Simultaneous ribosomal resistance to trichodermin and anisomycin in Saccharomyces cerevisiae mutants. A spontaneous mutant of Saccharomyces cerevisiae resistant to trichodermin has been isolated. It displays cross resistance both in vivo and in vitro to a number of sesquiterpene antibiotics (fusarenon X, trichothecin and verrucarin A) and to the chemically unrelated antibiotic anisomycin. The mutation conferring resistance to anisomycin and trichodermin is expressed in the 60-S subunit of the yeast 80-S ribosome. Mutant ribosomes bind [-14C]trichodermin much less efficiently than wild type ribosomes, suggesting that resistance may be due, at least in part, to this property. However, both types of ribosomes bind [-3H] anisomycin equally. These results suggest that anisomycin and trichodermin have different binding sites on the 60-S subunit of eukaryotic ribosomes, even though previous results have shown that both antibiotics bind to mutually exclusive sites.


Ineffectiveness of rifampicin in inhibiting RNA synthesis in Escherichia coli and T(4)-infected Escherichia coli cells after exposure to ultraviolet radiation. Resdiual RNA synthesis in Escherichia coli cells and T(4)-infected E. coli cells exposed to ultraviolet radiation is insensitive to rifampicin. On the other hand, residual RNA synthesis in these cells after gamma irradiation is further inhibited by rifampicin. The specific effect exerted by ultraviolet irradiation on transcription seems to arise from alterations in the DNA structure rather than in bacterial RNA polymerase since RNA synthesis in ultraviolet-irradiated E. coli cells infected with unirradiated T(4) is sensitive to rifampicin.


Tertiary structure in E. coli tRNA Arg and tRNA Val. 300 MHz proton NMR has been used to demonstrate that both Escherichia coli tRNA Arg and tRNA(1) Val have a tertiary structure base pair between 4-thiouridine (s-4U) at position 8 and A at position 14. Formation of this s-4U(8)-A(14) base pair leads to a very low field (14.8 ppm) resonance in the spectra of both molecules. When s-4U is converted to U the 14.8 resonance is replaced by a new resonance which appears at 14.3 ppm. The presence of the tertiary structure s-4U(8)-A(14) base pair greatly constrains the folding of these tRNAs in solution.


A simple method for the preparation of large quantities of pure plasmid DNA. Polyethylene glycol quantitatively precipitates plasmid DNA of molecular weight 6-123-10-6, from cleared lysates of plasmid-carrying bacterial strains, After resuspension and density-gradient centrifugation of the precipitated DNA, it is unchanged in length and in transformation efficiency for Escherichia coli K12. Plasmid DNA can be easily prepared in large quantities by including a polyethylene glycol precipitation step in standard plasmid isolation procedures.


Studies of insulin release and rat pancreatic islet metabolism with diastereomers of D-glucose. Studies of insulin release with diastereomers and other analogues of D-glucose demonstrated that only sugars which undergo oxidation to CO2 stimulated insulin release by the pancreatic islet. None of the non-metabolizable diastereomers of glucose stimulated insulin release in the presence of a sub-stimulatory concentration of glucose for fuel. Although 5.5 mM glucose formed 77% as much CO2 as 16.7 mM mannose and twice that of 16.7 mM fructose, 5.5 mM glucose did not stimulate insulin release whereas 16.7 mM mannose and fructose did stimulate insulin release. These results indicate that the important stimulus for glucose-induced insulin release involves metabolism of glucose, but that the stimulus does not involve solely a fuel function of glucose.


The effect of p-aminosalicyclic acid on iron transport and assimilation in mycobacteria. p-Aminosalicylic acid inhibits growth of Mycobacterium bovis BCG and Mycobacterium smegmatis more effectively if cells are growing with a sufficiency of iron (more than 1 mu g Fe/ml) in the medium than if cells are deficient in iron (smaller than 0.1 mu g Fe/ml). In iron-deficient cultures formation of mycobactin, an ionophore for iron transport, is strongly inhibited by p-aminosalicylic acid. Uptake of iron into cell suspensions is also inhibited and the activity of several iron-containing enzymes declines in cells exposed to p-aminosalicylic acid during their growth. p-Aminosalicylic acid is about 50 times more effective towards a mutant of M. smegmatis which required mycobactin under iron-deficient growth conditions than towards the wild-type parent. p-Aminosalicylate is taken up into cells by an active process independent of the salicylate uptake system, possibly by the route used for assimilation of p-aminobenzoate. (This could account for why p-aminobenzoic acid, but not salicylic acid, antagonizes the action of p-aminosalicylic acid.) With iron-deficient cells, salicylate assimilation is about 50 times greater than either p-aminosalicylate or p-aminobenzoate but with iron-sufficient cells and with the mycobactin mutant salicylate uptake is negligible whereas p-aminobenzoate and p-aminosalicylate uptakes are unaffected. p-Aminosalicylic acid at 3.3 mM (500 mu g/ml) partially inhibits the uptake of both p-aminobenzoate and, if it is occurring, that of salicylate as well. As p-aminosalicylic acid is always more effective when the intracellular concentration of salicylic acid is low, it probably acts as an anti-metabolite of salicylic acid, not, however, by inhibiting the conversion of salicylic acid to mycobactin, but probably somewhere along the metabolic pathway of iron uptake.


Structure of the glycopeptide storage material in GM 1 gangliosidosis. Sequence determination with specific endo- and exoglycosidases. 1. An endo-beta-galactosidase from Escherichia freundii, specific for the hydrolysis of desulfated keratan sulfate, quantitatively liberated a trisaccharide (Gal-GlcNAc-Gal) from a glycopeptide (Mr 1800) isolated from the liver of a patient with GM 1 (generalized) gangliosidosis. 2. The remaining glycopeptide was susceptible to sequential digestion with purified beta-N-acetylhexosaminidase and exo-beta-galactosidase from Jack Bean meal. 3. These and other studies established the structure of the stored glycopeptide to be:(see article) which probably represents the desulfated linkage region of skeletal keratan sulfate.


The S-n-propyl analogue of S-adenosylmethionine. A special strain of Saccharomyces cerevisiae responded to a supplement of S-n-propyl-L-homocysteine in the culture medium by synthesizing S-adenosyl-(S-n-propyl)L-homocysteine, the S-n-propyl analogue of S-adenosylmethionine. S-n-Butyl-L-homocysteine reacted sparingly with this strain, but S-isopropyl-L-homocysteine failed to form detectable quantities of the corresponding S-adenosylsulfonium compound. The S-n-propyl compound was isolated by extraction of the cells, followed by ion-exchange chromatography, which separated it from endogenous S-adenosylmethionine. The structure was determined by hydrolytic procedures leading to overlapping fragments of known structure, 5'-n-propylthioadenosine and S-n-propyl-L-homocysteine. The new sulfonium compound was examined for its activity as n-propyl donor by substituting it for S-adenosylmethionine in methyltransferase systems. Enzymatic transpropylation was observed with S-adenosylmethionine : L-homocysteine S-methyltransferase (EC 2.1.1.10). Its rate was low in the S-adenosylmethionine : N-acetylserotonin O-methyltransferase system (EC 2.1.1.4), and below recognition with S-adenosylmethionine : guanidinoacetate methyltransferase (EC 2.1.1.2) and S-adenosylmethionine : histamine N-methyltransferase (EC 2.1.1.8).


Microheterogeneity in yeast invertase.

Microheterogeneity in yeast invertase. Yeast external invertase (EC 3.2.1.25), a glycoenzyme consisting of equal parts by weight of protein and mannan, has been found to contain covalently bound phosphate. Three preparations (from two yeast strains) had mannose/PO4 ratios of 31-35, equivalent to 24-27 PO4 residues per mol of enzyme, while a fourth had only 7 PO4 residues per mol. From one of the high-PO4 enzymes, approx. 69% of the phosphorus was recovered as mannose 6-phosphate. No correlation was found between invertase activity and phosphorus content. The PO4 contents of the invertases exceeded those of the cell wall mannans from the respective yeasts. Thus, contamination of the invertases by cell wall phosphomannan is unlikely. Electrofocusing of the low-PO4 invertase yielded four components with pI values from 3.96 to 4.40, and yeast internal invertase (a mannan- and PO4-free, cytoplasmic isozyme) was isoelectric at approx. pH 4.5. The high-PO4 invertase was considerably more heterogeneous, with two major species of pI 3.65 and 3.32 and a highly acidic component of pI smaller than 2.7; however, the mannose/PO4 ratio of each species was approximately the same. PO4-gradient elution from hydroxyapatite resolved the high-PO4 invertase into five isozymes of increasing acidity and mannan content. Since the mannose/PO4 ratios of these invertase species are constant, the increase in the mannan/protein (and, therefore PO4/protein ratio is apparently responsible for the microheterogeneity of phosphoinvertase.23


The primary structure of the ribosomal protein L29 from Escherichia coli. The amino acid sequence of ribosomal protein L29 was determined utilizing an improved Beckman sequenator, a solid phase peptide sequenator, and more conventional techniques. L29 is composed of 63 amino acid residues and has a molecular weight of 7262. It lacks proline, cysteine, isoleucine, tyrosine and tryptophan. The N-terminal and C-terminal regions (residues 1-9 and 50-63) are basic, while the rest of the molecule is hydrophobic and neutral. Calculated P-a values show two helical regions: one from residues 1 through 32 and the other from residues 37 through 47. No beta-sheet regions are predicted. Short identical regions occur within the sequence of L29 as well as between L29 and other ribosomal proteins.


Energy requirement for the initiation of colicin action in Escherichia coli. 1. Starved cells of a strain of Escherichia coli and its mutant uncA, treated with colicin K, E2 or E3, remained fully rescuable upon trypsin treatment (stage I in colicin action). The transition to stage II in colicin action (cells no longer rescuable by trypsin) was promoted by the addition of either glucose or D-lactate. 2. Aerobically glucose-grown cells of the normal strain were irreversibly killed by colicin K, E2 or E3 under anerobic conditions, while similarly treated cells ot its mutant uncA remained fully rescuable. The stage I-stage II transition in colicin action was blocked in normal cells under anaerobic conditions when succinate was the sole carbon source. 3. Arsenate alone had little effect on the progression of the stage I-stage II transition in normal cells, treated with colicin K. However, this transition was abolished in the presence of both arsenate and anaerobic conditions. 4. The initiation of colicin action could be coupled to the anaerobic electron transfer systems formate dehydrogenase-nitrate reductase and alpha-glycerophosphate dehydrogenase-fumarate reductase. 5. These results indicate that an energized state of the cytoplasmic membrane is required for the initiation of colicin action and that no high-energy phosphorylated compounds are necessary.


Substrate activity of phosphonic acid analogues of CDPdiglyceride in the synthesis of phosphoglycerides in Escherichia coli. Two phosphonic acid analogues of CDPdiglyceride, D L-2-hexadecoxy-3-octadecoxypropylphosphonyl-O-(cytidine 5'-phosphate) (analogue (I), and D L-3,4-dioctadecoxybutylphosphonyl-O-(cytidine 5'-phosphate) (analogue (II), have been synthesized and examined as substrates for the enzymes involved in the synthesis of phosphoglycerides in Escherichia coli. Both compounds were substrates for CDPdiglyceride:sn-glycerol-3-phosphate phosphatidyl transferase. The analogues had similar Km values (Km of 0.060 mM for analogue (II): Km of 0.080 mM for analogue (I) and a V identical to that of CDPdipalmitin (Km of 0.044 mM). In contrast, the analogues were poor substrates for CDPdiglyceride:L-serine phosphatidyl transferase. The analogues had lower Km values (Km of 0.40 mM for analogue (II); Km of 0.80 mM for analogue (I) than CDPdipalmitin (Km of 1.4 mM). The V, although identical for both analogues, was ten-fold lower than that observed with the natural substrate. An analysis of the products of these enzymatic reactions suggests that phosphatidylglycerophosphate phosphatase and phosphatidylserine decarboxylase may also possess a certain degree of substrate specificity.


Mitochondrial and cellular inhibition by the folate analogue pyrimethamine in Saccharomyces cerevisiae: reversal of cellular effects by TMP. The inhibitory effect of pyrimethamine on the growth of TMP-permeable strains of Saccharomyces cerevisiae in a fermentable medium supplemented with adenine, glycine, methionine and pantothenate was substantially reduced by exogenous TMP. This compound also suppressed the drug's killing effect, and to some extent its ability to induce the mitochondrial petite mutation. In a non-fermentable medium, TMP failed to reduce growth inhibition, in line with our earlier finding that as well as blocking synthesis pyrimethamine prevents mitochondrial protein synthesis.


Synthesis of heteropolyribonucleotides by toluene-treated Escherichia coli cells. Escherichia coli cells, made permeable to ribonucleoside-5'-diphosphates by treatment with toluene, efficiently promote the synthesis of homo- and heteropolynucleotides. This synthesis is catalyzed by polynucleotide phosphorylase because, among other things, it is inhibited by orthophosphate, and E. coli Q13, a mutant having a Mn-2+-dependent polynucleotide phosphorylase, promotes polynucleotide synthesis in the presence of Mn-2+ but not of Mg-2+. Cells of E. coli B and E. coli MRE 600 (A Mutant lacking ribonuclease I) are about equally active in promoting poly(A, U, G, C) synthesis. Sucrose density gradient and agarose gel electrophoretic analysis of the product show that it is polydisperse with sedimentation coefficients ranging between 4 S and 27 S. The synthesized polynucleotides can be translated by the toluene-treated cells.


Gene activation in human diploid cells. Age-dependent modifications in the stability of messenger RNAs for nonhistone chromosomal proteins. Serum stimulation of early as well as late passages of nondividing WI-38 human diploid fibroblasts to proliferate, results in DNA synthesis beginning at 12 hours and MITOSIS AT 20 HOURS. A 2-fold increase in the transcriptional activity of chromatin isolated from early and late passage W2-38 cells is evident one hour following serum stimulation. An increased synthesis and association with the genome of two defined molecular weight classes of nonhistone chromosomal proteins one hour following serum stimulation of early and late passage cells is also observed. The increased chromatin template activity and nonhistone chromosomal protein synthesis occur in early passage cells stimulated to proliferate in the presence of actinomycin D. However, when late passage WI-38 cells are stimulated in the presence of antinomycin D, increases in chromatin template activity and nonhistone chromosomal protein synthesis are not observed one hour following serum stimulation. The possibility that nonhistone chromosomal protein synthesis and activation of transcription early during the prereplicative phase of the cell cycle in early passage human diploid fibroblasts may be regulated at the translational level is discussed. Consideration is also given to the possibility that there may be an age-dependent modification in such a regulatory mechanism.


The effect of double-stranded cowpea mosaic viral RNA on protein synthesis. The effect of double-stranded cowpea mosaic viral RNA on several in vitro protein synthesizing systems was studied. No inhibitory effect of this RNA at concentrations up to 16 mug/ml was found in wheat germ protein synthesis programmed with cowpea mosaic viral-, alfalfa mosaic viral- or globin 9 S-RNA. At high concentrations of this double-stranded RNA, inhibition of Escherichia coli in vitro protein synthesis programmed with MS-2- and cowpea mosaic viral-RNA was found, whereas at low concentrations its inhibitory effect on rabbit reticulocyte in vitro protein synthesis was strong. The implications of these observations for the suggestions of other authors, based on the study of mammalian protein synthesizing systems, are discussed.


Stimulation of insulin release by thiols. The effects of thiol compounds on insulin release were studied in microdissected pancreatic islets of non-inbred ob/ob micemin control experiments the reactivity of thiols against 6,6'-dithiodinicotinic acid and the degradation of mouse insulin were measured. At a concentration of 0.1 mM, 1-thio-D-glucose or reduced glutathione potentiated the insulin-releasing action of 10 mM D-glucose without affecting glucose oxidation. When tested at a concentration equivalent to about 0.1 mM reactive thiol, dextran-linked L-cysteine also potentiated the glucose-induced insulin secretion. In microperifusion experiments the insulin-releasing action of 1-thio-D-glucose was found to exhibit a rapid onset followed by a decline of the secretory rate to values lower than those observed with 10 mMD-glucose alone. No thiol stimulated insulin release in the absence of glucose. It is suggested that thiol compounds stimulate insulin release by splitting membrane disulphides in the beta-cells.


Stereoselective reduction of cobalt(III) complexes by bacteria. A strain of Enterobacter cloacae, isolated from soil, reduces racemic abdtriglycinatocobalt(III), triglycinatocobalt(III), stereoselectively under anaerobic conditions; Washed suspensions oc cells, grown anaerobically in the absence of triglycinatocobalt(III) initially reduce the L-enantiomer stereospecifically under argon yielding a labile Co(II) chelate. An approximately 5-fold increase in the rate of reduction of the complex occurs using cells disrupted by 2-phenylethanol; decomposition now proceeds with a slight preference for the D-enantiomermreduction of triglycinatocobalt(III) under argon by cell-free extracts, prepared by sonication, exhibits similar stereoselectivities to cells disrupted by 2-phenylethanolmhowever, extracts contain a factor capable of reducing D-triglycinatocobalt(III) with high stereoselectivity under molecular hydrogenmthe behaviour of Enterobacter cloacae is compared with that of Aerobacter aerogenes, Proteus vulgaris, Escherichia anaerogenes and Serratia marcescensmstereoselective effects are also observed in the bacterial reduction of other cobalt(III) complexes.


Mode of action of the cloacin DF13-immunity protein. 1. Cells of Enterobacter cloacae harbouring the bacteriocinogenic factor Clo DF13 produce an immunity protein which inbhbits the in vitro activity of cloacin DF13. The amino acid composition of purified immunity protein was determined. 2. Experiments about the protection of ribosomes against cloacin DF13 in the presence of the immunity protein show that one molecule of immunity protein neutralized the activity of one molecule cloacin. 3. Direct and specific interaction of cloacin DF13 with the immunity protein has been demonstrated by the analysis of mixtures of both proteins on polyacrylamide gels and by changes in the fluorescence response of cloacin DF13-bound 1-anilinonaphthalene-8-sulfonate in the presence of immunity protein.


Preparation, properties and biological activities of succinyl derivatives of vitamin B12. Three new derivatives of vitamin B12,0-2'-succinyl-, 0-5'-succinyl-, and 0-2', 0-5'-disuccinyl-vitamin B12, whose alpha-ribose moieties of the nucleotide ligand are succinylated, were prepared by reaction of the vitamin with succinic anhydride. The first succinylation took place rapidly and almost predominantly on 5'-OH of alpha-ribose, and the second succinylation much more slowly on 2'-OH. From the behaviors in paper electrophoresis and the lability to CH- of cobalt-base bond of 0-2'-succinylated vitamin B12 derivatives, it was suggested that the terminal COOH of the 0-2'-succinyl group forms an inner salt with the imidazole nucleus of 5,6-dimethylbenzimidazole. Monosuccinyland disuccinyl-vitamin B12 by mild acid or base hydrolysis. Heating at 130 degrees for 5 min also led to the complete severance of the succinyl group of 0-5'-succinyl-vitamin B12. None of the three succinly derivatives inhibited the diol dehydrase reaction when added with coenzyme B12, SUggesting that the ability to bind to the apoenzyme is strongly diminished or almost lost by succinylation on 2'- or 5'-OH of alpha-ribose. None of the succinyl vitamin B12 compounds showed either biological activity or anti-vitamin B12 activity when tested with Escherichia coli 215, a methionine-B12 auxotroph. None of them significantly inhibited [3-H] vitamin B12 uptake by E. coli 215 cells. This observation implies that succinyl derivatives of vitamin B12 are hardly incorporated into the cells of E. coli.


Cardiac output measurement by indicator dilution. The measurement of cardiac output by the indicator dilution method is reviewed. Theoretical and practical problems relating to the direct and indirect Fick methods and the continuous and bolus injection methods are considered in detail. Choice of indicator is also discussed. Problems remain with all of these methods, but reasonable accuracy and consistency may be achieved if attention is paid to detail.


Nerve excitability--toward an integrating concept. Although numerous experimental data have been accumulated in the various fields of research on bioelectricity, the mechanism of nerve excitability is still an unsolved problem. Many mechanistic interpretations of nerve behavior cover only a part of the facts, are thus selective and unsatisfactory. An attempt at an integral interpretation of basic data well-established by electrophysiological, biochemical, and biophysical investigations was inspired by the late Aharon Katchalsky and a first attempt had been made previously (Neumann et al., 1973). The present account is a further step toward a quantitative physiochemical theory of bioelectricity. We have further explored the previously introduced notion of a basic excitation unit in excitable membranes. This notion is of fundamental importance for modeling details of sub- and suprathreshold responses, such as threshold behavior and strength-duration curves, in terms of kinetic parameters for specific membrane processes. Our integral model of excitability is based on the original chemical hypothesis for the control of bioelectricity (Nachmansohn, 1959, 1971b). This specific approach includes some frequently ignored experimental facts on acetylcholine-processing proteins in excitable membranes. According to the integral model, acetylcholine ions are continuously processed through the basic excitation units within excitable membranes: axonal, presynaptic, and postsynaptic parts. Excitability, i.e., the generation and propagation of nerve impulses, is due to a cooperative increase in the rate of AcCh translocation through the cholinergic control system.


Anomalous sedimentation behaviour of the E.coli ribosomal system: 50S-30S forms 50S PLUS 30S. An experimenal and theoretical study has been made into the effect of association-dissociation reactions on the sedimentation of the E.coli ribosomal 50S-30S forms 50S plus 30S. It has been found that (a) the sedimentation pattern is strongly dependent on the rotor speed: (b) the ratio of components as measured using high-speed ultracentrifugation (30000-40000 r.p.m.) is independent of rotor speed; and (c) the speed of ultracentrifugation has a strong effect on the sedimentation coefficeint of the ribosomal system as determined by the mean square second moment. The results of this paper demonstrate that ribosome sedimentation at low-speed ultracentrifugation is affected by some artefactual processes. A theoretical analysis of the experimental findings has shown that the observed effects cannot be attributed to the effect of the association-dissociation reaction nor to the pressure dependence of the equilibrium constant of that reaction. On the other hand, at high-speed ultracentrifugation the ribosomal system sediments as a heterogeneous mixture of non-interacting components. Consequently, the shape of the boundary in this case will reflect the equilibrium composition of the ribosomal system.


High pressure effects on the activity of glycolytic enzymes. High hydrostatic pressure inhibits growth in most organisms; this may be explained by a deactivation of enzymes involved in essential metabolic pathways. In order to check this hypothesis the enzymic activity of rabbit muscle lactic dehydrogenase and yeast glyceraldehyde-3-phosphate dehydrogenase was investigated in the presence of the coenzyme and excess of substrate at pressures up to 2kbar. Kinetic analysis of an initial phase of pressure induced activation and of a second phase of reversible deactivation shows that the two enzymes respond to high pressures in different ways leading to a volume of activation of increment V is not equal to (LDH) equal 0 plus or minus 1 cm-3 mol-1 and increment V is not equal to (GAPDH) equals 60 plus or minus 4 cm-3 mol-1, respectively. Comparing the lower limits of pressure deactivation, LDH is found to be more stable towards pressure than GAPDH. At p is approximately equal to 2 kbar total deactivation of both enzymes is observed. A concentration dependent lag of GAPDH reactivation proves dissocation to participate in the process of deactivation, while the effects for LDH are explicable on the basis of reversible denaturation alone.


Defective mononuclear leukocyte chemotaxis in the Chediak-Higashi syndrome of humans, mink, and cattle. Chemotaxis of mononuclear leukocytes from humans, mink, and cattle was evaluated in vitro using a morphologic Boyden chamber technique and a new 51-Cr-labeled mononuclear radioassay with a double micropore filter system. Significantly decreased mononuclear leukocyte chemotactic response were noted when human, mink, or cattle Chediak-Higashi cells were tested using autologous serum or endotoxin-activated autolotous serum. A similar Chediak-Higashi mononuclear leukocyte defect was noted in humans when kallikrein or dialyzable transfer factor were used as the chemotactic stimulus. Studies using smaller pore filters in the chemotactic chamber exaggerated the chemotactic defect. Serum from Chediak-Higashi subjects had normal chemotactic activity. Additional studies on the spontaneous (random) locomotion of Chediak-Higashi mononuclear leukocytes revealed normal results when a capillary tube assay system was used, but abnormal results were obtained when a Boyden chamber micropore filter assay was used, demonstrating fundamental differences in these two assays of random locomotion. It is clear from these studies that defective mononuclear leukocyte chemotaxis is another feature of the imparied host defenses in the Chediak-Higashi syndrome that may contribute to the marked susceptibility to pyogenic infections so characteristic of this dease.


Further experience with lateral wedge resection mammaplasties. The lateral wedge resection method of reduction mammaplasty results in breasts with a single oblique radial scar in the outer quadrant, good contour, the nipples with sensation, erectile capacity and forward projection. It is suitable for cases of moderate enlargement and for ptotic breasts.


Relay transplantation: a new method of expanding a free skin graft. A method of skin transplantation is presented whereby a wound may be successively sown with epithelium by the repeated transfer of the same strips of split thickness skin.


The back tube pedicle in head and neck reconstruction. The use of a back tube pedicle in 19 patients, presenting for reconstruction of defects in the head and neck region, is shown and aspects of surgical technique discussed. In general, satisfactory results were achieved and it is recommended that the back should be considered more often as a donor site when the more convenient deltopectoral flap is not available, not desirable.


Somersault flap for reconstruction of the helix. An original technique for reconstruction of the helix has been successfully applied. Posterior auricular skin ia attached to the medical aspect of the helical rim, then somersaulted laterally into position, recreating the helical curl.


Lip-plug carcinoma and its management by modified Abbe flap. From Tanzania 2 cases are reported, and reference made to a third, of carcinoma arising in the upper lip in relation to a lip-plug, a traditional wooden adornment worm within an orifice in the tissues of the upper lip. Mangement was by excision and repair with a modified Abbe flap.


Lithium in non-manic-depressives: antiaggressive effect and red blood cell lithium values. Lithium was given to eight aggressive, non-manic-depressive female defectives in a doubleblind placebo-controlled study. The group as a whole showed a reduction in aggression scores while on lithium (p greater than 0.01): three patients became less aggressive,one became worse and two were unchanged. Both affective and predatory aggression seemed to be reduced. Two patients had to be withdrawn from the trial at an early stage because of the development of neurotoxicity.


The lesion in stereotactic suscaudate tractotomy. The anatomical distribution of 25 stereotactic tractotomy lesions is described. The posterior half of these lesions lie in a subcaudate position and the anterior half, for the most part, lies beneath the central segment of frontal white matter.


Mathematical method to utilize a computer for diagnosis of site and type of intracerebral mass lesions. A mathematical process has been devised which can utilize full clinical data of symptoms and signs, neuroradiological procedures, EEG and isotope scanning to predict the site and pathological process in a patient presenting with disturbance of central nervous system function. The work is a further expansion and modification of the computer program described by Du Boulay and Price (1968).


Movement of criticall ill patients within hospital. Critically ill patients were observed during routine movement inside the hospital to and from the intensive therapy unit. One patient a month suffered major cardiorespiratory collapse or death as a direct result of movement. Renewed bleeding of a pelvic fracture, cardiac arrhythmia, cardiac embarrassment due to a haemothorax, and cardiovascular decompensation were seen. It was difficult to continue treatment during movement, especially maintaining an airway or providing adequate intermittent positive pressure ventilation. Seventy postoperative patients suffered few ill effects on being moved. Greater awareness of the dangers of moving critically ill patients within hospital is needed. Thorough preparation for the move and adequate maintenance of treatment during movement requires the skill of experienced medical staff.


Untoward effects associated with practolol: demonstration of antibody binding to epithelial tissue. An antibody which sticks to the intercellular region of xenogenic epidermal tissue has been shown by indirect immunofluorescence to be present in the serum of patients with practolol-induced eye damage. These antibodies and those found in patients with pemphigus were compared for their ability to bind to isolated epidermal cells. Binding was achieved only with the pemphigus antibody, which suggests that it may have a different specificity from the antibody associated with practolol-induced eye damage.


Prolactin studies in "functionless" pituitary tumours. Hyperprolactinaemia was found in all 17 women and in one out of six men who presented with hypogonadism and a radiologically enlarged sella turcica but no other clinical endocrine dysfunction. Some of the women also had galactorrhoea. The greater the level of hyperprolactinaemia in these 18 patients the larger their sellae turcica except in two patients with unusual features. The sella turcica was usually asymmetrically enlarged and there was rearly an upward extension of tumour, though the sella floor often showed some erosion on tomography. An oral dose of bromocriptine suppressed the hyperprolactinaemia in mose patients at the same rate as in normal post-partum women. Nine of the 18 patients with hyperprolactinaemia had low basal luteinizing hormone (LH) levels. The LH responsiveness to 100 mug of LH-releasing hormone (LHRH) was tested in 12, and eight showed subnormal values. Of eight biopsy specimens obtained four showed acidophil granules on light microscopy, and in five granules of various sizes were seen on electron microscopy.


Prophylaxis of postoperative leg vine thrombosis by low dose subcutaneous heparin or peroperative calf muscle stimulation: a controlled clinical trial. In a randomized, controlled clinical trial of two methods of preventing postoperative leg vein thrombosis patients undergoing major surgery were divided into three groups. One received intermittent electrical calf muscle stimulation during surgery, the second subcutaneous heparin calcium 5000 IU every eight hours for six days, and the third no specific prophylaxis. Leg vein thrombosis was detected by the 125-I-fibrinogen uptake test. Neither method was effective in patients undergoing open bladder or prostatic surgery. Stimulation did not reduce the incidence of leg vein thrombosis in patients with malignant disease undergoing laparotomy, but heparin calcium was highly successful in this group (P smaller than 0-001). When the laparotomy was for a benign condition, however, both heparin calcium (P smaller than 0-001) and stimulation (P smaller than 0-01) were effective.


New serological test for malaria antibodies. In an enzyme-linked immunosorbent assay test for malaria antibodies, antibodies to Plasmodium vivax and P. falciparum in man are detected using a crude antigen prepared from the simian malaria parasite P. knowlesi. The test may be suitable for epidemiological studies.


Dextran 70 in prophylaxis of thromboembolic disease after surgery: a clinically oriented randomized double-blind trial. A randomized double-blind trial of prophylaxis of thromboembolism in surgical patients judged by clinical morbidity has been completed. Altogether 831 patients over 40 years of age who underwent elective surgery of the stomach, biliary system, or colon received either dextran 70 or normal saline before the operation. Thirteen of the 435 patients on saline and three of the 396 on dextran developed pulmonary embolism. Eight of these 16 patients died of pulmonary embolism--seven in the saline group and one in the dextran group. As detected either clinically or by 125I-fibrinogen scanning the incidence of deep vein thrombosis was similar in the two groups. There was no increased incidence of excessive bleeding in patients on dextran though clinical impression suggested that some patients on dextran bled excessively. This trial showed that dextran 70 administered by intravenous drip during operation is effective in preventing pulmonary embolism and, in particular, reducing mortality from this cause. It seems to be as effective as subcutaneous heparin but is easier to administer and places less of a burden on nursing services.


Comparison of two methods of administering bronchodilator aerosol to asthmatic patients. In 78 patients with chronic asthma the increase in forced expiratory volume in one second (FEV-1) after the administration by intermittent positive-pressure ventilation (I.P.P.V.) of 10 mg of salbutamol was compared with that recorded after the inhalation of a conventional dose (200 mug) from a pressurized canister. The mean increase was significantly greater after I.P.P.V. administration, and the superiority of this method was greatest in patients with the lowest pretreatment FEV-1.


Treponema pallidum in nerve fibres.

Treponema pallidum in nerve fibres. Ultrathin sections of a rabbit scrotal syphiloma were examined by electron microscopy. Treponemes were observed in the endo-, peri-, and epineurium of the nerve fibre. The significance of these findings, in that infection may be transmitted via the nerve fibres and pain reduced by damage to the afferent fibres, are discussed.


Pharmacokinetics of tinidazole and metronidazole in women after single large oral doses. Serum concentrations of tinidazole and metronidazole have been measured in healthy female volunteers who received a single dose of 2 g. of each drug in a cross-over study. Bioassays against T. vaginalis showed that metronidazole achieved higher peak concentrations (mean 81 mug./ml.) than did tinidazole (mean 67 mug./ml.), while assays for unchanged drug showed higher peak concentrations of tinidazole )mean 51 mug./ml;) than of metronidazole (mean 40 mug./ml9). This discrepancy is probably due to the presence in the serum of active metabolites of metronidazole. The longer half-life of tinidazole led to significantly higher serum concentrations (by bioassay and chemical assay) of tinidazole than of metronidazole from 6 hrs onwards.


Trichomonal vaginitis. A 24-hr regimen of nimorazole compared with a 7-day regimen of metronidazole. A 24-hr regimen of nimorazole (1 g. orally at 12-hrly intervals for three doses) was compared with metronidazole (200 mg. three times daily for 7 days) in the treatment of trichomonal vaginitis. The two treatment schedules were given to alternate patients, pregnant women being excluded. One hundred cases were treated on each schedule; roughly one-fifth of the patients in each group defaulted. There were no observed failures with either schedule. The reasons for these exceptionally good results are discussed.


Radiological changes in controlled hypervolaemic pulmonary oedema in dogs. Chest radiographs taken under ideal conditions and reviewed by a radiologist experienced in looking for pulmonary oedema are an accurate technique for detecting early oedema, differentiating between congestion and oedema, monitoring the increases in oedema up to the stage of alveolar flooding and in determining the effects of CPPV on an oedematous lung. However, ideal conditions do not exist in the I.C.U. Our radiologist had the advantage of a fast exposure, a normal film for comparison in the sequence and only one lesion, conditions unlikely to occur in the I.C.U. It becomes apparent that it is important to obtain the best possible image in these complicated patients. Films in the erect position, for vascular distribution, as well as fast exposures with a high MAS factor give the sharp detail required to best assess lung changes. Serial studies of the chest are a requirement of the I.C.U. patient and it is helpful if comparable films are obtained by using a fixed target-to-film distance in association with the short exposure factors. If this care is taken, chest radiographs are the most accurate non-invasive technique for detecting pulmonary oedema.


Coupling of glycine and alanine transport to respiration in cells of Escherichia coli. Energy coupling for uptake of glycine and alanine in glycerol grown cells of Escherichia coli differs from that of the aromatic amino acids. Respiration and uptake of glycine and alanine show similar inactivations in cells exposed to high intensity violet light or to various concentrations of cyanide. In contrast,uptake of phenylalanine, tyrosine, and tryptophan is resistant to effects of light or cyanide. Anoxia largely inhibits uptake of glycine and alanine while that of the aromatic amino acids is only partially affected. Furthermore, ferricyanide (but not ferrocyanide) completely restores active uptake of aromatic amino acids under anoxic conditions but is without effect on glycine and alanine uptake. Adenosine 5'-triphosphate (ATP) concentration does not increase in anoxic cells exposed to ferricyanide, indicating that ATP cannot be responsible for this restoration. The data suggest that glycine and alanine represent amino acids whose transport shows a complete dependence on energy derived from respiration, while the energy for transport of the aromatic amino acids may be obtained from other sources


Chemical modification of ribosomes with dimethyl sulfate: a probe to the structural organization of ribosomal proteins and RNA. Ribosomal proteins from [14-C]dimethyl sulfate treated with 30S and 50S subunits of Escherichia coli ribosomes were separated by two-dimensional polyacrylamide gel electrophoresis and the degree of methylation of each protein was determined. Comparison of the results from this relatively non-specific chemical modification procedure with results from the milerd lysine-specific reductive alkylation procedure reported previously (Moore, G. & Crichton, R.R. (1974) Biochem. J. 143, 607-612) has permitted a topographical classification of ribosomal proteins in terms of 'degree of exposure' in the 30S and 50S subunits. The reaction of dimethyl sulfate with ribosomal RNA, both in intact subunits and after isolation from the subunits, has indicated that approximately half of the RNA in 30S and 50S subunits is exposed on the surface of the ribonucleoprotein complexes, and that no large sections (extended sequences) of 16S RNA are concealed in the 30S subunit. It is proposed that modification of ribosomes with dimethyl sulfate is a potentially useful technique for probing exposed and hidden regions and also exposed single-stranded regions of RNA in ribosomes.


Acute undifferentiated neonatal diarrhea in beef calves. I. Occurence and distribution of infectious agents. Beef calves in a 48-cow herd were studied during one calving season from birth to ten days of age to determine the presence or absence of potentially enteropathogenic bacteria, viruses, and/or chlamydia in both normal and diarrheic calves. Calves were born and raised outside in large pens unless the ambient temperature was below minus 10 degrees F when calving was done inside. Fecal swabs, fecal aliquots, and nasal swabs were taken from each calf at 32, 128 plus or minus 3, and 248 plus or minus 3 hours of age and as soon after the onset of diarrhea as possible. Diarrhea was defined as that condition in which the feces contained less than 10% dry matter. Enteropathogenic Escherichia coli in feces were identified using the ligated gut loop procedure in calves and by feeding broth cultures to colostrum fed lambs seven to 16 hours old. Potentially enteropathogenic viruses were detected using a variety of methods which included tissue culture, fluorescent antibody, hemadsorption, and electron microscope techniques. Of the 40 calves studied, 32 (80%) developed diarrhea before ten days of age. Twenty-two strains of Escherichia coli which caused dilation of calf ligated intestinal loops were isolated from 11 scouring calves and from one normal calf. Nine out of ten strains of Escherichia coli which dilated ligated loops also caused diarrhea when fed to colostrum-fed lambs seven to 16 hours old. Using antibody technique a Reo-like virus was detected in the feces of 15 calves before, during, and after the onset of diarrhea. Four calves excreted both loop dilating strains of E. coli and Reo-like virus in the feces before ten days of age; in all cases the loop dilating E. coli were isolated from the feces prior to the demonstration of Reo-like virus. A Corona-like virus was also demonstrated in three of the 15 calves infected with Reo-like virus and a noncytopathogenic strain of bovine virus diarrhea virus was isolated from two of the 15 calves infected with Reo-like virus. A loop dilating strain of Citrobacter was isolated from one diarrheic calf. There was no consistent pattern of onset or duration of diarrhea in calves which excreted different infectious agents. Salmonella species, infectious bovine rhinotracheitis virus, parvovirus, adenoviruses, parainfluenza-3 virus, and Chlamydia species could not be demonstrated in any of the calves or their dams. No potentially enteropathogenic agents could be demonstrated in 11 of the 32 calves which scoured. These findings emphasize the complexity of the infectious aspect of the neonatal diarrhea syndrome and illustrate the difficulty in making an etiological diagnosis in field outbreaks of the calf scours complex.


Histochemical localization of hydrolytic enzymes during corneal graft reaction. We studied hydrolytic enzymes in the graft bed during the corneal graft reaction. Two enzymes, beta-glucuronidase and acid phosphatase, were used as the markers of lysosomal hydrolytic enzymes. These were traced histochemically at various times before and after the onset of the graft reaction in a corneal xenograft model. Results showed a relationship between the degree of graft opacity, cellular infiltration and enzyme localization.  It appeared that during the early stages of graft reaction, the granulocytes, and during the late stages, the agranulocytes were the main source of the enzymes.


Lethality of Candida strains as influenced by the host. A comparative study of the pathogenicity of Candida albicans morphological mutant strains was made to relate chlamydospore production, germ tube formation, and proteolytic activity to candidiasis in mice. It was observed that the mycelium strains were more lethal than the yeast-like strains and that neither chlamydospore production, germ tube formation, nor nutritional resquirements was related to pathogenicity in mice. Statistical analysis indicated that the culture media of the organisms and the strain and sex of the mice into which the cells were injected were important in the development of pathogenicity.


Determination of guanine plus cytosine content in Streptococcus pyogenes. The guanine and cytosine content of Streptococcus pyogenes DNA was determined by thermal denaturation and buoyant density analysis to be 36.7% and 38.7%, respectively.


Two modifications making membrane filtration more economical. Two economical membrane filtration techniques are described: (1) vacuum filtration through a single funnel into several sterile containers and (2) pressure filtration using an inexpensive combination of pressure source, vessel, and valve.


Surgery for coronary artery disease and congestive heart failure. A group of 41 patients presenting primarily with symptoms of congestive heart failure was investigated by coronary arteriography and myocardial revascularization. Of these patients 20 underwent resection of left ventricular aneurysm or left ventricular plication as well as revascularization. Revascularization plus resection of left ventricular aneurysm gives gratifying results, but revascularization in the presence of severe generalized hypokinesis is less satisfactory; however, the improvement in clinical condition in a sufficient number of patients is such that this approach to their management is justified. Accordingly, every patient with coronary artery disease and congestive heart failure should be investigated by angiography. Numerous factors influence the results of revascularization for the relief of congestive heart failure; the most useful as a criterion to aid patient selection is left ventriculography. In this group of 41 patients 66% were helped by myocardial revascularization.


Prophylactic antibiotic therapy in surgery. Prophylactic (preventive) antibiotic therapy initiated preoperatively, with antibiotics administered in moderately high dosage for short periods, is recommended on the basis of experimental and prospective, randomized clinical trials for patients who require surgery that is likely to expose tissue planes to contamination. The value of prophylactic antibiotics in clean operations is not presently supported but must be considered in patients with decreased resistance and in those in whom infection of a prosthesis would have catastrophic results. In these patients topical antibiotics might prove useful and less dangerous. It is clear that surgical technique remains an important but as yet unmeasured factor in wound infection.


Host defence mechanisms: evaluation and roles of acquired defects and immunotherapy. The development of an infectious process is a result of the interaction of the three determinants of infection: the infecting organism, the local site of infection and systemic host defences. Interaction of the various components is important in an understanding of the development of sepsis. Acquired defects of host defence mechanisms are attributable to a variety of factors and can be both the cause and the result of sepsis. The burn injury illustrates alterations in host defence and the interaction of the determinants of sepsis. Methods of evaluating the components of host defence are available, though sometimes difficult; in the future, evaluation of the effect of one component on another will become clinically feasible, allowing more complete assessment of acquired defects. Immunotherapy is not yet widely available; however, definition of the acquired defects of host defence mechanisms in surgical patients may eventually lead to introduction of effective treatment.


Results of minor foot amputations for ischemia of the lower extremity in diabetics and nondiabetics. Results of 208 minor amputations were analyzed in 179 patients who had no food pulses. Wound healing was assessed at 3 months in relation to diabetes and previous vascular surgery. The results suggest that simple removal of the toe or toes is not advisable unless the blood supply to the foot can be improved by vascular reconstruction or sympathectomy, or both. Transmetatarsal amputation should be considered more often as a conservative amputation for gangrene of the toes. The absence of a palpable posterior tibial pulse is a contraindication to the Syme's amputation.


The role of fomites in the transmission of vaginitis. A role for fomites such as toilet seats in the transmission of vaginitis has never been proved or disproved. A compilation of clinical data from a university community showed that the organisms found in vaginal cultures of patients with vaginitis were, in order of frequency. Candida albicans, Escherichia coli, beta-hemolytic streptococci, Hemophilus vaginalis and Trichomonas vaginalis. In a concurrent bacteriologic survey of washroom fixtures, staphylococci and other micrococci were isolated most frequently. The overt pathogens associated with vaginitis were never found, and gram-negative organisms appeared to be suppressed by the disinfectant used by the cleaning staff. It is clear that fomites are not an important mode of transmission in vaginitis, although a search for specific pathogens on toilets is to be continued.


Diseases associated with specific HL-A antigens. Significantly increased prevalences of particular HL-A antigens have been reported for many human diseases. The correlation is particularly striking in ankylosing spondylitis, Reiter's syndrome, psoriasis and some immunopathic disorders, so that HL-A typing may be of great value in diagnosis. The possible mechanisms whereby these associations may occur suggest the cause of certain disorders, and further investiatation will likely help in the understanding of the pathogenesis of many diseases.


Psychogenesis and somatogenesis of common symptoms. There are situations in clinical practice in which the physican should keep in mind the influence of emotional factors in the elaboration of symptoms and yet should not conclude hastily that "all is in the patient's mind". Symptoms are often the result of complex etiologic factors including life-threatening illnesses presenting psychologic symptoms as an early manifestation. Psychologic disorders and physical illnesses with similar symptoms may coexist in the same patient. There are also cases in which the symptoms are the result of the constant interaction of psychologic and physical factors. Some suggestions to help to clarify the diagnosis are given and a classification of the different clinical situations involved is presented. Becuase physicians should be constantly aware of the complexity of the factors involved in the elaboration of obscure symptoms, some recommendations are given in regard to undergraduate and graduate medical education.


Human blood-group MN and precursor specificities: structural and biological aspects. The human blood-group MM and NN antigens carry 2 to 4 immunodominant groupings per repeating subunit and differ only by one sialic acid residue per immunodominant group. This residue covers in the MM antigen the beta-D-galactopyranosyl group that is terminal in the N immunodominant structure and that, together with a terminal alpha-linked N-acetylneuraminic acid residue, is responsible for N specificity. M specificity was readily converted into N specificity by mild acid treatment. N structure is the immediate biochemical precursor of M structure, and M and N antigenic specificities are not determined by two allelic genes as believed hitherto. The NN antigen was inactivated by beta-D-galactosidase as well as by removal of N-acetylneuraminic acid. Some of the reactivities of the NN antigen, lost upon beta-D-galactosidase treatment, reappeared on subsequent partial N-acetylneuraminic acid removal. The structure uncovered by complete sialic acid depletion of MN antigens is the Thomsen-Friedenreich T antigen, the specificity of which is determined by beta-D-galactopyranosyl groups. Beta-D-Galactosidase treatment transformed the T antigen into one possessing Tnactivity. The significance of blood-group MN active substances extends to human breast cancer, where MN antigens were found in benign and malignant glands, but some of their precursors in cancerous tissue only.


Lymphocyte: erythrocyte (L.E.) rosettes as indicators of the heterogeneity of lymphocytes in a variety of mammalian species. Lymphocytes and red cells from various mammalian species have been mixed in vitro in conditions which favor their aggregation in the form of rosettes. The frequencies of rosette formation taken in conjunction with observations on surface bound immunoglobulin on the lymphocytes favor the interpretation that, in many species of animal, rosette formation can be used as an indicator of the thymic (T) or bursal equivalent (B) origin of lymphocytes.


The general affinity of lac repressor for E. coli DNA: implications for gene regulation in procaryotes and eucaryotes. By equilibrium competition experiments, the dissociation constant (K(RD)) of lac repressor for E. coli DNA carrying a deletion of the lac operon was measured at a variety of salt concentrations. These data are used in the consideration of several aspects of protein-DNA interaction: Quantitative estimates of specificity are made. Specificity changes only slightly with salt concentration. We calculate that in vivo, 98 percent or more of repressor is bound to DNA predominately at sites other than the lac operator. Inducers shift repressor from operator to nonoperator DNA, but do not free it from DNA. The general affinity of repressor for E. coli DNA is sufficient to support a model where repressor slides along DNA for significant distances. The effective dissociation constant of repressor for operator (K(eff)) is very sensitive to the total DNA concentration. We propose that "junk" DNA in eucaryotes functions to maintain total DNA at an optimum concentration. We consider the lac operon in the nucleus of a lymphocyte, point out that severe difficulties would be encountered, and suggest possible solutions.


Thy 1 (theta) antigen on the surface of morphologically distinct brain cell types. Surface cultures of 15-19 day old fetal mouse brain that do not initially express the Thy 1 antigen develop the antigen between 4 and 11 days in culture. The antigen can be detected by immunofluorescence of live cells on the culture plate on two morphologically distinct types of cells. Both neuronal-looking cells and a more general category of cells which includes fibroblastic cells can express the Thy 1 antigen. The antigen is not expressed on certain cells of the glial type. This method enables one to distinguish between different types of brain cells in culture both morphologically and immunologically at the same time.


Physical Factors in Denture Retention.

Physical Factors in Denture Retention. AAThis investigation was carried out to analyze the physical factors of saliva affecting denture retention. A model of examining denture retention is given by two parallel disks separated by a liquid layer. Metal, polyisobutylene (PIB) and poly (methyl methacrylate)(PMMA) were used instead of a denture and mucous membrane; and glycerol, olive oil and castor oil instead of saliva. The experiments were performed with three disk conditions: (1) Both upper and lower disks of metal, (2) both upper and lower disks of PMMA, (3) upper disk with PIB lining and lower of PMMA soley. A strain gauge was used in the experimental apparatus in order to obtain a measurement of high accuracy. In the experiments, the retentive forces developed in layers of 50 mu tickness were measured and compared with the values calculated from theoretical equations. The results are summarized as follows: (1)Retentive force must be resolved into static adhesive and separating forces, (2) surface tension of liquid may not highly influence the retention, and (3) viscosity of liquid plays an important role when two disks are separated.


Reticulosarcoma occurring during long-term hemodialysis. Reticulosarcoma occuring during long-term hemodialysis. A case of chronic renal failure due to polycystic disease of the kidneys with development of a reticulosarcoma with cerebral involvement during maintenance hemodialysis is described. Immunosuppression from uremia could have played an important part in tumor induction in this case and might also be a significant factor in the high incidence of de-novo malignancies in renal transplant recipients.


Endotoxinemia in renal transplant recipients. Endotoxinemia in renal transplant recipients. In immunosuppressed renal transplant recipients a high incidence of endotoxinemia was found during chest or urinary tract infections. Although the endotoxinemia was protracted, indicating inability to eradicate the infection, yet in general the effects were benign and adverse renal damage was not seen. The Limulus gelation test has a positive contribution to make in the diagnosis of illness in transplant recipients.


A new approach to total hip replacement without osteotomy of the greater trochanter. To be able to perform total hip replacement without osteotomy of the greater trochanter has specific advantages including reduced operating time, reduced blood loss and shorter rehabilitation time. However, the exposure is less wide than when the greater trochanter is osteotomized and likelihood of technical error is increased. A new approach is presented, involving complete capsulectomy without osteotomy of the greater trochanter, which provides wide exposure of the acetabulum and of the femoral neck. It permits total hip replacement to be done without osteotomy of the greater trochanter with satisfactory exposure in many instances. Specific contraindications against the use of this approach are those circumstances which require shortening of the limb, cases with severe distortion of the anatomy, cases of severe protrusio acetabulum and cases with marked scarring from previous surgery.


The present status of the problem of pes cavus. Notable historical aspects relating to the etiology and treatment of pes cavus have been critically examined. The characteristic features of the deformity are described and an explanation offered for the mechanism of their production. Although its etiology remains uncertain, a study of the literature and a great deal of clinical material has established certain well supported conclusions regarding the etiology and pathology of the condition. Certain aspects of cerebral palsy serve to strengthen impressions of earlier authors that the primary center of origin of pes cavus lies somewhere in the central nervous system. Localized foci of partial damage lying adjacent to tracts of nerve cells more seriously affected by a neurological disease could emit irritating stimuli capable of producing degrees of over-action of the invertor muscles varying from obvious spasm to clinically undetectable increase in muscle tone. Biral or other factors which stop short at creating nothing more than such a focus of irration could explain the insidious onset of the deformity in the idiopathic group. Over-action of invertor muscles for one reason or another, including ischemia, is almost certainly responsible for initiating the deformity, though primary contracture of the plantar fascia could possibly do so. With the appearance of supination of the heel, the calcanean tendon becomes an active invertor adding its force to that of the plantar fascia to produce structural varus of the calcaneum. Contracture of the plantar fascia and supination of the heel are regarded as features of major importance. Correction of the latter can be achieved more effectively by suitable osteotomy than by subtaloid fusion, which is regarded with great disfavor. Conservative treatment consists of exercises and shoe appliances. Surgical correction is based on calcanean osteotomy and plantar fasciotomy supplemented where necessary by suitable tendon transplantations, correction of clawing of the toes, and tarsal or metatarsal wedge resections. Preservation of the midtarsal subtaloid joint complex is essential. With the heel correctly aligned the degree of improvement to be expected in the forefoot deformity is such that any structural operation on it should be deferred until a fair period of walking has been tried.


Fracture treatment. The still unsolved problem. The problem of the best method for fracture treatment is unsolved and awaits in genuity and intensive research. It is not known whether it is better to treat a fracture by rigid immobilization or by cyclical loading systems. Reports on the treatment of healing bones by the various contemporary methods are contradictory and inconclusive owing to the inherent lack of control in clinical studies. Selected experimental studies on the various biomechanical factors in fracture healing suggest that mechanical variables definitely alter qualitatively the healing of fractured bone. Although no studies have been specifically designed to show which mechanical factors resulted in the most efficient fracture healing, investigations suggest that healing under conditions of rigid fixation results in qualitative structural differences which constitute a weaker bone.


The orthopaedic research society. Its first twenty years. The Orthopaedic Research Society represents one of the many organizations which has contributed to advances necessary to establish orthopedics as a distinct specialty. The foresight and dedication of its founders and leaders undoubtedly stimulated vital musculoskeletal research upon which much of our present day therapy is based. The prodigious growth of the society in a brief twenty years in number of members, papers presented, and, most importantly, in quality of research engendered, reflects the vitality of contemporary orthopedics. Undoubtedly the Society will contunue to serve as a forum where investigators, both experienced and beginner, may present results of their latest attempts to solve the all too many mysteries of the musculoskeletal system.


Synovectomy of the hip in juvenile rheumatoid arthritis. Review of the results of subtotal and complete synovectomy of 9 hips in 5 female patients with subluxation or progressive joint destruction (roentgenographically) than any 2 years showed improvement or retention of joint motion in 4 patients. Complete synovectomy, performed in 7 hips, necessitated surgical dislocation of the joint, but there was no evidence that this surgical dislocation comprised the proximal femoral blood supply. The mildest synovial and cartilagenous changes were present in the patient who has bilateral partial synovectomies. At follow-up these hips showed more severe destruction evaluated during a minimum of the hips treated by total synovectomy. No postoperative dislocations occurred. Synovectomy of the hip may be useful for progressive hip involvement in younger patients whose skeletal immaturity contraindicates major reconstructive procedures.


Bacteremia in pediatric patients following dental manipulations. A recent study has claimed that children who do not have gingivitis do not have bacteremia following dental manipulations and that these children do not require antibiotic prophylaxis. Postoperative blood cultures from 53 children and adolescents with and without gingivitis drawn within ten minutes of elevation of the gums, extraction of teeth, and extensive gingivectomies were sterile in all cases. The collection and laboratory methods and media were carefully evaluated and found satisfactory. However, the time interval between the dental procedure and the collection of the blood is believed to have been too short for reliable results and that the abandonment of the antibiotic prophylaxis in children is unwarranted.


Intertrochanteric osteotomy for degenerative hip disease. Indications. A retrospective study was carried out to determine what were the features of either success or failure of intertrochanteric osteotomy of the hip for degenerative hip disease. Seventy-three patients (78 hips) were reviewed clinically and roentgenographically with a follow-up of two to 12 years. The hips were classified into the superior, medial and intermediate types of the primary degenerative hip disease and into the dysplastic and coxa magna variety for the secondary degenerative hip disease and then further classified into Stage I and Stage II. Stage I was defined by the roentgenographic criteria common to most of the successful procedures (78%) and Stage II was defined by criteria common to the failures (77%). Each of the stages was defined for the various types of degenerative hip disease. The roentgenographic criteria for Stage I are suggested as prerequisitive for indicating intertrochanteric osteotomy for treatment of degenerative hip disease. The roentgenographic criteria for Stage II are suggested as an indication for an operative procedure other than osteotomy. The postoperative course in the successful case characteristically showed an immediate pain relief and gradual improvement in walking, motion and function over a period of at least 6 years.


Effect of tricyclic antidepressants and alcohol in psychomotor skills related to driving. Twenty healthy subjects took amitriptyline, doxepin, and placebo for 2 wk each in a double-blind crossover trial, and another 20 subjects similarly took nortriptyline, chlorimipramine, and placebo. The antidepressants were given three times daily in doses generally used for neurotic patients. The presence of antidepressants in tissues was checked with the tyramine pressor test. On the seventh and fourteenth days of each period, psychomotor skills (choice reaction, coordination, and attention) were measured after the administration of drugs in combination with an alcoholic or placebo drink. Dose-response graphs for the tyramine pressor effect were shifted to the right during the antidepressant treatment, indicating a blockade of the membrane pump in peripheral sympathetic terminals. This antityramine effect of antidepressants did not correlate with their psychomotor effects. No drug alone importantly impaired psychomotor skills. Amitriptyline in combination with alcohol increased cumulative choice reaction times, and doxepin in combination with alcohol increased both cumulative choice reaction times and inaccuracy of reactions. Coordination was impaired after both of these combinations on the seventh day. It seems as if doxepin and amitriptyline but not nortiriptyline or chlorimipramine, in combination with 0.5 gm/kg of alcohol, may be especially dangerous in driving.


Comparative respiratory depression of tillidine and morphine. Respiratory depression induced by tilidine was compared with that of morphine in a crossover study in 6 healthy subjects. Increments of tilidine, 150 mg/70 kg, and morphine, 10 mg/70 kg, were given intravenously and displacement of each subject's CO2 response curve was measured after each dose increment. Both tilidine and morphine caused dose-related displacement of the CO2 response curves to the right. Approximately 80 to 120 mg of tilidine can be expected to induce the respiratory depression of morphine, 10 mg, when given intravenously. Subjective effects after tilidine were qualitatively similar to those of morphine but were of longer duration with nausea and vomiting more frequent. The respiratory depression of both drugs was effectively antagonized by naloxone.


The pathology of Legg-Perthes disease and its comparison with aseptic necrosis. A review of pathological material obtained in cases of Legg-Perthes disease and in aseptic necrosis in the adult shows some similarities in distribution of the involved segment of the femoral head. X-ray signs of separation of the central avascular segment from the superior lateral and medial viable segments of the femoral head are recognizable. Crushing in of the weight-bearing segment then occurs and is recognized by flattening of the femoral head outline. At this point the child is in danger of suffering lateral displacement of the viable lateral segment leading to an incongruous extruded femoral head in relation to the acetabulum. Treatment measures must be taken prior to the occurrence of this lateral epiphyseal fracture in order to prevent the development of the stage of the disease where the prognosis is poor.


Deanol and methylphenidate in minimal brain dysfunction. Deanol, a putative acetylcholine precursor, has been used as a treatment for childhood hyperactivity for years. Efficacy has not been satisfactorily established, however. Seventy-four children referred for problems with learning, including many with hyperactivity, were screened for neurological or psychiatric illness, then given deanol, methylphenidate, or placebo in a double-blind fashion for 3 months. Maintenance dose for methylphenidate was 40 mg daily; for deanol, 500 mg. Behavior rating forms, reaction time, and a series of standard psychometric tests were given before and after treatment. Both drugs showed significant improvement on a number of tests; the pattern and degree of change differed slightly for the two. In this paradigm, deanol thus appeared to improve performance in children with learning and behavior disorders. The mechanism of action remains speculative; proof that deanol increases acetylcholine is scanty, and there is a theoretical basis for actually assuming an anticholinergic effect. Further clinical studies on deanol are indicated.


Interaction of ephedrine and theophylline. The effectiveness and safety of individualized theophylline doses administered as such and in combination with ephedrine and hydroxyzine was investigated in 23 children with chronic asthma who received these medications and a placebo for 1 week each, double-blind and in randomized sequence. Theophylline, determined by prior clinical titration in each patient, averaged 7.3 mg/kg per dose administered every 6 hr, with peak serum theophylline concentrations averaging about 16 mug/ml. Asthmatic symptoms were controlled with theophylline. Ephedrine, alone or in combination, was relatively ineffectual in these patients. None of the drugs given alone was associated with significant adverse effects but both ephedrine-theophylline combinations (with and without hydroxyzine) were associated with insomnia, nervousness, and gastrointestinal complaints. Since the combinations were not significantly more effective than theophylline alone, the apparent toxicity of these combinations suggests a contraindication for the routine use of ephedrine with theophylline in the management of chronic asthma.


Controlled trial of propranolol in intermittent claudication. Seven patients (5 with arteriosclerosis obliterans and 2 with Buerger's disease) completed a two-phase double-blind crossover trial of propranolol in intermittent claudication. Performance was measured on a moving treadmill. In the initial phase, the patients were hospitalized in order to determine an "effective" dose of propranolol. Improvement was noted in all: after 1,600 mg in 5 and after 240 mg and 600 mg in the others. The controlled phase was carried out on an outpatient basis over 8 weeks, the patients receiving propranolol and placebo in a random manner, each for two 2-week periods. Comparison of matched periods of drug and placebo revealed no advantage for propranolol. Patients' performances deteriorated with time. None of the patients evidenced deterioration of occlusive peripheral arterial disease that could be attributed to propranolol, in spite of the high doses used.


Fenfluramine in man: hypophagia associated with diminished serotonin turnover. A double-blind trial of orally administered fenfluramine was conducted in 7 non-obese adults with various neurological disorders. Caloric intake and body weight fell significantly after 8 days of treatment although there was no definite change in appetite ratings. Average central turnover of serotonin, as estimated by the cerebrospinal fluid (CSF) accumulation of 5-hydroxyindoleacetic acid (5-HIAA) during probenecid loading, decreased by 66%. No significant change in homovanillic acid, the major dopamine product, was apparent. The results support the contention that the effect of fenfluramine on human dietary intake may be mediated by alterations in serotonergic rather than dopaminergic mechanisms.


Lack of effect of rheumatoid arthritis on clonixin metabolism. The effect of rheumatoid arthritis on the metabolism of the analgesic, 2-(3-chloro-o-toluidino) nicotinic acid (clonixin), was evaluated in 12 patients with rheumatoid arthritis and in 12 matched healthy control subjects. Males, age-matched by decades, had no renal, gastrointestinal, or hepatic disease, and took no drugs during the study. Lower (p less than 0.02) serum albumins and higher globulins in the patients (albumin: 3.87 plus or minus 0.18; globulin: 3.14 plus or minus 0.28 gm/100 ml) than in the control subjects (albumin: 4.42 plus or minus 0.10; globulin: 2.36 plus or minus 0.08 gm/100 ml) were considered to be manifestations of rheumatoid arthritis. Fasting subjects were given single oral doses of 750 mg of clonixin. A spectrophotometric method was used to determine drug blood levels. Serum half-life was 1.45 plus or minus 0.12 hr in patients and 1.50 plus or minus 0.13 hr in control subjects (p greater than 0.5). Mean peak concentration developed at 1.7 hr and was 40.0 plus or minus 2.6 mug/ml for patients and 46.1 plus or minus 3.1 mug/ml for control subjects. Thus a single oral dose of clonixin results in comparable blood levels in male patients suffering from rheumatoid arthritis and in healthy control subjects.


Variation in the proportions of individual pepsins secreted by the cat in response to vagal stimulation and hypoglycaemia. 1. Gastric juice was collected at regular intervals during electrical stimulation of the vagus in anaesthetized cats and during insulin hypoglycaemia in both anaesthetized and conscious cats. The total amounts of acid and pepsin secreted were similar in the three groups. 2. Pepsins were examined by agar-gel electrophoresis. Resting juice contained two pepsins, and up to nine pepsins could be detected after stimulation. Three patterns of pepsin secretion were found. 3. The most noticeable feature was the variation in the proportion of total pepsin attributable to the pepsin which migrated most rapidly during electrophoresis (pepsin 1). In response to insulin hypoglycaemia, anaesthetized cats secreted only a small proportion of total pepsin 1 and conscious cats secreted a large proportion as pepsin 1. During direct electrical stimulation of the vagus, the proportion of pepsin 1 rose. 4. The possibility of a dependence of pepsin 1 secretion on vagal stimulation is discussed and the relevance of this to peptic ulcer and to vagotomy is considered.


Permanent hypertension after renal homotransplantation in man. 1. In forty-one patients who underwent renal homotransplantation the following measurements were made: (a) blood flow and its distribution in the transplanted kidney as measured by the 85-Kr washout method; (b) renin release in the renal vein of the transplant; (c) arteriovenous difference in plasma renin activity (PRA) of the recipient's remaining left kidney. 2. Eleven transplanted patients were normotensive. Renal haemodynamic data were comparable with those obtained in potential kidney donors. 3. Three hypertensive patients had chronic rejection. The mean renal blood flow and the percentage flow in the first component of the washout curve were reduced. Renin release from the transplant, however, was normal. 4. Ten hypertensive patients had transplant artery stenosis. In eight of them renin release from the grafts as well as peripheral PRA were within normal range. This result is similar to experimental data obtained in Goldblatt renovascular hypertension. The two patients with the tightest artery stenosis had an elevated renin release from the transplant. 5. Thirteen hypertensive patients had elevated arteriovenous difference in PRA of the recipient's own left kidney. Peripheral PRA was significantly higher than in normotensive patients. Left nephrectomy relieved hypertension in ten of them; three have not so far undergone nephrectomy. 6. In four other cases hypertension was also relieved by removal of the patient's own kidney; however, the arteriovenous difference in PRA of that kidney fell within normal range.


The fluorescent treponemal antibody-absorption (FTA-ABS) test for syphilis. The FTA test was developed at a time when immunofluorescence procedures were not well-defined. Through technique control and research, a modification of the FTA test, the FTA-ABS, has attained a position as one of the leading treponemal tests to confirm the reagin tests for syphilis. In this review of the FTA-ABS test, attention has been focused on reagent development, with the anticipation that reagent standardization may soon become a reality. The T. pallidum antigen obtained by extracting infected rabbit testicular tissue has evolved from a preparation in which the treponemes remained in the initial extracting fluid to a reagent that can be free of rabbit tissue and globulin. These washed antigen preparations improve visibility of the treponemes on the microscope slide, reduce background fluorescence, and reduce or prevent from occurring nonspecific reactions that are a result of tissue and globulin components. Both washed and nonwashed antigens are available commercially, and, to date, little differentiation has appeared on the product label. The predominant immunoglobulin that reacts with T. pallidum in the indirect fluorescent antibody tests appears to be IgG. This is the major immunoglobulin detected in the FTA-ABS test. IgM, although increased in early syphilis, is also increased in other clinical conditions. Several reports suggest that adult IgM detection in the present FTA-ABS test would be nonspecific. Until specific IgM antibody in adult syphilis can be detected without a risk to test specificity, the conjugate for the FTA-ABS test should continue to be an anti-IgG reagent. Class-specific, anti-IgG reagents are more expensive than other reagents; however, their use may eliminate the problem of nonspecificity resulting from IgM detection. Additionally, micromethods can be used to reduce cost, and this possibility should be investigated. The sorbent that contains an antigen to the Reiter treponeme may or may not specifically absorb the reactivity that occurs in normal sera; certainly, there are questionable aspects about this reagent. Group antibodies not related to Reiter treponemes may be responsible for some nonspecific reactivity; additionally, antiglobulin factors have been reported to participate in the reaction. Antigens free of rabbit serum factors and class-specific, antiimmunoglobulin reagents are available, and may lead to a better understanding of nonspecific reactions. These reagents should allow resolution of the possible multiplicity of reactivity. In this interim period, the sorbent, with its possible nonspecific nature, appears to maintain a biological balance between natural or group and immune antibodies when used to detect IgG antibody.


Response of patients with chronic obstructive lung disease to the regular administration of nebulized isoproterenol. A double-blind crossover study. The effect of the regular use of neublized isoproterenol in 14 patients with symptomatic chronic obstructive lung disease (COLD) was evaluated in a double-blind crossover 16-week study. FEV1, FVC and SGaw were measured before and 45 minutes after bronchodilator therapy every two weeks, while arterial blood gases were measured every eight weeks, before and 45 minutes after bronchodilator therapy. When the patients were considered as a group, there was no significant difference in mean symptom scores or objective pulmonary functions during the drug and placebo periods. Four patients had significantly higher (p less than .05) and two patients significantly lower mean values for at least one of the pulmonary function tests during the isoproterenol period. The patient who is most likely to benefit from isoproterenol on a regular basis appears to have the following characteristics; (1) consistent improvement in pulmonary function tests 45 minutes after use of nebulized bronchodilator; (2) moderate rather than severe COLD; and (3) a relatively normal DLCO.


Postoperative bronchopleural fistula: clinical and experimental study. It is a well-known fact that in pulmonary tuberculosis patients treated by resection, the quality of the suture material used for closing the bronchial stump plays an important role in the pathogenesis of postoperative bronchopleural fistula. Of 426 cases treated surgically and in whom silk suture thread was used, 23 developed bronchopleural fistula, whereas none of the 220 cases sutured with nylon monofilament developed abnormality. Statistical analysis of 100 surgical cases with silk thread suture and of 100 cases with nylon monofilament suture showed that the two groups had no marked differences as to background factors. Howevers, as compared with the silk-thread suture group, the nylon-monofilament suture group revealed more consistently favorable postoperative bronchoscopic findings. Experimental studies with dogs showed a similar lack of complications when the monofilament suture material was used, as contrasted were conducted in hospital by the same surgical personnel using the same procedures, it can be said that, to insure prevention of complications, the suture material for bronchial stump closure should be of non-irritating nature and preferably of monofilament strength and quality, such as nylon monofilament.


Treatment of cholerheic diarrhea with cholestyramine and a hydrophilic colloid. Eight patients with ileal-resection diarrhea who were being treated with cholestyramine took part in a trial comparing the effectiveness of cholestyramine with that of a hydrophilic colloid. Both drugs reduced overall stool frequency and improved consistency, but a larger dose of colloid was required. One patient planned to use the hydrophilic colloid instead of cholestyramine.


Low end-to-side rectoenteric anastomosis with single-layer wire. A study of 41 cases where a single layer of 5-0 monofilament stainless steel wire is used for low end-to-side rectosigmoid or ileorectal anastomosis has shown satisfactory results. The procedure should be considered particularly where there is gross disparity between the sizes of the approximated cut ends.


Simplified anterior resection: Use of the ta stapler. Forty consecutive anterior resections using TA stapler were studied. No mortality, no clinical leak, and no infection were encountered in this group. The stapler is recommended as an aid in simplifying the operation and lessening the operative time.


Alterations during the estrous cycle in the responsiveness of the pituitary to subcutaneous administration of synthetic LH-releasing hormone (LHRH). To  further evaluate the alterations in responsiveness of the pituitary to synthetic LHRH during the proestrous discharge of gonadotropins, LHRH was given SC in the hope of producing a release of FSH as well as LH, and blood samples were removed prior to and at various intervals after the injections of the neurohormone while the rats were anesthetized with tribromoethanol. The procedure of anesthesia and blood sampling produced small declines in both FSH and LH, but these only achieved significance in the case of FSH on the morning of estrus and diestrus day 2. An increase in plasma LH occurred in response to LHRH at all stages of the estrous cycle but was minimal during diestrus. The increment in plasma LH was already increased by 9 AM on proestrus and the titer remained elevated for 2 h. A further increase in response to LHRH occured at 2 PM associated with an increase in initial plasma LH. The maximum response occurred at 5 PM together with maximal initial plasma LH, and the characteristics of the response changed such that there was a much larger increase in plasma LH at 20 min and a rapid decline thereafter, so that the response became pulselike. Initial plasma LH had already declined significantly by 9 PM, and this was associated with a dimished pulselike release of LH in response to LHRH. By the morning of estrus, an even smaller pulse-like release occurred. Significant FSH release in response to LHRH occurred at all stages of the cycle as indicated by the increments in plasma FSH. The relative increase in plasma titers was much less than that for LH and responsiveness to LHRH did not increase until 5 PM on proestrus. Responsiveness had already begun to decline by 9 PM on proestrus and by the morning of estrus was similar to that obtained on diestrus. Initial plasma FSH titers were first elevated by 2 PM on proestrus and they remained elevated on the morning of estrus. The results indicate that maximal responsiveness to LHRH in terms of LH release is associated with the proestrous discharge of LH, but that the maximal responsiveness in terms of FSH release terminates long before the endogenous release of hormone ceases sometime on estrus. The increased responsiveness in terms of LH release may be related to prior estrogen secretion and to the priming action of endogenous LHRH. The continued release of FSH in the face of a return of responsiveness to LHRH to low levels indicates that release of FSH on late proestrus and early estrus is not caused by endogenous release to LHRH.


Quick release of FSH stimulated by repeated applications of synthetic luteinizing hormone-releasing hormone (LH-RH) in immature male rats. Serum FSH and LH levels were estimated by radioimmunoassay following single subcutaneous administration, and repeated subcutaneous administration at various intervals in immature male rats. Single injection of LH-RH induced slight increase in FSH levels in comparison with considerable increase in LH. By two successive injections, the release of FSH was markedly stimulated when the time intervals were 15, 30, and 60 minutes,and rapidly elicited to release after the second injection. The greatest response was observed by two injections at 60 minutes interval. Moreover, the elevation of serum FSH level after the third injection was particularly remarkable, and the response was much stronger than that to the second injection. On the other hand, serum LH levels following the repeated injections were quite similar to that of FSH. And both FSH and LHwere linearly responded to doses of LH-RH repeatedly administered. These results indicated that the repeated quick administrations of LH-RH under appropriate intervals caused the acute high release of FSH, which was quite similar to LH release, and that these acute release of FSH and LH showed the dose-response relationship.


Immobilized L-asparginase embedded in fibrin polymer. Immobilized asparaginase was prepared by embedding asparaginase (which is effective for remission in children with leukemia) into fibrin polymer formed by fibrinogen-fibrin conversion in the presence of thrombin. The immobilized asparaginase film did not dissolve in 6 mol/1 urea, suggesting that blood coagulation factor XIII participates in the cross-linking between fibrins and between fibrin and asparaginase.


Platelets, thrombosis and drugs.

Platelets, thrombosis and drugs. The development of thrombosis involves 4 main factors: the vessel wall, the formed elements of the blood, blood coagulation, and blood flow. In venous thrombosis, however, the major part in both the initiation and growth of thrombi is played by the platelets. In selecting drugs which inhibit platelet function it is helful to know which of the platelet reactions that contribute to thrombus formation can be inhibited by various agents. Platelets adhere to the damaged vessel wall, collagen being probably the most important constituent involved. They are then stimulated to release the contents of their storage granules. Release-inducing agents promote the discharge of adenosine diphosphate (ADP) which causes platelets in the vicinity to swell to a more spherical shape, extend pseudopods and adhere to each other. Platelet aggregation is reversible, and a number of drugs have been shown to be capable of inhibiting platelet function at various stages, both in vitro and in vivo. Adrenaline, noradrenaline, oestrogens and nicotine enhance aggregation. Drugs which inhibit platelet function include the non-steroidal anti-inflammatory drugs, the pyrimido-pyrimidines (e.g. dipyridamole), hydroxychloroquine, clofibrate, and dextran. In this review the effects of drugs which inhibit platelet function are outlined and the extent to which they can be used to influence the course of thromboembolic disease in man is discussed. It is suggested that combination of anti-platelet drugs with anticoagulants could prove clinically useful.


The involvement of sulphydryl groups in the peptidyl transferase centre of eukaryotic ribosomes. Treatment of mammalian ribosomes with N-ethylmaleimide enhances up to 100% the ribosome efficiency in the "fragment reaction assay" for peptide bond formation by increasing the affinity of the substrate C-A-C-C-A-Leu-Ac for the donor site. This stimulation in peptidyl transferase activity was not observed when yeast ribosomes were treated in a similar manner. Stimulation of the peptidyl transferase activity of mammalian ribosomes was also observed by treatment with either p-chloromercuribenzoic acid or 5,5'-dithiobis-(2-nitrobenzoic acid) or 5,5'-dithiobis-(2-nitropyridine) or the maleimide-derived antibiotic showdomycin. N-Ethylmaleimide treatment also enhances C-A-C-C-A-Leu binding to the acceptor site of the peptidyl transferase centre. However, neither binding of N-Ac-Phe-tRNA in the presence of ethanol, nor binding of Phe-tRNA to the ribosomes is stimulated by N-ethylmaleimide. The antibiotic tenuazionic acid (a selective inhibitor of peptide bond formation by mammalian ribosomes) appears to require for its inhibitory effect the ribosome sulphydryl residues, since its inhibitory action on the fragment reaction is greatly decreased in ribosomes treated with N-ethylmaleimide.


Diuretics: mechanism of action and clinical application. Despite the bewildering number of diuretics available to the physician, these drugs can be divided into 4 main groups, characterised by their site of action on sodium reabsorption in the kidney. Drugs acting on the ascending limb of the loop of Henle have a powerful but short acting diuretic effect; they include frusemide, ethacrynic acid and bumetanide. The benzothiadiazines and related compounds have a moderate diuretic action spread over a longer period, whilst the potassium-sparing diuretics, triamterene, amiloride and spironolactone, have only a weak diuretic effect but a marked ability to diminish urinary potassium excretion. The fourth group is made up of miscellaneous substances which function as vasodilator or osmotic agents. The pathogenesis of oedema formation in heart failure is outlined and a logical approach to treatment suggested. Duiretics are being increasingly used in the treatment of non-oedematous states, in particular hypertension, diabetes insipidus and hypercalciuria; their exact role in pregnancy and acute renal failure remains controversial. Side-effects can be related to their effect on electrolyte excretion and include hypokalaemia, hyponatraemia, hyperkalaemia and hyperuricaemia. The incidence of disturbed carbohydrate tolerance in previously normal individuals is low. Other less common side-effects are also discussed.


Properties of ATP and UTP analogues with P-S-C-5' bonds. Analogues of ATP and UTP bearing C-5'-S-P ester bonds were found not to be substrates but weak competitive inhibitors of Escherichia coli RNA polymerase. The K-i values of the analogues obtained in the transcription of poly[d(A-T)] or poly(dT) under various conditions are in the order of millimolar. Evidence was derived from proton magnetic resonance spectra that nucleotides with C-5'-S-P bonds do not exist in gauche-gauche conformation normally adopted by natural occurring nucleotides. This leads us to assume that the gauche-gauche conformation is an essental prerequisite for substrates of RNA polymerase. Ado-5'-S-PPP substituted for ATP as substrate of hexokinase from yeast rather effectively thus indicating that a distinct stereochemical orientation of the alpha-phosphate ester bond is not a stringent requirement for substrates of this enzyme.


Determination of the kinetic constants of glucose-6-phosphate 1-epimerase by non-linear optimization. 1. The overall kinetic constants of the reversible anomerisation of d-glucopyranose 6-phosphate from alpha to beta non-enzymatically as well as catalysed by glucose-6-phosphate 1-epimerase are determined by application of a novel computerized non-linear optimization technique. 2. The non-enzymic rate constants for the anomerisation of d-glucopyranose 6-phosphate from alpha to beta and reverse are 0.0658 and 0.0389s-minus 1, respectively. The Michaelis constants of the enzymic reaction are (see journal for formulas) with the turnover numbers of 1950s-minus 1 and 446s-minus 1 for the conversion of d-glucopyranose 6-phosphate from alpha to beta and reverse, respectively.


Left ventricular systolic time intervals during acute myocardial infarction. Left ventricular systolic time intervals (LVSTI) were measured several times daily during 10 days in 47 patients with acute myocardial infarction without major complications. Left ventricular ejection time (LVET) and the interval between the beginning of depolarization and the aortic component of the second heart sound (Q-A2) decreased progressively during the first 72 hr. Shortening of Q--A2 and LVET was most marked in patients with heart failure and persisted till the end of the observation period. Q-upstroke (Q-U) prolonged progressively during the first 3 days, mainly in patients with heart failure. After 10 days, Q-U tended to return to normal except in decompensated patients. Definite diurnal variation in LVSTI were observed; LVET and Q--A2 were longest in the morning hours. Multiple regression analysis of LVSTI with a series of clinical variables revealed that R-R interval, age, sex, digitalis administration, day after infarction, hour of the day, peak of SGOT, and survival are significantly and independently correlated with the changes in LVSTI.


Effects of the intra-arterial injection of bradykinin into the limbs, upon the activity of mesencephalic reticular units. The changes in firing rate of mesencephalic reticular units after intra-arterial injection into the limbs of a potent nociceptive agent, bradykinin, were studied in cats (unanesthetized, immobilized with flaxedil and hyperventilated). 30 per cent of the d35 studied cells were affected, 56 per cent were excited, 23 per cent inhibited and 5 per cent had mixed effects. Among the 75 excited cells, the activation of 16 of them seemed to related to the arousa- processes (group A); for 56 cells the increase seemed dire-tly dependent on the nociceptive stimulation itself (group B). The changes of firing rate were repruducible; their latencies and durations were of the same order as the latencies and duration of the nociceptive reactions and painful sensation s, which have been obtained in animals and men after bradykinin injections. The modifications induced by bradykinin administration were suppressed by Ketamin and Thiopental.


Ethical and social aspects of experimental gene manipulation. New genetic techniques for the isolation and rejoining of segments of DNA now permit construction of biologically active recombinant DNA molecules. Such recombinant DNA molecules can be multiplied many times by inserting them into the bacterium Escherichia coli. Thus, we now possess a powerful technology for cloning segments of DNA from any source and for adding new genetic capabilities to bacteria. Application of this technology promises to facilitate the solution of a variety of theoretical and practical biological questions. However, use of this technology will also result in the creation of novel organisms whose biological properties may not be completely predictable in advance. Some of these organisms may be hazardous to man or to the environment. This paper discusses some ethical and social control of the new genetic technologies.


Incidence of pregnancy, changes in menstrual pattern, and recovery of endometrial function after discontinuation of medroxyprogesterone acetate therapy. The incidence of pregnancy, recovery of endometrial function, and changes in menstrual pattern were studied in 62 women who had received two or more intramuscular injections (150 mg) of medroxyprogesterone acetate (Depo-Provera) every three months and oral diethylstilbestrol (1 mg) daily for seven days every month. Immediately after discontinuing this therapy, 71% of the patients had regular menstrual cycles, 10% had irregular cycles, and 19% had amenorrhea. All the patients had regular cycles by the end of one year except one women who was probably menopausal. The average time required to conceive after stopping therapy was 9.3 months, range, 3 to 21 months). Conception was definitely delayed as shown by endometrial biopsies and the incidence of pregnancy. Within six months, 25% of the patients conceived and within one year, 69% conceived. By two years, four had not conceived. The percentage of pregnancies seemed to decrease with increased patient age.


Preliminary human trial of a new male sterilization procedure: vas sclerosing. A new procedure developed in animals has been applied to produce male human sterilization. This involves the percutaneous injection of an ethanol and formaldehyde solution into the vasa deferentia. An initial clinical trial of eight human volunteers indicates that this is an effective method of producing male sterilization.