Dental visits, teeth remaining, and prosthetic appliances in a Norwegian urban population. Of a random sample (177 persons) of 35-year-old Oslo citizens, 117 subjects (66.1%) attended a dental examination. Questionnaires were returned by mail from 28 of the non-respondents. The most common reason for not attending was "difficulty in finding time for an appointment." About 89% of the respondents had visited a dentist regularly. Regular dental care seemed to be more common among people with a high level of education than among those with a low level of education. The most common treatment performed at the last dental visit was filling of cavities. The mean number of remaining teeth was 25.7. Females in the lower educational group had significantly less teeth than those in the higher educational group. No subjects were totally edentulous, but five persons had one edentulous jaw. Nine full or partial dentures were found. Twelve percent of the subjects had one or more fixed bridges, and 29.9% of the persons had one or more crown restorations. There seemed to be no differences between the sexes or educational levels in this respect.


Efficiency in clinical trials of caries preventive agents and methods. The idea sequence of tests required to establish a caries prophylactic agent or procedure on a public health basis is described and a clear distinction is drawn between an experimental clinical trial, carried out under ideal conditions, and a community clinical trial carried out under real life conditions. Because of the artificial nature of an experimental clinical trial there are strict limitations placed on its objectives and the inferences that can be drawn from its results. Bearing these limitations in mind and using the data collected during a 3-year trial of a fluoride mouthrinse, two methods of improving the efficiency of experimental clinical trials of caries prophylactic agents are considered. Firstly, a reduction in length is suggested either by planning the trial to run for a shorter period in the first place or, alternatively, by stopping the trial when the criteria for success have been satisfied. Secondly, it is proposed that the number of subjects participating in the trial be reduced by excluding those whose contributions to the aims of the trial are likely to be low.


Franz Kafka.

Franz Kafka. The hereditary and environmental influences on the genius of Kafka's personality are discussed. His exterior, somatic constitution is represented by photos taken during his lifetime as well as some posthumous, imaginary portraits and sculptures by various, mostly Prague, artists. The concept of the artist's psychic formation - his mental makeup - is documented from his diary, dreams, letters, literary work and reports by his friends. The whole proves his introversion, ambivalence, hypersensitivity, obstinancy, anxieties, behavioral anomalies, a life rich in fantasies and his underestimation of his own literary work. (He speaks about it as an idiosyncrasy, wishing it to be burned after his death.) Some little-known drawings by Kafka complement the picture of his talents and creativity. The psychological and psychopathological roots of his extraordinary position in the cultural awareness of his epoch are discussed.


Transformations of consciousness. A cartography, II. The perception-meditation continuum. The Japanese Zen and Indian Yoga meditation techniques of zazen, dhārnā, dhyān, savichār- and nirvichār-samādhi are cartographed on a perception-meditation continuum of increasing trophotropic arousal. Certain psychophysiological characteristics and experiential dimensions of these hypometabolic states are discussed and it is proposed that observer-observed interactions or trans-substantiation (commonly termed 'reality') may not be subject to Goedelian restrictions if they proceed in hyper- and hypoaroused states. The meaning of aroused, non-verbal and logically non-Aristotelean states cannot be conveyed to individuals in a non-aroused state. The converse is also true when the relationship of arousal levels is reversed.


Pictorial expression of ulcerative colitis. The most prevalent emotional characteristics of patients suffering from ulcerative colitis are illustrated in pictures spontaneously drawn by a young patient while hospitalized. With the onset of the illness, the pathological content of the drawings surfaced. Using anthropomorphism of animals, the patient was able to identify with the story-book characters and reveal the problems of her own inner world and masked depression, which she was not able to express otherwise. Although she viewed herself at the center of the world, innocent and sensitive, she felt inferior and estranged from society. In defense, she withdrew from the hostile world and tried to hide self-directed aggression.


Comparative study on gastric secretory function between benign gastric polyp and elevated type of early stomach cancer with special reference to histological findings of gastric mucosa. In cases of elevated type of early cancer and benign polyp of the stomach, gastric analysis was performed and the results were compared with histological findings of gastric mucosa. Both clinical entities were found to show lowered acid and pepsin secretory functions reflecting severe and extensive atrophic changes of gastric mucosa. Dissociation in secretory disturbance between acid and pepsin was also noticed.


Functional preservation of the mammalian kidney. IV. Functional effects of perfusion with dimethyl sulfoxide (DMSO) at normothermia. Rabbit kidney were perfused at 37degreesC with various concentrations of DMSO in a K+-Mg2+-rich perfusate. The effects of DMSO on various functional parameters of the rabbit kidney perfused for 60 min were compared with the functional effects of perfusion without DMSO under the same conditions. DMSO produced deviations in vascular resistance and perfusate flow rate from control values. In kidneys perfused with 1.4 and 2.8 M DMSO these vascular changes resulted in changes in GFR at relatively unchanged filtration fractions. The closely parallel relationship between changes in GFR and urine flow in all groups indicates that perfusion per se or perfusion with DMSO may shift the regulation of urine flow rate from tubular reabsorption, which obtains in the in vivo situation, to glomerular filtration. This view was supported by the relatively unchanged parameters of Na+ reabsorption and fractional water excretion during perfusion with all concentrations of DMSO. Additionally, DMSO perfusion resulted in significantly greater weight gains than those observed in kidneys perfused without DMSO, and significantly depressed clearances of PAH, with 2.1 and 2.8 M DMSO.


The effect of freeze rate, duration of phase transition, and warming rate on survival of frozen canine kidneys. The effect of cooling rate, warming rate, and duration of phase transition upon survival of frozen canine kidneys was investigated. In the present study, 11 kidneys out of 14 rapidly cooled (2--4degreesC/min) to --22degreesC and thawed (70--110degreesC/min) were viable following contralateral nephrectomy. The serum creatinine and BUN levels rose to a maximum of 8.4 and 30 mg%, respectively, on the eighth day post-contralateral nephrectomy. Average survival time was 10 days; however, two of the dogs in this group were allowed to survive, one for 3 months and one for over 2 years. Eight kidneys out of 16 slowly cooled (0.25-1.0degreesC/min) and either rapidly or slowly warmed (20-30degreesC/min) had function to produce small amounts of urine; however, they did not survive more than 5 days after contralateral nephrectomy. Cooling rates of 0.1 and 10degreesC/min were too harmful to the kidney to have renal function after reimplantation. The minimum renal cell damage as assessed by LDH and GOT in the post-freeze perfusate was found in the 2-4degreesC/min cooling rate following rapid warming (70degrees-110degreesC/min). Correlation of the duration of phase transition time to renal cell damage was linear for LDH and GOT (r=0.93). This result suggests that the duration of phase transition time also is an important factor during the freezing process, affecting post-thaw survival of canine kidneys.


Pulmonary function after recovery from the adult respiratory distress syndrome. Eight adult patients with acute respiratory distress syndrome were treated with positive end-expiratory pressure (PEEP) ventilation. The results of detailed examinations of pulmonary function in these eight patients obtained after different periods of time following discharge from the respiratory care unit were analyzed to determine the degree of disturbances in pulmonary function. For comparison, examinations of pulmonary function were also performed on two patients who were treated with zero end-expiratory pressure ventilation. This follow-up study showed remarkably few abnormalities. Whe present, restrictive disturbances in pulmonary function, especially decreased static compliance and diffusing capacity, were found. No correlation was found between the pulmonary-function results of the eight patients and the duration of the PEEP treatment, nor between the results and the time interval between treatment at the respiratory care unit and the moment of the pulmonary function studies.


Treatment of bronchopleural fistula during continuous positive pressure ventilation. Pneumothorax as a complication of continuous positive pressure ventilation may result in the formation of bronchopleural fistula. If positive end-expiratory pressure cannot be sustained, the functional residual capacity and the ratio of alveolar ventilation to perfusion may decrease, and pulmonary gas exchange may be severely impaired. Recommended therapy includes removal of positive airway pressure and institution of negative intrapleural pressure via thoracostomy tube, but this may cause severe hypoxemia in patients with acute respiratory failure in spite of potentially toxic inspired oxygen concentrations. We applied positive intrapleural pressure equal to the end-expiratory airway pressure of three patients who developed bronchopleural fistula during therapy for acute respiratory failure. Positive intrapleural pressure facilitated resolution of the bronchopleural fistula in each case.


The tethered spinal cord: its protean manifestations, diagnosis and surgical correction. 31 children with spina bifida occulta who have presented with back pain, scoliosis, a progressive neurological deficit involving lower limbs or a neurogenic bladder have been found to have a tethered spinal cord. Release of the tethered spinal cord has always relieved pain, frequently occrected a progressive scoliosis, and arrested or improved neurogenic foot deformities as well as neurogenic bladder.


[Lymphocele following renal transplantation]. Lymphoceles as seen after renal transplantation are cystic swellings filled with lymph, situated beneath the lower end of the transplant on the iliac vessels. It seems that the lymph originates from lymphatics cut during operation. 5 such cases have been seen in our series of 268 renal allotransplantations. Symptoms arose 1 to 6 months after transplantation. According to our own experience and to 39 cases of the literature, deterioration of renal function because of compression of the ureter is the most common symptom. Therefore, intravenous pyelography is the main diagnostic means. Some cysts can be visualized by lymphangiography. Marsupialisation to the peritoneal cavity is the treatment of choice.


[New formation of gallbladder calculi due to suture material--avoidable problem?]. Catgut material has proved to be perfectly stable in gall, thus facilitating precipitation and calculus formation. Therefore, polyglycolic acid suture material was tested under laboratory conditions. This material disintegrates completely within 9 weeks, and for this reason is recommended in operations on the biliary tract.


[Sclerosing of bleeding oesophageal varices (author's transl)]. Bleeding from oesophageal varices was stopped in two patients by percutaneous transhepatic transportal injection of 50% glucose and thrombin into the gastric coronary vein and the gastro-oesophageal varices draining into it. The only complication was a right-sided pleural effusion in one of the patients.


Hydrocortisone 17-butyrate: a new topical corticosteroid preliminary report. Hydrocortisone 17-butyrate is a new non-fluorinated topical corticosteroid for use in psoriasis, eczema and other inflammatory dermatoses. In double-blind paired comparisons with other topical corticosteroids, the efficacy of hydrocortisone 17-butyrate 0.1% has generally been indistinguishable from that of triamcinolone acetonide 0.1%, fluocinolone acetonide 0.025% or betamethasone 17-valerate 0.1% in patients with eczema or psoriasis. When applied to the face of patients with atrophy superimposed on rosacea and perioral dermatitis resulting from prolonged use of fluorinated topical corticosteroids, hydrocortisone 17-butyrate 0.1% did not prevent the beneficial effect of systemic tetracycline nor the disappearance of telangiectasis, and tended to be more effective than hydrocortisone 1%. This result suggests that hydrocortisone 17-butyrate may be suitable for long-term use on facial lesions, although the occurrence of moderate rebound eruption in about 10% of patients indicates the need for caution. The findings suggest that hydrocortisone 17-butyrate may be less liable to cause skin atrophy and adrenal suppression than some other potent topical corticosteroids, but trials to date have been too short to allow definite conclusions regarding possible long-term effects and have not involved infants or children.


Metoclopramide: a review of its pharmacological properties and clinical use. Metoclopramide, 4-amino-5-chloro-2-methoxy-N-(2-diethyl-aminoethyl) benzamide, is advocated for use in gastro-intestinal diagnostics, and in treating various types of vomiting and a variety of functional and organic gastro-intestinal disorders. Published data have indicated that metoclopramide assists radiological identification of lesions in the small intestine, facilitates duodenal intubation and small intestine biopsy, and eases emergency endoscopy in upper gastro-intestinal haemorrhage. Metoclopramide reduces post-operative vomiting and radiation sickness, and ameliorates some types of drug-induced vomiting. It may provide symptomatic relief in dyspepsia and possibly in vertigo, reflux oesophagitis and hiccups, but further controlled trials are needed to confirm the efficacy of metoclopramide in these proposed areas of use. It promotes gastric emptying prior to anaesthesia. Its effects in healing gastric ulcer and preventing relapse of duodenal ulcer remain unproven. Side-effects are few and transient, though alarming extrapyramidal reactions can occur in a small proportion of patients receiving therapeutic doses but more usually following excessive doses in young subjects. They respond rapidly to withdrawal of the drug.


Antithrombotic drugs: part II.

Antithrombotic drugs: part II. The defibrinating agent ancrod has had limited clinical trial, but appears to give no advantages over heparin. Intravenous infusion of dextran, a glucose polymer, has been shown to have an antithrombotic effect in many experimental models of thrombosis. However, the evidence that dextran is a clinically valuable antithrombotic drug is conflicting. A number of controlled randomized studies have shown that dextran can prevent postoperative venous thromboembolism when a large volume of dextran 40 or 70 was infused rapidly during and after surgery. However, blood volume expansion during dextran treatment prohibits its use in patients with reduced cardiac reserve, and infrequent though sometimes severe, allergic reactions have been reported. Evidence that dextran is of value for the treatment of venous or arterial thromboembolism comes from uncontrolled studies and is not convincing. Many compounds have been shown to inhibit platelet function in vitro but only five of these drugs have been extensively evaluated as prophylactic or therapeutic antithrombotic agents in man. These are aspirin, sulphinpyrazone, dipyridamole, hydroxychloroquine and clofibrate. They have been evaluated mainly in patients with cerebral vascular disorders, coronary artery disease, peripheral artery ischaemia, venous thromboembolism, prosthetic heart valves, and in patients with arteriovenous shunts. The evaluation of the clinical effect of the platelet function suppressing drugs is in its early stages, but they appear to differ from each other in the spectrum of their clinical effectiveness, and they may be more effective in arterial than in venous thromboembolic disorders. Their role in the management of cerebral vascular disease and coronary artery disease is still uncertain, and should be clarified by the results of a number of multi-centre, prospective, randomized studies which are currently in progress. Three types of thrombolytic drugs have been evaluated clinically; the plasminogen activators streptokinase and urokinase, proteolytic enzymes such as plasmin, and agents which increase the level of endogenous plasminogen activator (e.g. anabolic steroids). Of these, the plasminogen activators now have a definite place in clinical practice. The plasminogen activators accelerate the lysis of recent venous thrombi and pulmonary emboli, and of arterial thrombi or emboli. Thrombolytic therapy with these agents should be considered particularly in patients with recent major pulmonary embolism, as lysis of recent emboli is rapid and substantial. It should also be considered in patients with recent extensive venous thrombosis, because total lysis of venous thrombi has been reported to result in long-term preservation of valve function, and is likely to prevent postphlebitic syndrome, though this has not been proven. However, plasminogen activator therapy carries a higher risk of bleeding than heparin treatment...


Comparison of the anti-LH/FSH-RH and anti-ovulatory activities of (D-Phe2, D-Leu6)-LH-RH and (D-Phe2, D-Ala6)-LH-RH. The anti-LH/FSH-RH and antiovulatory activities of [D-Phe2, D-Leu6]-LH-RH and [D-Phe2, D-Ala6]-LH-RH were compared in rats. Both peptides inhibited the LH and FSH release induced by LH-RH in immature male rats, but, 4 hr after the injection, [D-Phe2, D-Leu6]-LH-RH still suppressed the LH and FSH release whereas the [D-Phe2, D-Ala6]-LH-RH did not. When the peptides were administered in equal doses on the afternoon of the day of proestrus in 4-day cycling rats, [D-Phe2, D-Leu6]-LH-RH more completely inhibited the ovulation occurring on the following morning than [D-Phe2, D-Ala6]-LH-RH. Thus, the incorporation of D-Leucine into position six of the decapeptide chain gives a more potent inhibitor than that resulting from the insertion of D-Alanine.


Effect of antihypertensive drugs on the renin-angiotensin system. Renin release from the kidneys is controlled by four major mechanisms - renal baroreceptors, the macula densa, the sympathetic nervous system and other humoral and ionic influences. Recently, the importance of the sympathetic nervous system in modulating renin release for a variety of stimuli has become apparent. The sympathetic adrenergic nerves act on a specific beta-receptor to stimulate renin release from the kidney. Those antihypertensive drugs that inhibit adrenergic nerve transmission tend therefore to lower plasma renin. beta-Adrenoreceptor blocking drugs also generally lower plasma renin by specific inhibition of renal renin release both in animals and humans. Diuretics and vasodilators in contrast elevate plasma renin levels. Plasma renin levels in hypertensive patients are the net result of many diverse influences, and similarly in patients treated with antihypertensive drugs the plasma renin level often is the result of opposing influences. Plasma renin levels tend to return towards normal levels after treatment in hypertensive patients. Plasma renin levels may offer a guide to a more rational basis for antihypertensive therapy in the future. However, the primary aim in treatment of the hypertensive patient should be to lower his blood pressure, independent of the effect of plasma renin levels.


The energetics of Escherichia coli during aerobic growth in continuous culture. 1. The energetics of Escherichia coli W growing aerobically in continuous culture have been investigated. Conditions were chosen such that growth was limited by the availability of carbon or oxygen (energy-limited cultures), or of ammonium of sulphate ions (excess energy cultures). 2. Under glycerol-limited conditions YmaxO2 (true molar growth yield with respect to oxygen) and YmaxATP (true molar growth yield with respect to ATP equivalents) were 50.9 g cells-mol O-02(-1) and 12.7 g cells-mol ATP equivalents-1 respectively; these values were not substantially altered during growth limited by oxygen, ammonium or sulphate. In contrast, M (the energy requirement for maintenance purposes) increased from approximately 2 mmol ATP equivalents-h-1-g cells-1 during energy-limited growth to 16.8 and 30.8 mmole ATP equivalents-h-1-g cells-1 when growth was limited by ammonium and sulphate ions respectively. 3. Replacement of glycerol by other limiting carbon sources caused YmaxATP to alter within the range 13.9 (glucose) to 7.1 (acetate) g cells-mol ATP equivalents-1 in the order glucose greater than galactose greather than arabinose greater than fructose greater than glycerol greater than fumarate greater than lactate greater than pyruvate greater than acetate. In each case the experimental value of YmaxATP was less than or equal to 55% of the theoretical value calculated from the known energy requirements for the biosynthesis of cell materials. 4. It is concluded from these results that neither M nor Ymax ATP are constant values for E. coli. M varies with the energy supply, being highest under excess energy growth conditions where it may reflect energy wastage by the cell. On the other hand, YmaxATP varies with the nature of the growth substrate and thus reflects the different energy requirements for the synthesis of cell material from different carbon sources.


Effects of antibodies to various molecular forms of a mutationally altered Escherichia coli alkaline phosphatase on its activation by zinc. Immunogenic and antigenic properties of a Zn2+ -deficient alkaline phosphatase produced in a mutant (U-47) of Escherichia coli have been studied. The native U-47 enzyme, that exists in a monomerdimer equilibrium, was used as immunogen. From the antisera obtained, four antibody populations directed to the various molecular forms of U-47 enzyme have been purified by affinity chromatography using specific antigens coupled to glutaraldehyde-activated beads of indubiose. 70% of the total antibody obtained was directed both to the monomeric and the dimeric forms, 9% was directed to the dimer but showed a low affinity for the monomer; 10% and 11% were specifically directed respectively to the monomer and the dimer. Each antibody population purified had a specific effect on the catalytic activity of the Zn2+ -activated U-47 enzyme. The anti-monomer-dimer and the anti-dimer-monomer inhibit to the same extent whereas the specific anti-monomer does not alter the activity significantly and the specific anti-dimer causes a 30% activation. The catalytic activity of the alkaline phosphatase produced in wild-type strains was also reduced by these anti-U-47 enzyme antibodies. However, whereas the anti-monomer had again very little effect, the anti-dimer-monomer and the anti-monomer-dimer inhibited this enzyme to different extents. The specific antidimer also inhibited this wild-type alkaline phosphate. Antibodies of high affinity to the dimeric form of U-47 enzyme, i.e. specific anti-dimer or anti-dimer-monomer, caused a 30% activation when they were added prior to the reactivation process by Zn2+. Specific anti-monomer strongly inhibited this reactivation process. The Fab fragment of the anti-wild-type phosphatase antibody, under the same conditions, caused a 300% activation. The extents of interactions of the various molecular forms of U-47 enzyme and of the wild-type enzyme with the anti-monomer-dimer and with the anti-dimer have been determined. U-47 enzyme monomeric form has three determinants exposed and the dimeric form has five determinants exposed for interacting with the anti-monomer-dimer antibody, the free wild-type enzyme has only two determinants exposed to this antibody. These determinants might be close to the active site or in another critical location since this antibody can reduce the catalytic activity of the wild-type enzyme to half the original value. The anti-dimer antibodies can interact with three determinants exposed at the surface of the free Zn2+ -reactivated U-47 enzyme and the non-covalent binding of one mole of inorganic phosphate results in the exposure of one more antigenic determinant.


L-Phenylalanine: tRNA ligase of Escherichia coli K10. The effect of O replaced by S substitution on substrate and ligand binding properties of ATP. The Km and V values of the tRNA-charging reaction have been measured for L-phenylalanine:tRNA ligase and the geometric isomers of adenosine 5'-O-(1-thio)triphosphate, adenosine 5'-O-(2-thio)triphosphate and for 5'-O-(3-thio)triphosphate. All ATP analogs were found to be substrates with values of Km similar or (up to 10-fold) higher, and with values of V in the range of 10--30% compared with the natural substrate. The dissociation constants of the binary enzyme-nucleotide and ternary enzyme-nucleotide-L-phenylalaninol complexes were analysed as a function of the position of the sulfur atom indicating those phosphate groups which are involved in an enzyme-triphosphate interaction. The results are consistent with a participation of the beta and gamma-phosphate in the binary complex formation and an additional interaction at the positions of the alpha and beta-phosphate groups in the ternary complexes.


Affinity labelling of tRNA nucleotidyltransferase from baker's yeast with tRNAPhe modified on the 3'-terminus. 2'-Deoxy-2'-amino-cytidylic acid can be incorporated into position 75 of tRNAPhe from yeast by tRNA nucleotidyltransferase yielding tRNAPhe-C-C(2'NH2). tRNAPhe-C-C(2'NH2) can be reacted with the N-hydroxysuccinimide esters of bromoacetic acid of mercuriacetic acid to yield the derivatives tRNAPhe-C-C(2'NHCOCH2Br) and tRNAPhe-C-C(2'NHCOCH2Hg+OH-). Each of these reactive tRNAs inactivates tRNA nucleotidyltransferase from yeast with similar kinetics. The enzyme can be protected against inhibition by its substrates tRNAPhe-C and tRNAPhe-C-C as well as ATP and CTP. A covalent, isolatable 1:1 complex between tRNAPhe-C-C(2'NHCOCH2Br) and the enzyme was formed, but could not be found when the enzyme had previously been inactivated with p-hydroxymercuribenzoate.


Geometry of the protein S4 from Escherichia coli ribosomes. The shape of protein S4 from Escherichia coli ribosomes in solution was determined by hydrodynamic methods and low-angle X-ray scattering. The molecular weight of 24000 determined by low-angle X-ray scattering is within 3% of that found by sedimentation equilibrium analysis and 8% of that determined by amino acid sequence work. The radius of gyration of 3.36 nm, the radius of gyration of the cross section of 0.41 nm and the hydrodynamic studies revealed that protein S4 is not spherical, but rather has a markedly extended shape. Calculations of different conformations, e.g. random coil, based on the parameters evaluated from hydrodynamic methods, revealed a rod-like structure of S4 with a length of 14 nm and a diameter of 1 nm. This is supported by a model of an equivalent scattering particle of uniform density based on all parameters obtained in this study.


Formation of dolichol monophosphate 2-deoxy-D-glucose and its interference with the glycosylation of mannoproteins in yeast. A crude membrane fraction from Saccharomyces cerevisiae has been found to catalyze 2-deoxy-D-glucose transfer from GDP-2-deoxy-D-glucose to endogeneous lipid and glycoprotein acceptor. Evidence will be represented that the glycolipid formed has properties characteristic dolichol monophosphate 2-deoxy-D-glucose. The 2-deoxy-D-glucosyl group can further be transferred from the glycolipid into a membrane-bound polymer fraction. More than 95% of the radioactivity incorporated can be released by beta-elimination, indicating an O-glycosidic linkage to serine or threonine. The only radioactive product obtained is 2-deoxy-D-glucose. When dolichol monophosphate 2-deoxy-[14C]glucose is incubated together with non-radioactive GDP-mannose subsequent beta-elimination yields no higher oligosaccharides in contrast to an experiment where dolichol monophosphate [14C]mannose and GDP-mannose are used as donors. The results are consistent with the assumption that the non-physiological nucleotide sugar interferes with GDP-mannose for mannosylation and terminates further elongation of the serine/threonine-bound oligomannose side chains. UDP-2-deoxy-D-glucose, used as donor, results also in the formation of a glycolipid. In this case, however, no polyprenol derivative is formed. Instead, the glycolipid displays properties characteristic of sphingolipid or a sterol glucoside.


Polypeptide-chain elongation promoted by guanyl-5'-yl imidodiphosphate. In a purified system from Escherichia coli containing ribosomes complexed with poly(uridylic acid) and N-acetyl-phenylalanyl-tRNA, the nonhydrolyzable analog of GTP, guanyl-5'-yl imidodiphosphate (Guo-5'-P2-NH-P), promotes polypeptide synthesis at a rate several times slower than GTP. The activity is completely dependent on elongation factors EF-T (i.e, EF-Ts + EF-Tu) and EF-G. Examination of individual steps of the elongation cycle in partial reactions shows that Guo-5'-P2-NH-P is as efficient as GTP in promoting the EF-T-dependent binding of phenylalanyl-tRNA to the ribosomal A site. In contrast, Guo-5'-P2-NH-P promotes the translocation-dependent binding of phenylalanyl-tRNA to a ribosome complexed with A-site-bound N-acetyl-phenylalanyl-tRNA much more slowly than GTP. This slow rate of binding is due to the presence of EF-G on the ribosome, and not to sluggish translocation, since (a) the rate remains slow even after translocation of N-acetylphenylalanyl-tRNA is completed, (b) it is greatly speeded up by removal of EF-G from the reaction mixture (after translocation has occurred), and (c) it is slowed down again by readdition of the factor. Moreover, with post-translocated ribosomes and in the absence of EF-G, formation of dipeptide subsequent to the EF-T-dependent binding of phenylalanyl-tRNA is much slower when binding of this substrate has been promoted by Guo-5'-P2-NH-P than it is when promoted by GTP. The results suggest that, during polymerization with Guo-5'-P2-NH-P, EF-G and EF-Tu are slowly released from the ribosome and, consequently, the steps of the elongation cycle subsequent to translocation and aminoacyl-tRNA binding (aminoacyl-tRNA binding and peptide bond formation, respectively) are delayed. Thus, durong elongation cycle, GTP hydrolysis is probably essential for fast release of the factors from the ribosome.


Purification, subunit structure and partial amino-acid sequence of anthranilate-5-phosphoribosylpyrophosphate phosphoribosyltransferase from the enteric bacterium Serratia marcescens. The enzyme anthranilate-5-phosphoribosylpyrophosphate phosphoribosyltransferase from Serratia marcescens was purified to apparent homogeneity. The purification procedure included ammonium sulfate precipitation, DEAE-cellulose chromatography, Sephadex gel filtration and hydroxyapatite chromatography. The molecular weight of the native protein as determined on a calibrated Sephadex G-200 column was 45000. Dodecylsulfate-polyacrylamide gel electrophoresis in the presence of reducing agent revealed a subunit molecular weight of 43000 +/- 900, suggesting that the enzyme exists as a monomer. The sequence of the amino-terminal 38 residues revealed that three amino amino acids, glutamine (six residues), glutamic acid (five residues) and serine (five residues) comprised 42% of the sequence composition.


The role of Escherichia coli dna A gene and its integrative suppression in M13 coliphage DNA synthesis. An F+ derivative of Escherichia coli E508 thermosensitive in dna A function (involved in DNA synthesis initiation), its revertant and an Hfr derivative of E508 (ts) in which the temperature-sensitive phenotype is suppressed by integrative suppression have been compared for their ability to support M13 phage DNA synthesis at the nonpermissive temperature. Upon infection at the nonpermissive temperature, both the revertant and the Hfr strain support normal phage replication while the temperature-sensitive mutant does not. However, when infection is carried out at a permissive temperature and the temperature is shifted up after infection, phage synthesis occurs in the temperature-sensitive mutant also, but in lesser quantity than in the revertant strain. Analysis of intracellular labeled phage DNA indicates: (a) parental replicative form DNA synthesis is not dependent on dna A function; (b) progeny replicative form DNA synthesis is strongly inhibited in the temperature-sensitive dna A mutant at the nonpermissive temperature; (c) progeny single-strand DNA synthesis does not absolutely require dna A function; (d) progeny single-strand DNA is present in the circular form. The implication of the host DNA replication in M13 DNA synthesis is discussed.


The role of Escherichia coli dnaG function in coliphage M13 DNA synthesis. Examination of the role of Escherichia coli dnaG function in different stages of M13 phage DNA synthesis by ultracentrifugal analysis of intracellular phage DNA in a thermosensitive dnaG mutant shows that: (a) the formation of parental double-strand replicative-form DNA (rfDNA) from the infecting virus is independent of dnaG function; (b) the synthesis of progeny rfDNA requires dnaG product; (c) after a pool of rfDNA is made up, dnaG function is not required for the progeny single-strand DNA (ssDNA) synthesis. The ssDNAs produced under nonpermissive condition are mostly circular and biologically functional.


The O9 antigen of Escherichia coli. Structure of the polysaccharide chain. The lipopolysaccharide from Escherichia coli O9:K30- was isolated in about 2% yield with aqueous 45% phenol at 65 degrees C, followed by ultracentrifugation. The polysaccharide moiety was obtained by graded hydrolysis and gel permeation chromatography. It consisted of a mannan which carried on its reducing end the core oligosaccharide of the R1 type. The mannan contained 1 leads to 2 and 1 leads to 3 linkages in a ratio of 3:2, as determined by methylation analysis and mass spectrometry. On periodate oxidation, 58% of the mannose residues were destroyed. Degradation of oligosaccharide mixtures with alpha-mannosidase from jack bean meal, as well as a specific rotation of [alpha]25D = +89 degrees indicated that all mannosyl linkages have the alpha-configuration. Smith degradation resulted in the liberation of mannosyl (1 leads to 3)-mannose (bound to glyceraldehyde), as established by methylation analysis. From these results we conclude that the O9 polysaccharide of E. coli has a pentasaccharide repeating unit of alpha-mannosyl(1 leads to 3)-alpha-mannosyl-(1 leads to 2)-alpha-mannosyl-(1 leads to 2)-alpha-mannosyl-(1 leads to 2)-mannose, which are joined in the polysaccharide through alpha-(1 leads to 3)-mannosyl linkages.


Raffinose metabolism in Escherichia coli K12. Purification and properties of a new alpha-galactosidase specified by a transmissible plasmid. The utilization by Escherichia coli K12 of raffinose as sole carbon source depends on a new raffinose transport system, an invertase and an alpha-galactosidase specified by the Raf-plasmid D1021. The alpha-galactosidase was purified to homogeneity from a mutant strain with constitutive synthesis of the enzyme. alpha-Galactosidase hydrolyzes p-nitrophenyl-alpha-D-galactoside (Km 0.14 mM), methyl-alpha-D-galactoside (Km 30mM), melibiose (Km 3.2 mM) and raffinose (Km 60 mM). The enzymatic activity is strongly inhibited by Ag+, p-chloromercuriphenyl sulfonic acid and, to a lesser extent, by iodoacetamide. Isoelectric focusing indicates the existence of one form of alpha-galactosidase with an isoelectric point of 5.1. The purified enzyme has an sw,20 value of 11.7 +/- 0.3S and a molecular weight of 329000 +/- 4000; this value is not reduced at high dilutions. When examined by dodecylsulphate gel electrophoresis, purified alpha-galactosidase yields a single subunit band of molecular weight 82000 suggesting that the intact enzyme consists of four subunits. Amino acid analysis indicates the presence of approximately 712 amino acid residues per quarter molecule including 8 half-cystine residues. No carbohydrate moiety has been detected. High resolution electron micrographs and Markham rotation of alpha-galactosidase show enzyme molecules of approximately 11 x 11 nm containing four globular subunits in a tetragonal arrangement. The plasmid-coded alpha-galactosidase differs from the homologous E. coli enzyme by substrate affinities, cofactor requirements, stability and toluene resistance. It can, therefore, be used as a marker enzyme suitable for the detection in vivo of Raf-plasmids.


Use of a sequence-specific DNA-binding ligand to probe the environments of EcoRI restriction endonuclease cleavage sites. The DNAs of bacteriophage lambda and adenovirus were incubated with the sequence-specific DNA-binding ligand 6,4'-diamidino-2-phenylindole. Digestion of the ligand-DNA complexes with EcoRI nuclease and subsequent agarose gel electrophoresis demonstrated that the ligand inhibited nuclease activity at some sites, but not at others. The results suggest that diamidino-2-phynylindole can be used to probe the immediate environments of the EcoRI cleavage sites.


Binding of aminoacyl-tRNA to reconstituted subparticles of Escherichia coli large ribosomal subunits. The activity of 50-S subunits to stimulate the binding of aminoacyl-tRNA to the 30-S subunits was lost when the particles were washed with LiCl concentrations higher than 1.0 M [Kazemie, M. (1975) Eur. J. Biochem. 58,501-510]. The particles could regain this activity when they were incubated with the corresponding LiCl washes. This effect of LiCl washes was used as an assay for identification of 50-S subunit proteins which are essential for binding of aminoacyl-tRNA. A protein mixture containing mainly Ll, Lll and L16 can reactivate 50-S "core" particles, consisting of 10 proteins and 23-S RNA, to bind aminoacyl-tRNAs in the presence of 30-S subunits. Besides 5-S RNA, protein L24 has a stimulatory effect on the binding of aminoacyl-tRNA. Proteins L2, L20 and L23 are possibly required for maintaining the 50-S subunits in the correct conformation for binding of aminoacyl-tRNAs.


Phospholipid and lipopolysaccharide in Proteus mirabilis and its stable protoplast L-form. Difference in content and fatty acid composition. Cells of the stable protoplast L-form of Proteus mirabilis contain 1.5 to 2 times more extractable lipid, mostly phospholipid, per dry weight than cells of the bacterial form. Under identical conditions of cultivation the qualitative and quantitiative composition of the phospholipid is very similar in both cell forms. The range of mole percentages of individual phospholipid species is 78-80 for phosphatidylethanolamine, 10-13 for phosphatidylglycerol, 3.9-5.5 for diphosphatidylglycerol and 1.0-2.1 for lysophospholipid. However, all phospholipid species in the L-form differ from those of the bacterial form by a lower content of long-chain fatty acids and a higher content of short-chain fatty acids. Growth of the L-form in the presence of growth-stimulating horse serum results in a change of phospholipid composition accompanied by the uptake of phospholipid and fatty acids from the serum into L-form phospholipid. L-form protoplasts synthesize the same two types of lipopolysaccharide, I and II, that were previously identified in the bacterial form of Proteus mirabilis. However, only small amounts of the more hydrophilic lipopolysaccharide II are present in the L-form. Lipopolysaccharides from both cell forms have virtually identical polysaccharide compositions but differ strikingly in the relative content of fatty acids in their lipid-A moieties. Molar ratios of tetradecanoic acid, hexadeconoic acid and 3-hydroxytetradecanoic acid are 5:1:6 in the bacterial form and 5:0:1:6 in the L-form grown in serum-free medium. The observated differences between the bacterial form and the protoplast L-form are interpreted as results of the adaptation of the L-form to life in the state lacking an envelope by formation of a physically more stable but still sufficiently fluid protoplast membrane. A rapid method based on fatty acid analysis for the simultaneous quantitative determination of phospholipid and lipopolysaccharide content of whole cells is reported.


Isolation and characterization of a growth-cycle-reflecting, high-molecular-weight protein associated with Escherichia coli ribosomes. A high-molecular-weight, acidic protein, acidic protein whose amount per ribosomal particle depends on the growth cycle is shown to be associated with Escherichia coli ribosomes. The protein is associated with ribosomes from cells harvested at different phases of the growth cycle, but a large increase in its amount is seen with ribosomes from post-exponential phase cells. The protein is only slightly washed off the ribosomes by 1 M NH4CL. When ribosomes are dissociated it remains entirely with the 30-S subunits. We have purified the protein to homogeneity. It has a molecular weight of 70 000 and its amino acid composition showed some resemblance to that of ribosomal protein S1. However, the two proteins ar-shown variation in the acetylation of L12 during the growth cycle, indicated that certain proteins of (or associated with) E. coli ribosmes may carry specific biochemical roles connected with cellular adaption toward the stationary phase.


Indolmycin inhibits prokaryotic tryptophanyl-tRNA ligase. Indolmycin specifically prevents the formation of tryptophanyl-tRNA in a prokaryotic system in vitro using Escherichia coli enzymes. However, the drug has little effect in an eukaryotic system in vitro (rat liver enzymes). Analysis of the type of inhibition revealed that indolmycin competes with tryptophan as a pure competitive inhibitor of prokaryotic tryptophanyl-tRNA ligase.


Insulin action on glucose transport and calcium fluxes in developing muscle cells in vitro. The glucose transport system of developing muscle cells in vitro is described. Uptake experiments showed stereospecificity but no saturation or competition. Km-values for early myoblasts could not be determined; with progressive development, the absolute amount of uptake increases and becomes insulin sensitive. Km-values of about 13 mM basal and 32 mM for insulin stimulation were determined and discussed with respect to the glucose transport mechanism. Basal and insulin-dependent transport were shown to be dependent on the presence of calcium in the medium. Moreover, the ionophore A 23187 could be shown to mimic the insulin effect on glucose uptake. 45Ca saturation and desaturation experiments showed that insulin enhances the "mitochondrial" calcium pool by 35% and increases the apparent "cytoplasmic" efflux rate constant by 50%. We propose that insulin increases the free cytoplasmic calcium concentration, which may be the intracellular signal for the stimulation of glucose transport.


DNA-dependent DNA polymerase from yeast mitochondria. Dependence of enzyme activity on conditions of cell growth, and properties of the highly purified polymerase. The activity of DNA polymerase was determined in gradient-purified mitochondria from yeast cells grown under a variety of conditions. The specific enzyme activity was found to be dependent on the degree of aeration of the cells, and on the carbon source used for the medium. It was sensitive to glucose repression, and was enhanced about two-fold by the growth of yeast cells in the presence of ethidium bromide. Mitochondria DNA polymerase was highly purified and several properties were determined. Sucrose density gradient centrifugation, and dodecylsulfate-polyacylamide gel electrophoresis revealed the following structure: a monomer of molecular weight around 60 000 aggregated under relatively high salt concentration (0.2 M phosphate buffer) to a dimer of about 120 000 which under low salt concentration (0.2 M Tris-HCl buffer) formed higher aggregates. For optimal activity an Mg2+ ion concentration of 50 mM was found necessary, Mn ions did not promote activity at any concentration tested (0.5--50 mM). Indeed, if added to Mg2+-containing assays, Mn2+ strongly inhibited enzyme activity at low concentrations. This might be an explanation for the inducation of mitochondrial mutants in yeast cells grown in the presence of Mn2+ ions. Mitochondrial DNA polymerase activity was strongly inhibited by low concentrations of the -SH reagent p-chloromercuribenzoate, the nucleotide analogue cytosine arabinoside triphosphate also exerted an inhibitory effect. An about 50% decrease of activity was observed in the presence of 1 mM o-phenanthroline in assay mixture containing DNA at about the Km concentration. The enzyme preferred a gapped template primer, poly(dA) - (dT)10, over nicked DNA and was unable to use a polyribonucleotide template, poly(rA) - (dT)10. In the purest preparations no exonuclease activity could be detected.


The primary structure of a non-initiating methionine-specific tRNA from brewer's yeast. tRNA3Met, one of the non-initiating methionine-specific tRNAs in brewer's yeast was purified from bulk tRNA labelled with [32P]phosphate by two column chromatographic steps. The primary structure of this tRNA was determined by the usual fingerprinting technique. Analyses of the isolated nucleotides and oligonucleotides from digests with pancreatic and T1 ribonucleases were in good agreement and stated that tRNA3Met consists of 76 nucleotide residues including 13 minor nucleotides. Overlaps from which the complete sequence could be deduced were derived from the analyses of 15 fragments obtained by partial digestion with T1 ribonuclease.


Molecular organization in bacterial cell membranes. Sulfhydryl groups and disulfide bridges in Streptomyces albus and Escherichia coli K 12 cytoplasmic membranes. Plasma membranes from Streptomyces albus had 5.2 mol of sulfhydryl groups and 6 mol of disulfide bridges/50 kg proteins whereas Escherichia coli membranes had 3.4 mol sulfhydryl groups and 4 mol disulfide bridges/50 kg protein. About 66% of the sulfhydryl groups of S. albus membranes and 22% of those of E. coli membranes were readily accessible to titration with 5,5'-dithiobis(2-dinitrobenzoic acid). o-[3 Hydroxymercuri-2-methoxypropyl)-carbamyl]-phenoxyacetic acid (mersalyc acid) and p-chloromercuribenzoate were effective in solubilizing membrane proteins from the two bacteria. Other sulfhydryl group reagents, such as N-ethylmaleimide, iodoacetamide and iodoacetic acid, were less effective. Dithiothreitol affected the dodecylsulphate gel electrophoresis patterns of S. albus membranes and soluble fractions. This effect resulted from the reduction of pre-existing disulfide intramolecular bridges and some interchain disulfide formed during solubilization and/or storage. Dithiothreitol also affected the dodecylsulphate gel electrophoresis patterns of E. coli membranes and their soluble fractions. These results suggest that sulfhydryl groups and disulfide bridges play a role in the structural organization of these prokaryotic membranes.


Restriction-enzyme-cleavage maps of bacteriophage M13. Existence of an intergenic region on the M13 genome. Replicative form DNA of bacteriophage M13 was cleaved into specific fragments by an endonuclease isolated from Hemophilus aegyptius (endoR.HaeII) and an endonuclease from Arthrobacter luteus (endoR.AluI). The fragments were ordered as to construct a circular map of the phage M13 genome by: (a) using each fragment as a primer for the synthesis in vitro of its respective neighbour and (b) digesting the isolated fragments with the Hemophilus aegyptius enzyme endoR.HaeII or the Hemophilus aphirophilus enzyme endoR.HapII and subsequent analysis of the overlapping sets of fragments. The resulting physical map was correlated with the M13 genetic map by marker rescue experiments with amber mutant phage DNAs and purified wild-type fragments. From the results of these analyses it has been concluded that gene II and gene V are contiguous on the genetic map. Evidence is provided that there is an internal start of RNA synthesis within the C-terminal region of gene II which then ultimately leads to the synthesis of X protein. Furthermore, we conclude that there is an intergenic space of considerable length (450-500 base pairs) which is located between gene II and gene IV on the M13 genome. The function of this intergenic region as the origin site for phage DNA replication is discussed.


Unusual response to continuous positive pressure ventilation. In a patient with acute respiratory failure due to aspiration pneumonia, PaO2 decrease and Qs/Qt increase were observed during continuous positive pressure ventilation. This paradoxical finding was attributted to vascular collapse in well ventilated upper alveoli associated with blood flow redistribution to dependent hypoventilated areas with low ventilation-perfusion relationships.


Synchronous bilateral lumbotomy.

Synchronous bilateral lumbotomy. The surgical technique of synchronous bilateral nephrectomy or nephrolithotomy is described. The operative details, the indications, advantages and complications are reported in this series of ten patients. These bilateral posterior vertical incisions with minimal cutting of abdominal musculature, together with rapid mobilisation of the patient and the absence of prolonged post-operative pain, provide a distinct advantage over conventional renal incisions.


Review: artifical ventilation with positive end-expiratory pressure (PEEP). Historical background, terminology and patho-physiology. CPPV (continuous positive pressure ventilation) is obviously superior to IPPV (intermittent positive pressure ventilation) for the treatment of patients with acute respiratory insufficiency (ARI) and results within a few minutes in a considerable increase in the oxygen transport. The principle is to add a positive end-expiratory plateau (PEEP) to IPPV, with a subsequent increase in FRC (functional residual capacity) resulting in re-opening in first and foremost the declive alveolae, which can then once again take part in the gas exchange and possibly re-commence the disrupted surfactant production. In this manner the ventilation/perfusion ratio in the diseases lungs is normalized and the intrapulmonary shunting of venous blood (Qs/Qt) will decrease. At the same time the dead space ventilation fraction (VD/VT) normalizes and the compliance of the lungs (CL) increases. The PEEP value, which results in a maximum oxygen transport, and the lowest dead space fraction, also appears to result in the greatest total static compliance (CT) and the greatest increase in mixed venous oxygen tension (PVO2); this value can be termed "optimal PEEP". The greater the FRC is, with an airway pressure = atmospheric pressure, the lower the PEEP value required in order to obtain maximum oxygen transport. If the optimal PEEP value is exceeded the oxygen transport will fall because of a falling Qt (cardiac output) due to a reduction in venous return. CT and PVO2 will fall and VD/VT will increase. Increasing hyperinflation of the alveolae will result in a rising danger of alveolar rupture. The critical use of CPPV treatment means that the lungs may be safeguarded against high oxygen percents. The mortality of newborn infants with RDS (respiratory distress syndrome) has fallen considerably after the general introduction of CPPV and CPAP (continuous positive airway pressures). The same appears to be the case with adults suffering from ARI (acute respiratory insufficiency).


Total replacement of both ureters by prostheses. Complete bilateral ureteric replacement by silicone prosthesis is described in a patient suffering from retroperitoneal involvement from prostatic carcinoma. Immediate and long-term results were very satisfactory from a functional and social point of view and encourage consideration of this new surgical procedure in certain forms of ureteric obstruction.


Preliminary evaluation of VM-26: a new epipodophyllotoxin derivative, in the treatment of urogenital tumours. VM-26, a podophyllin derivative, is cytotoxic in vitro against cell cultures of bladder tumours. Intravenous therapy of vesical carcinoma produces only occasional responses. One total regression was observed in our series. Intravesical instillations are more effective. Topical treatment of papillomatosis led to total or partial regression in one half of cases. A significant reduction of recurrence rate following transurethral surgery was obtained in patients treated intravesically with VM-26 at weekly intervals.


Experimental research on endotoxic shock in urology. The endotoxic shock in urological surgery is more frequent due to the increased incidence of the gram-negative infections. More toxic than septic it suggests the hypothesis of a generalized Sanarelli-Schwartzman hypersensitivity phenomenon with hypercoagulation and microthromboses of small vessels. The hypothesis experimentally tested hold good in most cases at the same time requiring an anti-coagulant therapy as an improving effect.


Ex vivo surgery on the renal allograft.

Ex vivo surgery on the renal allograft. Ex vivo surgery has brought an important contribution to the solution of renovascular problems. In our experience, the simplest application of ex vivo surgical techniques has been the revision of the arterial anatomy of the renal allograft to facilitate subsequent implantation into the recipient. We report herein four cases of renal transplantation illustrating this approach.


Severe renal insufficiency and renovascular hypertension. Investigation in a patient aged 46 years with decompensated heart failure and severe renal insufficiency demonstrated a small, poorly functioning right kidney and severe stenosis of the left renal artery. Cardiac decompensation was corrected and the left kidney revascularised by autotransplantation. Renal function recovered considerably (FG 75/min) and the severe hypertension was reduced. In hypertension patients by main renal artery stenosis, renal autotransplantation is recommended, since it is a safe method without technical difficulty and has given good results. The mutual dependence of hypertension and renal insufficiency is reviewed. When renal function is poor, revascularisation of the stenosed kidney will lead to recovery. The hypertension will usually improve but will always become more responsive to drug therapy.


Tumour-associated antibodies against renal cell carcinomas detected by immunofluorescence. Serum from 39 of 288 (13.5%) cancer patients contained antibodies detectable by immunofluorescence which reacted with frozen tumour sections from kidneys, prostate glands and ovaries. The serum did not react against areas of normal kidney taken from the same diseased organ. In comparison, 0.7% of normal persons and 3.8% of patients with non-malignant diseases had antibody activity. Sections from two colon carcinomas did not react with the serum. It is concluded that tumour-associated antibodies do not necessarily have histological type specificity and are worthy of further study.


Extracorporeal repair of the renal artery for renovascular hypertension: a case report. A case of successful correction of renovascular hypertension by means of extracorporeal repair of fibroplasia of the main trunk and an aneurysm of a secondary division branch of the left renal artery is presented. The ureter was not transected and a segment of the internal ilac artery with two branches was used for the substitution of the diseased renal artery segments. The kidney was preserved by intermittent flushing with iced Ringer's lactate solution. A probable post-operative arterial thrombosis of the repaired secondary branch was successfully treated with intravenous streptokinase. One year after the operation the patient is normotensive.


Urological complications in renal transplantation. The urological complications associated with 128 consecutive renal transplants performed in the Department of Urology of the University Hospital Heidelberg between February 1967 and January 1975 are described. Extravesical ureteroneocystostomy has shown to be the preferable method for urinary tract reconstruction, providing satisfactory results in our hands. The technique of ureteroneocystostomy at the dome of the bladder, performed since 1967 in our series, is described and its advantages discussed. There was an overall incidence of urological complications of 21.2%. Major urological complications occurred in 18 patients (14.1%), urinary fistulae in 11 patients (8.6%), ureteric obstruction in 4 patients (3.2%) and spontaneous parenchymal ruptures in 3 patients (2.3%). Only two grafts were lost, due to spontaneous parenchymal ruptures. The mortality directly due to major urological complications was 5.6%. Minor complications (hydrocele, epididymitis, urethral stricture, urinary calculi) were seen in 9 patients (7%). Lymphoceles were not encountered. The management and outcome of urological complications are described.


A new kidney transport container: a simple vessel for preservation and transport of kidneys and other organs. A new vessel which improves conditions of preservation and transport of kidneys and other organs is presented. A Dewar container which provides an almost complete thermal insulation against the environment is chosen. The vessel contains the kidney and a cooling solution which melts at 4 degrees C. When it is closed the organ is exposed to this temperature and measurements show this to be constant for 70 h. The melting point can be lowered or raised as required. By choosing a greater amount of the cooling solution the duration of the working period can be prolonged.


Reconstruction of the ureter: a review of operative and functional aspects. The importance of the urodynamic characteristics of the ureter are considered after plastic and reconstructive operations. Choice of the most suitable method is as important as good operative technique. The partial replacement of the lower end of the ureter by a bladder flap shows good results. Different types of bladder flap procedures do not influence the dynamics of the ureter as its continuity is preserved. Irrespective of the material used, failures of autoplastic or alloplastic segmental replacement are due to the lack of functional adaptation of the prostheses. By partial replacement good results may be obtained if vesico-ureteral reflux is avoided.


Urological aspects of primary retroperitoneal tumours. An analysis of 50 primary retroperitoneal tumours is presented with emphasis on the urological aspect. 70-80% of the tumours were malignant and sarcomas predominate. The tumour mass was palpable in over 70% of the cases. Frequent involvement of the urinary tract caused lumbar pain in 78% of cases. Intravenous urography and retrograde pyelography are the greatest single aids in accurate diagnosis of primary retroperitoneal tumours since over 70% show abnormalities. Selective angiograms may define the size and operability of the tumour. When diagnosed, extirpation of the tumour is possible in only 30-40% of cases. Postoperative mortality is about 10%. Since 70% of these tumours are radiosensitive, radiotherapy improves the prognosis. Survival for more than 2 years after surgery is exceptional.


Pulmonary excretion of foreign bodies and necrotic material from the bladder wall. Following injection of carbon suspension into the bladder wall of white rats, carbon particles were observed in the cytoplasm of cells located as the alveolar macrophages. Following injections of a solution of AgNO3 into the bladder wall of white rats, dark stained spots were observed in the cytoplasm of cells located as the alveolar macrophages. It is suggested that pulmonary excretion of carbon particles and silver stained necrotic material from the bladder wall takes place. These results may contribute to the problems involved by pulmonary changes observed in the X-irradiated patients with carcinoma of the bladder.


A comparison of the antihypertensive effect of atenolol (ICI 66 082) and propranolol. Propranolol was given to 30 patients with essential hypertension following randomised, double-blind administration of either placebo or a new cardioselective beta-adrenergic receptor antagonist, atenolol (Tenormin, ICI 66 082). Both atenolol and propranolol caused statistically significant reduction of recumbent and erect blood pressure and heart rate. There were no important differences between these variables on comparison of atenolol and propranolol.


Antagonism of endogenous mineralocorticoids in normal subjects by prorenoate potassium and spironolactone. The pharmacological activity of single oral doses of a new aldosterone antagonist, prorenoate potassium, has been compared with spironolactone and placebo in a balanced double-blind crossover study in six healthy subject. Endogenous mineralocorticoids were stimulated by administration of frusemide followed by dietary sodium restriction, and the urinary excretion of electrolytes in response to prorenoate potassium, spironolactone and placebo was measured over a 24 hour period. Significant activity of prorenoate potassium and spironolactone was observed between 2 - 24 hours after medication, with peak activity at 6 - 8 hours. The active drugs significantly increased sodium excretion and the sodium : potassium (Na/K) ratio, but changes in potassium excretion were not significant. The total urine Na/K response to prorenoate potassium 45 mg was significantly greater than to spironolactone 100 mg.


Arwin in peripheral arterial circulatory disorders: controlled multicentre trials. The effect of Arwin on peripheral arterial occlusive disease has been studied in two multicentre trials. In the first, in cases of severe peripheral arterial circulatory disorders of the lower extremities with permanent rest pain (stages III and III + IV according to Fontaine) Arwin had a better intravenous therapeutic effect than anticoagulant treatment. A further trial was done to investigate whether subcutaneous administration of Arwin would have an effect superior to classical conservative therapy with vasodilator drugs in this type of disease. The results were assessed by sequential analysis. Arwin was again shown to be a much better treatment. Problems of medical documentation and statistics are discussed in relation to the value of sequential analysis.


A controlled trial of intermittent oral acetylcysteine in the long-term treatment of chronic bronchitis. In 69 out-patients with chronic bronchitis in 6 centres the effects of acetylcysteine 600 mg daily, 3 days a week for 6 months, and a placebo have been compared in a double-blind controlled trial. Thirty-five patients were treated with the mucolytic and 34 with the dummy preparation. In the former the clinical course of the chronic bronchitis improved to a greater extent and a significantly lower number of exacerbations was observed. The advantages of long-term oral treatment with the mucolytic in chronic bronchitis suggest that it may be useful as an alternative to long-term antibiotic prophylaxis, or to complement brief courses of antibiotics, in addition to the usual physiotherapy.


Disparity between clinical and immune responses in a controlled trial of azathioprine in rheumatoid arthritis. Drugs that interfere with the immune response in vitro, such as azathioprine (AZ), have been used extensively since 1964 in clinical therapeutic trials of autoimmune diseases. However, few adequately controlled studies are available concerning the concurrent effect of AZ on the immune and clinical responses to treatment of rheumatoid arthritis (RA). Thirty patients suffering from classical seropositive RA received AZ (1.5 - 2.0 mg/kg/day) and placebo in a controlled clinical cross-over study for two 12-week periods. Other treatments were kept constant throughout the entire 6 months. In terms of the clinical responses of joint count and grip strength patients receiving AZ improved markedly, in contrast to the placebo group. After 2 months, joint scanning revealed no progress of the disease in patients undergoing AZ treatment. Corresponding with the remarkably beneficial clinical effect of AZ, a significant drop in immunoglobulins was observed. However, since AZ failed to suppress in vivo specific antibody synthesis in RA, the question remains as to whether this drug actually does interfere with the autoimmunogenesis of the disease.


Effect of paracetamol, mephenoxalone and their combination on pain following bone surgery. Sixty patients suffering moderate postoperative pain after bone surgery were divided randomly into 3 treatment groups on the day following operation. Under double blind conditions they received either 400 mg mephenoxalone, a weak sedative, or 900 mg paracetamol, or the same doses of these drugs simultaneously, three times daily for three days. Pain scores determined by a surgeon 1, 2, 3, and 6 hours after administration of the first dose of the drug indicated that paracetamol and paracetamol + mephenoxalone had similar analgesic effects and were more effective than mephenoxalone alone. However, during repeated administration over 3 days, the mean effect of the drug combination was slightly better than that of paracetamol or mephenoxalone alone. The drug combination did not induce more sedation or gastrointestinal side effects than either drug alone.


Determination of therapeutic serum concentrations of oral and parenteral meperidine by liquid chromatography. A sensitive and specific method for estimation of serum meperidine by gas-liquid chromatography and its application in a clinical study are described. Patients were given, under double-blind conditions, either oral (75 or 150 mg) or intramuscular (50 or 100 mg) doses of meperidine for postoperative analgesia. Serum meperidine levels were measured 0.5, 1, 2, 3, and 4 hours post-dose. Although wide variations of serum meperidine levels were observed among individuals within each group for each time period, the intramuscular route produced and sustained significantly higher serum levels than did the oral route. The mean concentration of meperidine (mug/100 ml +/- S.E.) for 100 mg i.m. was 37.7 +/- 3.8 at one hour and 23.4 +/-5.7 at three hours; for 150 mg orally it was 11.9 +/- 1.6 at one hour and 11.8 +/- 3.2 at three hours. A correlation observed between the intramuscular dose (in mg/kg body weight) and serum meperidine concentration attained at one hour indicated that 1 mg/kg meperidine i.m. will achieve a one-hour serum level of approximately 20 mug/100 ml, an apparent minimally effective level for analesia in most patients.


Pharmacokinetics and pharmacodynamics of methyl proscillaridin in healthy man. The aim of this study was to obtain data about the pharmacological properties of a new glycoside derivative in man. Plasma concentrations and ECG parameters were measured after oral and intravenous administration of a single dose of 1.2 mg methyl proscillaridin in 16 healthy volunteers, using a strictly randomized, two-period change-over design. Glycoside concentrations were measured using a modified 86Rb-erythrocyte-assay. QT-duration, corrected for frequency (QTc), was the principal variable measured in the ECG. By either route, there was a maximum plasma level after 1 hour, which had decreased to a minimum at 3 hours, followed by a second peak at 4 to 10 hours (orally greater than iv). From 10 to 72 hours the concentrations decreased with a median t 1/2 of 23.3 hours (iv) and 33.0 hours (orally). Comparison of the ratio of plasma concentrations following oral and iv administration resulted in a bioavailability of 69% using the 48 hour plasma levels, and 59% using the areas under the concentration-time curves. The mean QTc was maximally shortened to 28 msec at 1 hour after iv and to 19 msec at 10 hours after the oral dose. A distinct similarity between time-concentration and time-QTc curves was seen after the initial distribution phase, both after oral and intravenous administration. The new derivative shows a rapid elimination. Its bioavailability is reasonably high.


A double blind comparative trial of nomifensin and desimipramine in depression. Relationship between treatment and phenylethylamine excretion. The effect of nomifensin (Hoechst 36984), a synthetic psychotropic drug whose structure differs from MAO inhibitors and tricyclics, was studied in a double blind comparative trial with desimipramine in patients with various depressive syndromes. Forty-three patients (23 in the nomifensin group and 20 in the desimipramine group) were studied for 6 weeks. Clinical follow-up was done with the Wittenborn scale (WPRS), Hamilton's rating scale for depression (HRS), Zung's scale (SDS), and the PEN inventory. The average daily dose was nomifensin 84 mg and desimipramine 76 mg. Changes in HRS, WPRS and SDS showed statistically significant improvement with both treatments. A moderate anxiolytic effect was found in the nomifensin group, whereas medication had to be discontinued in two desimipramine-treated patients because of its drive-enhancing effect. Urinary phenylethylamine excretion rose in 2 out of 8 patients after 5 weeks of treatment with nomifensin.


Effect of analgesic agents on emptying of the gallbladder in man. A controlled study of the clinical pharmacology of the biliary tract has been made. The rate of gallbladder emptying induced by a fatty meal was taken as a parameter for assessment of the inhibitory effect of indoprofen, a new analgesic-anti-inflammatory drug, pentazocine and morphine. The compounds were administered as single doses by iv (indoprofen and pentazocine) or im (morphine) injection. Indoprofen up to 400 mg had no effect, whereas morphine and pentazocine exerted a significant inhibitory effect on emptying of the gallbladder. Adverse reactions of clinical significance were associated with morphine and pentazocine, but were negligible with indoprofen.


Differential antianginal responsiveness to acebutolol. Six unselected males suffering from documented coronary insufficiency and grade II to III angina were submitted to graded multistage treadmill exercise test on 3 separate occasions, 3.5 hours after ingestion of either 0, 200 or 400 mg of acebutolol, a new cardioselective beta-blocker. Control measures included the random allocation to 6 balanced sequences of administration, the rigid standardisation of double-blind experimental conditions and measurements, and two types of variance analysis (latin-square and split-plot). Performance was evaluated by measuring time elapsed before occurrence of anginal pain and ECG changes, peak heart rate, peak double product (heart rate x systolic pressure), and peak oxygen consumption. The mean values for all 5 criteria showed improvement with the 200 mg dose of acebutolol, and even more so with 400 mg, but this overall effect resulted mainly from the excellent response of 3 of the patients. When patients were grouped into 2 categories of responders and non-responders, a significant Dose x Category interaction was found for all criteria. Furthermore, maximal response under acebutolol was negatively correlated with values under placebo (0 mg); this correlation reached significance for peak heart rate and peak double product. It is concluded that (a) in responders, the beneficial effect of acebutolol was significant on all 5 criteria (p less than 0.05), (b) patients definitely fell into 2 categories of responsiveness and (c) the sensitivity of responders was partly linked to their performance under placebo and partly to unidentified individual factors.


Hypotensive effect of oxprenolol in mild to moderate hypertension: a multicentre controlled study. In a multicentre, double-blind, between-patient study the hypotensive effect of oxprenolol was investigated in 329 patients with mild to moderate hypertension. A factorial experimental design with three factors was chosen: oxprenolol--none or daily doses of 20, 40, 60 and 80 mg; dihydralazine and hydrochlorothiazide, respectively, none or 30 mg daily. Each treatment was given for 4 weeks after an adequate period of withdrawal from any other possible hypotensive therapy and one week of placebo wash-out. Irresponsive of the association with dihydralazine and/or hydrochlorothiazide, oxprenolol had a hypotensive effect linearly related to dose for standing systolic (P less than 0.05) and diastolic (P less than 0.01) pressure, and for lying diastolic (P less than 0.05) pressure. The additional of dihydralazine enhanced the time-course of the hypotensive effect of oxprenolol, particularly the 80 mg dose level. In general, the combination of oxprenolol with dihydralazine and hydrochlorothiazide caused larger reductions in blood pressure, particularly with oxprenolol 80 mg. In the latter group, the eventual falls in blood pressure were 30.5 and 14.4 mmHg for lying systolic and diastolic, respectively; and 32.1 and 20.0 mmHg for the standing systolic and diastolic pressures. The drug was well tolerated; major side effects (heart failure and bronchospasm) occurred in three patients.


Relation between plasma concentrations and cardiovascular effects of oral oxprenolol in man. Oxprenolol, 40, 80 and 160 mg, was administered orally to seven healthy volunteers. Over the following eight hours repeated measurements were made of the plasma concentrations and effects on heart rate, myocardial contractility (PEPc) and systolic and diastolic blood pressure in recumbency, in the upright position and during physical effort at a work load of 120 watts on a bicycle ergometer. The maximum plasma levels and the area beneath the plasma concentration curves increased roughly in proportion to the dosage increment. No evidence of first-pass inactivation in the liver was found. The half-life of the drug in plasma was approximately 80 minutes, irrespective of the dose administered. Oxprenolol slowed heart rate, prolonged PEPc and lowered systolic blood pressure, by comparison with values recorded after a placebo. The effects were generally least marked in the recumbent position and most marked during effort, when a clear-cut dose-response relation was found. The pharmacodynamic effects of oxprenolol were compared with its concentration in plasma. Marked beta-receptor blockade still persisted eight hours after dosing, although at this time, after doses of 40 and 80 mg, the drug could not be detected in plasma.


Bioavailability of m-octopamine in man related to its metabolism. The diminished sympathomimetic pressor activity of monohydroxylated phenylalkylamines after oral administration has been attributed to incomplete enteric absorption. Therefore, urinary excretion of the unchanged drug and its metabolites has been compared after intravenous and oral administration of 3H-m-octopamine to eight patients. Identical amounts of 3H-activity (80% of the dose) were excreted after the two routes of dosing, so enteric absorption has been assumed to be complete. Significant differences were found in the fraction of free urinary m-octopamine, which amounted to 10.5%  of the dose after infusion and 0.58% after oral administration. The only metabolic pathways for m-octopamine are deamination and conjugation. Following oral administration the percentage of conjugates was considerably higher than after intravenous infusion. This metabolic pattern appears typical of all phenylalkylamines with a hydroxyl group in the meta position. Ring hydroxylation to catecholamines was not observed. The enzymes mainly responsible for conjugation after oral administration are located in the gut wall. The resulting ""first pass effect'', i.e. metabolism prior to the access to the central compartment, can account for the diminished pharmacodynamic effect after dosing by this route.


Double blind cross-over study of a new appetite suppressant AN 448. The effects of a new appetite suppressant, AN 448, and a placebo have been compared in 30 obese individuals using a fully randomized double-blind cross-over design. 1 mg of AN 448 t.i.d. produced a significant degree of appetite suppression and a mean weight loss of more than 4 kg per individual over a 6 week period. Side effects were few and no haematological, renal or hepatic damage was observed.


Effect of nifedipine on exercise tolerance in patients with angina pectoris. To test if nifedipine, 10 mg sublingually, could increase exercise tolerance, ten patients with angina pectoris each performed two types of bicycle exercise test, one with a stepwise increase in load and the other with a continuously increasing load. The drug was given in a double-blind cross-over trial. Nifedipine raised the heart rate and diminished the systemic blood pressure at rest, on standing and during exercise at comparable loads. Work time was prolonged and higher work loads were achieved. The total work performed rose by 50 per cent in one of the tests and by 23 per cent in the other, about 50 minutes after taking the drug. The mechanism of the greater work capacity in angina pectoris after nifedipine was assumed to be diminished heart work due to a fall in systemic vascular resistance.


Pharmacokinetics of di-n-propylacetate in epileptic patients. The pharmacokinetics of the anti-epileptic drug di-n-propylacetate (DepakineR) have been studied in 7 patients, in whom plasma concentrations were determined during and following subchronic treatment. Elimination of the drug appeared to follow a monophasic exponential course; biological half lives were 8 to 15 hours. The data supported the assumption that an open one-compartment model can be used to describe the kinetics of dipropylacetate in man. The drug appeared to have a relatively restricted distribution: calculated relative distribution volumes ranged from 0.15 to 0.40 1/kg. There were large interindividual differences in clearance rate. The therapeutic range was considered to be between 50 and 100 mg/1 plasma. Plasma levels of phenobarbital were markedly raised during treatment with dipropylacetate for an unknown reason. Determination of the plasma concentrations of drugs at accurately fixed times appears to be a reliable method for pharmacotherapeutic monitoring of epileptic patients.


Bilateral surgical removal of impacted lower third molar teeth as a model for drug evaluation: a test with ibuprofen. It was considered that double-blind crossover studies of therapeutic efficacy after acute injury could well be done in patients who required surgical removal of impacted wisdom teeth from both sides of the lower jaw. In the present trial 24 healthy patients received either placebo or ibuprofen (Brufen: 400 mg three times daily), a non-steroidal anti-inflammatory agent, for 5 days commencing the day before surgery. Treatments were given on the two occasions when impacted wisdom teeth were to be removed from one side or other of the lower jaw. A number of objective and subjective parameters were recorded for paired comparison of the post-operative courses, including swelling, trismus and pain. A mechanical device which allows simple and accurate measurement of cheek swelling is described. On the 1st, 3rd and 5th post-operative days in the ibuprofen group the measured swelling averaged 93, 89 and 82%, respectively, of that in the placebo group; the corresponding alpha-values were 0.35, 0.06 and 0.07. Patients with less swelling after ibuprofen were not always those with a high serum concentration of the drug. Ibuprofen significantly reduced pain on the day of the operation. This may at least partly account for less trismus and the preference of the patients for their post-operative courses with ibuprofen. Examination of various haematological parameters did not reveal any significant difference between the two operations. Subjective scores indicated that neither wound-healing nor bleeding was affected by ibuprofen, nor were any side effects detected.


Effect of intravenous atropine and methylatropine on heart rate and secretion of saliva in man. Intravenous atropine sulphate (0.25, 0.40, 0.75 and 1.50 mg), atropine methylnitrate (0.08, 0.13 and 0.25 mg) and saline were given to 72 healthy medical students. The effects on heart rate and rhythm, systolic and diastolic blood pressure and salivary secretion were studied. Salivation was inhibited by all the doses of the two drugs. There was a clear dose-response relationship and methylatropine was about 3 times as potent as atropine. Heart rate was accelerated by 0.75 and 1.50 mg atropine, and 0.25 mg methylatropine, whereas 0.25 mg atropine and 0.08 and 0.13 mg methylatropine induced bradycardia, which was considered to be due to a peripheral action. It is suggested that the drugs act as partial agonists at muscarinic receptors. No clear effect on blood pressure was seen, except for the highest dose of atropine, after which the diastolic pressure was increased. 20 out of 59 subjects who received anticholinergics developed supra-ventricular arrhythmias; with both drugs periods of nodal rhythm were most common. They appeared shortly after the injection and usually lasted for a few minutes.


Exercise tolerance in patients with angina pectoris after pentaerythritol trinitrate and alprenolol studied by two different methods. Exercise tolerance has been studied by two different methods, heart-rate-controlled exercise and stepwise increased load, in 12 patients with angina pectoris. The response to a beta-adrenergic blocking agent, alprenolol, and an alkyl nitrate derivative, pentaerythritol trinitrate (PETRIN) was studied by the two methods after double-blind administration of the drugs. Rating scales were used to quantitate the degree of dyspnoea, angina pectoris and tiredness in the legs. After PETRIN both methods showed significant increases in exercise tolerance (19 and 21 per cent). The heart-rate-controlled test showed a significant increase (33%) after alprenolol, but the change was not significant by the other method. In the patients studied, heart-rate-controlled exercise discriminated between active drug and placebo better than the stepwise increased load test, what might have been due to more optimal matching of the loads obtained in the heart-rate-controlled test. Indications are given about how to design an exercise study in patients with angina pectoris.


Clinical pharmacology as seen through two of its journals. The following article gives an overall view of the manuscripts that have been published in two journals dedicated to clinical pharmacology. Such an analysis can only be a quantitative one, since it is not possible to categorize the papers according to their scientific value. One reason for the fact that pharmacokinetic problems have found so much interest among clinical pharmacologists may be the scarcity of data available until recently. It may be expected, indeed the past year the tendency was already evident in the 'Europ. J. clin. Pharmacol.; that other fields of clinical pharmacology will be increasingly considered when a basic knowledge of pharmacokinetics has become available for standard therapeutics.


Treatment of benign essential hypertension: comparison of furosemide and hydrochlorothiazide. Furosemide (Impugan) 12.5, 25 or 40 mg twice daily, has been compared as an antihypertensive with hydrochlorothiazide 12.5 mg twice daily and a placebo. A double blind, cross-over design was used with a run-in period of 4 weeks, preceding five 4-week periods of treatment with these compounds alone. There were 34 patients in the trial, 17 men and 17 women. Paired comparison showed that furosemide 25 or 40 mg twice daily and hydrochlorothiazide 12.5 mg twice daily had a similar hypotensive effect, irrespective of the initial blood pressure. Furosemide 40 mg twice daily and hydrochlorothiazide 12.5 mg twice daily caused a slight fall of blood pressure as compared with placebo (0.10 greater than p greater than 0.05, p less than 0.05). There was a distinct correlation between blood pressure and age. Serum K+ fell significantly during treatment, particularly with hydrochlorothiazide 12.5 mg twice daily, as well as with furosemide 25 or 40 mg twice daily. As compared with placebo, urinary output increased significantly after furosemide 12.5, 25 or 40 mg twice daily, but it rose only to a non-significant extent after hydrochlorothiazide. The fall of blood pressure and decrease in serum K+ were linearly related. There were only a few, mild side effects which did not necessitate discontinuation of the trial.


The serum level approach to individualization of drug dosage. The importance of individualizing the dosage of potent drugs in order to maximize their therapeutic effectiveness and safety is generally accepted. Whenever possible the dosage of a drug should be "titrated" directly in each patient against the intensity of its therapeutic or toxic actions. Unfortunately, for many drugs convenient clinical yardsticks of the intensity of their pharmacologic effects are lacking. Determination of the serum concentration of such compounds can help to guide adjustment of dosage during their therapeutic use. By measuring the serum level of drugs one bypasses the largest source of individual differences in dose-effect relationships-the pharmacokinetic variation between subjects. However, the relationship between the serum concentration of a drug and the intensity of its pharmacodynamic action is influenced by many other factors, which must always be considered in interpretation of serum levels. Therapeutic decisions should never be based soley on the serum concentration of a compound, nor can such measurements ever substitute for careful medical observation and judgement.


Effect of zinc sulphate on the absorption of tetracycline and doxycycline in man. A possible interaction between zinc sulphate and tetracycline or doxycycline was examined in a cross-over study in seven volunteers. A single dose of zinc sulphate (45 mg Zn++) was given simultaneously with tetracycline hydrochloride (500 mg) or doxycyline chloride (200 mg). The serum concentration of tetracycline, the area under the serum tetracycline concentration-time curve and the excretion of tetracycline in urine were reduced by about 30% (p less than 0.05) from the respective control values. The absorption of doxycycline was not influenced significantly by zinc sulphate. The clinical significance of the zinc-tetracycline interaction seems to be of limited importance.


Biotransformation and pharmacokinetics of sulfinpyrazone (Anturan) in man. The absorption, biotransformation and elimination of sulfinpyrazone, 1,2-diphenyl-3,5-dioxo-4-(2'-phenylsufinylethyl)-pyrazolidine, have been studied by administration of single 200 mg oral doses of a 14C-labelled preparation to two male volunteers. Absorption from the gastro-intestinal tract was rapid and complete and the plasma concentration of unchanged drug reached maximum values of 22.67 and 13.04 mug/ml, respectively, after 1 - 2 hours. The elimination half-life in the two subjects, calculated from the decline between 3 and 8 hours, was 2.7 and 2.2 hours. The integrated concentration of unchanged sulfinpyrazone in plasma, estimated from the area under the concentration curves (AUC), was almost as high as that of total 14C-substances, so the proportion of metabolized drug in plasma was low. In no case did the AUC of the three specifically determined metabolites. i.e. the sulphone G 31 442, the "para-hydroxy"=compound G 32 642 and the "4-hydroxy"- compound GP 52 097, exceed 4% of the sulfinpyrazone value. More than 95% of whole blood radioactivity was confined to plasma. The oral dose was rapidly and completely excreted, since within 4 days more than 95% was recovered, 85% from urine and 10% from faeces. A large proportion of the dose was excreted as unchanged drug in the two volunteers: 51 and 54% of total urinary radioactivity was present as sulfinpyrazone; 8.2 and 8.8% was present as "para-hydroxy"-metabolite, 2.7 and 3.0% as sulphone-metabolite, and 0.6 and 0.8% as "4-hydroxy"-metabolite. About 30% of urinary radioactivity consisted of highly polar metabolites. Spectroscopy of them showed that they were the C-beta-glucuronides of sulfinpyrazone (28%) and the corresponding sulfone (2%). In these metabolites the C(4) of the pyrazolidine ring was directly attached to glucuronic acid, and thus they represent a new type of biosynthetic conjugate.


The metabolism of (-)-ephedrine in man.

The metabolism of (-)-ephedrine in man. The metabolic fate of orally administered (-)-[14C]-ephedrine has been studied in 3 human subjects and the urinary excretion of metabolites determined quantitatively by solvent extraction, paper chromatography and reverse isotope dilution procedures. Following an oral dose of the drug (0.35 mg/kg, 1.6 muCi), 97% of the dose was excreted in the urine within 48 h, 88% in the first 24 h. Unchanged drug was the major urinary excretory product (53-74%), with N-demethylation occurring to a variable extent (8-20%) although there was little interindividual variation in urine pH. Oxidative deamination was also variable (4-13%); the main identified products of this were benzoic acid (free and conjugated) and 1,2-dihydroxy-1-phenylpropane (free and conjugated). No phenolic metabolites could be detected, and thus it would appear that these compounds cannot be implicated in the acquisition of tolerance to ephedrine which can occur on repeated dosage.


Comparison of the antihypertensive effect of propranolol and practolol combined with chlorthalidone. A double blind cross-over trial of fixed doses of propranolol (640 mg/day) and the cardioselective drug practolol (1600 mg/day) was performed in 28 patients with essential hypertension whose blood pressure was not adequately controlled by chlorthalidone (100 mg 3 times weekly) alone. Chlorthalidone alone was given during the first (control) period, and it was continued throughout the propranolol and practolol treatment periods, each of 10 weeks. The systolic and diastolic blood pressures were lowered significantly by both the beta blocking drugs. The changes in blood pressure caused by altering the patient's position were the same after both beta blockers. Propranolol produced slightly lower values than practolol, but the difference was significant only for diastolic blood pressure in the sitting and supine positions. In individual patients the final blood pressure after propranolol was correlated with the final blood pressure after practolol. Only minimal side-effects of either drug were noticed. It is concluded that the doses employed both of propranolol and practolol had a good and approximately equal antihypertensive effect when combined with chlorthalidone treatment. There was no correlation between the final blood pressure and plasma renin activity.


Combination therapy of essential hypertension with pindolol (Visken) and hydralazine. Thirty patients suffering from essential hypertension were treated successively with placebo, hydralazine alone, and pindolol (Visken) combined with hydralazine. Hydralazine caused a statistically significant reduction in blood pressure and an increase in pulse rate as compared with the placebo: palpitations were an irritating side-effect. The combination of hydralazine and pindolol resulted in an additional fall in blood pressure (p less than 0.001) and the pulse rate decreased (2 p less than 0.001). The combined treatment also had a favourable effect on palpitations and angina pectoris.


Effects of oxprenolol on the airways of normal and bronchitic subjects. In a double blind trial in 11 control subjects and 12 bronchitic patients against an inert control oxprenolol produced significant worsening in airways obstruction in 6 control and in 7 patients. There was marked individual variation in response and no way was found to predict the susceptible subjects. Objective measurement of indices of airways obstruction and the effects of oxprenolol on them is essential where there is significant respiratory impairment. Great care must continue to be exercised since a significant proportion of bronchitic patients will be adversely affected by this drug.


Diuretic action of bumetanide in advanced chronic renal insufficiency. The effect of bumetanide, a new potent diuretic, was studied in twelve patients with severe chronic renal failure (GFR 2.7 - 10.7 ml/min). Bumetanide 8 mg i.v. caused increased excretion of water and sodium in all patients. In some patients sodium excretion was greater than 50% of filtered load indicating an effect on proximal tubules. Bumetanide 2 mg i.v. was significantly less effective than 8 mg and a greater diuretic effect was produced by bumetanide 16 mg. In a comparative study bumetanide 8 mg was less potent than furosemide 250 mg, a finding in contrast to the potency rate ratio of 1/40 in other conditions. Side effects consisted of mild to moderate muscle pain and stiffness, especially localized in the neck, shoulders and calves. These side effects occurred only in patients with a GFR less than 5.3 ml/min. They were noted in all patients receiving 16 mg and in 3 out of 12 patients who took bumetanide 8 mg. There was no relationship between the occurrence of side effects and plasma bumetanide levels, electrolyte levels or the renal excretion of bumetanide and electrolytes.


Comparison of salmefamol with salbutamol aerosols in asthamatics. In twelve asthmatic patients 200 mug of salmefamol and salbutamol given by metered aerosol produced a similar initial effect on FEV1, FVC and PEFR without significant effect on heart rate or blood pressure. The duration of effect of salbutamol was approximately 4 hours; there was still an appreciable effect from salmefamol at 8 hours.


Salmefamol orally in asthmatics - two doses compared. The responses of twelve patients with chronic asthma to salmefamol 1 mg and 2 mg, taken orally, were compared in a double-blind cross-over study. Both produced a rise of 40-50% in PEFR and FEV1. Statistically significant improvements were maintained for three to four hours, and 20% improvements for four to six hours. There was no significantly different effect on ventilatory capacity between the two doses. After the 2 mg dose there was a statistically significant fall in diastolic blood pressure at 1 and 1 1/2 hours. Four patients experienced tremor and this was the only side-effect noted. The possible reasons for failure to demonstrate a greater effect with the higher dose are discussed.


Obituary--Prof. J. F. Heremans.

Obituary--Prof. J. F. Heremans. We sincerely regret to have to report the death of Professor Joseph F. Heremans on October 29th, 1975, at the age of 48. He was Professor of Internal Medicine and of Immunochemistry at the University of Louvain, Brussels and Director of the Department of Experimental Medicine at the new International Institute of Cellular and Molecular Biology, Brussels, of which he was a founder member. He had also been an active member of the Editorial Board of European Journal of Immunology since its founding in 1970. As one could always depend upon his clever but fair criticism, he has done a great deal to help the development of the journal. We are extremely grateful to have had him as a colleague, coworker and friend.


Cytophilic activity of enzymatically derived fragments of guinea pig IgG2. The hydrolysis products from short term exposure of guinea pig IgG2 to papain and pepsin have been characterized. Papain hydrolysis liberates 4 types of Fc fragment, only one of which retains both an interchain disulfide bond and an intact CH2 domain, cFc, mol.wt. 56 000. The other three fragments noncovalently linked Fc (nFc) (mol.wt. 56 000), incomplete Fc (iFc) (mol.wt. 39 000) and Fc' (23 000) represent further degradation products of covalently linked complete Fc (cFc). The cytophilic activities of these fragments as well as F(ab')2 and pFc' from pepsin hydrolysis, were studied to determine the domain(s) responsible for binding to homologous peritoneal macrophages. Only the native immunoglobulin and the intact cFc manifested cytophilic activity; in particular pepsin-derived pFc' and Fc' were inactive. Following mild reduction and alkylation, performed to affect only the interchain disulfide bonds, the cytophilic activity of cFc was markedly reduced. The low cytophilic activity in the pFc' fragment suggests that the CH2 domains play a major part in binding to the macrophage Fc receptor through a site(s) stabilized by the interchain disulfide bonds.


Effect of the concentration of inducing agent on the output of lymphokines in the guinea pig. The production of migration inhibition (MIF) and mitogenic (MF) factors by cultured guinea pig lymph node cells was examined as a function of the concentration of antigen or concanavalin A (ConA). Maximum output of MIF was achieved at comparatively low levels of antigen and was equal to the maximum output by ConA. In contrast, MF output increased up to the highest antigen concentrations tested. Kinetic and chromatographic analysis revealed no differences between the MF produced at high and low antigen concentration.