Properties of mutants of Escherichia coli lacking malic dehydrogenase and their revertants. Mutants of Escherichia coli lacking malic dehydrogenase activity (mdh) were incapable of growth on acetate", succinate- or malate/mineral medium. Revertants of mdh strains which had regained the ability to grow on C4-dicarboxylic acids could be divided into two distinct classes. One type of revertant had regained the ability to synthesize functional malic dehydrogenase. The other type of revertant still lacked malic dehydrogenase activity but possessed a suppressor mutation which altered the regulation of the synthesis or activity of the C4-dicarboxylic acid transport system, resulting in increased C4-dicarboxylic acid transport activity. This latter class of revertants apparently synthesized oxalacetate from malate via the sequential actions of the NAD-linked malic enzyme, phosphoenolpyruvate synthetase, and phosphoenolpyruvate carboxylase. Evidence has been presented that is consistent with the hypothesis that oxalacetate is the inducer of the C4-dicarboxylic acid transport system. The inability of mutants lacking malic dehydrogenase to grow with a C4-dicarboxylic acid as the carbon source can be attributed to the difficulty such mutants have in synthesizing oxalacetate.


Comparison of staphylococcal coagglutination, latex agglutination, and counterimmunoelectrophoresis for bacterial antigen detection. Soluble antigens of Haemophilus influenzae type b, Streptococcus pneumoniae, Neisseria meningitidis, and group B streptococcus were looked for in cerebrospinal fluid, serum, and urine by using the staphylococcal coagglutination test, latex agglutination test, and counterimmunoelectrophoresis. The staphylococcal coaggultination and latex agglutination tests were more sensitive than counterimmunoelectrophoresis in identifying antigens of H. influenzae type b, S. pneumoniae, and N. meningitidis. None of the three tests successfully detected group B streptococcal antigens in body fluids. Nonspecific reactions noted with the staphylococcal coagglutination test could be usually eliminated after premixing test specimens with soluble protein A.


Evaluation of blood culture procedures in a pediatric hospital. To determine optimal clinical laboratory techniques for detecting pediatric bacteremia, we studied 7,768 consecutive blood cultures in a 1-year period. Blood was inoculated into one vented 50-ml bottle of brucella broth with 0.05% sodium polyanetholsulfonate and one unvented 50-ml bottle of Columbia broth with 0.05% sodium polyanetholsulfonate and 0.05% cysteine. Bottles were visually examined for growth on days 1 through 7 and blindly subcultured aerobically and anaerobically on days 1, 2, and 7. There were 724 (9.3%) positive cultures, and 484 (6.2%) were clinically significant. The most frequent isolates from bacteremic patients were Haemophilus influenzae (24%) and Streptococcus pneumoniae (17%). Growth was noted in only one bottle in 25% of clinically significant isolates. Bottles inoculated with greater than or equal to 1 ml of blood became positive earlier than bottles inoculated with less than 1 ml. After 1 day of incubation, 48% of the clinically significant cultures showed growth on visual examination, whereas 85% showed growth on subculture. Only 19% of Haemophilus isolates were detected visually on day 1, whereas 88% were recovered on subculture. By day 7, 3.5% of all isolates (including 18% of pneumococcal isolates and 1% of Haemophilus isolates) could no longer be recovered on subculture. We conclude that a two-bottle blood culture system and blind subculture within 24 h will optimize detection of pediatric bacteremia.


Chromogenic cephalosporin spot test to detect beta-lactamase in clinically significant bacteria. lactamase production. Reacteroides melaniongenicus, 14


Modification of the bile solubility test for rapid identification of Streptococcus pneumoniae. A modified bile solubility test is described which can be used to presumptively identify Streptococcus pneumoniae recovered in blood culture.


Characterization of the molecular defect in infantile and adult acid alpha-glucosidase deficiency fibroblasts. Different clinical expressions of acid alpha-glucosidase deficiency have been described. The present study was undertaken to investigate the basic metabolic defect in the infantile and adult forms of the disease. Acid alpha-glucosidase (EC 3.2.1.20) was purified from normal and from adult acid alpha-glucosidase deficiency fibroblasts. The pH optimum; Michaelis constant; electrophoretic mobility in starch; thermal denaturation at pH 4.0 and 7.0; and inhibition by turanose, alpha-methylglucoside and trehalose were the same in purified enzyme from normal and mutant cells. Placental acid alpha-glucosidase was purified to, or near, homogeneity. Monospecific antibodies raised against the enzyme in each of three enzyme peaks obtained from the last purification step were found to cross-react with the enzyme of all three peaks, and with purified, normal fibroblast enzyme. Cross-reacting material (CRM) also was identified in fibroblast lysates from normal subjects and from both forms of acid alpha-glucosidase deficiency. The amount of CRM in the adult form appeared to be significantly less than in normal cells or cells from the infantile form. Enzyme activity was demonstrated in the immune complexes of the normal and adult acid alpha-glucosidase deficiency fibroblasts, but not of the infantile form. Competition for antibody binding sites was observed between normal and both types of mutant enzymes. The findings indicate that this case of infantile acid alpha-glucosidase deficiency is the result of a structural gene mutation which causes the synthesis of a catalytically inactive (CRM-positive) enzyme protein. It appears that in the adult form, the mutation causes a reduction in the amount of the enzyme protein present in the cells.


Adrenergic modulation of pancreatic A, B, and D cells alpha-Adrenergic suppression and beta-adrenergic stimulation of somatostatin secretion, alpha-adrenergic stimulation of glucagon secretion in the perfused dog pancreas. The effects of adrenergic substances on pancreatic insular secretions were studied in a completely isolated canine pancreas with exclusion of the duodenum from the perfusion circuit. To ensure adequate blockade, blockers were infused before agonists. A dose range of beta-receptor blockade was tested, and putative alpha-adrenergic effects were confirmed by combined alpha- and beta-adrenergic receptor blockade.beta-Adrenergic agonism (2 ng/ml isoproterenol) induced a mean integrated increase of 79+/-20% in somatostatin secretion, whereas glucagon and insulin secretion were increased by 185+/-45 and 495+/-146%, respectively. The stimulations of D, A, and B cells were abolished by propranolol.alpha-Adrenergic agonism (10 ng/ml epinephrine) after beta-adrenergic blockade) moderately decreased somatostatin (-37+/-7%) secretion, moderately increased glucagon (91+/-19%), and markedly decreased insulin (-85+/-3%) release. Similar effects on D-, A-, and B-cell secretion were induced with 2 ng/ml epinephrine or 10 ng/ml norepinephrine after beta-adrenergic blockade. The alpha-adrenergic effects on the D and A cell were abolished by either phentolamine or by phenoxybenzamine. This study showed that there are indeed alpha-adrenergic receptors on A cells and that the secretion of glucagon, a "stress" hormone, was stimulated either by alpha- or beta-adrenergic receptor agonism. D-cell secretion, like that of the B cell, was inhibited by alpha-adrenergic agonism and was stimulated by beta-adrenergic agonism. However, beta-adrenergic-induced changes in D-cell secretion were smaller in magnitude than those of B-cell secretion.


Some effects of the administration of endotoxin in mice. Specific cleavage of serum albumin by an acid protease and the generation of amyloid serum component. Endotoxin has been shown to induce amyloidosis in mice and to result in the appearance in serum of large amounts of amyloidrelated protein (SAA). After injection of 300 mug lipopolysaccharide Escherichia coli, SAA behaves as an acute phase reactant with levels reaching a peak of >600 mug/ml at 18-22 h and returning to base line (<50 mug/ml) by 48 h in each of four strains tested; only the endotoxin-resistant C3H/HeJ strain showed a smaller response. Lesser, though significant, elevations were also found after subcutaneous injection of 25 mg of casein, bovine serum albumin, ovalbumin, or monomeric immunoglobulin G, whereas pyrogen-free human serum albumin/U. S. Pharmacopeia failed to raise SAA levels. SAA generation may thus be a result of endotoxin contamination of these protein preparations. Also present in equivalent amounts in acidified serum from endotoxin-treated mice, but barely detectable in control sera, was a 3,000-dalton molecule whose amino acid sequence is identical to the amino terminal 24 residues of mouse albumin. The appearance of SAA and the amino terminal albumin fragment after endotoxin were unaffected by pretreatment with cobra venom factor, and equivalent levels were found in C5-deficient mice. Pretreatment with pepstatin in vivo, or before acidification in vitro, prevented the appearance of the albumin fragment but had no effect on the appearance of SAA, whereas leupeptin and antipain did not affect the appearance of either SAA or the albumin fragment. These studies suggest that the generation of SAA after endotoxin administration does not involve complement activation or intravascular proteolytic activity, whereas the liberation of a specific peptic-like cleavage product of albumin appears to be the consequence of an acid protease.


Dopamine during alpha- or beta-adrenergic blockade in man. Hormonal, metabolic, and cardiovascular effects. We studied the contribution of alpha- and beta-adrenergic receptor activation to the cardiovascular, metabolic, and hormonal effects of dopamine. At a concentration of 1.5 mug/kg.min, the infusion of dopamine in 12 normal volunteers was associated with a transient but significant rise in pulse rate, which was prevented by propranolol. Venous plasma glucose did not change throughout the experiments, and a mild increase in plasma free fatty acid levels observed during the administration of dopamine alone was antagonized by propranolol. In contrast, neither the beta-adrenergic blocker, propranolol, nor the alpha-adrenergic blocker, phentolamine, was effective in inhibiting the dopamine-induced rise in plasma glucagon (from 82+/-9 to 128+/-14 pg/ml; P < 0.005) and serum insulin (from 7.5+/-1 to 13+/-1.5 muU/ml; P < 0.005) or its suppression of plasma prolactin (from 8.5+/-1 to 5.2+/-0.8 ng/ml; P < 0.001). Although serum growth hormone levels did not change during the infusion of dopamine alone, an obvious rise occurred in three subjects during the combined infusion of propranolol and dopamine. Whereas some metabolic and cardiovascular effects of dopamine are mediated through adrenergic mechanisms, these observations indicate that this is not the case for the effects of this catecholamine on glucagon, insulin, and prolactin secretion, and thus provide further support for the theory of a specific dopaminergic sensitivity of these hormonal systems in man.


Resistance to the phosphaturic and calcemic actions of parathyroid hormone during phosphate depletion. Prevention by 1,25-dihydroxyvitamin D3. Recent observations indicate that in thyroparathyroidectomized (TPTX) rats fed a low (0.2 g/100 g) phosphorus diet, the tubular phosphaturic response to parathyroid hormone (PTH) remains markedly blunted even when it is assessed at normal or high plasma concentration and filtered load of inorganic phosphate (Pi). Because 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] decreases the tubular capacity to reabsorb Pi when chronically administered to TPTX rats, we have studied whether this vitamin D(3) metabolite could specifically increase the phosphaturic response to PTH in phosphate-deprived animals. The results show that in Vitamin D-replete TPTX rats fed a low (0.2 g/100 g) phosphorus diet, 1,25(OH)(2)D(3) (2 x 13 pmol/d i.p. for 7 d) markedly enhanced the acute tubular phosphaturic response to PTH (2.5 IU/h i.v.) without affecting the action of the peptide hormone on Ca reabsorption and cyclic-3',5'-AMP excretion. The influence of 1,25(OH)(2)D(3) on the phosphaturic response to PTH could not be ascribed to an increased plasma concentration and(or) filtered load of Pi during the administration of the peptide hormone. However, it could be, at least in part, related to the elevation in the basal level of plasma Pi which was observed in the 1,25(OH)(2)D(3)-treated animals. The results also indicate that 1,25(OH)(2)D(3) significantly enhanced the calcemic response to PTH, which was blunted in these conditions of phosphate deprivation. Unlike 1,25-(OH)(2)D(3), 25-hydroxyvitamin D(3) did not unmask the phosphaturic effect of PTH in phosphate-depleted animals, even when given in doses 100 times larger. Thus, 1,25(OH)(2)D(3) displays a selective and powerful activity in preventing the occurrence of tubular resistance to the phosphaturic action of PTH during Pi depletion. This finding suggests the existence of an important interaction between dietary Pi, 1,25(OH)(2)D(3), and PTH in the homeostasis of phosphate.


Pulmonary alveolar type II cells isolated from rats. Release of phosphatidylcholine in response to beta-adrenergic stimulation. It is unclear what factors control the secretion of pulmonary surface active material from alveolar type II cells in vivo. Other workers have suggested that cholinergic stimuli, adrenergic stimuli, and prostaglandins may all stimulate secretion. We isolated type II cells from the lungs of rats by treatment with elastase, discontinuous density centrifugation, and adherence in primary culture. beta-Adrenergic agonists, but not cholinergic agonists, caused an increase in the release of [(14)C]disaturated phosphatidylcholine, the major component of surface-active material, from type II cells in culture. The beta-adrenergic effect was stereo-selective, (-)-isoproterenol being 50 times more potent than (+)-isoproterenol. Terbutaline, 10 muM, a noncatecholamine beta-2 adrenergic agonist, caused a release of 2.0+/-0.5 (mean+/-SD) times the basal release of [(14)C]disaturated phosphatidylcholine in 3 h; the concentration of terbutaline causing half maximal stimulation was 800 nM. The terbutaline effect was blocked by propranolol, a beta-adrenergic antagonist (calculated K(d) = 6 nM), but not by phentolamine, an alpha-adrenergic antagonist. Isobutylmethylxanthine, a phosphodiesterase inhibitor, and 8-Br cyclic AMP, but not 8-Br cyclic guanosine monophosphate, also stimulated release. We conclude that type II cells secrete disaturated phosphatidylcholine in response to treatment with adrenergic stimulation.


Evaluation of dithiothreitol (DTT) for inactivation of IgM antibodies. A newly introduced sulphydryl compound, dithiothreitol (DTT), is evaluated for its optimal conditions of inactivation of IgM antibodies. The maximal effects of DTT reagent are observed when its final concentrations are between 0.0025 M and 0.005 M, pH between 7.0 and 8.0, and incubation at 37 degrees C. Concentrations over 0.01 M, pH values greater than 8.0, and an incubation temperature over 40 degrees C resulted in a gel formation of the specimen. Examination of both 'cold' and 'warm' type antibodies demonstrated that the results obtained by the DTT reagent are in close agreement with those obtained by 2-mercaptoethanol reagents and DEAE Sephadex treatment. Since the procedure is simple and rapid and lacks offensive odour, DTT is recommended for routine use in blood banking for the inactivation of IgM antibodies.


Serological identification of Bacteroides species by an enzyme-linked immunosorbent assay. An enzyme-linked immunosorbent assay was used to titrate antisera raised against live cultures of eight type species (biotypes) of Bacteroides with the EDTA-released outer-membrane complex from 29 characterised strains of Bacteroides species. With only minor exceptions, the strains investigated reacted to titre with the antisera raised against the homologous type species and not against the heterologous type species. Cross-reactivity between heterologous species and antiserum was only significant between closely related biotypes. This cross-reactivity could be removed by absorption of the antisera with whole cells. Significant correlation was found between serotype and biotype with this technique.


Fine structural analysis of the cortico-striatal pathway. Considerable evidence has accumulated indicating that one neurotransmitter in the excitatory cortico-striatal tract is glutamate. Lesions of the tract result in reductions in the striatum of glutamate levels as well as high affinity uptake of glutamate into synaptosomes. Furthermore, such lesions eliminate the neurotoxicity of the glutamate analog kainic acid when injected into the striatum. The fine structure of the cortico-striatal pathway was studied to provide evidence regarding the morphology of glutamate nerve endings. Seven days after injection of 3H-proline (20-25 mu Ci) into the rat frontal cortex, axonally transported label appeared in the striatum with uniform distribution in a single type of nerve ending. The labeled boutons had common round vesicles and made asymmetrical contacts, mostly with dendritic spines. This morphology is typical of excitatory synapses, and similar to that previously shown for cholinergic boutons in the striatum. In four animals similarly injected with 3H-proline, kainic acid was administered directly into the striatum to induce degeneration of postsynaptic elements eight to ten hours before sacrifice. In areas affected by these injections, grains appear in patches, possibly resulting from glial swelling. Labeled boutons were seen almost four times as often in synaptic contact with degenerating dendritic elements as with normal ones. The data provide morphological evidence as to the nature of the probable glutamatergic boutons in the striatum, and show the close relationship of such boutons with the neurotoxic effects of kainic acid. This would be anticipated in view of the dependency of kainic acid neurotoxicity on the integrity of the cortico-striatal pathway.


Role of the hypothalamus in the aging woman. Relationships between the hypothalamus and the pituitary in the aging woman are discussed under the following subheadings: synthesis and release of follicle-stimulating and luteinizing hormones, estrogen receptors, other releasing factors, neurotransmitters, and the mechanisms of hot flushes and migrainoid headaches. The hypothalamus is the main regulator of pituitary function. In the female the hypothalamic-pituitary axis appears to remain functionally intact well into old age.


[A case of Richner-Hanhart syndrome (tyrosinosis with ocular, cutaneous and mental manifestations]. A case of Richner-Hanhart syndrom with tyrosinemia is being reported. The diagnosis was suggested from clinical manifestations of this syndrom : superficial opacities of the cornea in an infant preceeding hyperkeratosis of the palms and soles and mild mental retardation. It has been confirmed by the high levels of blood tyrosine. The introduction of a diet low in tyrosine and alanine has lead to a rapid improvement and finally a complete cure of the ophthalmological and dermatological symptoms. The normal metabolism of tyrosine is recalled as well as the specific metabolic aberration responsable for this syndrom (deficiency of cytosol tyrosine amino-transferase). This case is being compared with those which have been previously reported.


[Obstetrical anaesthesia. Their place in the conduct of labour (author's transl)]. After having made an historical study of the principal works coming from the School in Toulouse concerning obstetrical anaesthesia, one can make an account of the criteria for fetal risk. These have been established by comparing with a standard that determines the physical and biological parameters found in normal labour. The fetal risk has been studied for four types of anaesthesia progressively. These are : general anaesthesia with Pentothal, general anaesthesia with Gamma OH, neuroleptanalgesia and finally epidural anaesthesia. By comparison with a normal standard, the evolution of the parameters concerning uterine contraction, the changes in the fetal heart rate the, acid-base balance of the fetal blood and how it changes, and the Apgar score have been studied for each type of anaesthesia. The same has been done for maternal risk. After having completed this study we have come to the conclusion that there is no single anaesthetic that should particularly be recommended, and that for every phase of labour : before labour starts and after labour has been confirmed, and at the end of the first stage of labour, a different form of anaesthesia may well be indicated. Above all, the skill of the anaesthetist and of the obstetrician influence the efficiency of the anaesthetic.


Factors affecting the incidence and anti-salmonella activity of the anaerobic caecal flora of the young chick. Thirty-two different types of anaerobic bacteria isolated from chickens have been tested for anti-salmonella activity in vitro. Under the conditions of the test only Bacteroides hypermegas and a Bifidobacterium sp. were shown to inhibit the salmonellas and this was attributed to the production of volatile fatty acids (VFA's) coupled with a low pH. When these organisms were tested in newly hatched chicks no inhibition of S. typhimurium occurred. Possible explanations for this observation are considered. The pH value and concentration of VFA's in the caecal material were determined in chicks from 0-84 days. In vitro tests with S. typhimurium indicated that, whilst the organism would be able to multiply at the pH and concentration of VFA's found during the first few days after hatching, the rapid increase in VFA concentration during the first 21 days would make this increasingly difficult. The significance of the developing caecal flora in relation to VFA production and pH is discussed. Because certain feed additives are known to influence the carriage of salmonellas, the sensitivity of various caecal anaerobes to these compounds was determined in vitro, generally at 1, 10 and 100 microgram/ml. The additives tested included flavomycin, furazolidone, nitrovin, tetracyline, tylosin, sulphaquinoxaline, virginiamycin and zinc bacitracin. All the organisms tested were inhibited by 100 microgram/ml furazolidone; none were inhibited by 500 microgram/ml sulphaquinoxaline. Changes occurring in the VFA concentration, pH value and microflora of the caeca of chicks fed for 49 days or longer on a normal starter diet or the same diet containing 10 or 100 mg/kg nitrovin have been compared. When the chicks were fed on the diet containing 100 mg/kg nitrovin, the Gram-negative non-sporing anaerobes were eliminated as a significant part of the caecal flora. However, the VFA concentration combined with a low pH in chicks from 2 weeks onwards was still sufficient to inhibit salmonella multiplication. Other possibly interrelated factors which might lead to an increased salmonella carrier rate in the nitrovin-treated chickens are discussed.


Antivibrionic activity of some glycolytic cycle enzymes of animal cells. The antivibrionic activity of crystalline preparations of five enzymes of the glycolytic cycle of animals cells was investigated. Phosphorylase "a" (0.5 mg/ml), aldolase (15 mg/ml) and pyruvate kinase (0.1 mg/ml) were found to inhibit the proliferation of Vibrio cholerae cells; phosphoglucomutase and glyceraldehyde-3-phosphate dehydrogenase at a concentration of 0.25 mg/ml were found to be vibriocidal. A mixture of these enzymes containing 0.062 mg/ml of phosphorylase "a" and 0.125 mg/ml of each phosphoglucomutase, aldolase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase showed vibriocidal activity.


Differentiation markers in fetal epidermis: transglutaminase and transpeptidase. Two members of the transpeptidase family of enzymes, transglutaminase and gamma glutamyl transpeptidase, were assayed histochemically and biochemically in developing rat epidermis from day 15 of gestation through postnatal day 5. Electron microscopic examination of serial skin biopsies enabled precise dating of fetal epidermis and periderm and correlation of ultrastructural details of the cells with marker enzyme activities. Transglutaminase activity appeared histochemically in surface epidermis and in hair follicle inner root sheath on day 18 and day 21 of gestation, respectively, concomitant with the onset of terminal keratinization in these tissues. Enzyme activity was biochemically detectable 2 days before the histochemical stain became positive. Transpeptidase was active in fetal epidermis prior to keratinization but was only detectable in basal cells thereafter. Subsequent to birth, enzyme activity rose geometrically in hair follicles undergoing initial differentiation, and was thereafter found in all anagen hairs. Transglutaminase is active only in cells approaching terminal keratinization, while transpeptidase is associated with early phases of epidermal proliferation and differentiation.


A model for the use of physician's assistants in primary care. The function and long-term viability of physician's assistants in primary care is controversial. The authors hypothesize that to remain a viable entity the physician's assistant (PA) must meet criteria including ability to make independent decisions, to obtain the complete trust of the supervising physician, to deliver care of quality equal to that of physicians, and to produce revenue in excess of the PA's cost and overhead. A model for the use of a PA in primary care is described which has been in operation for four years. This model is tested against these criteria to see if conditions for long-term viability are met. The results show physician's assistants do have a valuable role im primary health care delivery which should not be eliminated by future increases in physician manpower.


Cholinergic features of photoreceptor synapses in Hermissenda. 1. A number of observations, as listed below, suggested a cholinergic basis for inhibitory interactions between photoreceptors of the eye in the nudibranch mollusk Hermissenda crassicornis. 2. The isolated eyes synthesized and accumulated acetylcholine but not other putative neurotransmitter substances. Synthesis and accumulation were determined by electrophoretic separation of products that incorporated radioactive label. Electron microscopic visualization of clear round vesicles within the photoreceptors' somata and axon hillocks was consistent with synthesis and storage of acetylcholine within these cells. 3. Pharmacologic experiments indicated the presence of cholinergic receptors on the terminal branches of the photoreceptors, which are pre- and postsynaptic to each other. Carbachol or nicotine produced hyperpolarization of the photoreceptors' membrane accompanied by a reduction of the input resistance. The reversal potential of carbachol-induced hyperpolarization coincided with the reversal potentials of the IPSPs that followed, one for one, impulses of neighboring photoreceptors. Eserine often caused blockade of the IPSPs. This blockade was associated with substantial membrane hyperpolarization and reduction of membrane resistance. 4. Neuronal endings within the optic tract in the area of the photoreceptor's terminal branches stained for acetylcholinesterase. 5. The results of these different experiments, especially when considered together, strongly suggest, although by no means unequivocally demonstrate, that the neurotransmitter of the photoreceptors is acetylcholine.


Principles of pain management. A short review. Information that contributes to our understanding of the processes that participate in the perception of and responses to pain has expanded rapidly in the last decade. Much of this information and many clinical observations demand new conceptual frameworks within which to modify and expand classical teachings of pain pathways and mechanisms. In this brief review, some of these new dimensions are considered. The limited references serve as an introduction to more comprehensive original and review material.


Studies of experimental cervical spinal cord transection. Part III: Effects of acute cervical spinal cord transection on cerebral blood flow. Regional cerebral blood flow (CBF) was measured by the microsphere technique in anesthetized, mechanically ventilated dogs before and after cervical laminectomy in four (control group), or cervical laminectomy followed by cervical cord transection (CCT) at the C-6 level in six (experimental group). No significant differences in arterial pH, pO2 or pCO2 were observed between control and experimental dogs. Baseline values for mean arterial pressure (MAP) were also similar in the two groups, but MAP fell in all experimental dogs after CCT (p less than 0.025). At 120 minutes after CCT, three of the six dogs had an MAP greater than 60 torr (66 +/- 4 torr), and in three the MAP was greater than 50 torr (45 +/- 3 torr). Regional CBF in cortical gray matter, white matter, and medulla did not change significantly after CCT in dogs with MAP greater than 60 torr. The CBF fell significantly at 120 minutes after CCT in all regions sampled in the dogs with MAP less than 50 torr (p less than 0.025). At 30 and 120 minutes after CCT, cerebellar blood flow fell significantly in all experimental animals (p less than 0.05). These findings indicate that, despite hypotension and sympathetic denervation of cerebral vessels, CBF in cortical gray matter, white matter, and medulla is maintained at normal levels after CCT by autoregulation as long as MAP exceeds 60 torr. Decreased cerebellar blood flow in the experimental group suggests redistribution of CBF after CCT with relative preservation of flow to gray matter, white matter, and medulla. Reduced CBF in the acutely cord-injured patient with significant hypotension (MAP less than 60 torr) may stimulate or complicate coexistent head injury.


Response of rat hepatic fatty acid synthesis and activities of related enzymes to changes in level of dietary fat. The rate of in vivo fatty acid synthesis as well as the levels of glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), malic enzyme (ME), citrate cleavage enzyme (CCE), acetyl-CoA carboxylase (ACX) and fatty acid synthetase (FAS) activities, have been studied in the liver of rats fed a fat-free diet for 7 days, followed by diets containing different amounts of soybean oil (0 to 24.79 kcal%) for 7 days. The dietary fat depressed activities of G6PD, 6PGD, ME, CCE, and FAS significantly at 1.24 or 2.48 kcal%. On the other hand, AC activity and the rate of fatty acid synthesis were decreased when the level of dietary fat was 12.39 kcal% or greater. These findings, as well as the pattern of decrement of enzyme activities and of lipogenesis, suggest a close correlation of fat feeding to ACX activity and fatty acid synthesis. The results also suggest that changes of G6PD, 6PGD, ME, CCE, and FAS activities may be largely independent of those modifications which occur in the substrate flux, concomitantly with the decrease of lipogenesis caused by the inclusion of fat in the diet.


Metabolism of niacin and niacinamide in perfused rat intestine. The metabolism of [14C]nicotinic acid and [14C]nicotinamide by perfused rat intestine was studied by analyzing the 14C-products formed at various time intervals after these substrates were administered intravascularly or intralumenally. Intermediates in the Preiss-Handler pathway contained isotope when [14C]nicotinic acid was administered by either route. Large amounts of isotope in niacinamide and some in nicotinamide mononucleotide (NMN) were also found indicating substantial NAD-glycohydrolase activity in this intestinal preparation. The products from [14C]nicotinamide also included the metabolites of nicotinic acid, due to deamidation of the substrate in the lumen when the exposure was prolonged. In short term studies the amide was absorbed rapidly by simple diffusion with little hydrolysis to nicotinic acid. The primary labeled form found in the perfusate when [14C]nicotinic acid was administered via the lumen for both recirculating and one pass perfusions was unchanged nicotinic acid. The primary forms found in the perfusate when the amide was given were both the amide and the acid for both one pass and for recirculating experiments. The rapid transport of nicotinamide from the lumen to the perfusate and the lack of 14C-metabolites of nicotinic acid in the intestinal tissue following intralumenal injection of [14C]nicotinamide in the living animal suggest that deamidation in the digestive tract is not a major fate of physiological quantities of niacinamide.


Changes in heart rate during administration of local anesthetics in neuropsychiatric patients. The effects on heart rate of injections of local anesthetics into the oral mucosa were studied in neuropsychiatric patients; these patients, in whom syncope had not occurred, had been hospitalized for a prolonged period. The heart rate in the neuropsychiatric patients decreased by only 3.9% in contrast to an average decrease of 12.6% in healthy adults. Diazepam was also effective in reducing the cardiac response. The lack of responsiveness in the trigeminal-vagal reflex may be a factor in protecting patients from syncope.


Alterations in cartilage metabolism by neurostimulant drugs. Suppression of growth without significant alterations in hormonal patterns has been demonstrated for the neurostimulant drug pemoline. Comparison of the in vitro effect of pemoline, methylphenidate, and methamphetamine on somatomedin-stimulated sulfate uptake by cartilage showed all three drugs to be inhibitory. Sulfate uptake by cartilage can be directly related to growth and glycosaminoglycan biosynthesis. Assay of two of the enzymes involved in the glycosaminoglycan biosynthetic pathway showed that methamphetamine and methylphenidate caused a marked depression of xylosyl- and galactosyltransferase enzyme activity. These data suggest an interference with cartilage metabolism as one possible mechanism for the growth retardation observed in children on neurostimulant drug therapy.


Percutaneous absorption: theoretical description. Equations are derived to describe the percutaneous absorption of a substance through the epidermal barrier. The treatment includes interfacial barriers and allows for the depletion of the substance in the external phase. The equations are derived both for the continuous application and for pulse experiments where the drug is applied for a time, then removed, and the response occurs some time after the removal of the drug. Competition between the drug diffusing through the keratinized cells (transcellular route) and diffusing in the interstitial channels around the cells (intercellular route) is also considered.


Percutaneous absorption: in vivo experiments. The percutaneous absorption of esters of nicotinic acid has been studied in vivo in man. The time for erythema to be produced has been measured both when the ester is applied continuously and in 'pulse' experiments when the ester is removed before the erythema develops. The results show that the erythema is produced long before steady state diffusion across the epidermis is established and the penetration of methyl nicotinate is characterized by D/l2 = 2.3 X 10(-4)s-1 where D is the diffusion coefficient and l the thickness of the barrier. Results using glycerol water mixtures in the external phase show that the route of penetration for methyl nicotinate is through the interstitial channels and not through the keratinized cells. Data for absorption from various creams and ointments (Barrett et al 1964) show that the route is independent of the nature of the external phase. Steady state data for the absorption of salicylic acid and carbinoxamine through the abdominal skin of guinea-pigs (Arita et al 1970) show that the route of penetration does not change as the experiment proceeds. Data for the absorption of other substances (Michaels et al 1975) also fit the interstitial route.


Stimulation of human platelets by carrageenans. The rank order of four carrageenans tested as inducers of human platelet aggregation was the same (iota greater than lambda greater than gelcarin greater than kappa) as their relative inflammatory potencies in vivo. All four carrageenans caused some precipitation of plasma proteins, and induced aggregation in platelet-rich plasma or washed platelet suspensions. The second phase of aggregation was citrate-dependent and associated with secretion of 5-hydroxytryptamine and lysosomal enzymes. Platelets could provide a useful model for investigating the actions of carrageenans on cell membranes.


Effect of paracetamol on amylobarbitone hydroxylation in man: a gas chromatographic method for simultaneous estimation of underivatized paracetamol and barbiturates. A rapid and specific technique for the simultaneous gas chromatographic estimation of underivatized paracetamol and barbiturates using an alkali flame ionization detector is described which is suitable for both forensic and pharmacokinetic investigations. An improved method for estimation of 3-hydroxyamylobarbitone is also detailed. These techniques were used in an investigation of the effects of oral administration of 1 g paracetamol 8 hourly on the formation of 3-hydroxyamylobarbitone from a single oral dose of 200 mg sodium amylobarbitone. No significant changes were found in the plasma concentrations and total body clearance of amylobarbitone nor was there any alteration in the urinary elimination of 3-hydroxyamylobarbitone.


The gastrointestinal absorption of paracetamol in the rat. The absorption of [3H]paracetamol by rat small intestine, colon and stomach was studied in vivo and in vitro. Small intestinal in vivo studies, using a wide range of drug concentrations, showed that absorption was efficient and uniform throughout the small bowel, no site showing preferential absorption. Double reciprocal and direct plots indicated first order kinetics. The pattern was not observed when uptake was occurring from high concentrations of paracetamol in suspension. Gastric and colonic in vivo studies showed that there was appreciable absorption of [3H]paracetamol from these sites. In vitro studies using everted intestinal sacs showed no effect on paracetamol transfer when the incubation temperature was lowered to 10 degrees C or when iodoacetate (5 X 10(-2)M) and 2.4 dinitrophenol (5 X 10(-4)M) was added to the incubation medium. There was, however, a significant reduction in transfer of paracetamol against a concentration gradient of 10:1 applied across the mucosa. These data suggest that the uptake of paracetamol is by a passive transport process and confirm the efficiency of paracetamol absorption observed indirectly by others.


Kidney function and lithium concentrations of rats given an injection of lithium orotate or lithium carbonate. A recent study by Kling et al (1978) noted the finding of higher lithium concentrations in serum and brain of rats after an intraperitoneal injection (2 mmol lithium kg-1) of lithium orotate as a slurry than of lithium carbonate in solution. The authors suggested that lithium orotate might offer advantages in the treatment of patients. We repeated the experiments of Kling et al but in addition examined the kidney function of the rats. Glomerular filtration rate and urine flow were markedly lower in rats given lithium orotate than in rats given lithium carbonate, sodium chloride or a sham injection. The renal lithium clearance was significantly lower, the kidney weight and the lithium concentrations in serum, kidney and heart significantly higher after injection of lithium orotate than after injection of lithium carbonate. The higher lithium concentrations could be accounted for by the lower kidney function. It seems inadvisable to use lithium orotate for the treatment of patients.


Pentobarbitone and skeletal muscle contractions: on the interaction with the effect elicited by the beta-adrenoceptor agonist, terbutaline. The soleus, a slow-contracting muscle, and the extensor digitorum longus (EDL), a fast-contracting muscle from guinea-pig were prepared for isometric recording in vitro. Subtetanic contractions were evoked by transmural field-stimulation. Pentobarbitone increased the force of contraction in both muscles. In the soleus it shifted the stimulation frequency-response curve to the left. Terbutaline caused a decrease in the force of subtetanic contractions of the soleus, an effect which was dependent on the stimulation frequency. In the presence of pentobarbitone, the stimulation frequency had to be lowered by about 2 HZ in order to maintain the optimum response to terbutaline. The EDL responded to terbutaline with an increased force of contraction. In this case the stimulation frequency was less critical and the effects were the same in the presence and in the absence of pentobarbitone. Experiments with alpha-chloralose yielded results similar to those obtained with pentobarbitone.


Additivity of action between polysorbate 80 and polymyxin B towards spheroplasts of Pseudomonas aeruginosa NCTC 6750. When polymyxin B and polysorbate 80 were used together against spheroplasts of Pseudomonas aeruginosa, the activities were found to be additive. These substances have previously been reported to act synergistically against P. aeruginosa, but little or no intrinsic activity towards intact cells has been attributed to polysorbate 80. We suggest that in addition to enhancing polymyxin B penetration to the cytoplasmic membrane, polysorbate 80 may also act as an antimicrobial agent when polymyxin-induced damage to the outer membrane facilitates the surfactant's passage through the cell envelope.


A comparative study of the microbiological assays currently available for nystatin raw material. The classical agar diffusion and turbidimetric methods of assay for nystatin are compared with the more recently documented assays for this antibiotic which depend upon physicochemical measurement of the response of micro-organisms. Liquid nitrogen stored inocula were used throughout. It is concluded that the newer methods of assay are as reproducible and reliable as the agar diffusion and turbidimetric methods and that they are generally more sensitive. The choice between the assay methods compared can thus be based on speed, cost and sample through-put.


Relationships between poloxamer structure and the solubilization of some para-substituted acetanilides. Saturation solubilities of several para-substituted acetanilides have been measured at 37 degrees C in aqueous solutions of structurally related polyoxyethylene-polyoxypropylene block copolymers-poloxamers L62, L63, L64, P65 and F68. These poloxamers differ only in the amount of ethylene oxide in the hydrophil. Solubilities increased with increasing poloxamer concentration. As the oxyethylene chain length of the poloxamer increased, then the solubilizing capacity per equivalent of oxyethylene decreased. The moles of acetanilide derivative solubilized per mole of poloxamer increased with poloxamer oxyethylene content in the case of the less hydrophobic acetanilides but was invariant in the more hydrophobic ones. The solubilizing capacities have been discussed in terms of the inter-relationships between the hydrophobic nature of the solubilizate and solubilizer and the site of solubilization on the poloxamer molecule.


The effects of alpha adrenergic agents on human platelet aggregation. The effects of alpha adrenergic agonists and antagonists on human in vitro platelet aggregation were studied to characterize further the platelet alpha adrenergic receptor. Aggregation induced by ADP and U46619; a stable prostaglandin endoperoxide analog, was potentiated by alpha adrenergic agonists, an effect which was completely blocked by the alpha adrenergic antagonist phentolamine (1 X 10(-6) M) but not by prazosin (1 X 10(-6) M). The order of potency for the alpha adrenergic agonists in potentiating ADP-induced aggregation was clonidine greater than or equal to epinephrine greater than alpha-methylnorepinephrine greater than norepinephrine greater than phenylephrine greater than methoxamine. Epinephrine-induced platelet aggregation was blocked by phentolamine, yohimbine, dihydroergotamine, clonidine and lofexidine but not by phenoxybenzamine (1 X 10(-5) M). These findings suggest that: 1)clonidine and lofexidine are partial agonists and 2) that the alpha adrenergic receptor of the platelet is different from the classical postsynaptic alpha adrenergic receptor and more closely resembles presynaptic alpha adrenergic receptors.


Stereospecific antidopaminergic and anticholinergic actions of the enantiomers of (+/-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene) piperidine (CTC), a derivative of cyproheptadine. (+/-)-CTC, a cyproheptadine derivative, possesses both antidopaminergic and anticholinergic activities which can be resolved, respectively, into its component (-)- and (+)-enantiomers. Both in vivo (antagonism of apomorphine-induced stereotypy, elevation of striatal homovanillic acid) and in vitro (inhibition of [3H]haloperidol binding), (-)-CTC was less active than haloperidol but more potent or equipotent compared to chlorpromazine. (+)-CTC was a more potent anticholinergic agent in vitro (inhibition of [3H]quinuclidinyl benzilate binding) than either thioridazine or clozapine, whereas in vivo (antagonism of the lethal action of physostigmine) the three compounds were similar. Comparison of the racemate with (-)-CTC in several in vivo test procedures to determine the influence of intrinsic anticholinergic activity showed that the presence of the anticholinergic (+)-enantiomer had little effect on the ability of (-)-CTC to antagonize apomorphine or elevate striatal homovanillic acid, whereas the activity of (-)-CTC was reduced in tests for postural asymmetry, avoidance and catalepsy. Stereoselectivity was also observed in terms of the alpha adrenergic blocking activity of CTC (inhibition of [3H]WB 4101 binding) which resides exclusively in the (-)-enantiomer. The ratios of (+)-CTC and (-)-CTC in terms of their anti-alpha adrenergic/antidopaminergic properties were large, suggesting a low propensity for the elicitation of orthostatic hypotension and sedation.


Anticonvulsant effects of benzhydryl piperazines on maximal electroshock seizures in rats. The anticonvulsant effects of four benzhydryl piperazines, SC-13504 (ropizine, an anticonvulsant), hydroxyzine (HDX, an anxiolytic), chlorcyclizine (CCZ, an antihistaminic) and buclizine (BUC, an antihistaminic), were investigated utilizing a modified maximal electroshock seizure test in rats. In addition to detecting the presence or absence of tonic hindlimb extension, the modified method quantified various phases of the seizure. All four benzhydryl piperazines exhibited anticonvulsant activity in maximal electroshock seizure, but SC-13504 was similar in efficacy to phenobarbital and phenytoin, and much more effective than HDX, CCZ or BUC. Additionally, SC-13504 possessed a therapeutic index much greater than any of the compounds tested. The duration of action of the benzhydryl piperazines, in hours was: SC-13504, 0.5 to 8; HDX, 0.5 to 2; CCZ, 0.5 to 16; and BUC, 2 to 8. Buc and CCZ are postulated to be converted to active anticonvulsant metabolites.


Activation of liver guanylate cyclase by paraquat: possible role of superoxide anion. Paraquat, a herbicide which is known to increase intracellular levels of superoxide anion (O2-), stimulated guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2.] activity. This stimulation by paraquat was seen at concentrations as low as 0.005 mM. The activation of guanylate cyclase by paraquat was not blocked by KCN, an inhibitor of superoxide dismutase [EC 1.15.1.1.], suggesting that the activation process probably does not involve superoxide dismutase which converts superoxide anion to hydrogen peroxide and ultimately to hydroxyl radical. Catalase [EC 1.11.1.6.] did not block the paraquat activation of guanylate cyclase indicating that hydrogen peroxide was probably not involved in the activation process. Butylated hydroxytoluene, a hydroxyl radical scavenger, also had no effect on the paraquat activation of guanylate cyclase activity. Superoxide dismutase inhibited the paraquat activation of guanylate cyclase. Thus, it would appear that superoxide ion itself can activate guanylate cyclase circumventing any requirement for hydroxyl radical formation.


Dual action of ouabain on transmitter release at neuromuscular junctions of the frog. Ouabain increased both spontaneous and evoked transmitter release in Mg++-treated frog neuromuscular junctions. This action developed as a two-step process which affected both miniature end-plate potential (m.e.p.p.) frequency and the binomial distribution of e.p.p.s. During the first part of its action, which lasts for approximately 60 min, ouabain (10(-5) M) increased the m.e.p.p. frequency following a saturable process. The increase in m.e.p.p. frequency was blocked by tetrodotoxin (15 nM). The quantal parameters of release, m and n, showed a significant increase but the parameter p was unaffected. Since the same changes in the binomial parameters were observed in Mg++-treated junctions exposed to low [Na+]0 in the absence of ouabain, it can be concluded that Na+ concentration played an important role in the increase of transmitter release. After 60 min in ouabain (10(-5) M) m.e.p.p. frequency increased by an exponential process. The binomial parameters of transmitter release, m and p, increased while n remained unchanged. This action was not influenced by TTX pretreatment nor was it reproduced by decreasing [Na+]0. The mechanism responsible for this action seems to be the Ca++- releasing effect of ouabain from the cytoplasmic sequestering sites.


Picrotoxin- and bicuculline-sensitive inhibition of cardiac vagal reflexes. Transmission in the cardiac vagal reflex pathway can be inhibited by stimulation of the hypothalamic defense region or somatic afferent nerves. A pharmacological analysis of inhibitory modulation of reflex vagal bradycardia was undertaken in the present study. Picrotoxin (0.5--1.5 mg/kg i.v.) or bicuculline (0.5--1.5 mg/kg i.v.) produced a dose-related blockade of inhibition of reflex vagal bradycardia elicited by stimulation of the lateral hypothalamus or branches of the brachial plexus in spinal (C1 or C8 transected) cats. In contrast, strychnine and pentylenetetrazol failed to change the heart rate responses produced by stimulation of the hypothalamus or brachial plexus afferents. Picrotoxin and bicuculline also blocked inhibition of reflex vagal bradycardia produced by stimulation of the inferior olive in decerebrate spinal cats. This observation supports the contention that these agents act in the brain stem to block inhibitory modulation of reflex vagal bradycardia. In addition, picrotoxin and bicuculline lowered basal heart rate in spinal cats but not in decerebrate spinal cats. This observation suggests that tonic suprabulbar inhibition of reflex vagal bradycardia also is sensitive to blockade by picrotoxin and bicuculline.


Use of the butaclamol template in a search for antipsychotic agents with lessened side effects. A number of molecular similarities between the antipsychotic agents butaclamol and clozapine were noted. Based on the premise that this was a strong indicator of a common mechanism of action (i.e., binding at the antagonist state of the dopamine receptor), a research approach was described. Three simplified analogues (4,8, and 12a) of butaclamol which still retained the molecular functionalities of the parent structure were synthesized and tested in the haloperidol receptor assay. 1-(5-Methyl-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene)-4-tert-butyl-4-piperidine (12a) displaced tritiated haloperidol with an IC50 value of 2.4 nM, as compared to a value of 0.5 nM for butaclamol However, when 12a was tested in vivo or in the spiroperidol receptor assay it was found to be considerably less potent.


Novel application of proton nuclear magnetic resonance spectroscopy in the identification of 2'-chloronordiazepam metabolites in the dog. The only metabolite of 2'-chloronordiazepam, 7-chloro-1,3-dihydro-5-(2'-chlorophenyl)-2H-1,4-benzodiazepin-2-one (1), previously identified in the dog is lorazepam (2), which is a product of 3-hydroxylation. Two phenolic metabolites (3 and 4) in the dog corresponding to 4'-hydroxylation of the 5-phenyl ring and 9-hydroxylation of the fused benzene ring, respectively, have now been identified. The structure of the 9-hydroxy isomer 4 is deduced simply from the observed NMR spectral AB (J meta = 2.5 Hz) pattern of the protons of the fused benzene ring. In contrast, since a 2'-chloro substituent is present on the 5-phenyl ring of the parent drug, the usual method of recognizing 4'-hydroxylation of this ring by observation of AA'BB' multiplets in the proton nuclear magnetic resonance (1H NMR) spectra is inapplicable. Hence, a novel method is introduced to identify the 4'-hydroxy isomer 3, based on attributing different sets of NMR substituent effect parameters to hydroxyl groups, depending on whether these groups are meta or para to the benzodiazepinimine function. The urinary plus fecal excretion of 2-4 by one dog given in a single oral 10 mg/kg dose of 14C-labeled 1 amounted to 20, 5, and 7% of the dose, respectively; the urinary metabolites were excreted predominantly as conjugates of glucuronic acid and/or sulfate.


Kinetics of dopamine oxidation by dialkylaminoalkylphenothiazine cation radicals. The kinetics of dopamine oxidatinon dialkylaminoalkylphenothiazine cation radicals (with two- or three-carbon side chains) were investigated. The two-carbon side-chain derivatives have reaction rates higher than the three-carbon ones. For chlorpromazine and promazine, extrapolation of pH 1-6 data shows that reaction rates become very fast at physiological pH.


Localization of low molecular weight 99mTc-labeled dimercaptodicarboxylic acids in kidney tissue. Kidney localization of low molecular weight 99mTc-dimercaptodicarboxylic acid complexes was examined in mice. The complexes 99mTc-dimercaptosuccinic acid, 99mTc-dimercaptoglutaric acid, and 99mmTc-dimercaptoadipic acid were formed by reducing sodium 99mTc-pertechnetate with stannous chloride in the presence of 2-10 fold excess ligand at pH 2.5 or 7.5. Kidney specificity decreased as chain length between the mercapto groups increased. Optimum kidney retention occurred with complexes formed at pH 2.5. Complexes prepared at pH 7.5 were rapidly excreted through the urine and feces. Kidney localization of complexes prepared at one pH was not altered if the pH was later changed.


Alkaline hydrolysis of 1,3-dimethylphenobarbital. The reaction of 1,3-dimethylphenobarbital (I) with 0.02-0.32 M KOH in aqueous methanol was studied. The barbiturate ring cleaved reversibly at the 1,6-position, forming a malonuric acid which was stable to further hydrolysis but which could readily recyclize to I. N,N-Dimethylethylphenylmalondiamide arose from decarboxylation of the carbamic acid formed by a 1,2-ring opening; this irreversible decarboxylation determined the diamide as the only final reaction product. The malonuric acid, which could be isolated in solid form, appeared as N-methyl-2-phenylbutyramide (GLC) following thermal decarboxylation and degradation of the acid. The I disappearance rate was biphasic, and the kinetics were consistent with the described reaction. The individual rate constants and the equilibrium constant for the reaction between I, the malonuric acid, and hydroxide were determined.


Evaluating a course in family and community health care. Described in this paper is an evaluation of the impact of a course in family and community health care on health associate students in the Johns Hopkins University. A simple before-after design was used. Students were observed interviewing an actor (simulated patient) and rated on their ability to obtain information about the "patient's" family situation. Results showed a significant increase in family orientation from pretest to posttest. The positive changes seemed to occur in the areas of family structure and family events, with no significant change being observed in the area of family dynamics. The investigator concluded that a clinical course can increase the family orientation of health associate students as evidenced in their clinical (history-taking) behavior.


Intergeneric and intrageneric inhibition between strains of Propionibacterium acnes and micrococcaceae, particularly Staphylococcus epidermidis, isolated from normal skin and acne lesions. Two hundred and forty-one strains or resident skin bacteria comprising 93 isolates of Propionob acterium acnes and 148 of Micrococcaceae derived from 36 acne patients and 8 control subjects were screened for their ability to inhibit 32 indicator strains, including 20 strains of P. acnes and 12 strains of Staphylococcus epidermidis derived from patients with all grades of acne and from normal skin. Fifty-three strains (22%) showed some activity against at least one indicator strain. Both broad- and narrow-spectrum inhibition was detected. Inhibitory isolates of P. acnes outnumbered inhibitory Micrococcaceae by four to one. There was a low frequency of inhibition of S. epidermidis by Micrococcaceae (2.7%) and by P. acnes (1.1%) and a higher frequency of inhibition of P. acnes by Micrococcaceae (9.5%) and by P. acnes (40.8%). Furthermore, 81.8% of the subjects sampled possessed strains inhibitory to P. acnes. The significance of this finding is, as yet, unknown. No difference in the prevalence of active strains in normal (20%) and acne (22.5%) skin was detected. These findings suggest that the possession of inhibitory strains and conversely the possession of sensitive strains does not predispose to acne.


Influence of some anti-inflammatory, antipyretic and analgesic agents on urinary enzyme level in rats. The influence of single oral dose of anti-inflammatory, antipyretic and analgesic agents on urinary enzymes was investigated in rats as a indicator of nephrotoxic effect. Urinary LDH activity was significantly elevated by aspirin, ketophenylbutazone, aminopyrine, phenacetin and acetaminophen. These drugs increased also H/M ratio of LDH isoenzymes. Although other test drugs have no effect on LDH in urine phenylbutazone and indomethacin elevated GPT and A1-P, oxyphenbutazone did gamma-GT and anthranilic acid derivatives did Al-P and gamma-GT. Other drugs such as sodium salicylate, ibufenac, ibuprofen, bucolome, aminopropylone, sulfinpyrazone, benzydamine and mepirizole did not significantly influence any enzyme activities measured in urine.


Novel antiviral activity found in the media of Sindbis virus-persistently infected mosquito (Aedes albopictus) cell cultures. Aedes albopictus (mosquito) cells persistently infected with Sindbis virus for a period of 6 months release into the medium a low-molecular-weight material capable of specifically reducing the yields of Sindbis virus during the "acute phase" of infection in mosquito cells. The antiviral activity was produced in detectable levels at 3 days after infection, and its concentration in the extracellular medium increased thereafter. The antiviral activity was inactivated by treatment with the enzyme protease K and heat. It was not activated by treatment with antibody prepared against extracts of Sindbis virus-infected BHK-21 cells. The antiviral activity differs from interferon produced by vertebrate cells in that it is virus specific as well as cell specific.


Epididymal abnormalities associated with undescended testis. In a prospective study of 42 patients with undescended testes 15 (36 per cent) had epididymal abnormalities. These anomalies were divided into 3 groups, including agenesis of the epididymis, atresia of the epididymis and loop or elongated epididymis. In the second group atresia could occur at the head, body or tail of the epididymis.


Meningitis from a pneumococcus moderately resistant to penicillin. Strains of pneumococci moderately resistant to penicillin were recovered from three patients at the Children's Hospital of Pittsburgh during 1978. One of these children had meningitis and showed signs of early relapse despite high doses of penicillin G potassium. Routine screening of pneumococci for penicillin resistance is recommended.


The nasopharyngeal culture in acute otitis media. A reappraisal of its usefulness. Simultaneous cultures of the nasopharynx and middle ear exudate (obtained by tympanocentesis) were obtained from 225 children (mean age, 34 months; median age, 41 months) with suppurative otitis media. A 72% prediction rate for middle ear pathogens was obtained by examining the nasopharyngeal cultures after the strict observance of two essential prerequisites: (1) the nasopharyngeal culture was immediately plated on appropriate solid agar and (2) a semiquantitative method for bacterial enumeration was employed in the reading of the nasopharyngeal culture plates. The technique was most valuable where 2+ (greater than 25% up to 50% of total number of colonies was a single pathogen) or greater of a single pathogen was recovered from the nasopharynx. In only one instance, the semiquantitative nasopharyngeal culture incorrectly predicted the middle ear pathogen if one was recovered. Quantitative nasopharyngeal cultures were particularly useful in predicting the presence of ampicillin-resistant Haemophilus influenzae and group A streptococci as causative agents in otitis media.


Myocardial metabolism and heart disease. Anoxia has been compared with ischaemia. The abrupt restoration of either oxygen of flow may accelerate cardiac damage. Anoxic stimulation of glycolysis (Pasteur effect) is inhibited during ischaemia by lactate and proton accumulation at the levels of phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase. Anaerobic glycolysis provides lactate and ATP; breakdown of the latter provides protons. During partial respiration thought to occur in partial ischaemia, continued production of CO2 is a factor contributing to intracellular acidosis; mitochondrial ATP when formed by continued respiration also yields protons when ultimately broken down. The endoproducts of aerobic glycolysis (pyruvate and NADH) are transported into the mitochondria by the malate-aspartate cycle and by pyruvate dehydrogenase activity. Adenine nucleotide transferase activity normally transfers the mitochondrially-made ATP to the cytoplasm, but acyl CoA accumulates in ischaemia (or during perfusions with high circulating free fatty acids) to inhibit the transferase. The mitochondrial creatine kinase is thought to transform ATP transported outwards into creatine phosphate which can permeate the outer mitochondrial membrane. Further compartmentation of ATP may be by other creatine kinase isoenzymes or in relation to the cell membrane. The glycogenolytic-sarcoplasmic reticulum complex links a glycogen pool to the sarcoplasmic reticulum. Cyclic AMP may regulate admission of calcium to the cell during the plateau of the action potential and promote calcium uptake by the sarcoplasmic reticulum by phosphorylation of phospholamban. The latter promotes the activity of the calcium-transport ATPase. Calcium and cyclic AMP may also interact at the level of the contractile proteins where cyclic AMP phosphrylates troponin. Cyclic GMP generally has opposite effects to cyclic AMP and undergoes opposite changes in the frog cardiac cycle to those of cyclic AMP. A present it is reasonable to suppose that physiological effects of adrenaline or of cholinergic agents on the myocardium are mediated by cyclic AMP or cyclic GMP, respectively, but this hypothesis still lacks firm support. There is an association between tissue cyclic AMP and ventricular fibrillation after coronary ligation, and direct evidence for a role of cyclic AMP in promoting arrhythmias has been obtained by studies on the ventricular fibrillation threshold in the rat heart. However, there are other mechanisms, involving first the effects of substrates on the action potential duration, and secondly, the fast channel, which can also give rise to the development of malignant arrhythmias.


[Increase in myocardial resistance to ischemia by excluding the heart from the circulation by using a beta-adrenergic receptor block]. The effect of propranolol on the function of the heart, its hemodynamics and metabolism was studied on dogs and rats. It was established that propranolol-induced block of the beta-adrenergic receptors is conducive to a decrease in the intensity of myocardial metabolism and increase of myocardial tolerance to ischemia.


[A sudden inexplicable deterioration of vision caused by bromcarbamide drugs (author's transl)]. On two female patients it was shown that intoxication by sedatives containing part bromecarbamide may result in various ocular diseases. The two patients complained of a sudden inexplicable deterioration of vision; semi-dilated slow-responding pupils were diagnosed. Only in one case could a sudden vertical nystagmus be observed. Many possible symptoms were shown. In most cases a discontinuation of drug together with therapy lead to a complete withdrawal of symptoms.


Cation-dependent phosphatase activites in a rat pancreatic islet plasma membrane fraction prepared by one-step gradient centrifugation. A plasma membrane-enriched fraction was prepared from homogenized rat pancreatic islets by a one-step sucrose gradient centrifugation. Using 125I-wheat germ agglutinin as a plasma membrane probe, a fraction was obtained at a sucrose density of about 1.10 that was enriched in 5'-nucleotidase, Mg2+-ATPase and alkaline phosphatase. The fraction contained little, if any, monoamino oxidase activity, insulin or DNA. Hydrolysis of 3-0-methyl-fluoresceinphosphate was stimulated by K+ (10mM) at a pH optimum of pH 8.2. Hydrolysis of ATP-gamma-32P in the presence of MgCl2 was of high specific activity and was optimum at pH 7.0 and 8.2. K+ did not affect ATP-hydrolysis. At pH 8.2, a small fraction of the total Mg2+-ATPase activity was inhibited by ouabain in the presence of Na+ and K+. Since K+-stimulated phosphatase activity does not correlate with Mg2+-ATPase, the two assay systems define separate enzymatic processes.


Formation of gamma-glutamyl-epsilon-lysine bridges between membrane proteins by a Ca2+-regulated enzyme in intact erythrocytes. A rise in the intracellular concentration of Ca2+-ions in human erythrocytes causes the formation of high-molecular-weight membrane protein polymers, cross-linked by gamma-glutamyl-epsilon-lysine side chain bridges. Cross-linking involves proteins at the cytoplasmic side of the membrane (band 4.1, spectrin, and band 3 materials) and the reaction is catalyzed by the intrinsic transglutaminase. This enzyme is regulated by Ca2+-ions and it exits in a latent form in normal cells. The protein polymer, isolated from the membranes of Ca2+-loaded intact human red cells, is heterogeneous in size and may contain as many as 6 moles of gamma-glutamyl-epsilon-lysine cross-links per 100,000 gm of protein. Synthetic compounds, which either compete against the epsilon-lysine cross-linking functionalities of the protein substrates (eg, histamine, aminoacetonitrile, cystamine) or directly inactivate the transamidase (eg, cystamine), inhibit the membrane polymerization reaction in intact human erythrocytes. They also interfere with the Ca2+-induced irreversible shape change from discocyte to echinocyte and inhibit the irreversible loss of membrane deformability. Thus, the transamidase-catalyzed production of gamma-glutamyl-epsilon-lysine cross-links in the membrane may be a common denominator in these cellular manifestations.


The public's view of physicians' assistants and nurse practitioners: a survey of Baltimore urban residents. This study of public attitudes toward physicians' assistants and nurse practitioners finds that the public regards the two groups of health workers as remarkably similar. A telephone survey of 2,583 households in the Baltimore, Maryland, metropolitan area indicates that about half  the population have heard of a PA or NP, though only 4 per cent report receiving care from such workers. In this urban sample, respondents accepted the principle that important medical care functions can be delegated, as long as the PA or NP is considered assistant to the physician. The public reported more acceptance of tasks performed by nurse practitioners than by physicians' assistants, though the differences are small.


Physician attitudes toward physician extenders: a comparison of nurse practitioners and physician assistants. A survey of all physicians in the Eighth District Medical Society (Western New York) was conducted in 1975 to determine physician attitudes toward employment of and task delegation to nurse practitioners. The results of this study and one other similar study of nurse practitioners are compared to results of two previous studies examining physician attitudes toward physician assistants. It appears that physicians are somewhat more willing to employ and delegate tasks to a physician's assistant. Some correlates of physician attitudes toward each of the two types of physician extenders are also compared and discussed.


[Necrotizing angiitis of small vessels. A clinical study of 25 patients with skin biopsy (author's transl)]. Necrotizing angiitis or vasculitis exhibits a wide clinical spectrum characterized by many different cutaneous manifestations. Diagnosis must be confirmed by histopathology. We studied in retrospect 25 patients whose conditions had been diagnosed by skin biopsy. Histologic examination revealed infiltration by polynuclear cells and fibrinoid necrosis of the walls of the blood vessels in the skin. The great variety of clinical manifestations and etiologies stands out in a review of the records of these patients. Necrotizing angiitis has been found associated with mixed cryoglobulinemia; administration of drugs, milliary tuberculosis, bacterial meningitis, rickettsiosis, staphylococcal sepsis, pharyngotonsillitis, and rheumatoid arthritis. Necrotizing angiitis is a group of diseases with a great variety of clinical manifestations, ranging from benign to fatal. The various entities described to date have been more like different clinical forms of the same disease that distinct conditions. In cases of necrotizing angiitis caused by basically immunological mechanisms, the walls of the blood vessels may be impaired in varying diffuse degrees. The prognosis of the disease depends on the intensity of the inflammation and its repercussions on the parenchymas of different organs. The kidney is the most susceptible organ in this case. Treatment should be directed toward the avoidance of predisposing and etiologic factors, detection of the immunological reaction, requiring careful and individual attention in every case.


[Panarteritis nodosa with positive Australia antigen (author's transl)]. A case of panarteritis nodosa with positive Australia antigen is presented. Panarteritis appeared following serum hepatitis and caused arthromyalgia, abdominal pain, prolonged fever of unknown origin, peripheral polyneuropathy, blood hypertension, and renal insufficiency. A muscular biopsy showed atrophy due to denervation and necrotizing arteritis in various stages causing serious damage to the arteries. Abdominal arteriography clearly demonstrated the existence of aneurismal dilations in the liver, pancreas, and kidneys. The angiographic findings in panarteritis nodose are discussed with special reference to the aneurysms localized in several organs. Their situation is described in detail; it is usually abdominal and more specifically intrarenal. The fact that they occur in a high percentage of cases is helpful when establishing the diagnosis. Lastly, the role of Australia antigen in the development of panarteritis nodose is discussed. It stimulates an immune response and the production of circulating immunocomplexes which are depostied on the vascular walls with complement fixation and damage to the blood vessels. The possibility that other viral agents may be present in the various types of necrotizing vasculitis in humans is commented on.


[Flunitrazepam with anterograde amnesia and reduction of blood pressure before local anaesthesia without intubation in 3000 ENT operations (author's transl)]. After premedication with flunitrazepam=Rohypnol 2 mg orally (2--3 hours preop.) and morphine-atropine (30 min preop.) the patient receives slowly "Ro" i.v. until the phenomenon of volume reduction when speaking is observed. This allows for the smallest possible dosis to achieve sufficient amnesia. After about 20 min the patient becomes responsive again, while his amnesia lasts for about 3 hours more. The cardiovascular functions remain stable with a 25% decrease of systolic blood pressure. Vomiting is reduced. The dry operative field makes microsurgery much easier and improves the final result of the operation. After gaining sufficient experience of the staff, 100% amnesia was achieved in all operations during the last 3 months.


[Clinical Investigations about the behaviour of pulmonary respiration and cardiovascular circulation after the application of Rohypnol for basis-sedation for microsurgical operations in otolaryngology in local anesthesia (author's transl)]. The influence of analog-sedation on pulmonary respiration and cardiovascular circulation caused by the action of pentazocine/flunitrazepam respectively in microsurgical operations under local anesthesia in otolaryngology is investigated in two collectives of patients. The results are presented and the hazards, especially the hypoxemia and its avoidance are discussed.


Solubilization and characterization of the partially purified penicillin sensitive D-alanine carboxypeptidase of Neisseria gonorrhoeae. Treatment of crude gonococcal cell envelopes with a solution of 2 M KCl + 1% Brij 36T resulted in the solubilization of a portion of the D-alanine carboxypeptidase activity of Neisseria gonorrhoeae envelopes. This soluble enzyme preparation was partially resolved by chromatography on a column of DEAE-cellulose. The partially purified enzyme eluted from the column with a gradient of NaCl (0-1 M), catalysed the release of D-alanine from a radioactively labelled UDP-N-acetylmuramyl-pentapeptide with a pH optimum of 8.6. The Km for the soluble enzyme acting on this substrate was 0.18 mM. The enzyme activity was sensitive to inhibition by low concentrations of the beta-lactam antibiotics, penicillin G, ampicillin, oxacillin and mecillinam.


Pneumococcal peritonitis in adolescent girls. Two cases of pneumococcal peritonitis, which occurred after puberty in previously healthy adolescent girls, are described. In each case, the infection was caused by a Type 1 tetracycline-resistant pneumococcus.


Quiescence and/or pathogenicity of the ascomycete micro-organism as one of three separate entities in a living animal or human host. Experimental studies on I.C.R. mice with induced ascitic fluid suggest that the mold micro-organism of the ascomycete family when inoculated in a living host, with a lowered pH, may survive but only initially in a conidial phase as a distinct and separate entity. It may reside quiescently as a sexual conidium within a cell of the reticulo-endothial system or with provocation multiply as the asexual form. Because of their altered physiomorphological status these conidial bodies cannot be identified accurately either by a microscopic study on a cytobiological wet smear basis or by a stained slide, nor be readily recaptured by utilizing the conventional culture techniques. Revised culturing methods utilizing the elements carbon dioxide, sodium chloride, calcium and magnesium in Sabouraud's Agar slant aerobically may help recover the adult micro-organism for positive identification. Sometimes, however, under deteriorating or moribund status of the host the conidia may revert, in ascitic fluid, to the autonomous form spontaneously. The transformation-reformation potential of the ascomycete in vivo, the non-recognizable status of the conidial bodies, and the inability to recapture the adult autonomous form by conventional laboratory means, despite their known presence, suggests a possible relationship of this micro-organism to certain of the acute, chronic inflammatory diseases, pleomorphic tumors, granulomas, and the malignancies. These diseases despite signs of an acute or chronic inflammatory process usually give a "no growth" result. The conidial phase of the ascomycete may very well, I believe, be the malefactor in these conditions that hitherto have defied etiological explanation.


[The influence of a combined diurectic-beta-receptorblocker therapy on elevated exercise blood pressures. Ergometric investigations in hypertensive patients (author's transl)]. In hypertensive patients physical exercise can induce considerable increases of blood pressure. This means particularly for elder patients a high risk of cardiovascular complications. Therefore we investigated in 13 elder patients suffering from arterial hypertension the effect of a hypotensive combined therapy with a diuretic and a beta-receptorblocker on elevated blood pressures during and after ergometric work. Apart from the reduction of the blood pressure at rest, especially the systolic and diastolic blood pressure during exercise was lowered significantly. In addition to a diuretic hypotensive therapy a beta-receptorblocker can be of great benefit also for elder patients particularly in order to reduce elevated exercise blood pressures.


[Saralasin in resistant hypertensive crisis (author's transl)]. 4 patients with hypertensive crisis (glomerulonephritis [n = 2], phaeochromocytoma [n = 1], reno-vascular hypertension [n = 1] combined with encephalopathy, showed a normalisation of blood-pressure up to 18 days during angiotensin-II-blockade with saralasin. Prior, blood pressure was treated insufficiently by intravenous diazoxide and Na-nitroprusside. Increased plasma-renin-activity and plasma levels of catecholamines pointed to an activation of the renin-angiotensin- and sympathico-adrenergic system. A trial of therapy with saralasin--especially, if blood-pressure response to diazoxide and sodium-nitroprusside is insufficient--could be indicated. Side-effects like pressor-reactions are excluded by very low priming doses (0,1 microgram/kg/min); rebound-hypertension at the end of the therapy is avoided by an overlapping therapy with renin suppressing drugs (beta-receptor blockers, clonidine, guanfacinum).


[Familial endocrine adenomatosis (author's transl)]. The combination of pituitary and thyroid gland adenomatosis is reported in four family members of two generations. This finding of dominant inheritance is discussed with special reference to multiple familial adenomatosis, also known as Wermer's syndrome. The endocrine status including dynamic function tests is presented. It is our intention to point out that in cases of monoglandular adenomatosis clinical attention should be directed not only to anterior pituitary and thyroid gland but also to their possible incidence with tumours of the parathyroid gland and the islet cell organ.


[Hyperacute encephalomyelitis following lyssa vaccination]. A case of hyperacute disseminated encephalomyelitis following lyssa-vaccination is reported. Clinical symptoms occurred on the tenth day after the vaccination and the patient died three days afterward. Demyelinization and glia proliferation was observed histologically in the spinal cord. No alterations could be seen in the peripheric nerves. 1. The spinal and cerebral forms of the postvaccinial encephalomyelitis can not be sharply distinguished. 2. In the postvaccinial encephalomyelitis there are also severe infiltration, demyelinization and gliosis in the opticus. 3. Post-vaccinial lyssa encephalomyelitis is a rare, but unavoidable complication of the lassa-vaccination. 4. The State Insurance Company have to pay damages.


Aberrations of suppressor T cells in human graft-versus-host disease. To determine whether imbalances in immunoregulatory T-cell subsets exist in patients with graft-versus-host disease, we analyzed T cells in three patients with acute and in six patients with chronic graft-versus-host disease after bone-marrow transplantation. The normal human peripheral-blood T-cell compartment is composed of 80 per cent TH2-and 20 per cent TH2+ T cells, and defined by reactivity with subset-specific heteroantiserums. Human suppressor cells are TH2+, whereas helper cells are TH2-. Patients with acute and chronic graft-versus-host disease had abnormalities in these populations, and their T cells frequently bore la-like antigens. Patients with acute disease lacked TH2+ cells, and the reappearance of this subset preceded the cessation of disease activity. Chronic disease, in contrast, was more heterogeneous. Suppressor cells were lacking in two patients but increased in the other four. Two of these four patients had TH2+, la+ T cells, suggesting in vivo activation of suppressor cells. Studies showing that these TH2+, la+ cells actively suppressed the in vitro immune response support this hypothesis and suggest that the immunoregulatory cells may profoundly affect the overall immune response.


Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. To determine whether allogeneic bone-marrow transplantation is associated with a graft-versus-leukemia effect, we examined the relation between relapse of leukemia and graft-versus-host disease in 46 recipients of identical-twin (syngeneic) marrow, 117 recipients of HLA-identical-sibling (allogeneic) marrow with no or minimal graft-versus-host disease, and 79 recipients of allogeneic marrow with moderate to severe or chronic disease. The relative relapse rate was 2.5 times less in allogeneic-marrow recipients with graft-versus-host disease than in recipients without it (P less than 0.01). This apparent antileukemic effect was more marked in patients with lymphoblastic than nonlymphoblastic leukemia, and in those who received transplants during relapse rather than during remission, and was most evident during the first 130 days after transplantation. Survival of all patients was comparable since the lesser probability of recurrent leukemia in patients with graft-versus-host disease was offset by a greater probability of other causes of death.


New neural cell lines derived from experimentally induced rat tumors and from human neuroblastomas. We have isolated a series of new cell lines from tumors of the nervous system. Two approaches have been used. In the first, tumors were induced in neonatal rats with the potent carcinogen ethylnitrosourea. Tumors were put into cell culture and cloned after several passages. The resultant cell lines were characterized for a variety of presumptive neuronal and glial functions. Our second approach, designed to identify lines with neuronal characteristics, has been to culture and analyze cells derived from human neurolbastomas. Five lines have been characterized for the Na+ action potential ionophore and several enzyme markers.


Therapeutic antagonism between anticholinergic antiparkinsonism agents and neuroleptics in schizophrenia. Implications for a neuropharmacological model. Systematic data from three studies suggest that anticholinergic antiparkinsonism agents, when added to ongoing neuroleptic treatment in schizophrenics, have the effect of arresting or reversing therapeutic changes, and when given alone to untreated patients, tend to further worsen their psychosis. The countertherapeutic effects of anticholinergic drugs are reflected particularly in parameters which represent features of schizophrenic psychosis most consistently responsive to neuroleptics. It is proposed that these anticholinergic effects are central in origin and point to the involvement of cholinergic mechanisms in the expression of schizophrenic psychosis and its improvement with neuroleptic medication.


Catastrophe theory: a model interaction between neurochemical and environmental influences in the control of schizophrenia. Catastrophe theory is a new mathematical technique relating variables in a novel, discontinuous way. It suggests ways in which neurochemical and environmental influences could interact so that very small changes in either variable may produce rapid changes in intensity of psychosis that are characteristic of schizophrenia. Other behavioural and pharmacological characteristics of schizophrenia previously considered paradoxical may be similarly explicable, and the model predicts factors most likely to generate relapse.


Bromolysergide and methysergide protection against ECS-induced retrograde amnesia. Bromolysergide (BOL 148) and methysergide (UML 491), 2 mg/kg intraperitoneally, and saline were administered to rats 45 min before one-trial passive-avoidance conditioning followed by electroconvulsive shock (ECS) or sham-ECS (ECS). On test session (24 h later), the groups treated with both BOL 148 and UML 491 exhibited a clear-cut retention in comparison to saline-ECS rats. On the other hand, all drugged groups, regardless of their submission to ECS, showed a little less pronounced consolidation than saline-ECS rats. The antiamnestic effect brought about by the two drugs was discussed in terms of receptor antagonism against ECS-released brain serotonin, whereas the lower passive-avoidance level observed in treated animals was considered in relation to a possible antipunishment effect of antiserotoninergic treatment.


Lergotrile in Parkinson disease: further studies. Lergotrile was administered to 53 patients with advanced Parkinson disease (PD), who had increasing disability despite optimal treatment with levodopa/carbidopa (Sinemet). Thirty-nine patients who could tolerate at least 20 mg per day lergotrile (thus considered "adequately treated") had significant descreases in rigidity, tremor, bradykinesia, gait disturbance, and total score without increased involuntary movements. Twenty-one of these 39 patients improved by at least one stage. Among the 39 patients, 23 had "on-off" effects, and in 13 of these the "on-off" effects decreased on lergotrile. The mean daily dose of lergotrile in adequately treated patients was 49 mg, permitting a 10 percent reduction in the dose of levodopa. Lergotrile was discontinued in 33 of the 53 patients because of adverse effects, including hepatotoxicity (11 patients), mental changes (12 patients) and orthostatic hypotension (8 patients). Although lergotrile, when added to levodopa, has a definite antiparkinsonian effect, the incidence of adverse effects, particularly hepatotoxicity, makes it unlikely that this ergot alkaloid will become widely available for the treatment of PD. Analogues of lergotrile have been synthesized, and it is hoped that they will duplicate the antiparkinsonian effect of this drug without its toxicity.


[The treatment of acid-base imbalance in the intensive care of respiratory diseases]. After giving an outline of pneumogenic respiratory insufficiency, signally that deriving from chronic obstructive bronchopulmonary disease, the Authors describe the intensive care of respiratory insufficiency, first from the anesthesiologist's point of view and then in a broader medical sense. In regard to the latter, the Authors emphasize the importance of material equipment and staff training and teamwork; they also list a number of possible iatrogenic disorders in intensive care. Next they discuss medical aids and more specifically the machinery designed to assist respiration, such as pulmonary ventilators and the "iron lung", as implements that can be used to advantage in medical wards. Then they describe the elements to be used for a correct assessmnet of the severity of respiratory insufficiency, under the following subheadings:--state of coma, if present;--state of acid-base balance, oxemia, and water and electrolyte balance;--circulatory compensation or failure;--need for correcting bronchial obstruction. Through several representative examples concerning the medical correction of alterations of CO2, pH, electrolyte composition, and water and blood volumes, they describe the therapeutic measures to be undertaken particularly as regards the metabolic sequels (alkalosis or acidosis) that may occur in the course of treatment. Coming next to intensive care utilizing mechanical devices, they stress the importance of monitoring the parameters of humoral balance during (and even more so, after) said treatment, in view of avoiding the emergence of iatrogenic disturbances such as the reventilation syndrome and the syndrome of post-hypercapnic metabolic alkalosis.


[Changes in the acid-base and water-electrolyte balance induced by salbutamol. "In vivo" studies in patients with chronic broncho-pulmonary disease and "in vitro" by tonometry of venous blood]. The Authors studied the effects of e.v. Salbutamol evaluating the acute "in vivo" variations of acid-base and hydro-electrolitic balance in 16 chronic obstructive lung patients undergoing e.v. drug administration, and also ionic variations "in vitro" of venous blood samples incubated and tonometrated with the drug. The results "in vivo" do not show variations of acid-base equilibrium (paO2, paCO2, pH, HCO3-); whereas diminution of haematocrit (Ht), rise of urinary osmolarity and variations of hydro-electrolitic balance (Na+, K+, Cl-) are demonstrated. The results "in vitro" do not show considerable variations on ionic assessment. These data, according to the other latest result, indicate the possible role of haemodilution. We think that the explanation of these phenomena could be a modification of renal water and electrolytes reabsorption, likely under the influence of antidiuretic hormone (ADH), stimulated in the hypothalamus and activated also by the beta-stimulant drug at tubular cell receptors.


[Comparative evaluation of the respiratory function and the acid-base equilibrium in patients with chronic bronchopulmonary disease after intravenous administration of 5 beta receptor agonists]. The Authors studied lung mechanics, acid-base balance parameters, arterial blood pressure and pulse rate in five different groups of chronic obstructive lung disease patients, undergoing e.v. different bronchodilators. The drug were: 1. group: 500 gamma of orciprenalina; 2. group: 500 gamma of idrossi-fenil-orciprenalina; 3. group: 200 gamma of salbutamolo; 4. group: 100 gamma of trimetochinolo; 5. group: 500 gamma of terbutalina. The comparative analysis of bronchodilators, their cardiovascular effects and on acid-base balance indicate that mainly salbutamol and trimetochinol have negligeable adverse effects.


[Floctafenine in the treatment of painful syndromes of neurologic interest]. The clinical results obtained with phloctaphenin in an "open" study comprising cases of real neuralgia and spinal radicular pain syndromes and in a "double-blind" study comparing the preparation with a placebo, and involving algico-vasomotor syndromes of the face, are reported. The results obtained confirm the antalgic power of phloctaphenin for by the third day, subacute or chronic pain syndromes already presented a significant improvement in simptomatology, while in algico-vasomotor syndromes of the face, the treatment proved effective in eliminating pain attacks.


Physiological mechanisms of flooding (implosion) therapy. Desensitization of psychological and physiological complex structures may be the most important element of flooding treatment. The implosive sessions are assumed to represent a supramaximal stimulation of pathologically excited and inert complex structures resulting in protective inhibition, irradiation of excitation, reduction of the excitation and inertness, and a decrease of the overshooting autonomic reactivity of the complex structures, leading to reduction of anxiety, aggression, and other pathologically increased feelings. Advantages such as stronger and improved flooding can be achieved by a flooding in hypnosis. The therapeutic indications go beyond the usual treatment of phobic states. In order to establish the psychological and physiological mechanisms in implosion there is a need for psychophysiological investigations. However, much is unknown about mechanisms. Controlled comparisons with other treatments give limited answers. Perhaps an international case history bank might establish which clinical conditions might benefit by technical modifications of flooding.


Effect of organic acid absorption on bicarbonate transport in rat colon. The absorption of organic anions and the influence of these anions on the movement of HCO3- were studied in vivo in rat colon using a perfusion technique. The absorption of short chain fatty acids (SCFA's) such as acetate, propionate, and butyrate was much greater than that of succinate or lactate. With increasing initial concentration of SCFA up to 100 mmol . 1-1, SCFA absorption increased linearly in correspondence with HCO3- appearance. Final pCO2 level of the perfusion solution with SCFA was the same as the plasma level. Among the SCFA's, no significant differences in absorption or their effects on HCO3- appearance were observed. The presence of Na+ stimulated SCFA absorption, and the maximum value was obtained at more than 100 mmol . 1-1 of Na+. These results suggest that a specific system for HCO3- secretion activated by SCFA exists in the colon, and that this system may control the intraluminal pH by the alkalization of intestinal contents.


Transient hypoxia: ventilatory response after vagotomy and during artificial phasic inflation. The early ventilatory response to transient hypoxia was examined in the anaesthetized rabbit. In intact spontaneously breathing animals, an increase in tidal volume (VT) with an accompanying slight increase in inspiratory duration (TI) and a decrease in the expiratory duration (TE) was observed. After vagotomy, the ventilatory response was distinguished by a greater increase in VT and a significant decrease in TI and TE. In another group of artificially ventilated rabbits, an increase in inspiratory volume with a simultaneous decrease in breathing frequency was found to involve a smaller reflex increase in phrenic inspiratory discharge after onset of transient hypoxia. These observations suggest that afferents from pulmonary vagal stretch receptors inhibit those from arterial chemoreceptors.


A cholinergic mechanism involved in the neuronal excitation by H+ in the respiratory chemosensitive structures of the ventral medulla oblongata of rats in vitro. The mechanism of neuronal excitation by H+ in the medullary chemosensitive structures was analyzed in brains slices of the rat in vitro. Responses of neurons to H+ in the ventral surface layer were compared with responses to various transmitter substances. Neurons excited by H+ were always also excited by acetylcholine (ACH). ACh increased the activity of 70% of superficial ventral medullary neurons. Effects of noradrenaline and serotonin on the activity of neurons were largely opposite to that of H+. Cholinergic blocking agents like atropine, hexamethonium and mecamylamine depressed the H+-elicited excitation of neurons. The cholinesterase inhibitor, eserine, increased the neuronal activity. In the presence of eserine, a solution of low pH caused further increase in discharge of most neurons. The low pH solution prolonged and augmented the excitatory action of ACh on the ventral medullary neurons. It is concluded that the H+-elicited excitation of neurons in the "chemosensitive" structures is dependent upon intact cholinergic transmission in the surface layer. This may be interpreted as resulting from facilitation and/or prolongation of such a chemical transmission by H+.


99mtc-unithiol complex, a new radiopharmaceutical for kidney scintigraphy III. Studies of labelling unithiol with 99mtc. Labelling of 2, 3-dimercaptopropane sodiumsulphonate (Unithiol) with 99mTc resulted in essentially three components in the GCS pofile: the top zone, a low-molecular Complex A and a high-molecular Complex B. In the presence of tin metal a fourth component, Complex C, could be distinguished. Complex A was relatively independent of pH, the proportion of Complex B increased with increasing pH. Methods were developed for preparing, with over 80% labelling efficiency, either Complex A or Complex B, each having high stability in the preparation vials and in human blood.


Antimicrobial activity of chloramphenicol in solid dispersion systems. The effect of solid dispersion techniques on the antimicrobial activity of chloramphenicol has been studied and it was proven that the antimicrobial activity of chloramphenicol is not affected when the drug is present as a coprecipitate with carbowaxes (4.000, 6.000, 12.000), and PVP 11.000 and 40.000) also in fusion systems with these polymers. In contrast, the antimicrobial activity of the drug is enhanced when it is present in the from of a solid dispersion system.


[Conditions of exolipase biosynthesis by the fungus Oospora fragrans]. The fungal strain Oospora fragrans isolated from sunflower seeds had a high lipase activity, especially on the media containing soybean flour and various oils. The fungal lipase showed inductive characteristics, the best inducers being olive and soybean oils. The biosynthesis of lipase from O. fragrans occurred at the optimal temperature of 26-30 degrees C and strong aeration. Maximun of lipolytic activity did not coincide with maximum accumulation of biomass and developed at the log-phase of the fungal growth. With age the lipid content in the mycelium increased in parallel with the biomass accumulation. Mycelial lipids of O. fragrans contained nine fractions, among which fatty acids and triglycerides were in predominance. The study of properties of O. fragrans lipase showed a high pH value and thermal stability, the capacity to function at low temperatures, and activity towards many substrates. The enzyme readily hydrolyzed not only natural vegetable (olive, linseed and mustard) oils but also oils of microorganisms grown on petroleum hydrocarbons.


Microvascular free transfer of human testes. This clinical study was undertaken to demonstrate the feasibility of free transfer of undescended human testes with microvascular anastomoses. We have performed 4 microvascular free transfers of such testes in children aged 5, 6, and 8 years, with follow-up periods of one to three years. All 4 testes have remained clinically viable. The final proof of functional viability will have to await puberty, of course.