Recent developments in the supportive therapy of acute myelogenous leukemia. The prognosis for patients with AML is improving, but mortality due to bleeding and infection remains significant. HLA compatibility has been the cornerstone of matching for prophylactic platelet transfusion; while HLA matched platelets are often of benefit, we have observed that HLA matching does not reliably predict transfusion responses. The platelet migration inhibition assay is, however, consistently predictive. The matching problem may be circumvented by the use of frozen autologous platelets, which circulate and function hemostatically. In the granulocytopenic patient with de novo fever (frequently due to bacterial sepsis), the immediate empiric use of broad spectrum antibiotics is mandatory. If the marrow begins to recover from chemotherapy shortly after the onset of infection, such that the peripheral granulocyte count will approach normal within 10 days, the likelihood of survival from an episode of septicemia after antibiosis now approaches 80%. If the marrow does not recover shortly, however, the likelihood of survival with antibiosis alone is poor. In this setting, survival is improved if patients are given granulocyte transfusions in addition to antibiotics. Patients who receive chemotherapy in a laminar air-flow room (LAFR) experience fewer severe infections than do patients in a conventional ward. However, most patients who are unresponsive to initial chemotherapy remain so in spite of protection from infection. Thus, the available results do not suggest that the LAFR is likely to improve appreciably the rate or duration of remission. Using malignant lymphoma as a model, we have found that cryopreserved autologous marrow infusions can hasten hematopoietic recovery in man after high-dose chemotherapy, and earlier reconstitution may be of clinical benefit to the patient; techniques are at hand that might permit the application of this concept to AML.


Marrow transplantation for acute leukemia. Marrow transplantation enables the physician to ignore the complications of marrow toxicity which limit the chemotherapy of leukemia and makes it possible to explore new drugs and regimens. The results of marrow transplantation for 154 cases of end-stage acute leukemia carried out by the Seattle Marrow Transplant Team are summarized. Even with the use of an HLA matched sibling as a donor, allogeneic marrow transplantation is followed by graft-versus-host disease in about 2/3 of the patients which is of life-threatening severity in approximately 20%. An actuarial plot of the recurrence rate of leukemia following transplantation shows that about 2/3 of the recipients of either allogeneic or syngeneic (identical twin) marrow will relapse within 2 years. However, about 1/3 will not relapse and recurrence of leukemia has not been observed after 2 years. A Kaplan-Meier plot of the survival of 29 syngeneic marrow recipients and 110 recipients of allogeneic marrow shows an almost flat survival curve in the period f om 2 to 7 years after transplantation. The leukemia free survival of these patients on no maintenance chemotherapy constitutes an operational definition of cure in these patients.


Effects of cysteine upon tumor cells.

Effects of cysteine upon tumor cells. Cysteine had been reported to increase survival time in thymoma-bearing mice and the interpretation suggested was that this was due to inhibition of a collagenase activity associated with some tumor cells by a chelating action of cysteine. In the present work it was shown that cysteine was a particularly potent inhibitor of amino acid transport into S37 ascites tumor cells, raising another possible interpretation of the earlier data. Sarcomas have previously been reported to lack collagenase activity; a survival study using S37 cells was therefore undertaken in an attempt to distinguish between possible interpretations of the earlier data involving thymomas. A null result was obtained with either cysteine or EDTA, reinforcing the earlier interpretation that survival enhancement with thymoma-bearing mice was due to an effect on collagenase. Other sulfhydryl analogs were found to inhibit transport also, and the effect was more pronounced with system L than system A. The reason for cysteine's particularly potent action on amino acid transport may be associated either with chelation of a metal ion involved in transport, or the involvement of the gamma-glutamyl cycle in the support of amino acid transport.


Polyvalent pneumococcal polysaccharide vaccines. A 14-valent pneumococcal vaccine has recently been licensed for general use after extensive testing in human subjects. Antibody production was satisfactory in 92% of individuals and a highly significant (76-92%) reduction was found in the rates for pneumococcal pneumonias caused by the capsular types present in the vaccine. Children over 2 years of age respond well to the vaccine, but younger children may not respond satisfactorily to some capsular types. In adults, the duration of the protective effect is at present unknown, but no substantial booster response was seen after a second dose at 1 year. Such a booster dose, in fact, induced a marked increase in the degree of local reaction at the injection site.


Use of a sulfate: hydrogen sulfate buffer to preserve urine for steroid analysis. 1. HCI, commonly used to preserve urine for steroid analysis, cannot safely be supplied to out of town patients. 2. An equimolar mixture of Na2SO4 and NaHSO4 is a safe alternative which may be used to protect specimens en route to the laboratory. 3. Addition of bisulfate buffer to urine (20 g/l) reduced the pH to 2.0-3.5 (31 specimens; 24 hr urine volumes, 560-3320 ml). 4. Little change in pH was observed when buffered urine (12 specimens) was kept at 30 degrees for 14 days (initial pH 2.62 +/- 0.38 (mean +/- standard deviation); PH after 14 days, 2.59 +/- 0.48). 5. Analysis of the creatinine, 17-oxosteroids, 17-oxogenicsteroids, estrogens, pregnanediol, androsterone + etiocholanolone and estriol in urine samples acidified to pH 2-3 with HCl, and in the same samples acidified with buffer, gave results which were indistinguishable from each other. 6. Almost no change in steroid and creatinine concentrations was observed in samples of buffered urine kept for 10 days at room temperature (20-26 degrees).


Measurement of free calcium ion in capillary blood and serum. We describe a new calcium ion-selective electrode for measurement of the substance concentration of free calcium ion [Ca2+] in the plasma phase of whole blood and in serum at 37 degrees C. A sample volume of 50 microliter suffices to obtain simultaneous values of pH and [Ca2+]. We found the within-series analytical standard deviation for serum to be 0.013 mmol/litre (CV, 1.1%) and day-to-day precision to be 0.022 mmol/litre (CV, 1.7%). The reference interval for [Ca2+] (at pH 7.40) in serum was found to be 1.184 +/- 0.054 mmol/litre (2 SD) from measurements on sera from 121 healthy blood donors. Measurements on capillary blood from 29 healthy volunteers gave a mean (+/- 2 SD) value for [Ca2+] (at pH 7.40) of 1.22 +/- 0.072 mmol/litre.


An "oncometer" of clinical measurement of colloid osmotic pressure of plasma. Measurement of colloid osmotic pressure complements measurements of pulmonary artery wedge pressure for assessing the risks of pulmonary edema and constitutes an increasingly important reference for purposes of guiding selection of colloid or crystalloid fluids in patients with acute cardiac disease. We describe a simple device for its routine clinical measurement. A membrane, selectively impermeable to molecules of relative molecular mass (Mr) greater than 30000, is rigidly mounted between a sample chamber and a reference chamber filled with isotonic saline. A pressure transducer measures the negative pressure developed in the reference chamber and displays it on a digital panel meter. The sensor chamber accommodates samples of 50 to 300 microliter. Equilibration is completed within 2 min. A control solution of human serum albumin (50 g/liter) is measured to confirm the accuracy of calibration of the system, with reproducible readings of 25.9 g/cm2 within one SD (equivalent to 0.4 g/cm2). Technical simplicity of operation and modest costs of disposables have made feasible the routine measurement of colloid osmotic pressure.


Quality control of measurements of pH, carbon dioxide tension, and total carbon dioxide in plasma. We have measured total carbon dioxide in plasma with a new carbon dioxide analyzer, and compared the results with total carbon dioxide data derived from measurements of carbon dioxide tension and pH. The results agree sufficiently well to demonstrate that the new instrument provides a simple, efficient procedure for monitoring the precision and accuracy of pH, carbon dioxide tension, or total carbon dioxide in plasma.


Gaucher's disease. Factors affecting the 4-methylum-belliferyl-beta-D-glucosidase activity of cultured skin fibroblasts. Phosphate-buffered saline was found to inhibit acid beta-glucosidase activity of cultured cells. This effect was attributable to both the pH and the chloride content of the phosphate-buffered saline. Washing the cells in sucrose (0.25M) to remove residual phosphate-buffered saline effectively eliminated this inhibition.


Doses and dosage intervals of drugs--clinical practice and pharmacokinetic principles. Outpatient prescriptions dispensed to 17,000 individuals in the county of Jämtland, Sweden, have been analyzed with regard to doses and dosage schedules. Two groups of drugs were studied; one group with marked interindividual variability in metabolism (antidepressants, beta receptor blockers, and phenytoin), the other group excreted unchanged in the urine (digoxin, nitrofurantoin, sulfonamides, and tetracycline). A 25-fold-15-fold variability in daily doses was found for amitriptyline and nortiptyline, respectively. Four-fifths of the prescriptions were for doses between 30 and 75 mg, making the mean dose remarkably low-58 and 48 mg, respectively. The variability in doses was higher for the beta receptor blockers propranolol and alprenolol. Daily doses of phenytoin varied between 0.1 and 0.6 gm, 93% of the doses falling between 0.2 and 0.4 gm. Generally, doses of sulfonamides and nitrofurantoin prescribed to children were correctly reduced. In the elderly the doses of these drugs and tetracycline and digoxin were only moderately reduced in discrepancy with the physiologic impairment of kidney function. The clinical significance of these findings has not been evaluated. The effect of drug information programs on dosage intervals prescribed for procainamide, phenytoin, and beta receptor blocking drugs is demonstrated. It is suggested that more emphasis be given to general pharmacokinetic principles in drug information programs.


Impaired absorption of desmethyldiazepam from clorazepate by magnesium aluminum hydroxide. Ten healthy volunteers ingested single 15-mg doses of clorazepate dipotassium (CZP) with 60 ml of water, or with 60 ml of magnesium aluminum hydroxide (Maalox), on two occasions in a randomized, two-way crossover study. Plasma concentrations of desmethyldiazepam (DMDZ) were determined in multiple samples drawn during 48 hr after each dose. Mean kinetic variables for DMDZ in CZP-water and CZP-magnesium aluminum hydroxide treatment conditions, respectively, were: peak measured concentration, 273 and 188 ng/ml (p 0.001); time of peak concentration, 1.8 and 2.8 hr after dose (p less than 0.01); apparent absorption half-life, 14.8 and 30.7 min (p less than 0.02); area under the 48-hr plasma concentration curve, 6,028 and 5,433 ng/ml X hr (p less than 0.02). Self-rated sensations of feedling "spacey," "thinking slowed down," and of generalized sedation, were reported with both treatment conditions, but these subjective effects occurred earlier and were more profound when CZP was taken with water as opposed to magnesium aluminum hydroxide. Thus administration of single doses of CZP with usual doses of a commonly prescribed antacid reduces the rate and extent of appearance in blood of DMDZ (the compound responsible for clinical activity) and attenuates self-rated clinical effects.


Abnormal sodium transport in leucocytes from patients with essential hypertension and the effect of treatment. 1. In seventeen patients with untreated essential hypertension the sodium and water contents of leucocytes were significantly increased, whereas the rate constant for ouabain-sensitive sodium efflux was significantly reduced. 2. These abnormalities were not found in fourteen other patients with well-controlled hypertension. 3. Preliminary observations in accelerated hypertension suggest a different pattern of abnormality in leucocyte sodium metabolism.


Effect of pyratrione (a tyrosine hydroxylase inhibitor) in essential hypertension. 1. A clinical study of pyratrione, a tyrosine hydroxylase inhibitor, has been carried out in essential hypertension. 2. Out of thirty-nine patients who received pyratrione, twenty-eight showed a significant decrease in blood pressure.


The brain as a possible site for the cardiovascular effects of beta-adrenoceptor blocking agents in cats. 1. DL-Propranolol, L-propranolol, DL-alprenolol, pindolol (LB46), practolol, ICI 66082, sotalol and oxprenolol all produced prolonged falls in blood pressure and heart rate after intracerebroventricular administration in conscious normotensive cats. 2. Transient initial pressor responses and tachycardias were observed after intracerebroventricular infusions of all the beta-adrenoceptor antagonists used, except ICI 66082. 3. D-Propranolol, D-alphrenolol, procaine and lignocaine all produced initial increases in blood pressure and heart rate but did not subsequently cause any reduction in either blood pressure or heart rate. 4. The time of maximum hypotension and bradycardia after intracerebroventricular infusion of beta-adrenoceptor antagonists coincided with the maximum inhibition of the centrally mediated tachycardia observed after intracerebroventricular isoprenaline.


beta-Adrenergic receptors and renin release: studies with beta-adrenoreceptor-blocking agents in the conscious rabbit. 1. Plasma renin activity (PRA) and mean blood pressure were studied in conscious rabbits infused with beta-adrenoreceptor antagonists. 2. Oxprenolol and DL-propranolol each significantly reduced PRA and blood pressure, but prindolol, which had a strong blood pressure-lowering effect, increased PRA. 3. When prindolol was given to animals in which PRA and blood pressure had been reduced by DL-propranolol, PRA returned to control values but blood pressure remained low. Thus the increase in PRA caused by prindolol is not mediated by hypotension. These findings, together with the observation that compound H35/25 reduced PRA without altering blood pressure, suggest that the effects of the beta-adrenoreceptor-blocking drugs on blood pressure are unrelated to their effects on renin release. 4. Studies with D-propranolol and with blocking agents with either beta-1 or beta-2 specificity indicated that the effects of beta-adrenoreceptor blockade on renin are directly dependent upon their action on beta-adrenergic receptors, probably of the beta-2 type.


Effect of drugs on the stimulation threshold of the human heart. Clinical measurements were made of the effects of various drugs on the stimulation threshold of human heart [right ventricle]. Of antiarrhythmic drugs, a marked and prolonged elevation of the stimulation threshold was produced by procainamide, quinidine, and aimaline. Relatively short-lasting elevation was elicited by local anaesthetics [trimecaine, lidocaine]. Beta-blockers were little effective. No detectable effect on the stimulation threshold was produced by phenytoin and digitalis glucosides from the group of antiarrhythmics. The deepest and most prolonged depression of the stimulation threshold was achieved with anabolics [nandrolone phenylpropionate, nandrolone decanoate] and with high doses of prednisone and of 6-methylprednisolone sodium succinate. Hydrocortisone was ineffective. A slight and brief depression was produced by atrophine. The effects of sympathomimetics were complicated: at stimulation with short pulses the threshold was always raised. At stimulation with long pulses the effects were variable, mostly biphasic [occasionally triphasic]: a transitory depression of the stimulation threshold was followed by a marked elevation. The I-t curve's slope altered. In exit block, sympathomimetics are indicated because of their chronotropic effect, not because of their questionable effect on the stimulation threshold. A number of drugs, often administered to stimulated patients, produced no effect on the stimulation threshold: antibiotics, nitrites, purine compounds, opiates, and others.


What are the driving forces for the proximal tubular H+ and Ca++ transport? The electrochemical gradient for Na+ and/or ATP. The H+ ion secretion in the proximal tubule as revealed by the reabsorption of the glycodiazine buffer vanishes when the ambient solutions are sodium-free. The same holds for other Na+-dependent transport processes such as Ca++, phosphate, glucose and amino acid reabsorption. If Na+ transport is blocked by ouabain the latter transport processes are abolished, the secretion of H+ ions, however, remains unchanged suggesting H+ to be not exclusively driven by active Na+ transport. These observations agree with electrical measurements which show an electrogenic component of H+ secretion to exist in rat proximal tubule. In experiments with isolated membrane vesicles an electroneutral Na+/H+-exchange mechanism could be demonstrated in the brush border membrane and an ATP-driven Ca++ pumpt as well as Na+-Ca++ countertransport in the baso-lateral cell membrane. These data suggest that both, the Na+ gradient and ATP, are used to drive H+ ion secretion across the luminal brush border and Ca++ reabsorption across the baso-lateral cell side. The biochemical nature of the various systems and their relative importance for the transepithelial ion movement remain to be elucidated.


Cytoplasmic gamma-glutamyltransferase: isolation, product formation and physiological role. These results establish the existence of a cytoplasmic glutaminase-gamma-glutamyltransferase enzyme as a distinct entity. Its products are ammonia and activated glutamate. Ammonia liberation is obligatory to the utilization of the amide bond energy in forming gamma-glutamyl-PO4. This activated glutamate can then be utilized in the gamma-glutamyl cycle for the synthesis of gamma-glutamylcysteine. The cytoplasmic glutamine utilizing pathway is closely coupled to gamma-glutamyl cycl activity: loading the cycle stimulates increased renal glutamine uptake into this pathway. Consequently, the pathway, stimulated by elevated ADP levels, appears to function as an auxilary source of gamma-glutamyl moieties for the gamma-glutamyl cycle. Although insignificant compared to the mitochondrial pathway's contribution to ammonia production in metabolic acidosis, it is highly significant from the perspective of the Unitary Hypothesis. The existence of this dual system allows the demonstration of a shift in glutamine utilization from predominant cytoplasmic to overwhelming mitochondrial glutamine utilization in metabolic acidosis corresponding to a rise in the NH3/gln ratio from 1.2 to 1.9 and a quantitative recovery of gln carbon as CO2 and glucose. The fact that this shift in pathways is induced by acidosis (through adrenosteroids) and that it represents a 10 to 20 fold activation of the mitochondrial pathway is completely consistent with a glucocorticoid mediated glutamine permeability increase of the inner mitochondrial membrane.


alpha-Ketoglutarate regulation of glutamine transport and deamidation in renal mitochondria. alpha-Ketoglutarate (KG) is a potent inhibitor of renal mitochondrial glutamine transport and deamidation at physiological concentrations. The concentration-inhibition relationship observed between KG and mitochondrial glutamine transport and deamidation indicates that changes in renal KG concentration occurring during alterations in acid-base balance would have significant effects on mitochondrial ammonia production in vivo. A rapid-mixing, rapid-filtration method was developed to measure the effects of KG on initial rates of mitochondrial glutamine transport. Transport was linear for only a few seconds and approached steady-state conditions by 30 seconds. KG (0.3 mM) raised the glutamine transport Km approximately two-fold. We propose that KG may play a major regulatory role in the early adaptation of renal ammonia production to acidosis.


Neuropharmacological aspects of the neural control of prolactin secretion. The use of neuropharmacological agents in neuroendocrine studies has had a significant impact on our knowledge about the neurotransmitter systems that are involved in the control of prolactin secretion. Selective drugs have played a key role in the identification of the dopaminergic inhibitory and serotonergic stimulatory influences. With the development of additional specific neuropharmacological agents in the future, we can expect to gain a better understanding of the complex neural interrelationships involved in the control of anterior pituitary hormone secretion. In view of what we already know about the neurotransmitters involved in the control of prolactin release, a tentative neuronal configuration can be proposed. The following neuronal network most probably does not include several components that may be shown by future studies to be involved in prolactin control, but it does represent a possible functional network based on what knowledge is at the present time (Fig. 4).


Effects of maleate on CoA metabolism in rat kidney. CoA transfer from acetoacetyl-CoA to maleate catalyzed by purified CoA transferase was studied. The thioester product of the reaction undergoes further chemical transformations and the final product appeared to be stable CoA derivative showing neither free SH group nor hydrolyzable thio-acyl bond. Similar product was obtained as the result of the reaction of addition of CoA to the double bond of maleic anhydride. This was confirmed by DEAE-chromatography. The decrease of free CoA and acid soluble acyl-CoA in kidney mitochondria respiring in the presence of maleate or in the kidney of maleate-treated rats occured without appreciable changes in acid insoluble acyl-CoA derivatives. As the result substantial loss of total content of CoA was found. The data indicate that maleate binds and removes CoA in the form of stable and metabolically inert compound.


Metabolic changes induced by acute phosphate loading in acutely thyroparathyroidectomized rats. Phosphate loading in acutely thyroparathyroidectomized rats is followed by a decline of phosphate reabsorption. In addition, a mixed respiratory and metabolic alkalosis and hypocalcemia develop. Normalization of plasma calcium concentration, unlike the reversal of the alkalosis, prevents the fall in phosphate reabsorption.


Biochemical, immunological and ultrastructural studies on brush-border membranes of human kidney. Brush border (BB) membranes, isolated from human kidney cortex by density gradient centrifugation, revealed a distinct pattern of structural proteins as could be shown by bio- and immunochemical studies. Marker enzymes such as gamma-glutamyltranspeptidase (GGTP) and alanine-aminopeptidase (AAP) were characterized as extrinsic; alkaline phosphatase (AP) was characterized as an integral constituent of the BB membrane. The surface of the BB membranes exhibited numerous 5 nm particles bound through a linear component to the peripheral BB matrix (negative staining). Increase of AAP and GGTP (30%) activity in the supernatant after proteolytic treatment of BB fragments paralleled selective release of these constituents from the membranes. The surface components were found to be part of BB concanavalin A and wheat germ agglutinin receptor sites. Labelled antisera directed against surface glycoprotein fractions gave a specific immuno fluorescence staining of only the luminal plasma-membrane from the proximal tubule epithelia.


[Successful therapy of a severe dextran incident using histamin H1- and H2-receptor blockaders]. A case of a severe systemic anaphylactoid reaction is reported in a patient treated with dextran 60 to prevent venous thrombosis. Significant improvement of clinical symptoms occurred after the usual treatment of such incidents with corticosteroids, histamine H1 receptor antagonists, and plasma substitutes was supplemented with a histamine H2 receptor antagonist. We would therefore like to recommend that for such cases a histamine H2 receptor antagonist should be given in addition to the usual medication with corticosteroids and histamine H1 receptor antagonists. However, the value of complete histamine antagonism in these rather rare occurrences, can only be determined after furtherexperience has been gained.


The biotransformation of p-xylene to a toxic aldehyde. Rats given a single ip injection of p-xylene suffered 65% loss of pulmonary microsomal p-xylene hydroxylase activity. The activity was protected by pretreating the rats with phenobarbital, which increased hepatic p-xylene hydroxylase and cytosolic aldehyde dehydrogenase activities, but had no effect on alcohol dehydrogenase activity in hepatic cytosol. Pretreatment of rats with pyrazole caused a 60% inhibition of liver alcohol dehydrogenase but had no effect on liver aldehyde dehydrogenase activity. This treatment partially protected the pulmonary microsomal p-xylene hydroxylase from inactivation by p-xylene. Experiments in vitro showed that inactivation of cytochrome P-450 by p-xylene required the metabolic conversion of p-xylene to p-tolualdehyde. The reactive intermediate (p-tolualdehyde) required the presence of NADPH to carry out the inactivation. Inasmuch as lung tissues cannot form p-tolualdehyde (because of the low activity of p-methylbenzyl alcohol dehydrogenase), it is assumed that the inactivation of lung enzymes in vivo following exposure to p-xylene was due to the aldehyde intermediate which is formed in the liver and transported to the lung.


Microsomal metabolism of cyclohexene. Hydroxylation in the allylic position. Hydroxylation of cyclohexene at the allylic position has been shown to occur in hepatic microsomes and 9000 g supernatant fractions of rats and rabbits. The formation of the product, 2-cyclohexen-1-ol, requires the presence of a NADPH-generating system, is inhibited by CO, metyrapone, and SKF 525-A, and is induced by pretreatment with phenobarbital. A small amount of 2-cyclohexen-1-one is also formed in preparations from phenobarbital-pretreated rats. No 2-cyclohexen-1-ol could be detected in the beta-glucuronidase-hydrolyzed urine of rats given cyclohexene orally; however, these rats excreted a small quantity of 2-cyclohexen-1-one.


Synthesis and characterization of glucuronides of 5'-hydroxy-delta9-tetrahydrocannabinol and 11-hydroxy-delta9-tetrahydrocannabinol. Glucuronides of two metabolites of delta9-tetrahydrocannabinol, 11-hydroxy-delta9-THC and 5'-hydroxy-delta9-THC, have been synthesized and characterized. Two isomeric monoglucuronides were isolated from the incubation of each metabolite with UDP-glucuronyltransferase immobilized on beaded Sepharose. The structures of these conjugates were assigned primarily on the basis of combined gas chromatography-mass spectrometry.


In vitro metabolism of phenylacetone, phenyl-2-butanone, and 3-methyl-1-phenyl-2-butanone by rabbit liver preparations. Phenylacetone, phenyl-2-butanone, and 3-methyl-1-phenyl-2-butanone were incubated with rabbit liver 9000g supernatant fraction for 30 and 60 min to yield primarily the alcohols, plus small amounts of 1,2-glycols and ketols (2-one-1-ols). Phenylacetone incubations produced small amounts of benzoic acid, which was confirmed as a true metabolite by incubation of 2H5 (phenyl-labeled) phenylacetone and corresponding recovery of phenyl-labeled benzoic acid. No benzoic acid was detectable from incubations of phenyl-2-butanone and 3-methyl-1-phenyl-2-butanone. 3-Methyl-1-phenyl-2-butanone yielded eight metabolites in addition to the corresponding alcohol, and structures are proposed for some of these metabolic products.


Reductive metabolism of nitrofurantoin in the rat. The reductive metabolism of nitrofurantoin under anaerobic conditions was characterized in various tissues from control, germ-free, and germ-free acclimatized rats. Nitrofurantoin metabolism was highest in homogenates of cecum and colon contents of germ-free acclimatized and control rats, but was absent from those of germ-free animals. Appreciable levels of activity were also present in homogenates of liver and of small intestine walls with lesser rates of metabolism observed in kidney homogenates. The major metabolite of nitrofurantoin, which was isolated and purified by high-pressure liquid chromatography, was identified as 1-[[(3-cyano-1-oxopropyl)-methylene]amino]-2,4-imidazolidinedione. A second, minor metabolite with high-pressure liquid chromatography and ultraviolet absorption characteristics similar to those of 1-[[(5-amino-2-furanyl)methylene]amino]-2,4-imidazolidinedione (aminofurantoin) was detected in cecum and colon contents.


Differential effects of Walker 256 carcinosarcoma cells growing subcutaneously, intramuscularly, or intraperitoneally on hepatic microsomal mixed-function oxygenase activity. Walker 256 rat carcinosarcoma cells growing as solid subcutaneous or intramuscular tumors depressed hepatic microsomal mixed-function oxygenase activity to less than 20% of control activity, but the same tumor cells growing as free ascites cells in the peritoneal cavity did not. Necrosis of the core area of solid tumors was observed. Tumor cells may release a substance that depresses hepatic microsomal mixed-function oxygenase activity only upon their death.


The fate of a major biliary metabolite of digitoxin in the rat intestine. In the rat, the major water-soluble biliary metabolite of digotoxin is digitoxigenin monodigitoxoside glucuronide (mono-gluc). Despite its preponderance in the bile, only small amounts of mono-gluc are found in the feces. The compound may be absorbed from the intestine as the glucuronide conjugate, or it may be hydrolyzed to the parent compound, digitoxigenin monodigitoxoside (mono); the parent compound might then be absorbed from the intestine. The purposes of this study were to determine the ability of closed duodenal and cecal strips in vivo to absorb the conjugate and the parent compound, to hydrolyze the glucuronide, and to conjugate the parent mono. Absorption of mono was found to be more rapid than mono-gluc in both intestinal locations. Absorption of mono in the cecal strip was slower than in the duodenal strip. Considerable hydrolysis of mono-gluc occurred in the cecal strip; in the duodenal strip, the net process was conjugated of the parent mono. Thus, the disappearance of mono-gluc between its appearance in the bile and excretion in the feces is explained mainly by hydrolysis in the lower intestinal tract. Paradoxically, absorption of the hydrolysis product, mono, proceeds more slowly in the lower intestine, where it is hydrolyzed, than in the duodenum, where hydrolysis does not occur.


Metabolism of benzo[a]pyrene by the isolated perfused rabbit lung. The metabolism of benzo[a]pyrene (BP) was studied in the isolated perfused rabbit lung and in rabbit pulmonary microsomes. Pretreatment of rabbits with 3-methylcholanthrene did not increase the metabolism of BP by microsomal preparations, and the pretreatment did not induce cytochrome P-448 in pulmonary microsomes. In the isolated perfused lung, BP was metabolized at a rate of about 6 nmol/min/g of lung. The intermediate arene oxides formed from BP in the isolated perfused lung were metabolized nonoxidatively by epoxide hydrase and glutathione S-transferases. The rates of the latter reactions were at least an order of magnitude less than the overall rate of metabolism. Pretreatment of the animals with 3-methylcholanthrene increased only the apparent rate of the epoxide hydrase reaction. In the isolated perfused lung, BP and some of its less polar metabolites (i.e., quinones and phenolic derivatives) were preferentially partitioned into lung tissue, precluding accurate measurement of metabolic rates by analysis of the perfusion medium alone. Covalent binding of BP-derived radioactivity to lung tissue occurred, but relatively high variability in this parameter in lungs from 3-methylcholanthrene-pretreated animals did not allow measurement of a significant difference from control lungs.


Binding of iophenoxate and iopanoate to human serum albumin. Determination of the binding affinities of 125I-labeled cholecystographic agents to human serum albumin by ultrafiltration techniques is complicated by the appearance of radiochemical impurities resulting from radiolysis of the parent compound. With labeled compounds purified daily by two extractions through chloroform, iophenoxic acid has an extremely high binding affinity. The dissociation constant (K) is 0.013 micronM for iophenoxate, compared to 0.15 micronM for iopanoate, its close analogue. However, at the weaker sites, iophenoxic acid is less strongly bound than iopanoate. The exceptionally high affinity of iophenoxate for a single site of serum albumin appears to underlie its unusual persistence in plasma. Binding in vivo is reversible and not covalent in nature. The choleretic compounds cinchophen and taurocholate have differential effects on the biliary excretion of iophenoxate and iopanoate. This cannot be attributed to selective inhibition of binding to plasma protein.


Competition for binding to multiple sites of human serum albumin for cholecystographic agents and sulfobromophthalein. The binding of two cholecystographic agents, iophenoxate and iopanoate, to human serum albumin was studied with 11 putative competitors; the results were qualitatively consistent with competitive binding to common sites. A more precise analysis of competition was achieved with four pairs of compounds for which the free and bound concentration of each was determined. The results were analyzed by a computer program and the dissociation constants calculated for both binder and competitor at specified sites on albumin. With numbering based on the rank order of dissociation constants for iophenoxate, the highest binding of the four compounds occurs at different sites: iophenoxate at site I; iopanoate at site II, sulfobromophthalein at site III; and bromphenol blue at site II. For a given compound, there is close agreement in the calculated affinities at different sites regardless of the competitor.


Prolonged impairment of the plasma-protein binding of phenytoin in the rat after a single dose of sodium oleate. The plasma-protein binding of phenytoin in rats was impaired for more than 14 days after a single injection of sodium oleate compared to that observed in saline-treated controls. A maximum free (unbound) phenytoin fraction value of about 0.30 was found between 30 and 120 min after oleate administration. The free fraction decreased to about 0.20 after 14 days. The free fraction of phenytoin in control rats was essentially constant over this period and averaged about 0.17. The impaired plasma-protein binding of phenytoin was unaffected by prolonged dialysis but was effectively reversed by charcoal treatment of the plasma. Comparison of the in vivo and in vitro effects of sodium oleate on phenytoin binding in plasma indicates that the reduction in binding is unrelated to the in vivo oleate concentration in plasma at the time of the binding determination. For example, 5 min after a bolus injection of oleate, the plasma free fraction of phenytoin was about 0.33. A comparable concentration of oleate in control plasma resulted in a free phenytoin fraction of only 0.21.


Disposition of 4,5-diphenyl-2-oxazolepropionic acid (oxaprozin) in beagle dogs and rhesus monkeys. Following intragastric doses of 14C-oxaprozin to beagle dogs and rhesus monkeys, oxaprozin was rapidly absorbed and was essentially the only drug-related substance in the plasma for at least 24 hr. Recovery of radioactivity in the excreta was 87% in both species, with the fecal route accounting for almost all of the excretion by the dog, and the urinary route predominating in the monkey. The drug was slowly eliminated by both species. The concentrations in tissues of monkeys were generally less than those in plasma, and their decline with time paralleled that in plasma. High concentrations of 14C were found in the bile and urine. Qualitative and quantitative metabolite patterns of both fluids were similar. About 90% of the 14C in both bile and urine was recovered as identified compounds in the free, ester conjugate, and ether conjugate fractions. The ester conjugate fraction, mainly consisting of oxaprozin glucuronide, was quantitatively the most important in both fluids. Two phenolic metabolites were characterized by mass spectrometry and co-chromatography. They were present in free form and as ester and ether glucuronides.


The fate of [7-3H]isoproterenol in cats after intravenous administration. The fate of intravenously administered [7-3H]isoproterenol was investigated in cats. Ten minutes after injection the concentration of 3H was highest in the heart, lungs, adrenals, and kidneys, but after 5 hr most of the radioactivity was found in the liver. The concentration of the unchanged drug in the serum declined in a biphasic manner with half-lives of 2.1--2.5 min for the first phase, and 58--77 min for the second phase. The drug was rapidly metabolized to 3-O-methylisoproterenol (MISP) and then conjugated. In 5 hr 44--55% of the administered 3H was excreted in the urine, 2--2.5% as unchanged drug, 21--41% as MISP, and 12--22% as conjugated MISP. Conjugated MISP was also found in the bile. The results indicate that the rate of formation of MISP in cats is much faster than its rate of conjugation and excretion.


O-methylated catechol-like metabolites of propranolol in man. Two isomeric methoxyhydroxy metabolites of propranolol have been identified in man during chronic antihypertensive propranolol therapy. The identification was based on the mass-spectral fragmentation pattern of their trifluoroacetylated derivatives. Both isomers were detected in urine as well as in plasma, mainly as glucuronic acid and/or sulfate conjugates. The amounts of these metabolites excreted in urine were linearly related (r = 0.84) to the oral propranolol dose, 10--320 mg per day. Plasma concentrations at the 320-mg daily dose ranged from 20 to 112 ng/ml. Similar isomeric methoxyhydroxy metabolites of propranolol containing a glycol or a lactic acid side-chain were also identified.


Comparative metabolism of hydrocodone in man, rat, guinea pig, rabbit, and dog. The metabolism of hydrocodone was studied in man, rat, guinea pig, rabbit, and dog. Routes of metabolism included O-demethylation, N-dealkylation, and 6-keto-reduction to the corresponding 6-alpha- and 6-beta-hydroxy metabolites, where each metabolic pathway produces an active metabolite. Mean total recovery of drug and metabolites as percentage of administered dose ranged from a low of 10.6% for the rabbit to a high of 46.8% for the guinea pig; man was intermediate at 25.7%. For man, approximately 70% of the total drug recovered was excreted in the first 24 hr, and the remainder by 72 hr. Considerable species differences were observed in the patterns of metabolism of hydrocodone. Also, stereoselectivity of 6-keto reduction to the beta-form was observed for all species in the reduction of hydrocodone and hydromorphone with the exception of the reduction of hydrocodone by man.


[The effect of etilefrine and dihydroergotamine on sympathetic nervous system activity when standing up (author's transl)]. Systolic blood pressure, heart rate and concentrations of adrenaline, noradrenaline and dopamine as well as plasma dopamine-beta-hydroxylase (DBH) were measured in 22 subjects in recumbency and on standing up. Six subjects each had previously been given intravenously dihydroergotamine (0.5 mg) or etilefrine (0.25 mg/min) or a placebo. It was demonstrated that orthostasis leads to an increased activity of the sympathetic nervous system and the adrenal system. After administration of dihydroergotamine there was a diminished reaction of the sympathetic nervous system with an increase of venous tone which counteracted the decrease in cardiac output. Etilefrine, on the other hand, inhibited the sympatho-adrenal reaction on orthostasis and decreased the liberation of adrenaline. It acts directly via stimulation of alpha-and beta-receptors and is thus predominantly indicated if there is insufficient response of the baroreceptor reflex at its efferent limb.


Characterization of glucuronide metabolites of carbamazepine in human urine by gas chromatography and mass spectrometry. Glucuronide metabolites of carbamazepine (5 H-dibenz[b,f]azepine-5-carboxamide) were identified in human urine following chromatography on XAD-2 resin, permethylation, and combined gas chromatography and mass spectrometry with an SE-30 capillary column. Eight glucuronide metabolites, previously unidentified in man, were characterized as their permethylated derivatives. These included carbamazepine N-glucuronide (M+. 482), three isomers of dihydroxycarbamazepine O-glucuronide (M+. 542), three isomers of hydroxymethoxycarbamazepine O-glucuronide (M+. 542), and one isomer of hydroxycarbamazepine O-glucuronide (M+. 512). Other glucuronide metabolites, previously identified following enzymatic hydrolysis, were characterized as the unhydrolyzed, permethylated glucuronides, 10,11-dihydro-10,11-di--hydroxy carbamazepine O-glucuronide (M+. 544), and three isomers of monohydroxycarbamazepine O-glucuronide (M+. 512).


[Comparative trials on sultopride and fluanisone]. A therapeutic trial has been carried out on 50 patients, most of them being hospitalized, in order to compare the characteristics of a new benzamide, Sultopride, to those of a butyrophenone, Fluanisone, for the treatment of important and chronic agitation states. Clinically, they were essentially psychotic states, with dissociation. From this trial it appeared that sultopride is superior to fluanizone with regard to their sedative effects and that it has specific characteristics: a very powerful antipsychotic action, an increasing efficiency over time, as well as an improvement of incoercible agitation in children. Thus, the present trial has checked out the well-known sedative action of Fluanisone, and has revealed a new major antipsychotic drug, Sultopride, the superiority of which lies on a much wider therapeutic field.


[Mental complications of neuroleptic drugs. Confusional oneiric states]. The author reports five cases of relatively young women, in good general health, except that one of them had alcoholic liver disease, who presented a confusional state on taking neuroleptics: a widely used butyrophenone, prescribed for a psychotic condition. Owing to the low incidence of this side effect, these clinical cases were worth reporting. Furthermore, a trial of interpretation led us to believe that these reductions in consciousness were due to resistance to treatment.


beta-adrenergic blocking drugs in psychiatry: present status, future approaches and research. Clinical trials with propranolol were performed in 44 carefully selected psychiatric patients. Propranolol was administered in 8 equal doses over 24 hours and increased at a daily rate of 400 mg. Treatment was monitored by patient's reactions and by periodic examination of pulse rate and blood pressure. Results showed marked to moderate improvement, often within 24 to 48 hours, in two-thirds of the patients treated. Concurrent with stabilization of heart rate and blood pressure at about 60/min and 90/60 mm Hg respectively, improvement was noted in anxiety, psychomotor hyperactivity, thought process disturbance, hallucinations, and disturbances in affect. Our studies and those of other investigators indicate that propranolol and oxprenolol, and possibly other beta-adrenoceptor blocking drugs, may have a beneficial influence on psychotic syndromes. Further well-controlled clinical trials seem warranted. Indications for use, dosages, and combinations with other drugs, mainly phenothiazines, must be delineated. Laboratory investigations may add considerably in these respects ans may lead to safe treatment regimes with minimal side effects.


Alkylation of 6-phosphogluconate dehydrogenase from Candida utilis with coenzyme analogues. The mechanism of the inactivation of 6-phosphogluconate dehydrogenase from Candida utilis with two coenzyme analogues can be differentiated on the basis of kinetic studies and of the properties of the inactivated enzyme. 3-Chloroacetylpyridine--adenine dinucleotide phosphate is clearly an affinity label and 3-choloroacetylpyridine--adenine dinucleotide a second-order reagent. For 3-chloroacetylpyridine--adenine dinucleotide phosphate, there is a loss of one thiol per subunit at complete inactivation whereas for 3-chloroacetylpyridine--adenine dinucleotide 2.7 thiol groups are lost. The fluorescence of the protein is quenched after alkylation by 3-chloroacetylpyridine--adenine dinucleotide phosphate and there is no quenching after the inactivation with 3-chloroacetylpyridine--adenine dinucleotide.


Cryoenzymologic studies on arginine kinase: solvent, temperature and pH effects on the overall reaction. The overall reaction catalyzed by the phosphotransferase arginine kinase was studied at normal and subzero temperatures. Ethylene glycol was used as the antifreeze and its effects on the Km values of substances, kcat and pH profiles were investigated in detail. a) The Km values for the substrate (2 mM for ATP and 0.6 mM for arginine) were little affected by the solvent composition or temperature of the reaction mixture. b) At concentration of ethylene glycol higher than 40% there was a sharp drop of enzyme activity. c) Ethylene glycol induces a large shift in the enzymic pK D) At -5 degrees C in 40% of solvent there was a break in the Arrhenius plot suggesting a change of the rate-limiting step. The relevance of these results to the reaction pathway of arginine kinase is discussed. In addition, controlled perturbations induced by cosolvent and temperature appear as useful tools for further kinetic investigations.


Production of NADPH in the mannitol cycle and its relation to polyketide formation in Alternaria alternata. The enzymes mannitol-1-phosphate dehydrogenase, mannitol-1-phosphatase, mannitol dehydrogenase and hexokinase participate in an enzymatic cycle in the fungus Alternaria alternata. One turn of the cycle gives the net result: NADH + NADP+ + ATP leads to NAD+ + NADPH + ADP + Pi. The cycle alone can meet the total need of NADPH formation for fat synthesis in the organism. A polyketide producing strain of A. alternata shows a lower mannitol oxidation as well as a lower fat synthesis than a nonproducing mutant, supporting the hypothesis that polyketide formation is favoured at limiting NADPH production. It is further suggested that the mannitol cycle is regulating the glycolytic flux by substrate withdrawal from phosphofructokinase.


Factors modifying equilibrium between activated and non-activated forms of steroid-receptor complexes. Steroid-receptor complexes formed in concentrated cytosol at low temperature, low ionic strength and neutral pH are unable to bind to nuclei. Various procedures are known to promote their 'activation'. In the present work it is shown that an increase in temperature only enhances the rate of the reaction whereas no change in the equilibrium between activated and non-activated complexes is observed. On the contrary an increase in ionic strength or pH, as well as a removal of a low-molecular-weight inhibitor, not only accelerate the reaction but also increase the concentration of activated complexes at equilibrium. Using two steroids differing 3-fold in their affinity for the receptor, no difference was seen in the effect of the bound steroid on receptor activation. When combining various activation procedures it was observed that they acted independently of each other and additively. In all cases they retained their property of either modifying only the rate of the reaction or both its rate and equilibrium. Using changes in pH, it was also possible to induce shifts in the equilibrium between activated and non-activated complexes. After activation at pH 6.5, a first equilibrium was attained. When the pH was increased to 8 the equilibrium was displaced towards higher concentrations of activated complexes. A lowering of the pH resulted in a reversal of steroid-receptor complexes from the activated to the non-activated state. To clearly establish that this was not due to irreversible damage of the receptor, which would render it unable to bind to nuclei, it was shown that the complexes which had reverted to the non-activated state were still susceptible to activation. Regulatory events may thus exist which, for a given level of hormone and receptor, modulate the concentration of activated steroid-receptor complexes.


Initial potassium loss and hypokalaemia during chlorthalidone administration in patients with essential hypertension: the influence of dietary sodium restriction. To investigate the initial potassium loss and development of hypokalaemia during the administration of an oral diuretic, metabolic balance studies were performed in ten patients with essential hypertension who had shown hypokalaemia under prior oral diuretic treatment. Chlorthalidone (50 mg daily) was given for 14 days. Six patients received a normal-sodium diet and four a low-sodium (17 mmol/day) diet. All patients had a normal initial total body potassium (40K). The electrolyte balances, weight, bromide space, plasma renin activity, and aldosterone secretion rate were measured. In both groups a potassium deficit developed, with proportionally larger losses from the extracellular than from the intracellular compartment. In the normal-sodium group the highest mean potassium deficit was 176 mmol on day 9, after which some potassium was regained; in the low-sodium group the highest deficit was 276 mmol on day 13. The normal-sodium group showed an immediate but temporary rise of the renin and aldosterone levels; in the low-sodium group renin and aldosterone increased more slowly but remained elevated. It is concluded that dietary sodium restriction increases diuretic-induced potassium loss, presumably by an increased activity of the renin-angiotensin-aldosterone system, while sodium delivery to the distal renal tubules remains sufficiently high to allow increased potassium secretion.


alpha- and beta-receptor blockade of isoproterenol- and norepinephrine-induced effects on regional blood flow and blood flow acceleration. The effects of the beta-receptor blocking agent propranolol (100 microgram/kg i.v.) and of the alpha-receptor blocking agent dihydroergotamine (50 microgram/kg i.v.) on hemodynamic responses to isoproterenol and norepinephrine (both 1--1024 ng/kg) were investigated in anesthetized dogs. The effects studied were: (1) flow in the ascending aorta and the coronary, common hepatic, gastroduodenal, splenic, cranial mesenteric, renal and femoral arteries: (2) maximal flow acceleration in the splenic, cranial mesenteric and femoral arteries; (3) maximal rate of change of left ventricular pressure (LV dP/dt max). Propranolol shifted the dose-response curves for the isoproterenol-induced flow increases in the common hepatic, gastro-duodenal, and cranial mesenteric arteries to the right. It did not influence the flow responses to isoproterenol in the ascending aorta or the coronary, splenic, renal and femoral arteries. Propranolol prevented the decrease of arterial pressure evoked by isoproterenol. Propranolol shifted the isoproterenol-induced increase of LV dP/dt max and maximal blood flow to the same extent. Propranolol blocked the flow to the liver and gastrointestinal tract to a greater extent than the LV dP/dt max and maximal flow acceleration. Propranolol had no effect on the norepinephrine-induced increases in flow in the splenic, femoral and coronary arteries, but blocked the norepinephrine-evoked increases of flow accelerations and LV dP/dt max to the same extent. Dihydroergotamine inhibited the norepinephrine-induced increase in flow in the femoral artery and the decreases in flow in the hepatic, splenic, cranial mesenteric and renal arteries, and reversed the reduction of flow in the gastroduodenal artery. It is argued that dihydroergotamine may inhibit the increase in femoral flow through two mechanisms: (1) blocking the flow reduction to norepinephrine in the abdomen, and thereby passively shunting blood from the abdomen in preference to the femoral bed; (2) attenuating the norepinephrine-evoked reflexogenic femoral vasodilatation. It is concluded that: (1) propranolol is a beta-receptor blocking agent with a preference for blockade of isoproterenol-induced vascular effects; (2) norepinephrine-induced flow increases are not direct actions on vascular beta-receptors; (3) the increase of maximal blood flow accelerations after isoproterenol and norepinephrine is mediated by stimulation of cardiac beta-receptors; (4) dihydroergotamine is an alpha-receptor blocking agent particularly in the splanchnic vascular region.


The action of CNS drugs on an isolated sympathetic nerve preparation of rabbit. The effect of some centrally active drugs on the transmission of nerve impulses through the isolated cervical sympathetic nerve and superior cervical ganglion of the rabbit has been studied by recording both preganglionic and ganglionic responses to single square wave stimuli. Chlorpromazine, trifluoperazine and haloperidol have a greater axonal depressant action than the known local anaesthetics procaine and xylocaine. Chlordiazepoxide and diazepam are similar in local anaesthetic potency to procaine while meprobamate and sodium pentobarbitone possess only slight axonal depressant properties. Meprobamate, sodium pentobarbitone and possibly diazepam have ganglion blocking properties while procaine, chlorpromazine, trifluoperazine, haloperidol and chlordiazepoxide reduce the ganglion potential by virtue of their preganglionic action.


Micro-electrophoretic studies in the cat pulvinar region: effect of acetylcholine. 1. In the posterior half of the pulvinar of cats anaesthetized with halothane and nitrous oxide, the majority of neurons were fired by ACh released with small electrophoretic currents. In the anterior part of that nucleus, ACh had more variable effects: excitation, depression or none. 2. In comparison with L-glutamate, DL-homocysteic acid and DL-aspartic acid, ACh appeared to be the most potent excitant. 3. ACh-induced discharges were easily and reversibly blocked by low doses of atropine. In most cases, ACh effects could not be blocked selectively by mecamylamine or dihydro-beta-erythroidine. 4. Nicotine failed to mimic ACh, whereas carbachol was a potent excitant and was readily blocked by low doses of atropine. 5. The histochemical reaction to acetylcholinesterase was moderate in the pulvinar. 6. These observations support the view that pulvinar cells differ from other thalamic cells.


Response characteristics of semicircular canal and otolith systems in cat. I. Dynamic responses of primary vestibular fibers. 1. The activity of cat semicircular canal and otolith afferents was studied during yaw and roll rotations, respectively, to examine their dynamic behavior. 2. A sinusoidal analysis of the canal afferent activities showed that their dynamic characteristics are similar to those of second order vestibular neurons, except for a two to three-fold lower absolute gain. This agrees with earlier studies using angular acceleration steps. 3. Both divisions of the eighth nerve were sampled so as to examine afferents from both the utriculus and sacculus. Within the range of inputs used (+/- 25 degrees lateral tilt), the presumed sacular afferents (inferior division) showed either a gamma- or beta-response. However, the gain of their response was generally much less than for the afferents of the superior division (mostly utricular). This behavior is to be expected on the basis of receptor orientations and the components of gravity acting upon the macular receptors. 4. In response to ramp changes in angular position, some otolith units showed a phasic-tonic response pattern, i.e., an overshoot followed by an adaptation to a new steady state level of activity. The majority of units showed predominantly tonic responses proportional to displacement. 5. During sinusoidal rotations the predominantly tonic units showed small phase leads of 0 to 15 degrees at 0.025 Hz which remained constant or decreased to 0 to -15 degrees at 1.0 Hz. The gains were flat or increased by up to 2 fold. The phasic-tonic units showed greater phase leads, 10 to 50 degrees, and gains which increased from 2 to 8 fold. 6. This behavior of otolith afferents suggests that they can provide information about both the magnitude and the rate of change of linear acceleration stimuli.


Biochemical and anatomical adaptation of the lung to oxygen-induced injury. A review of anatomical and biochemical responses of the lung to high concentrations of oxygen leads us to postulate a biphasic adaptive response. The early phase entails a defense against life-threatening pulmonary edema engendered by destruction of oxygen susceptible cells forming most of the air-blood interface. This defense is brought about by type II alveolar cell replication to reform a continuous epithelial layer in the alveoli; its success would depend upon the rapidly with which this continuity can be reestablished. Factors favoring a successful defense would include an initial large population of type II cells or the ability of type II cells to divide fast enough to reestablish continuity before of oxygen-sensitive cells (type 1 alveolar epithelial and endothelial cells) proceeds to fatal pulmonary edema; both conditions probably exist in young animals, which are known to be more resistant to hyperoxia than old animals. The second phase of adaptation would require the development of increased tolerance of previously susceptible cells to continued exposure to high oxygen concentrations to prevent their total destruction. We postulate that here the development of new biochemical defenses or the augmentation of those previously present would play a major role.


Hemolytic assay of complement and its components from Syrian hamster (Mesocricetus auratus) and Mongolian gerbil (Mariones unguiculatus). Syrian hamster sera may be assayed for hemolytic complement (C) activity by standard procedures with sensitized sheep erythrocytes as used for human sera, but mongolian gerbil sera had higher complement titers when tested with sensitized guinea pig erythrocytes as target cells. The optimal conditions for in vitro testing of hamster C were pH 7.3, ionic strength 0.15, and presence of 1 micrometer of Mg2+ and 0.3 micrometer Ca2+. For gerbil C the optimum pH was 8, ionic strength 0.074, and the same concentration of Mg2+ and Ca2+ as for hamster. Incubation at 37 degrees C for 60 minutes yielded optimal results. Complement components in the serum of both species could be tested with commercially prepared intermediates of sheep erythrocytes pretreated with guinea pig C1 and human C4 respectively, using purified human C2 through 9 and standard methods applied for testing human C components. Both species have all nine components of the complement system.


Benign hydatidiform mole in Ibadan, Nigeria. A study was conducted to analyze 61 patients with benign hydatidiform mole (HM) who were admitted to the University College Hospital in Ibadan, Nigeria, during a 5-year period. The hospital incidence of HM was 1:205 pregnancies, and the condition was seen most commonly in young women, probably because early marriage is customary in our culture. Management of the condition generally was conservative because of the patients' youth. There was no correlation between HM and parity. Vaginal secondaries due to an embolic phenomenon were detected in 5% of the patients. Subsequent pregnancies followed within 6 months of treatment because the majority of the patients failed to heed medical advice to delay pregnancy for 2 years. No diagnostic problems were encountered in the patients who became pregnant during the follow-up period.


Hydatidiform mole in southern Iran: a statistical survey of 113 cases. A statistical review of 113 cases of hydatidiform mole (HM) seen at Pahlavi University Hospital from January 1970 to December 1975 is presented. The incidence of the disease was found to be 1:314 pregnancies. In this study, 73.5% of the patients presumably had acceptable socioeconomic circumstances. The highest incidence of the disease was found in patients 15-25 years old, and it increased with parity. All patients presented with a period of amenorrhea and vaginal spotting. More than 50% of the patients sought treatment after 1-2 weeks of uterine bleeding. Signs and symptoms of the disease are discussed. The management of patients with HM and coexisting difficulties are presented.


High frequency of hydatidiform mole in native Alaskans. The frequency of hydatidiform mole per delivery in the native Alaskan for fiscal years 1969 through 1974 was 1:257. Nutritional studies do not support the suggestion of protein deficiency as an etiologic factor. It is suggested that genetic factors may be involved.


Myomectomy in infertile Jamaican women.

Myomectomy in infertile Jamaican women. One hundred nineteen Jamaican women who underwent myomectomy from 1964 to 1969 were followed up for 5 to 9 years. Infertility was the most common presenting complaint. Preoperative hysterosalpingograms were performed on 61 patients and were abnormal for the majority of these patients. Surgery revealed submucous fibroids in 41 patients and pelvic inflammatory disease in 51 patients. The pregnancy rate following myomectomy was 18.5%, but successful outcomes occurred in only 9.2% of the cases. Pregnancy was unsuccessful for all patients who underwent both myomectomy and tuboplasty. Twenty-three patients had a recurrence of myoma, and 13 of these underwent subsequent hysterectomy.


Unification of a septate uterus: Mahgoub's operation. A simple surgical technique for unification of a septate uterus is described. The septum and a small strip of fundus are removed with scissors inserted through two small fundal stabs, and the opening is closed with one mattress suture, which forms an anteroposterior suture line no more than 1 cm long. At the end of the operation an intrauterine contraceptive device is inserted to prevent uterine adhesions. The operation has several advantages: (a) it leaves a capacious uterine cavity of normal appearance, (b) it avoids large uterine incisions, and thus the possibility of postoperative adhesions or weak uterine scars, and (c) it avoids possible injury to the cornual ends of the Fallopian tubes. This article reports favorable results in 17 women treated with this surgical technique.


Rupture of the uterus.

Rupture of the uterus. Sixty-four cases of rupture of the uterus were managed from March 1967 to March 1977. The maternal morbidity was 81.0%, and there were six maternal deaths (9.4%). Fifty-two patients (85.5%) had hysterectomies. The average hospital stay for patients who survived was 15.5 days. The fetal mortality rate was 89%. The etiology, diagnostic evaluation and the mode of prevention are discussed.


The present and future of immunologic approaches to contraception. A vaccine capable of causing active immunity against one or more key elements of conception would have several advantages over currently available methods of fertility regulation. It would be amenable to mass use, would require only periodic follow-up, and would not require continuous user motivation. Although natural infertility attributable to immunologic factors has been amply documented, the natural mechanism has been only partially delineated. Consequently, researchers trying to develop a workable vaccine are taking various approaches. This report includes a discussion of autoimmune aspermatogenesis, anti-zona pellucida, anti-nonhormonal placenta-specific protein vaccines, and immunization against female and/or early embryonic antigens, including current approaches to the development of an anti-human chorionic gonadotrophin (HCG) vaccine. The potential advantages and disadvantages of the various immunologic methods are discussed, and the author concludes that although the problems associated with present methods of immunologic contraception are substantial they can be resolved.


Inducing labor with oral prostaglandin E2 tablets. Labor was successfully induced by forewater amniotomy and oral administration of prostaglandin E2 tablets in 91.3% of 153 women with singleton pregnancies. Deliveries occurred within 12 hours for more than 90% of the successfully induced patients. Although not statistically significant, a higher pelvic score appeared to be associated with shorter induction-to-delivery intervals. There were no harmful side effects for either mother or baby; only 14.5% experienced minor side effects, primarily gastrointestinal upsets.


Preoperative cervical dilatation with 15(S)15-methyl PGF2alpha methyl ester pessaries. A clinical trial comparing two vaginal dose schedules of 15(S)15-methyl prostaglandin F2alpha (PGF2alpha) methyl ester (4 or 6 mg) for preoperative dilatation of the cervix is described. The trial included 28 patients at 8-12 weeks' gestation. Vaginal pessaries containing either 1.0 mg (15 patients) or 1.5 mg (13 patients) of the prostaglandin analogue were administered every 3 hours (maximum, 4 doses). The success rates for the two groups were 93% and 100%, respectively. Sixty percent of the patients aborted before the planned vacuum aspiration. Minor side effects, primarily vomiting and diarrhea, occurred in approximately 80% of the cases and were more prominent with the higher dose pessary. It is concluded that the vaginal administration of 15(S)15-methyl PGF2alpha methyl ester is highly effective for preoperative dilatation of the cervix before suction curettage abortion.


Menstrual regulation in Ibadan, Nigeria. Menstrual regulation (MR) (i.e., vacuum aspiration of the uterus with a small diameter, flexible cannula before pregnancy can be determined by a conventional pregnancy test) has been proven safe and effective in many clinics around the world. The present study, which we believe is the first such study of MR in Subsaharan Africa, shows that, for women in an urban African setting, MR is an acceptable backup for other contraceptive methods. Data on 507 MR patients treated at the University College Hospital in Ibadan, Nigeria, between January 1974 and April 1976, showed that the procedure was both safe and effective for 93.4% of the study subjects: there was an overall complication rate of 3.4% and MR failed in seven cases (3.2%). Data also showed that MR is an effective method of recruiting new contraceptive acceptors, as well as an effective back-up procedure in case of contraceptive failure.


A comparison of metal and plastic cannulae for vacuum aspiration. A comparative study of the safety and effectiveness of metal (Purandare) versus plastic (Karman) cannulae for first trimester abortion was conducted on 400 women. Two hundred vacuum aspiration procedures were performed using each type of cannula. All aspirations were performed by a single physician, and patient follow-up was performed by a second physician. The complication rates, amount of retained tissue, rates of cannula obstruction and procedure times of the two cannulae were compared. Our findings showed no significant difference in any of these evaluation criteria for the metal and plastic cannulae.


Second trimester abortion with 5% intraamniotic saline--a pilot study. The risk of hypernatremia and related postabortion complications resulting from the intraamniotic administration of a 20-25% hypertonic saline solution, a widely used procedure all over the world, prompted this trial of 5% saline. Midtrimester abortion was induced in 150 women with a 5% saline solution administered intraamniotically at the National Medical College, Calcutta, India, from August 1974 to October 1975. The abortion was complete within 48 hours in 90% of the cases. All the fetuses were delivered dead. In one case, hysterotomy was performed because of severe bleeding. The immediate complication rate was 36% (12% serious). The follow-up complication rate was 2%. One patient died on the seventh postabortal day due to severe, uncontrolled septicemia. The authors conclude that because this procedure is simple and low cost and because it reduces the risk of hypernatremia it should be a welcome addition to service programs in developing countries.


Hospital counseling in Khartoum: a study of factors affecting contraceptive acceptance after abortion. This study examines the impact of contraceptive counseling on 3 263 women hospitalized in Khartoum for treatment of incomplete abortion. The analysis which focused on education and parity/child desire, revealed that the counseling program produced contraceptive acceptance among 47.0% of those followed up. In spite of the counseling efforts, half of the women in this study did not accept contraception following the abortion-regardless of education or parity/child desire. It is difficult to determine why 50% of those who had recently undergone an incomplete abortion were willing to put themselves at risk again. Apparently, future efforts to increase the impact of counseling programs must also examine patients' motivation to accept (or not to accept) contraception.


Advances in sterilization equipment.

Advances in sterilization equipment. From the array of sterilization procedures that are safe, simple and effective, the service provider must select procedures that fit his or her logistical criteria, which include the cost and maintenance of equipment, availability of supplies, and training of the requisite personnel. In this paper, these criteria are discussed for each of the various sterilization procedures. Information about female sterilization equipment for conventional postpartum laparotomy, minilaparotomy, colpotomy, laparoscopy, and culdoscopy is presented, together with facts about the related tubal occlusion techniques. The standard ligation techniques for male sterilization are compared with the newer electrocoagulation and thermocoagulation methods. A variety of methods for both female and male sterilization that are in the research stage are also mentioned. It is concluded that, from a programmatic point of view, vasectomy and postpartum ligation via laparotomy are the optimal sterilization procedures. For women who have not recently been pregnant, minilaparotomy with a standard tubal ligation technique is recommended, except in large teaching hospitals where laparoscopy can be performed efficiently.


Laparoscopic electrocoagulation and tubal ring techniques for sterilization: a comparative study. From August 1975 through May 1976, a comparative study was made of the effects of sterilization by standard electrocoagulation and tubal ring application techniques. The two techniques were randomly assigned to 300 patients. Results show that standard electrocoagulation and tubal ring procedures can easily and safely be performed on an outpatient basis, using local anesthetics and analgesics. Rates of surgical complications for both techniques were clinically acceptable, although tubal risk patients had a higher rate. Pain during the procedure and during the immediate recovery period was more severe for tubal ring patients. Despite the higher incidence of surgical complications and pain associated with the ring, many physicians prefer this method of sterilization because it eliminates the possibility, inherent in electrocoagulation, of inadvertent serious electrical burns.


Training physicians of developing nations in female surgical contraception. The majority of developing nations in the Third World (including Thailand) face similar medicosocioeconomic situations arising from uncontrolled population growth which outstrips developmental planning. One of the most effective medical means of combating these problems is surgical contraception. This study describes how the Ramathibodi National Training Program was developed and implemented in Thailand to increase the availability of sterilization services by training local physicians to perform the necessary operations. The success of this program is measured by the increase in the number of service delivery stations (182) and in the number of sterilization procedures performed (24 436 in a 32-month period).


The water and nitrogen composition of the placenta in anemic women. A study was conducted to determine the water and nitrogen content of the placentae from anemic and nonanemic Nigerian women. The mean water content values were 84.9% and 85.3%, respectively, and this difference was not statistically significant. Placental nitrogen values were higher in anemic women than they were in nonanemic women, but the difference was not statistically significant. The results of this study indicate that placental hypertrophy which is associated with anemia is not due to water retention by the placenta.


Effects of x-ray on a gravida with severe hemoconcentration: a case report. A gravida with severe hemoconcentration was studied with intravenous urography because of right upper quadrant pain. She subsequently developed renal failure. The potential hazard of urography in the presence of a severe blood volume contraction state is noted.


Coarctation of the umbilical cord: a cause of intrauterine fetal death. This article presents 16 cases of coarctation of the umbilical cord, resulting in fetal death in utero in pregnant women of more than 6 months' gestation. Coarctation of the umbilical cord can occur in any phase of the gestational period and is not related to parity. The stricture of the cord is usually accompanied by torsion and characterized by a fibrosis of the Wharton's jelly and a thickening of the vascular walls which obstructs the fetoplacental circulation, leading to anoxia and fetal death. Although this entity must occur frequently, it is not often reported by obstetricians because the umbilical cord is not carefully examined in all cases of stillbirth.


Controlled assessment of oral bronchodilators for asthmatic children. Various pulmonary function changes were determined in twenty paediatric patients after a single oral dose of theophylline, ephedrine, or their combination in a double-blind crossover study. The possible contributions of guaifenesin and butabarbital, components of some formulations in clinical use, were also examined. Bronchodilatory efficacy in decreasing order, when compared to placebo, was observed for theophylline-ephedrine and theophylline (nearly comparable), and for ephedrine-butabarbital and ephedrine (nearly comparable). Butabarbital and guaifenesin did not enhance or decrease bronchodilatory effect. Adverse reactions appeared to be more frequently related to ephedrine intake, although no serious reactions were noted.


Comparative efficacy of triazolam, flurazepam and placebo in out-patients insomniacs. The short-term hypnotic efficacy of triazolam was compared to that of flurazepam and placebo in 120 out-patient insomniacs. Each patient was studied with a two-night, double-blind crossover trial. Triazolam (0.5 mg) was compared to placebo and flurazepam (30 mg). Triazolam (0.25 mg) was compared to flurazepam (15 mg and 30 mg). Triazolam (0.5 mg) was preferred to both placebo and flurazepam (30 mg). Triazolam (0.5 mg) was superior to placebo in improving quality of sleep, shortening sleep onset, increasing sleep duration, and reducing the number of night-time awakenings. Triazolam (0.5 mg) was superior to flurazepam (30 mg) in speeding sleep onset and increasing the quality of sleep. Triazolam (0.25 mg) was preferred to flurazepam (15 mg) and was significantly better than flurazepam on all sleep questions. Triazolam (0.25 mg) was preferred by more patients than flurazepam (30 mg) and was judged equally efficacious on individual sleep questions. Reports of side-effects were minimal for both drugs.


A clinical comparison of triazolam with placebo and with secobarbital in insomniac patients. Seventy-six out-patient insomniacs participated in three different two-night, double-blind crossover trials investigating the hypnotic efficacy andsafety of triazolam. Triazolam 0.5 mg was compared to placebo in one trial conducted K Kay Okawa, MD, and triazolam 0.5 mg was compared to secobarbital 100 mg in trials conducted by K Kay Okawa, MD and George S Allen, MD. The results of the later two studies were combined and the data analyzed jointly. Triazolam 0.5 mg was found to be preferred and to be significantly better than both placebo and secobarbital 100 mg in the treatment of insomnia. Analysis of sleep questionnaire data showed triazolam to be superior to either placebo or secobarbital on the following parameters: how much the medication helped the patients sleep; onset of sleep; duration of sleep; and number of nocturnal awakenings. No differences were observed between treatments in any trial with regard to the patient's feeling of alertness the next morning. The side-effects reported for all treatments did not significantly interfere with the patient's ability to function.


Arbovirus isolations from mosquitoes in South Slovakia. In the years 1973 and 1975 mosquitoes and some other Diptera (Tabanidae, Simuliidae, Hippoboscidae) were tested for virus. 13,924 mosquitoes, 75 horseflies and 60 blackflies were processed in 1973. Five strains of Tahyna virus were isolated from mosquito species Aedes vexans. 3,378 mosquitoes and 12 sheep keds were tested for virus in 1975. Twelve strains of Calovo virus were isolated from Anopheles maculipennis and one strain of Tahyna virus was obtained from Aedes vexans mosquitoes.


Chinese health system gets down to basics. Preventive medicine and primary health care, rather than advanced medical technology, appear to be the focus of health care delivery in China. In fact, the author says, one could imagine a decision being made not to install a CT scanner so that more physician extenders could be trained to improve nutritional standards, help eliminate infectious diseases, and provide health education information to people who would not otherwise be exposed to these services.


Identification of a new serum protein polymorphism as transferrin. By isoelectric focusing at pH 3.5--9.5, Kühnl and Spielmann (1977) recently demonstrated a new genetically determined serum protein polymorphism designated 'Hpa' because of an apparently specific reaction with antihaptoglobin. In this study the polymorphism was reproduced, but the components were found to focus at pH 5.8, which is different from the pI of haptoglobin, and immunologic relation to haptoglobin could not be confirmed. Using pure transferrin as a reference, the results of isoelectric focusing, crossed immunoelectrophoresis, and immunofixation indicated that the polymorphic components were identical to transferrin. This polymorphism does not correspond to the already known transferrin polymorphism, as the two usual genes, tentatively designated Tf1 and Tf2, in my population sample (n = 132) were 0.19 and 0.81, and, further, all individuals except three in the sample belong to type Tf-C.


Preparation and long-term cultivation of porcine tracheal and lung organ cultures by alternate exposure to gaseous and liquid medium phases. Conventional methods of organ culture have proved unsatisfactory for mammalian lung because of the rapid collapse of the tissue and the loss of its normal structure. In an effort to circumvent this problem and to provide a means for visualizing the cellular relationships throughout the culture period, respiratory organs consisting of trachea and lungs of fetal or hysterectomy-derived 1- to 4-week-old pigs were embedded in warm 3% Noble agar in phosphate buffer silicone solution and cooled to firmness. By use of a described cutting device, the respective organs were sliced into thin, 0.5- to 1.0-mm tracheal ring or lung explants. These organ sections then were cultured by exposure to alternate gaseous and liquid-medium phases by rotation (12 rev per hr) in sealed Leighton tubes fitted in a described rotator. In short-,erm culture experiments, explants were best maintained in a culture-support medium containing Eagle's minimal essential medium, 20% fetal bovine serum, 0.5% lactalbumin hydrolysate, and other supplements in a pH range of 6.5 to 8.2, and a NaCl concentration of 0.1 M or less. By bright-field and scanning-electron microscopy, tracheal ring and lung explant cultures incubated for 2 months showed intact, uniform and active ciliated epithelial surfaces which compared favorably with those of fresh preparations. The lung cultures showed alveoli that remained expanded, and the cellular integrity of the tissues remained normal in appearance. This new method provides respiratory organs as continuous records with exceptional cellular clarity and readily available for histological processing. The organ cultures lend themselves well to pathogenesis studies in which subtle cellualr changes or a sequence of changes induced in pulmonary tissues are difficult to observe in the host.


Adherence of Mycoplasma gallisepticum to human erythrocytes. Pathogenic mycoplasmas adhere to and colonize the epithelial lining of the respiratory and genital tracts of infected animals. An experimental system suitable for the quantitative study of mycoplasma adherence has been developed by us. The system consists of human erythrocytes (RBC) and the avian pathogen Mycoplasma gallisepticum, in which membrane lipids were labeled. The amount of mycoplasma cells attached to the RBC, which was determined according to radioactivity measurements, decreased on increasing the pH or ionic strength of the attachment mixture. Attachment followed first-order kinetics and depended on temperature. The mycoplasma cell population remaining in the supernatant fluid after exposure to RBC showed a much poorer ability to attach to RBC during a second attachment test, indicating an unequal distribution of binding sites among cells within a given population. The gradual removal of sialic acid residues from the RBC by neuraminidase was accompanied by a decrease in mycoplasma attachment. Isolated glycophorin, the RBC membrane glycoprotein carrying almost all the sialic acid moieties of the RBC, inhibited M. gallisepticum attachment, whereas asialoglycophorin and sialic acid itself were very poor inhibitors of attachment. Only part of the (125)I-labeled glycophorin bound to mycoplasmas could be removed by neuraminidase or by exchange with unlabeled glycophorin. It is suggested that glycophorin, representing the isolated major RBC receptor for M. gallisepticum, binds to the mycoplasmas both specifically, through its sialic acid moieties, and nonspecifically, through its exposed hydrophobic polypeptide moiety.


Increased susceptibility of splenectomized mice to infection after exposure to an aerosolized suspension of type III Streptococcus pneumoniae. Most reported experimental studies concerning the effect of splenectomy in animals have shown enhanced mortality from pneumococci injected either intravenously or intraperitoneally. We have developed a laboratory model in which mice are exposed to type III Streptococcus pneumoniae via an aerosolized atmosphere, thus closely approximating the route of human infection with this organism. Ninety-one male Swiss mice (mean weight 26 g) were divided into three approximately equal groups of control, sham-operated, and splenectomized animals. Two weeks later they were exposed for 30 min in individualized compartments within a confined chamber to an aerosolized atmosphere producing a uniform challenge of 5.9 X 10(9) colony-forming units per ml of pneumococci. A statistically significant increase (P less than 0.01) in mortality was demonstrated in the splenectomized group over the pooled sham-operated and control groups. The animal model used in these investigations can be applied to the study of infections acquired by the respiratory route in numerous experimental designs.


Respiration and oxidative phosphorylation in Treponema pallidum. Exogenous and endogenously generated reduced pyridine nucleotides caused marked stimulation of O(2) uptake when added to treponemal cell-free extracts, which indicated that terminal electron transport was coupled to the consumption of O(2). Oxidation of reduced nicotinamide adenine dinucleotide (NADH) was shown to correlate stoichiometrically with O(2) reduction, suggesting that NADH was being oxidized through a mainstream respiratory chain dehydrogenase. Oxygen evolution in treponemal extracts was observed after the completion of O(2) uptake which was stimulated by exogenous NADH and endogenously generated reduced NAD phosphate. Oxygen evolution was inhibited by both cyanide and pyruvate, which was consistent with O(2) release from H(2)O(2) by catalase. The addition of exogenous H(2)O(2) to treponemal extracts caused rapid O(2) evolution characteristic of a catalase reaction. A spectrophotometric assay was used to measure ATP formation in T. pallidum cell-free extracts that were stimulated with NADH. P/O ratios from 0.5 to 1.1 were calculated from the amounts of ATP formed versus NADH oxidized. Phosphorylating activity was dependent on P(i) concentration and was sensitive to cyanide, N, N'-dicyclohexylcarbodiimide, and carbonyl cyanide m-chlorophenyl hydrazone. Adenine nucleotide pools of T. pallidum were measured by the firefly luciferin-luciferase assay. Shifts in adenine nucleotide levels upon the addition of NADH to cell-free extracts were impossible to evaluate due to the presence of NAD(+) nucleosidase. However, when whole cells, previously incubated under an atmosphere of 95% N(2)-5% CO(2), were sparged with air, ATP and ADP levels increased, while AMP levels decreased. The shift was attributed to both oxidative phosphorylation and to the presence of an adenylate kinase activity. T. pallidum was also found to possess an Mg(2+) - and Ca(2+) -stimulated ATPase activity which was sensitive to N, N' -dicyclohexylcarbodiimide. These data indicated a capability for oxidative phosphorylation by T. pallidum.


The application of covert conditioning procedures to the outpatient treatment of drug addicts: four case studies. The purpose of this study was to determine the effectiveness of covert conditioning procedures in the outpatient treatment of drug addicts who wished to decrease or cease use of drugs. A desensitization design proved unsuccessful in reducing craving in an opiate user with a 2-year history of abuse. Three sensitization designs with addicts who had abused opiates from 2 to 13 years produced no more than a temporary decrease in drug craving or taking. Although there appeared to be some potency in the application of covert aversive counterconditioning and mixed aversive conditioning, the procedures were not capable of producing an enduring decrease in drug craving or taking in any of the subjects. Problems in the outpatient treatment of drug addicts using covert conditioning procedures are discussed. Recommendations for further study are made, with an emphasis on use of a multiform approach.


A comparative study of three different citrate combinations of litholytic action. Three different combinations--the Eisenberg solution, Uralyt-U and Magurlit--have been compared for their litholytic effect on urate calculi in a homogeneous patient material. Magurlit and Uralyt-U have been found superior to the Eisenberg solution, insofar as they are dispensed in a hygienic form easy to handle and require for the production of the litholytic pH levels a shorter time than does the Eisenberg solution. In opposition to other citrate combinations, Magurlit may be used with success even if the urate calculus contain an additional component, unless its distribution is unfavourable and its proportion exceeds 15 to 20%.


Antibiotics excretion in canine vaginal and urethral secretions. Trimethroprim, erythromycin, ampicillin, and rosamicin, a new macrolide antibiotic, were administered to dogs by constant intravenous infusion. Their concentrations in plasma, urine, vaginal and urethral secretions, saliva, and tears were determined by bioassay. Trimethoprim, rosamicin, and, to a lower degree, erythromycin were concentrated in the secretions of the vagina and the urethra whereas the ampicillin concentrations in these secretions never exceeded the simultaneous plasma concentrations. Inasmuch as rosamicin and trimethoprim have antibacterial spectra well suited for the treatment of bacterial urethritis and vaginitis they should be investigated clinically in this respect.


NADP-dependent dehydrogenases in rat liver parenchyma. I. Methodological studies on the qualitative histochemistry of G6PDH, 6PGDH, malic enzyme and ICDH. At present soluble NADP-dependent dehydrogenases are histochemically demonstrated in three different ways: according to the standard method incubation in aqueous media leads to the precipitation of formazan, the formation of which depends entirely on the presence of endogeneous NADPH2-tetrazolium reductases. With the two more recently established methods these reductases are by-passed with the use of intermediate electron acceptors incorporated in the medium. In addition, enzyme diffusion is inhibited either by an increased viscosity of the medium (PVA) or by a semipermeable membrane separating the medium from the section. Depending on the technique applied different distribution patterns have been described. By altering the concentrations of substrates, coenzyme, tetrazolium salt and cytochrome oxidase inhibitor, it was possible to improve both the PVA and membrane methods. Although similar results were obtained, because of its advantages the PVA method is recommended in this report and a detailed description is given. Using the latter for the demonstration of glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), malic enzyme (ME) and isocitrate dehydrogenase (ICDH), characteristic distribution patterns were obtained in the liver parenchyma of male and female rats. For the first time a high G6PDH activity could be demonstrated in nonparenchymal cells which are mainly found in zone 1 of the liver acinus.


Isoelectric focusing studies on the neutral 5'-nucleotidase from Wistar rat hippocampus: evidence for the absence of isoenzymes. The pattern and some substrates characteristic of the rat brain 5'-nucleotidase were studied using the isoelectric focusing technique, which revealed that the enzyme is present in a single form in hippocampus extracts. An alkaline phosphatase, which is also able to split nucleoside monophosphates, is not active at neutral pH values. The isoelectric points were found to be 6.4 +/- 0.1 for the specific 5'-nucleotidase and 6.8 +/- 0.1 for the phosphatase.


Improved localization of thiamine pyrophosphatase activity in mounted cryostat sections using gel fixation and gel incubation media. The presence of 1% agar in the fixation and substrate solutions for the histochemical demonstration of thiamine pyrophosphatase (4.4 mM TPP; 3.6 mM Pb2+; 0.025 Tris-maleate buffer, pH 7.2) clearly facilitates the localization of the enzyme in Golgi apparatus in cold microtome sections prepared from unfixed specimens.


Differentiation of two types of endocrine cells which take up amine precursors using their capacity to take up the fluorescent dihydroisoquinoline derivative of dopamine. A study was made of the accumulation of the strongly fluorescent 2-carboxymethyl-6,7-dihydroxy-3,4-dihydroisoquinolinium compound (2-Carb. Me-DIQ) derived from the condensation reaction of dopamine with glyoxylic acid in endocrine cells possessing the capacity to take up and store biogenic monoamine precursors. Thin-layer chromatographic studies of urine showed that 2-Carb. Me-DIQ was metabolized into two strongly fluorescent metabolites, possessing at least one hydroxyl group in the phenol moiety of the molecule, which were excreted in urine together with the parent compound. Histochemical observations, however, indicated that the tissue fluorescence showing maximal emission at 480 nm was due to 2-Carb. Me-DIQ. Generally, the injection of 2-Carb. Me-DIQ induced a strong fluorescence in those tissue components possessing the extraneuronal uptake mechanism of catecholamines. In the endocrine cells strong fluorescence was seen in the pineal glandular cells and in some cells of the pars distalis of the hypophysis, of which some cells also took up DL-5-HTP, as was seen following formaldehyde vapour treatment. No accumulation of 2-Carb. Me-DIQ was observed in the pancreatic islet cells, the C cells of the thyroid gland or the tracheal enterochromaffin-like cells. These findings lead to the conclusion that biogenic monoamines in the cells of the pars distalis of the hypophysis might use the phenolic moiety of the molecule to bind to some intracellular receptor. Thus, the pars distalis cells may have an intracellular binding mechanism for biogenic monoamines that is different from other endocrine cells showing the uptake and storage of biogenic monoamines. On the other hand, the findings gave further support to the suggestion that in the pancreatic islet cells, the thyroidal C cells and the tracheal enterochromaffin-like cells biogenic monoamines are stored by a mechanism in which the basic, positively charged amino group of biogenic monoamines is bound electrostatically to the anionic, negatively charged carboxyl group of a hormone storage granule. The pars distalis cells and the pineal glandular cells seemed to take up amines and amine derivatives in a similar manner. This suggests that in the pars distalis cells, too, biogenic monoamines have an active metabolism and possibly some regulative role in hormone synthesis and/or secretion.


Determination of the metabolites of bezitramide in urine. II. The basic metabolite. A high-performance liquid chromatographic method for the determination of low levels (less than 1 microgram/ml) of the basic metabolite of bezitramide, 1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one, in human urine is described. Special attention is given to the separation from the basic metabolite of droperidol, a drug frequently co-administered with bezitramide.


Prevalence of self-injurious behaviors in a large state facility for the retarded: a three-year follow-up study. A combined informant questionnaire and interview survey of self-injurious behavior (SIB) at a large state facility for the retarded was conducted independently three times over a 3-year period. Prevalence consistently was about 10% of the population. SIB cases tended to be younger and institutionalized longer than the rest of the population. Severe cases had a longer history of chronic SIB. SIB cases had more seizure disorders, severe language handicaps, visual impairments, and severe or profound retardation than the rest of the population. They appeared to fulfill most of the Rutter (1966) criteria for autism. But unlike the severely autistic, there was little relation of sex to incidence of SIB. Over 90% of SIB cases changed status over 3 years, suggesting that SIB was amenable to behavior modification in most cases (94%). Psychotropic behavior control medications helped in some intervention programs (32%). SIB remitted spontaneously in 21% of SIB cases where there had been no behavioral or drug intervention.


Autolysins and shape change in rodA mutants of Bacillus subtilis. The biochemical phenotype of rodA mutants was not affected by the simultaneous presence in double mutants of the lyt gene which makes them 90 to 95% deficient in autolysin action. The only morphological effect of this deficiency on the expression of the rod gene was that both the rod and the coccal forms of the mutant failed to separate and grew as long chains of cells. Inhibition of protein synthesis stopped the increase in peptidoglycan that occurred when the growth temperature for the mutants was raised to 45 degrees C. These observations support the idea that a derepression of peptidoglycan synthesis occurs at this temperature. The increased amount of cellular peptidoglycan at the higher growth temperature is not likely to be the result of the concomitant switching off of autolytic enzyme action.


ATP activation and properties of the methyl coenzyme M reductase system in Methanobacterium thermoautotrophicum. The requirement of ATP for the methyl coenzyme M methylreductase in extracts of Methanobacterium thermoautotrophicum was found to be catalytic; for each mol of ATP added, 15 mol of methane was produced from methyl coenzyme M [2-(methylthio)ethanesulfonic acid]. Other nucleotide triphosphates partially replaced ATP in activation of the reductase. All components of the reaction were found in the supernatant fraction of cell extracts after centrifugation at 100,000 X g for 1 h; optimal reaction rates occurred at 65 degrees C, at a pH range of 5.6 to 6.0, and at concentrations of ATP and MgCl2 of 1 mM and 40 mM, respectively. Chloral hydrate, chloroform, nitrite, 2,4-dinitrophenol, and viologen dyes (compounds known to inhibit methanogenesis from a variety of substrates) were found to inhibit the conversion of methyl coenzyme M to methane. Methyl coenzyme M methylreductase was shown to be present in a variety of methanogens.


Psychoactive drug interactions.

Psychoactive drug interactions. Interactions can arise from serial or simultaneous administration of 2 or more drugs. Interactions with other medications can enhance or diminish either the clinical usefulness of a drug, or its toxic effects. Interactions can arise from changes in absorption, protein binding, metabolism, excretion or activity at a common site of action. Drug interactions of clinical interest to psychiatrists are described. The drugs include: stimulants, neuroleptics, tricyclic antidepressants, monoamine oxidase inhibitors, lithium, anticonvulsants, and sedatives and hypnotics.