Changing pattern of residual tumor in Burkitt lymphoma: findings at autopsy. Autopsies were performed on 47 patients who died of Burkitt lymphoma in Uganda between 1967 and 1971. The patients were separated into four groups based on the duration of survival from the time of diagnosis. Twenty patients survived less than three weeks; all had massive tumors. Six patients died between 10 and 16 weeks after diagnosis, usually from side effects of drug therapy. Of 16 patients who died between 24 and 52 weeks after diagnosis, 13 showed involvement of the central nervous system. Five patients died one year or more after diagnosis; two had a late relapse following a disease-free interval of one and four years, respectively; the other three had survived with clinically apparent tumor that was not responsive to therapy. In recent years, there has been a steady reduction in the proportion of patients showing residual systemic involvement at autopsy. This reduction is balanced by an increase in the proportion of patients with lesions of the central nervous system.


[Disopyramide phosphate: electrophysiological and inotropic effects in isolated cat papillary muscles and comparison with quinidine (author's transl)]. The effects of 4-diisopropylamino-2-phenyl-2-(2-pyridyl)-butyramide monophosphate (disopyramide phosphate; D; 10(-6)--10(-4) M) on transmembrane resting potential, action potential, effective refractory period and twitch tension were simultaneously studied in electrically driven (frequency 1 Hz) papillary muscles isolated from the right ventricles of cats. The experiments were performed at 35degrees C with intracellular glass microelectrodes. Quinidine sulfate (10(-6)--10(-4) M) was used for comparison. D increased the duration of the action potential during phase 3 (90% repolarization) in a concentration-dependent manner. The effective refractory period was prolonged by nearly the same extent whereas the maximal rate of rise of the action potential was reduced. The overshoot was slightly decreased only at 10(-4) M. Resting potential and plateau phase of the action potential were not affected by D. The effects of D on the electrical events were accompanied by concomitant decreases in twitch tension. The effects of quinidine were essentially similar to those obtained with D. It is concluded that the effects of D on dV/dtmax and effective refractory period observed in cat papillary muscle may account for the clinically observed efficacy of D to overcome ventricular arrhythmias. The results suggest also that the mechanism of the ventricular effects of D is similar to that of quinidine.


[Absorption studies with purines. Part 2. In vitro experiments with a diffusion apparatus (author's transl)]. Various purines were investigated with the Desaga Resomat II, their diffusion speed constants calculated according to Stricker and compared with one another. The drugs investigated showed a proportinal relationship between diffusion speed and lipoid solubility. The effect of different membranes on the absorption experiments, with and without applied alternating pressure, was investigated. The results from the Sartorius Absorption Model and the Desaga Resomat II were compared.


Interaction of homopyrimidazole derivatives with biopolymers. II. Binding to chemically modified albumins; attempt to correlate chemical structure and binding affinity. The degree of human serum albumin (HSA) binding for 16 different homopyrimidazole derivatives has been studied. The positions of UV absorption maximum, the corresponding molar extinction coefficients and the binding parameters obtained by equilibrium dialysis experiments at 4 degrees C, in pH 7.35 phosphate buffer, are surveyed. In most cases compounds with high toxicity show low binding tendency. Saturation of the ring system decreases binding, while an increase of the number of double bonds enhances the binding affinity. Important requirements for HSA binding of homopyrimidazole derivatives are the presence of a carbethoxy (or carboxyl) group in position 3 and a C6-methyl group. The highest binding affinity could be demonstrated in the case of MZ 211, an acid-type metabolite of 1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-(1,2-alpha)-pyrimidin-1-ium-methyl-sulphate (MZ 144, Probon). Binding of MZ 144 to chemically modified albumins was studied under standard conditions. Binding studies with acetylated and methylated HSA indicated that the presence of free carboxyl groups is a requirement for binding, while the amino groups play a less important role. More selective chemical modifications of HSA were realised with acetylsalicylic acid, diethylpyrocarbonate (DEP) and o-nitrophenylsulfenyl-chloride (NPS-C1). Modifications with DEP and acetylsalicylic acid result in an increase of affinity in the binding area, probably due to blocking of a particular amino group in the vicinity of the binding site. Histidine residues are believed to be of minor importance in the binding process. When the indole ring is modified with NPS-C1, affinity at the strong binding site is significantly reduced, indicating that the Trp residue must be involved in the binding of MZ 144.


[Kinetics of the anti-staphylococcal activity of bakuchiol in vitro (author's transl)]. The growth curve of Staphylococcus aureus in a liquid medium with and without bakuchiol, the main component of Psoralea corylifolia Linn., has been studied for in vitro evaluation of the antibacterial activity. The dynamics of the antibacterial action has also been studied by finding the generation time and number of generations of the microbial growth before stationary phase is reached. This study of the growth curve of the test bacteria gives in general an accurate method of evaluating the in vitro antibacterial activity of drugs with exact mathematical implications, besides serving also as a means for studying the kinetics as well as the mode of antibacterial action.


[Identification of two S-containing metabolites of 1-allyl-3,5-diethyl-6-chlorouracil in rabbit urine (author's transl)]. The synthesis of 2-14C-1-allyl-3,5-diethyl-6-chlorouracil (2-14C-Aclu; Acluracil) is described. After application in rabbits, 2-14C-Aclu is biotransformed in one S-free major metabolite I and two S-containing minor metabolites II and III, which are more polar than Aclu. The metabolites have been isolated and purified by thick layer-, column- and gaschromatography. With the help of 1N-NMR- and mass spectroscopy, metabolite II could be identified as 1-allyl-3-ethyl-5-(2-hydroxy ethyl)-6-methylmercaptouracil and metabolite III as 1-allyl-3,5-diethyl-6-methylmercaptouracil. The introduction of methylmercapto group (-SCH3) in metabolites II and III represents a new biochemical pathway which to the best of our knowledge has not been reported in the literature up to now.


[Pharmacological studies of a new antitussive, 1-phenethyl-4-hydroxy-salicylamido-4-methyl-piperidine-hydrochloride (S 1592) (author's transl)]. 1-Phenethyl-4-hydroxy-salicylamido-4-methylpiperidine-hydrochloride (S 1592) markedly inhibits coughing induced in laboratory animals by chemical or mechanical irritation of respiratory tract or by electrical stimulation of the superior laryngeal nerve. The drug has low acute toxicity in mice and rats. The new compound possesses bronchodilating and antianaphylactic properties and does not affect gastrointestinal propulsion. Cardiovascular effects are absent.


Protective effect of dexamethasone on enhancement of blood-brain barrier permeability caused by electroconvulsive shock. Penetration of Evans blue from the brain blood vessel into the brain tissue was increased by electroconvulsive shock (ECS), indicating the enhancement of the bloodbrain barrier (BBB) permeability. The staining with Evans blue was most prominent in the thalamus. The enhancement was scarcely observed 60 min after ECS, suggesting that the effect is of a temporary nature. Dexamethasone could protect BBB from its enhancement caused by ECS.


Effects of various amino acids on gastric lesions induced by acetylsalicylic acid (ASA) and gastric secretion in pylorus-ligated rats. The simultaneous oral administration of various amino acids such as L-lysine, L-arginine, L-histidine, L-serine and others at 750, 250 or 83.3 mg/kg in pylorus-ligated rats produced a marked prevention of the gastric mucosal damages caused by oral acetylsalicylic acid (ASA) at 100 mg/kg. In regard with L-lysine and L-arginine, it was assumed that these amino acids might inhibit the ASA-induced gastric lesions through neutralization of acid because of the high alkalinity of these amino acids. In addition, the lesser effect of the hydrochoride salts of these amino acids as compared with the free form on ASA-induced gastric lesions was observed. The other effective amino acids markedly prevented the back diffusion of acid in response to ASA, suggesting as one of the possible mechanisms of lesion formation. However, L-cysteine, which exerted insignificant effect on ASA-induced gastric lesions, also prevented the back diffusion of acid even though the Na+ concentration had not returned to the control level.


Urinary metabolites of 2-formyl-17 alpha-methylandrosta-1,4-diene-11alpha, 17beta-dihydroxy-3-one in the rat. The principal urinary metabolites of 2-formyl-17alpha-methylandrosta-1,4-diene-11alpha,17beta-dihydroxy-3-one (for myldienolone) are 2-carboxy- and 2-hydroxymethyl-17 alpha-methylandrosta-11alpha,17beta-dihydroxy-3-one, whose structures were confirmed by comparing them with synthesized samples.


[Effects of diuretics after pretreatment with reserpine and 6-OH-dopamine (author's transl)]. Experiments were performed on groups of 10 rats each with respect to the influence of systemic denervation by 6-OH-dopamine or reserpine on the diuretic effect of furosemide (3 mg/kg). In order to get a measure for the effectiveness of denervation, the tissue content of norepinephrine in kidneys, submaxillary glands, and hearts was determined by fluorimetric analysis. Neurotransmitter content: Chemical sympathectomy with 6-OH-dopamine resulted in a decrease of tissue norepinephrine down to 25% of the initial value in the kidneys, and down to 29 and 17% in submaxillary glands and hearts, respectively. After reserpine pretreatment the kidney norepinephrine was found decreased down to 28% of the initial concentration. Plasma electrolytes: Pretreatment with 6-OH-dopamine increased the plasma magnesium concentration considerably. Further administration of 3 mg/kg of furosemide had no additional effect. Plasma sodium, however, was significantly decreased, whereas potassium and calcium concentrations remained unchanged. After reserpine administration plasma calcium was found decreased. The effect was additionally enhanced by furosemide. Plasma sodium was found decreased, too, after furosemide, whereas potassium and magnesium remained unchanged after both reserpine and furosemide treatment. Fluid and electrolyte excretion: The diuretic effect of furosemide was not significantly influenced by both 6-OH-dopamine and reserpine pretreatment. In the reserpine pretreatment group, however, post furosemide sodium excretion was significantly increased as compared to the controls. In the 6-OH-dopamine pretreated group furosemide did not result in an enhanced natriuresis. In spite of a comparable depletion of intrarenal neurotransmitter after 6-OH-dopamine and reserpine, the kaliuretic effect of furosemide was obviously different in both groups. Reserpine pretreatment resulted in a decrease of the kaliuretic fuorsemide effect, whereas after 6-OH-dopamine this decrease could not be observed. The post furosemide calcium excretion was significantly increased after reserpine and unchanged after 6-OH-dopamine. Basic magnesium excretion was increased by the factor 2 in both groups, as compared to the controls. Administration of furosemide completely abolished this difference.


[Autoradiographic investigation into the influence of factor XIII on wound healing in the animal experiment (author's transl)]. 1. In Wistar rats pretreated with factor XIII, placebo (human albumin solution), or physiological saline, a muscle wound was produced. For pre- and postlabelling purposes the animals received 3H-thymidine. 2. Autoradiographic and histological examinations revealed wound healing promoting activity of factor XIII from 72 h post operationem onwards. 3. 7 days after surgery, in contrast to the controls, the animals pretreated with factor XIII displayed sturdy, directed connective tissue in the wound bed with ample vascularization. 4. The method with pre- and postlabelling with 3H-thymidine elucidates that wound healing through factor XIII prevailingly occurs by faster fibroblast formation.


[Teratologic studies in rabbits and rats with the morphine derivative codeine (author's transl)]. Codeine was administered to rabbits and rats during the organogenetic phase (days 6--18 and 6--15, resp.) in oral doses of 5, 12.5 and 30 mg/kg and 10, 35 and 120 mg/kg, resp. The tests in rabbits yielded no indication of a teratogenic or embryolethal action of the substance under investigation. Even in the experiments on rats no teratogenicity could be realised. The highest dose of 120 mg/kg led to an increased mortality of rat embryos around the time of implantation. As this dose was toxic even to adult rats the described experiments give no indication of an increased risk during pregnancy.


Metabolic effects and mortality rate in diabetic Chinese hamsters after long-term treatment with 5-methoxyindole-2-carboxylic acid (MICA). Chronic oral treatment of male diabetic Chinese hamsters with 100 mg/kg/day 5-methoxyindole-2-carboxylic acid (MICA) causes a depression of blood glucose in fasted animals and an improvement in the glucose profile in fed animals. Glycogen levels in the liver and body weight are decreased. Treated animals die at a higher rate than do controls. It is concluded that treatment with a potent inhibitor of gluconeogenesis like MICA will not provide a useful tool in managing diabetes.


Dry polyacrylamide batch method for studying drug protein binding. The validity of a new technique for studying drug protein binding is tested. By this gel diffusion or batch method using dry polyacrylamide, sulfadiazine and sulfafurazole are bound by human plasma proteins to the same extent as reported by other authors with different techniques. The binding of warfarin to fresh human plasma was quantitatively less than expected. This might be due to the possibility that other plasma constituents of non-fasted test persons displace warfarin from protein binding sites, since it is bound more in buffer solutions containing physiological concentrations of human albumin. Phenylbutazone displaced warfarin from its binding sites in diluted human serum albumin concentrations. Quinidine was found to be adsorbed by the otherwise inert polyacrylamide gel and the method is therefore not applicable to quinidine binding studies.


[Enteral availability and therapeutic activity of proscillaridin-4'-methyl ether (author's transl)]. 20 cardiac patients with the clinical and radiological signs of heart failure were treated alternately intravenously and orally with proscillaridin-4'-methyl ether in a 2-period change-over procedure. With medium rate full saturation a steady state was maintained under observation of electrocardiographic parameters. The maintenance dose was determined to be 1.00 mg intravenously and 1.71 mg orally. Thus, relative enteral availability was 60%. In 70% of patients cardiac recompensation could be reached only by treatment with proscillaridin-4'-methyl ether. In 9 of 20 patients undesirable side effects consisted of laxative effects.


Digitoxin plasma half-life in the dog after administration of toxic doses. Digitoxin plasma levels were determined in the dog by radioimmunoassy after i.v. infusion of this cardenolide in toxic amounts (388 +/- 13 mug/kg). Plasma values found immediately after the administration of this dose were 588.5 +/- 91 ng/ml and attained very low levels (10 ng/ml) 96 h later. The dominant half-life of digitoxin in the dog was found to be 49.6 +/- 6.5 h, but this value was attained only in the final part of our study. The results found are compared with previous data and controversial aspects are discussed.


[Animal experimental study on spasmolytic and analgesic activities of pramiverine, metamizole and their combination (author's transl)]. In two pharmacological in vivo tests a comparative study was performed on the spasmolytic and analgesic effects of 4,4-diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin), metamizole and a combination of both active principles in equal dose ratio (1 : 1000). The results demonstrated that pramiverine showed a potent spasmolytic effect which was potentiated by the combination with metamizole, and that the positive analgesic effect of metamizole was fully displayed in the combination with pramiverine, but that for pramiverine alone no analgesic effect was detected.


[Experimental studies on pramiverine (author's transl)]. A preventive effect of 4,4-diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) was determined on the experimental gastric ulcer in rats. In 14 patients with duodenal ulcers the maximally stimulated gastric secretion was significantly reduced by 50% after pramiverine, which may serve as a reliable criterium for the evaluation of prospective surgical vagotomy. Electromyographic examinations of stomach and duodenum demonstrated the decrease of spontaneous pressure waves in patients and the pressure increases induced by neostigmine. During hypotensive duodenography without the introduction of a probe, pramiverine by a prolonged reduction of motility permits excellent radiological diagnosis in the duodenum and jejunum.


Toxicological study on pramiverine (author's transl). 4,4-Diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) was investigated alone and in combination (1 + 1000) with N-methyl-N-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)-aminomethanesulfonate (metamizole) in various species for acute toxicity after oral and intravenous administration, for local tolerance and subacute toxicity. In addition, long-term trials and reproduction toxicity studies were performed with pramiverine. Pramiverine was only slightly toxic and was well tolerated locally as an ampoule solution also in combination with metamizole. The acute trials of the two compounds in mice and rats like the subacute study in rats showed that the toxicity of metamizole was not increased by pramiverine. Rats tolerated in the long-term trial all pramiverine doses examined (0.5; 5.0; 50.0 mg/kg), while cholinolytic concomitant effects were observed in dogs under higher doses (5.0 and 20.0 mg/kg). Pramiverine did not have a foetotoxic and teratogenic effect in mice, rats and rabbits. In the perinatal and postnatal experiment in rats no effect on foetal development, viability and growth of the offspring as well as the course of labour and lactation ability of the dams was observed.


[Organ distribution of 14C-pramiverine in the rat]. Distribution of 4,4-diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) following single and repeated i.v. and p.o. administration, resp., has been studied in rats. After i.v. administration, pramiverine is rapidly taken up by tissue. Most organs attain higher concentrations than does the blood plasma, especially the lungs and also kidneys, liver, heart and endocrine organs. After p.o. administration, a marked first-pass effect of the liver is observed. The metabolites thus formed show a somewhat less pronounced affinity for organs and tissues. Higher concentrations are found only in the excretory organs, i.e. liver and kidneys. 14C-Pramiverine is rapidly eliminated, 24 h after application the level of radioactivity has fallen below detection limit. After repeated applications of 14C-pramiverine higher concentrations, as compared to one single administration, were observed only in liver and kidneys, especially after i.v. injection. An organ-specific accumulation of the drug can be excluded. No placental transfer of pramiverine and/or its metabolites could be observed.


[Gaschromatographic determination of pramiverine in body fluids (author's transl)]. A method for the quantitative determination of 4,4-diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) in serum and urine was developed. After the addition of a known amount of a pramiverine homolog as an internal standard the basic pramiverine and standard are separated from acidic and neutral constituents of the sample by the following extraction sequence: Extraction from the alkalized sample into n-hexane/ethyl acetate; reextraction into 0.1 N hydrochloric acid; alkalisation of the hydrochloric acid phase and reextraction into n-hexane/ethyl acetate. The constituents of this final extract are concentrated and separated on an OV 17 silicon oil phase. A thermoionic nitrogen-selective flame ionisation detector was used. The determination limit for 5-ml serum samples is about 0.5-1 ng pramiverine/ml. For samples in the concentration range of 4 ng/ml a relative standard deviation of 12% was found.


[Eosphagomanometric finding in man after intravenous administration of a new cholinolytic (pramiverine), atropine and scopolamine butylbromide]. The tone depressing effect on deglutition peristaltic processes in the esophagus by i.v. application of 4,4-diphenyl-N-isopropyl-cyclohexylamine hydrochloride (pramiverine, Sistalgin) (0.03 and 0.045 mg/kg body weight), atropine (0.5 mg) and hyoscine-N-butylbromide (scopolamine-butylbromide, SBB) (20 mg) was tested on trained subjects. During the first 30 min following the larger dose of pramiverine, the effect is not quite so pronounced as it is seen after the usual atropine dose; from the 30th to the 60th min, however, the tone depressing effect of pramiverine is superior to that of atropine, 1 h after application of pyramiverine the pressure amplitude is still reduced to 54.3% of the initial value, while after atropine the effect has returned to 70.9% of the initial value by this time. Neither atropine nor pramiverine were able to exert a tone depressing effect as pronounced as that of SSB. But 30 min after application of the  effect of SBB was not statistically significant any longer and after 40 min it could not be measured at all. Following atropine and SBB, the side effect of tachycardia was correlated exactly to the main effect tested. Further side effects, such as dryness of mouth and disturbed accomodation, were most pronounced after atropine. With pramiverine at the effective doses of 0.03 and 0.045 mg/kg, the side effects were not appreciable; neither objective measuring nor subjective reports of the subjects indicated any conspicuous deviations.


[The effect of the combination pramiverine/metamizole in colic pain (author's transl)]. A combination of 4,4-diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) and N-methyl-N-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)-aminomethanesulfonate (metamizole) (Sistalgin comp.) was injected in 250 patients with severe colic pain. In 94% of the cases prompt relief from pain was observed. In addition to the reliable effect in colics of the gastrointestinal tract and the biliary duct, the high rate of success in colics of the urinary tracts should be mentioned. Good therapeutic results were also observed in pancreatitis. Only isolated cases of slight undesirable anticholinergic concomitant effects were noted. There was no effect on blood pressure and pulse rate.


Phosphatidylcholine synthesis and pulmonary oxygen toxicity. Oxygen at hyperbaric pressure causes a reduction of lung surfactant and inhibits the synthesis of phosphatidylcholine, the principal component of lung surfactant. Rabbit lung slices and broken cell preparations were used to determine whether phosphatidylcholine synthesis in general is inhibited or whether there is selective inhibition of surfactant dipalmitoyl-glycerophosphocholine synthesis. The incorporations of palmitate, oleate and choline into the phosphatidylcholine of lung slices are reduced to 44, 49 and 45% of the normal, respectively, in animals exposed to 100% oxygen at 3 atm. absolute for 4 h. The similarity of the level of phosphatidylcholine synthesis from these three precursors, as well as of the degree of inhibition, suggests a non-specific mechanism of inhibition of whole cell phosphatidylcholine synthesis. Broken cell preparations of lung incorporate palmitate and oleate into lysophosphatidylcholine at comparable rates when optimal amounts of precursors are used. This system is reduced to 60 and 73% of the normal for palmitate incorporation in homogenates and microsomal fraction, respectively and to 75 and 82% of the normal for oleate incorporation. Although the greater inhibition of palmitate incorporation over that of oleate is not statistically significant, an inhibition of the deacylation-reacylation mechanisms leading to palmitate incorporation may still be implicated as a factor in the toxicity of oxygen for surfactant phosphatidylcholine synthesis in view of the fact that with whole lung preparations, only one-tenth of the pulmonary cell population constitutes the surfactant producing type II alveolar cells (granular pneumocytes).


Inhibition of turnip yellow mosaic virus synthesis by pyrimidine analogues. The pyrimidine analogues 2-thiouracil, 2-thiouridine, 6-azauracil and 6-azauridine all inhibited the synthesis of turnip yellow mosaic virus (TYMV) and increased the synthesis of empty virus protein shells in infected Chinese cabbage leaf discs. Uracil and uridine reversed these effects. 2-Thiouracil also reduced the UTP pool in TYMV infected leaf discs. The results are consistent with the suggestion that these analogues or their in vivo derivatives affect virus synthesis by inhibiting the biosynthesis of uridylic acid, possibly by inhibiting orotidylic acid decarboxylase.


[Factors of post-transcription regulation of the rate of liver catalase synthesis in tumor-bearing rats]. The factors-regulators of post-transcriptional regulation of the rate of catalase synthesis in the rat liver were studied under normal conditions and in carcinogenesis (the 2nd, 7th and the 14th days after the transplantation of Pliss lymphosarcoma). Factors Fact and Fing were purified from the supernatant and PH5-supernatant fractions of the rat liver by means of chromatography and rechromatography on DEAE-cellulose. A simple method of determination of the biological activity of these factors in vivo was proposed. Synthesis of catalase took place when (see article) (the 2nd and 14th days after the inosulation). The enzyme synthesis was absent when (see article) (7th day after the inoculation).


Comparison of intensive versus moderate chemotherapy of lymphocytic lymphomas: a progress report. In an Easter Cooperative Oncology Group trial, Cytoxan-prednisone (CP) Induction was compared to BCNU-prednisone (BP) in 273 patients with lymphocytic lymphoma. Response rates were comparable, with 21% achieving complete response and 40%, partial response. Patients with a nodular pattern responded better. Maintenance phase comparing cyclic intensive therapy (BCVP) with intermittent chlorambucil revealed the superiority of BCVP as demonstrated by improvement of the quality of response and somewhat longer remissions. The value of the Rappaport classification in the evaluation of lymphoma chemotherapy results is discussed. It is suggested tha NHL be separated into "favorable" and "unfavorable" groups, based on the presence or absence of nodularity and treatment schedules devised accordingly.


Conversion of a benign lymphoepithelial salivary gland lesion to lymphocytic lymphoma during dilantin therapy: correlation with dilantin-induced lymphocyte transformation in vitro. A patient with a classical salivary gland benign lymphoepithelial lesion (BLL) that converted to a lymphoblastic lymphoma (LSA) localized to the salivary glands is described. The malignant transformation of the BLL was preceded by Dilantin anticonvulsant therapy, and in vitro tests subsequent to the development of LSA demonstrated positive Dilantin-induced lymphocyte transformation. The lymphoma was treated successfully by local irradiation, chemotherapy, and discontinuation of Dilantin. The case illustrates the "prelymphomatous" nature of BLL in certain patients, as well as the possible potential danger of Dilantin and other lymphoid-stimulating drugs in discussed. Further study of drugs capable lymphocyte transformation in patients with prelymphomatous disorders is warranted.


The pathogenesis of Graves' disease.

The pathogenesis of Graves' disease. Graves' disease may prove to be due to a genetic defect in immune surveillance or control, which then permits a randomly mutating thyroid-directed clone of T-lymphocytes to survive, interact with previously normal thyroid cell membrane antigen, and set up a localized cell-mediated immune response. The T-lymphocytes so interacting then cooperate with and direct groups of B-lymphocytes, which consequently produce TSI's: the stimulation of the thyroid parenchymal cells is a direct result of TSI stimulation. PHA stimulates Graves' lymphocytes to produce TSI's by first stimulating T-lymphocytes, which in turn interact with B-lymphocytes, which produce the TSI's. Normal thyroid antigen can stimulate sensitized lymphocytes to produce TSI's, which in turn can interact with normal thyroid cell membranes. This and other evidence suggests that there need not be any thyroidal antigenic change necessary to initiate hyperthyroidism. Stress may be related to the immunologic induction of the disease; it appears that remissions, other than those due to thyroid cell destruction, are immunologic. Exophthalmos may also prove to be an autoimmune disorder resulting from a closely related, but possibly not identical, defect in immunologic surveillance. Other related autoimmune diseases may result from similar related defects in immunologic surveillance, as well as from the random mutation of the appropriate forbidden clone.


Pulmonary manifestations of Sjögren's syndrome. A review of 343 patients with classic Sjogren's syndrome seen at the Mayo Clinic from 1967 through 1974 revealed pulmonary involvement in 31 patients (9 percent). Cough dyspnea, recurrent pneumonitis, and pleuritic pain were the primary complaints. Chest roentgenographic features included diffuse interstitial patterns, diffuse alveolar patterns, and pleural effusions. Laboratory studies revealed hypergammaglobulinemia in 16 of 22 patients tested, and 23 of the 31 patients had positive tests for anti-nuclear antibody, rheumatoid factor, or lupus erythematosus cells. Pulmonary function tests showed a restrictive ventilatory impairment or low diffusion capacity (or both in all 18 patients studied. Pathologic diagnosis included the full range of pulmonary lesions described in Sjogren's syndrome syndrome, ie, lymphocytic interstitial pneumonitis, pseudolymphoma, malignant lymphoma, diffuse interstitial pulmonary fibrosis, and bronchopneumonia. The clinical pulmonary diagnosis included diffuse interstitial fibrosis, recurrent pneumonitis, pleural effusions, and suspected lymphoma or pseudolymphoma. We conclude that pulmonary lesions occur in Sjogren's syndrome more frequently than previously reported.


A severe infantile micromelic chondrodysplasia which resembles Kniest disease. This paper describes 3 infants with a severe, generalized chondrodysplasia with short limbs, shortness of stature, relative micrognathia and neonatal respiratory distress in all cases, cleft palate in two and dislocation of lenses in one. They died at 7 and 10 weeks and at 17 months respectively. No autopsy was performed on any of the 3 patients. Roentgenological manifestations include short, broad tubular bones with metaphyseal widening, bowing of leg, thigh and forearm bones, neonatal accelerated carpal bone maturation, short, broad pelvis with wide, flared iliac wings, many gross vertebral abnormalities including most prominently coronal clefts of almost any vertebral body, and short ribs with flared anterior ends. Roentgenographically the condition has some similarities with Kniest disease, or more correctly, the Kniest chondrodysplasia. However, we think that the clinical and roentgenological manifestations are sufficiently unique to permit delineation of the condition of our 3 patients as a "new" entity different from the Kniest chondrodysplasia. Similar cases have been described by Rolland et al. from France and by Dinno et al. from the U.S.A. The later case and our 3 patients were sporadic cases, but the former had a probably affected sibling, suggesting that this disorder is an autosomal recessive trait.


Natural antibodies directed against murine lymphosarcoma cells: variability of level in individual mice. Natural anti-tumor antibodies (NAA) were revealed, by a complement-dependent cytotoxicity test on el4 lymphoma cells, in the serum of C3Hf but not of C57BL mice. Hybrids between the positive C3Hf and the negative C57Bl mice were NAA producers. Individual variability of NAA level was found in C3Hf and in the hybrids. The study of mice housed in the same or in different cages and of mice belonging to the same or to different litters demonstrated a randomly distributed variability. These observations seem to exclude environmental influences on the natural immune response or genetic mutations in the C3Hf strain with the appearance of variants with different NAA content. The NAA level was age-dependent with a peak around 20-24 weeks of age. Inoculum of lymphoma cells induced an increase in the NAA level both in C3Hf and in the hybrids but not in C57Bl mice which seem therefore incapable of making guinea-pig complement-fixing NAA. The individual variability of NAA level and the stimulating effect of tumor cells support a potential role of NAA in immunosurveillance of oncogenesis.


Fluidity difference in the surface membrane lipid core of human lymphoblastoid and lymphoma cell lines. Twenty-five human hematopoietic cell lines established from patients with malignant and non-malignant diseases have been studied for membrane fluidity. The degree of fluidity in the surface membranes was quantitatively monitored by fluorescence polarization analysis of the fluorescence probe, 1,6-diphenyl 1,3,5-hexatriene, when embedded in the lipid region of the surface membrane of intact cells. The results have shown that cells derived from malignant diseases have a more fluid lipid layer in their surface membrane than cells derived from non-malignant disorders. It is, therefore, suggested that a quantitative analysis of fluidity differences in the cell surface membrane lipid core can be of value to the studies on basic differences between normal and malignant cell lines established from the human hematopoietic system.


Acute leptomeningeal reaction to the subarachnoid injection of ethyl iodophenylundecylate in dogs. The effects of the subarachnoid injection of ethyl iodophenylundecylate were observed serially in dogs. The results of neurologic examination and cerebrospinal fluid analysis as well as the gross and histologic apppearance of the brain and spinal cord were evaluated. In 8 dogs, progressive nonpurulent leptomeningitis peaked in 5 days and regressed thereafter. The reaction appeared to be related to the physical properties of ethyl iodophenylundecylate.


Lymphocyte transformation in response to human thyroid extract in patients with subacute thyroiditis. Seven patients with subacute thyroiditis were studied for evidence of cell-mediated immunity (CMI) to human thyroid extract, as judged from lymphocyte transformation responses, measured by the increase in labeled thymidine uptake in vitro. Significant transformation was observed in lymphocytes from five of the seven patients with active subacute thyroiditis, and in the lymphocytes from only three of 15 patients with Graves disease (x2, P EQUALS 0.036). Repeated studies of lymphocyte transformation were done in four of the patients with subacute thyroiditis, three of whom initially showed abnormal responses. By eight weeks after initial studies, when all patients were in clinical remission without treatment, transformation responses were within the normal range. Thyroid antibodies were absent or present in low titer (is less than 1:100) in sera of patients with subacute thyroiditis, and became undetectable by eight weeks in those patients initially positive. In contrast, significant titers of antithyroid antibodies were frequently present in patients with Graves' disease. The present studies have shown the occurence of CMI to thyroid antigens during the active phase of subacute thyroiditis. The abnormality was transient, however, since it disappeared when the disease had resolved. These findings strongly suggest that the release of thyroid antigen leading tothe development of a cell-mediated immune responses is not in itself sufficient to initiate chronic immunological disease of the thyroid. If, as some have suggested, Hashimoto's disease or Graves' disease are characterized by a permanent disorder of CMI, then in these diseases either the antigenic stimulus is persistent or there exists an intrinsic disorder of immune surveillance.


Sensitivity to lithium in treated Graves' disease: effects on serum T4, T3 and reverse T3. Seven patients judged to be euthyroid following treatment of diffuse toxic goiter were studied to determine if they were susceptible to lithium induced hypothyroidism. Lithium carbonate was administered for 4-7 weeks in a dosage (900 mg/day) which maintained serum lithium levels between 0.5-1.0 mEq/l. Blood was obtained weekly for the determination of serum 3,5,3'-triiodothyronine (T3), thyroxine (T4), 3,3',5'-TRIIODO-L-thyronine (reverse T3, rT3) and thyrotropin (TSH). Values observed during lithium therapy were compared to those obtained prior to, and approximately one week after discontinuing lithium. During the pretreatment preiod, mean (+/- SE) serum T3, T4, and rT3 concentrations were 130 +/- 21 ng/100 ml, 7.6 +/- 0.4 mug/100 ml and 48 +/- 8 ng/100 ml, respectively, and decreased during lithium administration with the lowest T3, T4 and reverse T3 concentrations of the lowest T3, T4 and reverse T3 concentrations of 92 +/- 8 ng/100 ml, 4.9 +/- 0.6mug/100 ml, and 33 +/- 6 ng/100, ml, respectively, being reached between the fourth and sixth weeks of study. Thereafter, and in spite of continued treatment with lithium, values for serum concentrations of T3, T4, and rT3 plateaued, or actually increased in 4, 6, and 5 subjects, respectively. Serum TSH concentrations remained 3.0 muU/ml or less throughout the study in 6 patients; 2 of these subjects had no TSH response to thyrotropin-releasing hormone (TRH), even though they had been euthyroid for 3 and 10 months. These data suggest that patients euthyroid following treatment of diffuse toxic goiter display sensitivity to the antithyroid effects of lithium. Furthermore, these observations support the thesis that the inhibitory effects of lithium and iodine upon thyroid hormone synthesis or secretion may involve a similar mechanism of action since increased thyroidal iodine content may be a consequence of therapy with either agent.


Cytochemical observations on the extracellular carbohydrate produced by Streptococcus cremoris. Electron microscopy showed that a varying proportion of cells of Streptococcus cremoris NCDO 924 grown in autoclaved skim-milk possessed a layer of extracellular material attached to the cell wall. Occasional filamentous extensions of this layer made contact with neighbouring casein micelles. The same surface-staining material persisted during the production of cheese-curd, but after maximum scald it was predominantly filamentous in appearance. These filaments made frequent contact with the adjacent curd matrix and with milk-fat globules. Str. cremoris NCDO 1986 produced similar surface material when in curd, but not when grown in skim-milk. In all situations, the extracellular material stained with colloidal iron hydroxide, ruthenium red and periodic acid-thiosemicarbazide-silver proteinate, indicating that it was largely composed of an acidic carbohydrate. It is suggested that this carbohydrate facilitates the adhesion of starter bacteria to the cheese-curd matrix and that during the initial stages of syneresis this serves to prevent their expulsion from the curd with the whey.


Pulmonary arterial thrombo-embolism and pulmonary arterial mycotic aneurysms in cattle with vena caval thrombosis: a condition resembling the Hughes-Stovin syndrome. Sixteen cattle affected by thrombosis of the posterior vena cava were examined post mortem and the various lesions are described. The thrombus was in the hepatic portion in 12 animals and in the intrathoracic part in four. Thrombi had formed as a result of phlebitis in 13 cases in which hepatic or post-diaphragamatic abscesses were present but the aetiology of the other three was not discovered. Embolism from the vena cava thrombus resulted in pulmonary lesions in every case: these included pulmonary arterial thrombo-embolism, pulmonary arteritis, pulmonary endarteritis, chronic suppurative pneumonia and the formation of multiple pulmonary abscesses. The pulmonary arterial lesions had given rise to mycotic aneurysms of that vessel and rupture of these was followed by massive haemoptysis or intrapulmonaary haemorrhage. Pulmonary arterial aneurysms are not common in man and are very rare in animals, except in association with vena cava thrombosis of cattle. However, the "Hughes-Stovin" syndrome of man has some features in common with the condition described in cattle and these are discussed. The different sequelae of posterior vena cava thrombosis and infective endocarditis of the right heart in cattle are also considered.


Myelography wiht perfluoroctylbromide. Comparison with Pantopaque. The efficacy and toxicity of perfluoroctylbromide in myelography were studied in dogs. Perfluoroctylbromide moves freely in intrathecal space and provides satisfactory radiopacity for diagnosis of subarachnoid structures. The outstanding feature of this substance is its low toxicity. The dog tolerates 0.5-1.0 ml/kg intrathecally without toxic manifestation. Histological studies and CSF analyses show that it is much less irriating than Pantopaque. Because of the long retention of the perfluorocarbon removal may be necessary. Perfluoroctylbromide shows promise as a diagnostic contrast medium, particularly in cases where the currently available contrast media are not suitable.


Carbohydrate homeostasis in chronic lymphocytic thyroiditis: increased incidence of diabetes mellitus. Twenty-one patients were seen with the diagnosis of chronic lymphocytic thyroiditis in the Endocrine Clinic during 1965-1972. Three patients developed clinical diabetes mellitus at intervals from one month to three years after the diagnosis of thyroiditis was confirmed. An additional patient, a member of the study group reported here, had asymptomatic glucose intolerance initially and developed insulin-dependent diabetes mellitus six months after the diagnosis of thyroiditis was established. Standard glucose tolerance tests were performed on 12 additional patients. One of these patients had unequivocal evidence of chemical diabetes; one other had a borderline abnormal oral glucose tolerance test. The remaining ten patients had normal glucose and insulin values during the OGTT. These studies indicate that children with chronic lymphocytic thyroiditis are at increased risk of developing diabetes mellitus when compared with the normal childhood population.


Fear appeals and attitude change: effects of a threat's noxiousness, probability of occurrence, and the efficacy of coping responses. Three factorial experiments examined the persuasive effects of the noxiousness of threatened event, its probability of occurrence, and the efficacy of recommended protective measures. A total of 176 students participated in separate studies on the topics of cigarette smoking, driving safety, and venereal disease. The results disclosed that increments in the efficacy variable increased intentions to adopt the efficacy variable increased intentions to adopt the recommended practices. Interaction effects revealed that when the preventive practices were effective, increments in the noxiousness and probability variables facilitated attitude change; however, when the coping responses were the preventive practices were effective, increments in the noxiousness and probability either had no effect or a deleterious effect, respectively. These interaction effects were discussed in terms of a defensive avoidance hypothesis, the crucial component of which was an inability to ward off the danger. Furthermore, the effect of the emotion of fear upon intentions was found to be mediated by the cognitive  appraisal of severity of the threat. Finally, similarities with and extensions of previous studies were reviewed.


Nonfatal cervical spine injuries in interscholastic football. The incidence of nonfatal neck injuries in high school football was determined by performing preseason examinations in 104 active high school players and 75 college freshman candidates. Coaches of all 430 Iowa high schools were asked to recall the number of players experiencing significant neck pain during the season. A detailed questionnaire for each injury was also completed by a sample population of 60 coaches. The incidence of roentgenographic evidence of neck injuries was as high as 32% and was related to years of experience. Injury was most likely to occur to a linebacker or a defensive halfback when they tackled the ball carrier. In the preseason examination, half the players who volunteered a history of significant neck pain had abnormal x-ray films.


Cough-induced cardiac compression. Self-administered from of cardiopulmonary resuscitation. Eight patients undergoing coronary angiography were successfully resuscitated from ventricular fibrillation (VF), and three of these patients remained conscious and alert for 24 to 39 seconds after VF by coughing every one to three seconds. The mean aortic systolic pressure induced by cough was 139.7 mm Hg (+/- 3.8) and only 60.7 mm Hg (+/- 5.1) by external cardiopulmonary resuscitation (CPR). Cough-CPR, accomplished by abrupt, forceful coughing maintains consciousness by rhythmic compression of the heart, has several advantages over external CPR in the catheterization laboratory, and may be applicable to other situations where serious rhythm disturbances are recognized before unconsciousness occurs.


Clinical decision analysis. The hazard of using additional data. Acquisition of laboratory data bearing on a clinical problem may make patient care worse rather than better. The hazards of obtaining new information, that go beyond the monetary costs and risks to physical well-being, are frequently not appreciated by physicians. In the complex and many-faceted practice of medicine, intuition, even when expressed by experienced clinicians, may lead to faulty judgments. Decision analysis gives a systematic exposition of clinical management, and lessens, if not eliminates, the influence of biased and unreliable intuition. With practice, most physicians could employ decision analysis to help solve moderately complicated problems at the bedside or in the office. Use of this tactic will make gaps in knowledge explicit, and may thereby stimulate investigations to ensure better clinical judgments in the future.


Fever--a manifestation of preleukemia.

Fever--a manifestation of preleukemia. A patient had a preleukemic syndrome in which the major manifestation was a chronic relapsing fever over an 18-month period. A review of the literature shows that fever may be present in a considerable number of patients with preleukemia.


Gonorrhea in preschool- and school-aged children. Report of the prepubertal gonorrhea cooperative study group. Single-dose antibiotic therapy was evaluated in 108 episodes of culture-confirmed, uncomplicated gonorrhea in 100 prepubertal children. There were 15 boys and 85 girls between 14 months and 14 years of age. Penicillin G procaine, 100,000 units/kg intramuscularly, was compared with amoxicillin trihydrate, 50 mg/kg orally. Probenecid, 25 mg/kg, was given simultaneously. Both drugs provided prompt bacteriological and clinical response. Multiple episodes of gonorrhea, presumably caused by reexposure, occurred in six girls. Oral and anal cultures were negative in all of 47 Costa Rican cases but were commonly positive in US children. Anal cultures yielded gonococci in 52% of girls and 25% of boys, and oral cultures were positive in 18% and 13%, respectively. In three instances, rectal cultures confirmed the diagnosis when vaginal cultures were negative. Gonorrhea should be considered in every child with vaginal or urethral discharge. Single-dose penicillin-probenecid or amoxicillin-probenecid treatment is curative.


Randomized prospective trial of continuous vs intermittent heparin therapy. Forty-one patients with clinical indications for heparin therapy were randomized to receive continuous intravenous heparin sodium therapy or intermittent (four-hourly bolus) heparin therapy, with control by the activated partial thromboplastin time. Seven of 21 patients receiving intermittent therapy had major bleeding episodes, whereas none of the 20 patients receiving continuous heparin therapy had major bleeding (P = .005). One patient on continuous therapy had a pulmonary embolus, while none on intermittent therapy had recurrent thromboembolism. Two heavily bleeding patients on intermittent therapy were switched to continuous treatment after bleeding was controlled. The use of continuous heparin therapy appears significantly safer with regard to hemorrhagic complications than the use of intermittent therapy.


Capillary abnormalities in polyvinyl chloride production workers. Examination by in vivo microscopy. Examination by wide-field capillary microscopy of the hands of 152 workers in vinyl chloride (VC) polymerization plants demonstrated scattered, scleroderma-like microvascular abnormalities in 21 workers and isolated capillary abnormalities in 27, as compared with only three isolated abnormalities in 50 manual workers not exposed to vinyl chloride. Thirteen of 17 VC workers with objective evidence of VC-associated abnormalities (angiosarcoma or fibrosis of liver, acroosteolysis, or scleroderma-like skin lesions) were observed to have microvascular abnormalities. If prospective studies confirm the implications of this study, capillary microscopy may become a useful mass-screening procedure in the early detection and prevention of VC-associated disease.


Drug addiction among physicians. The Virginia experience. Drug addiction among physicians appears to be an occupational hazard, with chronic pain, depression, and the easy availability of drugs major factors leading to addiction. In this study of 46 cases of physician addicts handled by the Virginia State Board of Medicine, meperidine hydrochloride (Demerol) was the most frequent addictive agent. The Virginia disciplinary and therapeutic plan for addicted physicians was effective in successfully rehabilitating and returning to medical practice 72% of the 46 physician addicts reported to the board from 1949 to 1974.


Immunological impairment and susceptibility to infection after splenectomy. Asplenic patients or those who have undergone splenectomy are prone to overwhelming and often fatal sepsis, which is sometimes associated with disseminated intravascular coagulopathies. Although several pathogens are involved, the most common organism found in these subjects is the pneumococcus, and the infections respond poorly to antibiotic therapy.


Tooth fragments lodged in unexpected areas. Broken, lost, swallowed, or aspirated teeth can be a hazard in dental and medical practice. Because of the magnitude of soft-tissue trauma associated with minor tooth fracture, the physician may be the first to see the child. Every attempt should be made to locate the missing tooth structure before the wound is closed. This can be accomplished through a detailed history of the accident, careful examination, and roentgenograms, if necessary. Three cases are reported in which tooth fragments were imbedded in wounds.


Proximal myopathy caused by latrogenic phosphate depletion. Severe proximal myopathy associated with hypophosphatemia developed in three patients with chronic renal failure who had been treated with aluminum hydroxide gel. The syndrome was characterized by severe pain, muscular stiffness, and weakness. The illness was originally misdiagnosed both as uremic myopathy and as an exacerbation of rheumatoid arthritis. In one patient, the correct diagnosis was made when symptomatic relief corresponded to the rise of serum phosphate levels. Discontinuation of antacid therapy was followed by gradual recovery. Oral sodium phosphate brought prompt alleviation of muscular pain and stiffness.


Rifampin, oral contraceptives, and pregnancy. Rifampin is a drug used in the treatment of tuberculosis. In the literature, there are reports of seven patients who became pregnant while taking a combination of rifampin and oral contraceptives. We report an eighth case involving a woman who became pregnant twice on this drug combination.


Midtrimester amniocentesis for prenatal diagnosis. Safety and accuracy. This prospective study of the safety and accuracy of midtrimester amniocentesis involved 1,040 subjects and 992 controls. Immediate complications of amniocentesis (vaginal bleeding or amniotic fluid leakage) occurred in approximately 2% of the women. There was no statistically significant difference between the two groups in rate of fetal loss (3.5% for the subjects, 3.2% for the controls) or incidence of complications of pregnancy of delivery. Newborn examination indicated no significant differences between the two groups in incidence of congenital anomalies and no evidence of physical injury resulting from amniocentesis. The two groups did not differ significantly in physical, neurological, or developmental status at one year of age. Diagnostic accuracy was 99.4%. Midtrimester amniocentesis is a highly accurate and safe procedure that does not significantly increase the risk of fetal loss or injury.


Mortality in patients treated for pulmonary embolism. The hospital course of 144 consecutive patients with pulmonary embolism (PE) demonstrated by pulmonary angiography was reviewed to determine the mortality of patients with treated PE. Twelve patients (8%) died of PE, and eight died of causes other than PE; 124 (86%) survived. Pulmonary embolism was the primary cause of death in only four of the 12 patients who died of PE. Pulmonary embolism contributed to the death of eight other patients, each of whom had associated potentially lethal disease, particularly heart disease. The most important factor affecting mortality was shock due to acute right ventricular failure secondary to massive PE (mortality, 32%). Mortality was not related to magnitude of PE per se; the mortality of patients with massive PE without shock (6%) was the same as that for patients with submassive PE (5%. Patients with PE who survive long enough to have the diagnosis established and appropriate prophylactic therapy begun have an excellent prognosis, unless they have associated severe medical disease.


Continuing medical education. The philosphy and use of audit. In 55 audits of 37 topics totaling 5,499 patient records, 94% of deficiencies were in the area of performance, while only 6% occurred in the area of lack of knowledge. In addition to defining problems, audit serves as an educational experience and a stimulus to improve practice.


Infectious mononucleosis. Death due to agranulocytosis and pneumonia. Infectious mononucleosis (IM) is usually considered a benign disease. Agranulocytosis developed in a young college student 14 days after the onset of IM. Fulminant staphylococcal pneumonia and bilateral pulmonary infarcts resulted, and the patient died 4 1/2 hours after admission to a hospital. Agranulocytosis secondary to IM may be more prevalent than previously thought. A review of the literature indicated that infection developed in 57.9% of the patients with IM and extreme neutropenia and 45.4% of the infected patients died.


Chronic urticaria and intermittent anaphylaxis. Reactions to lophendylate. In a case of chronic, severe urticaria and intermittent episodes of anaphylaxis due to an iophendylate injection (Pantopaque) given in the course of myelography, almost complete relief was obtained from the removal of approximately 8 ml of residual iophendylate from the spinal canal. Data obtained from direct skin testing, Prausnitz-Küstner testing, peptide inhibition of Prausnitz-Küstner testing, and IgE levels quantitated before and after removal of iophendylate indicate that these symptoms were mediated via an IgE anti-iophendylate reaction.


Mitral valve repair for patients with pure mitral insufficiency. 1- to 15-year follow-up. Mitral valve repair rather than replacement was performed in 133 of 183 patients (73%) with considerable mitral valve insufficiency requiring surgery. There were seven operative deaths (50%) and 16 late deaths in the 133 patients followed up from 1 to 15 years. Only four of the late deaths were possibly related to the underlying valvular heart disease. Repair is preferable to replacement with present-day mitral valve prostheses.


Abnormal aminopyrine metabolism in patients with hepatic neoplasm. Detection by breath test. Aminopyrine metabolism was assessed by the aminopyrine breath test (ABT) in 153 patients with malignant disease, of whom 75 had hepatic neoplasm and 78 had none. Radioactive carbon dioxide (14CO2) exhalation was measured two hours after oral administration of a trace dose of carbon-14 labeled aminopyrine. The ABT was correct in 62 of 75 (83%) patients with hepatic neoplasm and in 73 of 78 (94%) patients without. It  was correct in 16 of 22 (73%) patients who had hepatic neoplasm without abnormal serum biochemistry. Aminopyrine metabolic clearance rate (AMCR) was 32.4 ml/min in patients with hepatic neoplasm and 103.4 +/- 18.8 ml/min in the patients without. There was a highly significant correlation between ABT and AMCR (r =.76, P less than .01). We conclude that aminopyrine metabolism is depressed in most patients with hepatic neoplasm and that the ABT affords a useful method for detecting malignant tumors of the liver.


Gaps--anionic and osmolal.

Gaps--anionic and osmolal. Gaps is a bedside diagnostic game. It is played in two versions by nephrologists. It deserves wider application by the practicing physician. The more popular version, Anion Gaps, shows the presence of undetermined anions and alerts the physician to the possibilities of laboratory error, severe derangements in serum protein metabolism, or the ingestion of certain ionic compounds that directly or indirectly alter the concentration of routinely undetermined anions. A second version, Osmolal Gaps, shows the presence of unmeasured osmoles or of increased plasma solids and can be used in a variety of clinical situations to direct attention to laboratory, error, hyperproteinemia, hyperlipidemia, or the presence of unmeasured osmoles in the serum.


Unusually high levels of blood alcohol?

Unusually high levels of blood alcohol? A consecutive three-month study of alcohol-intoxicated patients admitted to the casualty ward showed 24 patients with an initial serum alcohol concentration above 110 millimols/liter. Eight patitents were excluded because of insufficient data. Eight of the remaining 16 patients showed surprisingly slight depression of the central nervous system (CNS).


Colitis and hepatitis caused by methyldopa. Acute, severe colitis and hepatitis developed in a 55-year-old man on two occasions in relation to administration of methyldopa. He also had fever, skin rash, and eosinophilia, suggesting drug allergy. All symptoms and signs remitted after he stopped taking the drug. It appears that this agent is capable of producing acute colitis as well as the previously recognized hepatitis.


Failure of vancomycin treatment in Staphylococcus aureus endocarditis. In vivo and in vitro observations. In a case of staphylococcal endocarditis, we failed to eradicate Staphylococcus aureus from the blood stream with vancomycin hydrochloride therapy. The strain involved was sensitive to vancomycin by disk diffusion studies but showed a wide disparity between minimal inhibitory and minimal bactericidal concentrations. The lack of a bactericidal effect was probably responsible for the failure of treatment. A synergistic effect was demonstrated for the combination of gentamicin sulfate and methicillin sodium, and the patient was ultimately cured with this combination plus vancomycin. Bactericidal tests are important in choosing an antimicrobial agent for treatment of endocarditis.


[Non-pigmented extrabulbar sarcomas of the eye-region (author's transl)]. The authors report on 30 cases with non-pigmented extrabulbar sarcomas of the eye-region which occurred in our clinic within the period of 1955 till 1975. The primary sarcomas of the orbit predominate with 11 cases over the secondary involvement with 9 cases. More seldom (5 cases) is the involvement of the lids and the epibulbar space. The various groups of lymphosarcoma predominate with 16 cases over the spindle-cell sarcoma with 6 cases. The age distribution shows that these tumors prefer the first three decades and the fifth and the following decennia. The prognosis is bad for the conservation of the eye as well as for the preservation of life. With reference to the localisation the distribution at the time of the beginning of the therapy as well as the histological findings an intensive therapy (operation, radiation, chemo-therapy) has to be accomplished.


[Psychotropic drugs and glaucoma (author's transl)]. The i.o. pressure and tonography were studied on 51 patients with endogenous depressions. The patients were treated 10-43 days with psycho-pharmacological drugs (Indoline, Imipramine, Amitriptyline, Noxiptiline and Phenothiazine). In no case does the therapy with the drugs induce an increase of i.o. pressure or-in normal eyes-of tonography. In latent of manifest glaucoma (7 patients) Clomipramine increased the tonography in 1 case, whereas Amitriptyline and Noxiptiline reduced it in 4 cases. The study demonstrated that the commonly used psycho-pharmaca are no contraindication to wide-angle glaucoma.


A two year follow-up of infants with respiratory distress syndrome. Forty-seven of 74 infants with idiopathic respiratory distress syndrome who had received intensive care in the neonatal period were examined between the ages of 15 and 24 months to assess their progress. All the children (including the premature infants) had caught up with their peers in height, weight and head circumference. Although 11 infants had a history of respiratory problems, only two showed residual lung changes on radiological examination. Only one infant who had frequent apnoeic spells had serious eye problems due to retrolental fibroplasia. A definite neurological deficit was found in one case, in which a congenital infection could not be ruled out.


Cottonseed colour fixed pigments. Part I. Selectivity of hexane isomers. The selectivity of hexane isomers towards cottonseed pigments and colour fixed pigments was illustrated by using spectrophotometric analysis of crude, refined and bleached oils, and by refinability and bleachability criteria. Crude cottonseed oil contains besides the alkali-refinable gossypol and gossypurpurin, several colour fixed pigments. Anhydrogossypol, gossyfulvin, anthocyanins and carotenoids seem to be responsible for the colour-fixation of the oil. Only carotenoids are eliminated by bleaching. Selectivities of hexane isomers towards colour fixed pigments are in the following order: isohexane less than n-hexane less than cyclohexane less than benzene less than methylcyclopentane.


Biochemical changes in cottonseed during development and maturity. The changes in cottonseed constituents at different boll ages ranging from 5 to 60 days after flowering are reported. A gradual depletion of sugars coincided with gradual formation of oil has been found. Proteins are accumulated at a more or less even rate. Gossypol starts its appearance in 10 days old boll, and continuously increases. The iodine value of the oils shows gradual increase, while the acid value continuously decreases. Continuous decrease in total saturated fatty acids during development and maturity was observed while linoleic acid continuously increases. The total phospholipid content of the oil continuously decreases. The total saturated fatty acid contents of the phospholipids are generally higher than that of their corresponding oils.


Aroma values--a useful concept?

Aroma values--a useful concept? Rapidly increasing knowledge about the high complexity of food aromas requires selection or ranking procedures as to the importance of the particular components for flavour impression. For this purpose the concept of aroma values has been discussed which calculates quantitative data in connection with aroma effectiveness of the compounds. The simplification of the concept with respect to the practical application, however, can change the natural system and lead to erroneous conclusions. There are not only interactions between aroma substances of sensoricphysiological character which may not be ignored. Physical conditions like lipid content, distribution of aroma compounds between aqueous and lipid phase or the sorption of volatile substances to the polymer nutrients in foodstuffs are of influence, too.


Substrate mobilization: a new hypothesis for the aetiology of the idiopathic respiratory distress syndrome. This hypothesis for the aetiology of the idiopathic respiratory distress syndrome of the newborn (IRDS) proposes that, although the aetiology is multifactorial, the factor of prime importance is the mobilization of substrate for surfactant synthesis. All factors known to influence the incidence, treatment, and prognosis of the IRDS can be shown to be associated with the mobilization of substrate and thereafter its continued availability for the synthesis of adequate surfactant. Thus factors which promote an antenatal increase in the breakdown of energy stores will be associated with a reduced incidence of the IRDS. On the other hand, despite adequate mobilization, factors associated with a lack of substrate secondary to poor transport of substrate, a reduction in pulmonary circulation or an alteration in fetal or neonatal metabolism which involves an increased utilization of substrate to provide energy, will be associated with an increased incidence of the IRDS.


Chromatographic column fractionation and fatty acid composition of different lipid classes of linseed oil. Linseed oil is fractionated on silicic acid column, with subsequent identification of different lipid classes by thin layer chromatography. Sterol esters, triglycerides, free fatty acids, sterols and phospholipids represent 0.15, 92.25, 3.30, 1.15 and 1.16%, respectively of linseed lipids. The total saturated fatty acid content of the phospholipid fraction is higher than that of the oil, the triglyceride fraction and the free fatty acid fraction. Linolenic acid, which is the major fatty acid in linseed triglycerides (47.5%), makes 18.2% of the phospholipid fatty acids. Oleic acid is the major fatty acid in the phospholipid fraction (35.2%), while it constitutes 19.3% of the triglycerides fatty acids.


[Artificial macaroni. 2. Biological value of synthetic macaroni]. The authors determined (in vitro) the amino-acid composition and the enzymatic cleavage of protein and starch as well as (in vivo) the biological value of synthetic macaroni produced on the basis of casein, soybean protein and cotton-seed protein. The products based on casein and soybean protein have a great biological value. Cotton-seed protein has a toxic effect. The biological value of synthetic macaroni is mainly determined by the composition of the initial mixture. The processes of production and culinary processing exert no essential effects on protein content, amino-acid composition of the protein and enzymatic cleavage.


Cottonseed colour fixed pigments. Part II. Role of hexane isomers on oil quality. Colour fixed pigments can be detected in refined and bleached oils rather than in crude oils, since in the latter their absorption is masked up by the gossypol pigments. Isohexane is the most desirable hexane isomer. Though it produces darker crude oils, yet refinability and bleachability increases as the percentage of isohexane in normal hexan increases. It has also the advantage of extracting oils with lowest refining loss and with the highest gossypol content. Recovery of gossypol, which is alkali refinable, with the oil results in a superior quality of meal. Benzene, on the other hand, is the least desirable constituent in commercial hexane. Its presence with n-hexane results in darker coloured crude, refined and bleached oil colours, indicating the selectivity of benzene to colour fixed pigments. Highest refining loss were found in oils extracted with benzene or benzene-hexane solvent mixtures. Cyclohexane presence with n-hexane (35% to 60%) and methycyclopentane (6.0% to 12.0%) do not increase the degree of extraction of colour fixed pigments, however increase the refining loss of the extracted oils.


[Effects of plant protective agents and pesticides on the processibility of milk with special consideration to microbiological technology]. The authors studied the effects of the active ingredients contained in 43 pesticides and insecticides on dairy cultures and the suitability of milk contaminated in vitro with selected organophosphorus insecticides. The acid-forming property of yoghurt, kefir, butter and cheese cultures, the clotting property of milk and the ripening process of Camembert were used as testing criteria. The herbicides 2-methyl-4,6-dinitrophenol (DNOC), 2,4, 5-trichlorophenol, 2-methyl-4-chlorophenoxyacetic acid (MCPA), 4-(2-methyl-4-chlorophenoxy) butyric acid (MPCB), 2,4-dichlorophenoxyacetic acid (2,4-D), 2,2-dichloropropionic acid (dalapon), the chlorinated insecticide heptachlorepoxide and the fungicide pentachlorophenol exerted inhibitory effects when applied at concentrations of more than 100 p.p.m., whereas most of the organophosphorus and chlorinated insecticides under investigation produced no detectable effects on the culture activity when used at concentrations up to 100 mg/kg. The clotting property of milk was not impaired by the pesticides and insecticides at concentrations up to 100 mg/kg; the same was true of the ripening process of Camembert.


[Surgical indications in ventral sacral meningocele]. Comparison of some cases in adults to an extensive malformation in the small pelvis in a 4 years old girl. Sacral ventral meningoceles are rare spinal malformations which probably result from a dysrhaphic disorder in an early embryonal stage (spina bifida). The dysrhaphic malformation extends towards the os sacrum with a defect in ventral direction. In this paper, we present the cases of one child and three adults. The malformative tumor in the small pelvis of the child was so large that an obstruction of the urinary tract and of the rectum resulted. In addition to this there was a paralysis of the peroneal muscles caused by a congenital defect in the nervous system. The large space occupying tumor in the small pelvis was surgically reduced and separated from the subarachnoid space, after which considerable postoperative improvement was observed. In the cases of the three adults, suffering from lumbal ischialgy, similar but much smaller malformations had been discovered through myelography. Two of these patients improved after removal of degenerated discs, and one by conservative treatment. There was no relation between the neurologic symptoms and the small ventral meningoceles. A surgical removal of sacral ventral meningoceles is indicated, when these appear as space occupying tumors in the small pelvis. The tumor can then be reached from the CSF-space in order to relieve the obstruction of the urinary tract and the rectum.


[Parinaud's syndrome in non-tumorous hydrocephalic intracranial hypertension]. Four cases (3 children and one adolescent) are presented in which Parinaud's syndrome developed in the course of progressive non-tumorous hydrocephalus. The vertical gaze palsy completely disappeared in all cases some days after raised intracranial pressure had been successfully treated. Neuroradiological findings indicate that Parinaud's syndrome can be elicited by a dorsal midbrain compression due to a markedly dilated suprapineal recess. Other contributing factors as distortion and compression of distal branches of the posterior cerebral artery in the cisterna ambiens region and an axial caudal displacement of the oral brain stem may be involved. According to the few cases published in the literature, the vertical gaze palsy seems to occur predominantly in benign connatal aqueduct stenosis and may then be regarded as a relatively early symptom of decompensating hydrocephalic intracranial pressure.


Sleep and brain malformation in the neonatal period. Polygraphic recordings of 20 neonates with brain malformations and/or chromosomal anomalies were compared with those obtained in 29 normal fullterm neonates. Seep assessment was made with different methods described in the literature. These methods of sleep scoring gave similar results in the normal newborn babies but discrepant results in many pathological neonates. Thus sleep was also studied by other approaches; assessment of cycling of the 5 parameters (EEG, REM, EMG, Motility, Respiration) and study of the discrepant parameters during a sustained period of Active sleep (AS) or Quiet Sleep (QS), defined by the most flexible method. Newborn babies with brain malformations appeared to be poor sleepers. Amount of wakefulness is higher than in normal neonates. Some babies were nearly insomniac. Correlations of sleep patterns and anatomical lesions were possible in five cases where brain anatomy was available. A good sleep organization has been seen in babies with normal brain-stems but a normal brain stem with a normal locus coeruleus has been found in a baby with absence of AS. Absence of sleep organization has been seen in babies with an abnormal brain stem; but this anomaly was not isolated as these babies also had lesions of the forebrain. The sleep of human neonates shows a greater liability in the coordination of the different parameters than the sleep of human adults or adult animals. It appears that sleep mechanisms at the pontine level present more plasticity than the rigid mono aminergic model would suggest.


Isoelectric enzyme patterns of leukocyte peroxidase in normal controls and patients with neuronal ceroid-lipofuscinoses. Using macro- and microanalytical isoelectric focussing techniques for separation of the soluble leukocytic peroxidase (hydrogen donor: p-phenylenediamine) we found 4 main isoenzyme components with pI at 9.6 (9.0), 7.6 (7.5), 6.2 (6.2) and 4.2 (4.7), which exhibited additional heterogeneities. The isoenzymes of the membrane-bound peroxidase displayed a similar pattern. The isoelectric subfractions of peroxidase in controls and patients with late-infantile (Jansky-Bielschowsky), juvenile (Spielmeyer-Sjögren) and adult (Kufs) types of neuronal ceroid-lipofuscinosis did not reveal any significant differences. Based on these findings, a deficiency of an isoenzyme component cannot be held responsible for producing neuronal ceroid-lipofuscinoses, neither in patients with normal nor in patients with reduced total activity of leukocyte peroxidase.


Sleep and heart rate variations in premature and full term babies. Heart rate was studied in 47 newborns babies during 67 polygraphic recordings by histograms and sequential curves of the length of 600 consecutive R-R-intervals selected during sleep stages lasting at least 5 minutes. In normal babies: (14 babies born at Gestational Age, G.A., 37 weeks, 6 babies born between 28 and 36 weeks). Before 37 weeks of G.A., the sequential curves show periodic variations of heart rate (including 15 to 70 beats) present both in active and quiet sleep. After 37 weeks of G.A., slow periodic variations are still present in active sleep but superimposed by fast variations synchronous to respiratory cycles. Fast variations are prevailing in quiet sleep. In pathological babies: Small variability is favoured by prematurity, young age at recording, and hypercapnia but can be very transient. Pronounced variations similar to those of normal babies are observed in 2/3 of the cases with or without respiratory assistance, with or without PEEP.


Observations on the differentiation of hydrocephalus occlusus in infancy and early childhood using computerized axial tomography (CAT). Hydrocephalus occlusus in children is caused by obstructions of the aqueduct and occasionally by cystic deformations of the posterior cranial cavre presented which were initially discovered by computerized axial tomography (CAT). The value of CAT becomes obvious since it can clearly demonstrate cystic and other lesions, size of ventricles and the course of a hydrocephalus. The method is non-invasive and there is no stress for the patient at all.


An autopsy case of the Lesch-Nyhan syndrome: normal HGPRT activity in liver and xanthine calculi in various tissues. An autopsied case of the Lesch-Nyhan syndrome did not indicate the specific pathological features except delayed physical development. 2. Xanthine calculi caused by allopurinol administration scattered in the kidneys, brain, thymus, and thyroid glands, but its excretion into urine was not observed during his life. 3. Activities of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in various tissues indicate complete deficiency, but HGPRT in liver was normal.


Treatment of Candida ventriculitis and septicaemia with 5-fluoro-cytosine. Combined peroral and intraventricular administration. A 9-months old patient with a ventricular shunt due to hydrocephalus was treated with intraventricular administration of 5-FC due to Candida ventriculitis with satisfactory clinical response. The intraventricular dose given was 5 mg twice daily for 14 days. The same patient was treated four months later with combined peroral and intraventricular administration of 5-FC also with good clinical response. On both occasions there was no evidence of drug toxicity. The peroral dose given was 100 mg/kg bodyweight/day divided in four doses. A few CSF and serum samples were taken to estimate the concentration of 5-FC. The local installation of 5-FC in an isolated ventriculitis seems to be of special beneficial value whereas fungal septicaemia with ventriculitis needs combination of peroral and intraventricular administration. No increase in resistance against 5-FC could be registered.


Follow-up study of a case of generalized ceroidlipofuscinosis of childhood with special reference to the finding of an abnormal serum lecithin fatty acid pattern. In quest of a more precise and stringent diagnosis for a case of generalized ceroidlipofuscinosis the patient was reexamined and additional laboratory tests were performed. For the third time myeloperoxidase activity was normal. On two separate occasions the serum lecithin fatty acid pattern was found to be abnormal and to resemble closely the pattern reported to be characteristic of polyunsaturated fatty acid lipidosis. The tau fraction was measured on one occasion and found to be normally present. Head circumference was confirmed to be normal. Pigmentary retinal changes were observed by fundoscopic examination. The child had prominent epileptic activity in form of myoclonic jerks. The case does not fit exactly into the picture reported recently for children with polyunsaturated fatty acid lipidosis. Doubt is voiced that these children have other than an infantile type of generalized ceroidlipofuscinosis. Thus, for the time being we regard ours as a case of generalized ceroidlipofuscinosis of infantile onset with an abnormal serum lecithin fatty acid composition. Furthermore, it seems to us that the infantile form, in the same manner and to the same extent as the late infantile and juvenile forms, does not constitute an entirely homogeneous group within the ceroidlipofuscinoses.


The uptake of DH-ergotoxine by different parts of the cat brain. The distribution pattern of 3H-DH-ergotoxine, labelled by a direct hydration with tritium, was investigated in the cat brain. Apart from the pituitary gland, the brain shows an average DH-ergotoxine concentration of 10(-7) M. A 15% greater incorporation of DH-ergotoxine occurs in the cerebellum than in the cerebrum. In gradient centrifugation studies it is seen that 60% of the incorporated DH-ergotoxine is localized in the synaptosomal fraction. This finding seems to verify the microhistautoradiographic results of this investigation. The observation of a DH-ergotoxine binding in selected structures of the CNS , predominantly the synapses, could explain central nervous activities of DH-ergotoxine.


The effect of anti-parkinsonian drugs on chlorpromazine-induced depression of operant behaviour. Rats were conditioned in automatic Skinner boxes on a discrete trial avoidance-escape schedule. The chlorpromazine-induced conditioned reflex inhibition could be reversed by apomorphine and amantadine, but not by atropine, trihexyphenidyl and diethazine. These findings seem to provide an additional tool for differentiating the atropine-like and dopaminergic anti-parkinsonian drugs.


The protective effects of methysergide, 6-hydroxydopamine and other agents on the toxicity of amphetamine, phentermine, MDA, PMA, and STP in mice. The ability of various drugs to prevent the lethal effects of 4-methoxyamphetamine (PMA) and 3, 4-methylenedioxyamphetamine (MDA) were reduced by pretreatment with phentolamine and 6-hydroxydopamine suggesting that release of norepinephrine from peripheral adrenergic nerves contributed to their toxicity. Pretreatment with methysergide reduced the lethal effects of (+)- and (-)-amphetamine, MDA, PMA and 2, 5-dimethoxy-4-methylamphetamine (STP) suggesting that an action on serotonergic receptors contributed to their toxicity. Pretreatment with 4-chloroamphetamine, practolol and haloperidol did not alter the lethal effects of the agents studied.


[Characteristics of the genus Glugea (Protozoa, Microsporidia) based on the example of the type species Glugea anomala (Moniez, 1887) Gurley 1893 and its varieties]. A study of the life cycles of some varieties of Glugea anomala has shown that the genus Glugea is a distinct genus having the following diagnosis. Sporoblasts and spores are formed as a result of step by step decay of the multinuclear plasmodium situated inside the sporogonal vacuole (sporont). Ripe spores either remain connected together in groups with irregular (6 to 32) often uneven number of spores of lie singly, seldom in pairs. Microsporidia are able to cause extremely strong hypertrophy of the host's infected cell which is transformed into a round white cyst filled with the parasite's spores.


The detection of penicillin in buttermilk. When 59 buttermilk samples were tested for the presence of antibiotics or chemostherapeutic substances by a method using the spores of Bacillus stearothermophilus var. chalidolactis all samples gave a positive reaction corresponding to about 0.01 IU penicillin per ml. When the buttermilk samples were diluted 1:1 (v/v) by a phosphate buffer, pH 6.8, only 2 were positive which were confirmed to contain penicillin. The mean pH of the unbuffered buttermilks was found to be 4.53 +/- 0.11 and when buffered 6.46 +/- 0.05. An in vitro addition of benzylpenicillin to buttermilk, to a concentration of 0.01 IU per ml, resulted in a significantly higher concentration of penicillin in the casein fraction than in the buttermilk or in the whey (Table I).


DDT in human milk. What determines the levels? In a study of fifty-five human milk samples from eastern Pennsylvania, the total DDT derived products exceeded the DDT content of cows milk and canned infant formula. Total DDT in human milk exceeded the U.S. Food and Drug Administration's tolerance for total DDT in cows milk in 47% of the samples. Four factors were identified statistically as accounting for 54% of the variance on total DDT levels in human milk. These factors are: (1) number of children nursed; (2) number of cigarettes smoked per day; (3) use of non-persistent pesticides; and (4) diet in calories.


Platelet adhesion, release and aggregation in flowing blood: effects of surface properties and platelet function. Platelet adhesion to natural and artificial surfaces and adhesion-induced aggregation were investigated in vitro using an annular perfusion chamber. The surfaces were exposed to anticoagulated blood under identical flow conditions (approximately arterial shear rates). The initial attachment of platelets (contact) appeared less surface specific than spreading and release. Fibrillar collagen was the most powerful inducer of platelet degranulation whereas elastin, microfibrils and epon were virtually inactive. Fibrillar collagen caused release also in the absence of spreading. Surface coverage with platelets did not exceed 25% unless spreading occurred. Perfusion with platelet-free plasma or platelet-poor blood did not remove adhering platelets. However, platelets were translocated from mural thrombi to the surface by such perfusion. In addition, platelets which detached from mural thrombi adhered more readily to elastin or microfibrils than platelets from the circulating blood. The initial attachment of platelets to subendothelium was inhibited in von Willebrand's disease, the Bernard-Soulier syndrome and at high concentrations of dipyridamole; spreading was inhibited in storage pool disease of rats, at low temperature (20 degrees C), with EDTA (3 MM) and Prostaglandin E1 (1 muM); and adhesion-induced aggregation was inhibited in thrombasthenia, storage pool disease and after ingestion of sulfinpyrazone or Aspirin. It is concluded that the initial attachment (contact) of platelets, spreading and surface-induced release of platelet constituents are at least partially indendent phenomena, the latter two being highly surface specific. At flow conditions which cause the disappearance of platelet adhesion appears as an irreversible process.


Role of surface glycoproteins in human platelet function. Glycoproteins present at the external surface of cells probably play specific roles in cellular function. Increasing evidence suggests that the glycoproteins span the plasma membrane with the bulk of the bound carbohydrate asymmetrically distributed on the outer surface. Micellar association of glycoproteins in membranes leads to pore formation and functional roles in transport through the membrane, while surface glycoproteins have been shown to be enzymes, to determine cell specificity and contribute to the cell surface change. The platelet plasma membrane contains 3 major glycoproteins, glycoproteins I, II and III as characterized in order of their decreasing molecular weight. Glycoprotein I appears to have the highest sialic acid content and to give rise to a platelet specific acidic macroglycopeptide on trypsin digestion. Specific glycoprotein abnormalities in the platelets of patients with Glanzmann's thrombasthenia suggest that the glycoproteins play a role in the mechanism of platelet aggregation. A much reduced content of glycoprotein I in the platelets of 2 patients with the Bernard Soulier syndrome may be associated with their defective adhesion to subendothelium and indicates a possible relationship on the platelet surface with the von Willebrand factor protein. Preliminary evidence suggests that in common with other plasma membranes the platelet membrane has a fluid structure and that the organization of the glycoproteins on the platelet surface is extremely sensitive to stimuli and susceptible to change.


Intimal histolysis as an early stage of atherosclerotic involvement. Observations on the human coronary arteries. Investigation of the coronary arteries in 330 subjects aged 11 to 50 years showed that the "missing link" between age-dependent changes and atherosclerotic lesions appeared as a process of intimal histolysis. This term refers to focal disintegrations of the intimal connective tissue involving successively ground substance, reticular networks, collagen fibers, elastic fibers and smooth muscle cells. The resulting gelatinous plaques and detritus cavities represent the starting point for the development of fibrous plaques with or without necrotic centers (atheroma).


The dissociation of factor VIII by reducing agents, high salt concentration and affinity chromatography. Incubation of a factor VIII-rich fraction of plasma with a high concentration of salt confirmed the production of both high (HMW) and low (LMW) molecular weight factor VIII clotting activity (FVIIIC) as determined by agarose gel filtration but with considerable overlap. The electrophoretic mobility of factor VIII related protein (FVIIIRP) detected by precipitating rabbit antiserum was not affected by this treatment and LMW FVIIIC devoid of FVIIIRP was apparently produced. At low concentration the reducing agent dithiothreitol (DTT) altered the electrophoretic mobility of FVIIIRP. At higher concentrations it altered both its mobility and antigenicity and an LMW FVIIIRP was produced. Contrary to the findings of other workers no LMW FVIIIC devoid of FVIIIRP was produced. In further studies factor VIII-rich plasma fraction was treated with sepharose beads to which had been coupled a non-coagulation inhibitory precipitating rabbit antibody to FVIIIRP. Both FVIIIRP and FVIIIC were taken up by the beads but after elution with 1.5 M NaCl, FVIIIC of LMW and devoid of FVIIIRP was selectively removed. Antisera raised to LMW FVIIIC produced with 1.5 M NaCl either by the gel filtration or affinity chromatography methods inhibited FVIIIC and precipitated with HMW factor VIII-rich fractions. The results were consistent with the possibility that factor VIII clotting activity and FVIIIRP exist in plasma as a non-covalently bound complex.


Electrocardiographic diagnosis of experimentally-induced myocardial infarction during cardiac electrostimulation. The sequential ECG changes were studied by the Sodi-Pallares' method in 10 dogs before and after experimentally induced myocardial infarction of the left ventricle during right and left artificial stimulation. Right ventricular endocardial stimulation produced patterns of left bundle branch block in 9 dogs and of right bundle branch block in one, while left ventricular stimulation caused right bundle branche block patterns in 9 animals. Records during right ventricular stimulation after myocardial infarction showed in the peripheral leads myocardial necrosis only in two animals, while in the epicardial leads necrosis was certain in 2 animals (Q wave) probable in 6 (S-T segment elevation) and suggestive in 2 (T wave negatively). Myocardial necrosis during left ventricular stimulation was evident in the peripheral leads in 2 animals, probable in 6 and suggestive in one. The experimental data suggest that myocardial necrosis can be diagnosed in some cases during right and left ventricular artificial stimulation.


The effects of hepes buffer on clotting tests, assay of factors V and VIII and on the hydrolysis of esters by thrombin and thrombokinase. Shorter clotting times were found in the presence of 50 mM Hepes (N-2-hydroxyethylpiperazine-N1-2-ethanesulfonic acid) buffer than of 50mM Imidazole buffer in one-stage assays of factors V and VIII, in modified APTT and PT tests and in tests of the clotting of human plasma by purified human thrombin. All tests were performed at ionic strength 0.155 in the presence of either Hepes. NaOH or Imidazole. HCl buffer, pH 7.4 at 37 degrees. The faster clotting in the presence of Hepes buffer, therefore, is probably due, at least in part, to acceleration by Hepes of thrombin's enzymatic action on fibrinogen and/or of the polymerization of the fibrin monomers. Hepes may also have effects of other blood clotting reactions. Rates of hydrolysis of TAME or BAME (p-toluenesulfonyl- or benzoyl-L-arginine methyl ester) at pH 7.4 37 degrees by purified human bovine thrombin were essentially the same in 200 mM Hepes as in 250 mM Tris. HCl buffer (rates in Hepes. NaOH or Hepes. KOH buffers were compared with those in Tris. HCl plus NaCl for KCl). However, with purified bovine thrombokinase, rates of TAME hydrolysis in Hepes buffer were accelerated and rates of BAME hydrolysis slightly inhibited. Hepes, therefore, reacts with thrombokinase but whether this accelerates (or inhibits) the rate of converting prothrombin to thrombin remains to be determined. In addition, Hepes has an inhibitory effect on clotting since increasing the concentration of Hepes from 50 mM to 200 mM inhibits clotting in the PT, APTT and bovine thrombin-human plasma tests. Hepes buffer is being added to some plasmas and to some reagents used in clotting tests. It is, therefore, important to realize that its concentration must be monitored closely or erroneous results may be obtained in clotting tests and assays of clotting factors. The clotting times were the same in the presence of 50 mM Tris. HCl as in Imidazole. HCl buffers in APTT tests at three ionic strengths but they differed slightly in plasma-thrombin tests. Depending upon the ionic strength, 17 mM Barbital Sodium. HCl buffer inhibited APTT tests but accelerated plasma-thrombin tests. All the buffers tested, therefore, have individual effects on the clotting tests.


Purification of human factor IX by chromatography of a coagulation factor concentrate. A purification procedure for, and some properties of, coagulation factor IX are described. The coagulation factor concentrate used for the treatment of hemophilia B patients was employed as the starting material. The isolation procedure consists of chromatography in DEAE-cellulose, two chromatographies in hydroxyapatite gel and two gel filtrations in Sephadex G-200. Only trace amounts of factors II, VII and X were present in the final preparation and the specific activity of factor IX was 159 corresponding 10,300 times purification from plasma. The molecular weight was estimated to be 76,000 in gel filtration and 86,000 in sodium dodecyl sulfate disc gel electrophoresis. Three activity peaks with pIs 4.15, 4.25 and 4.40 were obtained by isoelectric focusing.


Study of a proposed international standard for blood coagulation factor IX. An International Collaborative Study was organized to establish a standard for factor IX. Two freeze-dried concentrate preparations, C1 and C2, and one freeze-dried plasma P were compared with each other, with fresh normal plasmas and with local standards in 13 laboratories. One of the concentrate preparations (C1) contained heparin and this gave rise to non-parallel assays in laboratories testing concentrate C1 in dilutions containing more than 0.05 i.u. of heparin per ml. Assays of factor IX showed good precision for both plasma and concentrate in all laboratories; no systematic effect of method, operator or day of assay was detected. The plasma preparation P and the concentrate preparation C2 were compared with 59 individual fresh normal plasma samples, and a mean potency ratio of 0.78 (95% confidence limits 0.73-0.84) for plasma and 5.62(95% confidence limits 5.13-6.16) for the concentrate C2 obtained. Only 21 estimates of concentrate C1 in terms of fresh plasma were obtained giving a mean potency ratio of 3.85 (95% confidence limits 1.87-7.92). The estimated loss of potency for freeze-dried plasma stored at -20 degrees C is approximately 0.4% per year. The concentrate C2 is apparently more stable and only very small losses occurred even at higher storage temperatures. All participants agreed that the preparation C2 would be suitable to serve as an International Standard for factor IX; they also agreed that the figure assigned for the unitage should be based on the number of ml of 'average fresh normal plasma' estimated to contain the factor IX activity of one ampoule of the preparation. It is proposed to recommend to the World Health Organization that the preparation of factor IX concentrate C2, in ampoules coded 72/32, be considered for establishment as the International Standard for factor IX, and that the international unit for factor IX be assigned on the basis of 5.62 units per ampoule of this preparation.


Effect of platelet antiserum on the precipitation of soluble fibrin by endotoxin. Rabbits were injected with a platelet antiserum to examine the role of thrombocytopenia of the precipitation of soluble fibrin by endotoxin.dotoxin. Platelet antiserum removed more than 98% of the circulating platelets, and the resulting thrombocytopenia with platelet counts below 10,000 per mul persisted during the entire 10 hr-period of the experiment. Leukocyte counts were not significantly influenced by the platelet antiserum. Since the rabbits were treated with high doses of heparin, activation of intravascular coagulation by the antiserum did not occur. Precipitation of soluble fibrin was achieved by injection of endotoxin into rabbits with ancrod-induced circulating soluble fibrin. Thrombocytopenia did not prevent the occurrence of glomerular microclots after ancrod and endotoxin administration. On the contrary, if endotoxin was injected into antiserum- and heparin-treated rabbits with circulating soluble fibrin, glomerular microclot formation occurred even in a higher percentage than in control rabbits treated with absorbed platelet antiserum. This investigation indicates that platelet antiserum-induced thrombocytopenia does not protect against precipitation of soluble fibrin by en


Platelet aggregation by thimerosal: role of ADP and SH groups. Thimerosal, a sulphydryl inhibitor, induces aggregation of normal platelet rich plasma over a wide range of concentrations. Low doses induce a monophasic response preceded by a lag phase, high doses produce an immediate biphasic response. Thimerosal induces platelet aggregation through its binding by sulphydryl groups. Thimerosal induced aggregation is not mediated by ADP, it is not influenced by fibrinogen, von Willebrand factor, calcium, and magnesium ions of the medium. Thimerosal induced platelet aggregation is normal in patients affected by thrombocytopathia (defect of ADP release) but not in patients affected by Glanzmann's thrombasthenia. Mercaptopropionglycine, a substance which tends to preserve SH groups, inhibits platelet aggregation induced by thimerosal, thrombin, collagen, and ADP. A mechanism is proposed for thimerosal induced aggregation and the role of SH groups also in ADP, thrombin and collagen induced aggregation is indicated.