History and development of mixed opioid agonists, partial agonists and antagonists.

1 A brief history of the development of narcotic antagonists is outlined. 2 The clinical and pharmacological observations leading to the discovery of dualism of opiate receptors are reviewed. 3 An extension of this theory to a three-receptor model (mu, kappa and sigma) is required to rationalize the pharmacology of the antagonists analgesics cyclazocine, pentazocine and nalorphine. 4 The methodologies available for the study of compounds with dual agonist-antagonist activity are discussed in the light of the above receptor multiplicity, and data appertaining to the kappa-partial agonist, nalorphine and the mu-partial agonist buprenorphine are outlined.


A trial of sublingual buprenorphine in cancer pain.

1 Buprenorphine is a new antagonist analgesic which was offered sublingually to 141 patients with moderate cancer pain as an alternative to their current analgesic. These patients were not on regular strong morphine-like analgesics. 2 Forty-seven patients used the drug on demand in unit doses ranging from 0.15-0.8 mg for an average of 12 weeks. A full-time nurse-observer was used throughout the studies. 3 Good analgesic results were obtained. Certain difficult chronic dull aching pains in the head and neck were especially helped by the drug. There was no indication of dependence or tolerance in this study. 4 The main side-effect was drowsiness which lessened with usage of the drug. A major advantage of the drug was the absence of constipation as a side-effect. 5 This sublingual preparation seems worthy of addition to the commercially available range of analgesics in clinical practice.


Anti-tumour activity of ICI 118630, a new potent luteinizing hormone-releasing hormone agonist.

Experiments were undertaken with DMBA-induced mammary tumours of the rat to determine the anti-tumour properties of a new and potent luteinizing hormone releasing hormone (LH-RH) agonist, [D-Ser(But) 6Azgly10]-LH-RH (ICI 118630). Tumours were classified according to their oestrogen-receptor (ER) content. Twice daily i.m. injections of either 5 micrograms or 0.5 micrograms ICI 118630 in saline were as effective as ovariectomy or tamoxifen therapy in causing the regression of ER+ DMBA-induced mammary tumours. ER- mammary tumours showed a more equivocal overall response to ICI 118630, some tumours progressing, others regressing. About one-third of the ER+ tumours disappeared in the 20-day treatment period. Those tumours which did regrow after the cessation of treatment proved to be hormone-dependent. In addition to the inhibitory effects of the LH-RH agonist on pre-existing tumours, ICI 118630 also reduced the total number of new tumours formed during and after treatment.


Effects of high doses of a series of new luteinizing hormone-releasing hormone analogues in intact female rats.

A new series of LH-RH analogues containing an Azgly10 modification and having potent agonist properties were given in high concentration to intact female rats. Plasma LH and FSH were raised to extremely high levels after 14 days' administration of the compounds (5.0 and 0.5 microgram/rat twice daily), but plasma oestradiol concentrations were reduced to those in ovariectomized rats. The weights of the ovary and uterus were also markedly reduced, suggesting that these compounds are, on this treatment regime, producing the effects of chemical castration.


Prostacyclin activity in rat kidney stimulated by angiotensin II.

Prostacyclin (PGx, PG12) activity can be found in renal tissue as indicated by platelet aggregation inhibition. The activity of the medullary tissue in terms of wet weight is significantly higher (P less than 0.01) than that of cortex. The activity decreases with time and has almost entirely gone within 1 h. Boiling for 30 s destroys the inhibitory effect of the prostacyclin on platelet aggregation. Angiotensin II is able to stimulate the prostacyclin availability of the tissue after incubation for 3 min. Addition of angiotensin II to platelet-rich plasma (PRP) has no significant effect on ADP-induced platelet aggregation. The spontaneous generation of prostacyclin as well as that stimulated by angiotensin II can be suppressed by previous incubation of the tissue with a prostaglandin synthetase inhibitor such as ketoprofen. Tissues which have only a small amount of basal release in buffer show an increased platelet aggregation inhibitory effect after addition to PRP. The difference between medulla and cortex is statistically significant. This different release of prostacyclin cannot be related to different endothelial surface area, because the endothelial surface in medulla and cortex is quite similar. It is suggested that prostacyclin has an important influence on the renal function. The different capacity of renal medulla and cortex in generation of prostacyclin could be of great importance for a fuller understanding of the physiology of renal function.


Procollagen synthesized by newborn rat skin in culture.

Newborn rat skin explants in culture have been found to synthesize and secrete into the medium a considerable amount of collagen precursors (procollagens). Gel-electrophoresis analysis of the material extracted from the medium indicates that it is constituted mainly by procollagen Type I with a small percentage of procollagen Type III. Antibodies have been raised to the extracted procollagen and, although no attempt has been made to render these antibodies specific to one procollagen type by appropriate immunoadsorption, the immunofluorescence patterns that have been obtained are in good agreement with those reported on procollagen Type I by other groups. When unfixed cultured fibroblasts are examined by indirect immunofluorescence in the presence of the antiprocollagen antibody, a fluorescent network of interwoven fibres on the cell surface is observed which is similar to the network formed by fibronectin (LETS) on the fibroblasts' cell membranes.


Hairy-cell leukaemia: a B-lymphocytic disorder.

Fifteen cases of histologically proven hairy-cell leukaemia (HCL) were studied with immunofluorescence, rosette, and phagocytosis techniques. Unfixed hairy cells (HC) bound all kinds of labelled antiserum; but after fixation with formaldehyde a much more selective binding was observed. In two cases no surface-bound Ig was detected; four cases showed gamma and in nine cases two or three heavy chains were found, alpha and delta being the most frequent. Few cases were clearly positive for mu. The picture was invariably monoclonal with respect to light chains. Cytoplasmic Ig was present in only 3/15 cases; it was always IgM. HC did not form E-rosettes or react with a fluorescent anti-T cell antiserum. No EAIgMC-rosettes were formed. All cases showed Fc receptors, which were detected with EAIgG-rosettes (13/13) or with antigen-antibody complexes (6/6). The density of Fc receptors varied widely. Incubation with latex particles resulted in cell-associated particles in 16-63% of the HC; with Staphylococcus epidermidis, the percentage was 2-36. After enzyme treatment (lysostaphin), however, no ingested bacteria were found, which suggests that HC are essentially non-phagocytic. At least 13 cases were therefore classified as B-cell malignancies.


Abnormal peripheral blood lymphocytes and bone marrow infiltration in non-Hodgkin's lymphoma.

The blood lymphocytes of 21 normal blood specimens, 20 patients with various malignant disorders and 63 patients with non-Hodgkin's disease lymphoma, all with lymphocyte counts below 6 x 10(9)/l, were examined by sheep red cell rosetting, fluorescent antisera to surface immunoglobulin and for sensitivity to colchicine. The results were correlated with bone marrow infiltration and lymph node histological findings. The ratio of kappa to lambda light chains in the surface immunglobulin was used to determine if an abnormal clone of lymphocytes was present. In the normals and the non lymphoma controls the expected normal ratio of approximately 2K to 1 lambda was found with a narrow spread. In non-Hodgkin's lymphoma cases there was a wide spread of ratios with half the cases outside the range of the controls. These cases were considered to have a clone of abnormal lymphocytes in the blood although their routine blood and differential counts were usually normal. There was a very significant correlation of the presence of a clone with ultrasensitivity to colchicine and with involvement of the bone marrow. 81% of the cases with a histological diagnosis of well-differentiated diffuse lymphocytic lymphoma, 64% of those with poorly differentiated diffuse but only 22% of those with diffuse histiocytic had an abnormal lymphocyte clone demonstrated by an abnormal K:lambda ratio.


Concentrations of the prostacyclin metabolite, 6-keto-prostaglandin F1 alpha, in amniotic fluid during late pregnancy and labour.

Concentrations of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the stable metabolite of prostacyclin, PGI2) have been measured in amniotic fluid obtained during late pregnancy and labour. Samples taken at amniotomy during spontaneous labour contained a significantly greater concentration of 6-keto-PGF1 alpha than samples taken at amniotomy before the onset of labour (p less than 0.01). There was no correlation between the level of 6 keto-PGF1 alpha in amniotic fluid before labour and gestational age (p greater than 0.1). It is suggested that prostacyclin may have a functional role in the mechanism of parturition in man.


Treatment of pruritus vulvae by multiple intradermal injections of alcohol. A double-blind study.

A double blind study is described in which 17 patients with intractable pruritus vulvae were treated by multiple intradermal injections of absolute alcohol. In each patient half the vulva was treated with alcohol whilst the other half was injected with water. Treatment with alcohol was significantly better than treatment with water (p less than 0.001).


A double-blind cross-over study of the effect of doxycycline on mycoplasma infection and infertility.

Forty-two couples in an infertility clinic were examined for genital infection with Mycoplasma hominis or Ureaplasma urealyticum (T strains). In 21 couples one or other partner was found to be infected; no chlamydiae, trichomonads, or gonococci were isolated from any of these couples. All patients were then included in a double-blind crossover doxycycline/placebo study lasting 8 months. Pregnancy was achieved in one of the 21 couples who were free of infection. Of the 21 couples who were infected, one achieved a pregnancy while still infected, and 19 lost their infection on doxycycline, of whom four achieved a pregnancy. These four pregnancies all occurred among the 10 couples who received doxycycline first. One further pregnancy occurred after the trial was over. Since 5 of the 7 pregnancies occurred in the first 4 months of the trial, they were probably due to the psychological effect of treatment rather than the effect of the drug on infection.


HLA and eye disease.

This review article discusses the evolution and function of the histocompatibility system, the nature of the HLA antigens and their classification, the phenomenon of linkage disequilibrium, and the mechanisms of HLA and disease susceptibility. The reported associations between HLA antigens and various eye diseases are analysed and their significance is discussed. Problems in designing studies on HLA and disease associations are highlighted and suitable statistical procedures for the analysis of the results are outlined.


Nocardia asteroides keratitis.

Nocardia asteroides has been reported as the cause of keratitis in only 7 cases and of other ocular disease in another 12 cases. We report a case of N. asteroides keratitis that presented 3 weeks after rural trauma and progressed despite trials of appropriate antibiotics. Seven weeks after the origianl injury a successful conjunctival flap was placed over the cornea. The morphology and the sensitivity testing of N. asteroides to antibiotics appears necessary before reliable information can be obtained for clinical use. Moreover, our case did not show the relatively benign course of other reported cases of nocardia keratitis.


Some clinically observed phenomena in extended contact lens wear.

Two groups of volunteer subjects wearing extended-wear soft lenses were monitored over a period of 20 weeks. Of 6 factors measured only 1, corneal touch threshold, was found to show evidence of progressive change. However, a high incidence of lens surface deposits was encountered.


Role of lacrimal scintigraphy and subtraction macrodacryocystography in the management of epiphora.

Fifty-one patients were investigated by subtraction macrodacryocystography (SMDCG, 103 systems) and by lacrimal scintigraphy (LS, 105 systems). It was found that these investigations complemented each other and between them the precise site of obstruction in the lacrimal drainage apparatus could be determined in 80%. The radiation dosage to the lens in SMDCG significant, and it is therefore recommended that the patients with lacrimal obstruction should: (1) have lacrimal puncta dilated with a probe to No. 1 diameter and be forbstruction is still uncertain, then and only then should SMDCG be performed.


In vivo determination of body composition by tritium dilution in the rat.

Total body water was determined in vivo by tritium dilution in thirty-two male and female rats. Body water obtained by tritium dilution and body fat calculated from this value correlated significantly with body water and fat obtained by analysis (r 0.985, 0.855 respectively). There was no significant difference between values for fat assessed by the direct and indirect methods.


Nucleophile in the active site of Escherichia coli galactose-1-phosphate uridylyltransferase: degradation of the uridylyl-enzyme intermediate to N3-phosphohistidine.

The [32P]uridylyl-enzyme intermediate form of Escherichia coli galactose-1-P uridylyltransferase can be converted to a [32P]phosphoryl-enzyme by first cleaving the ribosyl ring with NaIO4 and then heating at pH 10.5 and 50 degrees C for 1 h. After alkaline hydrolysis of the [32P]phosphoryl-enzyme the major radioactive product is N3-[32P]phosphohistidine. A lesser amount of 32Pi is also produced as a side product of the hydrolysis of N3-[32P]phosphohistidine. No N1-phosphohistidine, N-phospholysine, or phosphoarginine can be detected in these hydrolysates. It is concluded that the nucleophile in galactose-1-P uridylyltransferase to which the uridylyl group is bonded in the uridylyl-enzyme intermediate is imidazole N3 of a histidine residue. This degradation procedure should have general applicability in the degradation and characterization of nucleotidyl-proteins.


Escherichia coli phosphoenolpyruvate dependent phosphotransferase system. Copurification of HPr and alpha 1-6 glucan.

A rapid, high-yield procedure has been developed for the purification of HPr from the Escherichia coli phosphoenolpyruvate dependent phosphotransferase system. During this procedure, the protein copurifies with a 2500-dalton homopolysaccharide which we have identified as alpha 1-6 glucan. The results of steady-state kinetic measurements of the phosphotransferase activity demonstrate that the polysaccharide works as an activator of the phosphotransferase system probably at the level of the HPr:P-E1 complex or the P-HPr:E11 complex.


Potentiometric titrations and oxidation-reduction potentials of manganese and copper-zinc superoxide dismutases.

Bovine erythrocyte superoxide dismutase and two manganese-containing superoxide dismutases have been reduced by the indirect coulometric titration method with methylviologen as the mediator-titrant. On the basis of the titration data the manganese-containing superoxide dismutases contain 1 g-atom of metal per mol of enzyme (dimer). E0' = +0.31 V for the enzyme from Escherichia coli which exhibits a complicated pH dependence above neutral pH. The Bacillus stearothermophilus manganese-containing enzyme has an E0' = +0.26 V and delta Em/pH is 50 mV. Bovine erythrocyte superoxide dismutase exhibits anomalous behavior in the coulometric titration curves, which is indicative of two nonequivalent copper centers in the enzyme. Addition K3Fe(CN)6 or K2IrCl6 to the enzyme solution, prior to coulometric titration, indicates that these anions bind preferentially to one of the copper centers.


Proton nuclear magnetic resonance of minor nucleosides in yeast phenylalanine transfer ribonucleic acid. Conformational changes as a consequence of aminoacylation, removal of the Y base, and codon--anticodon interaction.

The assignments of the resonances of the methyl and methylene groups belonging to the residues dihydro-uridine-16 and -17 (C5 and C6), dimethylguanosine-26, N-2-methylguanosine-10, and 7-methylguanosine-46 of yeast tRNAPhe at low temperature are reported. Observing the high-field proton NMR spectral region at different temperatures, the effects of aminoacylation, removal of the Y base, and codon-anticodon interaction on the tertiary structure of yeast tRNAPhe were investigated. The following are the results of this study. (1) The two dihydrouridine residues of tRNAPhe have different environments in aqueous solution: dihydro-uridine-16 is more shielded than dihydrouridine-17. (2) The ribothymidine residue from the fragment (47--76) of yeast tRNAPhe and from a tRNA with a partially disrupted structure exhibits multiple conformations arising from different stacking modes between the ribothymidine-54 and the guanosine-53 residue. (3) Upon aminoacylation the type of guanosine-53 interaction with ribothymidine-54 in the tRNAPhe changes. (4) Removal of the Y base from the anticodon loop of yeast tRNAPhe weakens the thermal stability of the tertiary interactions. (5) The interaction of two complementary anticodons in the absence of proteins and of ribosomes results in stabilization of the tertiary structure. Codon-anticodon interaction dependent rearrangement of the tertiary structure of yeast tRNAPhe was not observed. The spin-lattice relaxation times of the methyl and methylene groups of the minor nucleosides in yeast tRNAPhe demonstrate that the minor nucleosides undergo rotational reorientation (tau c) in the nano-second range. The observed differences in these tau c values indicate a similarity of structure of tRNAPhe in solution and in crystalline form.


Reversible modification of Escherichia coli ribosomes with 2,3-dimethylmaleic anhydride. A new method to obtain protein-deficient ribosomal particles.

Treatment of Escherichia coli ribosomes with the protein reagent 2,3-dimethylmaleic anhydride is accompanied by inactivation of polypeptide polymerization and by dissociation of ribosomal proteins. Regeneration of the modified amino groups at pH 6.0 is followed by reactivation and reconstitution of the ribosomes. Prior to regeneration of the amino groups, ribosomal particles and split proteins can be separated by centrifugation, which allows the preparation of new protein-deficient particles. The ribosomal particles obtained by three successive treatments with 2,3-dimethyl-maleic anhydride at a molar ratio of reagent to ribosome equal to 16,000 lack proteins S1, S2, S3, S5, S10, S13, S14, L7, L8, L10, L11, L12, and L20 and have lost part of proteins S4, L1, L6, L16, and L25. This new procedure to obtain protein-deficient ribosomal particles is mild and might be useful to dissociate other protein-containing structures in addition to ribosomes.


Cyclopropane fatty acid synthase of Escherichia coli. Stabilization, purification, and interaction with phospholipid vesicles.

The cyclopropane fatty acid (CFA) synthase of Escherichia coli catalyzes the methylenation of the unsaturated moieties of phospholipids in a phospholipid bilayer. The methylene donor is S-adenosyl-L-methionine. The enzyme is loosely associated with the inner membrane of the bacterium and binds to and is stabilized by phospholipid vesicles. The enzyme has been purified over 500-fold by flotation with phospholipid vesicles and appears to be a monomeric protein having a molecular weight of about 90 000. The enzyme binds only to vesicles of phospholipids which contain either unsaturated or cyclopropane fatty acid moieties. CFA synthase is active on phosphatidylglycerol, phosphatidylethanolamine, and cardiolipin, the major phospholipids of E. coli, and also has some activity on phosphatidylcholine. The enzyme is equally active on phospholipid vesicles in the ordered or the disordered states of the lipid phase transition. Studies with a reagent that reacts only with the phosphatidylethanolamine molecules of the outer leaflet of a phospholipid bilayer indicate that CFA synthase reacts with phosphatidylethanolamine molecules of both the outer and the inner leaflets of phospholipid vesicles.


Localization and characterization of cytochromes from membrane vesicles of Escherichia coli K-12 grown in anaerobiosis with nitrate.

Cytochromes b of anaerobically nitrate-grown Escherichia coli cells are analysed. Ascorbate phenazine methosulfate distinguishes low and high potential cytochromes b. Reduction kinetics performed at 559 nm presents a very complex pattern which can be analysed assuming that at least four b-type cytochromes are present. The electron transport chain from formate to oxygen would contain a low potential cytochrome b-556, a cytochrome b-558 associated to the oxidase, and a cytochrome d as the principle oxidase. Cytochrome o is also present, but seems to be functional only at low oxygen concentrations. A cytochrome b-556 associated to nitrate reductase is shown to belong to a branch of the formate-oxidase chain. 2-N-Heptyl-4-hydroxyquinoline-N-oxide affects the reduction kinetics in a very complex way. One inhibition site is in evidence between cytochrome b-558 and cytochrome d; another between the cytochrome associated to nitrate reductase and the nitrate reductase. A third inhibition site is located in the common part of the formate-nitrate and the formate-oxidase systems. Ascorbate phenazine methosulfate is shown to donate electrons near cytochrome b-558.


Isolation of mutants of Escherichia coli uncoupled in oxidative phosphorylation using hypersensitivity to streptomycin.

Mutants of Escherichia coli, harbouring the uncA401 or uncB402 alleles, were found to take up streptomycin more rapidly than the coupled parent strains. The increased rate of uptake results in greater sensitivity of the uncoupled strains, compared to the parent strains, to low concentrations of streptomycin. Studies with unc+ revertants showed that hypersensitivity to streptomycin is attributable to the mutation causing uncoupling. The uptake of streptomycin in an unc- strain is abolished by addition of the chemical uncoupler carbonylcyanide m-chlorophenylhydrazone. The phenotype of hypersensitivity to streptomycin can be used as a selection procedure for the isolation of uncoupled strains. In an experiment reported here, nine out of 12 strains isolated as being sensitive to streptomycin (at 2.5 micrograms/ml), were found to be unable to grow on succinate as a sole source of carbon. Five of the nine Suc- strains were found to be uncoupled in oxidative phosphorylation, and two of the five uncoupled strains lacked Mg2+-ATPase activity. The mutations causing uncoupling were cotransducible with the ilv genes.


Assays for the fidelity of DNA polymerases in cell-free extracts of Escherichia coli are complicated by contaminating nucleoside triphosphatases.

In the presence of DNA and a divalent cation, an enzyme activity in cell-free extracts of Escherichia coli readily hydrolyses dATP to dADP. dGTP is degraded to a smaller extent, dCTP and dTTP being hardly affected. The artificial template primers poly(dC) . oligo(dG) and poly(dT) . oligo(dA) are also effective cofactors for this triphosphatase activity. As a consequence, assays measuring the misincorporation, by cell-free extracts, of dATP and dGTP into these defined templates are difficult to interpret, since the triphosphate substrate is being rapidly degraded during the polymerase reaction. A partial characterization of the dATPase activity was performed, demonstrating that the optimal conditions for its activity resemble those commonly used for assaying polymerase activity. Thus in crude extracts both polymerase and dATPase compete for the same substrate. The inclusion of an ATP-generating system in the reaction mixture maintains the levels of deoxynucleoside triphosphates and changes the kinetics of misincorporation of dAMP into poly(dC) . oligo(dG). No reproducible difference in such misincorporation has been found between lysates prepared from tif-1 cells grown at either permissive or restrictive temperature.


Binding sites for ribosomal proteins S8 and S15 in the 16 S RNA of Escherichia coli.

A fragment of the 16 S ribosomal RNA of Escherichia coli that contains the binding sites for proteins S8 and S15 of the 30 S ribosomal subunit has been isolated and characterized. The RNA fragment, which sediments as 5 S, was partially protected from pancreatic RNAase digestion when S15 alone, or S8 and S15 together, were bound to the 16 S RNA. Purified 5 S RNA was shown to reassociate specifically with protein S15 by analysis of binding stoichiometry. Although interaction between the fragment and protein S8 alone could not be detected, the 5 S RNA selectively bound both S8 and S15 when incubated with an unfractionated mixture of 30-S subunit proteins. Nucleotide sequence analysis demonstrated that the 5 S RNA arises from the middle of the 16 S RNA molecule and encompasses approximately 150 residues from Sections C, C'1 and C'2. Section C consists of a long hairpin loop with an extensively hydrogen-bonded stem and is contiguous with Section C'1. Sections C'1 and C'2, although not contiguous, are highly complementary and it is likely that together they comprise the base-paired stem of an adjacent loop.


Quantitative data on the Bombyx mori L. silkworm: a review.

This paper summarizes a variety of quantitative data on the silkworm Bombyx mori, collected in the literature, to help building models on silk gland differentiation. The properites of the silk gland and their changes especially during the last larval instar have been reviewed (size, DNA, RNA amino acids, enzymes). The components of the silk (fibroin and sericin) are also studied (molecular weight, composition). Thus translation and transcription rates have been estimated. The relevant data on the fat body and the haemolymph are also given, as well as some characteristics of the oocyte/egg system.


Heart rate and blood pressure biofeedback: I. A review of the recent experimental literature.

The experimental literature on the use of biofeedback with heart rate and blood pressure, published since 1972, was reviewed and summarized along several dimensions: magnitude of change, effects of extended training, type of feedback, temporal feedback factors, motivational factors, instructional effects, individual differences, and the mediation/specificity issue. The research on biofeedback and heart rate was found to be fairly well developed.  Research on biofeedback and blood pressure, however, was found to be much less advanced. Moreover, most of the studies were done with hypertensive subjects.


[Isolation and properties of DNA-cytosine-methyltransferase EcoRII and E. coli K12].

The methods of isolation and partial purification of two DNA-cytosine-methylases (DC-methylases) EcoRII and E. coli K12 are described. After chromatography on phosphocellulose the enzymes were purified 100-fold, the yield being 30%. Further purification of the enzymes was performed by sedimentation in a sucrose concentration gradient. Both enzymes have native molecular weights of 50,000; DC-methylase from E. coli K12 may simultaneously occur in the forms with molecular weights of 70,000, 90,000 and 110,000. Both DC-methylases modify identical nucleotide sequences of DNA, have equal numbers (90) of methylation sites in phage lambda DNA and provide in vitro a complete protection of phage lambda DNA against restriction endonuclease EcoRII. DC-methylases E. Coli K12 and EcoRII differ in their chromatographic behaviour on phosphocellulose and capacity to form compexes with the cell DNA-adenine-methylase.


[Steady-state kinetics of reactions catalyzed by serine sulfhydrases of Saccharomyces serevisiae].

The steady-state kinetics of the two substrate reaction of L-cysteine desulfation in the presence of 2-mercaptoethanol catalyzed by serine sulfhydrase from bakers yeast -- a pyridoxal phosphate-containing enzyme of the beta -- substituting lyase type -- were studied. Highly purified enzyme preparations (approximately 90% purity) of Saccharomyces cerevisiae with specific activity of 25 mumoles of H2S per 1 hr per mg of protein were used. The values of V, KS1, KS2 and alpha were calculated from the initial rates of the reaction under constant concentration of L-cysteine (S1) and variable concentration of 2-mercaptoethanol (S2) and vice versa. The data obtained suggest that under conditions of a two-substrate reaction catalyzed by serine sulfhydrase and in case of beta-cyanoalanine synthase of blue lupin the substrate binding to the enzyme is interdependent and obeys a unordered mechanism with o formation of a ternary aminosubstrate-pyridoxal phosphateenzyme-cosubstrate complex (alpha = 2.6).


[Modification of the alpha-subunit of phenylalanyl-tRNA synthetase from E. coli MRE-600 with N-chlorambucilyl-phenylalanyl-tRNA].

L-Phenylalanyl-tRNA synthetase from E. coli MRE-600 (EC 6.1.1.20) was alkylated with N-chlorambucilyl-[14C] phenylalanyl-tRNA. After removal of the affinity reagent tRNA moiety bp alkaline hydrolysis of the ester bond between the N-chlorambucilyl-phenylalanyl residue and the 3'-end of tRNA, The enzyme was dissociated into subunits in the presence of SDS. Separation of the subunits was performed by SDS electrophoresis. The bulk of the radioactivity of the N-chlorambucilyl-[14C] phenylalanyl residue was found at the position of the alpha-subunit of the enzyme. The results obtained are consistent with a specific binding of the phenylalanyl-tRNA analog to the alpha-subunit of the enzyme followed by covalent binding of the N-chlorambucilyl-phenylalanyl moiety to the protein.


[Quantitative spectrophotometric determination of non-identified nucleotides in DNA].

A method for calculation of molar extinction coefficients (epsilon) and for quantitative spectrophotometric determination of non-identified nucleotide analogs from nucleic acids of some bacteriophages is proposed. The method is based on spectral properties of known and unknown nucleotides and of their dinucleotide isolated from the DNA studied.


[Reconstruction of native bakers' yeast inorganic pyrophosphatase from its subunits].

The subunits of inorganic pyrophosphatase were obtained both in the presence of 4 or 6 M Gu--HCl and in an alkaline medium at pH 10.5. The reassociation of the subunits into an active dimeric form was carried out using dialysis. After reconstruction the enzyme exhibits the same activity as does native pyrophosphatase.


Immunohistochemical study of crystallin synthesis during morphogenesis of the crystalline lens in mice.

Using indirect immunofluorescence, the sequence of the synthesis of various classes of crystallins during normal morphogenesis of the crystalline lens in mice was shown: The alpha- begin to be synthesized first, then the gamma-, and finally the beta-crystallins. Using mice with hereditary anophthalmia (genotype ey-1/ey-1 ey-2/ey-2) permitted it to be established that the synthesis of alpha-crystallins occurs even when there is no morphogenesis of the crystalline lens. In mice of this genotype, the lens placode, which is reduced as compared to the norm, is resorbed as a rule, and does not develop into the crystalline lens vesicle. Separate cells containing alpha-crystallins were found in cranial epithelium on serial cross sections of the eye area of 13-day-old mutant embryos. Consequently, in ey-1/ey-1 ey-2/ey-2 embryos, alpha-crystallin synthesis takes place even in cells of the resorbed lens placode after brief inducing influence of the optic vesicle. As opposed to alpha-crystallins, synthesis of gamma- and beta-crystallins is detected only when lens fibers have formed. This is characteristic for embryos of ey-1/ey-1 ey-2/ey-2 genotype, as well as for mouse embryos homozygous for the fi gene. Data of the present work indicate that the inducing influence of the optic vesicle is necessary for activation of the genes controlling alpha-crystallin synthesis, while the influence of the retinal rudiment is necessary for derepression of the genes for gamma- and beta-crystallin synthesis.


[Substrate thermostabilization of soluble and immobilized glucoamylase].

A new kinetic approach to the study of enzyme thermal inactivation in the presence of a substrate, which influences the rate of inactivation has been developed. The method was applied to investigation of inactivation kinetics of soluble and porous silica-immobilized glucoamylase. It was found that the binding of a substrate (maltose or maltodextrines Star-Dri 24-R) increases the thermal stability of glucoamylase, the stabilizing effect being more pronounced in the case of the soluble enzyme (40-fold stabilization) as compared to the immobilized one (15-fold stabilization). The stabilizing effect does not depend on the length of the substrate (maltose, d. p. 2 or dextrines, d. p. 7). Glucose, a product of the enzymatic hydrolysis, has a much lower stabilizing effect. It was concluded that the main role in the glucoamylase thermostabilization is played by the substrate stabilization rather than by the immobilization itself (3-fold stabilization). However, a combined effect of thermostabilization of glucoamylase due to both immobilization and/or substrate stabilization is restricted by the same limit of value for immobilized and soluble enzymes, which is equal to 40--50-fold in comparison with the soluble enzyme in the absence of the substrate.


Implantology for correction of cranio-facial defects with an elastomer composite and bone.

The correction of cranio-facial disfigurement in the upper part of the face is the most difficult to achieve. Various materials have been utilized and are still in use. Each has advantages and disadvantages. Autogenous bone has been used with good results, except for the unacceptable irregularities of the forehead and upper orbital region. The combination graft offers the advantages of both: the bone graft will be in contact with the dura, the periorbita and the contaminated sinuses. The polyrane implant produces a smooth and contoured forehead and immediately protects the vital structures during osteoneogenesis. Twenty-six selected patients had this technique used to correct their deformity without any incidence of major complication.


Design and materials evaluation for a dental implant system: carbon coated tooth replicas.

32 carbon coated tooth replicas were implanted in the jaws of 8 mongrel dogs for periods ranging from 3 months to 2 years. Fourteen of 16 molor implants and 10 of 16 premolar implants had 0.5 min. of mobility or less. Histology of specimens from 4 dogs sacrificed at 3 months showed new bone directly in contact with the implant surface.


Bone maintenance: implant versus transplant.

Bone maintenance based on various attachment mechanisms is the key to tooth-root replacement safety and efficacy. The dental implant has broad applicability based on design, but demonstrates progressive peri-implant bone loss. The allogeneic tooth transplant, significantly less applicable because of size, is antigenic and rejected by bone-replacement root resorption. Since the predictability and survival times of these implant and transplant modalities are similar and there is less residual bone loss with the transplant, it is suggested that for clinical situations such as the fresh extraction socket, where there is room, the allotransplant, rather than implant, is the root-replacement of choice.


A rotational diffusion coefficient of the 70S ribosome determined by depolarized laser light scattering.

We have obtained a rotational diffusion coefficient of the 70S ribosome isolated from Escherichia-coli (MRE-600), from the depolarized light scattering spectrum measured by photon correlation spectroscopy. The intensity correlation function of depolarized scattered light contains contributions due to multiple scattered and anisotropy scattered light from the ribosomal particle. We discuss extensively the subtraction procedure used to obtain the rotational correlation from the time from the experimental correlation function. We have also obtained the translational diffusion coefficient from the same sample by determining the polarized correlation function. The hydrodynamic radius determined from the rotational diffusion coefficient is only slightly larger than the radius obtained from the translational diffusion coefficient. Therefore the ribosomal particle has a non-spherical shape. This conclusion, however, could be impaired by the effect of free draining of the ribosome.


Relaxation kinetics of E. coli ribosomes: evidence for the reaction of 30S . IF3 complex with 50S ribosomal subunits.

Addition of initiation factor IF3 to solutions of E. coli ribosomes dramatically alters their behavior in pressure-jump relaxation kinetic experiments in which 90 degrees light-scattering is used to monitor the macromolecular reaction. The effect of IF3 on relaxation processes attributed to "tight" couples is strongly dependent on the Mg2+ concentration. At 2.5 mM Mg2+, addition of 1 molar equivalent of IF3 decreases the relaxation amplitude by a factor of 3 relative to ribosome solutions without IF3. However, at 5.0 mM Mg2+, addition of 1 molar equivalent of IF3 produces a marked increase in the relaxation amplitude, by a factor of 2-8 fold relative to ribosomes in the absence of IF3. IF3 has no effect on the relaxation process attributed to "loose" couples at 10 mM Mg2+. While we are unable to propose a precise mechanism for IF3 action with the data on hand, our results require that the 30S . IF3 complex either reacts with the 50S subunit, forming a 70S . IF3 intermediate, or acts as a pool of reactive 30S subunit. Further kinetic evidence is required to distinguish between these possible pathways.


Current concepts of the etiology of central nervous system malformations.

We have seen that what must be applied to dysmorphology is the doctrine of multifactorial causality, ie dysmorphogenetic events have both genetic and nongenetic etiologic components to varying degrees. Complicating matters is the extent to which there is etiologic and/or mechanistic heterogeneity (Fig. 1). This is nicely illustrated by the holoprosencephaly anomaly. In addition, there are numerous CNS malformations that have major single gene, chromosomal, or environmental initiating agents of malformation mechanisms. Still a mystery is the common neural tube malformations. It is now clear that the "multifactorial/threshold" model is an inadequate explanation of the observed data and until the etiologic heterogeneity of these malformations is clearly defined, our knowledge remains primarily empiric. A potential area of fruitful investigation is likely to be the identification of maternal genotypes which do not allow detoxification of potential environmental teratogens.


[Detection of B-cell antigen on the blast cells in chronic myeloid leukemia].

The presence of the common antigen on B lymphocytes of healthy donors and myeloblasts of patients with chronic myeloid leukemia in blastic crisis was observed with antimyeloblastic serum in the indirect surface immunofluorescence test. The cytotoxic test showed this antigen in the blastic cells in 27 out of 57 patients with CML BC, in 3 of 11 patients with acute lymphoid leukemia, in 1 of 8 patients with chronic lymphoid leukemia and in 2 of 2 patients with undifferentiated leukemia. The antigen was not found in the peripheral blood cells of healthy donors.


[Method of culturing amniotic fluid cells].

The influence of pregnancy term and the concentration of cell suspension, introduced into culture, on the growth of amniotic fluid cells have been studied on 29 specimens. Optimum term of amniotic fluid cells sampling for the best growth was 17 weeks of pregnancy. It is recommended to take into account the concentration of cell suspension in the amniotic fluid before introducing the cells into the culture depending on pregnancy terms.


[Effect of GABA-ergic substances on the analgesic effect of morphine in rats].

The effect of GABA-ergic compounds on morphine-induced analgesia was studied to reveal probable interaction of GABA and opiates. As an index for morphine effect the reaction of vocalization in response to electrical stimulation of the rat tail was used. It was shown that thiosemicarbazide, the inhibitor of glutamate decarboxylase and bicuculline, GABA-ergic receptor blocking agent, which were proposed to be joined in a group of GABA-negative compounds, reduce and shorten the effect of morphine. Depakine, the inhibitor of alpha-ketoglutarate-GABA-transaminase, as well as GABA itself administered in high doses (GABA-positive actions) make morphine analgesia more pronounced and longer. Probable causes of the described interrelationship between GABA and opiates are discussed.


[Cytophilic immunoglobulins on the surface of neutrophilic granulocytes in mice perorally immunized with a live vaccine made from the supressor revertant S. typhimurium Rev 8].

The reaction of the spleen cell migration inhibition in the presence of monospecific antisera against mouse G, A and M immunoglobulins was used to detect cytophilic antibodies on the surface of mouse granulocytes. The oral administration of ACR live vaccine from suppressor revertant Salmonella typhimurium Rev. 8 protected the mice against infection induced by virulent species of mouse. Salmonella typhimurium. The immunized mice showed an increase in cytophilic IgG on the surface of neutrophile granulocytes.


[Comparative study of rosette and plaque formation in rats infected with Mycoplasma arthritidis and Acholeplasma laidlawii].

M. arthritidis suppresses rosette- and plaque-formation in rats infected with this strain of mycoplasma. On the 15th day the immune response was restored in the control and experimental groups of animals. In later stages a strong stimulation of RFC and PFC was recorded, which levelled on day 150. On the contrary,  A. laidlawii stimulated RFC and PFC in all stages of infection. A relationship between the phenomena described and pathogenic properties of the mycoplasma is discussed.


Diminished platelet adenylate cyclase activation by prostaglandin D2 in acute thrombosis.

Prostaglandin D2 (PGD2) produced by platelets can inhibit aggregation via activation of platelet adenylate cyclase. PGD2 activation of platelet cyclase in platelet membrane fractions was studied in 20 consecutive patients hospitalized with acute deep-vein thrombosis and/or pulmonary embolism. In nine patients, PGD2-stimulated enzyme activity was decreased at all concentrations of PGD2 studied. This altered enzyme sensitivity was specific for PGD2 as basal enzyme activity, and prostaglandin E1, prostaglandin I2, and sodium fluoride stimulated adenylate cyclase was normal. The effect of PGD2 on platelet aggregation and 14C-serotonin release was also studied in one patient where a four-fold higher concentration of PGD2 was required to inhibit collagen-induced 14C-serotonin release. Binding studies using [3H]PGD2 as a radioligand indicated that this patient's platelets bound 10 fmole PGD2/10(8) platelets compared to 30 fmole/10(8) platelets in a normal control. Five patients had follow-up studies between 2 and 7 mo after their acute thrombotic event, and PGD2-stimulated adenylate cyclase activity returned towards normal in four. Since PGD2 is synthesized in platelets at concentrations sufficient to inhibit aggregation and activate adenylate cyclase, diminished platelet sensitivity to this prostaglandin could result in "hyperactivity" and contribute to the thrombosis observed in these patients.


Successful allogeneic bone marrow retransplantation with the same donor after graft rejection: application of a modified conditioning regimen.

A 26-year-old man with severe aplastic anemia was treated with high-dose Cyclophosphamide followed by the infusion of bone marrow cells from his HLA-identical sister. After initial intake of the graft, rejection ensued by day 46 which was followed by a permanent complete aplasia. After 4 months, bone marrow retransplantation with the same donor was attempted after a more intensive conditioning regimen. This led to permanent engraftment with rapid normalization of the blood counts lasting now for over 12 months. The patient has since remained in excellent clinical condition without signs of graft-versus-host disease.


Selected list of books and journals for the small medical library.

This revised list of 492 books and 138 journals is intended as a selection guide for small or medium-sized hospital libraries or for the small medical library serving a specified clientele. It can also be used as a core list by small hospital library consortia. Books and journals are categorized by subject, with the books being followed by an author index and the journals by an alphabetical title listing. Items suggested for initial purchase by smaller libraries are indicated by an asterisk. To purchase the entire collection of books and to pay for annual subscriptions to all the journals would require an expenditure of about $22,500. The cost of only the asterisked items, recommended for first purchase, totals approximately $6,100.


Core lists of medical journals: a comparison.

Five core lists of medical journals are compared with respect to size, intended users, and content. Despite variations in scope and depth, there is significant agreement among the lists. A list of the seventy-two titles appearing on four or all of the five lists is appended. There is no clear relationship between frequency of inclusion in these core lists and citation frequency as reported in Journal Citation Reports.


Study on the possible entry of bacterial endotoxin and prostaglandin E2 into the central nervous system from the blood.

1 A study has been made of the possible entry of 51Cr-bacterial endotoxin and [5,6,8,11,12,14,15(n)-3H]-prostaglandin E2 ([3H5-PGE2) into the CNS of the anaesthetized cat. 2 No radioactivity was detected in perfusates of the preoptic-anterior hypothalamus or in the cerebrospinal fluid (c.s.f.) in vivo, or in brain tissue post mortem following intracarotid infusion of 51Cr-bacterial endotoxin. 3 Intracarotid administration of [3H]-PGE2 resulted in the entry of radioactivity into the CNS of endotoxin pretreated cats. Chromatographic analysis indicated the radioactivity in c.s.f. to be associated with PGE2 and a metabolite similar to 13, 14-dihydro-15-keto PGE2. 4 Intracarotid administration of 13, 14-dihydro-15-keto [5,6,8,11,12,14(n)-3H]-PGE2 resulted in the presence of the compound in the CNS of the anaesthetized cat after pretreatment with bacterial endotoxin. 5 It is concluded that PGE2 and possibly 13,14-dihydro-15-keto PGE2 but not bacterial endotoxin may enter the CNS from the cerebral circulation to elicit the febrile response to bacterial endotoxin in cats.


The influence of wound drainage on the infection rate in kidney transplant patients.

The frequency of wound infection was studied in 92 patients who had received cadaver kidneys. Wound drainage was performed in 26 patients and not performed in 66 patients. Wound infection was found in 31% of the wounds with drainage and in 14% of wounds without primary drainage. The results were compared with the frequency of 34% infected wounds in a previous report where wound drainage was performed routinely. It is advised that, when possible, wound drainage should be avoided.


Endourethral urethroplasty: a simple method for treatment of urethral strictures by internal urethrotomy and primary split skin grafting.

Primary endourethral split skin grafting was performed in 4 patients operated upon for stricture of the bulbous urethra by internal urethrotomy. Post-operatively, all grafts were found to have taken. Follow-up has ranged from 4 to 12 months. The results were considered good in all patients and after release from the hospital they had no subjective symptoms. Further urethral dilation has not been necessary in any of the patients.


Calculi in renal transplants.

Three patients who underwent live donor renal transplantation subsequently developed calculi in their allografts. Hypercalcaemia and secondary hyperparathyroidism were present in 2 cases and these were treated by subtotal parathyroidectomy. Urinary stagnation and infection were contributory factors in the third case and reimplantation of the ureter was necessary. In all patients no further calculi have developed following treatment and allograft function remains satisfactory.


The diagnosis and treatment of lymphocoeles associated with renal transplantation. A report of 6 cases and a review of the literature.

Six patients have developed a lymphocoele after renal transplantation, an incidence of 4%. A lymphocoele should be suspected in a patient who develops a rising creatinine with a pelvic mass or pressure effects on the pelvic veins 1 or more months after operation. The diagnosis is confirmed by intravenous urography, venography and ultrasonography: the use of the latter as a diagnostic measure is recommended. Treatment is by marsupialisation into the peritoneum or external drainage with breakdown of all loculi. Aspiration is unsatisfactory.


Polyglycolic acid versus chromic catgut in bladder surgery.

The clinical importance of calcified deposits on sutures in bladder surgery was evaluated in a blind paired randomised trial of 3/0 chromic catgut versus polyglycolic acid 3/0. Cystoscopy with photographic recording was performed 8 weeks after operation in 40 patients without and 8 patients with previous or present bladder stones. None had visible calcified deposits at that time and sutures were only visible in 1 patient from each of the 2 groups without bladder stones. It was concluded that neither chromic catgut nor polyglycolic acid sutures carry any significant risk of bladder stone formation, whether infection is present or not; the conclusion includes both patients with and without previous bladder stones, but is less firm in the former because of the small number of patients studied.


Inosine: clinical results of ischaemic renal surgery.

Ten patients requiring ischaemic renal surgery for calculus or tumour were operated on with the kidney protected by perfusion with a room temperature solution of inosine. The warm ischaemic times ranged from 35 to 75 min (mean 57.1 min). Post-operative recovery was uneventful in all patients. No adverse cardiodynamic effects due to inosine were noted. There was only moderate transient depression in renal function as assessed by gamma camera renography and serum creatinine estimations. Three of the 10 patients have now been followed for over a year. The results with inosine perfusion are comparable to those obtained with hypothermic protection.


The use of pure carbon stomata (Biocarbon) in urinary diversion.

A new synthetic material, Biocarbon, has the advantages of tissue compatibility and chemical inactivity, so that there is minimal salt sedimentation. Experiments with animals extending over a period of more than 2 years showed good healing after various surgical and urological operations. Biocarbon stomata were then used for vesicostomies in 6 patients. The period of follow-up has been months. We conclude that Biocarbon implants used for ureterocutaneostomies and for various conduit operations can improve tthe care of stomapatients.


Late results of skin inlay urethroplasty.

Sixty-two patients undergoing either one-stage or two-stage skin inlay urethroplasty for stricture of the urethra have been reviewed. The success rate and incidence of complications are discussed. The technique of skin inlay urethroplasty requires a considerable degree of surgical expertise and a similar skill in clinical evaluation is required in the selection of patients for this procedure.


The one-stage island patch urethroplasty.

Dartos-predicled scrotal skin island patch urethroplasties were performed in 72 patients and followed up for up to 7 years. Restenosis was seen at the site of the stricture in 5 cases and one developed a new meatal stenosis. There were no deaths. Hair-stones occurred in 4 patients and were removed endoscopically. One too-large pouch was trimmed. No patient was incontinent. More than one patch may be used for long or multiple strictures.


Surgical treatment of the massively dilated primary megaureter in children.

From 1964 to 1975, of 83 children with primary megaureter 33 had unilateral and 8 bilateral massively dilated ureters that required surgical treatment, and of these 73% had febrile infection, 5% were septic and 10% were azotaemic. Surgical treatment consisted of ureteric reimplantation with excision of the atonic distal segment, preceded by diversion when indicated. Tailored reimplantation was successful in 98% of ureters and non-tailored reimplantation was uniformly unsuccessful. All failures were successfully corrected by tailored reimplantation. Thus the requirements for successful surgical management of massive ureteric dilatation in children secondary to an atonic ureteric segment are excision of the atonic segment, transvesical or extravesical tailoring of the ureter and reimplantation.


A double blind trial of bromocryptine in the treatment of idiopathic bladder instability.

Fifty-one patients (aged 20 to 68 years) entered a 6-week double-blind trial of Bromocryptine, a dopamine agonist. All patients complained of the complex: frequency, nocturia, urgency and urge incontinence which was due to demonstrable bladder instability. No significant improvement in either symptoms or cystometric findings was seen in the Bromocryptine treated as compared with the control group. A high incidence of nausea was noted in the treated groups. The results of this study suggest that Bromocryptine does not have a therapeutic role in the treatment of idiopathic bladder instability.


Releasing factor tests in men with oligozoospermia.

FSH levels were assayed in 300 men attending with infertile marriages. From this number, releasing factor tests were carried out in 24 men with oligozoospermia and an initial FSH below our normal mean. In all of these cases there was a response to releasing factor. Isolated FSH deficiency is likely to be rare in adult men presenting with infertility and no previous endocrinological history.


Applied diagnostic techniques: a decisive factor in the long-term T-year survival rate in prostatic carcinoma.

Ii is shown from statistical data reported to the Swedish Cancer Registry that in cases of prostatic carcinoma the long-term T-year survival rate is the final outcome of a complex interplay of multiple factors including diagnostic technology and techniques for staging and grading. Assessment of the value of specific therapy is not possible except in controlled clinical trials. The T-year survival rate per se does not give an accurate estimate of the effect of treatment.


Urological complications in 119 consecutive renal transplants.

One hundred and nine patients undergoing 119 transplants have been followed up from 8 months to 9 years. Urological complications occurred in 16 transplants, an incidence of 13.4%. Ureteroneocystostomy was performed primarily in all cases; in 98 by the conventional Politano-Leadbetter technique with 9 (9.2%) urological complications and in 32 by an extravesical technique with 7 (21.8%) urological complications. One patient died as a result of ureteric obstruction, without operation. In 3 patients with lower ureteric obstruction, transurethral ureteric meatotomy was successful in 2 cases and resulted in no change in renal function in the third. Two patients with urinary fistulae were managed successfully by continuous drainage with indwelling urethral catheters. The remaining 10 patients required 12 open surgical procedures for relief of ureteric obstruction, with improvement in function in 7 patients.


Carcinoma of the renal pelvis following the abuse of phenacetin-containing analgesic drugs.

Five cases of renal pelvic carcinoma are reported in female patients who abused phenacetin-containing analgesics. The mechanism of carcinogenesis in analgesic abuse is discussed and epidemiological factors are considered. The possibility of development of a renal pelvic tumour in patients with analgesic nephropathy is emphasised.


Primary vesical sensory urgency. A clinical trial of bromocriptine.

A randomised double blind crossover trial of Bromocriptine against an inert placebo was performed in 14 patients with primary sensory urgency. Bromocriptine was found to have no therapeutic advantage for these patients and the possible explanations for this finding are discussed.


An objective look at acid phosphatase determinations: a comparison of biochemical and immunological methods.

Measurements of serum and bone marrow acid phosphatase were made by 3 enzymatic methods, alpha-naphthyl phosphate, beta-glycerol phosphate, and thymolphthalein monophosphate, and ocmpared to a double antibody radioimmunoassay. Serum and bone marrow acid phosphatase levels were studied in 46 controls with histologically proven benign prostatic hyperplasia and in 135 patients with various stages of prostatic carcinoma. In the control group the upper limit for bone marrow acid phosphatase was found to be significantly higher than the corresponding serum limit with respect to the enzymatic assays studied. The radioimmunoassay was the only method suitable for the analysis of the prostatic acid phosphatase content of bone marrow. A larger number of elevations were noted in patients with extracapsular and metastatic disease when prostatic acid phosphatase measurement was carried out by radioimmunoassay as compared to enzymatic methods. However, only 8% of the patients with intracapsular disease had elevations of prostatic acid phosphatase as measured by radioimmunoassay. Additional standardisation of immunological methods and clinical trials is required before comparison can be made of results from various centres using immunological methods for the measurement of prostatic acid phosphatase and a true assessment made of the usefulness of this procedure.


Subcutaneous Corynebacterium parvum in bladder cancer: a controlled study of its immunological effects.

Fourteen out of 26 patients with invasive bladder cancer were randomly assigned to receive weekly subcutaneous injections of Corynebacterium parvum (CP) in addition to standard treatment. Peripheral blood T lymphocyte percentage, K cell activity, mitogen responsiveness, and monocyte and polymorph leucotaxis were measured at intervals over a period of 1 to 2 years. The only consistent difference between the CP-treatment patients and the controls was a slightly higher level of K cell activity in the former, who, however, fared rather worse than the controls in terms of survival.


Faecal and introital bacteria and urinary tract infection.

The faecal, introital, and urinary bacterial flora have been studied in 3 normal women and 5 women with recurrent urinary infection. In the normal women urinary abnormalities were uncommon, but the patients regularly had episodes of bacteriuria and pyuria, only a quarter of which were symptomatic. Symptoms tended to be associated with high white cell excretion rates and with the longer episodes. Introital colonisation was heavier and more frequent in the patients than in the control subjects. Organisms recovered from the urine had previously colonised the introitus in most cases. It appears that symptomatic episodes constitute only a small part of the disease process in patients with recurrent urinary tract infection.


Intrarectal metronidazole in the prevention of anaerobic infections after emergency appendicectomy: a controlled clinical trial.

A series of 102 patients with presumptive acute appendicitis entered a prospective, randomized, clinical trial of intrarectal metronidazole given over a 48-h period commencing before surgery. Adequate levels of circulating metronidazole were achieved. A significant reduction in the incidence of anaerobic wound infection was observed in the treated group (P less than 0.02). The convenience and short duration of the prophylactic regimen allowed early discharge from hospital. No untoward effects were observed.


A double-blind trial of a single intravenous dose of metronidazole as prophylaxis against wound infection following appendicectomy.

One hundred patients undergoing appendicectomy through a right iliac fossa incision were randomized to receive normal saline or 500 mg metronidazole as an intravenous infusion during the operation. One patient in the saline group developed an erythematous rash. There were 13 wound infections (as defined by the discharge of pus), 12 (out of 51) in the saline group and 1 (out of 49) in the metronidazole group. Bacteroides spp. were frequently cultured from the lumen of removed appendices and from pus obtained from infected wounds. This work supports the value of metronidazole but suggests that a single-dose regimen is adequate for prophylaxis.


Short term metronidazole therapy contrasted with povidone-iodine spray in the prevention of wound infection after appendicectomy.

In a prospective, randomized trial metronidazole was found to be significantly better than povidone-iodine in reducing the incidence of wound infection after appendicectomy (P less than 0.005). The metronidazole was given as a established 7-day course. Over 65 per cent of the wound infections presented after the patients had been discharged from hospital.


Use of circular stapling gun with peranal insertion of anorectal purse-string suture for construction of very low colorectal or colo-anal anastomoses.

A technique is described for construction of the colorectal or colo-anal anastomosis in low rectal resection by using an automatic circular stapling device and inserting the anorectal purse-string suture peranally from below. This method was employed in 4 patients resulting in complete healing in 3 cases and a moderate leak in 1, which, however, eventually healed satisfactorily.


Cimetidine in the treatment of peptic ulceration following renal transplantation.

Seven patients who developed peptic ulceration following renal transplantation have been treated by cimetidine. One died before its value could be assessed. The remaining 6 were symptom-free within 48 h. In 3 patients the ulcer appeared healed on gastroscopy, in one there was no change, another required operation for gastrointestinal bleeding 1 month after beginning cimetidine and the other patient has been lost to follow-up after 5 months' treatment. Two patients had a significant rise of serum creatinine whilst on the drug, but there is no evidence of increased immunological reactivity towards the graft and no agranulocytosis.


A study of basal cell carcinoma of the inner canthus, 1967-72.

Basal cell carcinoma was the commonest malignant lesion at the inner canthus. Reconstruction following excision was most commonly achieved with a post-auricular full thickness graft. Provided excision is adequate, a local flap is a good alternative. There is no evidence that the use of a graft increased recurrence, but it may have allowed earlier detection. The primary recurrence rate after primary surgical excision was 3.6 per cent. Recurrence occurred in several cases when histology indicated incomplete excision. Follow-up under these circumstances should be continued for up to 10 years. When adequate primary surgical excision was performed, there was no evidence that rodent ulcer of the inner canthus behaves differently or has a worse prognosis than at other sites. There has probably been undue concern in the past about epiphora following resection of the lacrimal drainage system.


Failure of low-dose heparin to prevent significant thromboembolic complications in high-risk surgical patients: interim report of prospective trial. Groote Schuur Hospital Thromboembolus Study Group.

The efficacy of low-dose subcutaneous heparin (5000 IU eight-hourly) is being studied in a single-centre, prospective randomised trial of patients aged over 40 submitted to major elective intra-abdominal surgery. The trial end-points are the objectively defined incidence and extent of deep vein thrombosis (as seen on uptake of 125I-labelled fibrinogen, Doppler ultrasonography, and bilateral ascending phlebography) and non-fatal pulmonary embolus (as measured by preoperative spirometry and preoperative and postoperative chest radiography and perfusion lung scanning performed on a routine, unselected basis). An interim analysis of the first 200 patients indicates that low-dose heparin significantly reduces the incidence of calf-vein thrombosis but does not reduce the incidence of proximal segment thrombosis or non-fatal pulmonary embolism. Thus the routine use of low-dose heparin prophylaxis in all major surgical procedures in patients aged over 40 may not be advisable.


Vaginal microbial flora in normal young women.

Vaginal swabs were taken from 1498 women attending a family planning clinic. The flora was assessed in the absence of any information about the women to whom the swabs related. Yeasts and fungi were present in 311 women (21%) and were no more prevalent among "pill" users than others. Candida albicans was significantly associated with vulval itching and with a vaginal discharge described as heavier than normal or curdy on clinical examination, though these abnormalities were present in only a minority of women with the organism. Trichomonas vaginalis was found in 14 women (1%) and was associated with abnormalities of vaginal discharge in all but one. Gram-negative anaerobic bacilli were significantly more common in women with a troublesome vaginal discharge and those who used an intrauterine device than others. No associations were found between fungi other than C albicans or the other bacteria sought and either symptoms or clinical abnormalities of vaginal discharge.


Variation in plasma prednisolone concentrations in renal transplant recipients given enteric-coated prednisolone.

Renal transplant recipients receiving intermittent haemodialysis and kept under normal ward conditions showed appreciable differences in plasma prednisolone concentrations after therapeutic doses of enteric-coated prednisolone tablets. This gross day-to-day variation occurred irrespective of the dosage used. Breakfast given before prednisolone tended to reduce the rate of absorption of the drug, the effect being quantitatively most pronounced with large doses. Haemodialysis had no apparent effect on the elimination of prednisolone from plasma. Such erratic blood concentrations of prednisolone as observed in these patients, possibly resulting from variable absorption, may be potentially hazardous. Hence use of enteric-coated tablets in renal transplant recipients should be viewed with caution.


Dr Samuel Johnson's movement disorder.

Dr Samuel Johnson was noted by his friends to have almost constant tics and gesticulations, which startled those who met him for the first time. He also made noises and whistling sounds; he made repeated sounds and words and irregular or blowing respiratory noises. Further, he often carried out pronounced compulsive acts, such as touching posts, measuring his footsteps on leaving a room, and performing peculiar complex gestures and steps before crossing a threshold. His symptoms of (a) involuntary muscle jerking movements and complex motor acts, (b) involuntary vocalisation, and (c) compulsive actions constitute the symptom complex of Gilles de la Tourette syndrome (Tourette's syndrome), from which Johnson suffered most of his life. This syndrome is of increasing interest recently because it responds to haloperidol, and because there are new insights into a possible biochemical basis for the tics, vocalisations, and compulsions.


Haemodialysis and transplantation in Wegener's granulomatosis.

Two men with Wegener's disease began immunosuppressive treatment during severe renal insufficiency. Despite an initial temporary remission new lesions appeared and renal failure progressed. Haemodialysis was started, cytotoxic drugs were stopped, and steroid dosage was reduced. All extrarenal manifestations of the disease remitted, however, suggesting a favourable effect of either the immunosuppression induced by terminal renal failure or the haemodialysis itself. Renal transplantation was then undertaken in both patients. Thirteen and 55 months after the operations respectively renal function was satisfactory and no signs of reactivation of Wegener's disease had appeared. These results show that whatever the activity of Wegener's disease and its initial response to immunosuppressive agents, dialysis and transplantation are fully warranted once irreversible renal failure is established.


Flunisolide nasal spray for perennial rhinitis in children.

Twenty-seven children with perennial rhinitis entered a double-blind cross-over study comparing nasal sprays of flunisolide---a new topical corticosteroid---and placebo. Symptoms were assessed over two consecutive monthly periods with each treatment. Weekly diary cards, monthly clinical assessments, and end-of-trial preferences all favoured the active drug. At the end of the trial 20 patients preferred the treatment month with flunisolide, four preferred the placebo month, and two rated the periods equally. Side effects were mild, the commonest being transient nasal stinging. Seventeen children who derived benefit from flunisolide continued with the treatment for a six-month open-study period. Many reduced the dosage from three times to twice or once daily without losing benefit. The effect of flunisolide on the pituitary-adrenal axis was assessed in seven children by measuring the 0900 blood cortisol concentrations at two-month intervals over the six months. No effect was observed. The results show that flunisolide is effective and safe for the treatment and prophylaxis of perennial rhinitis in children.


Haematuria presenting in outpatients attending a department of genitourinary medicine.

Of all the patients attending a department of genitourinary medicine during a 10-month period, about 2% (1 out of 50) presented with haematuria, or haematuria was discovered on initial examination. In about 25% of cases, the haematuria was due to Escherichia coli infection of the lower genitourinary tract. Gonococcal infection was the next commonest cause; one patient with gonorrhoea presented with frank urethral bleeding. In the remaining patients other causes of haematuria, which included renal cyst. carcinoma of the ureter, bilharziasis, and IgA disease, required more extensive investigations and follow up.


Hyperthermic effect of prostacyclin injected into the third cerebral ventricle of the cat.

Prostaglandin E2 may not be solely responsible for hyperthermia produced by central administration of sodium arachidonate. To determine its effect, if any, on body temperature prostacyclin sodium salt, another product of prostaglandin endoperoxides, was injected into the third cerebral ventricle of unrestrained, unanesthetized cats while deep body temperature was recorded automatically. Doses of 2--25 microgram, in a volume of 0.05 ml saline solution, did not appreciably alter body temperature. A 100 microgram dose produced hyperthermia in five of six animals. Administration of 1 mg prostacyclin caused prolonged hyperthermic responses in four cats with a maximum increase in temperature of at least 2.1 degrees C. Prostaglandin E1 (1 microgram) produced hyperthermic responses which were intermediate between responses to 100 and 1000 microgram prostacyclin. Indomethacin (2 mg/kg), given IV to two cats during recovery from prostacyclin-induced hyperthermia, did not hasten the rate of recovery. These results indicate that, if a sufficient concentration of prostacyclin is achieved at a central site of action after injection of arachidonate or during pathologic processes which release arachidonic acid, prostacyclin could contribute to the development of hyperthermia.


Effects of diet upon hypothalamic vulnerability to goldthioglucose in male mice.

Three groups of male mice were fed three different diets for about 3 weeks: powdered chow (C), a high fat (F) diet (chow:Crisco, 2:1), and a high dextrose (D) diet (chow:dextrose, 2:1). Food and water intake and body weights (BWts) were measured daily. On Day 20 of the study, mice were injected IP with 0.3 mg/g of goldthioglucose (GTG). Two days later, the mice were sacrificed and brains were removed for histological examination of GTG-induced lesions in the ventromedial hypothalamus (VMH). It was found that (1) F-fed mice ate more and gained more BWt than C- and D-fed mice, and (2) the average GTG lesion volume of F-fed mice was twice as large as those of C- and D-fed mice. In view of known alterations in sensitivity of the VMH to goldthioglucose with changes in glucose metabolism, it is suggested that the larger goldthioglucose induced lesions in F-fed mice may be due to elevated blood levels of goldthioglucose or altered glucose metabolism in goldthioglucose sensitivity cells in the VMH.


Midbrain central gray: LHRH infusion enhances lordotic behavior in estrogen-primed ovariectomized rats.

Ovariectomized rats were implanted with 23 gauge stainless steel cannulae in the ventrolateral midbrain central gray. Twelve sexually active rats were estrone-primed and infused with saline and 50 ng luteinizing hormone-releasing hormone (LHRH) in counterbalanced order. Infusion of luteinizing hormone-releasing hormone significantly enhanced the lordotic response to coital stimulation compared to saline infusion. These results support the role of hypothalamo-mesencephalic LHRH-containing pathways in modulating lordotic behavior in estrogen-primed ovariectomized rats.


Fentanyl-oxygen anaesthesia for coronary artery surgery: cardiovascular and antidiuretic hormone responses.

This study demonstrates that large doses of fentanyl, as the sole anaesthetic with ventilation with oxygen, produces complete anaesthesia and minimal changes in cardiovasuclar dynamics in patients with coronary artery disease. It also indicates that high dose fentanyl anaesthesia blocks the increase in plasma anti-diuretic hormone and cardiovascular dynamics which are so common with morphine and other anaesthetic techniques during tracheal intubation and surgical stimulation in patients with coronary artery disease. Our findings suggest that fentanyl-oxygen anaesthesia is an attractive technique in patients with coronary artery disease.


The early history of anaesthesia in Newfoundland.

The early history of anaesthesia in Newfoundland is described by reference to newspapers and other writings of the time. News of ether first reached Newfoundland in February 1847 with a report from England of Robert Liston's amputation of a leg on December 21, 1846. Ether was first used in St. John's some days before July 30, 1847, for an operation to amputate both legs, the surgeon being Edward Keilley. Chloroform was used in St. John's a few days before May 4, 1848 by Samuel Carson in an obstetrical case, and on May 10, 1848 it was used during the amputation of a leg by Edward Keilley. Also discussed are some other items of anaesthetic interest which occurred during the years following until the appointment of the first (albeit part-time) anaesthetist in St. John's in 1912.


Psychiatric illness in physicians.

Psychiatric illness and behavioural problems among physicians are reviewed in this paper. Some studies suggest that the medical profession has a high rate of alcoholism, drug abuse and marital discord. As well, physicians appear to commit suicide and to seek admission to psychiatric institutions more frequently than comparable populations. Considered as etiologic factors in psychiatric illness among physicians are the role strain inherent in the profession and the personality development of individual practitioners prior to their entering medical school. The review concludes with suggestions for an improved approach to treatment and prevention.


Survival following renal transplantation in Saskatchewan, 1970--74: follow-up study using medical insurance records.

The patient history file of a medical care insurance plan can be used for statistical purposes in many ways. This is illustrated by the use of the records of the Saskatchewan Medical Care Insurance Commission to study the survival of patients receiving kidney transplants in the period 1970--74. During this period 48 males and 23 females received at least one renal transplant; these patients represented 34% of all males and 28% of all females undergoing regular renal dialysis. These period prevalence estimates are consistent with calculations based on incidence and point prevalence reported elsewhere. Life-table calculations showed the 4-year survival rate following first kidney transplantation in Saskatchewan to be 45% for all patients, 55% for those less than 45 years of age and 26% for those 45 years of age or older.


The Canadian certification examination in psychiatry. I: Historical notes.

There has been much criticism of the format and process of the certification examination in psychiatry, and some of this is based on lack of information regarding the history of the specialty certification procedures, the Royal College of Physicians and Surgeons and the Board of Examiners. In this first of three reports the history of the Royal College as the certifying organization is traced, and the relevant College structures are briefly described, including the Specialty Committee on Psychiatry which is instrumental in appointing the clinical examiners. The clinical examiners since 1965 are identified.


The adventures of Dr. Duncan McNab McEachran in western Canada.

Duncan McNab McEachran's early history and involvement in the formation of the Montreal Veterinary College as well as in livestock inspection were reviewed. His contribution to the beginning of the ranching industry in western Canada was explored in detail. In 1881, McEachran helped to establish the Cochrane Ranche, which was the first great ranch to be started in southern Alberta. He was employed as the ranch's resident general manager until 1883, in which year the Waldrond Ranch was established. McEachran was this ranch's president and general manager until approximately 1909. During this time, he came under considerable criticism from both The MacLeod Gazette and The Calgary Herald. As Dr. McEachran maintained his obligations to the ranches while he was directing the veterinary college in Montreal as well as chief inspector of livestock for Canada, it was concluded that this feat alone would rank him as a remarkable historical figure.


Proceedings of the Workshop on Amino Acid Imbalance in the Treatment of Cancer. Introduction: possibilities for biochemically rational chemotherapy for some malignancies with depleting enzymes and antimetabolites of specific amino acids.

A number of recent investigations have documented that, in several cancers, the malignant cells are no longer capable of synthesizing a specific amino acid, while the normal cells continue such biosynthesis at a normal rate. Enzymes degrading amino acids have demonstrated therapeutic value against such cancers. Significant progress was made recently in technology related to enzyme preparations. These are highly specific, have long half-lives, and can be chemically modified to eliminate their immunogenicity to man or animals. A practical in vitro system for detection of antimetabolites of different amino acids in natural materials was developed. It appears reasonable to expect that, in a specific malignancy, after the available pools of such deficient amino acids are exhausted by administration of the depleting enzyme, an additional, perhaps synergistic, effect could be obtained by utilizing an analog of such an amino acid. A brief review of the pertinent existing information will be presented in this communication.


Azaserine, DON, and azotomycin: three diazo analogs of L-glutamine with clinical antitumor activity.

A review of the clinical data on azaserine, DON, and azotomycin reveals that these agents have limited but definite antitumor activity. All three drugs are analogs of L-glutamine and contain a diazo group. They have been studied as single agents in a wide variety of human malignancies and have also been included in trials using combination chemotherapy. Most of these studies were performed early in the history of clinical trials and, therefore, the method of reporting results and the evaluation criteria were quite different from those in use today. A renewed interest in these agents has been triggered by the remarkable activity of DON and azotomycin against human tumor lines implanted into nude mice. On the basis of this activity and the clinical data we have compiled, we feel that new clinical trials with these agents are warranted.


Phase I-II study of piperazinedione in adults with solid tumors and acute leukemia.

Piperazinedione was administered to 79 patients with solid tumors on an intermittent schedule with single doses of 1.5-36 mg/m2. Courses were usually repeated at 4-week intervals. Twenty-five patients with leukemia were treated at doses of 18-36 mg/m2 (occasionally for 2 successive days) every 1-4 weeks. Of 48 evaluable patients with malignant melanoma, three (6%) achieved partial remission and nine (20%) had stable disease. Eight of 17 (47%) patients with adenocarcinomas and one of two (50%) patients with lymphomas also had stable disease. Six of 14 (43%) patients with acute myelogenous leukemia showed hematologic improvement, as did one of 11 (9%) patients with blast cell crisis of chronic myelogenous leukemia. The principal toxic effect was myelosuppression, which occurred in 69% of the patients with solid tumors. Profound bone marrow aplasia occurred in 19% of the patients, resulting in six deaths (8%). Risk factors for marrow aplasia included extensive prior therapy, prior nitrosoureas, cumulative toxicity from piperazinedione, and abnormal liver function tests. The recommended doses for further studies are 9 mg/m2 for patients with risk factors for marrow aplasia, 12 mg/m2 for patients with prior therapy, 15 mg/m2 for previously untreated patients, and 24-36 mg/m2 for patients with acute leukemia.


Phase II study of VM-26 in acute leukemia, neuroblastoma, and other refractory childhood malignancies: a report from the Children's Cancer Study Group.

VM-26, a semisynthetic podophyllotoxin, was tested for antitumor activity and clinical toxicity in 181 children. The drug was administered iv at weekly intervals, beginning at a dose of 130 mg/2/week. The dose was increased, as tolerated, after 3 and 6 weeks to 150 and 180 mg/m2/week, respectively. The only major toxicity was hematologic, with neutropenia predominating. Anaphylaxis occurred in one patient. The drug demonstrated significant activity in acute lymphocytic leukemia (four responses among 15 patients) and neuroblastoma (ten responses among 31 patients). Objective responses were also noted in one patient each with acute myelogenous leukemia, Hodgkin's disease, histiocytic lymphoma, Wilms' tumor, Ewing's sarcoma, undifferentiated carcinoma, and sacrococcygeal sarcoma. Further trials of VM-26 in these childhood malignancies are warranted.


Levamisole in squamous cell carcinoma of the head and neck.

One hundred and thirty-four patients (118 males and 16 females) with epidermoid carcinoma of the head and neck were studied. After treatment of the primary lesion, they were randomized into two groups: 69 received levamisole, 150 mg/day orally for 3 consecutive days every other week, and 65 received placebo. Immune status was also evaluated. Positive reactions to dinitrochlorobenzene increased significantly after primary tumor therapy in both levamisole- and placebo-treated patients. There were no significant differences in immune responses between the two groups, except in recall antigen reactivity, which was decreased in both groups overall recurrence and death rates at 36 months did not differ between the two groups of patients. However, stage I and II patients treated with levamisole had a significantly higher incidence of recurrence than the placebo-treated patients (P less than 0.02), while there was some evidence that levamisole-treated stage IV patients did better. It is concluded that the overall outcome in patients with squamous cell carcinoma controlled locally by surgery or radiation was not favorably affected by levamisole in the dose and schedule used in this protocol.


Combination of adriamycin and cyclophosphamide in the treatment of metastatic prostatic carcinoma: a phase II study.

A prospective trial of Adriamycin and cyclophosphamide was undertaken in the treatment of patients with hormonally refractory prostatic carcinoma. Of the 20 patients evaluable, three (15%) had a partial remission and five (25%) had stable disease for a total response of 40%. All patients who responded had subjective improvement consisting of weight gain (greater than or equal to 10% of body weight), improvement of performance status (greater than or equal 10% in Karnofsky index), and a decreased need for pain medication.


Spectrophotometric determination of oxygen saturation of blood independent of the presence of indocyanine green.

The strong absorbance of indocyanine green in a broad band around lambda = 800 nm invalidates the usual spectrophotometric two-wavelength methods for measuring oxygen saturation operating in the red and near infrared region. By proper wavelength selection, however, the effect of the dye can be eliminated. With the two-wavelength method utilising lambda = 660 and 860 nm oxygen saturation is measured virtually independent of the presence of indocyanine green.


The location of LH-RH neurons in the rat hypothalamus and their pathways to the median eminence. Experimental immunohistochemistry and radioimmunoassay.

The location of the perikarya of LH-RH neurons in the rat hypothalamus and their pathways to the median eminence were studied by immunohistochemistry and radioimmunoassay after placing stereotaxic electrolytic lesions in several parts of the hypothalamus. The principal location of the cell somata was found to be in the ventral part of the medial preoptic area; their pathways were classified into a main baso-lateral pathway and an accessory descending pathway branching off from the former. The main pathway was found to cross in the vicinity of the corresponding neuronal perikarya. The central median eminence and the dorsal and ventral walls of the tubero-infundibular sulcus of the caudal part of the median eminence are innervated mainly by the baso-lateral pathway. On the other hand, the rostral and most caudal protions of the median eminence are innervated principally by the descending pathway and have a subsidiary dual innervation. The projection of LH-RH neurons to the OVLT is believed to originate from perikarya adjacent to this circumventricular organ.


Distribution of actin and myosin in muscle and non-muscle cells.

Specific anti-actin and anti-myosin antibodies were shown to react in single and double immunofluorescence sandwich tests with identical sites in non-muscle cells in frozen sections of tissues and in cultured cells. In tissues, both antibodies reacted with liver cell membranes, parts of renal glomeruli, brush borders and peritubular fibrils of renal tubules, brain synaptic junctions, and membranes of lymphoid cells in thymic medulla, lymph nodes and spleen. Both antibodies reacted strongly with long parallel cytoplasmic fibrils in cultured fibroblasts, and with disrupted fibrils in cytochalasin-B treated cells. In neuroblastoma cells both antibodies gave prominent staining of growth cones and microspikes. The observation that the distribution of myosin parallels that of actin in non-muscle cells argues strongly in favour of a functional interaction between the two molecules in the generation of contractile activity in non-muscle cells.


Immunohistochemical localization of secretory proteins in the endometrial epithelium of the rabbit.

Proteins of uterine fluid and lung homogenates of the rabbit were separated by gel and ion exchange chromatography. Purified protein fractions were used for immunisation and antiserum production. By means of several absorptions, six monospecific antisera against uteroglobin and five other proteins were obtained. Using immunohistochemistry, four of them could be localised in the uterine epithelium from oestrus and the first and the seventh day post coitum, and also in the blastocyst. The present study indicates the involvement of different endometrial cells in the synthesis and release of the various proteins of uterine secretion.


Metabolic and mutagenicity studies on DDT and 15 derivatives. Detection of 1,1-bis(p-chlorophenyl)-2,2-dichloroethane and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethyl acetate (kelthane acetate) as mutagens in Salmonella typhimurium and of 1,1-bis(p-chlorophenyl) ethylene oxide, a likely metabolite, as an alkylating agent.

Using a novel in vitro technique, whereby microsomal enzymes were embedded in an agar layer to prolong their viability, 1,1-bis(p-chlorophenyl) ethylene(DDNU), a mammalian metabolite of 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), was converted by microsomal mono-oxygenases of mouse liver into 1,1-bis(p-chlorophenyl)-1,2-ethanediol (DDNU-diol). The putative epoxide intermediate, 1,1-bis(p-chlorophenyl)ethylene oxide (DDNU-oxide), a new compound, was synthesized; it showed weak alkylating activity with 4-(4-nitrobenzyl)pyridine but was not mutagenic in Salmonella typhimurium strains TA100 and TA98. DDT and 13 of its metabolites or putative synthetic derivatives, including 1,1-bis(p-chlorophenyl)-2,2-dichloroethylene (DDE), 1 1,1-bis(p-chlorophenyl)-2-chloroethylene (DDMU), 1,1-bis(p-chlorophenyl)-2-chloroethane (DDMS)-DDNU, 2,2-bis(p-chlorophenyl)ethanol (DDOH), bis(p-chlorophenyl)acetic acid (DDA) and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethanol (Kethane), caused no mutagenic effects in S. typhimurium strains TA100 or TA98, either in the presence or absence of a mouse-liver microsomal fraction. 1,1-Bis(p-chlorophenyl)-2,2,2-trichloroethyl acetate (Kelthane acetate) was a direct-acting mutagen in strain TA100, whereas 1,1-bis(p-chlorophenyl)-2,2-dichloroethane (DDD) was mutagenic in TA98, only in the presence of a mouse-liver microsomal system. The results are discussed in relation to possible pathways whereby DDT is activated to mutagenic and/or carcinogenic metabolites.


Ellipticines as potent inhibitors of microsomes-dependent chemical mutagenesis.

9-Hydroxyellipticine (9-OHE), an inhibitor of microsomal monooxygenase activities has been shown to exert a large or even complete decrease of the mutagenicity, on the Salmonella strains of a great number of compounds (aromatic amines, polycyclic aromatic hydrocarbons, fungal toxins, azo compounds, tobacco smoke condensate). 9-OHE and 9-fluoroellipticine are more potent inhibitors than ellipticine itself. The inhibitions exerted by 9-OHE are not even equalled by 10-fold higher doses of 7,8-benzoflavone (7,8-BF). There is a good correlation between these data and the interaction properties of ellipticines with microsomal cytochromes P-450.


Mechanisms of action of carcinogenic aromatic amines: an investigation using mutagenesis in bacteria.

The mutagenicities of groups of N-acetoxy-N-arylacetamides, nitroarenes, arylamides and arylamines were determined in the Salmonella typhimurium tester stains TA98, TA1538, TA100, TA1535 and TA1537. Three broad classes of mutagenic activity were found, interpreted as follows: class A, including 2-naphthylamine, produced essentially only base-pair substitution without induction of error-prone repair; class B, including 4-aminobiphenyl, caused consideration induction of error-prone repair, accompanied by a lower level of frame shifting; class C, including N-acetoxy-2-acetamidofluorene, produced high levels of frame shifting, with some induction of error-prone repair. Correlation of these results with known reactions of certain aromatic amine derivatives with nucleosides and nucleic acids, and with molecular orbital calculations, suggests that the effect of class A is produced by small aromatic groups attached to extranuclear heteroatoms in DNA bases, the effect of class B is caused by large aromatic groups attached to extranuclear heteroatoms or by arylamines attached to C-8 of guanine, while the effect of class C is caused by arylamides attached to C-8 of guanine, probably rotating into the helix, as proposed by others. The data also suggest that the N-acetoxy-N-arylacetamides are generally useful models for ultimate metabolites derived in vivo, even if the in vivo metabolites do not carry an acetyl group. Finally, there is a rough correlation between the sum of reversions induced in TA98 and TA100 by the N-acetoxy-N-arylacetamides and their previously determined local carcinogenicities. There is a poor correlation between mutagenicity in any one tester strain and carcinogenicity.


[Cancer of the gastric stump (author's transl)].

On the evidence of 24 cases of cancer of the gastric stump the authors discuss the real incidence of this dread complication; they conclude that starting 8 years after primary surgery, all patients carrying a gastric stump must be regarded as high-risk subjects for malignancy; further, they recommend that pyloro-gastrectomy after Billroth (II) be considered for execution in young patients with all possible reluctance.


[Paraneoplastic syndromes in cancer of the kidney (author's transl)].

Starting with the description of their own observations of paraneoplastic syndromes in adult patients with cancer of the kidneys, the authors discuss the possible pathogenetic mechanisms and the more characteristic clinical features of said syndrome. They conclude by advocating a systematic search for such paraneoplastic syndromes as an aid to early diagnosis of renal malignancy and also as a working parameter for assessing the evolution of the tumor and the effectiveness of treatment.


[Osteosarcoma: current views on pathology and new therapeutic perspectives. II: Criteria of prognosis and treatment (author's transl)].

The authors review recent studies and trials concerning the treatment of osteosarcoma, with special attention to current trends in immunology, radiology, surgery, and chemotherapy. Progress in immunobiological research seems to promise interesting practical developments; even today, however, modern chemotherapy combined with suitable ablative surgery affords a remarkably better prognosis for this malignancy.


Lipid metabolism in endotoxic shock.

A brief overview of the alterations in the control of free fatty acid (FFA) and triglyceride (TG) turnover following the administration of Escherichia coli endotoxin is presented. Hormone-sensitive lipase activity was increased following either in vivo or in vitro administration of endotoxin. In conscious dogs, the rate of appearance of glycerol was also increased while that of FFA was not changed, indicating that in addition to increased lipolysis, increased reesterification in the adipose tissue may also be present. Myocardial utilization of FFA was decreased and that of lactate increased following endotoxin both in vivo and in vitro using isolated myocytes. Both myocardial and adipose tissue lipoprotein lipase activity were decreased following endotoxin, indicating a possible decrease in TG removal by these tissues. Additional studies are warranted to further elucidate the interrelation between the changes of lipid and carbohydrate metabolism and those of hemodynamics in shock.


Ketotifen in childhood asthma: a double-blind placebo controlled trial.

In a three week double-blind cross-over controlled trial in twenty asthmatic children, ketotifen (HC 20-511, 'Zaditen', Sandoz) showed no significant difference from placebo, although there was a consistent trend in favour of the active drug.


Multi-channel, probe colorimeter for use with the micr-ELISA test, which makes use of disposable flat-bottom microhemagglutination plates.

We describe a multiprobe colorimeter that permits the reading of enzyme-linked immunosorbent assays (ELISA) in situ, by use of microhemagglutination plates. The use of dipping probes eliminates interference from meniscus effects and air-bubble entrapment. Detailed validation tests have been done and potential sources of inaccuracy identified.


Enzyme immunoassay for serum lidocaine in antiarrhythmic therapy.

We have adapted the commercially available EMIT kit [Clin. Chem. 23, 1161 (1977)] to the Gilford System 3500 Analyzer. Sample volume is 10 microliter. We compare reagent blank-corrected absorbance changes at 340 nm between 15 and 55 s for samples and a series of calibrators, and calculate results with use of a logarithmic transformation. Within-run precision (CV) for a serum pool with 4.0 mg of added lidocaine per liter was 2.7% (n = 45); day-to-day precision was 3.3% (n = 15). Analytical recoveries of 2 to 6 mg of lidocaine per liter were 90-102% (average, 97.3%). Results correlated significantly with those by a gas-chromatographic technique. No clinically significant interferences by concomitantly administered medications were observed. The procedure is rapid (42 samples per hour) and is well suited to the fast response required in monitoring lidocaine therapy. Usefulness of the assay data in the management of arrhythmias in the coronary care unit is discussed.


Importance of blood-collection tubes in plasma lidocaine determinations.

In 25 clinical samples serum lidocaine concentrations fell from a mean of 6.5 +/- 2.1 mg/L (mean +/- SD) to 4.9 +/- 1.8 mg/L (p less than 0.001) when the blood sample was allowed to make contact with the stopper of the Vacutainer collection tube. In vitro experiments showed that this effect of the stopper occurred only with whole blood and was dependent on sample concentration. The plasma binding of lidocaine decreased from a normal value of 56% +/- 2.2 (mean +/- SD) to 28% +/- 2.2 (p less than 0.001) when exposed to the Vacutainer stopper. We conclude that a chemical leached from such stoppers displaces lidocaine from its plasma-binding sites and that the drug is then redistributed into the erythrocytes, producing spuriously low lidocaine concentrations in plasma or serum. Such artifacts are important in therapeutic drug monitoring and can lead to erroneous clinical decisions.