Potentiation of apomorphine action in rats by l-prolyl-l-leucyl-glycine amide. Although the antiparkinsonian activity of 1-prolyl-l-leucyl-glycine amide (PLG=MIF-I) has been previously observed in several clinical trials, little is known of the mechanism of action of this tripeptide on the brain. Our study demonstrated potentiation of the action of apomorphine by PLG on the rotational behavior of mature rats which received unilateral 6-OHDA (16 microgram) lesions of the striatum as neonates. No change in tyrosine hydroxylase or dopa decarboxylase activities in rat striatal homogenates was found after addition of PLG (10(-8-10(-3) M). The results suggest that PLG modifies the dopamine receptor, making it more responsive to stimulation by the agonistic agent apomorphine and perhaps by the natural neurotransmitter dopamine.


[Isolation and properties of preparations the branching enzyme of muscles, amylose isomerase]. The paper describes a modified method of isolating the branching enzyme of amylose isomerase from muscles and a study of the enzyme activity at different stages of purification. By enzyme fractionation on biogel R-150 and Sepharose 6B the fractions containing different RNA amounts have been isolated. The activity of fractions has been shown to depend on their content of RNA. The paper presents a procedure used to isolate a highly purified fraction of amylose isomerase and its properties (pH and temperature optima, enzyme optimal concentration and Michaelis constant).


Specific immune recognition by lymphocytes: an evolutionary perspective. In this review, we analyze data pertinent to the origins of specific immune recognition by lymphocytes. The phenomena of immunity in invertebrates and the cells that might be involved in these processes are considered. We conclude that the existence of vertebrate-type immunocompetent lymphocytes in invertebrates is not yet proven. All vertebrates apparently possess immunologically competent lymphocytes, and the following conclusions may be drawn: (1) Specific antigen recognition by lymphocytes of all vertebrates appears to be mediated by membrane-bound immunoglobulins. These immunoglobulins are, in all probability, distinct from secreted, serum immunoglobulins (antibodies), although serum and surface immunoglobulins share combining sites for antigen which are formed of variable regions. (2) There is evidence for similar functional divisions among the immune systems of all vertebrates, as reflected in the results of anatomical, functional, and physicochemical investigations of lymphocytes from animals as diverse as fish and mammals.


An analysis of measured and calculated calcium quantities in serum. Potentiometrically measured ionized calcium (Ca2+) was compared with total and albumin corrected S-Calcium and calculated Ca2+ in serum samples from blood donors and patients, for whom a request of S-Calcium has been made. Total S-Calcium, Ca2+ and S-Albumin in donors conformed with a simple mass law equation with a mean KCaAlb = 95 l/mol, whereas apparent albumin binding affinity rose with decreasing S-Albumin in patients (due to rise of other calcium binding proteins) with resulting overestimation of albumin corrected and particularly of calculated Ca2+. The frequency and severity of hypoalbuminaemia in patients make calculated Ca2+ unreliable and albumin corrected S-Calcium the clinically most satisfactory routinely practicable substitute for direct Ca2+ measurement.


The value of immunoelectroosmophoresis (IEOP) for etiological diagnosis of acute respiratory tract infections due to pneumococci and Mycoplasma pneumoniae. Immunoelectroosmophoresis (IEOP) has been used to detect pneumococcal and Mycoplasma pneumoniae antigen in 324 sputum samples from 224 patients. Pneumococcal antigen was found in 30/37 samples from which pneumococci had earlier been isolated and in 72/243 specimens where they had not been found. Of these 72 samples 69 were from patients treated with antibiotics. Mycoplasma antigen was found in 9/57 sputum samples from which Mycoplasma had been isolated and in 2/32 other samples from patients with a serologically verified diagnosis of mycoplasmal infection. As to pneumococci, the IEOP is of value because of its rapidity and especially because antigen findings can be made in patients treated with antibiotics. In spite of sonication and concentration, mycoplasma antigen was too rarely found for the method, as now carried out, to be useful in diagnostic work.


Serological diagnosis of pneumococcal disease with enzyme-linked immunosorbent assay (ELISA). Antibody response to pneumococcal type-specific polysaccharide was measured with enzyme-linked immunosorbent assay (ELISA). The test was shown to be up to 500 times more sensitive than indirect hemagglutination using chromic chloride-treated red blood cells. In 16/17 patients with pneumococcal pneumonia a significant antibody increase was seen as measured with ELISA. Only 6/23 patients with pneumonia caused by Mycoplasma pneumoniae gave a pneumococcal antibody rise and in those cases the increase was very slight. The authors consider ELISA a valuable contribution to the serological diagnosis of pneumococcal disease.


[Left ventricular function in hypertension treated with beta blockers]. In 14 patients with essential hypertension, left ventricular function was assessed echocardiographically before and after 4 and 8 weeks of treatment with the betablocking agent atenolol. Atenolol was given orally in a dose of 100 mg/day. After 4 weeks of treatment systolic blood pressure decreased from 160 to 138 mm Hg(p less than 0.001) and diastolic pressure from 105 to 91 mm Hg(p less than 0.001). Heart rate decreased from 76 to 64 beats/min (p less than 0.05). Systolic shortening of the left ventricular transverse diameter declined from 41 to 36% (p less than 0.01), though in no instance did it fall below the lower limit of normality (30%). After 8 weeks of betablocking therapy, blood pressure and heart rate remained essentially unchanged. Systolic shortening increased slightly but insignificantly to 38%. The left ventricular enddiastolic diameter did not change throughout the study. It is concluded that longterm betablocking therapy is associated with a significant reduction of left ventricular function which improves in the later stage of treatment. Since the diminution of left ventricular function is slight, the induction of left heart decompensation is unlikely, at any rate in patients with initially normal left ventricular function.


Light stimulates tyrosine hydroxylase activity and dopamine synthesis in retinal amacrine neurons. Retinal dopamine-containing amacrine neurons are rapidly activated by light, as shown by an increase in the rate of dopamine formation in vivo and a concomitant increase in the activity of tyrosine hydroxylase, measured in vitro with a subsaturating concentration of pteridine cofactor. Activation of tyrosine hydroxylase also occurs when isolated eyes from rats killed in the dark are exposed to a strobe light. Studies of amacrine neurons should provide basic data about the biochemical processing of visual information, as well as the physiological presynaptic regulatory mechanisms of dopamine-containing neurons.


Detection of an auditory nerve--activating substance. A substance or substances capable of increasing the firing rate of primary auditory fibers is detectable in the perilymph of frogs and guinea pigs subjected to sound stimulation. The increase in firing rate occurs in single units of the frog auditory nerve after perilymph obtained from frogs or guinea pigs during sound stimulation is infused into the frog perilymphatic sac. Perilymph collected from animals maintained in silence failed to cause an increase in firing rate of primary auditory fibers of the frog.


Kainic acid injections result in degeneration of cochlear nucleus cells innervated by the auditory nerve. When kainic acid, a putative neurotoxin for neurons with glutamatergic input, is injected into the brainstem, it produces a selective pattern of degeneration in the cochlear nucleus. The rate and extent of degeneration is correlated with the distribution of the primary auditory fibers. This evidence supports the hypothesis that glutamate is the neurotransmitter for primary auditory fibers.


Pharmacologic management of asthma in childhood. New drugs such as inhalable corticosteroids, disodium chromoglycate, and selective beta2 sympathomimetic agents, as well as new understanding of pathophysiologic mechanisms of older drugs, enable better pharmacologic management of the child with asthma. Emphasis is on educating patient and parents and on using doses calculated for weight of anhydrous theophylline equivalent as well as for beta agonists. Preventive environmental measures should always be used in conjunction with drug therapy.


The management of inflammation in rheumatic diseases. Drugs used to control inflammation in the rheumatic diseases are extremely diverse. Despite this, the pattern of clinical response and similarities in side-effects allow them to be subdivided into groups. These patterns also provide clues about the mode of action of the drugs. Conversely, studies of the mechanisms of action of drugs  used to treat rheumatoid arthritis are beginning to throw light on the pathological process.


[Concerning the treatment of a late dyskinesia by Tiapridal (author's transl)]. The authors study the effects of Tiapridal on the late dyskinesia resulting from the continuous use of neuroleptics. They present a conclusive observation of the effectiveness of this product on this syndrome. They have come to the conclusion that it is not necessary to prescribe anti-Parkinson drugs, the side-effects of which are well-known, firstly by diminuing the neuroleptic doses as soon as the first symptoms of extra-pyramidal syndrome appear, and secondly, when these symptoms appear by adding some Tiapridal to the dose of neuroleptics already taken.


Sex and drugs.

Sex and drugs. Quackery has for centuries used aphrodisiacs to exploit vulnerable victims, 30% of whom, through the power of suggestion, have achieved sexual success from potions, powders and genital pomades. In the 1970s we still have no magical alchemy for sexual joy, but we are for the first time becoming aware of the complexity of human sexual functioning. We realize that new horizons of knowledge regarding cerebral as well as peripheral genital pathways and controls await discovery. Sexual side-effects requiring treatment must not only be noted but carefully and scientifically studied by physicians since these may offer important avenues of understanding of the many unsolved riddles of the neurophysiology of the human sexual response.


Physiologic monitoring goals for the critically ill patient. Definition of the appropriate therapeutic goals for physiologic monitoring of patients postoperatively was approached by analyzing more than 50,000 values of the 20 most commonly monitored variables in a series of 113 critically ill patients throughout their immediate postoperative course. In general, normal values were poor criteria for monitoring, since normal values were restored in an average of 75 per cent of the survivors and 76 per cent of the nonsurvivors for the five most frequently measured variables; that is, arterial pressure, heart rate, central venous pressure, wedge pressure and cardiac output. Moreover, an average of 56 per cent of the 20 most commonly monitored variables of nonsurvivors was restored to the normal range. Furthermore, 34 per cent of all the nonsurvivors' values were within the normal range; this was only 2.4 per cent less than the percentage of normal values for the survivors. The empirically determined median value of the survivors taken in the late stage during periods remote from therapy was found to be a better criterion for therapeutic goals for most variables, including blood flow, oxygen transport and most intravascular pressures. However, normal values were satisfactory for arterial pressure, peripheral resistance, pH, mixed venous oxygen tension and arterial carbon dioxide tension, largely because of the biphasic patterns of these variables.


A new method of preparation of segmental pancreatic grafts for transplantation: trials in dogs and in man. A new method of eliminating the exocrine function of the pancreas by obstruction of pancreatic duct with neoprene was investigated in dogs and applied to three cases of human segmental pancreatic transplantation. Neoprene is  a liquid synthetic rubber which flocculates with changes in pH. In animals, progressive fibrosis of the pancreatic tissue occurs after injection of neoprene in the main pancreatic duct, leaving islets well vascularized and functioning for prolonged periods. Using this technique, three severely diabetic patients received a cadaver segmental pancreatic allograft. Blood sugar returned to normal levels within the first hours or days after operation. All three grafts continue to function 1.5, 2, and 8 months, respectively, following transplantation. If these results are confirmed by further clinical experience, this method may be of considerable assistance in the treatment of severe diabetes by pancreatic transplantation.


Enhancement of chlorcyclizine teratogenicity in the rat by coadministration of calcium chelating agents. Chlorcyclizine and structurally related drugs induce a high incidence of cleft palate and skeletal malformations in fetal rats. We have shown previously that these teratogens bind tightly and reversibly to chondroitin sulfate of cartilage and compete with calcium for binding. Experiments reported here demonstrate that co-administration of calcium chelating agents with chlorcyclizine significantly increases both the frequency of malformations and retention of [14C] chlorcyclizine by embryos. Retention of radioactive teratogen by embryos is inverse to retention of [45Ca]calcium. These findings suggest that drug binding to embryonic glycosaminoglycans is involved in the pathogenesis of malformations produced by chlorcyclizine.


Chlorcyclizine induction of cleft palate in the rat: degradation of palatal glycosaminoglycans. Administration of the cleft palate teratogen chlorcyclizine or norchlorcyclizine to pregnant rats causes an alteration in glycosaminoglycans (GAGs) in embryonic palatal shelves. Pulse-chase experiments in vitro indicate that norchlorcyclizine enhances the degradation of hyaluronic acid and chondroitin sulfate but has little or no effect on their synthesis. These changes in GAGs are caused by concentrations of norchlorcyclizine that have no appreciable effect on DNA or protein synthesis. These findings suggest that degradation of palatal GAGs may be the primary biochemical defect responsible for the inhibition of palatal shelf elevation by norchlorcyclizine.


An anatomic and genetic study of canine cryptorchidism. Twelve cases of cryptorchidism were found in a colony of Minature Schnauzer purebred and crossbred dogs. At least nine affected dogs were derived from the same sire directly or indirectly. Of 12 affected dogs, five cases were unilateral and seven were bilateral. Eight of the 12 cases were subjected to anatomic study. Fixation of affected organs was by vascular perfusion or immersion. Testes were separated from epididymides and both were weighed. All unilateral retained testicles were on the right side, and right sided bilaterally retained testes were always smaller than their left sided counterparts. With only one exception, ectopic testes were in the abdominal positon. Developmentally, the morphologic appearance of the epididymis of abdominal testes was very primitive in bilateral cases but nearly normal in the unilateral cases. Degree of inbreeding was greater for bilateral cases than unilateral cases. High incidence of cryptorchidism in this colony provided good evidence for hereditary nature of the condition in the Miniature Schnauzer dog. Morphologic observations were suggestive of a multiple gene defect.


Effect of pH on bile salt degradation by mixed fecal cultures. Stoll specimens from 3 healthy volunteers were cultured under an-aerobic conditions in brain heart infusion broth with and without the addition of cholate, deoxycholate of chenodeoxycholate. The initial pH of the medium was adjusted to 5.5, 6.3, 7.3 (unadjusted), 8.0, and 9.0. Cell-free extracts prepared from the resulting bacterial growth contained increased levels of NAD- and NADP-dependent 3alpha-, 7alpha-, and 12alpha-hydroxysteroid oxidoreductases when the initial pH was 8.0 or 9.0 and depressed levels of these activities when the initial pH was 5.5 or 6.3 (as compared to control values obtained at 7.3). At pH 5,5 all activities except NAD-dependent 7alpha-hydroxysteroid oxidoreductase were absent. A powerful selective effect was imposed on NAD-dependent 7alpha-hydroxysteroid oxidoreductase when deoxycholate or chenodeoxycholate were incorporated into or chenodeoxycholate were incorporated into the medium. Thin-layer chromatography of either extracts of cholate-containing, acidified spent bacterial medium showed alkaline or neutral (optimal at pH 8). The precent hydroxyl group estimations at the 3alpha-, 7alpha-, and 12alpha-positions revealed an increase in disappearance of OH groups at all three positions with increasing initial pH value. The order of extent of bioconversion was 7alpha-OH greater than 3alpha-OH; at pH 8 AND 9, approximately 90% 7alpha-OH bioconversion was observed. Spent bacterial media and a number of commercial secondary bile salts were all negative in the Ames' assay for mutagenicity.


The preparation of pregnancy urine for an estrogen profile. A method is described for purifying the estrogen content of pregnancy urine with little loss of the labile estrogens. The procedure makes use of the initial 50-fold purification effected by their precipitation whith ammonium sulphate, with simultaneous elimination of most urinary corticosteroids and 50--60% of urinary ketosteroids. It also employs the antioxident ascorbic acid as an additive in most stages of the procedure. The mild organic-solvent-HIO partition system of Brown is used for separating the strongly polar, 2including all "labile" estrogens, and of the weakly polar estrogens, from neutral steroids. The remaining neutral steroid still interfering with the assays were removed by an ascorbic acid treated ion exchange resin (AG 1). The final residues were revealed by mass-spectroscopy to consist almost solely of estrogens. Gas-liquid chromatography in which just 2 chromatograms are required yields a total of 12 "estrogen" peaks (for 12 estrogens which are excreted in amounts greater than 0.1 mg/day) in normal pregnancy urine, including all the known labile estrogens. Identification as estrogen for all but a few minor peaks of the gas chromatogram was obtained by mass-spectroscopy. The practical significance of the method lies in the fact that some labile estrogens are much more important in the estrogen metabolism of pregnant and nonpregnant women than heretofore generally thought.


3beta-Hydroxysteroid dehydrogenase activity in human fetal membranes. A 3beta-hydroxysteroid dehydrogenase (3betaHSD) was demonstrated in term human fetal membranes (chorion and amnion) with both dehydroepiandrosterone (3beta-hydroxy-5-androsten-17-one) and pregnenolone (3beta-hydroxy-5-pregnen-20-one as substrates, and the subcellular distribution substrate and nucleotide specificity of the enzyme was studied. In both membranes the microsomal fraction (particles which sedimented at 105,000 g after 90 min) had the highest specific activity. The chorion was more active than the amnion but the enzyme in both tissues had similar substrate and nucleotide specificity. NAD was the preferred cofactor, and pregnenolone was a better substrate than dehydroepiandrosterone in the presence of NAD. However, with NADP as cofactor both steroids were equally good substrates. When the 3beta-hydroxysteroid dehydrogenase activity of chorion microsomes was compared with that of placental microsomes, the specific activities were found to be of the same order of magnitude, and the substrate, nucleotide specificity and steroid binding properties were almost identical.


Effects of 2-mercaptoethanol and aging in vitro on 17beta-hydroxysteroid oxidoreductase of guinea pig liver microsomes. When microsomes were prepared in 2-mercaptoethanol Vmax for 17beta-hydroxysteroid oxidoreductase (17beta-HSD) was greater, the Km for NAD+ was greater and the Km for testosterone lower than in its absence. During storage at 4 degrees Vmax increased in the presence of 2-mercaptoethanol and decreased in its absence; Km values for testosterone and NAD+ increased during storage in both cases. The presence or absence of 2-mercaptoethanol did not affect the extent or time-course of inactivation of 17beta-HSD by trypsin or phospholipase A. Furthermore, no differences were detected in sedimentation properties on sucrose density gradients suggesting that the differences and changes in the kinetic behavior of 17beta-HSD reflect a conformational flexibility at the active site and are not due to extensive changes in the structure of the microsomes. 17beta-HSD exposed to 2-mercaptoethanol was subject to substrate inhibition by testosterone, a type of inhibition not previously reported for this enzyme.


[The hepatocyte in acute alcoholic hepatitis. Histoenzymological and ultrastructural analysis (author's transl)]. The interpretation of the morphological features of alcoholic hepatitis is discussed in terms of a comparison with the results of an ultrastructural and histoenzymological study of the liver biopsies of nine patients. In these patients liver biopsies were performed in the initial stage of the illness and fifteen days after five were re-biopsied, when the clinical and biological signs were improved. The correlations between morphological and biological data were good, especially for the levels of serological and histoenzymological alkaline phosphatase and gamma-glutamyltranspeptidase evaluations. However, when histological appearances had returned to normal, after two weeks of abstinence from alcohol several histological and ultrastructural features of the initial hepatitis persisted. The presence of evolving cirrhosis was a contributing factor to the severity of the changes seen. Morphologically, apart from the changes due to chronic alcoholic intoxication (steatosis, mitochondrial alteration), the hepatitic lesions comprise Mallory's bodies, cytoplasmic oedema and mitochondrial swelling. Cholestasis was invariably present. Histo-enzymologically there was a reduction in ATPase activity suggesting a metabolic failure in the energy producing pathways. In addition, in the periphery of lobules an active cirrhotic process was present, with tubular de-differentiation of hepatocytes and an increase in gamma-glutamyltranspeptidase on the cytoplasmic membrane. Because of the absence of any topographical relationship between hepatitis and cirrhosis, the presence of lymphocytes in the neighbourhood of the ductules suggested an indirect relationship between both processes, perhaps an autoimmune response initiated by Mallory's bodies.


[Disordered regulation of cell membrane adenyl cyclase and guanyl cyclase activity as a possible factor in carcinogenesis]. The author suggests an interpretation of the recently recognized significant enzymatic imbalance in cancer cell as a result of the shift in the balance of cell memrane adenyl- and guanylcyclase activities in favour of the former. The alternative patterns of the development of hypothetical central and peripheral regulatory disturbances are dealt with. The prospective new therapeutic approaches offered by the pathomechanism under study are pointed out.


[Treatment of general psychovegetative disorders with a single night dose of dipotassium-clorazepate within a multicenter study (author's transl)]. The therapeutical effect of Tranxilium was studied in an open multicenter study by 66 general practitioners and 26 specialists. 1.027 patients were treated with Tranxilium 20, given in a single dose at night, for a period of three weeks. During this time, the patient's psychic status and functional organic disorders were assessed by means of rating scales. A complete medical assessment followed at the end of the study. States of anxiety, restlessness, depressive mood, irritation and insomnia as well as functional organic disorders improved significantly (p is less than 0.001) already after the first week of treatment. At the end of treatment, with the majority of patients the above symptoms had either completely disappeared or were found only to a small extent. In 85% of the patients, all investigators rated the stabilization and brightening effect on psychic conditions as well as the harmonizing effect on disturbed organic functions as "very good" to "good". In 89% of the patients, the overall therapeutic success was judged as "very good" to "good". The overall tolerance was excellent in 96% of the cases.


[Experience obtained in the treatment of recurrent aphthous stomatitis (author's transl)]. Three different methods employed within the framework of complex therapy were used to treat 195 patients with recurrent aphthous stomatitis: 1. Alterative therapy using prodigiosan, a bacterial polysaccaride. 2. Desensitizing treatment using histaglobulin, an antihistaminic agent. 3. Symptomatic local treatment. The methods of treatment are described in detail. General therapy allowed the frequency of relapses and the duration of disease to be reduced and shortened, respectively. The use of a complex form of therapy is recommended.


[Chemical parameters in coastal waters in correlation with microbiological parameters (author's transl)]. Nearly 4600 samples of coastal water from the Baltic Sea were characterized by microbiological parameters as well as by pH, ammonium, nitrite, nitrate, phosphate, and oxidizability by permanganate. Correlation of E. coli with chemical parameters varies strongly according to parameter, region, and season. Sanitary assessments can only be based on microbiological findings.--As regards eutrophication, we should expect special and more comprehensive chemical test programmes to give us substantial knowledge, whereas chemical tests after the EC guidelines for bathing waters along the Baltic Sea coast would mean considerable work and costs without getting any new results.


[Abiotic synthesis of peptides containing a dicarboxylic acid and their catalytic properties]. Studies have been made on thermal synthesis of peptides containing amino acids (glycine, alanine, leucine, threonine, and histidine) and succinic acid. The synthetic products were found to be heterogeneous, comprising mostly linear polymers. In the peptides obtained, the ratio between individual amino acids differed from the initial one. It was demonstrated that glycine exhibits high capacity for polymerization. At the same time, most polymerized peptides contained large amounts of leucine. In hydrolyzates of some of the peptides, a new non-identified amino acid was found which was formed from threonine. The peptides obtained exhibited catalytic properties: they hydrolyzed-p-nitrophenyl-phosphate, increased the breakdown of ascorbic acid by hydrogen peroxide and splitted inorganic phosphate from ATP. These activities depended on PH of the medium, the duration of action and substrate concentration. Synthetic products which contained threonine residues, exhibited higher activities as compared to other peptides. The data obtained reveal a possibility of incorporating the organic acids into polypeptide chains during abiogenic synthesis of biologically active substances. Such compounds with non-specific catalytic properties could serve as one of the steps in evolution of biocatalyzers.


Localization of the immunoglobulins G, A and M, beta-trace protein and gamma-trace protein on isoelectric focusing of serum and cerebrospinal fluid by immunofixation. The mobility of the immunoglobulins G, A and M, beta-trace protein and gramma-trace protein on isoleectric focusing of serum and CSF was determined by immunofixation using specific antisera. Polyclonal IgG migrated as multiple bands between pH 4.7--8.6, polyclonal IgA as multiple bands between pH 4.9--6.1 in CSF and serum. IgM could not be identified in normal CSF or serum. beta-trace protein gave three bands at pH 8.0, 8.4 and 7.4--7.5, respectively, while gamma-trace protein gave one single band at pH 9.5--greater than 9.5. Oligoclonal IgG in CSF in multiple sclerosis and neurosyphilis migrated between pH 8.6--greater than 9.5 and was easily discriminated from other proteins.


Comparison between agarose gel electrophoresis and isoelectric focusing of CSF for demonstration of oligoclonal immunoglobulin bands in neurological disorders. Isoelectric focusing and agarose gel electrophoresis of CSF and serum revealed similar frequencies of oligoclonal bands in multiple sclerosis (100% with both methods), infectious CNS disorders (38 and 23%) and other neurological diseases (8 and 10%). In selected cases with unsure CSF oligoclonal bands on agarose gel electrophoresis, isoelectric focusing displayed definite oligoclonal bands. In contrast to agarose gel electrophoresis, isoelectric focusing revealed evidence for oligoclonal bands in serum as well as in CSF in 41% of the multiple sclerosis patients, indicating diffusion from CSF to serum. In 4 cases with gammaglobulin bands appearing in both CSF and serum on agarose gel electrophoresis, isoelectric focusing revealed normal CSF and serum protein patterns at pH above 6.4 where most IgG is migrating.


Excretion of antiepileptic drugs in sweat. In eight epileptic patients receiving chronic antiepileptic treatment, a study of the excretion in sweat of phenytoin, phenobarbitone and carbamazepine was performed. All three drugs were found to be present in sweat. Phenytoin sweat concentration was found to correspond to the free fraction in plasma and to be independent of sweat flow. Phenobarbitone sweat concentration was found to increase with increasing sweat flow. Regarding drug level monitoring it is proposed that under changing climatic conditions the phenomenon may be of clinical significance.


beta-D-galactosidase activities in juvenile GM1-gangliosidosis. beta-Galactosidase activity was investigated in one case of juvenile GM1-gangliosidosis. This patient exhibited normal activity of the neutral form of beta-galactosidase (measured as beta-glucosidase activity) and normal pH curve of residual acid beta-galactosidase activity in leucocytes and fibroblasts. A shift towards more neutral pH optimum was seen in the beta-galactosidase enzyme occurring in serum. The communication also presents a study of the relationship of the different beta-galactosidases in human liver using isolated urine oligosaccharide from this patient as a beta-galactoside substrate. The other natural beta-galactoside substrates used in this investigation were different oligosaccharides, one glycopeptide and ceramide-beta-galactosidase. The beta-galactosidase forms with acidic pH optimum towards synthetic substrate (A forms) exhibit activity towards the natural substrate (except ceramide-beta-galactoside). The "neutral" beta-galactosidase with broad substrate specificity (B form) which includes beta-glucosides had no activity towards the natural substrates used. It could also be shown that the activity towards ceramide-beta-galactoside was a third type of beta-galactosidase different from A and B forms.


Renal sequelae to nephropathia epidemica. Clinical data and renal biopsy findings were studied in 9 patients 4-5 years after the acute phase of Nephropathia epidemica. Laboratory data suggested slightly depressed tubular function, but glomerular function was normal. Light microscopy of renal biopsy specimens showed slight residual interstitial fibrosis and occasionally atrophic tubuli, tubular casts, increased number of hyalinized glomeruli, and minor changes in other glomeruli. Two specimens showed fibrotic scars in the cortex. Electron microscopy revealed degenerative changes in the glomeruli, arterioles and tubules. The immunohistochemical study showed no fixed immunoglobulins in the kidney. The study shows that practically complete and lasting clinical recovery follows the acute phase of Nephropathia epidemica and that the disease does not leave diagnostic structural changes in the kidneys.


Protection against experimental Proteus mirabilis pyelonephritis in rats and significance of immunity. Intraperitoneal immunization with formalin-killed bacteria as well as previous hematogenous infection with Proteus O3H1 showed a protective effect against hematogenous pyelonephritis in rats when the homologous strain was used. Transfer of hyperimmune antisera protected against hematogenously induced infection. Neither intravesical or intraperitoneal immunization with formalin-killed bacteria nor transfer of urines containing antibodies of the IgG class protected against ascending pyelonephritis when the O3H1 strain was used. Data are presented indicating that a rise of pH might decrease the biological effect of antibodies, suggesting that Proteus urease activity is a virulence factor of importance in this context.


Sudden deafness in relapsing polychondritis. A scanning electron microscopy study. The left ear of a 57-year-old female who suffered sudden deafness during the course of relapsing polychondritis was examined under a scanning electron microscope. Marked degeneration of the organ of Corti in all turns and dislocated and encapsulated tectorial membrane were found in the cochlea. Marked decrease in number of the sensory cells in the utricular and saccular maculae and total loss of sensory hair bundles in the ampullary cristae of the semicircular canals were seen in the vestibule. These findings strongly suggest that the cause of sudden deafness in this case might be viral. The usefulness of scanning electron microscopy in human temporal bone pathology is stressed.


Differential effect on the sympathetic transmitter level in uterus and other organs of guinea-pig by drugs interfering with adrenergic nerve functions. 5 types of adrenergic blocking agents with different modes of action were administered and the rate of transmitter depletion was studied in different uterine regions of guinea-pig, and compared with that in the heart and submandibular gland by a combination of fluorescence histochemical and spectrofluorimetric methods. The tyrosine-hydroxylase inhibitor, H 44/68, as well as reserpine and guanethidine, produced a more efficient reduction in neuronal noradrenaline in the heart and submandibular gland than in the uterus. A differential action on the sympathetic transmitter, though less clearcut, was seen with 6-hydroxydopamine. The noradrenaline-depleting effect of metaraminol did not distinguish between those adrenergic nerves supplying the uterus from those of the control tissues. It is suggested that the differential effects may be related to a lower activity in the uterine adrenergic nerve system, probably because this system is to a large extent composed of short adrenergic neurons, which appear to have a particularly slow transmitter turnover.


On the capacity of the beta-oxidation of palmitate and palmitoyl-esters in rat liver mitochondria. The beta-oxidation of palmitate, palmitoyl-CoA and palmitoyl-L-carnitine proceeded at a high rate in isolated rat liver mitochondria. At high concentrations (100 nmol/mg protein) the oxidation of palmitate and palmitoyl-CoA was only partly carnitine dependent. All substrates were most rapidly oxidized in the presence of oxaloacetate and state 3 conditions. Succinate inhibited beta-oxidation especially in state 4 conditions. beta-Oxidation was faster in hypotonic than in isotonic medium both in state 3 and state 4 conditions. Hypertonicity inhibited beta-oxidation. The initial formation of palmitoyl-CoA from palmitate, CoA and ATP was faster than the oxidation of palmitate under identical conditions. The presence of bovine serum albumin inhibited the beta-oxidation, especially with palmitoyl-CoA or free palmitate as the substrates. Mitochondria contain a palmitoyl-CoA hydrolase which may influence the available intramitochondrial palmitoyl-CoA. The present results demonstrate no single rate limiting step in the beta-oxidation in vitro. Both the NADH/NAD ratio, competition for the respiratory chain, the level of ADP, binding of palmitoyl-CoA to extramitochondrial protein, and possibly intramitochondrial hydrolysis of palmitoyl-CoA all seem to influence the rate of beta-oxidation in vitro. It is suggested that in vivo the most important factor is the availability of acyl-CoA to the outer carnitine palmitoyl-transferase of the mitochondria.


Effect of metrizamide on whole blood oxygen affinity. The effects on whole blood oxygen affinity following addition to human blood of either ionic (diatrizoate) or non-ionic (metrizamide) contrast medium were investigated in vitro. No medium changed whole blood oxygen affinity. Solutions of metrizamide produced less changes in plasma pH than solutions of diatrizoate. This difference is explained by lower buffer capacity and lower osmolality of metrizamide solutions. Low osmolality gives less redistribution of anions between plasma and red cells and therefore less decrease in plasma pH.


Time-blind videotaped evaluation of injectable diazepam, lorazepam and placebo. Eighteen inpatients suffering from a severe anxiety received in double-blind and crossover conditions iv and im injections of 10 mg diazepam, 5 mg lorazepam or saline t.i.d. during 5 days. The morning injections was made iv in a CCTV studio. Before injection and 20 mn after it, the patient filled out a 100 mm Visual Analogue Scale; his doctor-in-charge proceeded to a standard interview and to physiological measurements (tremor of hand, patellar reflexes, blood pressure, pulse rate). The videotaped interviews were randomly, i.e. time-blind, rated by two independent observers on 3 scales: the VAS, the Hamilton Anxiety Scale and an ad hoc Verbal and Non-Verbal Anxiety Scale (VNVA). The statistical analysis was completed by a logical analysis according to Lewis Carroll. The results demonstrate the superiority of lorazepam over diazepam on psychic anxiety, somatic anxiety, sleep and blood pressure, the only significant side-effect being drowsiness.


Phosphopyridoxal cyclic compounds with histamine and histidine. 7: The properties of pyridoxal and phosphopyridoxal cyclic compounds with histamine and histidine. Cyclic compounds synthesized from histamine (Hi) or histidine (His) with pyridoxal (PL)--[Hi-PL, His-PL] and Hi or His with pyridoxal 5'-phosphate (PLP)--[Hi-PLP, His-PLP] were tested for stability in buffer, acid and base solutions, crude homogenates of various tissues and in the presence of enzymes which metabolize Hi or His. The cyclic pyridoxal compounds were stable in all experimental conditions, whereas phosphopyridoxal cyclic products were degraded by rat intestinal DAO and rat intestine homogenate, apparently enzymatically. In acidic and basic solutions changes in migration velocity and u.v. absorption spectrum occur. The characteristic fluorescence of these cyclic compounds is described.


Anti-inflammatory drug actions on allergic responses in guinea-pig skin. Five non-steroidal anti-inflammatory drugs (indomethacin, naproxen, meclofenamic acid, feprazone and phenylbutazone: NSAIDs) and three glucocorticosteroids (dexamethasone, hydrocortisone and prednisolone) have been tested as local inhibitors of increased vascular permeability in guinea-pig skin. Lesions were induced by histamine or by antigen to evoke type I (passive cutaneous anaphylaxis), type III (reverse passive Arthus) and type IV (delayed hypersensitivity) allergic reactions. NSAIDs and glucocorticosteroids caused either weak, inconsistent inhibition or slight, high-dose inhibition of the response to histamine. None of the drugs tested showed significant inhibition of the type IV response. The NSAIDs caused dose-related inhibition of both type I and type III responses whereas glucocorticosteroids were ineffective. Maximum inhibition with the NSAIDs was never greater than 50--60% Feprazone, meclofenamic acid and indomethacin were the most potent inhibitors of histamine, PCA and Arthus responses respectively. The possible significance of the effects of these anti-inflammatory agents on vascular permeability is discussed.


The effects of fractions (chalones) obtained from lymphoid organs on the immune response in vivo. Aqueous extracts of calf and pig lymphoid organs were prepared and fractionated by means of gel filtration, ion exchange chromatography, and isoelectric focusing. These fractions, which had been previously assessed on mitogen-stimulated mouse spleen lymphocytes and other cells in vitro, were tested for their in vivo activity on humoral (haemolytic PFC in mice) and on cell-mediated immunity (skin allograft survival in mice, lymph node weight assay in rats, and systemic GvH-reaction in mice). None of these several fractions elicited either biologically significant or reproducible inhibitory effects. In particular, two fractions, a high and a small molecular weight fraction which were strongly inhibitory in vitro, remained without any chalone-like activity in these in vivo assays. Our results therefore failed to support the existence of a lymphocyte chalone.


Management of intraoral injuries.

Management of intraoral injuries. Primary closure of intraoral wounds can be done up to 24 hours after the injury. A mucosal seal decreases the possibility of infection and allows the wound to heal more rapidly and less painfully than a wound left open to heal by secondary intention. Defects of the lips must be closed with exact alignment of the vermilion-cutaneous margins. Nerve repairs must be done without tension at the repair site. Parotid duct repairs are mandatory to prevent cyst and fistula formation. Anterior permanent teeth may be replanted.


Takayasu's arteritis associated with glomerulonephritis. A case report. Takayasu's disease is a nonspecific arteritis of unknown cause with predilection for the aortic arch and its branches; approximately 20% of those affected are children or adolescents, predominantly females. The purpose of this article is to report the case of a young girl in which the mode of presentation was microscopic hematuria and proteinuria. Subsequently, aortic valvular insufficiency developed and there was evidence of aortitis in the thoracic and abdominal aorta, as well as in the arch. All functional and anatomical cardiac derangements were documented by ultrasound and angiocardiography. Renal biopsies showed progressive glomerular involvement characterized by focal and segmental glomerulonephritis. It is postulated that a common immunologic mechanism was responsible for the aortic and glomerular lesions.


Treatment of acute otitis media of infancy with cefaclor. The emergence of ampicillin-resistant Haemophilus as a clinical problem in otitis media necessitates a search for alternative, effective therapy. An orally absorbable cephalosporin derivative, cefaclor, is equally effective in vitro against ampicillin-susceptible and -resistant Haemophilus and against other bacteria that cause acute otitis media. Two dosage schedules of cefaclor (40 and 60 mg/kg/day) were evaluated in 95 infants with acute otitis media. Bacterial origin was determined by a culture of tympanocentesis fluid. Success rates using the smaller dosage were inferior to those using the larger dosage. Results of therapy for pneumococcal and Haemophilus infection with 60 mg/kg/day were comparable to those previously found with amoxicillin trihydrate or with combinations of trisulfapyrimadines with erythromycin or penicillin V. One patient with an ampicillin-resistant Haemophilus infection responded well to cefaclor and did not have a relapse. Cefaclor was well tolerated and caused an acceptably low incidence of minor, adverse effects. Cefaclor deserves further testing as a candidate for preferred status as a single-drug treatment of acute otitis media.


Azulfidine- (sulfasalazine-) induced hepatic injury. A patient with Azulfidine-related hepatotoxicity in which prompt recurrence of symptoms, fever skin rash, and laboratory evidence of hepatocellular injury occurred upon readministration of Azulfidine is reported. The clinical and biochemical features support the fact that this was an example of an acquired hypersensitivity reaction to Azulfidine.


Effectiveness of high-dose spironolactone therapy in patients with chronic liver disease and relatively refractory ascites. Ten patients with ascites due to chronic liver disease were treated with spironolactone as the sole diuretic in doses of 300 to 600 mg daily. Prior to spironolactone treatment ascites was relatively refractory as indicated by baseline 24-hr urine sodium values of less than 5 mEq and natriuresis of less than 30 mEq following 200 mg hydrochlorothiazide. With spironolactone, mean daily weight loss was 540 g and natriuresis 74 mEq; diuresis was considered satisfactory in nine of ten patients. Untoward effects were limited to a single episode of hepatic encephalopathy, a small fall in serum magnesium in several patients, and three instances of hyperkalemia (5.5, 5.6, and 7.5 mEq/liter). In spite of the tendency to hyperkalemia, urinary potassium excretion increased in seven of the ten patients. There was no rise in serum urea nitrogen or creatinine. Hydrogen ion excretion decreased initially leading to mild hyperchloremic acidosis. Serum urate did not increase.


Plasma secretin concentrations in fasting and postprandial state in man. Plasma immunoreactive secretin concentrations were determined in both healthy subjects and patients with duodenal ulcer. The modified radioimmunoassay method could detect significant increases in the plasma secretin concentrations when 0.05 N HCl was infused intraduodenally at a rate of 1.1 and 2.2 ml/min. The mean fasting plasma secretin concentration of 13 normal healthy subjects was 4.4 +/- 0.38 pg/ml which was significantly less (P less than 0.01) than that of 13 duodenal ulcer patients, 6.9 +/- 0.64 pg/ml. In both groups ingestion of a meat-containing meal resulted in significant increase in the plasma secretin concentrations. Recording of pH from proximal duodenum indicated that pH fell periodically below 4.5 during the postprandial period, indicating that only a short segment of proximal duodenum was exposed to acid after meal. The postprandial rise in plasma secretin levels was abolished when antral pH was raised 5.5 by intragastric infusion of 0.3 N NaHCO3 solution. These observations indicate that although fasting plasma secretin levels are low, the plasma secretin levels increase significantly after ingestion of a meal. This increase appears to be attributable to an increased amount of acid delivered to the proximal duodenum, and patients with duodenal ulcer were found to release more secretin during the postprandial period than normal subjects.


Does secretin influence rat colonic absorption and secretion? In rats, a secretin (Jorpes) intravenous infusion superimposed on an intracolonic sodium acetate perfusion elicits, with respect to control values, a significant depression of Na+ absorption (0.16 mEq./h-0.00 mEq./h.) and mucus secretion (230-40 mg.). When the hormone is superimposed upon an intracolonic infusion of acetic acid, mucus secretion is also significantly inhibited (790-340 mg.). The influence of secretin on organic anion movement was pH related. At pH values of 7.0, absorption was unchanged (0.34--0.33 mEq./h.), at pH values of 2.9, absorption was significantly reduced (0.67-0.41 mEq./h). The secretin impairment of colonic mucus secretion could influence the transport of watersoluble (Na+) and lipid soluble (acetic acid) substances, probably through changes at the "unstirred layer" level.


Improved ventilation of prematurely delivered primates following tracheal deposition of surfactant. Twelve rhesus monkeys were delivered prematurely at 129, 130, or 131 days. The first breath was inhibited while tracheotomy was performed and a catheter introduced into the umbilical artery. Into the tracheal tubes of six of the newborn monkeys was instilled 0.20 to 0.27 ml. of a natural surfactant (SA) suspension, obtained from lung wash of adult rabbits. Nothing was given to six control monkeys. Breathing was then supported with a ventilator. Although its settings were adjusted in attempts to maintain normal blood gases, the control monkeys developed severe hypercapnia and acidosis, and two died after 4 1/2 and 5 1/2 hours. The remaining four control monkeys and the six treated monkeys were killed after six hours. Pulmonary pressure-volume characteristics were conspicuously better following SA treatment. It was concluded that instillation of SA in the upper airways of premature primates prior to their first breath holds promise as an effective way of preventing respiratory distress.


Circulatory shock in pregnant sheep. IV. Fetal and neonatal circulatory responses to hypovolemia--influence of anesthesia. Hemodynamic responses to hypovolemia were investigated in unanesthetized, unstressed fetal lambs and in acute fetal and neonatal preparations. The unstressed fetus tolerated twice the amount of blood loss of the acutely studied fetus or newborn lamb and with a lesser hypotension. Hemodynamic behavior of the newborn lamb and fetus anesthetized with pentobarbital during hypovolemia was markedly different from that of the fetus studied under spinal anesthesia or chronically. Besides tolerating greater blood loss, the unstressed fetus reversed the state of hypovolemic shock rapidly as contrasted to the stressed fetus which was unable to do so even with total blood reinfusion. All animals exhibited bradycardia in response to hypovolemia. The following conclusions were drawn: (a) cardiovascular response to hypovolemia in the perinatal period depends on the initial status of the animal, (b) the fetus tolerates a greater degree of blood loss than a newborn or adult animal, and (c) anesthesia and stress of surgery modify considerably circulatory behavior during blood loss.


Urea and dilatation of the cervix.

Urea and dilatation of the cervix. The minimal elasticity of the uterine cervix has been related to its high collagen content. By interfering with cohesive forces that hold the collagen fiber bundle together, it is possible to diminish the physical strength of collagen. Urea has been used in collagen chemistry to dissociate collagen by interfering with hydrophobic linkages and hydrogen bonds. This results in a change of mechanical properties such as a decrease in tensile strength and an increase in elasticity. Basic studies of rat tail tendon demonstrated the additive effects of pH, concentration of urea, and temperature on the mechanical characteristics of collagen fibers. In vitro testing was performed using an injection of 30 per cent urea at pH 4. Serial measurements with a spring gauge instrument showed a reduction in cervical resistance. A cervical injection technique has been developed and toxicity of urea studied.


Thymic epithelial injury in graft-versus-host reactions following adrenalectomy. In four separate experiments 140 adults A(H-2a) x C57BL/6(H-2b) F1hybrid mice were surgically adrenalectomized and divided into three experimental groups. Seventy-one additional adult F1hybrids (AXC57BL/6) which had not been adrenalectomized were divided into three similar groups. In Group 1 (GvH group), GvH reactions were induced by the injection of 50 x 106 pooled parental lymphoid cells intravenously. The second group (syngeneic group) received 50 x 106 pooled F1 hybrid lymphoid cells intravenously. The third group (uninoculated group) received no lymphoid inoculum. At regular intervals the animals were killed, autopsied, and histologically studied. Visceral alterations of GvH reaction were recorded in the thymus, lymph nodes, spleen, and liver in the GvH groups; none was present in the other groups. The thymuses in the nonadrenalectomized GvH group underwent prompt involution characterized by size reduction and cortical lymphoid cell depletion. These changes were not apparent in the GvH adrenalectomized group. Both GvH groups, however, demonstrated an effacement of the medulla, lymphocyte incursion into the medulla, lymphocyte emperipolesis of medullary epithelial cells, gradual disappearance of Hassall's corpuscles, epithelial cell injury, and an ingress of macrophages laden with nuclear and cellular debris. This study suggests that the stress and corticosteroid response which accompany a GvH reaction account for the reduction in the thymic size and cortical lymphoid cell mass. The medullary alterations, therefore, would appear to be initiated by the GvH reaction per se.


Cimetidine as a single oral dose for prophylaxis against Mendelson's syndrome. Cimetidine, a histamine H2-receptor antagonist which inhibits gastric acid secretion, was administered as a single 400 mg oral dose before anaesthesia to forty-six patients undergoing elective gynaecological surgery. The incidence of gastric residue pH above 2.5 was significantly greater (P less than 0.001) in cimetidine treated patients than in thirty-seven control patients. No patient who received cimetidine between 4 and 6 h prior to anaesthesia had a gastric residue pH less than 2.5. These findings suggest that cimetidine may be effective as a prophylaxis against acid pulmonary aspiration (Mendelson's) syndrome.


Arterial blood gas analysis: potential errors due to the addition of heparin. The effect of sodium heparin on the determination of the major arterial blood gas parameters was studied. The addition of heparin produced errors in all three parameters tested, i.e. PO2, PCO2 and pH. The PCO2 determination was most affected, a 12% decrease being introduced into a 1.5 ml blood sample by the volume of heparin which fills the deadspace of a syringe and needle. Small but statistically significant errors were also produced in PO2 and pH by this heparin concentration. The clinical implications of these findings are discussed and certain measures outlined to avoid such errors.


Effects of testosterone upon feeding in male mice. Food intake and pattern of feeding were recorded in intact and castrate male mice. Intact adults are larger and eat more than pre-pubertal castrates, due to rapid growth at puberty. Castration in adulthood has little effect upon food intake, but feeding becomes concentrated into large, infrequent meals. The change in meal size appears primary and is reversed by testosterone. During rapid growth at puberty, both meal size and frequency are high. It is suggested that testosterone affects feeding in two ways. Rapid weight gain at puberty leads to high meal size and frequency, but in adulthood meal size is depressed. Meal size in adults is further depressed by stimuli from females, and it is argued in this case that testosterone affects a general mechanism for altering feeding when other activities have a high priority.


[Thrombolysis: biochemical basis of fibrinolysis. Fibrinogen]. Fibrinogen is synthetised in the parenchymatous cells of the liver. It is broken down in the plasma by cells equipped with the appropriate enzymes. The fibrinogen molecule is a dimer with a molecular weight of 340,000. Each monomer consists of three polypeptidie chains (alpha A, beta B and gamma) joined by disulphide bridges. The N-terminal region is rigid and constitutes the N-DSK (N-disulphide knot) around which the three C-terminal free extremities are rolled, thereby giving a symmetry and spherical form to the molecule. The existence of several types of alpha A chains explains their important role in polymerisation.


[Hemodynamic effects of equipotent doses of phenoperidine and fentanyl in man]. The haemodynamic effects of phenoperidine and fentanyl were studied in ten patients with craniocerebral trauma who presented no surgical indications. They were all mechanically ventilated with a constant tidal volume and rate and their cardiovascular state was stable. The patients were given 5 gamma/kg of fentanyl intravenously; the haemodynamic measurements were performed at two mn interval for 20 mn. Three hours later, the patients were given 30 gamma/kg of phenoperidine intravenously and the haemodynamic measurements were performed similarly. Phenoperidine and fentanyl had the same effects: a significant fall in heart rate, mean arterial pressure and cardiac index without any change in pulmonary wedge pressure. These changes do not dangerously alter the haemodynamic condition of the patients and thus are not a contra-indication to the general use of phenoperidine and fentanyl in anaesthetic practice and in intensive care.


[Action of proteolytic enzymes on fibrinogen]. The principal substrate of protealytic enzymes is fibrinogen. Thrombin severs four ARG-GLY bonds in the alpha A and beta B chains of its molecule, on the side of the terminal-N. It thus liberates two fibrinopeptides A and B, and leads to the formation of fibrin. Plasmin, by contrast, acts upon the fibrinogen molecule first by hydrolysis of the alpha and beta chains liberating the X fragment and three peptides A, B and C. It continues on the alpha, beta and gamma chains of fragment X, leading to the appearance of fragments Y and D. Fragment Y is in turn hydrolysed into a second fragment D and fragment E. The initial (X and Y) or terminal (D and E) fibrinogen breakdown products each possess their own anticoagulant properties together with immunological properties which may be used in their estimation.


[Enzymatic fibrinolytic agents].

[Enzymatic fibrinolytic agents]. Urokinase (UK) and streptokinase (SK) transform plasminogen into plasmin by rupture of a ARG-VAL bond and the liberation of a peptide with a molecular weight of 6000 to 8000. Urokinase is a physiological activator with a direct action. By contrast, streptokinase is an enzyme of bacterial origin and two hypotheses may be advanced to explain its mechanism of action: the formation of a SK-plasminogen complex capable of activatiing new molecules of plasminogen or the formation of a SK-plasminogen complex within which plasminogen is transformed to plasmin.


[Non-enzymatic fibrinolytic agents].

[Non-enzymatic fibrinolytic agents]. Non-enzyme fibrinolytic agents include pharmacological agents which are active in vivo but inactive in vitro and synthetic chemical compounds which when added to blood or plasma in vitro directly induce fibrinolysis. There are a number of drugs with a short duration of action such as adrenalin, nicotinic acid, vasopressin and histamine. Vasoactive drugs probably act by stimulating the liberation of vascular activator. The effect of nicotinic acid is rapidly exhausted when injections are repeated. By contrast, the biguanides and certain anabolic steroids are capable of exerting a long term stimulation of endogenous fibrinolysis. Amongst these substances, phenformin, metformin, ethyloestrenol, stanozolol and a new substance, moroxydine chloride, have been studied. The biguanides appear to be capable of exerting an effect upon the synthesis and liberation of plasminogen vascular activator. The combination of an anabolic steroid and a biguanide would appear to be the most powerful. These various drugs have been used with success in cases of recurrent venous thrombosis in patients with an abnormally low level of plasminogen activator in the venous walls and/or low fibrinolytic activity after venous stasis. Chemical fibrinolytic agents were studied only in vitro, since the use of these substances in human therapeutics would seem to be still difficult in view of the fact that they are active only in a narrow range of concentrations.


[Fibrinolysis].

[Fibrinolysis]. A large number of methods may be used in the study of fibrinolysis. They are either so-called direct when they demonstrate abnormal lytic activity and indirect when they analyse the results of this activity. In practical terms, the examinations used most widely are the euglobulin lysis test, evaluation of the plasminogenplasmin pair, and estimations of fibrinogen and of its breakdown products.


[Thrombolytic treatment (theoretical basis, therapeutic protocols, monitoring)]. Thrombolytic therapy is aimed at dissolving thrombi. Streptokinase (SK) and urokinase (UK) are currently used in France but their mode of action has not been completely elucidated, which renders the establishment of therapeutic protocols and the choice of doses difficult. This treatment has a certain number of contraindications which must be strictly respected. The effectiveness of SK and UK in high doses has been demonstrated, in particular in pulmonary embolism and acute arterial obstruction of the limbs, but there is a risk of haemorrhage, whilst UK in moderate doses is usually well tolerated but has yet to prove its effectiveness in randomised double blind trials. Laboratory control has been simplified but it is essential not to forget the importance of clinical monytoring. Finally, drugs have recently been used in association with thrombolytics and more particularly the administration of plasminogen or defibrinating agents before or after thrombolytics.


[Streptokinase in the treatment of deep venous thrombosis and pulmonary embolism]. Fifty-two deep venous thromboses and 35 pulmonary emboli were treated by Streptokinase administered in accordance with a standard protocol. Radiological examinations revealed total lysis of clots in 22 cases, partial lysis in 42 and failure in 23. The latter more commonly involved venous clots than pulmonary emboli. Early treatment was more effective (21 total lyses out of 22) than late treatment. However, in venous thrombosis, late treatment may give partial lysis and free important venous junctions. With standard treatment, lysis was biologically correct in 70 p. 100 of cases. It was inadequate in 20 p 100 of cases and nil in 10 p. 100 of cases. The results could thus have been improved by treatment established and adjusted in the light of laboratory results. The extent of the thrombosis played an important role. Total lysis was obtained in 9 out of 10 cases of localised deep venous thrombosis. In pulmonary embolism there was an average gain of approximately 30 p. 100 in obstructed surface area. However, in these latter cases, it is important to take into account not only the pulmonary surface area obstructed but also the origin of the clots.


[The treatment of myocardial infarct with streptokinase]. The current situation concerning the use of Streptokinase in the treatment of recent myocardial infarction does not make it possible to draw any definite conclusions with regard to its therapeutic value:--mortality would not appear to be significantly modified in the majority of series;--the occurrence rate of major complications during the acute phase is not notably altered but it seems possible that the electrocardiographic course of the necrosis is more favourable under the influence of Streptokinase when treatment is begun early. The long term course cannot be assessed. Finally, it is certain that the tolerance of Streptokinase therapy has been good in all the published series. In particular, Streptokinase does not appear to have been associated with severe haemorrhagic complications nor a higher prevalence of cardiac rupture.


[Moderate doses of urokinase (UK) in the treatment of myocardial infarct and pulmonary embolism]. Since 1972, UK in moderate doses have been used in the treatment of severe or massive pulmonary emboli (PE) and of myocardial infarction (MI) present for less than 24 hours. The standard dose is 2,700,000 CTA units per 24 hours administered as a continuous infusion, in association with appropriate heparin therapy and a platelet anti-aggregant agent in order to palliate the hyperagregant effects of thrombolytic drugs. Laboratory surveillance has now been greatly simplified and is limited to that of the associated heparin therapy. In the acute phase of myocardial infarction, a personal randomised study of 120 cases consisting of 60 treated with heparin + UK and 60 with heparin alone showed that UK decreased mortality, cardiac arrhythmias and cardiac failure. Comparative studies at lower doses have failed to show any significant difference between the two groups of patients treated and the authors feel that the use of UK should be reserved for very recent infarctions in young subjects. In PE, the effectiveness of UK was assessed in 180 severe cases. It depended upon the length of time for which the thrombus had been present. Before the 5th day, there was early average revascularisation of 40 p. 100 of the avascular territory. Mortality was reduced to 15 p. 100 and at the 3rd week 32 p. 100 of the survivors had complete revascularisation, and 68 p. 100 partial but adequate revascularisation. Adjuvant therapy such as a combination of Lysil Plasminogen and/or defibrinating agent currently make it possible to reinforce therapeutic thrombolysis.


[Thrombolytic treatment of arteriopathies]. Systemic streptokinase has shown its effectiveness in the treatment of recent arterial obstruction of the limbs. The haemorrhagic and embolic complications of this type of treatment nevertheless limit its indications. Streptokinase should be reserved for acute thromboses present for less than two months, and responsible for severe ischaemia without the possibility of surgical treatment. The intra-arterial administration of urokinase limits the risks of systemic fibrinolysis, though the effectiveness of the therapeutic protocols proposed has yet to be demonstrated.


The spectrum of vasculitis: clinical, pathologic, immunologic and therapeutic considerations. Vasculitis is a clinicopathologic process characterized by inflammation and necrosis of blood vessels. Certain disorders have vasculitis as the predominant and most obvious manifestation, whereas others have various degrees of vasculitis in association with other primary disorders. Within the entire spectrum of vasculitis virtually any size or type of blood vessel in any organ system can be involved. Most of the vasculitides can be associated directly or indirectly with immunopathogenic mechanisms. In this regard, immune complex mediation is being increasingly recognized as the underlying mechanism in several of the vasculitides. With clinical, pathologic, and immunologic criteria, certain vasculitic disorders can be clearly recognized and categorized as distinct entities, whereas in others there is an overlap of different diseases within a broader category. In recent years, several of the more serious vasculitides, such as Wegener's granulomatosis and the systemic necrotizing vasculitides of the polyarteritis nodosa group, which formerly had extremely poor prognoses, have been shown to be extraordinarily responsive to chronic low-dose cytotoxic therapy, particularly cyclophosphamide.


Trends in bacterial virulence and antibiotic susceptibility: streptococci, pneumococci, and gonococci. Antibiotic usage and improved living conditions may have contributed to a dilution of "rheumatogenic" strains of group A streptococci and to their replacement by attenuated streptococci with less rheumatogenic potential. Whether this is due to decreased virulence or to loss of specific bacterial antigens or toxins in prevalent strains is not yet known. The pneumococcus, which has been moderately resistant to antibiotics only in isolated cases, has appeared in South Africa in strains that are highly resistant to at least five major antibiotics; plasmid transmission of resistance is suspected. The newly available pneumococcal vaccine may become very important if such strains spread. Gonococci isolated from urogenital lesions have developed only moderate drug resistance. Gonococci causing disseminated infection have retained their exquisite sensitivity to penicillin; the most virulent strains are associated with greatest sensitivity. However, the newly discovered penicillinase-plasmid in gonococci is transferable to these virulent strains as readily as to others.


Protective environment for marrow transplant recipients: a prospective study. Laminar air flow isolation and decontamination procedures were evaluated in a prospective randomized study in patients with aplastic anemia or acute leukemia undergoing marrow transplantation from HLA-matched siblings. Patients transplanted in the laminar air flow group had significantly less septicemia and major local infections than did patients in the control group. Nineteen of 46 laminar air flow patients and six of 44 control patients are alive at present. In patients with aplastic anemia the survival was 13 of 17 in the laminar air flow group compared with four of 17 in the control group. In patients with acute leukemia the survival was six of 29 in the laminar air flow group versus two of 27 in the control group. These differences were not statistically significant. Death in both the laminar air flow and control groups was predominantly due to interstitial pneumonitis or recurrent leukemia, which were unaffected by isolation and decontamination.


[Process of fumigatin and spinulosin formation by Aspergillus fumigatus Fres and polarographic assay of these toxins (author's transl)]. A strain of Aspergillus fumigatus (Fresenius) isolated from a milk food for calves was grown on a culture medium containing added saccharose. The purpose was to study the synthesis of two recently discovered mycotoxins, fumigatin and spinulosin. The work was performed under many different conditions of temperature, pH and inoculum. These mycotoxins were measured by analytical differential pulse polarography. Correlations were observed between the growth rate of A. fumigatus and variation in pH of the medium and the formation of fumigatin, which is only possible when pH falls to less than 4.0. Fumigatin appears promptly at the beginning of the growth phase of the fungus but quickly disappears. The production of metabolite depends on limited conditions of culture. Spinulosin, very similar to fumigatin, is substituted for fumigatin in slightly different conditions. During growth, the fungus degrades both metabolites. The nature of the substitution and the reason of these modifications have not been investigated. Fumigatin and spinulosin formation is observed in both toxigenic and non-toxigenic strains.


Trimolol: effect on intraocular pressure in chronic open-angle glaucoma. Timolol maleate is an effective agent of reducing intraocular pressure in patients with chronic open-angle glaucoma. To date, there are no adverse side effects demonstrable with use of this medication. Its mechanism of action is not clearly delineated but preliminary data suggest an effect on outflow facility.


Optimal conditions for the estimation of ammonium by the Berthelot reaction. A technique for optimising reagent concentrations on the AutoAnalyzer has been applied to the estimation of ammonia by the Berthelot reaction in the determination of urea and organic nitrogen. Comparison of the use of phenol and salicylate revealed that the optimum concentration of the latter is about four times that of the former. The optimum concentration of hypochlorite is five times greater with salicylate than with phenol, and for the catalyst, sodium nitroprusside, the factor is two. The precision obtained with the different methods is similar.


Cyclic pharyngeal lymphoiditis: immunological considerations. This communication presents the concept that recurrent infections of the lingual tonsils, lateral pharyngeal lymphoid bands and lymphoid follicles on the posterior pharyngeal wall, occurring with the same periodicity, is a cyclic clinical and immunological entity. These patients lacked resistance to the normal flora of the nasopharynx and pharynx. They were accordingly treated with a mixed respiratory bacterial vaccine, administered intradermally and according to a formulated program, to improve resistance or immunity of the lymphoid tissue. These patients showed definite improvement by this method of therapy. It is suggested that the effectiveness of therapy was accomplished through the immunological process of cell-mediated immunity. The immunobiologic development of cell-mediated immunity by T thymic-dependent cells and humoral immunity by B cells is briefly discussed.


Depression of synaptic transmission by diphenylhydantoin. Diphenylhydantoin (phenytoin, DPH) depresses synaptic transmission at the frog neuromuscular synapse by presynaptic and postsynaptic mechanisms. In normal Ringer's solution the amplitude of the neurally evoked end-plate potentials and their quantal content are reduced. Somewhat paradoxically, miniature end-plate potential (mepp) frequency is increased by the drug. These effects could result if DPH blocked both calcium transport at the axonal membrane and intracellular calcium sequestration. Mepp amplitude is reduced, and DPH also induces nerve conduction block at high rates of stimulation. The relevance of these effects to the anticonvulsive activity of DPH is discussed.


Niemann-Pick disease type D: lipid analyses and studies on sphingomyelinases. Lipids and sphingomyelinase activity were studied in spleen, liver, and brain tissues of a 13-year-old boy with Niemann-Pick disease type D (NPD-D). The greatest lipid changes occurred in spleen; cholesterol, cholesterol esters, total phospholipids, sphingomyelin, and bis-(monoacylglyceryl)phosphate were increased above normal range. In liver, striking increases were observed in cholesterol and bis-(monoacylglyceryl)phosphate. Minor changes in neutral and acidic glycolipid patterns occurred in liver, spleen, and brain. Sphingomyelinase activity (optimal at pH 5.0) was elevated above mean control levels in liver and spleen, but not in brain, kidney, or leukocytes. Enzyme properties were generally normal. Activity of NPD-D liver crude homogenate, but not that of normal liver homogenates, was inhibited at high protein concentrations. Activity levels of a second sphingomyelinase, optimal at pH 7.4, in NPD-D brain were apparently normal. These findings are generally consistent with the classification of NPD-D as a sphingomyelin lipidosis.


Importance of antimicrobial susceptibility testing of Streptococcus pneumoniae. Six of 36 strains of Streptococcus pneumoniae isolated in our laboratory during 1977 showed relative resistance to penicillin G. This level of resistance was detectable only by the broth dilution method. Using the disk diffusion method, all six strains appeared susceptible (zone size > 29 mm).


Gamma glutamyl transpeptidase levels in arthritis: a correlation with clinical and laboratory indices of disease activity. Gamma glutamyl transpeptidase (GGTP) was measured in 62 patients with rheumatoid arthritis (RA) and 27 with osteoarthrosis (OA). The values for GGTP were significantly higher in the subjects with RA compared with the OA group. The prevalence of elevation of GGTP was higher in the RA subjects (77%) than in the OA patients (33%). Levels of GGTP correlated significantly with a number of objective indices of activity of RA in a separate group of 28 patients. Following treatment with penicillamine, GGTP levels showed a significant drop towards normal levels.


Hyperprolactinemia in multiple endocrine adenomatosis, type 1. Three cases are described in which hyperprolactinemia occurred as a feature of multiple endocrine adenomatosis, type 1 (MEA-1); enlargement of the sella turcica varied from gross to absent, and serum prolactin (PRL) levels ranged from 21 to 1,000 ng/ml in these cases. Since PRL-secreting pituitary tumors may occur with variable presentation in MEA-1, periodic measurements of serum PRL levels should be carried out to detect this abnormality.


Nitrogen assimilation in Rhodopseudomonas acidophila. Rhodopseudomonas acidophila strain 7050 assimilated ammonia via a constitutive glutamine synthetase/glutamate synthase enzyme system. Glutamine synthetase had a Km for NH+4 of 0.38 mM whilst the nicotinamide adenine dinucleotide linked glutamate synthase had a Km for glutamine of 0.55 mM. R. acidophila utilized only a limited range of amino acids as sole nitrogen sources: L-alanine, glutamine and asparagine. The bacterium did not grow on glutamate as sole nitrogen source and lacked glutamate dehydrogenase. When R. acidophila was grown on L-alanine as the sole nitrogen source in the absence of N2 low levels of a nicotinamide adenine dinucleotide linked L-alanine dehydrogenase were produced. It is concluded, therefore, that this reaction was not a significant route of ammonia assimilation in this bacterium except when glutamine synthetase was inhibited by methionine sulphoximine. In L-alanine grown cells the presence of an active alanine-glyoxylate aminotransferase and, on occasions, low levels of an alanine-oxaloacetate aminotransferase were detected. Alanine-2-oxo-glutarate aminotransferase could not be demonstrated in this bacterium.


Studies of relationship among terrestrial Pseudomonas, Alcaligenes, and enterobacteria by an immunological comparison of glutamine synthetase. Antibody to purified glutamine synthetase from Escherichia coli was prepared and used for an immunological comparison of glutamine synthetases from species of Salmonella, Citrobacter, Enterobacter, Serratia, Proteus, Erwinia, Aeromonas, Pseudomonas, Acinetobacter, Xanthomonas, Alcaligenes, and Paracoccus. The results of Ouchterlony double diffusion experiments and quantitative microcomplement fixation studies indicated that the amino acid sequence of this enzyme was highly conserved in different organisms. The order of relationship to E. coli was found to be similar to that derived from immunological investigations of other enzymes. In addition, congruence was observed between ribosomal RNA homology and the results of the microcomplement fixation experiments. The results also suggested that some species of Alcaligenes were more closely related to species of Pseudomonas than to each other. Immunological comparisons of glutamine synthetases appear to be very useful for the elucidation of relationships among distantly related species and genera.


Hydrolysis and synthesis of ATP by membrane-bound ATPase from a motile Streptococcus. ATPase was detected in the membranes of a motile Streptococcus. Maximal enzymic activity was observed at pH 8 and ATP/Mg2+ ratio of 2. Mn2+ and Ca2+ could replace Mg2+ to some extent. Besides ATP, GTP and ITP were substrates. The enzyme was inhibited by N,N'-dicyclohexylcarbodiimide but not by sodium azide, uncouplers or bathophenanthroline. An electrochemical gradient of protons, which was artificially imposed across the membranes of Streptococcus cells by manipulation of either the K+ diffusion potential or the transmembrane pH gradient, led to ATP synthesis. ATP synthesis was abolished by proton  conductors, an inhibitor of the ATPase or an increase in the extracellular K+ concentration. A comparison between the phosphate potential and the electrochemical proton gradient showed that the data found are in agreement with a stoichiometry of 2 protons translocated per molecule ATP synthesized.


Uptake and metabolism of alpha-aminoadipic acid by Penicillium chrysogenum Wis 54-1255. The uptake of 1-14C-DL-alpha-aminoadipate in resting mycelium of Penicillium chrysogenum Wis 54-1255 and its metabolism during benzylpenicillin formation were studied. The pH optimum for uptake at 25 degrees C was 6.4. Over a range of concentrations from 0.01--1.0 mM, approximately 45% of 1-14C-DL-alpha-aminoadipate was taken up by carbon-starved mycelium. 14CO2 was formed at a low rate, and the total formed amounted to only 1--3% of the 1-14C-DL-alpha-aminoadipate supplied. The intracellular pool of alpha-aminoadipate appears to be expandable, depending on the concentration of alpha-aminoadipate in the medium. The rate of penicillin synthesis depended on the intracellular concentration of alpha-aminoadipate. Penicillin biosynthesis achieved half of the maximum rate at an intracellular concentration of 0.06 nmol alpha-aminoadipate/mg dry cell weight. This low concentration, the result of adding 0.01 mM DL-alpha-aminoadipate to the medium, was sufficient to reverse the inhibition of penicillin biosynthesis caused by 10 mM extracellular L-lysine. Aminoadipate appears to be recycled during penicillin formation. Labeled alpha-ketoadipate was formed from alpha-aminoadipate to the extent of about 25%.


Inosine nucleosidase from Azotobacter vinelandii. Purification and properties. An enzyme catalyzing the hydrolysis of purine nucleosides was found to occur in the extract of Azotobacter vinelandii, strain O, and was highly purified by ammonium sulfate fractionation, DEAE-cellulose chromatography, hydroxylapatite chromatography and gel filtration on Sephadex G-150. A strict substrate specificity of the purified enzyme was shown with respect to the base components. The enzyme specifically attacked the nucleosides without amino groups in the purine moiety: inosine gave the maximum rate of hydrolysis and xanthosine was hydrolyzed to a lesser extent. The pH optimum of inosine hydrolysis was observed from pH 7 to 9, while xanthosine was hydrolyzed maximally at pH 7. The Km values of the enzyme for inosine were 0.65 and 0.85 mM at pH 7.1 and 9.0, respectively, and the value for xanthosine was 1.2 mM at pH 7.1. Several nucleotides inhibited the enzyme: the phosphate portions of the nucleotides were suggested to be responsible for the inhibition by nucleotides. Although the inhibition of the enzyme by nucleotides was apparently non-competitive type with respect to inosine, allosteric (cooperative) binding of the substrate was suggested in the presence of the inhibitor. The physiological significance of the enzyme was discussed in connection with the degradation and salvage pathways of purine nucleotides.


[The influence of umbilical cord structure on the course of pregnancy and parturition (author's transl)]. A series of 549 not selected placentas and umbilical cords were examined to show the influence of the different development of the umbilical cord structure on the umbilical cord perfusion and the course of parturition. For this purpose the quantity of Wharton's jelly, the spiraling of the umbilical vessels as well as the length of the cord are defined. At the same time anatomical pecularities and complications like umbilical cord torsions and true knots are considered. To judge the decisive condition of the newborn and with that the course of parturition, the pH-value of umbilical artery blood is determined. The analysis results that umbilical cords with much Wharton's jelly and with spiraling vessels are converted into an association with extremely better value than those with little jelly and less spiraling vessels. Short and rich jellied umbilical cords show a significantly lower incidence of loops around the fetal body. A similar trend can be demonstrated for umbilical cords with strong spiraling arteries. Rare phenomena like velamentous insertion, haematomas, edemas and true knots of the cords etc. proved to have no influence on the course of parturition in our relatively small examination series.


Effects of group systematic desensitization on female orgasmic dysfunction. This study investigated the impact of group systematic desensitization (SD) on varied aspects of sexual functioning in primary and secondary nonorgasmic women. After serving as their own controls, 22 women (eight primary, 14 secondary) received 15 sessions of group SD using four common hierarchies of sexual scenes. The measures were administered to each subject and her regular sex partner at each of the testing periods. Significant positive treatment effects were found on measures of general and specific sexual adjustment and in extracoital orgasmic frequency. Treatment also enhanced sexual communication among subjects and their partners, increased the females' acceptance of their mates as being satisfactory sexual partners, and increased the females' self-acceptance as sexual beings. All but one of the treatment effects (degree of pleasure experienced during extracoital stimulation) were maintained at the 6-week follow-up. Secondary subjects reported significantly greater pleasure from coital and extracoital stimulation and significantly increased frequency of orgasm in response to extracoital stimulation than primary subjects. Primary and secondary subjects did not differ in their evaluation of the experiment. The need for controlled comparative treatment investigations is stressed.


Detoxication methods for bromureide poisoning. Comparison of haemodialysis, haemofiltration and haemoperfusion on bastard dogs. The efficiency of different detoxication methods for Carbromal intoxications was evaluated on bastard dogs using haemofiltration, haemodialysis and haemoperfusion with coated charcoal and polystyrene resins. Clearance rates and eliminated amounts of Carbromal and bromine were compared. Haemoperfusion is most effective in the elimination of Carbromal and haemodialysis for removal of bromide ions. Haemofiltration was least effective for both and should therefore not be used for the treatment of Carbromal intoxications.


[On the toxicology of carbromal. IV. Binding of carbromal and its hypnotically active metabolites to human plasma proteins (author's transl)]. The binding of carbromal and its metabolites bromoethylbutyramide and ethylbutyrylurea to human plasma proteins was investigated in vitro by use of Sephadex-gelfiltration, equilibrium dialysis and ultrafiltration. No differences appeared in the binding characteristics of human plasma and of human albumine. In a concentration range between 3.10-8 and 1.5.10-6 moles/ml about 40% of the carbromal, and in a concentration range between 3.10-8 and 1.10-5 moles/ml about 30% of the bromoethylbutyramide are bound to plasma proteins. Proteinbinding of ethylbutyrylurea was found to be less than 5%. The binding constants, Ka, to human albumine and the binding energies deltaF 0 were found to be in the range of 0.5--1.2.10(3) L/Mol and 1.7--4.4 kcal/Mol, respectively. Protein binding of carbromal, bromoethylbutyramide, their chlorinated analgous compounds, chloroethylbutyrylurea and chloroethylbutyramide, and of ethylbutyrylurea is strongly correlated to the partition coefficients of these compounds between n-octanol and water, indicating that the intensity of proteinbinding depends on the hydrophobic character of the substances tested.


Behavioral sequelae of closed head injury. A quantitative study. We determined the profile of behavioral disturbance in relation to closed head injury of graded severity. Patients with severe injuries, as defined by duration of coma and the presence of neurological deficit, were differentiated from a group of mildly injured patients by behavioral ratings that reflected cognitive disorganization, emotional withdrawal, and motor retardation. Neurologic measurements of injury related to the severity of behavioral disturbance included hemiparesis, aphasia, and abnormalities on computerized axial tomography. Agitation during the acute phase of injury was also predictive of residual behavioral disturbance. Hemispheric lateralization of the site of greatest injury had no discernible effect on behavioral sequelae.


Premedication with lorazepam for bronchoscopy under general anaesthesia. Lorazepam 3 or 4 mg i.m. was given to 100 patients as premedication before bronchoscopy under thiopentone-suxamethonium anaesthesia. Forty-nine of the patients assessed as anxious received oral lorazepam as preoperative night sedation also. Lorazepam was an effective night sedative. Forty-two of the 49 patients slept well and were calm and co-operative in the morning. Following the i.m. injection of lorazepam, 64% of patients had complete lack of recall for 4--10 h following premedication. Only 5% recalled correctly a simple objective test of memory initiated in the anaesthetic room. The frequency of recall was higher in those who consumed alcohol regularly and in females. There was one case of awareness during bronchoscopy in a patient who received only a small dose of lorazepam (2.8 mg per 70 kg). Side-effects were minimal and patient acceptance was impressive. These results show an advance on previous studies using pethidine and diazepam. Further improvement is needed, particularly in adjusting the dose of lorazepam to body weight and to factors such as age, sex and alcohol intake.


Effect of intravenous infusion of betasympathomimetic agents on plasma renin activity during pregnancy. The plasma renin activity (PRA) was measured in 26 pregnant patients before and during ritodrine infusion (10 patients), during isoxsuprine infusion (12 patients), and during glucose infusion (4 control patients). All patients were in the third trimester of pregnancy, not in labour and not hypertensive. A low dose of ritodrine, a beta2 adrenergic agent, caused a rise of PRA but no simultaneous rise in heart rate; this suggests that beta2 activity is involved in renin release. Normal doses of ritodrine and isoxsuprine increased the maternal heart rate to 110 to 120 beats/minute and also doubled the PRA level. Two hours after the end of the ritodrine infusion the PRA level was still above that before the infusion. The results suggest high reserves of renin during pregnancy.


Absorption of magnesium by the young steer. 1. Steers with rumen and simple duodenal cannulas were allowed to graze pasture or were given diets of dried grass or flaked maize with or without hay. For an experiment a solution or suspension of magnesium chloride, polyethylene glycol (molecular weight 4000) and either 144Ce (as cerous chloride) or chromic oxide was added to the rumen with a morning feed. Conditions in the rumen were sometimes modified by adding sodium chloride or hydrochloric acid. 2. Changes in magnesium:marker in samples of strained rumen contents with time interval after adding the dose were due partly to changes in Mg distribution between different phases. Results indicated, but not unequivocably, that negligible amounts of Mg were absorbed in the first few hours. 3. Relative recoveries of Mg and markers at the duodenum indicated that proportions of Mg intake absorbed (net) varied from approximately zero for pasture to 0.2--0.5 for flaked maize. Significant correlations between absorption efficiency and sodium:potassium in rumen contents (positive) and rumen pH (negative) were observed. 4. Steers with simple duodenal and re-entrant ileal cannulas were given a diet of flaked maize and hay supplemented with different amounts of magnesium oxide. Little net change in Mg relative to an unabsorbed marker was found between these sites even for a diet containing an Mg supplement of 8 g/kg dry matter.


Electrophoretic mobilities and diffusion coefficients of hemoglobin at high pH. Diffusion studies by photon correlation of scattered laser light confirm the dissociation of the tetrameric form of human carboxyhemoglobin to dimers above pH 10 and provide new estimates of the subunit dissociation equilibrium constants in this pH range. Electrophoretic light-scattering experiments under the same conditions reveal that the electrophoretic mobilities of tetramers and dimers are indistinguishable to within instrumental resolution (ca. 7% in these experiments). The data imply an increase of the electrical charge on the dimer of at least 2.8 to 4.4 net negative charges upon dissociation. Mechanisms for the accumulation of negative charge by the dimer upon dissociation of the tetramer are proposed.


The polymorphic phase behaviour of phosphatidylethanolamines of natural and synthetic origin. A 31P NMR study. 1. The polymorphic phase behaviour of aqueous dispersions of phosphatidylethanolamines isolated from human erythrocytes, hen egg yolk and Escherichia coli have been investigated employing 31P NMR techniques. All species exhibit well defined, reversible bilayer to hexagonal (H11) phase transitions as the temperature is increased. The temperatures at which these transition take place (10, 25--30 and 55--60 degrees C for erythrocyte, egg yolk and E. coli phosphatidylethanolamine, respectively) are sensitive to the fatty acid composition, occurring at a temperature up to 10 degrees C above the high temperature end of the hydrocarbon phase transition as detected by differential scanning calorimetry. In some cases the bilayer to hexagonal (H11) transitions may also be detected employing calorimetric techniques. 2. The addition of equimolar concentrations of cholesterol to these naturally occurring phosphatidylethanolamines does not dramatically affect the bilayer-hexagonal (H11) transition temperature, producing changes of up to 10 degrees C. 3. 18 : 1t/18 : 1t phosphatidylethanolamine undergoes the bilayer to hexagonal (H11) phase transition as the temperature is increased through the interval 50--55 degrees C. Alternatively, hydrated 12 : 0/12 : 0 phosphatidylethanolamine remains in the bilayer phase at temperatures up to 90 degrees C (50 degrees C above the hydrocarbon phase transition temperature). 4. The presence of 100 mM NaCl or 10 mM CaCl2 in aqueous dispersions of egg yolk phosphatidylethanolamine does not alter the temperature-dependent polymorphic phase behaviour significantly. However, at 40 degrees C, increasing the p2H above 8.0 results in progressive inhibition of the hexagonal (H11) phase and the appearance of a phase possibly of cubic structure at p2H 9.0. At p2H 10.0 the bilayer phase is preferred. 5. It is suggested that in biomembranes containing phosphatidylethanolamine as a majority species (such as that of E. coli) the fatty acid composition may primarily reflect the need to maintain bilayer structure. Alternatively, it is pointed out that in mammalian membranes such as that of the erythrocyte, phosphatidylethanolamine tends to destabilize bilayer structure. The resulting possibility that transitory non-bilayer lipid configurations may occur may be directly related to many important properties of biological membranes.


Bacteriorhodopsin vesicles. An outline of the requirements for light-dependent H+ pumping. A systematic study was performed to determine under which conditions bacteriorhodopsin can be applied as an energy generator in reconstituted systems. It is concluded that reconstitution of an active light-driven proton pump is possible over a wide range of conditions. High extents (per bacteriorhodopsin molecule) of proton uptake by reconstituted vesicles are found at a high lipid to protein ratio, after long sonication and at high pH. No active proton pump is obtained if reconstitution is attempted at high pH with neutral phospholipids or at low ionic strength with negatively charged lipids. Attention was also paid to the requirement of a crystalline array for active pumping; most likely, monomeric bacteriorhodopsin molecules can effectively pump protons.


Na+-dependent methyl beta-thiogalactoside transport in Salmonella typhimurium. We have studied the role of sodium ions in methyl beta-thiogalactoside (TMG) transport via the melibiose permease (TMG II) in Salmonella typhimurium. TMG uptake via TMG II in anaerobic, straved and metabolically poisoned cells is dependent on an inward-directed Na+ gradient. Cells which have been partially depleted of endogenous substrates show H+ extrusion upon sodium-stimulated TMG influx. Measurements of the electrochemical H+ gradient in cells, starved in different ways for endogenous substrates, suggest that this proton extrusion is probably not linked to the actual translocation mechanism but is the result of metabolism induced by TMG plug Na+ uptake.


Light-induced pH changes inside bacteriorhodopsin vesicles as measured by 31 P NMR. 31P NMR has been used to measure light-induced pH changes inside bacteriorhodopsin vesicles containing entrapped sodium glucose-6-phosphate. Reversible light-induced pH changes were observed at various pH values. The results indicate that our vesicle preparations were not homogeneous with respect to the generation of pH gradients.


Hyperanodic forms of human glucose-6-phosphate dehydrogenase. Pure glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate:NADP+ 1-oxidoreductase, EC 1.1.1.49) is transformed into 'hyperanodic forms' when incubated at acidic pH and in the presence of NADP+ with excess of glucose-6-phosphate or with some 'NADP+ modifying proteins' purified from the same cells. The enzyme hyperanodic forms exhibit low isoelectric point, altered kinetic properties and high lability to heat, urea, and proteolysis. Differences between hyperanodic and native forms of glucose-6-phosphate dehydrogenase are also noted by microcomplement fixation analysis, ultraviolet absorbance difference spectrum and fluorescence emission spectrum. Drastic denaturation of the enzyme by urea and acid treatment did not suppress the difference of isoelectric point between native and hyperanodic forms of glucose-6-phosphate dehydrogenase. From our data we suggest that the conversion into hyperanodic forms could be due to the covalent binding on the enzyme of a degradation product of the pyridine nucleotide coenzyme. This modification could constitute a physiological transient step toward the definitive degradation of the enzyme.


Interaction of pyridoxal 5-phosphate with apo-serine hydroxymethyltransferase. The interaction of pyridoxal 5-phosphate with beef liver serine hydroxymethyltransferase (5,10-methylenetetrahydrofolate:glycine hydroxymethyltransferase, EC 2.1.2.1) has been investigated using sedimentation velocity, kinetic and equilibrium techniques. No evidence for an aggregating system could be found in sedimentation velocity experiments in the presence or absence of pyridoxal 5-phosphate. Reassociation of pyridoxal 5-phosphate with apoenzyme and reacquisition of enzymic activity follow identical kinetics. An initial fast step is followed by a second order process with a rate constant of 66 M-1. s-1. A dissociation constant of 27.5 micrometer was obtained from equilibrium studies. No interaction of binding sites was exposed by altering pH or in the presence of glycine or folate. Maxima observed in pH profiles with both binding and reactivation are interpreted as the composite fo two overlapping processes, one of which is ionization of the pyridinium nitrogen of pyridoxal 5-phosphate and the other a functional group on the apoenzyme. Evidence is presented to indicate the necessity for the formation of an enzyme . pyridoxal 5-phosphate Schiff's base complex during catalytic turnover.