A new purification scheme for elongation factor 1 from rabbit reticulocytes and investigation of the homology of the subunits with those of initiation factor 2. The aim of this work was to compare the subunits of the elongation factor EF-1 and the initiation factor eIF-2 from rabbit reticulocytes. We devised a simple procedure for the purification of EF-1: stepwise chromatography on heparin-Sepharose, separation of the heavy form by sucrose gradient centrifugation, and a final step of stepwise chromatography on RNA-Sepharose. The heparin-Sepharose column also clearly separated EF-1 and EF-2 within one chromatographic step. The EF-1 was 350-fold puried and the yield was 10%. This preparation showed after electrophoresis on polyacylamide gels in the presence of sodium dodecyl sulfate three bands corresponding to those described by others as the subunits, with Mr of 54000, 49000 and 29200. An additional band of Mr 34000 was present but no others. The 49000-Mr and 34000-Mr bands corresponded exactly in molecular weight to two of three subunits of eIF-2. A more detailed comparison was therefore made of all subunits of EF-1 and eIF-2. This was done by examination of chymotryptic fingerprints on polyacrylamide gel electrophoresis. No evidence for homology between EF-1 and eIF-2 was found. However, the two larger subunits of eIF-2 had a majority of chymotryptic fragments in common, thus indicating some homology between these polypeptides.


Identification of the translation products of human fibroblast interferon mRNA in reticulocyte lysates. Messenger RNA was purified from human foreskin fibroblasts FS11, a high interferon-producer line, after induction with synthetic double-stranded RNA. The mRNA was translated in a cell-free protein-synthesis system from rabbit reticulocytes. The translation products, containing biologically active human interferon, were immunoprecipitated by a serum from rabbits immunized against partially purified interferon. Analysis of the immunoprecipitate by polyacrylamide gel electrophoresis in dodecylsulfate shows that the product of human fibroblast interferon mRNA is a 23000-Mr polypeptide. Methods are described for the synthesis and rapid identification of this polypeptide, which should be useful for structural analysis of interferon and isolation of its mRNA.


Phosphorylation in vivo of a vaccinia-virus structural protein found associated with the ribosomes from infected cells. When vaccinia-virus-infected cells were labeled with radioactive phosphate in the absence of viral gene expression an additional phosphoprotein, containing phosphoserine, was found specifically associated with the ribosomes. The phosphoprotein was removed from the ribosomes following a 0.5 M KCl washing or after EDTA treatment. This additional phosphoprotein was found in infected cells after either a long (3-4 h) or a short (30 min) labeling period; it was detected when the infected cells were incubated in the presence or absence of an inhibitor of RNA or protein synthesis. This phosphoprotein originated from the phosphorylation of vaccinia virion structural protein VP11b (Mr 11,000) at a specific site since only a single major phosphopeptide was obtained after trypsin digestion. This phosphoprotein was also present in purified vaccinia virions labeled with radioactive phosphate. VP11b protein was phosphorylated in vitro by the protein kinase associated with the cores. When the reaction was carried out at an alkaline pH the phosphorylation in vitro occurred at different sites in the protein; at neutral pH the phosphorylation of VP11b was more specific and, as judged by tryptic peptide analysis, occurred mainly at the same site as in the phosphorylation in vivo. A role for the involvement of phosphoprotein VP11b in the establishment of the shut off of host protein synthesis by vaccinia virus is suggested.


Catalytic activity of aspartate aminotransferase in the crystal. Equilibrium and kinetic analysis. Natural substrates and analogs rapidly diffuse through crystals of pig heart mitochondrial aspartate aminotransferase and react at the active sites causing spectral changes that can be measured by single-crystal microspectrophotometry. Dissociation constants for natural substrates and rate constants of transamination for slowly reacting substrates have been determined. A comparison between the data obtained in the crystal and in solution shows that the crystalline enzyme is catalytically competent and that events occurring in the crystal essentially parallel those occurring in solution, even though minor differences have been detected.


The role of chloroplast-membrane-protein synthesis in the circadian clock. Purification and partial characterization of a polypeptide which is suggested to be involved in the clock. A polypeptide (polypeptide P39), which is presumed to involved in the photosynthetic circadian rhythm in the green alga Acetabularia, was purified from the EDTA-insoluble chloroplast membrane fraction by means of preparative dodecylsulfate gel electrophoresis and then partially characterized. The purity of the isolated polypeptide P39 was confirmed by a further electrophoresis on an analytical dodecylsulfate gel and further elucidated by amino-terminal analysis which shows that glycine is the only amino-terminal amino acid of the purified polypeptide material. The molecular weight of the polypeptide P39 was found to be about 39,000 on analytical gel electrophoresis and the value was further supported by those obtained from amino acid composition and peptide mapping. The amino acid composition of polypeptide P39 showed that the proportion of intermediate amino acid groups is high while the proportion of hydrophilic amino acid groups is well balanced by that of hydrophobic amino acid groups, a property characteristic of membrane proteins.


Transcription activity of a DNA-protein complex isolated from spinach plastids. A DNA . protein complex of about 150 S is isolated from purified spinach chloroplasts by Sepharose 4B gel filtration. A DNA-dependent RNA polymerase activity is found associated with the complex. This DNA protein complex is able to initiate RNA chains in vitro. The RNA synthesis is more dependent on CTP than other nucleoside triphosphates. 50% of the activity is still present with 0.6 M KCl. The temperature optimum occurs between 30 degrees C and 35 degrees C. Rifampicin and rifamycin SV have no inhibitory effect. TNA products have been characterized by gel filtration and by hybridization with chloroplast DNA (ctDNA). At the beginning of transcription DNA products are linked to the transcription complex and are later detached. The molecular weight of the product ranges between 0.07 X 10(6) and 2 X 10(6). A part of the product (3--4%) has a molecular weight higher than 2 X 10(6). No endogenous RNase activity was present during the molecular weight determinations experiments. Hybridization experiments show that at least 75% of the RNA products are hybridizable with ctDNA and that 40% of these products are composed of chloroplast ribosomal RNA, showing that rDNA is preferentially transcribed.


Distribution of polypyrimidine . polypurine segments in DNA from diverse organisms. Polypyrimidine . polypurine segments are regions of duplex DNA which contain a highly asymmetric distribution of pyrimidine and purine nucleotides. A polypyrimidine in single-stranded DNA can be detected by its ability to form a complex and poly(A, G) which will bind to hydroxyapatite. We tested DNA from a variety of organisms and found that most contained polypyrimidines. From the shape of the curve relating DNA size to percentage bound to hydroxyapatite, we conclude that polypyrimidine . polypurine segments occur widely in DNA from higher organisms, at intervals of 6000--8000 base pairs throughout the majority of the genome. Lower levels occur in DNA from yeast and Drosophila.


Properties of succinylated wheat-germ agglutinin. The physicochemical and binding properties of succinylated wheat germ agglutinin are described in comparison with these of unmodified wheat germ agglutinin. Succinylated wheat germ agglutinin is an acidic protein with a pI of 4.0 +/- 0.2 while the native lectin is basic, pI of 8.5. The solubility of succinylated wheat germ agglutinin is about 100 times higher than that of the unmodified lectin at neutral pH. Both lectins are dimeric at pH down to 5, and the dissociation occurs at pH lower than 4.5. The binding of oligosaccharides of N-acetylglucosamine to both lectins is very similar on the basis of fluorescence and phosphorescence studies. The minimal concentration required to agglutinate rabbit red blood cells is about 2 microgram/ml with both lectins and the concentrations of N-acetylglucosamine and di-N-acetylchitobiose which inhibit agglutination are similar with both lectins. The number of succinylated wheat germ agglutinin molecules bound to the surface of mouse thymocytes was ten times lower than that of the unmodified lectin although the apparent binding constant was only slightly different between the two lectins. The dramatic decrease of the apparent number of cell surface receptors upon succinylation of  the lectin is discussed on the basis of the decrease of the isoelectric point and of the acidic properties of the cell surface.


Isolation and characterization of a sulfated glyceroglucolipid from alveolar lavage of rabbit. A major acidic glycolipid of the rabbit alveolar lavage has been isolated and characterized. The isolation procedure involved extraction of lipids, column fractionation on DEAE-Sephadex and silicic acid, and thin-layer chromatography. Chemical analysis of the glycolipid revealed the presence of glucose, fatty acids, glycerol mono-ethers and sulfate. By partial acid and alkaline methanolysis, oxidation with periodate and chromium trioxide, and methylation analysis of the native and desulfated compound, the structure of this glycolipid is proposed to be: SO3H-6Glc alpha 1 leads to 6Glc alpha 1 leads to 6Glc alpha 1 leads to 6Glc alpha 1 leads to 3-1,(3)-O-alkyl-2-0-acylglycerol.


The use of equilibrium density-gradient ultracentrifugation in the isolation and characterisation of glycoproteins with blood group P1 activity from sheep hydatid-cyst fluid. Equilibrium density-gradient ultracentrifugation in caesium choride and caesium sulphate has been used in the isolation and fractionation of the glycoproteins specific for blood-group P1 from hydatid cyst fluids. The fractions obtained have distinct and systematic differences specifically related to their buoyant densities, chemical compositions and specific-activities for group P1. High levels of specific-activity were maintained over a large range of chemical compositions. The peptide content varied systematically from 2.5% for the densest fraction to 37% for the least dense fraction. The amino acid composition was essentially constant over all fractions. The proportion of glucosamine decreased and the proportions of galactosamine, mannose and glucose increased with increasing peptide content of the fractions. The data presented suggest the present of oligosaccharide side-chains of various lengths and compositions and/or the presence of oligosaccharide side-chains with very different chemical compositions, of which only some are associated with the specificity for group P1. The properties of the glycoproteins from hydatid cyst fluids have been compared with those of the glycoproteins from human ovarian cysts. Although some similarities have been demonstrated there are significant differences.


Biochemical research on oogenesis. Transfer RNA is fully charged in the 42-S storage particles of Xenopus laevis oocytes. 1. Transfer RNA makes up 30-40% of total RNA in previtellogenic oocytes of Xenopus laevis. The bulk of tRNA is associated with 5-S RNA and two proteins in a high-molecular-weight complex sedimenting at 42S. 2. We show here that all kinds of tRNA are present in the 42-S particles and all of them sediment coincidently. Particle tRNA is fully charged in vivo. During purification of the 42-S particles tRNA becomes partially uncharged. When purified particles are incubated in vitro with amino acids and ATP a charging reaction occurs without disruption of the nucleoprotein complex. Many aminoacyl-tRNA synthetases can be shown to co-sediment with the 42-S particles. We conclude that complete aminoacylation of tRNA within the storage particles results from the activity of particle-bound aminoacyl-tRNA synthetases.


Hormonal regulation of glucokinase in primary cultures of rat hepatocytes. Glucokinase activity in rat hepatocyte cultures declined with a half-time, t1/2, of 32 h during 3 days under serum-free conditions. Addition of insulin and triamcinolone to the culture medium prevented this decay. Glucokinase levels in hepatocytes derived from fasted rats could be elevated from 7.4 to 16.4 mU/mg protein in the presence of insulin and triamcinolone. In 2-day-old cultures glucokinase was induced in the presence of both hormones with a half time, t1/2, of 5.1 h. In cultures treated for 2 days with triamcinolone, insulin induced a 80% increase of glucokinase even in the absence of glucocorticoids. Insulin induction was dependent on protein synthesis but occurred in the absence of RNA synthesis. Glucocorticoid action, however, depended on RNA synthesis suggesting that glucocorticoids control transcription. Insulin evoked half-maximal effects at 3 nM and dexamethasone and triamcinolone at 0.1 and 1 nM respectively. Degradation of glucokinase was initiated in 2-day-old hepatocytes after removal of triamcinolone and insulin. Protein synthesis was essential for the onset of degradation and glucagon did not affect the rate of glucokinase degradation.


Synthesis of cytochrome f by isolated pea chloroplasts. Chloroplasts, isolated from the leaves of 7-day-old pea seedlings, were incubated in the light with [35S]methionine or [3H]leucine. After extraction from the washed chloroplast membranes using a mixture of ethyl acetate, ethanol and ammonia, cytochrome f was precipitated with a monospecific antiserum and resolved by gradient polyacrylamide gel electrophoresis in sodium dodecylsulphate. The cytochrome f band was identified by its intrinsic fluorescence in ultraviolet light and was shown to be radioactive by autoradiography or fluorography of dried polyacrylamide gel. One-dimensional peptide mapping of the products of papain hydrolysis confirmed that the radioactivity was an integral part of cytochrome f. The incorporation of [35S]methionine into cytochrome f was inhibited by D(-)threo-chloramphenicol but not by cycloheximide and did not occur in the dark. The synthesis was resistant to ribonuclease. It is concluded that cytochrome f is synthesised in intact isolated pea chloroplasts.


Determination of the kinetic constants of glucosephosphate isomerase by non-linear optimization. Isomerization and anomerization function. The rate constants for the anomerization and isomerization reactions catalysed by glucosephosphate isomerase (EC 5.3.1.9) are determined from kinetic measurements by non-linear optimization technique, employing the simplest reaction pathway with only one enzyme-substrate complex.


The karyosphere during late oogenesis in Rana ridibunda. The organization of the nucleus in the oocytes of Rana ridibunda was examined during late diplotene at the light and electron microscopic level. At this stage the chromosomes are relatively condensed and assembled in the centre of the nucleus, constituting a karyosphere. The chromosomes here are associated with the central "protein sphere" (15--20 microns in diameter), obviously at their telomeres. Numerous nucleoli are accumulated around the chromosomes, forming a karyosphere capsule and contain segregated fibrillar and granular components; structures resembling perinucleolar chromatin and fibrillar bodies (spherules) are associated with the nucleoli. Granules 30 to 40 nm in diameter are seen to surround the fibrillar spherules. "Nucleolus-like bodies" consisting of granules 10 to 15 nm in diameter which are embedded in finely fibrillar material are often associated in contact with the chromosomes. The central sphere is an accumulation of annular structures similar to those of the pore complexes of the nuclear envelope. These structures are bound to the chromosome material, the "nucleolus-like bodies" and the fibrillar bodies. A participation of "nucleolus-like bodies" in the formation of the central sphere is suggested. A possible role of the nuclear protein matrix in the construction of the karyosphere elements is discussed.


On the association of centrioles with the interphase nucleus. Preparations of nuclei from rat liver and bovine spleen purified by centrifugation through dense sucrose solutions are shown to contain centrioles. These centrioles retain their in situ ultrastructure and are surrounded by a network of filaments adjacent to the nucleus and probably attached to it. The number of centrioles in isolated nuclei depends on the conditions of cell homogenization. Under certain conditions of homogenization, the fraction of purified nuclei contains almost all centrioles of the original tissue. The number of centrioles in isolated nuclei sharply decreases if the nuclei are rehomogenized under conditions that do not cause damage to nuclei. The number of nucleus-associated centrioles does not decrease after solubilization of nuclear membranes by Triton X-100. Nuclei retain the associated centrioles after treatmentwith RNase-free DNase I. It is concluded that in interphase the centrioles are associated with the nucleus and that this association which is probably mediated by filaments involves nuclear structures other than nuclear membranes or whole chromatin.


Cell cycle dependent changes of chromosomes in mouse fibroblasts. Mouse fibroblast interphase nuclei stained with quinacrine dihydrochloride show distinctive differences in their fluorescent characteristics analogous to those which we have already observed in human and Syrian hamster cells. These patterns reflect the position of any given nucleus within the cell cycle. The brightly fluorescent chromocenters in the mouse nuclei were found to be in absolute aggreement with those stained by the C-banding technique, indicating that they represent centromeric heterochromatin. Furthermore, their number and size per nucleus were shown to vary in relation to the progress of the cell cycle.


Intermitochondrial bridge junctions in fat body cells of the pre-hatch larvae of the forest tent caterpillar Malacosoma disstria HBN. An electron microscopic feature of fat body cells of diapausing Malacosoma disstria pre-hatch caterpillars, experimentally held at certain controlled time-and-temperature conditions, is an elaborate bridge junction, between mitochondria, strikingly similar in appearance to the septate junction which has frequently been described as occurring between cells of many invertebrate species. It is suggested that the intermitochondrial unctions may well represent elaborate forms of interaction between organelles in order to enhance metabolic efficiency in times of stress.


Effects of 5-bromo-deoxyuridine on chloroplast structure in gametophytes of Anemia phyllitidis L. Sw. Application of 5-bromo-2-deoxyuridine causes servere changes in the ultrastructure of chloroplasts. These modifications include an increase of thylakoid layers ("giant"-grana), coiling of thylakoids, and lastly vacuolization of the entire membrane system of the chloroplast. Such observations can be correlated with types of membrane aberrations reported for natural mutants.


Apparent heterogeneity of hepatic lysosomes due to membrane-bound acid phosphatase. Hepatic lysosomes have been fractionated by rate sedimentation and by isopycnic banding. In all experiments, the distribution of acid phosphatase differed from that of the other lysosomal enzymes. Evidence is presented that this difference is due not to the separation of lysosomes from different cell types, but simply reflects the membrane location of a part of the acid phosphatase.


[Identification of neurosecretory reservoirs in the mayfly Ephemera danica Müll. (ephemeroptera: ephemeridae) (author's transl)]. Neurosecretory reservoirs were found in the head of Ephemera danica. In the region where the nervus corporis cardiaci 1 is leaving the brain, the diameter of this nerve increases considerably. Different types of axons were observed, filled with great amounts of electron opaque secretory granules with mean diameters of 170 nm and 110 nm, respectively. Another neurosecretory reservoir is situated in the rostral part of the corpus cardiacum containing a secretory material of a different kind. Most of the granules have diameters of about 90 nm, and are electron opaque. A relatively small number of axons contains nearly electron lucent vesicles with the same mean diameter.


Fine structure of a spider joint receptor and associated synapses. The fine structure of a joint receptor (R10) in a spider leg (Zygiella x-notata) was examined with light and electron microscopy. The R10 receptor consists of a compact ganglion which is situated near the dorsal joint membrane of the femur/patella joint. Each of the ten sensory cells comprising the ganglion sends one branching dendrite into the hypodermis underlying the joint membrane. All dendritic branches together form a sheet-like meshwork 50 microns wide and 1 microns thick, which is traversed obliquely by hypodermis cells. When the joint is stretched shearing forces are apparently transmitted to the receptive dendritic branches via microtubular bundles inside the hypodermis cells. The soma and dendrites of the sensory cells receive numerous synaptic input from presumably efferent fibres. The fine structure of these synapses is described and compared with other peripheral and central spider synapses. All R10 synapses contain small synaptic vesicles (32 nm diameter), whereas motor endplates possess large vesicles (38 nm). Central synapses have two significantly different vesicle populations which are either of the small or large variety. Since synapses with small vesicles are supposedly inhibitory, receptor cells in spiders might be under efferent control. Such a system is unknown in insects or crustaceans, but may be typical for arachnids.


Normal versus alpha-amanitin induced cellular dynamics of the midgut epithelium in female Aedes aegypti L. (Insecta, Diptera) in response to blood feeding. In midgut epithelial cells (stomach) of untreated female A. aegypti an increase in the surface area of the rough endoplasmic reticulum (rer) and in the ratio of membrane-bound to free ribosomes is morphometrically measured during digestion of the first blood meal. This can be correlated with the synthesis and release of digestive proteases. The dynamics of the ribosomes in A. aegypti are similar to those in A. stephensi. 3 ng alpha-amanitin per mosquito prevent normal blood digestion, the proliferation of the rer and the increase in the ratio of bound to free ribosomes. On the other hand, some synthesis of new ribosomes takes place.


Differences in surface morphology of microtubules reconstituted from pure brain tubulin using two different microtubule-associated proteins: the high molecular weight MAP 2 proteins and tau proteins. Microtubules were reconstituted from homogeneous brain tubulin and homogeneous preparations of two different microtubule associated proteins, the high molecular weight MAP 2 proteins or the tau proteins. The resulting microtubules were characterized by three electron microscopical procedures: Thin sectional analysis of embeded material, negative staining analysis using a STEM microscope and high resolution metal-shadowing analysis. By all three procedures MAP 2 microtubules have a much rougher surface morphology than tau microtubules, in agreement with the much higher molecular weight of the MAP 2 proteins. Tau microtubules, however, do not show the very smooth surface of microtubules assembled from pure tubulin in the absence of any microtubule associated proteins. In the case of MAP 2 microtubules thin sectional analysis as well as metal shadowing reveals that the globular protrusions seen in negative staining analysis appear as linear side arms which may extend by as much as 30 nm on both sides from the microtubular wall proper, giving rise to an overall structure with a diameter close to 100 nm. The possible implication of such structures for in vivo situations is briefly discussed as is the possibility that the "halo-effect" around microtubules seen in vivo may be due to a structural organization similar to that of MAP 2 tubules in vitro.


The estimation of velocity distribution profile of Paramecium cytoplasmic streaming. Cytoplasmic streaming of Paramecium bursaria and Paramecium tetraurelia was investigated by cinematographic techniques. Analysis of the records reveals the paraboidal character of the velocity distribution profiles in all arbitrarily chosen zones along the whole route of moving cytoplasm in the cell. According to the date obtained from cytoplasmic streaming analysis and food vacuole path, the geometry of the "channel" was described in terms of ellipsoid axes. Total volume changes of cytoplasm flowing through a given cross section in a given time unit were computed and no significant differences were found. The participation of a pressure gradient in motive force generation in cytoplasmic streaming is discussed.


Alterations of crossbridge angle induced by beta, gamma-imido-adenosine-triphosphate. Electron microscope and optical diffraction studies on myofibrillar fragments of abdominal muscles of the crayfish Orconectes limosus. The molecular basis of muscle contraction is thought to consist of cyclic movements of parts of the myosin molecules (crossbridges). Unitl now different states of the proposed crossbridge cycle could be stablilized and demonstrated by electron microscopy only in the case of highly specialized insect flight muscles. In this paper evidence is presented that it is also possible to induce crossbridge positions corresponding to the rigor [16] and the pseudorelaxed state [3] in non-insect muscles. Homogenization of myofibrils of the abdominal flexors of the crayfish Orconectes limosus in rigor or AMP.PNP-containing solutions brings about two different crossbridge patterns: The formation of crossbridges attached to the actin filaments in a mainly acute (rigor) or in a mainly perpendicular angle (pseudo-relaxed). Optical diffraction patterns taken from electron micrographs of sarcomere fragments are likewise compatible with those taken from sarcomeres of insect flight muscles fixed in comparable conditions [2,3].


Phenytoin binding to human albumin.

Phenytoin binding to human albumin. Binding of phenytoin to human plasma proteins and to human serum albumin is studied using equilibrium dialysis method at pH 7.4 and 37 degrees C. Phenytoin is mainly bound to albumin, the percentage of bound drug being constant over a wide range of total drug concentrations. Calculation of the drug binding parameters show a low affinity, k = 745 M-1, and a high number of binding sites, n = 8. Palmitic acid and some acidic drugs, warfarin and phenylbutazone added to human serum albumin, decreased phenytoin binding in a non competitive way. Basic and non-ionizable drugs, on the other hand, did not modify phenytoin binding.


In vitro studies on the metabolism of dibenzo[c,f]-[1,2]diazepine. Dibenzo [c,f]-[1,2] diazepine is a new compound with a tricyclic structure and a double bond between two nitrogen atoms in positions 1 and 2 of the molecule. Its in vitro metabolism has been studied, incubating the compound with rat liver microsomes. Two metabolites have been identified: dibenzo [c,f] - [1,2]diazepine-1-N-oxide and a monohydroxyderivative in the aromatic ring.


Pharmacokinetics of intravenous amikacin after rapid and slow infusion with special reference to hemodialysis. The pharmacokinetics of amikacin, a recently introduced aminoglycoside structurally related to kanamycin, were determined in healthy volunteers after rapid and slow constant-rate intravenous administration of a 7.5 mg/kg dose. The elimination profile of amikacin can be described by two compartment open model kinetics. Peripheral distribution of the drug is extremely rapid, and beta-phase concentrations decay with a half-life averaging about 2 hours, while inter-compartmental equilibrium is achieved in a little over 30 minutes. The volume of distribution averages about 25% of body weight. During hemodialysis, amikacin extraction from the blood reaches 97% +/- 17% (mean +/- 95% confidence interval) that of creatinine and 89% +/- 20% that of blood urea nitrogen. A method of administration adapted to the kinetic properties of the antibiotic is proposed.


Comparative distribution of two antidepressant drugs (imipramine and indalpine) in the rat as determined by analog computer simulation. A ten-compartment analog computer model is presented to determine the precise distribution and excretion of two antidepressant drugs, LM 5008 AND Imipramine. Eight patterns were simulated using experimental data and drug distribution in the two undetermined compartments were obtained by the analog model. Close agreement with existing experimental data lends confidence in the model as a valuable tool for predictions in a variety of therapeutic situations.


Lesions of the dorsal renal artery in surgery for renal pelvic calculus. A potential cause of renovascular hypertension. 2 cases of lesions of the dorsal renal artery in surgery for renal pelvic calculus are described. In 1 of the cases hypertension developed. Anatomic factors and previous operations predispose to this complication. An arterial complication should be suspected when hypertension develops postoperatively. The blood pressure of patients with known renal vascular complications should be checked repeatedly for several months postoperatively. The diagnosis is radiological, renal angiography being the definite procedure although a reduction of kidney size observed at urography may indicate the vascular lesion.


Ureteroureterostomy in complete ureteral duplication. Homolateral pelvic ureteroureterostomies were performed in 25 patients presenting with complete duplication of the pyeloureteric tract. The procedure was performed in 16 cases of ureteroceles, in 7 cases of reflux in duplicated ureters, in 1 case of ectopic ureter and in 1 postoperative stenosis of one segment of a double ureter. According to the authors' experience this is the surgical treatment of choice in conservative surgical treatment.


Regeneration of the ureter and the renal pelvis in dogs from transversely transected and anastomosed strips of the ureteral wall. Influence of long administration of azathioprine and prednisone on the newly formed wall. I. Experimental. Regeneration of the ureter and renal pelvis from a transected and anastomosed strip of the ureteral wall was examined in 20 dogs. The latter were divided into two groups: group A, dogs operated without receiving any drug, and group B, dogs which received 1.5 mg prednisone and 1.5 azathioprine/kg body weight/day before the operation and throughout the postoperative period. Provided the ureteral splint was maintained for at least 28 days, good results were obtained in both groups. Long-term administration of the drugs thus had no adverse effects on the regeneration. Microscopic examination of the newly formed wall, showed more numerous and better arranged muscular fibers and less connective tissues in group B.


Modulatory effects of oestrogen on immunologic responsiveness. I. Inhibition of DNA synthesis in peripheral blood lymphocytes from patients with Peyronie's disease, prostatic cancer and transsexuals and a commentary. A reduction in the phytohaemagglutinin-induced transformation of peripheral blood lymphocytes from patients with Peyronie's disease and prostate cancer and transsexuals cultured in autologous and homologous serum following the receipt of oestrogen therapy has been  observed. Reduction of lymphocyte transformation in patients with prostatic cancer and without malignancy receiving oestrogen, i.e., Peyronie's disease and transsexuals, suggests that this reduction is related to the mode of therapy rather than to malignancy or a particular pathologic state. No direct evidence exists that the observed in vitro aberrations of lymphocytic responsiveness are reflective of host compromise, but these observations are of potential relevance in terms of their implications in the therapeutic management of patients with prostatic cancer and other hormonally-dependent tumours, e.g., of the breast, as well as responsive diseases, through their effect on cellular immunocompetence and suitability of hormonally treated patients as prospective candidates for adjuvant immunotherapy. The possible relevance of the present observations to the suggested association between uterine cancer and prolonged administration of diethylstilboesterol, as well as that between development of vaginal tumours in offspring and maternal ingestion during pregnancy, also remains of potential concern, pending further investigation.


Pelvic lipomatosis: a nonsurgical diagnosis. Pelvic lipomatosis is rare in Europe. Preoperative diagnosis is seldom reached and subsequent explorative procedures are necessary. Typical roentgenographic findings are presented. The possibility of an early presurgical diagnosis is emphasized.


Hypertensive renal rhabdomyosarcoma.

Hypertensive renal rhabdomyosarcoma. A case of renal rhabdomyosarcoma is presented. Besides the rarity of this tumor, the case is unique because an increased level of renin and hypertension was found, which was not due to compression of the main vessels.


Relationships between hemodynamic profiles and topography of acute myocardial infarction. Initial hemodynamics were studied in 101 patients with acute myocardial infarction complicated by shock or left heart failure. 59 had anterior myocardial infarction (AMI); 42 had inferior myocardial infarction (IMI). Data were processed by univariate analysis and correspondence analysis. AMIs and IMIs were significantly different on conduction disturbances, heart rate, left ventricular filling pressure, mean pulmonary artery pressure and right ventricular function indices. Both patients and parameters were projected on the most meaningful factorial plane generated by correspondence analysis. This two-dimensional graphical representation showed that all the information was roughly distributed along the 2 orthogonal axes defining this plane. Survivors and nonsurvivors were fairly well separated along the first factorial axis (prognostic axis) which was highly correlated with both outcome and left ventricular function parameters. AMIs and IMIs were grossly separated along the second factorial axis (topographical axis) which was rather well correlated with location and right ventricular function parameters. These studies suggest that AMI and IMI hemodynamic profiles are modulated by the presence or absence of right ventricular dysfunction. Moreover right ventricular dysfunction may be held responsible of some lack of information about left ventricular function status.


Comparative effects of nifedipine, verapamil, isosorbide dinitrate and propranolol on exercise-induced angina pectoris. According to the experimental model of a 5 X 5 Latin square, 5 treatments were studied single blind in 5 patients, affected by stable-effort angina, by means of exercise tests. In the period of maximal supposed effect the following treatments were investigated: placebo (P), 1 tablet, orally; isosorbide dinitrate (ISDN), 5 mg, sublingually; propranolol (Pr), 40 mg, orally; nifedipine (N), 10 mg, orally; verapamil (V), 160 mg, orally. Placebo, compared with its own control tests, did not change any of the examined parameters. Comparison of the 'active' treatments with P showed the following results. All the treatments increased the duration of work before ECG positivity appearances. An increase in duration of work and total work performed before angina was seen after administration of ISIDN, N and V; the improvement observed after treatment with Pr was not significant. Comparison of treatments showed that work performance before angina was the same after administration of ISDN, N and V; these treatments were more effective than that with 40 mg Pr. Duration of work before ECG positivity was significantly longer after ISDN and N than after Pr. The changes in heart rate, maximal arterial pressure, ejection time index and triple product confirmed the activity of the administered doses. According to the observed effects on exercise tolerance, in comparison with P the same level of work was performed with the same triple product after Pr, and with lower triple products after ISDN, N and V.


Myocardial ischemia. Relationship between local flow, function and ST-segment elevation. The significance of reductions in local myocardial flow on mechanical function and intramural electrocardiograms (ECG) was studied in anesthetized open-chest dogs. Local dimensional changes in the anterior wall of the left ventricle were recorded by ultrasonic technique. By platinum electrodes in the same region, both intramural ECG and hydrogen tension were recorded. Local flow was calculated from hydrogen desaturation curves. At approx. 25% flow reduction (constriction of the left anterior descending coronary artery (LAD)) local enddiastolic dilation and reduced systolic shortening appeared. Significant ST-segment elevation first appeared with flow reduction of 50%. After complete LAD-occlusions, enddiastolic dilation appeared within 20 sec, ST-segment elevation 40 sec later. It is concluded that mechanical and electrical events can be dissociated during acute myocardial ischemia: enddiastolic dilation and reduced systolic shortening are more sensitive indicators of moderate reductions in myocardial tissue flow than ST-segment elevation.


Failure to recognize a His bundle potential in complete atrioventricular block. This report concerns a patient with complete heart block, in whom electrophysiological studies showed at times an escape rhythm with narrow QRS complexes preceded by His potentials with normal HV intervals (35--40 msec) and at other times an escape rhythm of similar rate, having wide QRS complexes of left bundle branch block configuration with no preceding His bundle activity. Complexes intermediate in width and configuration and preceded by His potentials with an HV interval inversely proportional to QRS width were also recorded. These observations are explained by a site of block proximal to the His bundle and competition between two pacemaker foci having similar discharge rates, one situated in the junctional region below the site of block and the other more distally in the right bundle branch or right ventricle. It is proposed that the combination of a proximal site of block and a distally situated dominant pacemaker may be a common reason for failure to record a His potential in patients with complete heart block.


Ectopic ventricular tachycardia in association with a concealed accessory pathway. Ventricular tachycardia may result in retrograde atrial depolarization. In all previous examples studied by intracardiac recording techniques retrograde conduction to the atria has been thought to occur via the normal conduction system. In the patient reported here, 1 : 1 retrograde conduction with atrial preexcitation during ventricular tachycardia indicated the presence of a concealed accessory pathway. This was confirmed by the phenomenon of exact atrial capture. The achievement of atrioventricular dissociation during tachycardia by atrial overdrive pacing excluded a reentrant tachycardia involving such a pathway. The widely variable H--V interval in the presence of a constant V--A interval during tachycardia suggested anterograde His bundle depolarization following atrial activation over the accessory pathway. This hypothesis was supported by the long V--H interval during tachycardia and the relationship of the ventricular, atrial and His bundle electrograms of the first and least beat of the tachycardia. This report illustrates the value of careful electrophysiological investigation in evaluating the relationship of an accessory pathway to the tachycardia mechanism.


Echocardiographic diagnosis of congenital left ventricular - right atrial communication. 2 patients, aged 8 mth and 48 yr, referred for a clinical diagnosis of ventricular septal defect, were studied by ultrasound. In both a fluttering and an anterior bowing of the systolic segment of the tricuspid valve was found, consistent with a left ventricular--right atrial communication. Diagnosis was confirmed by angiography and open-heart surgery, showing in 1 patient a supravalvular defect, and an infravalvular one in the other. The postoperative echocardiograms of the tricuspid valve were normal. Ultrasound appears to be a safe and simple method in detecting this rare cardiac abnormality.


Antibody-dependent cellular cytotoxicity against tumor cells. I. Cultivated bone marrow-derived macrophages kill tumor targets. Mouse bone marrow cells are cultivated in a liquid culture system in the presence of fibroblast conditioned medium. Under these conditions, proliferation of macrophage and granulocyte precursor cells is induced. Cells of a 5-day-old culture are shown to act as cytotoxic effector cells against tumor targets such as P815, E14, YAC and L5178Y. The effector cell is of macrophage origin since it is susceptible to treatment with the alloantiserum Mph-1.2 plus complement. The kinetics of the reaction resembles the kinetics for killer (K) lymphocyte lysis. In contrast to bone marrow cells, peritoneal macrophages do not show cytotoxic activity against antibody-coated tumor targets although they are susceptible to activation to cytotoxicity by lymphokines. The possible relationship of bone marrow effector cells and K lymphocytes is discussed.


Antibody-dependent cellular cytotoxicity against tumor cells. II. The promonocyte identified as effector cell. Macrophage precursor cells were cultured from the bone marrow of mice in a liquid culture system in the presence of conditioned medium. To separate their different maturation stages, they were passed through a discontinuous Ficoll density gradient, treated with iron plus magnet or passed through glass bead columns. The different maturation stages have been tested for their function in antibody-dependent cellular cytotoxicity (ADCC) against tumor target cells and in lymphokine-induced macrophage-mediated cytotoxicity. It is shown that the promonocyte, a nonadherent, nonphagocytic precursor cell, is a highly potent cytotoxic effector cell against antibody-coated tumor targets but is totally inactive as an effector cell in lymphokine-induced macrophage-mediated cytotoxicity. In contrast, in the lymphokine-induced macrophage-mediated cytotoxicity the cytotoxic effector cell is a mature macrophage. Thus, ADCC seems to be a function of the macrophage precursor promonocytes, whereas lymphokine-induced cytotoxicity is performed by mature macrophages. The relationship of promonocytes and killer (k) cells in ADCC against tumor targets is discussed.


The distribution of HLA on human lymphoid, bone marrow and peripheral blood cells. The cellular distribution and the differential expression of HLA on cell suspensions and tissue sections has been investigated using the monoclonal antibody W6-32, which reacts with the high molecular weight chain of the major histocompatibility antigen. Lymphocytes and platelets, as assessed by autoradiographic and immunoperoxidase labeling, were the most densely labeled cells. Myeloid precursors showed more labeling than mature neutrophils. Electron microscopic immunoperoxidase labeling showed a continuous distribution of HLA antigen on lymphoid and myeloid cell membranes. Erythroid precursors (including reticulocytes), although very weakly labeled, were clearly positive, in comparison with mature erythrocytes. In the thymus, HLA-negative, thymocyte antigen-positive cells (85%) can be distinguished from HLA-positive, thymocyte antigen-negative cells (15%). By using immunofluorescence techniques on tissue sections, the former cells were shown to be cortical thymocytes and the latter medullary cells.


A functional comparison of tumor cell killing by activated macrophages and natural killer cells. This report compares the sensitivity of 17 tumor cell lines to cytolysis mediated by natural killer (NK) cells or by activated, bone marrow-derived macrophages (AM) from 15 inbred mouse strains. Some tumor cell lines, notably P815, were highly sensitive to AM-mediated lysis but almost completely insensitive to NK cells, whereas other cell lines were lysed by NK cells but not AM. In a genotype survey, some low-responder strains in the NK system, such as A/Sn, were high responders in the AM system, and conversely, one intermediate to high-responder strain (C3H/HeJ) in the NK system was a low responder in AM-mediated cytolysis. In addition, macrophage cytotoxicity factor was necessary to activate macrophages, but this lymphokine did not augment NK activity. Furthermore, the NK population did not contain pre-activated macrophages since pre-activated cells were removed on glass bead columns or by iron carbonyl and a magnet; treatments which have been previously shown not to affect NK cells. These results suggest that NK cells are distinct from AM in physical characteristics, target selectivity, genotype distribution and the mechanism of cytolysis.


Studies on the inhibitory action of somatostatin in the electrically stimulated rat vas deferens. Somatostatin (SS) inhibits in a dose-dependent manner electrically evoked contractions in the rat vas deferens. This action was not modified by yohimbine, naloxone or a mixture of antagonists containing atropine, phentolamine, methysergide, burimamide, propranolol and indomethacin, but was markedly potentiated by reducing the Ca2+ concentration of the medium from 2.5 to 1.25 mM and greatly inhibited when increasing the Ca2+ concentration of the medium from 2.5 to 5.0 mM. Clonidine (CLO), but not beta-endorphin (ENDO) was affected similarly to SS by changing the Ca2+ concentration of the medium. The contractile effect of norepinephrine in unstimulated rat vas deferens was not altered by SS. These results were taken as an indication that SS produces its inhibitory action in the rat vas deferens by interacting with specific SS and its receptors presumably located in the cell membranes of adrenergic nerve terminals. The interaction between SS and its receptors may provoke a decreased diffusion of Ca2+ ions into the nerve terminals and/or a decreased mobilisation of Ca2+ ions from intraneuronal stores thus leading to a reduction in electrically evoked release of norepinephrine.


Effect of estradiol and progesterone on the isometric tension developed by longitudinal and circular isthmus of rabbit fallopian tube. The effect of estradiol and progesterone on the isometric tension developed by longitudinal and circular muscle of isthmus of rabbit fallopian tube to various agonists was studied. The isometric tension developed was reduced by about 50% under progesterone dominance as compared to estrogen dominance. This inhibition was of non-specific nature and did not involve adrenergic receptors. The non-specific effect of progesterone may have a role in regulating the entry of ova into the isthmus after their initial retention at the ampullary--isthmic junction.


The effect of neurotensin on the plasma cholesterol levels in the rat. The effect of the hypothalamic tridecapeptide neurotensin (NT) on the plasma cholesterol levels was studied in the rat. 15 min after the intravenous administration of 1.25 pmol/100 g body weight NT, the concentration of the total plasma cholesterol was increased about 25% above the control values (P less than 0.001) and remained at about the same level 30 min after the injection. The hypercholesterolemic response to the intravenous administration of NT increased dose dependently (12.5 and 125 pmol). Adrenalectomy and hypophysectomy did not modify the hypercholesterolemic effect of NT. The data suggest that NT may have a role in cholesterol transport.


Evaluation of the anticholinesterase activity of metronidazole and misonidazole. Contrary to an earlier report that metronidazole exhibited anticholinesterase activity on isolated organ preparations, a direct spectrophotometric assay was unable to demonstrate any significant inhibition of either true or pseudocholinesterase activity in the presence of this drug. The related nitroimidazole, misonidazole, was also found to be inactive when tested in this  system. This report demonstrates that the clinical neurotoxicity of these two compounds cannot be attributed to any direct effect on the cholinesterase enzymes.


An analysis of the stimulant effects of 5-hydroxytryptamine on isolated, blood-perfused rat heart. In rat isolated hearts perfused at a fixed low rate, single injections of 5-hydroxytryptamine (5-HT) (0.1--3 microgram) into the coronary perfusion produced dose-dependent increases in left ventricular (LV) dP/dt max and perfusion pressure (PP), but no clear changes in heart rate. The increases in the LVdP/dt max and PP were not significantly affected by treatment with propranolol, while they were abolished by methysergide. The present study indicates that the positive inotropic and vasoconstrictor responses of the rat heart to 5-HT are not mediated by endogenous catecholamine release, but are induced by a direct action on 5-HT receptors.


Release of beta-endorphin from rat hypothalamus in vitro. The rate of release of beta-endorphin-like immunoreactivity (beta-EI) from rat hypothalamic slices was increased 3- to 4-fold over the spontaneous release during exposure to a depolarizing concentration of potassium ions. This augmented outflow was abolished in the absence of calcium. The amount of beta-EI released from slices exposed to a second pulse of potassium was reduced by approximately 50% compared to that in the first. 70% of the potassium-induced released immunoreactive material migrated on a calibrated Sephadex G-50 column like synthetic human beta-endorphin. These findings are discussed in terms of a neuronal release of beta-endorphin and may be taken as supportive evidence for a neurotransmitter and/or neurohormonal role of beta-endorphin in the hypothalamus.


K-stimulated release of leu- and met-enkephalin from rat striatal slices: lack of effect of morphine and naloxone. The release of leu- and met-enkephalin from rat striatal slices was determined by superfusing the slices in vitro and running the superfusates directly over columns of Amberlite XAD-2 from which the peptides were eluted with methanol and measured by radioimmunoassay. Depolarization by high K concentrations increased the release of both pentapeptides many fold; the degree of increase, however, depended in part on the length of time chosen for the stimulation period, suggesting that the stimulation effect was very short lived. The stimulated release of both peptides (but not the resting release) was at least partially dependent on Ca in the medium and was totally inhibited by high Mg concentrations. Selected concentrations of naloxone and morphine in the superfusing medium had no effect on the resting or stimulated release of the peptides. The results support the hypothesis that these peptides serve as neurotransmitters in the striatum, but autoregulation of their release by morphine and naloxone could not be demonstrated.


Effect of prostaglandin E1 and indomethacin on responses of longitudinal muscle of guinea-pig ileum to cholecystokinin. The effect of prostaglandin E1 (PGE1) and indomethacin (IND) cholecystokinin (CCK)-induced contractions of guinea-pig isolated ileum longitudinal muscle were studied. PGE1 (2.8--28 nM) consistently and dose dependently increased the contractions evoked by CCK (indirect muscle stimulation) or by ACh. IND (2.7 microM) decreased the contractions to both compounds and this was reversed with 2.8--7 nM PGE1. Pretreatment of the preparations with phentolamine (2.6 microM) or pretreatment of the animals with reserpine (2 mg/kg i.p. 24 h before killing) did not affect PGE1 potentiation or IND inhibition of CCK-induced contractions. The results indicated that PGE1 potentiated CCK-induced contractions of the longitudinal muscle of guinea-pig ileum by increasing the response to released ACh. Experiments with IND suggested that endogenous PGs may modulate the effect of CCK or related gastrointestinal hormones.


Interaction of sulfpride and ergot derivatives on rat brain DOPAC concentration and prolactin secretion in vivo. Sulpiride, which differs from classical neuroleptics by not producing major extrapyramidal side effects, is a potent antiemetic agent and stimulates prolactin secretion in both laboratory animals and man. In parallel it increases dopamine synthesis in both striatum and nucleus accumbens. Bromocriptine and metergoline are two effective agents in suppressing prolactin release and postulated to stimulate dopamine receptors. The interactions of these two ergot derivatives with sulpiride have been investigated on prolactin release and on striatal and limbic DOPAC accumulation. Bromocriptine at all doses tested was able to suppress the increased in vivo prolactin secretion observed after sulpiride administration. Metergoline antagonized the sulpiride-induced prolactin increase only at low doses; on the contrary higher doses potentiated it. High concentrations of bromocriptine suppressed the sulpiride-induced increased of DOPAC levels in striatum and n. accumbens, while metergoline potentiated the sulpiride-induced accumulation of brain DOPAC.


Effect of 6-hydroxydopamine treatment on TSH secretion in basal and cold-stimulated conditions in the rat. 6-Hydroxydopamine (6-OHDA) (two doses of 200 micrograms each, administered intraventricularly at a 48 h interval) caused a marked decrease of hypothalamic noradrenaline content and blocked the TSH rise elicited by cold exposure. Clonidine (0.4 mg/kg i.p.), a noradrenaline receptor agonist, was able to reverse the 6-OHDA of cold-induced TSH surge. The plasma TSH levels after cold stress in rats treated with 6-OHDA + clonidine were significantly higher than in vehicle + clonidine-injected animals, thus suggesting the presence of noradrenaline receptor supersensitivity in 6-OHDA-pretreated rats. 6-OHDA did not modify the basal concentrations of TSH but the administration of clonidine to 6-OHDA-injected animals caused a significant increase in thyrotropin secretion when compared with the vehicle + clonidine group.


Effects of diethylcholine in two animal models of Parkinsonism tremors. (2-Hydroxyethyl) methyldiethylammonium iodide (diethylcholine; DEC) was tested against trihexyphenidyl for its ability to block tremors in two animal models of Parkinsonism tremors. Both DEC (75 mg/kg) and trihexyphenidyl (10 mg/kg) antagonized physostigmine tremors in mice. Both drugs also blocked tremors in rats which received intracaudate injections of carbachol. DEC was more efficacious than trihexyphenidyl in the rat model. No dose-related inhibition of tremors was seen for trihexyphenidyl (5--20 mg/kg) but inhibition by DEC was dose-related (25--50 mg/kg). The ED50 for tremor inhibition in the rat model by DEC was 33 mg/kg. DEC was also shown to cross the blood-brain barrier in mice. The probable mechanism of action of DEC is discussed.


Angiotensin II facilitates the potassium-evoked release of 3H-noradrenaline from the rabbit hypothalamus. Antiotensin II facilitated in a concentration-dependent manner the potassium-evoked 3H-noradrenaline over-flow from the rabbit hypothalamus. This effect which is probably mediated through presynaptic angiotensin facilitatory receptors on noradrenergic nerve terminals was blocked by the specific angiotensin receptor antagonist, saralasin. These results demonstrate that angiotensin II also facilitates the stimulation-evoked release of noradrenaline in the central nervous system.


An attempt to differentiate the effects of angiotensin II, substance P and bradykinin on the field-stimulated guinea-pig vas deferens. The ability of the angiotensin antagonists 1-Sar,8-Ala-angiotensin II (saralasin) and 1-Sar,8-Leu-angiotensin II (sarleusin) and the bradykinin-potentiating peptide B (BPP) to modify the twitch-enhancing effect of angiotensin II, bradykinin, and substance P, was studied in the isolated field-stimulated guinea-pig vas deferens. The twitch-enhancing effect of angiotensin, bradykinin and substance P underwent tachyphylaxis which was strongest after angiotensin. Saralasin and sarleusin were without influence on the twitch response and antagonized the effect of angiotensin, but not that of bradykinin or substance P, respectively. The features of the antagonism to angiotensin were compatible with the notion that saralasin is a competitive and sarleusin a dual antagonist. BPP did modify either the twitch response or the effects of angiotensin, bradykinin, and substance P. In the non-stimulate vas, the contracting effect of noradrenaline did not undergo tachyphylaxis and was not mofified by angiotensin, bradykinin, or substance P. It is concluded that there exist in the guinea-pig vas specific peptide receptors, one of them having the properties of a "typical" angiotensin receptor.


Effect of ergotamine on cranial arteriovenous shunting in experiments with constant flow perfusion. The effect of the antimigraine drug, ergotamine, was studied on the distribution of flow throughout the cranial microcirculation of the cat, using microspheres suitable in size to separate capillary flow from flow through the arteriovenous anastomoses. A constant flow perfusion experiment was used in order to eliminate the secondary effect of ergotamine on the microcirculation through a reduction in carotid blood flow per se. Under the experimental conditions, ergotamine decreased in a dose-dependent way the fraction of perfusion flow shunted through the arteriovenous anastomoses. This mode of action of ergotamine sheds new light on the so-called migraine shunt theory.


Dopamine vascular actions of N-substituted derivatives of 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN). N-ethyl, N-n-propyl, N-n-butyl, N,N-di-n-propyl and N-n-propyl-N-n-butyl derivatives of 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) were screened for dopamine vascular agonist activity. Effects of intraarterial injections of the drugs on renal and femoral blood flow were measured in pentobarbital-anesthetized dogs before and after phenoxybenzamine (POB), 5--10 mg/kg. All DDTN derivatives were more potent vasoconstrictors than dopamine (DA) before POB. The di-substituted analogs were approximately 1/4 and the mono-substituted derivatives were about 1/16 as active as norepinephrine as vasoconstrictors. After POB the two di-substituted analogs were about 1/4 as active as DA in causing renal vasodilation. The three mono-substituted analogs produced relatively minor and inconsistent effects on renal blood flow, and were more than 100 times less effective than DA as vasodilators. The two di-substituted analogs markedly increased blood pressure with little effect on cardiac contractility in doses up to 32 micrograms/kg; whereas, the threshold dose of DA is 4--8 micrograms/kg. This and our previous results show that structure activity relationships of DA and ADTN, a semi-rigid analog of DA, are similar. However, the rigid analogs tend to be more potent vasoconstrictors than their flexible chain homologs.


Actions of somatostatin on excitatory and inhibitory nerves in the intestine. Isolated segments from the guinea-pig ileum and colon were used to investigate the sites of action of somatostatin on intestinal nerves and muscle. Somatostatin reduced the amplitude of the contraction caused by stimulation of cholinergic nerves in the ileum, without antagonizing receptors for acetylcholine on the muscle, which indicates that somatostatin inhibits the release of transmitter from the cholinergic nerves. Somatostatin caused the intestinal muscle to relax. The relaxation was blocked by tetrodotoxin but not by guanethidine, indicating that somatostatin stimulates enteric non-adrenergic inhibitory nerves. The threshold of concentration for these actions of somatostatin was low (2 to 6 X 10(-10) M). At higher concentrations, somatostatin caused a transient inhibition of peristaltic reflexes and it also stimulated cholinergic nerves. No evidence was obtained for a direct action of somatostatin on intestinal muscle. It is concluded that somatostatin is possibly a neurotransmitter in the intestine that is released at neuro-neuronal junctions and causes an inhibition of intestinal movements.


Effect of cardiotonic polypeptide anthopleurin-A on canine Purkinje and ventricular muscle fibers. Effects of Anthopleurin-A (AP-A, polypeptide from sea anemone) were studied on electrophysiological properties of isolated canine Purkinje and ventricular muscle fibers. Ap-A (in concentrations above 20 micrograms/l) produced a dose-dependent increase in action potential duration (APD) and the refractory period (RFP) in electrically driven Purkinje fibers, but had no effect on other parameters. Similar but less prominent change in APD and RFP was observed in ventricular muscle fibers. AP-A in high concentrations (200 micrograms/l or higher) did alter the spontaneous firing rate of Purkinje fibers. Since AP-A in low concentrations will increase the refractory period of conducting fibers without affecting a conduction velocity, it may abolish some re-entrant arrhythmias.


Tetrahydronorharmane modulates the depolarisation-induced efflux of 5-hydroxytryptamine and dopamine and is released by high potassium concentration from rat brain slices. Tetrahydronorharmane (THN), a compound which occurs in man and in rats is supposed to act as a modulator of 5-hydroxytryptaminergic neurones. It is reported here that THN stimulated the potassium-induced release of the neurotransmitter from brain slices. This suggests enhancement of the efflux as a mechanism for the 5-hydroxytryptamine-like action of THN in pharmacological experiments. Furthermore, THN decreased the potassium-evoked efflux of (3H)-dopamine. This is consistent with the inhibition of dopaminergic neurones by THN as seen previously in various in vivo experiments. Finally it is demonstrated that a high concentration of potassium evokes the efflux of (14C)-THN from brain slices. This finding suggests that THN is taken up into neurones and exerts its modulating action on serotonergic neurones either inside or outside the cell.


Electrophysiological study of the action of neurotensin on the smooth muscle of the guinea-pig taenia coli. The effects of neurotensin on the membrane potential and conductance, and on the tension of the guinea-pig taenia coli were investigated using the sucrose gap method. In preparations spontaneously active at 37 degrees C, neurotensin (0.5--10 nM) increased the frequency of spikes and induced a smooth muscle membrane depolarization which led to a block of spike discharges. These electrical events were accompanied by phasic and tonic contractions of the smooth muscle. At 20 degrees C the guinea-pig taenia coli exhibited little or no spontaneous activity. Neurotensin (50 nM) rapidly depolarized the smooth muscle membrane and increased its conductance. Concentration--response curves of neurotensin-induced depolarization and contraction gave an EC50 of 1.7 nM and 4.5 nM respectively, with a maximally effective concentration of peptide around 50 nM for both effects. Studies in modified or substituted salt solutions indicated that the neurotensin-induced increase in smooth muscle membrane conductance was primarily due to an increase in Na+ and Ca2+ conductances.


Studies on the protective effect of prostacyclin in acute myocardial ischemia. The ability of prostacyclin (PGI2) to alter responses to acute myocardial ischemia was studied in open-chest, anesthetized cats. PGI2 was infused intravenously at 0.5 nmoles kg-1 min-1 in cats subjected to 5 h of myocardial ischemia by occlusion of the LAD coronary artery, and in sham-operated controls. GI2 infusion resulted in significantly decreased arterial blood pressure and inhibition of platelet aggregation. Coronary ligation resulted in significant S-T segment elevations lasting 5 h in vehicle-treated animals but only 1 h in cats with myocardial ischemia and receiving PGI2. At 5 h, cats with ischemia and given the vehicle showed S-T segment elevations significantly greater than the other two groups. Ischemic myocardium from vehicle-treated animals exhibited significantly less creatine phosphokinase (CPK) specific activity than normal tissue from the same hearts or myocardial tissue from the other two groups. This loss of CPK from ischemic myocardium of the cats given vehicle was reflected in plasma CPK specific activities which were significantly greater than those of sham-operated cats. The cats with ischemia and treated with PGI2 exhibited lower plasma CPK activities. These changes were moderated by PGI2 infusion during myocardial ischemia. PGI2 infusion may protect the ischemic myocardium by reducing oxygen demand, primarily through reductions in cardiac work, and by perhaps inhibiting platelet aggregation and preserving myocardial cell integrity.


Reticulospinal connections with limb and axial motoneurons. Responses of motoneurons supplying muscles of the forelimbs, hindlimbs, back, and neck to stimulation of the medial pontomedullary reticular formation were studied with intracellular recording in cerebellectomized cats under chloralose anesthesia. Stimulation of the midline or of a reticular region consisting of nucleus reticularis (n.r.) pontis caudalis and the dorsorostral part of n.r. gigantocellularis produced monosynaptic excitation of ipsilateral motoneurons supplying axial muscles and flexor and extensor muscles in both proximal and distal parts of the limbs. This widespread excitation appears to have been produced by rapidly conducting medial reticulospinal fibers. Stimulation of a second region consisting of n.r. ventralis and the ventrocaudal part of n.r. gigantocellularis produced monosynaptic excitation of ipsilateral neck and back motoneurons but only longer latency, apparently multisynaptic excitation of limb motoneurons. Collision tests indicated that this monosynaptic excitation did not involve fibers descending along the midline. It therefore appears to have been produced by lateral reticulospinal fibers. Reticular stimulation also produced short latency, monosynaptic inhibition of neck motoneurons, long latency, apparently polysynaptic inhibition of limb motoneurons and intermediate latency inhibition of back motoneurons. The latencies and properties of inhibitory responses of back motoneurons indicated that they were produced either disynaptically by fast fibers or monosynaptically by slower fibers. The data indicate that the medial pontomedullary reticular formation can be divided into a number of different zones each with a distinct pattern of connections with somatic motoneurons. These include the dorsorostrally located medial reticulospinal projection area, from which direct excitation of a wide variety of motoneurons can be evoked, the ventrocaudally located lateral reticulospinal projection area from which direct excitation of neck and back and direct inhibition of neck motoneurons can be evoked and the dorsal strip of n.r. gigantocellularis which has direct excitatory and inhibitory actions only on neck motoneurons.


Ultrastructural data, with special reference to bouton/glial relationships, from the hypoglossal nucleus after a second axotomy of the hypoglossal nerve. The left hypoglossal nerve of adult male albino rats was prevented from regenerating to the tongue after a distal axotomy by implanting the proximal stump into normally innervated left sternomasoid muscle. Eighty-four days after implantation, the hypoglossal nerve was transected again and its regeneration to the tongue unimpeded. From 8 to 70 days after this second axotomy the left hypoglossal nuclei were processed for quantitative ultrastructural analysis. The first aim of this study was to compare regeneration success in the hypoglossal nucleus after second axotomy with that accompanying outgrowth of the hypoglossal nerve into denervated sternomastoid muscle. During quantitative analysis a second aim developed, of elucidating bouton/glial relationships. The second axotomy induced loss and return of subsurface cisterns, dispersal and reassembly of Nissl substance, increase and decrease of microglial numbers, slight further loss and partial return of boutons with clear spherical vesicles and symmetrical synapses, slight increase and decrease of boutons with clear flat vesicles and symmetrical synapses, regrowth of retracted dendrites and restoration of their synapses, and gradual diminution of numbers of electron-dense neurones and dendrites. Astrocytes remained hypertrophied throughout. When compared with events in the hypoglossal nucleus accompanying innervation of denervated sternomastoid muscle by the hypoglossal nerve, the results suggest (1) that regeneration of the hypoglossal nerve to its own tongue muscle instead of to a foreign muscle caused no acceleration of recovery in the hypoglossal nucleus, and (2) that the microglial response is dependent on nerve integrity and not on bouton behaviour.


Hypercomplex cell types in area 18 of the cat. Single unit recording has revealed the same orientation sensitive cell classes in cat area 18 as are to be found in area 17. These include particularly the various types of hypercomplex cell belonging to the S, C, and B cell families.


Electrophysiological evidence for axonal sprouting of cerebellothalamic neurons in kittens after neonatal hemicerebellectomy. Changes in cerebello-cerebral responses after hemicerebellectomy were investigated in 19 kittens by laminar field potential analysis in the cerebral cortex. In all of 11 kittens operated on before 11 days of age and kept for more than 16 days after surgery, marked cerebello-cerebral responses were evoked not only contralaterally as in intact animals but also ipsilaterally. In none of 16 intact kittens ranging in age from 2 to 14 days was there a detectable response in the cerebral cortex to stimulation of the ipsilateral cerebellar nucleus. Pathways responsible for the ipsilateral cerebello-cerebral responses were investigated by destruction of the thalamic VL nucleus and by unitary recordings from cerebellar nuclear neurons with antidromic activation on stimulation of the thalamus. From the latter investigation, a remarkable increase in the number of neurons with bilateral projections upon the thalamus was seen in the surgically treated kittens. Stimulation of the VL thalamic nucleus contralateral to the remaining hemicerebellum induced a marked response in the frontal cortex not only ipsilaterally as in intact animals but also contralaterally. The latter response was considered to be mediated by an axon reflex of the bilateral projection neurons. Destruction of that VL nucleus abolished the contralateral cerebello-cerebral response whereas the ipsilateral cerebello-cerebral response remained unchanged. It is concluded, that in kittens, hemicerebellectomized in the early postnatal period, nuclear neurons in the remaining cerebellum sprout axon collaterals growing into the thalamus ipsilateral to the spared hemicerebellum and that these sprouting axon collaterals make synpases on the thalamic neurons projecting upon the cerebral cortex.


Pineal response types in the frog's brain under white light exposure. Responses to white light stimulation can be recorded with electrophysiological methods at the level of (1) the pineal system (2) different diencephalic nuclei and (3) the mesencephalic tegmentum. The neurons are classified in six groups according to their discharge characteristics. As some responses present a higher complexity than the classical messages, an integration of the pineal informations during their course toward the brain is suggested in order to support phototactic behavior.


Hemisphere contributions to the composition of the pattern-evoked potential waveform. The transverse distribution of scalp-recorded potentials evoked by pattern reversal stimulation was studied in 50 healthy subjects. In most individuals the full-field responses were symmetrical over the occipital scalp, but important variations in distribution, symmetry and waveform were recorded in some cases. Asymmetrical responses were similar for each eye (i.e., they were "uncrossed" or homonymous asymmetries). Full-field peak latencies and amplitudes in the lateral channels were more variable than those at midline electrodes. Half-field responses were markedly asymmetric with well-lateralised components widespread over occipital-parietal scalp. In contrast to the full-field responses, component values measured near the midline were less consistent than those from lateral channels due to waveform distortions in this area ("transitional zone"). Upper field stimulation is particularly likely to produce such midline waveform distortions. Activity recorded from the scalp contralateral to the half-field stimulated shows more inter-individual and inter-hemispheric variation than that recorded from ipsilateral electrodes. Variants in the full-field waveform can be accounted for by relative differences in amplitude and distribution of the ipsilateral and contralateral components from each half field. The algebraic sum of these half-field components does not differ significantly from the components of the separately recorded full-field response. Furthermore, responses from the surviving half-field in patients after total hemispherectomy contain all the ipsilateral and contralateral half-field components seen in healthy subjects.


The role of the corpus callosum in the development of interocular eye alignment and the organization of the visual field in the cat. In young cats, the posterior portion of the corpus callosum was sectioned 13--29 days after birth. The animal's eyes were photographed at weekly intervals for six months using the pupil-reflex method. From the corneal reflection evident in the photographs the degree of alignment for the optical axes of each cat was estimated (Sherman, 1972). The 17 experimental cats all showed a significant tendency toward permanent divergent strabismus, as compared to six normal cats. The limits of the visual field were determined for both groups of cats using a perimetry technique similar to that of Sprague and Meikle (1965) and Sherman (1973). With one eye open normal cats responsed from 90 degrees ipsilateral to 45 degrees past the vertical midline into the contralateral visual field. With either eye the experimental cats responsed from 90 degrees ipsilateral to approximately the vertical midline. The loss of visual responsiveness is within the contralateral region of the normally binocular zone. Three cats received the same operation at 9, 13, or 20 months old. Eye alignment and visual field perimetry were unaffected by the surgery. It is not known whether the observed abnormalities result from arrested development, or disruption of intrinsically determined ocular alignment.


The effect of raising the scala tympani potassium concentration on the tone-induced cochlear responses of the guinea pig. Scala tympani (ST) in guinea pig was perfused with modified Ringer's solutions containing 5--50 mM potassium; tone-induced cochlear responses from the basal turn of ST were compared before, during and after perfusions. The compound nerve action potential (N1) and afterpotential (a/p) amplitudes were reduced, especially above 20 mM; the summating potential (SP) was variable, but its onset shape changed consistently with 13--20 mM levels. However, the cochlear microphonic amplitude (CM) remained substantially unchanged even at the 35 mM level. K+ concentration was monitored in ST with ion-sensitive pipettes. Stable levels were reached within 2 min, but N1 responses continued to fall beyond this time. Recovery to normal K+ levels took place spontaneously and the concentration curve which resulted showed a 2-slope characteristic. These experiments question whether elevated potassium concentration in scala tympani depolarizes the hair cells, and if it does, whether the hear cell resting potential is involved in the generation of the CM.


Exchange and efflux of tryptophan from superfused cerebral cortex slices. The efflux and exchange of L-tryptophan (Trp) from rat cerebral cortex slices were studied in a superfusion system. The substrate specificity of Trp exchange was assessed by measuring the stimulation of [3H]Trp exit provoked by other extracellular amino acids. Large neutral amino acids were the most potent, but also glutamic acid, lysine and glycine had some effect. The stimulation caused by extracellular Trp and phenylalanine persisted also at 0 degrees C though severalfold attenuated. Only intracellular histidine provoked slight inhibition of [3H]Trp efflux and intracellular Trp, phenylalanine and lysine had a small stimulatory effect. The results suggest an involvement of carrier-mediated processes in the exchange and efflux of Trp. The substrate specificities of the exchange and efflux are not apparently identical.


Tubular explant culture of fetal Syrian golden hamster tracheae. Two types of organ culture technique (stationary and rocking) were compared for their ability to maintain the epithelial structures in the tubular explants of fetal Syrian golden hamster tracheae. A simple new technique has been devised for the organ culture of small tubular explants of fetal tracheae. A large pore-sized membrane filter is introduced into the rocking culture, which improves unfavourable in vitro effects of the stationary technique.


The occurrence of lipid droplets in the proximal and distal tubules of the rat kidney after folic acid treatment. Folic acid in high doses gives rise to an accumulation of lipid droplets in the kidney in addition to other changes in the epithelial of both proximal and distal tubules. With the administration of methionine a decrease of lipid droplets and an improvement of the structures of most of the membranes and mitochrondria are observed. These findings have been discussed in regard to the theory of the "chemically induced hyperplasia of the kidneys" related to folic acid.


The glutathione status of the rat liver. For the determination of cellular total glutathione, a new method is presented based on a fluorometric procedure. The relation between reduced glutathione, mixed glutathione disulfides and disulfide glutathione will be designated the glutathione status.


Effect of temperature on the activity of AMP-deaminase from rat heart. In the presence of 1 mM ATP, the plots of Michaelis dependence of the reaction catalysed by AMP-deaminase from rat heart were hyperbolic at all temperatures between 10 and 40 degrees C. Calculation of the energy of activation for ATP-activated enzyme and of the enzyme-substrate complex formation is presented.


Recovery of renal lactate dehydrogenase (LDH) isoenzyme pattern after obstruction relief in experimental hydronephrosis. The release of ureteral occlusion leads to a progressive recovery in LDH isoenzyme pattern with gradual increase of anodic fractions and decrease of middle and cathodic ones. Our findings demonstrate that the recovery is accomplished on the 10-14th day, in agreement with morphological and metabolic observation.


Development of oxidative metabolism in the non-innervated optic lobe of the chick. Early removal of the optic cup of the chick embryo prevents innervation of the contralateral optic lobe. This reduces the rate of development od citrate synthetase. The posthatch increase of the level of this enzyme related to oxidative metabolism is not impaired by denervation of the chick optic lobe.


Isolation of di-N-2-propylpentyl phthalate from human urine. A higher percentage of di-N-2 propylpentyl phthalate isolated from the urine of the normals and a lower quantity in the patients suffering from Eales' disease accompanied with the occurrence in patients of another compound which is also most likely a phthalate ester has been correlated with the Eales' disease.


2/8 translocation in a Japanese Burkitt's lymphoma. A new translocation between chromosomes 2 and 8, t(2p-; 8q+), was found in fresh lymphoma cells from a Japanese patient with Epstein-Barr virus-carrying Burkitt's lymphoma, and in a lymphoma cell line derived from this patient. There was no 14q+ translocation, as has been previously described in African and North American Burkitt's lymphomas.


Differential scanning calorimetry of chromaffin granule membranes. Differential scanning calorimetry thermograms of native chromaffin granule membranes exhibit several peaks in the 15-35 degrees C region. Extraction of cholesterol increases the size of the melting peaks. Addition of Ca2+ ions does not seem to influence the lipid transitions.


The invasion and growth of Babesia bovis in tick tissue culture. Erythrocytic forms of Babesia bovis inoculated into cell cultures of the tick Boophilus microplus invaded the tick cells and showed multiplication for up to 48 h after inoculation.


Histochemical and cytochemical observations on the acetylcholinesterase (AChE) localization in the superior cervical ganglion (SCG) after preganglionic sympathectomy of the neonatal rat. Results of histochemical and cytochemical reactions show that after the section of preganglionic nerve trunk performed in newborn animals, the appearance and the individual increase in AChE activity in non-innervated nerve cells follow the pattern of normally innervated ganglion cell.


Hageman factor activation and tight junction disruption in mice challenged with attenuated endotoxin. Endotoxin treated with chromium chloride is less toxic to mice than the parent molecule, but can disrupt intestinal permeability barriers and has an enhanced ability to activate Hageman factor.


Binding of cytophilic rabbit IgG to homologous hepatocytes. Rabbit liver cells were able to bind cytophilic monomeric and polymeric homologous IgG via their Fc receptor binding sites (FcR). On the other hand, non-cytophilic rabbit IgG did not bind to hepatocytes, even after its aggregation. The present findings suggest that FcR on rabbit liver cells are specific for cytophilic monomeric IgG but do not significantly bind non-cytophilic, polymeric IgG.


Effects of increased potassium in scala tympani on auditory nerve sensitivity. Raising the K+ concentration in scala tympani of the guinea-pig cochlea generally caused a substantial increase in the spontaneous firing rate of single auditory nerve fibres. This effect was not accompanied by any observed reduction in the threshold sensitivity of these fibres. These findings cast doubt on current theories of cochlear transduction.


Why do patients with respiratory muscle paralysis require artificial hyperventilation? The primary reason for the need of hyperventilation in patients with respiratory paralysis is the insufficiency of the inhibitory Hering-Breuer reflex. The artificial distension of the lungs with normal tidal volume cannot inhibit the respiratory centre in contrast to the normal state.


Hyperventilation and inhibitory synapses. Injection of a subconvulsive dose of strychnine (which blocked the inhibitory synapses) increases respiratory muscle activity evoked by stimulation of a sciatic nerve as well as by inhalation of hypercapnic gas mixture. Thus the inhibitory synapses prevent an excessive hyperventilation.


Frog's tongue receptive areas: neural organization and gustatory function. Lateral and medial branch of the frog's IXth nerve innervates rostral third and caudal two-thirds of the tongue surface, respectively. The amounts of gustatory signals in these branches differ in proportion to the area they supply.


Daily variation in the eye's 5-HT stores. Eyes from mice have been assayed for 5-HT content at various times during the day. 5-HT levels are highest midway in the light period and lowest during the dark period. In general this daily variation conforms with other published reports for variation of 5-HT stores in brain and pineal.


Pentagastrin activation of adenylate cyclase in human gastric biopsy specimens. Adenylate cyclase activity of human fundic mucosa is log-normally distributed and equally stimulated by pentagastrin and histamine. Cimetidine inhibits the histamine, but not the pentagastrin effect, which is even intensified by H2-receptor blockade. The results indicate that pentagastrin and histamine activate adenylate cyclase via distinct receptors.


Brain stem projections to the cerebral cortex in the rat. By means of the HRP method it was shown that the entire cerebral cortex, but in greater proportion the frontal and posterior temporo-parietal regions, receive fibres from the dorsal and medial raphe nuclei and from the locus coeruleus. In contrast, the pars compacta substantiae nigrae and the tegmental area send projections to the motor and cingular areas respectively.


The human urinary gastric inhibitor displays blood-group activity. The human urinary glycoprotein with gastric antisecretory activity displays a marked blood-group activity corresponding to the blood-group of the subject examined. Several studies exclude the possibility that the activity is due to contaminants.


Maternal behavior in two rat lines selected for differences in the acquisition of two-way avoidance. The maternal behavior of Roman high- and low-avoidance (RHA/Verh and RLA/Verh) rats was studied, using  a time-sampling method. It was concluded that: a)RLA/Verh mothers spent more time with their young, b) RHA/Verh mothers were more active, and c) the mothers of both lines mostly "blanketed' their young during nursing, although the RHA/Verh mothers assumed the side-nursing position more often than their counterparts.


Velocity gradient and contraction frequency of the pyeloureteral system. An optical detection method, using video imaging, is used to quantitatively record the frequency and velocity profile of the renal pelvis of the rabbit. It is demonstrated that concentric waves originating at the periphery of the pelvis have an initial velocity of 3.2 cm/sec, accelerating toward the pelviureteral junction reaching a final velocity of 6.4 cm/sec.


Blocking by picrotoxin of nigra-evoked inhibition of neurons of ventromedial nucleus of the thalamus. The transmitter substance realeased by nigro-thalamic fibres is proposed to be gamma-aminobutyric acid, since picrotoxin blocked nigra-evoked monosynaptic inhibition of thalamic neurons.


Antibiotic sensitivity testing by flow microcalorimetry. The proposed flow microcalorimetric method for the diagnosis of bacteriuria has been extended to include antibiotic sensitivity testing. Sensitive organisms rapidly (4-8 min) show thermal responses to the added antibiotics over the normal range of concentrations (1 x, 2x, MIC value).


The effect of piroxicam on platelet aggregation. Piroxicam inhibited aggregation of human and dog platelets caused by collagen, but not by adenosine diphosphate (ADP). Release of platelet ADP was inhibited by piroxicam.


Percutaneous penetration of indomethacin. 14C-Indomethacin (ID) was applied to the skin of guinea-pigs as an ointment. After several applications, the concentration of ID in the skin and muscle under the applied site reached a constant level. The concentration of ID in the muscle as well as the skin may be enough to exert an anti-inflammatory effect.


Antihypertensive activity of some novel pyridinylidene arylurea derivatives in spontaneously hypertensive rats. 3 novel pyridinylidene arylurea derivatives were found to lower arterial pressure in spontaneously hypertensive rats. Their relative oral potency ranged from 6 to 32 times that of guanethidine. The onset of antihypertensive action following their oral administration was less than 1 h and the duration of action ranged from 8 to over 24 h. The antihypertensive activity of the pyridinylidene arylureas was found to be assoicated with depletion of tissue catecholamines. Compound C depleted cardiac norepinephrine with little or no effect on total brain norepinephrine levels. It is suggested that compound C may have useful antihypertensive properties without CNS depressant activity.


Inhibition of human leucocytes locomotion by anti-inflammatory drugs. In this study we have demonstrated that acidic non-steroidal anti-inflammatory drugs in low concentrations inhibited human PMN locomotion in vitro. A speculative mechanism of action is proposed.


Renal injury after muscle extract infusion in rats: absence of toxicity with myoglobin. A crude muscle extract infused into rats produced oliguria, a precipitous drop in total hemolytic complement, and in circulating white cell and platelets counts. A mild vaso-depressor effects was noted. These changes were not produced by myoglobin or saline infusion. Muscle constituents other than myoglobin are responsible for the systemic and renal nephrotoxic effects observed.


Choleretic and cholestatic effects of infused bile salts in the rat. In rats, at low infusion rates taurocholate (TC), taurochenodeoxycholate (TCDC) and taurodeoxycholate (TCD) each produced an increase in bile flow of 20-50%. However, at high infusion rates (5-20 mumoles min-1kg-1) the cholestatic effects of the bile salts were revealed and the relative toxicity of the bile salts was seen to be TDC greater than TCDC greater than TC.


Changes in molecular species of pepsinogens in the development of the chick. The potential peptic activity of the chick forestomach increases rapidly at the time of hatching. Together with this, the electrophoretic pattern of the pepsinogens shifts to the adult type. These changes take place even under the complete starvation of a newly hatch chick.


Density gradient centrifugation of cells separated from multicellular tumor spheroids. Cells from a murine fibrosarcome (FSa) have been grown in vitro as multicell tumor spheroids (MTS). The growth rate of these MTS was determined. Following selected periods of growth, MTS were made into a single cell suspension and separated on linear density gradients of Renografin. While only 1 population of cells were separated from small spheriods (400 mum diameter), at least 3 subpopulations of tumor cells were separated and isolated from large spheroids (800 mum in diameter).


Release of plasminogen activator from normal and neoplastic endometrium. In the medium of endometrial carcinoma cultures, anti-urokinase-reacting plasminogen activator was released in contrast to cultures of normal or hyperplastic endometrium.


Immunological profile of breast cancer patients in early or advanced disease. Immune reactivity of patients with early or advanced breast cancer, compared with healthy controls, has been measured using in vivo and in vitro tests. The results of our study show that impairment of cellular responsiveness occurred in women with advanced disease.


Lymphatic metastasis of tumour; persistent transport of cells. A model of lymphatic metastasis established by injecting Walker rat carcinoma cells into the rat footpad was used to study the output of tumour cells from the footpad. The lymphatic efferent from the footpad was cannulated in a group of rats with advanced neoplasm; it was shown that the output of tumour cells was continuous over periods up to 90 min and ranged from 10(2)-10(5) cells/min.


Copper-induced heart malformations in hamsters. The injection of copper citrate into pregnant golden hamsters induces a specific pattern of cardiovascular malformations in their embroys. The syndrome consists of double-outlet right ventricle, pulmonary hypoplasia and a ventricular spetal defect.


Studies on the activity of phorbol myrystate acetate on the human polymorphonuclear leukocytes. Phorbol myrystate acetate (PMA) activates nitroblue tetrazolium reduction in human polymorphs. The activation is inhibited by dibutyryl cyclic AMP, theophylline and phenylbutazone, but is not influenced by hydrocortisone in vitro, nor is it inhibited by leukocytes from patients treated with prednisone. Peptide analogues of Tuftsin also had no effect on this stimulatory activity. We conclude that the action of PMA on the nitroblue tetrazolium reduction is mediated through cyclic nucleotides.


Preparation of lymphocytes from small volumes of peripheral mouse blood. A method was developed which allowed for the isolation of lymphocytes (95% of leukocytes in the final suspensions) from small volumes of peripheral mouse blood (38% recovery). The method proved of value for studies of murine lymphocytes which required biochemical analysis of samples from individual animals on a serial basis.


Decrease of cholesterol and free fatty acids in cortisone-resistant lymphoid cells incubated with allogeneic tumor cells. A marked decrease of cholesterol and free fatty acids was found in the cortisone-resistant lymphoid cells from thymus or spleen of mice immunized with Ehrlich carcinoma cells when incubated with the tumor cells.


Shape change reaction of platelets in protein-free medium: ultramorphology. Transmission and scanning electron microscopy indicate that rabbit platelets incubated in protein-poor medium retain their reactivity to shape change-inducing agents such as 5-hydroxytryptamine, adenosine-5'-diphosphate and chlorpromazine. Such platelets may be used as models for drug-membrane interactions, e.g. in neuronal cells.


Thymectomy modifies androgenizing effects of a testis transplant during critical period for neuroprogramming. Thymectomy simultaneous with transplantation of a syngeneic testis from a littermate to Fischer 344 rats ameliorated the androgenizing effects of the testis transplant on ovarian morphology at 90 days of age.


A new stimulation technique of the crista ampullaris of the lateral canal in the adult cat: study of the action potential of the vestibular nerve. The stimulation of the crista ampullaris of the lateral canal by a short ampullopetal liquid flux produces on the pre-ganglionic vestibular fibres the appearance of a bimodal action potential. The amplitude of this action potential increases with the intensity of the stimulation. This stimulation also provokes the birth of an evoked potential at the level  of the vestibular nuclei as well as an ocular jerk.


A method for the determination of glutamate oxaloacetate transaminase in sperm plasma from boars and bulls. A method is described for the determination of glutamate oxaloacetate transaminase (GOT) activity in sperm plasma from boars and bulls as a test for fertilizing ability.


[Chemical and pharmacological research on pyran derivatives. XIII. Derivatives of 2H-pyrano/3,2-c/quinoline]. Treatment of N-alkylanilines or diphenylamine with N,N-dialkylethoxycarbonylacetamides in the presence of phosphorus oxychloride afforded 6-alkyl(phenyl)-4-dialkylaminopyrano [3,2-c] quinoline-2,5-(6H)-diones, two molecules of amide being involved in the reaction. In some instances 6-alkyl(phenyl)-4-alkylaminopyrano [3,2-c] quinoline-2,5(6H)-diones were obtained through a partial dealkylation of the amino group. Pharmacological evaluation of some compounds showed no activity on the CNS.


[Synthesis of O-(beta-diethylaminoethyl)cinchoninaldoxime with local anesthetic activity]. The synthesis and the pharmacological evaluation of a new series of O-(beta-diethylaminoethyl)aldoxines derived from cinchonine-aldehydes substituted at position 2 by alkyl and alkoxyl groups are described.


Amide, 1-adamantylamide of leu-enkephalin and leu-[D Ala2]enkephalin. The synthesis of Leu-enkephalinamide, Leu-enkephalin-1-adamantylamide, Leu-[D Ala2]enkephalinamide and Leu-[D Ala2]enkephalin-1-adamantylamide are described. Preliminary results of pharmacological tests in vitro are reported.


Psychopharmacological study with K 8409, a 1H-naphtho[2,1-b]pyran 3-dialkylamino substituted derivative. A 1H-naphtho[2,1-b]pyran derivative (K 8409) has undergone pharmacological investigation for psychotropic activity. The results show potential antidepressant action quantitatively similar to that of imipramine and amitriptyline, but due rather to MAO inhibition than to imipramine-like activity; interestingly enough, anti-MAO activity was particularly selective for the serotonin-converting enzyme, both centrally and peripherally. The outcome of the other tests suggests that the incidence of untoward effects is likely to be limited.


On the interpretability of quantitative structure-activity relationships (QSAR). QSAR are a powerful tool to obtain information on the molecular mechanism of drug action as well as on properties of receptors. They can be evaluated at different levels of sophistication using different parameters to describe physical chemical properties of the drugs and different mathematical methods. In this presentation only QSAR at the level of extrathermodynamic parameters will be considered. Interpretation of QSAR is always connected with two basic questions: 1) Which requirements must be met in order to get meaningful (interpretable) QSAR and what can be done to satisfy these requirements? 2) What information can be gained (and in which way) from QSAR? Some of the most important aspects of these questions to be discussed in this paper are: 1) Interrelationships between parameters and the separability of hydrophobic, electronic and steric effects. 2) Description of hydrophobic interactions. 3) Separation of hydrophobic effects connected with transport and hydrophobic bonding. 4) Estimation of the biological point of attack. 5) Selection and informational content of biological response data. Factor analysis will be shown to be a useful data preprocessing step allowing one to systematize data and to recognize and to eliminate collinearities. Another multivariate method, principal component analysis, may be used to separate pharmacokinetic and pharmacodynamic effects.


QSAR in a series of muscarinic agents.

QSAR in a series of muscarinic agents. The results of a pharmacological investigation on a series of 3-substituted benzyltrimethylammonium salts possessing muscarinic activity are reported. Correlative analysis shows that the pharmacodynamic activity is a function of the hydrophobic-lipophilic and steric parameters associated with the substituents. In particular, it is revealed that a lipophilic pocket of limited size is present in the muscarinic receptor at an optimal distance from the electron--rich site with which the cationic termination interacts.