Development of parathyroid hormone- and calcitonin-activated adenylate cyclases in embryonic chicken limb and in cultured cells from embryonic chicken limb.

Activation of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] by parathyroid hormone (PTH) and calcitonin was measured as a function of stage of development in embryonic chicken limb buds. Responsiveness to both hormones develops in the tissue at the time when nascent bone is forming. In addition, a temporal sequence of development of hormone response was observed, with a PTH-activated adenylate cyclase appearing earlier than the calcitonin-activated enzyme. The responsiveness to the two hormones was additive, indicating the presence of two receptor populations. Undifferentiated cells obtained from limb buds prior to appearance of hormonal responsiveness were cultured and were found to develop a PTH-activated adenylate cyclase in vitro. However, a calcitonin-stimulated enzyme did not appear in such cultures. The PTH-activated enzyme was found to be similar to that present in bone in regard to its sensitivity to PTH. The enzyme did not respond to other hormones, and myoblast cultures did not develop a PTH-activated adenylate cyclase, indicating that a true bone adenylate cyclase was being measured.


A gene on human chromosome 6 functions in assembly of tissue-specific adenosine deaminase isozymes.

In human tissues, adenosine deaminase (ADA) (adenosine aminohydrolase; EC 3.5.4.4) activity can be separated by gel electrophoresis into several isozymes. A structural gene (ADA) on chromosome 20 codes for the "erythrocyte" isozyme, ADA-1, which is also expressed in some nonerythroid tissues. Nonerythroid cells also differentially express five ADA "tissue isozymes" of a greater molecular weight than ADA-1. Each ADA tissue isozyme has a characteristic electrophoretic mobility and tissue distribution. It has been suggested that these ADA tissue isozymes are composed of ADA-1 and other components. We report that the expression of one of these tissue isozymes, ADA-d, is dependent upon ADA on chromosome 20 and another gene on chromosome 6 which functions in the assembly of the ADA tissue isozymes. In human-mouse hybrids segregating human chromosomes, chromosome 6(+),20(+) hybrids express both ADA-1 and ADA-d; chromosome 6(-),20(+) hybrids express only ADA-1; while 6(+),20(-) hybrids have no human ADA activity. ADA-d formation also occurs in vitro by self-assembly when an extract of human erythrocytes or chromosome 6(-),20(+) hybrids is mixed with a homogenate of chromosome 6(+),20(-) hybrids. The gene on chromosome 6, designated ADCP, codes for an adenosine deaminase complexing protein. The product of ADCP presumably combines with ADA-1 to form the ADA tissue isozymes. The data are consistent with the hypothesis that the distribution of enzymatic activity between ADA-1 and the tissue isozymes depends on the expression of the gene for ADA complexing protein, while the differences in the electrophoretic mobilities of the ADA isozymes, except ADA-1, are generated, as suggested by others, by the degree of glycosylation of the complexing protein.


Multiple related immunoglobulin variable-region genes identified by cloning and sequence analysis.

We have identified at least six EcoRI fragments of mouse DNA that encode variable-region gene sequences closely related to the mouse kappa light chain, MOPC-149. Two of these fragments have been cloned, and the entire nucleotide sequence of the variable-region genes encoded on each has been determined. Both genes encode closely related variable-region sequences extending from codon position 1 through position 97. Neither fragment encodes a constant-region sequence. Although both genes are closely related, they differ from one another and from the sequence expressed in the MOPC-149 cell from which they were cloned. These few differences cluster within the complementarity-determining regions although several occur in framework sequences as well. We therefore conclude that an antibody-producing cell contains genetic information corresponding to its expressed sequence and several other closely related but silent sequences. These initial results raise the possibility that similar sets of genes might exist corresponding to each of the many subgroups already identified among mouse kappa light chains. If true, this would further suggest that the mouse genome might be rich enough in variable-region genes so as to encode a major portion of the variable-region repertoire.


Effect of inbreeding on IQ and mental retardation.

Both decline of IQ and increase of mental retardation are consistent with rare recessive alleles at about 325 loci. There is no suggestion of a discrepancy that might be due to polygenic dominance or confounding of consanguinity with unfavorable environment. These data indicate that the risk for mental retardation in matings of normal parents increases from 0.012 with random mating to 0.062 for first-cousin parentage but that dominance deviations are a negligible cause of family resemblance of IQ. Implications for frequencies, mutation rates, and radiation response are detailed.


Developmental change in human intestinal alkaline phosphatase.

Starch gel electrophoresis and inhibition studies with L-phenylalanine, L-homoarginine, L-leucine, L-leucylglycylglycine, and L-phenylalanylglycylglycine were carried out on a series of human alkaline phosphatases [orthophosphoric-monoester phosphohydrolase (alkaline optimum); EC 3.1.3.1] derived from fetal and adult liver, kidney, bone, and intestine. No differences between adult and fetal liver, kidney, or bone alkaline phosphatases were observed by either electrophoretic or inhibition studies. However, the fetal intestinal enzyme could be clearly distinguished from the adult intestinal enzyme by its greater anodal electrophoretic mobility and its retardation after treatment with neuraminidase. Even after extensive neuraminidase treatment, its anodal mobility was still slightly greater than that of adult intestinal alkaline phosphatase. Fetal and adult intestinal enzymes showed the same inhibition profiles with the series of inhibitors both before and after treatment with neuraminidase. A survey of intestinal samples from fetuses and premature infants of various gestational ages indicated that the changeover from the synthesis of fetal to adult intestinal enzyme begins at about 28-32 weeks of gestation. The difference between the fetal and adult forms of intestinal alkaline phosphatase may represent the expression of different gene loci or a difference in post-translational modification.


Requirement of S-adenosyl-L-methionine-mediated methylation for human monocyte chemotaxis.

The chemotactic response of motile bacteria requires the methylation of specific proteins by S-adenosyl-L-methionine. To determine whether methylation is required for the chemotaxis of human leukocytes, we studied the effects of inhibition of S-adenosyl-L-methionine-mediated methylation on monocyte chemotactic responsiveness. Methylation was inhibited in monocytes by treating the cells with substances that produced elevations in intracellular S-adenosyl-L-homocysteine, a competitive inhibitor of S-adenosyl-L-methionine methylation. Treatment of isolated monocytes with the adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, plus exogenous adenosine and L-homocysteine thiolactone increased intracellular S-adenosyl-L-homocysteine levels by as much as 1500-fold. Concomitant with increases in S-adenosyl-L-homocysteine were a decrease in monocyte protein carboxy-O-methylation as well as a marked inhibition of monocyte chemotactic responsiveness. Conditions that almost completely inhibited methylation and chemotaxis did not depress monocyte phagocytosis, indicating that this latter function either is independent of S-adenosyl-L-methionine-mediated methylation or is extremely resistant to inhibition of such reactions by S-adenosyl-L-homocysteine. These studies indicate that S-adenosyl-L-methionine-mediated methylation is required for the chemotaxis of eukaryotic cells and that the chemotactic and phagocytic functions of human monocytes have different requirements for methylation.


Visualization of specific antibody and C1q binding to hapten-sensitized lipid vesicles.

Specific IgG antibodies directed against the spin-label nitroxide group present as a lipid hapten in single-compartment lipid vesicles have been visualized by using freeze-etch electron microscopy. Individual "particles" with diameters of the order of 20 nm are identified as single IgG molecules bound to lipid hapten. No significant aggregation of these IgG molecules was observed over a period of 1 hr in a dipalmitoyl phosphatidylcholine vesicle at 22 degrees. Binding of the human complement component C1q results in the formation of large (approximately 50-100 nm) asymmetric particles having a partially resolved substructure that may arise from individual IgG molecules bound to the membranes as well as to C1q. The binding of C1q appears to result in a clustering of membrane-bound IgG molecules. Samples containing a serum factor (perhaps anti-IgG antibodies) exhibit some IgG clustering distinct from that produced by Clq.


Monoclonal antibodies against rabies virus produced by somatic cell hybridization: detection of antigenic variants.

Somatic cell hybrids (hybridomas) between mouse myeloma cells and spleen cells derived from BALB/c mice immunized with inactivated rabies vaccine were found to produce antibodies to rabies virus. Monoclonal antibodies with different specificities were obtained either from the mass culture directly after fusion or from clones derived from a single-cell cloning procedure. Several strains of fixed or street rabies virus were analyzed by virus neutralization procedures which demonstrated differences in their antigenic composition. Hybridoma antibodies were able to protect experimental animals from lethal rabies virus infection.


Demonstration of specific C5a receptor on intact human polymorphonuclear leukocytes.

Human C5a, a complement-derived anaphylatoxin, is a potent mediator of human leukocyte chemotaxis. Using a homogeneous preparation of C5a that was 125I-labeled, we have demonstrated the presence of a specific cellular receptor for this glycoprotein on intact human polymorphonuclear leukocytes. Cellular uptake of the radiolabeled ligand occurred rapidly and the rate of dissociation was extremely slow. Cellular binding was saturable with respect to 125I-labeled C5a, and half-saturation occurred at a concentration of 3-7 X 10(-9) M. The number of C5a binding sites per cell was estimated as 1-3 X 10(5). The ligand (C5a) displays specific structural features that are required for binding because analogs of C5a such as C5ades Arg or a yeast carboxypeptidase-digested C5a derivative C5a-(I-69) inhibited the binding but C3a anaphylatoxin, which resembles C5a chemically, did not. Both C5a-mediated leukocyte chemotaxis and C5a-induced lysosomal enzyme release from cytochalasin B-treated cells closely paralleled uptake of the ligand, clearly indicating that it is a receptor-C5a interaction that leads to stimulation of these cellular responses.


Initiation of the alternative pathway of complement: recognition of activators by bound C3b and assembly of the entire pathway from six isolated proteins.

An intact alternative pathway of complement activation was assembled from six isolated proteins present at their respective physiological concentrations (C3, 1200 microgram/ml: factor B, 200 microgram/ml; factor D, 2 microgram/ml; beta1H, 560 microgram/ml; C3b inactivator, 34 microgram/ml; and native properdin, 20 microgram/ml). Initiation of the pathway required the presence of five of these proteins not including properdin. The initial C3 convertase of the system was shown to be a fluid-phase rather than a surface-bound enzyme. The ability of the pathway to discriminate between activator and nonactivator was found to reside in the bound C3b molecule. When bound to the surface of an activator through its labile binding site, C3b interacts with surface structures of the activator through another site on the molecule. This interaction results in diminished beta1H binding to C3b and thereby allows the bound C3b molecule to escape control and participate in C3 convertase formation. Thus, initiation of the alternative pathway is a two-step process, the first being non-specific and the second being discriminatory.


X-ray sensitivity of diploid fibroblasts from patients with hereditary or sporadic retinoblastoma.

Fibroblasts derived from patients with hereditary retinoblastoma appear to be more sensitive to the lethal effects of x-rays than do fibroblasts from patients with sporadic retinoblastoma or normal controls. A defect in DNA repair is postulated to account for the high incidence of second tumors in these patients. Retinoblastoma appears to be an interesting model for the study of genetic susceptibility to the development of spontaneous or radiation-induced tumors.


Neurocytotoxic antibodies in serum of patients with systemic lupus erythematosus.

Sera from patients with systemic lupus erythematosus (SLE) have been tested for antibody to a human neuronal cell line, SK-N-SH, derived from a metastatic neuroblastoma. With a complement-dependent (51)Cr-release cytotoxicity assay, 75% of SLE sera had antineuronal activity mediated by IgM antibody. Most of the sera containing this IgM neurocytotoxic antibody were also cytotoxic to the human glial cell lines A-172 and U-118MG. The sera did not mediate complement-dependent (51)Cr release when tested against normal human fibroblasts or peripheral blood lymphocytes. IgG antineuronal antibody was detected in 17% of SLE sera by an antibody-dependent, cell-mediated cytotoxicity assay with SK-N-SH cells as targets. The relationship of IgM and IgG antineuronal antibodies to the antilymphocyte antibodies present in SLE sera was evaluated by a series of crossabsorption experiments using SK-N-SH cells to remove neuronal antibodies and WI-L2 (human lymphoblasts) to remove antilymphocyte antibodies. Most of the complement-dependent neurocytotoxicity was not removed by multiple lymphoblast absorptions, although the WI-L2 cells readily removed lymphocytotoxic activity as assayed on normal lymphocytes. Absorption with SK-N-SH cells removed most, but not all, of the lymphocytotoxic antibody. Thus, although lymphocytotoxic antibodies reactive with membrane antigens shared by lymphocytes and brain may constitute a subset of the antibodies to neural cells, most of the antineuronal activity in SLE serum is directed at other cell surface antigens expressed on neuronal and glial cells. Should they gain access to the brain, these antibodies have the potential to produce neuropathology, but their presence in the nervous system of patients with the neuropsychiatric manifestations of SLE is yet to be documented.


Relative loss of oncogenic potency of mouse leukemia virus (Gross) after prolonged propagation in tissue culture.

Since the initial development of the "passage A" mouse leukemia virus in 1957, this virus has been propagated in our laboratory by serial passage in newborn C3H(f) mice. At the present time, 10(-2)-10(-3) dilutions in physiological saline solution of this mouse-passaged virus induce lymphatic leukemia in practically all inoculated mice after a latency of 3-5 months. On the other hand, when the same virus was propagated on NIH 3T3 mouse embryo cells in tissue culture for more than 10 years, its leukemogenic potency became considerably reduced. Recent bioassay experiments carried out in our laboratory demonstrated that after such prolonged propagation in tissue culture this virus now induced leukemia in less than 15% of the inoculated suckling C3H(f) mice; only undiluted or 10% dilutions of the tissue culture fluid (very occasionally 10(-2) or 10(-3) dilutions) induced leukemia after a prolonged latency varying from 5.5 to 18 months. The passaged and the tissue-culture-grown virus strains are identical immunologically and indistinguishable in their morphology when examined by electron microscopy. The tissue-culture-grown virus, attenuated in its leukemogenic potency, does not, however, confer immunity against a challenge with the mouse-passaged virus.


Induction of pulmonary indoleamine 2,3-dioxygenase by intraperitoneal injection of bacterial lipopolysaccharide.

Indoleamine 2,3-dioxygenase [indoleamine: oxygen 2,3-oxidoreductase (decyclizing)] activity in the supernatant fraction (30,000 X g, 30 min) of the mice lung homogenate increased approximately 30- to 50-fold after an intraperitoneal administration of bacterial lipopolysaccharide. In all other tissues tested, no significant increase in enzyme activity was observed. The effect appeared to be specific for the lipopolysaccharide fraction because glycogen and zymosan were almost ineffective under the same experimental conditions. In the lung, the enzyme activity increased almost linearly during the first 24 hr after a single injection of the lipopolysaccharide fraction (20 microgram per mouse). The enzyme activity started to decrease after 48 hr and reached a normal value after about 6 days. The increase in enzyme activity was completely abolished by cycloheximide or actinomycin D. Other enzymes in the lung such as beta-glucuronidase, acid phosphatase, and monoamine oxidase did not change significantly with this treatment.


Specific immunosuppression of experimental autoimmune myasthenia gravis by denatured acetylcholine receptor.

Specific immunosuppression of experimental autoimmune myasthenia gravis (EAMG) was achieved by the use of a denatured preparation of the acetylcholine receptor (AcChoR) that did not in itself induce the disease. Torpedo californica AcChoR was irreversibly denatured by complete reduction and carboxymethylation in 6 M guanidine hydrochloride. Rabbits immunized with reduced carboxymethylated receptor (RCM-AcChoR) produced antibodies that reacted with both RCM-AcChoR and intact AcChoR. The specificity of anti-RCM-AcChoR antibodies is different from that of anti-AcChoR antibodies because the former are directed to only part of the antigenic determinants present in the intact receptor. RCM-AcChoR, which by itself is completely nonmyasthenic, was shown to be capable of both preventing the onset of EAMG and of reversing the clinical symptoms in myasthenic rabbits. In all cases the therapeutic effect of RCM-AcChoR administration on EAMG was accompanied by a change in the immunological specificity of the antibodies. The crossreactivity between AcChoR and RCM-AcChoR and the nonpathogenicity of RCM-AcChoR appear to be crucial in governing the specific immunosuppressive effects of RCM-AcChoR on EAMG.


A factor from neurons increases the number of acetylcholine receptor aggregates on cultured muscle cells.

There is an increase in the number of acetylcholine (AcCho) receptor aggregates on striated embryonic mouse myotubules when they are cocultured with clonal neuroblastoma-glioma hybrid cells. Medium conditioned by hybrid cells contains a factor which increases the number of AcCho receptor aggregates on myotubes cultured from mouse, rat or chick muscle. AcCho receptor-aggregating activity was present in medium conditioned by the neuroblastoma parent clone but was not detected in medium conditioned by cells of the parent glioma clone, fibroblasts, or HeLa cells. The factor increased the aggregation of AcCho receptors within 24 hr without a significant increase in the total number of AcCho receptors, and its action did not depend on myotube protein synthesis. The factor appears to rearrange the distribution of myotube AcCho receptors either by aggregating mobile AcCho receptors or by stabilizing labile receptor aggregates.


Release of neurotransmitters and depletion of synaptic vesicles in cerebral cortex slices by alpha-latrotoxin from black widow spider venom.

The effect of alpha-latrotoxin on cerebral cortex slices was studied by both biochemical and morphological methods. This toxin greatly stimulates the release of preloaded gamma-amino[3H]butyric acid from cortex slices. The response increases linearly with dose. The release is not dependent on the presence of extracellular Ca2+, and therefore it is not mediated by the release of other transmitters from other types of neurons. In contrast, no significant increase in the release of a nontransmitter substance alpha-amino[14C]isobutyric acid is observed. Since previously we have shown that alpha-latrotoxin stimulated the release of acetylcholine and norepinephrine from cortex slices, it appears that the toxin probably selectively releases all neurotransmitters. The toxin also profoundly depletes the synaptic vesicle population in boutons in the cortex slices. The results suggest that the release of neurotransmitter and the depletion of synaptic vesicle in boutons are manifestations of a single action of the toxin. Therefore, alpha-latrotoxin can be used as a good tool for the identification of neurotransmitters and in studies on the mechanism of neurotransmitter release.


High molecular weight opioid-containing proteins in striatum.

Striatal extracts of guinea pigs, rats, and cattle were found to contain two large proteins (greater than 40,000 and greater than 100,000 daltons) that on treatment with trypsin yield opioid peptides differing chromatographically from the opioid nonapeptide generated by trypsin digestion of endorphins, beta-lipotropin, or pro-opiocortin. Furthermore, the large opioid proteins found in the pituitary do not appear to be present in the striatum. These and other findings indicate that the striatal enkephalins are produced via a pathway from the one deduced from studies on the pituitary.


Purification of an endogenous protein inhibitor of the high affinity binding of gamma-aminobutyric acid to synaptic membranes of rat brain.

In a medium without Na+, gamma-aminobutyric acid (GABA) binds at 0 degrees to freshly prepared crude synaptic membranes from rat cerebral cortex with an apparent dissociation constant of 218 nM. An endogenous inhibitor of the Na+-independent GABA binding was removed from these membranes by freezing and thawing and by repeated washing with Tris citrate buffer (50 mM, pH 7.1) containing 0.01% Triton X-100. As a result, the crude synaptic membranes bind GABA at 0 degrees with two dissociation constants, 20 nM and 111 nM. The endogenous inhibitor is a thermostable (95 degrees for 15 min) acidic protein of approximately 1.5 X 10(4) daltons. It was purified (about 500-fold) with a series of procedures including gel chromatography on Sephadex G-100 and ion exchange chromatography on Dowex 50W-X8 (H+). Recombination of the purified endogenous inhibitor with crude synaptic membrane preparations deprived of the endogenous inhibitor showed that the purified inhibitor blocked noncompetitively the sites for high-affinity GABA binding. A role of this endogenous regulator in the functional of GABA-ergic synapses is discussed.


Involvement of an interneuron in the generation of the slow inhibitory postsynaptic potential in mammalian sympathetic ganglia.

Acetylcholine (AcCho) was applied electrophoretically to cells of isolated rabbit superior cervical ganglia, and the response was recorded by means of intracellular recording techniques. In the presence of d-tubocurarine (5 micron), AcCho applied by tetanic current pulses elicited three distinct membrane potential changes: a slow depolarization, a slow hyperpolarization, and a biphasic response consisting of an initial hyperpolarization followed by a depolarization. Atropine (1 micron) abolished all the membrane potential changes elicited by AcCho. On the other hand, superfusion with a low-Ca/high-Mg solution, tetrodotoxin (0.1 micron), or haloperidol (0.1 micron) selectively and reversibly blocked AcCho-induced hyperpolarization without appreciably affecting the depolarization. The membrane resistance remained relatively constant during the course of hyperpolarization. Application of steady depolarizing and hyperpolarizing currents decreased and increased, respectively, the amplitude of hyperpolarization. These results demonstrate that the hyperpolarization elicited by AcCho is electrophysiologically and pharmacologically similar to the slow inhibitory postsynaptic potential induced by nerve stimulation; furthermore, they support the view that the slow inhibitory postsynaptic potential elicited by presynaptic stimulation is a disynaptic phenomenon involving the release of a second transmitter, possibly dopamine, from an interneuron.


Temperature-sensitive mutants of mouse hepatitis virus produce a high incidence of demyelination.

Mutagenesis of mouse hepatitis virus with 5-azacytidine or 5-fluorouracil yielded several temperature-sensitive mutants. Mutants have been isolated that dramatically enhance the production of demyelinating disease over that previously noted with the wild-type virus. This reproducible model should now make possible the precise elucidation of the pathogenic mechanism and molecular basis of this virus-induced demyelination.


Nerve growth factor in mouse and rat serum: correlation between bioassay and radioimmunoassay determinations.

High levels of nerve growth factor (NGF) determined by competition radioimmunoassay do not agree with values obtained by bioassay. This discrepancy is illustrated here with rat and mouse serum as examples in which values up to 1000 ng/ml have been found by using competition radioimmunoassays. An explanation for the discordant results is presented: serum components bind NGF with an intermediate affinity (Kd = 10(-7) M) but with a very large capacity (up to 0.5 mg of NGF per ml of rat serum). The binding of 125I-labeled NGF to serum components competes with the binding to the solid-phase antibodies (Kd = 10(-9)M) present in limiting amounts, according to the principle of competition radioimmunoassays. Thus, less radioactivity is recovered bound to the antibodies and this gives the erroneous impression that NGF is present. To overcome this difficulty, a two-site radioimmunoassay has been developed which utilizes nonlimiting numbers of antibody binding sites. This assay provides a reliable determination of NGF levels in serum and it can be shown that in rat and mouse serum (either sex) there is less than 5 ng of NGF per ml, in agreement with the results of the bioassay.


Generalizing Fisher's "reproductive value": overlapping and nonoverlapping generations with competing genotypes.

How to go beyond Fisher's 1930 linear eigenvector definition of reproductive value has been established for dilute systems whose dynamic relations are first-degree-homogeneous functions so that intensive ratios are scale-free. Here such an extension is applied to standard mendelian models. It is shown that, aside from singular cases like that of the Hardy-Weinberg razor's-edge labile equilibrium, such general systems are irreducibly nonlinear and admit of reproductive value functions that are calculable only in an infinite number of steps.


Trisomy of 1q in preleukaemia with progression to acute leukaemia.

Marrow cells from an untreated man with preleukaemia were found to have trisomy for the long arm of chromosome 1 which was translocated to the end of the long arm of number 11, i.e., 46,XY, -11,+t (1:11) (q11 or q12; q25). The same abnormality was found in metaphases from 8 individual granulocytic colonies. With development of acute myelomonocytic leukaemia, in addition to the basic chromosome abnormality, trisomy of chromosome 8 and an extra chromosome number 19 with partial deletion were found. Fibroblasts grown from marrow biopsy material showed a normal diploid complement, 46,XY.


A preventive therapy of the central nervous system complications in acute leukemias. Preliminary report.

A new therapeutic schedule for preventive therapy of the central nervous system (CNS) complications by intrathecal (i.t.) injections of methotrexate (MTX) was applied in two groups of 6 and respectively 13 adults with acute lymphoblastic or non-lymphoblastic leukemias. Instead of starting this treatment only in the remission stage, i.t. MTX was given from the very beginning of cytostatic therapy. In most of the patients this drug proved to be effective in preventing CNS involvement. In some cases, however, it was not well, tolerated owing probably to a neurotoxic effect. This suggested continuation of the study with Ara-C.


Trisomy 8 in the chronic phase of Philadelphia negative chronic myelocytic leukaemia.

An unusual case of Philadelphia negative chronic myelocytic leukaemia and an extra chromosome 8 in all bone marrow cells is described. The abnormality was present at diagnosis of the disease and throughout the chronic phase which lasted for somewhat less than 2 years. The patient died soon after the blastic transformation with no other chromosomal abnormalities.


A near haploid clone: 24,XY, t (9; 22) (q34; q11) from a patient in blast crisis of chronic myeloid leukaemia.

Chromosome studies on bone marrow in a patient with chronic myeloid leukaemia (CML) revealed a mosaic picture with a dominant clone of 24,XY, t(9; 22) (q34; q11). This corresponded to a preponderance of minute blasts in smears of bone marrow aspirate. It is suggested that a haploidy event rather than progressive hypodiploid loss, is responsible for the genesis of the miniature blast cells.


The effect of intravaginal electrical stimulation on the feline urethra and urinary bladder. Electrical parameters.

Intravaginal electrical stimulation (IVS) in cats caused urethral closure and bladder inhibition. The aim was to ascertain the electrical parameters most appropriate for these effects. Minimum voltage was used as main criterion to select an effective, non-destructive stimulation when the shape, frequency and duration of the pulses were systematically varied. Urethral closure was achieved at minimum voltage (3 V) with alternating pulses at a frequency of 50 Hz and a pulse duration of 1.5 ms. Corresponding optimal parameters for bladder inhibition were: alternating pulses, 10 Hz and 1.5 ms. Minimum voltage was 1 V. Moreover, the positions of the electrodes were of significance for the responses. The clinical implications of these findings are that: 1)more differentiated treatment of incontinence could be achieved by adapting the stimulation parameters to the cause of incontinence, and 2) specific electrode positions would probably give optimal responses.


[Technic and indications for cytodiagnosis for the early detection of cancer].

It is possible to detach cells from the surface of mucous membranes for cytodiagnostic purposes. The method is simple and does not involve discomfort to the patient. It can be repeated at any time and many times. The method should be used when observing changes in the mucous membranes during examination in order to detect precancerous formations and for tumor diagnosis.


[The origin of class II].

Profound knowledge of craniofacial growth is of utmost importance to the clinician in order to establish a treatment plan which respects the growth type of each patient. Different growth processes and possible etiological factors leading to a skeletal Class II are discussed. Only a comprehensive analysis in all three dimensions will allow adequate choice of treatment procedure.


[Class II--vertical dimension].

The vertical dimension and its implication in the etiology of the class II are described. This dimension is analysed at the level of the cranial base, the maxillary and mandibular bones and alveolar processes. Then, the facial architecture as a whole is considered and particularly the key position of the upper molar. The dorsal and low position of these teeth in the hyperdivergent cases is fundamentally different from the one they occupy in the hypodivergent cases. The therapeutic approach is completely different in both cases and is illustrated by means of three deep overbite and three open bite cases.


[Class II--sagittal dimension].

Normal facial growth displaces maxilla and mandible forward and downward. The result is the skeletal and facial equilibrium described by Angle. In classe-II and class-III cases, growth patterns are modified as well as sagittal and vertical dento-facial dimensions. Development and differential diagnosis of skeletal and dental class-II cases are presented, in relation to their sagittal parameters only. The evolution of a class-II can be predicted with the help of several cephalometric measurements, so that the adequate therapy can be used in time to reestablish proper growth.


Hemolysis in vitro by sorbose, sorbitol and xylitol.

L-sorbose, xylitol and sorbitol solutions (56 mM) were not hemolytic when incubated with erythrocytes of 30 healthy volunteers, 14 thalassemic heterozygotes and in 30 horses, 30 cows and 30 Osborne-Mendel rats. Lysis of dog erythrocytes was most pronounced when incubated with L-sorbose but was also significant in xylitol and sorbitol solutions.


[Experiences with sole radiation therapy of primary osteogenic sarcomas (author's transl)].

In the course of the previous six years, nine osteogenic and three juxtacortical sarcomas have been irradiated for the single purpose of local tumor sanitation and final cure of the patient. Of nine cases with osteosarcomas, six are still alive. Two are surviving without recurrences these five years, three without metastasition. The 3-year survival amounts to 3/5. Radiation effects from high-dosage treatment are remarkably small. The cure rate after radiation therapy seems not to be inferior to the results after surgery.


[Added caries prevention by means of topical fluoride application in children of a district with fluoridation].

The effects of weekly mouth-rinsings with a 0.5% sodium fluoride solution were clinically and radiologically investigated in 58 children (age 13.6 years) from a town with water fluoridation (Karl-Marx-Stadt, 1.0 +/- 0.1 p.p.m.F) by means of a longitudinal study on the premolars and canines. As compared to an untreated control group (48 subjects), a 42% inhibition of fissure caries increment (DF/S index) was stated after 57-fold application (over 24 months).


[Therapeutic aspects of odontogenic maxillary sinusitis].

On the basis of observations in 90 patients with odontogenic maxillary sinusitis who had been re-examined clinically and radiologically, the authors deal with the optimal utilization of all possibilities of conservative treatment. 74% of the patients were symptom-free, 55% presented a radiologically well pneumatized sinus. The healing quality of inflammatory alterations of the sinusal mucosa is once again confirmed by the observation of the course of the disease.


[Clinical and radiological control examinations after cyst surgery in the permanent juvenile dentition].

The present study involves 23 patients with 25 cysts whose conditions were assessed postoperatively by means of clinical and radiological criteria. The radicular and follicular cysts were most frequently located in the anterior region of the upper jaw. With 17.4% of the total number of bone cysts, the percentage of cysts on juvenile permanent teeth is relatively low. Teeth that did not respond to irritants were the most frequent complication in the operating area. Nevertheless, the clinical and radiological findings tell against the non-vitality of these teeth.


[Unusual displacements of the lower molars].

Two unusual cases of maleruption of mandibular third molars associated with the retention of adjacent teeth and the presence of supernumerary teeth, respectively, are described. Due to the position of the crowns to each other, this phenomenon is termed "kissing teeth" in our clinic.


[Scientifically founded drug prescription in surgical stomatology].

Scientifically founded drug prescription is necessary to secure optimal therapeutical success with a minimum of risks. Dosage must conform to pharmacokinetics and consider the patient's age and diseases, especially affections of the liver and kidney. Furthermore, the possibility of drug interferences, which might lead to serious complications, should be borne in mind if several drugs are prescribed simultaneously. The present paper deals only with drugs frequently prescribed in surgical stomatology.


[Combined study of leukemic blasts using DNA autoradiography and cytophotometry].

The 3H-thymidine incorporation capacity and DNA contents were studied in the same bone marrow blasts in 4 patients suffering from acute leucaemia. The blast populations were both proliferating and non-proliferating. Actively proliferating cells were blasts of large and medium diameters. Mitotically inactive cells were blasts of medium and small diameters. Cells that stopped dividing were established as being in period G1 of the cell cycle. A high variation in DNA contents was noted in blasts unlabeled with 3H-thymidine, a possible reason of the above phenomenon being discussed.


[Acute leukemia and pregnancy].

It is reported on an undifferentiated cell leukosis of the type PAS in the 2nd trimenon of a pregnancy. The paralymphoblastosis could well be influenced by a prednisolone monotherapy so that a healthy baby was born. After birth very quickly developed a severe recidivation of leucosis which no more could be influenced therapeutically so that the patient dies on the 10th day after birth. The problems of the therapy of undifferentiated cell leucosis during pregnancy are discussed and possible hormonal protective mechanisms are taken into consideration.


Sepik granuloma.

An unusual infection occuring in the East Sepik Province of Papua New Guinea is reported. The patients come from villages on the Sepik River or its tributaries. The lesions consist of cutaneous nodules and papillomas which are slowly progressive. An unidentified organism, apparently a gram positive bacillus, is seen in large numbers in the lesions; a natural habitat in soil or water or on vegetation seems likely.


Traditional medicinal plants used in the treatment of gastric ailments.

A recent paper discussed plants used in traditional medicine for fevers and malaria throughout Papua New Guinea (Holdsworth, 1975 a). This paper summarises information now available on plants used to treat gastric ailments, especially diarrhea and dysentery.


A study of the feeding habits and nutrition of children in Anguganak area of West Sepik.

During November/December 1976 we surveyed 255 children of known age 5 years and under, and we questioned their parents about the foods given to them. We compared our results with previous survey results from this area. Despite the much earlier introduction of solid foods, there was no significant change in the mean weights of infants in this area since 1967. Sixty-four percent of the children were below 80% of the standard weight for age, and 57% of the children over one year of age had a mid upper-arm circumference of less than 14 cm. Health education needs to be supplemented by the use of high density weaning foods and the control of infection to overcome the very high prevalence of malnutrition.


An epidemic of dengue fever in Wewak.

143 clinical cases of dengue fever were reported in Wewak between April and August 1976. 15 patients demonstrated a diagnostic rise in antibody titre for Group B arbovirus. Tests for complement-fixing antibody to dengue viruses did not indicate what type of dengue virus was responsible for the epidemic. Vector species Aedes aegypti and Aedes scutellaris were found before control measures were adopted but were not found four months later.  The epidemiology of dengue fever is discussed and measures for prevention and control of epidemics are recommended.


Abnormal haemoglobins, thalassaemias, and hereditary ovalocytosis in the Papuan Gulf area.

In 50 Kerema or Kairuku individuals of the Papuan Gulf Area, the amount of beta thalassaemia as indicated by the finding of a raised level of Hb A2 was found to be 6%, and of hereditary ovalocytosis 16%. There was one example of both conditions occurring together. No haemoglobin abnormalities apart from raised Hb A2 level were found.


Measurement of heated skin O2 diffusion conductance and PO2 sensor induced O2 gradient.

A large cathode heated transcutaneous PO2 electrode was used to measure the resistance of skin to diffusion of O2 from the capillary bed to the surface. With a non-O2-consuming tcPO2 electrode, one would read ideal tcPO2, Pi, which approximates PaO2 between 50 and 100 mmHg due to approximate cancellation of the rise by heating and the fall by skin O2 consumption. When a large cathode tcPO2 electrode is used, its O2 consumption causes a PO2 gradient across skin resistance, Rs, which depends on electrode membrane resistance RM (with Mylar), or RT (with Telfon). Surface PO2 will fall below Pi, and assuming no change in capillary PO2: PT/Pi = RT/(RT + Rs) and PM/Pi = RM/(RM + Rs) (1) 12 micrometer Telfon is 50 times as permeable to O2 as 6 micrometer Myler. When an electrode, covered alternately with these two membranes, was mounted on the same skin site in six subjects, the mean observed PT/PM was about 0.3. Substituting in equation (1) yields RT/Rs = 0.4, Rm/Rs = 20, and PM/Pi = 0.95. Using the known O2 permeability of Teflon, we computed skin O2 conductance to be 6.6 pmol O2/(cm2 .s .kPa), or 15 nl O2/(cm2 .s .atm). This method thus provides a way of determining ideal tc PO2 and stirring effect, phi, of other electrodes and various membranes.


Safe and effective use of transcutaneous blood gas monitors.

The Medical Devices Amendments of 1976 (PL 94-295) will compel users of transcutaneous monitors to comply with Class II, Performance Standards. These standards will have to provide reasonable assurance of the safety and effectiveness of the device. Similar standards are in preparation for other cardiac and respiratory monitors. Dangers of tcPO2 monitors include shock and burn, which requires attention to the insulation of the monitor from the power line and from recorders used to record the output. Optimal safe time vs. temperature limits have not yet used to record to output. Optimal safe time vs. temperature limits have not yet been established, and these may vary with age, skin site, blood pressure and body and environmental temperature. The usefulness of alarms for PO2, sensor temperature and heating power, and their limits remain ot be defined by extensive clinical use. Standards for drift, reproducibility, recalibration interval and accuracy will have to be set after more extensive clinical use especially by groups not involved in the initial prototype development and testing. In order to prove that these devices are also effective, physicians will have to document that care would have been different, and might have impaired patient safety, if the device had not been used.


Transcutaneous oxygen tension in imminent foot gangrene.

Transcutaneous oxygen tension at 44 degree C and maximal isotope clearance (90m Tc-pretechnetate + histramine) just proximal to the 1st toe and systolic toe blood pressure (strain gauge) were studied on a tilt table in patients with various degrees of obstructive arteriosclerotic disease. In legs with moderate obstruction, the oxygen tension reached zero at a toe systolic blood pressure of 5--10 mmHg (tilt toe up) and reached arterial oxygen tension at about 50 to 70 mmHg (tilt toe down). In legs withsevere arterial obstruction and ischaemic rest pain, oxygen tension rose from zero not before systolic toe blood pressure reached 20--50 mmHg.  Significant isotope clearance was seen at pressures below the limits just mentioned for both types of patients. This phenomenon here seen of a perfusion without oxygen supply is explained by a gas leak (rendered significant because of the slow flow rate) from the arterioles into the tissue sink and counter current gas shunting. The hypoxia in spite of a  positive perfusion pressure up to 50 mmHg explains our experience that ischemic ulcers in feet such low pressures never heal.


Transcutaneous blood gas measurement using a mass spectrometer.

We use a Perkin Elmer MGA 1100 mass spectrometer modified for blood gas tension measurements to study transcutaneous measurements of oxygen, carbon dioxide, nitrogen and helium in normal subjects. We use an aluminum sampling chamber heated to 42--44 degree C and connected to the mass spectrometer by about 2 m of stainless steel tubing. The sampling area of 5 cm2 is covered with a polytrifluorochloroethylene membrane 18 micrometer thick (Allied Chemical Co., Aclar 33c). The membrane is supported by sintered stainless steel disc with a thermistor incorporated for measurement of "membrane" temperature. The chamber is heated with a printed circuit heater (Minco) and is temperature regulated by a servo circuit. We have used the system to measure, O2, CO2 N2 and He via the heated skin in four normal subjects, breathing air and then 100% oxygen. We also observed the response to a single breath of helium. Helium appears at the skin within 10--15 sec. The time constant of its disappearance is about 70 sec. The average uncorrected gas tensions which we obtained breathing air were 11.2 kPa for oxygen, 5.1 kPa for carbon dioxide and 67.1 kPa for nitrogen. The corresponding values breathing oxygen were 41.1 kPa for oxygen, 4.4 kPa for carbon dioxide and 13.1 kPa for nitrogen.


Trancutaneous blood gas measurement by mass spectrometry.

A stainless steel, self heated, flat surface, skin surface probe, covered with a Mylar membrane, admits gases diffusing through the skin surface into a mass spectrometer at rates sufficiently low to provide reasonable measurement of blood PO2 and PCO2. A second thermistor against the Mylar and insulated from the probe monitors skin temperature as an index of blood flow. Advantages of the mass spectrometer method compared to electrodes are that a single sensor detects all gases, including anaesthetics, the sensor is simple in design, the same mass spectrometer can monitor several patients simultaneously, anaesthetics do not interfere (as with halothane and the O2 electrode), comparative checks with blood gas may be done using the same mass spectrometer, and perhaps, by summing all gases it may be possible to determine how fully arterialized the skin is.


Reliability of cutaneous oxygen measurement by skin sensors with large-size cathodes.

The oxygen partial pressure may be measured cutaneously by directly heated PO2 sensors attached to the surface of the skin. The use of a large-size cathods (diameter 4 mm) allows one to obtain an average PO2 value over a sufficiently large skin area. The permeability of the membrane for oxygen has to be kept low to prevent a  disturbance of the oxygen profile in the cutaneous tissue as a result of the oxygen consumption of the sensor. When using of 6 micrometer Mylar membrane, the current can be limited by the diffusion of oxygen through the membrane and is a measure of the arterialized cutaneous PO2. One effect of using membrane of low permeability is that the response time of the sensor is long (tau 90% = ca 45 sec). The reliability of correctly reproducing cPO2 variations by sensors having different response times may be evaluated by determining the transfer function of the membrane which allows the calculation of the frequency characteristics for various membranes. The cutaneous tissue layer also acts as a filter for rapid PO2 fluctuations. The characteristic of this filter is essentially similar to that of a "slow" membrane such as Myler 6 micrometer. The information gained by using a "rapid" membrane such as Telfon 13 micrometer is negligible. In 490 comparative measurements in newborns performed with sensors heated to 44 degree C, the correlation between arterial PO2 and cutaneously measured PO2 is significant (correlation coefficient = 0.934) and the regression line does not deviate significantly from the identity line.


A transcutaneous PO2 electrode incorporating a thermal clearance local blood flow sensor.

Several possible methods for estimating and recording skin blood flow by thermal clearance are presented. The method chosen for trial with an O2 electrode was to thermoregulate an annular anode which covered the cathode, surrounding it like a heat shell, and to measure the cooling of the cathode by blood flow, by implanting a thermistor near the surface of the cathode. This device is far less affected by ambient temperature than is simple measurement of heating power in an uninsulated tcPO2 electrode.


Characteristics of non-aqueous electrolytes for transcutaneous oxygen electrodes.

We investigated the characteristics of non-aqueous solvents for tcPO2 electrolytes, using a tcPO2 electrode with three 15 micrometer platinum cathodes set in a polished glass surface, a 17.8 mm2 silver anode covered with a 25 micrometer Telfon membrane, with and without a 12 micrometer cellophane spacer, and polarized at--0.8v. We examined the effect of ethylene glycol (EG) concentration, in water, on O2 sensitivity, stirring effect, in vitro drift, in vitro response time, behaviour on the skin of newborn infants and in vivo response time. We found the following: (1) O2 sensitivity was reduced by increasing EG concentration. (2) phi, the stirring effect (gas/50% glycerine) was 1.01 at 90% EG with cellophane, but higher without cellophane. (3) In vitro drift at 44 degree C electrode temperature, in 43 degree C water (simulating skin), was reduced with 90% EG, 25 micrometer Telfon and no spacer, but increased with a spacer. (4) In vitro response time was increased with EG. (5) Correlations with arterial PO2 in a group of newborns was as excellent with an electrode made with 90% EG and 25 micrometer Telfon, without spacer, as it was with our previous study using aqueous electrolyte and 12 micrometer Telfon wint 12 micrometer cellophane: (tcPO2 = 1.32 + 0.988 PaO2 r = 0.987). In vivo response time was not prolonged. Using EG, the tc PO2 electrode membrane required changing only after 7--9 days, compared with 1--2 days when using aqueous electrolytes. No advantage of using cellophane spacers was identified in these in vivo studies.


A fast stabliization technique for oxygen sensors with low cathode current densities.

After application of the polarization voltage to a newly prepared oxygen sensor, an initial stabilization of several minutes to a few hours is required. The electrochemical phenomena accounting for this stabilization process are discussed. By far the slowest reaction is the change of the oxidation state of the noble metal cathode after application of the polarization voltage. During this process, reduction of surface oxides at the cathode causes a transient current. The contribution of this reaction to the total current is proportionately higher in the case of oxygen sensors with low cathode current densities (large cathode, membrane of low oxygen permeability) than in the case of sensors with microcathodes. For the first type of sensor, a technique has been developed which allows acceleration of this surface reaction by passing a high constant current across the cathode. With this technique, the stabilization time can be considerably shortened in a reproducible manner, and the sensor is ready to be used within 15 to 30 min of its preparation. This time is comparable to the stabilization time needed for sensors with microcathodes.


Problems of calibration and stabilization of tcPO2 electrodes.

The stirring effect factor phi, used to correct tcPO2 readings for gradient of PO2 induced in skin by electrode O2 consumption, was measured with 20 micrometer cathode electrodes at 44 degree C for various membrane, spacer and electrolyte combinations. Two in vitro models closely resemble skin phi values: (1) 50% ethylenge glycol/water equilibrated with air at 44 degree C, compared to air above this liquid; (2) a mock skin consisting of 25 micrometer Telfon on foam rubber, in air, dry. phi varied from 1.01 with 22 micrometer polypropylene over a 12 micrometer cellophane spacer, with either aqeous or non-aqueous, chloride-free alkaline electrolyte, to more than 1.10 when 25 micrometer Telfon was tested without a spacer. phi may be predicted: phi = 1 + 0.44 i/(M + 10C + 20) where i is pA/mmHg electrode sensitivity, and M and C are membrane and cellophane thickness, micrometer. Pressure sensitivity, tested agains foam rubber, was minimized by use of a spacer, and often increased with age of Telfon membrane. Drift may result from water vapour movements across membranes if calibration media have P(H2O) either too high or too low. Miminum drift on skin is also caused by a slow effect of PCO2 on reference electrode potential, and this is minimized by buffering electrolyte with K2B4O7.


Alkaline chloride-free oxygen electrolytes.

The initial and long-term drift of tcPO2 microcathode electrodes has been shown to be substantially less when chloride is removed from the electrolyte, despite the probability that reference electrode EMF is less well defined. In addition to virtually eliminating drift, these electrolytes eliminate silver deposition on the cathode. The most successful electrolyte tested thus far has been 0.2 M K2B4O7 in 95% ethylene glycol, 5% water, both with and without cellophane spacers. The buffering produced by borate appears to prevent the downward drift in CO2 free air probably caused by Ag2 CO3 formation on the anode, after exposure to skin.


Clinical limitations and advantages of transcutaneous oxygen electrodes.

We investigated the clinical use and limitations of the transcutaneous oxygen electrode described by Huch, Lübbers and Huch in 30 sick infants. One hundred and fifty-nine measurements of arterial oxygen tension (PaO2) and transcutaneous oxygen tension (tcPO2) were made. During the comparisons, arterial blood pressures, heart rate thoracic impedance were continuously recorded, skin axillary and environmental temperatures, hematocrit and skin thickness were measureed and the degree of peripheral perfusion noted. Despite a wide range of these variables, values of tcPO2 and PaO2 were similar (slope 0.963). Two groups of infants were identified in whom tcPO2 was lower than PaO2. These were infants receiving an intravascular infusion of tolazoline and infants with mean arterial blood pressures more than 2.5 s.d. below the predicted average value. Both of these situations represent extreme alterations in peripheral blood flow and give important information regarding the limitations of the method. Less extreme alterations in flow caused by mild hypotension, hypothermia, anemia, radiant warmers, and bilirubin lights did not adversely affect the transcutaneous PO2--arterial PO2 correlation. Advantages of transcutaneous oxygen monitoring over more conventional monitoring methods were assessed. We conclude that the transcutaneous oxygen electrode is safe, is easy to use, has few limitations and provides data which can help improve the management of most sick infants.


Experience and problems in the first six months of transcutaneous PO2 (tcPO2) monitoring in routine neonatal intensive care.

A transcutaneous oxygen monitor (Roche 5301), operated by regular intensive care nursery nurses,  was used in the routine management of 47 acutely ill infants over a six month period. The monitor was helpful as a trend monitor in showing immediate changes in oxygenation but in this clinical situation lacked accuracy. The overall correlation coefficient was 0.74 with a standard error of the estimate of 2.0 kPa (15 torr). This lack of accuracy was probably due to technical problems including the need for fairly frequent precise calibrations and proper, careful application of the skin electrode. Ill infants with poor skin perfusion may also have contributed to the lowering of the correlation coefficient.


Continuous comparison of transcutaneous and arterial oxygen tension in newborn infants with respiratory illnesses.

Transcutaneous oxygen tension (tcPO2) measured by two skin electrodes of different design, and arterial oxygen tension (PaO2) measured by an intravascular oxygen electrode, were continuously compared for periods of 6--27 h in 45 newborn infants with respiratory illnesses. One skin electrode (Dräger) had three microcathodes surrounded by a heated ring-shaped anode and the other (Roche) a large heated cathode. The electrodes were calibrated in vitro; 44 degrees C was found to be a suitable electrode temperature for the estimation of Pao2. tcPo2 recorded by the electrode with the microcathodes estimated Pao2 reasonably accurately for 6 h without the necessity for re-siting. tcPao2 recorded by the electrode with the large cathode gave a similar estimate of Pao2 for 3 h, but then tcPao2 often fell relative to Pao2. This fall was probably caused by skin changes at the electrode site. Poor skin perfusion causing underestimation of Pao2 by tcPo2 could not be identified by a number of methods tried.


Diffuse microglial proliferation after global ischemia in a patient with aplastic bone marrow.

Abundant proliferation of cells having the histologic and tinctorial features of microglia, were seen in the brain of 34-year old man who suffered cardiac arrest 10 days before death and whose bone marrow was nearly totally depleted of white-blood-cell precursors. It is suggested, that in adult human brains there are native microglial precursors which can take on a phagocytic function. Therefore, brain macrophages do not have to originate from circulating monocytes, as suggested by some animal studies.


The mucociliary activity of the upper respiratory tract. III. A functional and morphological study on human and animal material with special reference to maxillary sinus diseases.

Local mucociliary activity (mucociliary wave frequency) was recorded in vivo and in vitro in maxillary sinus diseases. Activity was fairly normal even in cases with chronic purulent sinusitis. Scanning electron microscopy (SEM) sometimes showed a quantitative reduction of cilia. The mucociliary wave frequency was mostly about 1000 waves/min, and there was no in vivo/in vitro discrepancy. Antral mucosa was compared to adenoids, nasal polyps and healthy rabbit trachea. The mucociliary wave frequency was about the same in all materials.


A new hypothesis on the plurifactorial etiology of Meniere's disease.

Meniere's disease is characterized by an extremely long trend: this fact, as in other diseases of very wide chronicity, permits one to formulate a special type of hypothesis regarding the aetiology and the pathogenesis of the disease; it is comprised of many individual factors, of differing chronology and which are connected to each other with successive causality. This hypothesis was founded on a large body of data concerning the multiple histopathological effects on the inner ear of an initially inflammatory disease of the middle ear.


A computer generated index for the assessment of coronary angiography.

Mortality in patients with coronary artery disease is related to its severity. The commonly used classification of 1, 2 or 3 vessel disease is relatively insensitive. We have designed a new classification which takes into account site, severity and effect of multiple lesions in the coronary circulation. Data is recorded on Mark Sense computer cards and a coronary index (CI) obtained. We have collected data from 1100 patients and shown correlations of the index with clinical variables, ventricular function and in particular, mortality.


Acute myelogenous leukemia following immunosuppressive therapy for rheumatoid arthritis.

A 51-year-old woman had acute myelogenous leukemia following log-term cyclophosphamide therapy for rheumatoid arthritis. After standard methods of management had failed, the rheumatoid arthritis showed considerable improvement in response to approximately 25 mg cyclophosphamide per day over a four-year period. At the end of this period, pancytopenia developed, and cyclophosphamide was discontinued. A bone-marrow aspirate showed nonspecific changes. However, four months later because of severe progressive pancytopenia, another bone-marrow examination was performed; it showed acute myelogenous leukemia. Therapy failed to induce a remission, and two months after diagnosis the patient died of aspergillosis. Autopsy confirmed the presence of leukemic infiltration of bone marrow, lymph nodes, liver and spleen. These findings suggest a possible leukemogenic role of cyclophosphamide in this case and suggest that caution should be exercised in treating non-fatal diseases with antitumor drugs.


Electrophoretic evaluation of sera from dogs with cancer.

A quantitative electrophoretic method was developed for evaluating sera from dogs with naturally occurring malignant tumors. Electrophoretic migration ratios (EMR) were devised to standardize characteristic protein components and to analyze alterations in mobility of these protein components, using a computerized densitometric technique. Sera values from dogs with lymphosarcomas, osteosarcomas, and mammary tumors were compared, using conventional methods of statistical analysis. Results indicate a statistical difference existed between mean values of EMR and alpha2-globulins of sera from dogs with tumors and those values from normal dogs. In addition, unique EMR and concentration of protein components were identified for dogs with lymphosarcomas, osteosarcomas, and mammary tumors.


[Long-term survival in childhood acute lymphocitic leukemia (author's transl)].

Long-term results in the treatment of 116 patients of acute lymphocitic leukemia with ages between six months and seven years are reported. A first group A, formed by 76 patients, was treated with prednisone and vincristine as induction protocol and maintenance therapy with 6-mercaptopurine or methotrexate. No neuromeningeal prophylaxis was made, except some cases in which intratecal methotrexate was applied. 27 patients are alive, 21 of them (27,6%) remain in complete remission for more than three years. A second group B, formed by 40 patients, was treated more recently; with an induction protocol composed by prednisone, vincristine and L-asparaginase. All patients in this group received cranial irradiation and intratecal methotrexate. 31 patients are alive (77,5%), 13 of them (32,5%) remain in complete remission for more than two years. The evolution period in this group B is shorter, but some features are exposed which suggest the possibility of long-term better results.


Hypnosis from the standpoint of a contextualist.

We set out to formulate a theory that makes counterexpectational conduct expectational. Our contextualist position has led us to the dramaturgical perspective. This perspective guided our examination of the hypnotic performance, and we noted that both the hypnotist and the subject are actors, both enmeshed in a dramatic plot, both striving to enhance their credibility. The dramatistic concepts of actor and spectator helped us make sense of the contradictory self-reports in Hilgard's analgesia studies. We underscore the proposition (long overlooked) that the counterfactual statements in the hypnotist's induction are cues to the subject that a dramatistic plot is in the making. The subject may respond to the cues as an invitation to join in the miniature drama. If he accepts the invitation, he will employ whatever skills he possesses in order to enhance his credibility in enacting the role of hypnotized person. This proposition emphasizes the need for analyzing the implied social communications contained in any interaction.


Hypnosis, suggestions, and altered states of consciousness: experimental evaluation of the new cognitive-behavioral theory and the traditional trance-state theory of "hypnosis".

Sixty-six subjects were tested on a new scale for evaluating "hypnotic-like" experiences (The Creative Imagination Scale), which includes ten standardized test-suggestions (e.g. suggestions for arm heaviness, finger anesthesia, time distortion, and age regression). The subjects were randomly assigned to one of three treatment groups (Think-With Instructions, trance induction, and Control), with 22 subjects to each group. The new Cognitive-Behavioral Theory predicted that subjects exposed to preliminary instructions designed to demonstrate how to think and imagine along with the suggested themes (Think-With Instructions) would be more responsive to test-suggestions for anesthesia, time distortion, age regression, and so on, than subjects exposed to a trance-induction procedure. On the other hand, the traditional Trance State Theory predicted that a trance induction would be more effective than Think-With Instructions in enhancing responses to such suggestions. Subjects exposed to the Think-With Instructions obtained significantly higher scores on the test-suggestions than those exposed either to the traditional trance-induction procedure or to the control treatment. Scores of subjects who received the trance-induction procedure were not significantly different from those of the subjects who received the control treatment. The results thus supported the new Cognitive-Behavioral Theory and contradicted the traditional Trance State Theory of hypnosis. Two recent experiments, by De Stefano and by Katz, confirmed the above experimental results and offered further support for the Cognitive-Behavioral Theory. In both recent experiments, subjects randomly assigned to a "Think-With Instructions" treatment were more responsive to test-suggestions than those randomly assigned to a traditional trance-induction treatment.


A betaLPH precursor model: recent developments concerning morphine-like substances.

In summary, the pituitary glands from at least four species contain betaLPH and and beta endorphins. We have shown that in slices of whole pituitaries betaLPH is actively biosynthesized and transformed into gammaLPH, thus releasing the COOH-terminus portion 61--91, which is now known as beta-endorphin. Newly radioactive biosynthesized beta-endorphin has been clearly and definitely identified. The release of betaMSH and possibly of beta-endorphin could well be under the control of CRF. The intermediate lobe of the pituitary seems to be the tissue that contains most of betaLPH and beta-endorphin, although these are also present in the anterior lobe. We have recently demonstrated its presence in human glands and the  structure is completely identical to the COOH-fragment 61--91 of human betaLPH. Thus far, these morphine-like peptides seem not to cross the blood-brain barrier in rats; it is conceivable (neurophysiologists will need to look into it) that an upward circulatory process could bring beta-endorphin into the brain where it is concentrated in different regions as either native or degraded products both of which have similar activities. Until somebody shows that betaLPH and beta-endorphin are actively biosynthesized in other tissues, one can only assume that the pituitary gland is the primary source of the endogenous opiate substance(s) and that betaLPH is its or their biologic precursor. We have worked on the proposed biosynthetic model for many years and we are continuing because all of the experiments, except one from another laboratory, 38indicate that we are moving slowly toward its confirmation. Thus far, there is no reason to believe the contrary, and we are following in some ways Konrad Lorenz's maxim, which appeared in his book Die Acht Todsunden Der Zivilisierten Menscheit, published in French in 1973: "Une bonne hypothése de travail gagne en vraisemblance lorsque, au cours de longues années de recherches, nulle donnée n'est venue la contredire." The major conclusion of our most recent studies on the biosynthesis of betaLPH and its related peptides have led us to the first in vitro biosynthesis of an endogenous morphine-like substance. This constitutes a major step in the comprehension of this exciting new field.


Iron nutrition.

This paper is a progress report on our present understanding of iron nutrition in man, particularly in developing countries. We will be concerned with the quantitative aspects of iron balance and in particular with the availability of dietary iron, the recognition of iron deficiency and its prevalence, the effects of iron deficiency on the well being of the individual, and the feasibility of modifying the iron balance of man by dietary means.


Aging, nutrition, and the continuum of health care.

The interrelations of aging, nutrition, and the continuum of health care have been discussed in terms of four issues, all of which focus on how to convince modern societies that meaningful attention to the triad is not only desirable but, in the light of the alternative, practically mandatory. The action steps required consist by and large of convincing societal leadership who in turn can convince their followers that meaningful attention to the aging-nutrition-health triad can produce better lives for all. The attention must be directed at all human life from conception to death. Properly applied throughout life, the attention can dramatically decrease the misery and waste currently imposed by life-style diseases and disabilities. To highlight the tangible and appeal to the pecuniary qualities of mankind, attention has been focused particuarly on the cost-effectiveness of such attention. The fractionation of the triad's components into individual units each furthered by its own proponents is not only wasteful of scarce resources but dangerous to individuals and their societies. Professionally trained scientists concerned with nutrition are keys to the catalysis of societal comprehension of the triad's interrelations. They have the education, training, experience and contacts at all levels to lead the leaders who in turn will convince societies worldwide that integration of aging, nutrition, and the continuum of health care at all phases of the life cycle is desirable, mandatory, effective, and economically sound.


Nutritional needs of special populations at risk.

The nutritional needs of special populations at risk require a concerned government, a concerned bureaucracy which funds and operates health, welfare and food delivery systems. Equally, if not even more important, is the concern and involvement of citizens at the "local-state-county-city" level. Some of the vulnerable groups, such as the migrant workers and the Native Americans, are the responsibiliity of the Federal Government. This does not mean that State and local citizens should do nothing, which by and large characterizes what has happened. The solution to provide optimum nutrition for the entire U.S. population is not merely a recitation of: food production figures, food costs, documentation of how much the Government spends on feeding people, how many free or reduced school lunches are served, how good or bad the problem is. We need to update and monitor programs that deal with the delivery of health, welfare and food; nutrition education for educators, Congress, doctors, and the public; food enrichment and fortification; nutrient analysis of foods; and nutrition research.


Phospholipid-exchange proteins as membrane probes.

Phospholipid-exchange proteins, first discovered in rat liver, have now been identified in a variety of animal and plant tissues. In rat liver one protein transfers phosphatidylcholine with a high degree of specificity. Another protein fraction is capable of transferring all major types of phospholipids as well as cholesterol. Beef heart is a good source of phospholipid-exchange protein, which transfers phosphatidylinositol and phosphatidylcholine. Studies with phospholipid-exchange protein from beef heart, beef liver and rat liver show that these proteins are useful for the study of membrane structure. When unilamellar vesicles of isotopically labeled phosphatidylcholine are incubated with nonlabeled mitochondria in the presence of phospholipid-exchange protein, only the outer portion of the phosphatidylcholine bilayer is exchangeable and translocation of lipids between inner and outer parts of the bilayer is exceedingly slow. Resealed red blood cell ghosts show an equilibration of phosphatidylcholine between the inner and outer portions of the bilayer with a t1/2 of two hours. An even faster equilibration of various phospholipids in the microsomal mmebrane appears to take place in rat-liver microsomes.


Mechanisms of reduction of antitumor drug toxicity by liposome encapsulation.

Actinomycin D, when encapsulated within liposomes, has been previously shown to be less toxic to mice than nonencapsulated actinomycin D, but to retain its tumoricidal activity. We have compared the toxic effects of Act D encapsulated either in the aqueous phase or in the lipid phase of liposomes (APL and LPL, respectively), and the nonencapsulated Act D on the blood forming system, on cell proliferation in the intestine, and on antibody production by spleen lymphocytes. At a single dose of 0.4 mg/kg, APL-encapsulated Act D wass less toxic to white blood cells and to the nucleated cells and colony-forming stem  cells of the bone marrow. During toxicity in the proliferating intestinal cells, measured by 3H-thymidine incorporation, was reduced by about a factor of 4 with encapsulation in APL, particularly 24 hours after Act D administration. The toxiciaty of LPL-encapsulated Act D to both the blood-forming system and the intestinal proliferating cells was, however, not significantly different from that of the nonencapsulated Act D. Effects of Act D on the antibody production by spleen cells, determined by the "limited hemolysis in agar" assay, showed that immunosuppression was most markedly reduced by liposome encapsulation either in APL or in LPL, when the drug was given one day before the antigen. These findings are important for considerations of liposome application in cancer chemotherapy.


Enhancement of chemotherapeutic effect by entrapping 1-beta-D-arabinofuranosylcytosine in lipid vesicles and its mode of action.

a-beta-D-arabinofuranosylcytosine (ara-C) trapped in multilamellar liposomes exerted enhanced chemotherapeutic effect against L1210 murine leukemia. Among four types of liposomes, the one composed of sphingomyelin, stearylamine and cholesterol was most potent in enhancing chemotherapeutic effect of ara-C. And the findings that ara-C was released gradually from liposome in vitro and that ara-C in liposome was chemotherapeutically effective against subsequently inoculated L1210 cells suggested that slow but long-lasting release of ara-C from liposome was partially responsible for enhanced chemotherapeutic effect.


Gilles de la Tourette syndrome: further studies and thoughts.

A possible association between the Gilles de la Tourette and Lesch-Nyhan syndromes has recently been postulated. Fourteen patients with Tourette syndrome demonstrated no similarity to Lesch-Nyhan based upon patterns of inheritance, behavioral changes, or alterations of purine metabolism. Despite a strong male predominance, a sex-linked pattern of inheritance could not be confirmed. Self-mutilating behavior was found in 4 male patients but was readily differentiated from that characteristic of the Lesch-Nyhan syndrome. Quantitation of hypoxanthine-guanine phosphoribosyltransferase and isoelectric focusing of its isoenzymes produced results that were indistinguishable from those in controls. We speculate that, pathophysiologically, Tourette syndrome represents an imbalance between the central neurotransmitters dopamine and serotonin rather than an alteration in purine metabolism.


Testicular damage due to cytotoxic drugs and recovery after cessation of therapy.

Testicular function was assessed in 32 patients who received standard chemotherapy regimens for disseminated lymphomas. Thirty-one had evidence of germ cell damage, as assessed by the finding of azoospermia and/or high plasma levels of follicle-stimulating hormone (FSH). In addition, five patients had persistently low plasma testosterone levels associated in three with elevated plasma luteinising hormone (LH) levels. Reproductive function did not recover in any patient while chemotherapy continued. Cessation of therapy was possible in 16 patients with prolonged remissions of disease. Among these, recovery of germinal epithelium differed greatly between the cyclophosphamide / vincristine / prednisone treated group and the mustine/procarbazine/vincristine/prednisone treated group. Seventy per cent of the former patients had evidence of recovery after 34 months of follow-up while only one (17%) of the latter had begun to recover at 52 months post-therapy. Serial measurement of plasma FSH levels proved useful in predicting likely recovery of spermatogenesis.


A quantitative review of the performance of implanted cardiac pacemakers, Medtronic Model No. 5944.

One of the service functions of the Sir Charles Gairdner Hospital Department of Biophysics since 1972 has been the routine performance testing of pacemakers implanted by the Hospital's Cardiologists. This service was set up to measure pacemaker pulse parameters with a view to detecting battery depletion. It was also found to be of great help in showing lead insulation deterioration, intermittent capture and movement of the catheter tip within the right ventricle, information that is frequently of help to the Cardiologists in planning acute or elective pacemaker replacement.


Treatment of amenorrhoea, galactorrhoea and hypogonadism with bromocriptine.

The effect of bromocriptine administration was studied in 34 patients, whose presenting symptoms included amenorrhoea, galactorrhoea, infertility, dyspareunia, delayed puberty, and impotence. Two patients were found to have raised plasma prolactin values during investigation for acromegaly. With the exception of three individuals all patients had hyperprolactinaemia. Pituitary fossa enlargement or asymmetry was reported in 16 patients and one patient had primary hypothyroidism. Virtually all patients complained of side effects when first starting bromocriptine but only two patients were unable to tolerate prolonged therapy with doses which ranged from 5--40 mg daily. A single oral dose of 2.5 mg resulted in a greater than 50% reduction in plasma prolactin within five hours in 22 of 26 patients. Over the course of one month, five patients with significant pituitary fossa enlargement appeared to show less rapid suppression of plasma prolactin than five patients without fossa enlargement. At two months this trend was still evident but eventually all patients showed acceptable control of plasma prolactin, with the exception of one patient who required pituitary surgery. Galactorrhoea ceased in 13 of 15 patients, menstrual periods resumed in ten of 13 patients, two patients becoming pregnant first. Potency returned and puberty proceeded in two hypogonadal males. Six of the nine patients requesting treatment for infertility became pregnant. It is concluded that bromocriptine provides effective treatment for galactorrhoea, amenorrhoea or gonadal disorders when there is associated hyperprolactinaemia.


The problem family and community medicine.

The characteristics of problem families are described and especially their dependency upon the social services. They are of increasing importance to community medicine since as shown by the literature their members form 5--10% of the total population and use from 50--80% of the total social and corrective services. The social pathology of 16 root and 110 sub-families was investigated; enquiries have also been made into the family dynamics and especially child rearing, learning problems and ill health. Infections, injuries and childhood disorders are particularly frequent. There are administrative advantages in regarding these families as socially handicapped.


Association of sick sinus and Lown-Ganong-Levine syndromes.

A 38-year-old woman presented with syncopal attacks for 27 years. The electrophysiology techniques which enabled the diagnosis of both sinus node dysfunction (sick sinus syndrome) and presence of an atrionodal bypass tract (Lown-Ganong-Levine syndrome) are illustrated.


Metformin associated lactic acidosis.

A case of lactic acidosis occurring in association with inappropriate and excessive metformin therapy and a high serum metformin concentration is described. In the other 23 cases of metformin associated lactic acidosis reported to December 1977, renal, cardiovascular and liver disease were common. Although metformin is less likely to cause lactic acidosis than phenformin, neither drug should be prescribed in the presence of renal, hepatic or cardiovascular disease.


Transient metastatic calcification in primary hyperparathyroidism.

Metastatic calcification has been visualised on bone scan in many hypercalcaemic states. This report illustrates the phenomenon occurring in a patient with primary hyperparathyroidism and its subsequent disappearance after therapy.


A variant chromosomal translocation found in a series of 24 patients with Philadelphia positive chronic granulocytic leukaemia.

The bone marrow chromosomes of 24 patients with Philadelphia positive (Ph 1) chronic granulocytic leukaemia (CGL) were studied using banding techniques. In 23 patients, the Ph(1) had been produced by the standard translocation between chromosomes 9 and 22, but in the remaining patient, the Ph(1) chromosome had been formed by a translocation between chromosomes 16 and 22. Clinical and haematological details of this patient are reported.


A status report on the management of solid tumours.

Progressive improvements in the management of certain paediatric and haematological malignancies have provided guidelines for the current approaches to the management of the more common solid tumours of adults. These include precise histopathological grading; comprehensive evaluation of extent of disease; staging classifications accurately correlated with prognosis and progressive evaluation of available therapeutic modalities for all stages of disease in an attempt to define the best combination of local and systemic forms of therapy. Breast cancer is reviewed in detail as an example of the more responsive tumours where screening programs; improvements in pathological and clinical staging and the introduction of systemic chemotherapy together with optimal use of other methods of treatment for the various stages of disease gives hope for a significant improvement in long term survival statistics. Lung cancer has also been reviewed as an example of the more resistant types of cancer where screening programmes and current therapy including the use of combination chemotherapy have given minor encouragement but not had a definite influence on long term survival. Some further gains may still be achieved with currently available techniques but major improvements will probably require the development of better therapeutic tools including radiotherapy with high linear energy transfer particles; new chemotherapeutic agents and specific forms of immunotherapy. It is also quite possible that completely different forms of therapy for these resistant tumours will be necessary to reach the desired goal of long term improvements in survival.


Evaluation and peer review of the role of specialist and general medical units in a teaching hospital.

The trend toward increasing specialization in the medical wards of teaching hospitals has important implications for future health care delivery and student teaching. A study of the likely implications of a change to a specialty oriented medical admission system at the Royal Adelaide Hospital has shown that already the general physicians are seeing little renal and endocrine disease and, that work satisfaction is greater on the specialty units than on the general medical units. Patient satisfaction marginally favoured the specialty units. A peer review audit method was introduced to try and discern whether the quality of care was significantly different on the two types of units. Most physicians cooperated in at least one or two audits which involved them in judgements about adequacy of casenotes, management decisions, follow-up arrangements, length of stay and investigations in randomly assigned specialty pairs of patients (cared for by specialist or general units). No clear-cut trend was discerned favouring specialist or generalist care amongst 17 randomly selected pairs, but this part of the study was never completed, perhaps partly because of lack of enthusiasm for it by busy clinicians. The importance of maintaining a model of generalism for medical students on the teaching hospital campus is discussed discussed in the light of the decline of the role of general physicians.


The blast crisis of chronic granulocytic leukaemia: megakaryoblastic nature of cells as revealed by the presence of platelet-peroxidase--a cytochemical ultrastructural study.

The origin of cells in the blast crisis of some cases of chronic granulocytic leukaemia (CGL) remains controversial. Difficulties arise from the lack of cytochemical characteristics of differentiation. This report concerns the nature of cells in the blast crisis of a case of CGL in which blast cells exhibited an undifferentiated or lymphoid appearance by light and electron microscopy. The majority (90%) of such cells contained a peroxidase in the endoplasmic reticulum distinct from myeloperoxidase. In addition, some micromegakaryocytes could be recognized among the peroxidase reactive cells, by the presence of typical granules and demarcation membranes. Since this peroxidase exhibited identical characteristics to that of normal megakaryocytic precursors, these blast cells could be identified as megakaryoblasts. These data emphasize the possible megakaryoblastic nature of cells occurring in other cases of CGL blast crisis.


Myeloid karyotype and the malignant phase of chronic granulocytic leukaemia.

During the course of a 30 month study period, 26 patients with typical chronic granulocytic leukaemia (CGL) developed karyotype abnormalities in addition to the Philadelphia (Ph1) chromosome. All cases had received at least 14 months continuous low dose busulphan, and the chromosome changes were found before clinical transformation in six patients and at the time this occurred in 20. Survival following the discovery of these additional abnormalities was short, with a median of 11 weeks for the whole group. Trisomy 8 was the commonest additional chromosome abnormality, but no one karyotype change was clearly associated with shorter survival than another. 23 of the 26 have died as a direct result of their disease, forming part of a total of 40 deaths from typical CGL encountered during the study period where karyotype analyses were performed during the terminal stages of disease. Of these 40, only two (5%) patients showed no chromosome abnormalities extra to the Ph1 prior to death. (The 17 non-study patients who died were similar in all respects to the 23 from the study group, but had no prior chromosome studies performed during the chronic phase of the disease.) It is suggested that an expanding aneuploid or pseudodiploid clone arising from the leukaemic cells during the benign phase of CGL can be used to mark the sometimes ill-defined onset of the malignant phase in all but a small proportion of cases.


A quantitative assessment of neutrophil marrow in seven patients with chronic granulocytic leukaemia.

Neutrophil marrow cellularity was determined in seven patients with chronic granulocytic leukaemia (CGL). The size of the mitotic pool (promyelocytes and myelocytes) and the number of metamyelocytes and bands and of segmented neutrophils in the postmitotic pool were determined from measurements of neutrophil--erythroid ratios in marrow biopsy sections and ferrokinetic estimates of marrow normoblasts. A section mitotic index was calculated in each patient from the numbers of mitotic figures and mitotic pool cells counted on marrow sections. Basal values previously established in normal subjects for the mitotic pool, for metamyelocytes and bands, and for segmented neutrophils, were 2.11 +/- 0.36 x 10(9) cells/kg, 3.33 +/- 0.61 x 10(9) cells/kg, and 2.26 +/- 0.42 x 10(9) cells/kg, respectively (+/- 1 SD, n = 13). The basal section mitotic index was 0.07 +/- 0.01 (+/- 1 SD, n = 13). In the seven patients with CGL the mitotic pool comprised 3.71--25.70 x 10(9) cells/kg, metamyelocytes and bands 7.70--51.02 x 10(9) cells/kg, and segmented neutrophils 3.45--28.81 x 10(9) cells/kg. Mitotic indices ranged from 0.04 to 0.10. No relationship was found between marrow cellularity and blood neutrophil count. A negative correlation existed between mitotic pool cellularity and mitotic index (r = -0.76, n = 7 pairs). The results provide quantitative affirmation of neutrophil marrow hyperplasia and of increased neutrophil production by the marrow in CGL.


Defective binding of thrombin to platelets in myeloid leukaemia.

Platelets from patients with myeloid leukaemia showed reduced aggregation with collagen or thrombin. These platelets also had a lower capacity to bind thrombin. This lower thrombin binding is due to a decrease in the total quantity of receptors available and not because of a change in the affinity. In the presence of the patients' plasma, the aggregation behaviour of normal platelets induced by thrombin as well as the clotting time of fibrinogen remained unchanged. The results suggest that the platelet dysfunction in myeloid leukaemia is partially due to a membrane defect involving the thrombin receptors which leads to an impaired induction of the initial stimulation.


Acute lymphoblastic leukemia followed by chronic myelocytic leukemia.

Second hematologic malignancies occur rarely in patients previously treated for leukemia. This report describes a patient with acute lymphoblastic leukemia who remained in complete remission for 5 yr and then developed chronic myelocytic leukemia (CML). The original lymphoblasts were associated with a partial deletion of chromosome 21, while CML was associated with a classic Philadelphia marker, indicating the independent origin of the two leukemias.


Variable globin chain synthesis in mouse erythroleukemia cells.

Various mouse erythroleukemia cell lines show unique responses to chemical inducers. Lines 745 and 707, from DBA/2 mice, produced 25%--48% beta-minor and 78%--52% beta-major globin following culture with DMSO. Butyric acid treatment led to approximately 40% beta-minor globin, while induction with hemin resulted in over 80% beta-minor synthesis. Line FSD was developed independently. DMSO induction led to less than 10% beta-minor globin, while hemin and butyric acid both resulted in approximately 40% beta-minor synthesis. T3C12 and 5000 originated in DDD mice. With these lines all inducers led to only beta-major and no beta-minor synthesis. The inducers did not influence protein stability or initiation of globin synthesis. Translation of poly A-containing cytoplasmic RNA in a wheat germ cell-free system led to proportions of beta-minor that were the same as those seen in the intact cells. Thus regulation of the type of globin chain produced in erythroleukemia cells following culture with several inducing agents occurs at either the level of gene transcription or posttranslational processing, or by growth of a selected cell population.


Delayed hypersensitivity skin reactions in the induction phase of remission in acute non lymphoid leukemias.

Delayed skin reactions to Tuberculin (10 units, intradermal) and Candidin (1:1000, intra dermal) were studies in a homogenous group of 41 patients with acute non lymphoid leukemias in their initial phase. Remission-rate is higher in non-anergic patients (63%) than in anergic patients (32%), (p less than 0.05). Death-rate (within 30 days after chemotherapy) is higher in anergic patients (50%) than in non-anergic patients (16%), (p less than 0.05). There is no correlation between delayed skin reactions and age, initial absolute counts of neutrophil-lymphocyte-monocyte-blast cells, and results of humoral immunity. Delayed skin reactions are interesting in defining a high-risk group in the induction phase of remission of acute non lymphoid leukemias.


Metaphyseal multifocal osteosarcoma.

Two patients, aged six and eight years, having metaphyseal osteolytic and osteoblastic multifocal osteosarcoma are described. The condition is named "metaphyseal multifocal osteosarcoma". The metaphyseal areas are the sites of the pathological process. It can be postulated that a certain intensity of growth activity is the predominant factor in this condition and that this accounts for its multicentered presentation.


Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate.

Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/m(2) methotrexate, followed three hours later by intravenous colaspase, 40 000 IU/m(2). Seven days later intravenous methotrexate, 120 mg/m(2) was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/m(2) with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/m(2) (median 200 mg/m(2)). Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/m(2) caused minimal myelosuppression and stomatitis, which suggested that colaspase given sequentially provides relative protection from methotrexate toxicity without the need for folinic acid (citrovorum factor) rescue.The combination of sequential colaspase and methotrexate is highly effective in reinducing remission in patients with acute lymphoblastic leukaemia or acute undifferentiated leukaemia. The regimen is easy to administer and relatively non-toxic, so it is suitable for use in outpatients, either alone or combined with other agents.


Pyrimethamine in prevention of relapses of meningeal leukemia: report of two cases.

Relapses of meningeal leukemia occurred in two children during hematologic remission of acute lymphoblastic leukemia. Treatment of CNS leukemia consisted of radiotherapy and repeated intrathecal injections of methotrexate and cytosine arabinoside. Intrathecal installations of the drugs were accompanied with increasing neurological side effects which seemed to be lifethreatening. To avoid them, repeated courses of pyrimethamine were introduced. No further relapse of meningeal leukemia occurred after pyrimethamine. Hematologic remissions in both children have lasted for over 7 years. All therapy was stopped 16 months ago.


Malignant histiocytosis: morphologic and cytochemical findings.

The clinical, morphologic, and cytochemical findings of 7 patients with malignant histiocytosis are presented in this study. The diagnoses were confirmed by the use of electron microscopy and cytochemistry (acid phosphatase and naphthol-AS-acetate-esterase). Two different types of malignant histiocytes were identified by the differentiation and development of cell organells. The relation of malignant histiocytosis to monocytic leukemia and to normal histiocytes (and their precursors) is discussed. And finally, there are statements on the origin and peculiarities of malignant histiocytes.


Comparison of tritiated thymidine labeling and suicide indices in acute nonlymphocytic leukemia.

Leukemic cells were obtained from the bone marrow or peripheral blood of patients with acute myelocytic leukemia or one of its variants. The tritiated thymidine labeling index of the leukemic cells and the suicide index of the cells that produce clusters in vitro were compared. The suicide index was 5 times greater than the labeling index (S.E.) [54 +/- 8% versus 12 +/- 3%], demonstrating the presence of a highly proliferative subpopulation of leukemic cells (in vitro colony-forming unit) among the relatively slowly proliferating leukemic cells. Since the leukemic in vitro colony-forming unit appears to be the progenitor of the recognizable leukemic cell population, the proliferative characteristics of the recognizable leukemic cells may not be reflective of that of leukemic stem cells.


Heterogeneity of murine erythroleukemia cells with respect to tumor promoter-mediated inhibition of cell differentiation.

Spontaneous and induced differentiation of murine erythroleukemia cells (strain 745A DS19 ) is reversibly inhibited by 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent promoter of mouse skin carcinogenesis, and by other tumor-promoting macrocyclic plant diterpenes, but it is not by nonpromoting diterpenes. Twelve clones randomly isolated from this strain vary in their response to TPA. All clones are induced to differentiate by several compounds, the most potent of which is hexamethylene bisacetamide. In six clones TPA (100 ng/ml) caused greater than 90% inhibition of differentiation, as measured by the appearance of benzidine-reactive cells. In two clones cell differentiation was not inhibited by TPA even at concentrations as high as 1 microgram/ml. In four clones, differentiation was only partially inhibited (16 to 47%) by TPA. Clones resistant to TPA inhibition of differentiation were also resistant to structurally related tumor-promoting agents. The isolation of variant cell lines, sensitive and resistant to TPA, provides a tool for elucidating the mechanism of tumor promoter-mediated inhibition of cell differentiation.


Phase 1 clinical investigation of 4'-(9-acridinylamino)methanesulfon-m-anisidide (NSC 249992), a new acridine derivative.

The compound 4'-(9-acridinylamino)methanesulfon-m-anisidide is a new derivative that was evaluated in a Phase 1 clinical trial. The schedule of drug administration consisted of daily i.v. injection for 3 consecutive days, repeated at 3-week intervals. Twenty-six patients received a total of 63 courses of 4'-(9-acridinylamino)methanesulfon-m-anisidide in a dose range from 4 to 50 mg/sq m/day. Hematopoietic toxicity was dose limiting, but it was of short duration and rapidly reversible. Mild nausea and vomiting were observed in 16% of the courses, and a mild degree of phlebitis was observed in 10% of the courses. Responses were observed in two patients with adenocarcinoma of the lung and one each of melanoma and acute myeloblastic leukemia. Phase 2 studies of 4'-(9-acridinylamino)methanesulfon-m-anisidide are planned at a starting dose of 40 mg/sq m/day for 3 days in good-risk patients and at 25 to 30 mg/sq m/day for 3 days in poor-risk patients. Course of treatment would be repeated at 21-day intervals.