D-arabinofuranosylcytosine diphosphate choline. This compound was characterized by (a) chromatographic behavior, (b) chemical and enzymatic hydrolysis, (c) phosphorus content, and (d) incorporation of [5-3H]ara-C and [methyl-14C]choline. Formation of 1-beta-D-arabinofuranosylcytosine diphosphate choline by RPMI 6410 cells was enhanced in the presence of 3-deazauridine (DU) and was preceded by that of 1-beta-D-arabinofuranosylcytosine triphosphate. The antiproliferative effects of ara-C and DU toward RPMI 6410 cells were potentiated when the agents were present together. The anabolism of ara-C during a 24-hr interval of culture was markedly enhanced by the presence of DU; cellular concentrations of 1-beta-D-arabinofuranosylcytosine triphosphate and 1-beta-D-arabinofuranosylcytosine diphosphate choline were 5- and 15-fold higher than those in the absence of DU. This enhancement appears to be the basis of the potentiation of cytotoxicity resulting from combination of the agents. Pretreatment of RPMI 6410 cells with DU resulted in enhanced rates of cellular uptake of ara-C. ara-C uptake under these circumstances was blocked by the inhibitor of nucleoside transport, nitrobenzylthioinosine.


Formation of 1-beta-D-arabinofuranosylcytosine diphosphate choline in neoplastic and normal cells.

1-beta-D-Arabinofuranosylcytosine diphosphate choline was formed from 1-beta-D-arabinofuranosylcytosine (ara-C) during incubation in vitro of peripheral myeloblasts from patients with acute myelogenous leukemia and cultured cells (nonleukemic human lymphocytes, mouse lymphoma L5178Y, and HeLa); as well, 1-beta-D-arabinofuranosylcytosine diphosphate choline was formed in vivo in mouse leukemia L1210 cells and mouse liver. 3-Deazauridine enhanced the anabolism of ara-C in nonleukemic lymphocytes in vitro and leukemia L1210 cells in vivo but did not influence ara-C anabolism in the other cell types. In acute myelogenous leukemia myeloblasts incubated in vitro with ara-C, concentrations of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate were maximal after 8 hr of incubation and formation of the latter preceded that of 1-beta-D-arabinofuranosylcytosine diphosphate choline.