Ruptured mycotic aneurysm: a complication of parenteral drug abuse.

Mycotic aneurysms occurred in five narcotics addicts treated between 1969 and 1975. Fever, localized tenderness, swelling, loss of distal pulses, and leukocytosis were common findings. The aneurysms were located in the femoral (two patients), brachial (two), and superior mesenteric arteries (one). They occurred at the site of arterial injection in three patients. In one patient with subacute bacterial endocarditis, an aneurysm of the superior mesenteric artery developed. In one patient, the pathogenesis was uncertain. All patients had rupture of the arterial wall, with hemorrhage contained by adjacent muscle or soft tissue. Four patients were treated by ligation and debridement. One, with preexisting ischemia, required amputation below the knee. One patient underwent repair with autogenous artery. Recurrent hemorrhage necessitated ligation of the artery. In all patients, extensive sepsis and tissue necrosis precluded repair with prosthetic material. All patients survived, without evident of ischemia.


Improved assay of neurotoxic esterase for screening organophosphates for delayed neurotoxicity potential.

The assay of neurotoxic esterase (NTE) in brains taken from dosed hens enables potential neurotoxicity of organophosphate pesticides, plasticers, etc. to be assessed. The original assay [Johnson, M.K. Biochem. J. 114, 711-717 (1969)] has been simplified to eliminate centrifugation and transfer steps and both the selectivity and the sensitivity have been increased. The procedures necessary to obtain stable reagent stocks are described.


Propoxyphene overdosage: a study of cases involving analgesic preparations containing dextropropoxyphene.

Propoxyphene and paracetamol concentrations have been determined in blood, urine, liver blood and stomach contents from 17 post mortem cases in which Distalgesic (a propoxyphene and paracetamol compound preparation) was involved. Five patients admitted to hospital with suspected Distalgesic poisoning have also been investigated. In most cases the propoxyphene concentrations, but not the paracetamol concentrations, exceeded the minimum lethal levels reported. On the basis of our results it appears that of the constituents of Distalgesic, propoxyphene has a far more immediate and dangerous effect than paracetamol.


Suicide by an overdosage of N-propylajmalinium bitartrate.

The toxicological findings after suicidal poisoning with N-propylajmalinium bitartrate (NPAB) are presented. For isolation of NPAB the biological material was homogenized and the drug was isolated by adsorption on Amberlite XAD-2. After column chromatographic purification on Sephadex LH-20 quantitative determinations were carried out by gas chromatography of the trifluoroacetate. The identity of the material finally obtained was checked by various chromatographic and spectrometric methods. The following concentrations of NPAB were found: liver 58 microgram/g, kidney 32 microgram/g, brain 16 microgram/g, muscle less than 10 microgram/g, heart less than 5 microgram/g, blood less than 5 microgram/g, gastric contents 600 mg (total). 1200 mg of NPAB had been swallowed; thus the amount of NPAB, that had crossed into blood, was approx. 500-600 mg corresponding to a dose of 9-11 mg/kg body weight.


Determination of cadmium in human milk during lactation.

During lactation, Cd-levels in human milk were determined by means of flameless atomic absorption spectrophotometry. The levels in colostrum were some 50-65% higher than in transitional and mature milk.


Biochemical and morphological changes in some organs of rats in nickel intoxication.

Biochemical and histological alterations in liver, kidney, testis and myocardium of albino rats were investigated at various intervals after daily administration of nickel sulphate. No significant changes were observed during the initial periods of the treatment, but longer exposures produced marked enzymatic and histopathological alterations in all the four organs examined. The severity of the histological lesions was found to be directly related to the duration of the treatment.


[Teratologic-neurotoxicologic studies on biglumide (K-2004) and thalidomide].

Comparison of the teratogenic and neurotoxic influence of thalidomide with the new hypnosedative preparation Biglumide (K-2004) revealed significant differences. Malformations could be seen only after treatment with thalidomide. Some results concerning the thalidomide-treated group of animals could be interpreted as a retardation of development in the posterior root ganglia.


Fatal poisoning with verapamil.

The toxicologic findings in a case of fatal poisoning with verapamil (Isoptin) are are presented. For isolation of verapamil the biologic material was subjected to protein precipitation. The aqueous solutions were acidified with hydrochloric acid, prepurified by extraction with ether, and subsequently the basic drug verapamil was isolated by ion pair extraction with chloroform. Quantitative determination of verapamil was carried out by gas chromatography using a nitrogen specific flame ionization detector. The following concentrations of verapamil were measured: liver 5500 ng/g, kidney 2000 ng/g, blood 590 ng/g, urine 250 ng/g, gastric contents 3 mg (total). During examination by the police it was claimed by a witness that two tablets of Isoptin had been taken before death. After application of a therapeutic dose of Isoptin peak concentrations of 11 and 30 ng/g of blood cells and of 30 and 65 ng/g of plasma were measured in two healthy subjects; the latter figures corresponded well to previous findings of other authors, who investigated plasma concentrations of verapamil after therapeutic administration. In the case presented here, the blood concentration of 590 ng/g clearly demonstrated that an extreme overdose must have been taken before death.


[Enzyme studies of synovial fluid from osteoarthritis knee joints (author's transl)].

In 40 patients who were operated on for meniscopathy, accompanied by more or less severe arthroses of the knee joints, the total activity of LDH-T and of the LDH-H isoenzyms could be evaluated. The data show that severe arthroses without any synovitic reactions as well as  cases with inactive chronic synovitis showed small total activities of LDH, whereas cases with clinical and macroscopic-anatomically active synovitis (including the so-called activated arthroses) showed a great total activity of LDH. Furthermore the dominance of LDH-H isoenzyms has been found to indicate an aerobic situation of the metabolism.


Middle ear mucosa and secretory otitis media.

Recent investigations have identified the viscous middle ear effusion in secretory otitis media (S.O.M.) as being of the same nature as true mucus--the "backbone" of which is glycoprotein. The source of the mucus is mucus-producing cells in greater number than found in the normal middle ear lining. The pathological state which leads to excessive mucus production and maturation of numerous mucus cells is an inflammation associated with deficient ventilation of the middle ear. In the presence of inflammation, especially when CO2 tension is high, mucosal stem cells differentiate metaplastically into numerous mucus-producing cells, as demonstrated by us in tissue cultures. The higher CO2 tension in S.O.M. is due to eustacian tube insufficiency (not blockage) which is a smaller than normal amount of air introduced into the middle ear per unit of time. Ventilating tubes restore CO2 tension to normal and equalize the slight barometric negative pressure (average 3.35 H2O)--the latter being related to mucociliary clearance. Evidence for an allergic factor as a pathogen is also not available. The mucus in the middle ear is probably not noxious by itself and ears should be ventilated surgically only when hearing is below social level perception. Most S.O.M. ears will clear sooner or later spontaneously. A minority of these ears will progress with time into atelectatic ears and some might perforate later on.


Ectopic muscle in the middle ear.

An ectopic muscle was found in the hypotympanum of a 31-year-old Japanese male. The muscle produced symptoms quite similar to those seen in cases of glomus jugulare tumor: a red mass visible through the ear drum, conductive deafness, a compressed jugular bulb demonstrable by retrograde jugulography, and VIIth and IXth nerve paresis. However, the audible pulsating tinnitus of glomus jugulare tumor was absent. The mass proved to be a muscle speculated as being a part of the levator veli palatini muscle. In view of our findings, ectopic muscle should be included in the differential diagnosis of glomus jugulare tumor.


Filter function of the guinea pig cochlea after degeneration of outer hair cells.

After kanamycin induced degeneration of outer hair cells from  guinea pigs the tuning properties of primary auditory nerve fibres are compared with those of normal untreated guinea pigs. The existence of fibres with no alteration of the tuning properties leads to the conclusion that there is no neural interaction between inner and outer hair cells needed to enhance the frequency selectivity.


Does promethazine (Atosil) influence the human's early acoustically evoked potentials in the same way as the late potential N1?

In a former investigation the effect of promethazine (Atosil) on the late acoustically evoked potential component N1 was examined. Now the cochlear and the brain-stem potentials were registered by the earlobe-vertex pick-up with i.m. application of 0.8 mg/kg (body weight) promethazine. There was no influence of promethazine either on the compound action potential (NAP) or on the brain-stem potentials (Pot. II-V), but sedation improves significantly the signal-to-noise ratio, therefore we sedate all patients when registering the five early acoustically evoked potentials.


[Influence of different fixation buffers on the quantitative cytoarchitecture of the cochlear spiral ganglion. A morphometric study (author's transl)].

The influence of two fixation buffers on the quantitative cytoarchitecture of the cochlear spiral ganglion in guinea pigs was evaluated morphometrically. After fixation with phosphate buffered 1.3% OsO4 granular spiral ganglion cells lost 45% of their average individual volume as compared to the volume after fixation with s-collidine buffered 1.3% OsO4. Using the two fixatives there was no significant difference of the volume proportion of cell nuclei, mitochondria, lysosomes and rough endoplasmic reticulum per unit volume cytoplasm of the granular spiral ganglion cells. The volume proportion of their ribosomes and their Golgi apparatus per unit volume cytoplasm increased 3.5fold after fixation with phosphate buffered OsO4. The volume density of the granular ganglion cells decreased by 30%, the volume density of the interganglionar space (= space between granular ganglion cells) showed an increase of 50% using phosphate buffer. Mostly the extracellular space was participating in this relative increase of the interganglionar space. As a result fixation of the spiral ganglion for morphometric studies should be performed using s-collidine buffered OsO4. The morphometric findings underline the presumption of semicompact myelin being a fixation artefact.


[Detection of noise-induced physiological stress and hearing loss in guinea pigs by means of an electro-cochleographic method (author's transl)].

One of the most essential prerequisites to the suitability of test animals used for studying the damage effect of noise on audition is the threshold determination with reasonable expenditure. Mention is made of an electro-cochleographic method to determine the click threshold and click threshold shift [TTS(C) and PTS(C)], resp., after an uninjured guinea pig has been subjected to noise. The temporary threshold shift following a short-term sonic exposure and the permanent threshold shift following a permanent sonic exposure reveal a far heavier effect on the guinea pig ear than on the human ear. However, the trends in stress and affection are so much alike in guinea pig and man that the former's involvement in studying the effects of audition-affecting noise on the human ear seems to be primising.


Intraoral nerve block for glossopharyngeal neuralgia.

Glossopharyngeal neuralgia was treated by a new method of intraoral block. The procedure consists of block for the tonsillar branch and block of the lingual branch by the injection of 5% Phenol in Glycerin. This can be applied for neuralgia with a trigger zone around the tonsil. The result is quite satisfactory. This is extremely safe and simple, and can be performed repetitively when recurrences occur. Also, this procedure does not preclude later operations as a final step.


Aerodynamic pattern of Eustachian tube dysfunction.

Detailed aerodynamic patterns for various disorders of the Eustachian tube function were reported. Simultaneous recording of the pressure in the ear canal and the pharyngeal cavity during Valsalva's maneuver and deglutition permitted an objective evaluation of different tubal dysfunctions. The patient with occluded tube showed either disturbance of the air flowing into the tube or outflowing from the tympanum to the pharynx. Depending on the degree of patency, the patulous tube showed either a synchronous change of the tympanal pressure with that of the pharyngeal cavity or an early and sudden drop of the tympanal pressure without deglutition. Through this rather simple aerodynamic technique, evaluation of different tubal dysfunction is possible.


[Changes of the motility of the pillar in case of intrathoracical affections (author's transl)].

It is shown that in the light of relevant cases the intensified movements of the pillar and the vocal cords during the respiration can indicate a pulmonary or cardiac respiratory insufficience. The increased appearance of respiratory movements of the pillar after the stress of motion goes to prove a reduced cardiorespiratory efficiency. The unilateral or bilateral reduction of motility, the ataxy and tremor of the pillar as well as disturbances of coordination of the automatically steered respiratory movements of the pillar may indicate lesions of the distal, thoracical and abdominal vagus trunk by neoplasms and operative traumas, even if this damage was done far below the offset of the Rr. pharyngici. An interpretation of these retrograde losses of motility of the pillar is given, which is also important for understanding the median and intermediary position of the paralysed vocal cord.


[Congenital torticollis with dislocation of the larynx and trachea caused by contracture of one omohyoides muscle (author's transl)].

Report on a boy with congenital torticollis by contracture of one omohyoid muscle with lateral displacement of the larynx and trachea, marked asymmetry of the face. Since surgery this asymmetry has nearly totally regressed, and the larynx is in median position.


[Determination of the perilymph density in the cochlea of guinea pigs (author's transl)].

The perilymph density of the sc. tympani, sc. vestibuli and the density of liquor cerebrospinalis in guinea-pigs are measured by determination from mass and volume of the fluid column in a glass capillary tube. For the density of perilymph in sc. vest. a value of (formula: see text) in sc. tymp. a value of (formula: see text), and for liquor a value of (formula: see text) was obtained.


[Model building in pharmacokinetics/Part I: General strategy (author's transl)].

A repetitive cycle: hypothesis-experiment-analysis is typical for construction and evaluation of models in pharmacokinetics. A general strategy is outlined to meet the requirements of correct modelling, proper experimental design, careful experiments, valid parameter estimation and model identification.


[Model building in pharmacokinetics/Part II: Generalized theoretical presentation of complete integration of linear compartment models of optional structure (author's transl)].

The method of Laplace transformation is used to obtain the integral of linear differential equations for pharmacokinetic models. A general solution uniform in structure for all types of models (mammillary, catenary, mixed) was established. Choice of one more application compartments, of kinetics describing the input procedure and of elimination pathways is free.


[Model building in pharmacokinetics/Part III: Simplified rules for the deduction of analytical solutions for linear compartment models (author's transl)].

Analytical solutions for any linear compartment model are obtained empirically by use of simple rules. Set up of differential equations and tedious integration procedures are thus avoided. The procedure is suited for automation by a calculator. Integrated equations are accessible then even more simply and rapidly.


Model building in pharmacokinetics/Part V: Simulation of blood level curves following repetitive dosing and their experimental verification (author's transl).

An equation is given to describe the plasma level curve of any linear compartment model following multiple dosing of various doses after various time intervals. The equation is especially suitable to be used with desk top computers equipped with a plotting device. A dosage regimen can be simulated using the parameters derived from single dose experiments. Experimental check-up of the predicted curves is necessary and illustrated by two examples. Systematic deviations from the prediction indicate changes in the biological system, e.g., in absorption, by enzyme induction, saturable processes, etc.


[Effects of reserpine and its derivatives on release of biogenic amines. Comparative study of the activity of reserpine and diethylaminoethyl-1-reserpine as bitartrates (author's transl)].

A comparative study of the activity of reserpine and its salt of diethylamineothyl on the central nervous system was performed. Palpebral ptosis in the mouse and depletion of catecholamines in the rat served for comparison. The reserpine salt of diethylaminoethane is a new derivative of reserpine the depleting activity of which on the central nervous system is considerably diminished.


Ibuproxam and ibuprofen. A pharmacological comparison.

The anti-inflammatory, analgesic and antipyretic effects and the tolerability of 2-(4-isobutylphenyl)-propionic acid (ibuprofen) were compared with those of its derivative 2-(4-isobutylphenyl)-propiohydroxamic acid (ibuproxam, Ibudros. Our experiments show that the interfering action of the two drugs with the reactive processes of the tibio-tarsic articulation, brought about by carrageenin, serotonin, dextrane and formalin is of the same intensity. Also, the analgesic activity is perfectly consistent with the antipyretic one. However, the tolerability of the two molecules is different; the acute toxicity is consistent in the case of the single parenteral administration and it differs in the case of a single or repeated oral treatment. When used under these conditions, ibuproxam is considerably less damaging to the gastroenteric tube than is ibuprofen. The hypothesis is put forth that the greater tolerability of ibuproxam is due to its pharmacokinetics: it is, as such, little or not toxic for the mucous membrane of the digestive apparatus, and it progressively releases ibuprofen, whose concentrations in the blood  would remain below those levels that cause systemic lesions in the gastroenteric tract.


Determination of ibuproxam and its metabolites in the plasma and urine of rats.

The metabolism of 2-(4-isobutylphenyl)-propio-hydroxamic acid (ibuproxam, Ibudros), a new molecule with anti-inflammatory, antipyretic and analgesic activity was studied by its administration orally and rectally to the rat. The analysis, carried out with gas chromatographic method and thin-layer chromatography, showed that the drug is present in blood as 2-(4-isobutylphenyl)-propionic acid (ibuprofen), an anti-inflammatory drug which is commonly used and the metabolites of which are already known. Using the same methods, it was observed that only a few traces of the hydroxamic acid appear in the urines of rats treated with ibuproxam, whilst the ibuprofen metabolite is absent. Therefore, we conclude that the drug ibuproxam changes rapidly into ibuprofen, following afterwards the same known metabolic process as the latter drug.


Charge-transfer complexes of hematoporphyrin having a pharmacological interest.

Complexes formed by hematoporphyrin with donor molecules were prepared and isolated. Among these complexes particular attention is given to that formed by reacting dimethylaminoethanol with hematoporphyrin. Some data are reported on the chemical evidence of formation like u.v. spectra. The product, named Hematodeanol, determines some sufficiently specific effects on the CNS; it remarkably cuts down the depression induced by pentobarbital, moderately hinders convulsions by metrazole, delays hypothermia by reserpine, facilites the learning of conditioned avoidance response (CAR) and improves the learning of a sound discrimination at variable interval. The actions become evident when tests are carried out after a continuous treatment for 7 days and according to the data of the investigation of pharmacokinetic kind, the phenomenon may be attributed to the fact that the drug concentration in the nervous tissue, when it is administered several times at intervals of 24 h, inclines to increase progressively.


[Diuresis and natriuresis following application of bemeticide and triamterence in rats on normal and low-potassium diet (author's transl)].

The investigations were carried out under identical conditions and were aimed at determining the effects of different doses of the two diuretics: 3-(alpha-methylbenzyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (bemeticide) and 2,4,7-triamino-6-phenylpteredine (triamterene) as well as for their joint administration at ratios of 1:2 and 1:4, resp., with regard to renal elimination of sodium and potassium as well as to urinary output in normally and low-potassium-fed rats. The 1:2 combination of bemeticide and triamterene resulted in an optimum diuretic and sodium elimination effect with potassium values within normal range, both in the normally and in the low-potassium-fed animals. An increase of the triamterene component from the 1:2 to the 1:4 ratio did not yield additional advantages.


Effect of temperature of perorally administered phenol red solution on gastric emptying in the rat.

Phenol red solutions of 5,25 and 45 degress C were administered perorally to rats. 15, 30 and 45 min after administration the rats were sacrificed and the residue of phenol red in the stomach and in the small intestine determined. Precent phenol red dose recovered from the stomach versus time was found to follow first-order kinetics. The data show a decrease of gastric emptying with increasing temperature of the phenol red solution administered.


[Pharmacological studies on the antiphlogistic effect of pentosanpolysulfate in combination with metamizol].

In the present study we investigated the antiinflammatory effect of pentosanpolysulfate (SP 54) in combination with metamizol using different forms of rat paw edema (induced by dextrane, hyaluronidase, trypsin, formaldehyde, carragenine or kaolin). After s. c. application Probaphen, a new drug containing pentosanpolysulfate, metamizol, and lidocaine, proved in our experiments to exert an antiphlogistic effect about 40% stronger than the equivalent amount of SP 54 alone. Since pentosanpolysulfate by itself has no analgetic activity, its combination with metamizol results in a formulation which is not only a more potent antiinflammatory drug but will aslo counteract pains which accompany most edematous reactions. Probaphen may therefore be suggested for the treatment of rheumatoid arthritis and similar inflammatory and edematous processes. First clinical studies and reports on Probaphen fully support our pharmacological results.


Rutosides and radiation induced regression of experimental tumours.

The effect of some flavonoids like O-(beta-hydro-xyethyl)-rutoside, alone and in combination with X-rays, was investigated on three transplantable mouse tumours. The growth characteristics of the tumours depending on the sex of the host animal and the application of flavonoids are described. Under the different experimental conditions exployed involving 1500 mice, flavonoids did not alter the radiation effect on the tumours as neither a protective nor a sensitizing effect was observed.


Variations in acid and neutral protease activity of rats with thermal oedema together with the influence of various benzopyrones.

The benzopyrones are known to be very effective in reducing thermal oedema. It is believed they do this by enhancing protoelysis of the abnormal accumulated protein. However, the enzymes which are affected were not known. The effect of the benzopyrones was examined on both acid and neutral proteases in normal and thermally injured animals. In normal animals the benzopyrones at first enhanced serum acid protease levels, while serum neutral protease levels were depressed. Acid and neutral protease levels of the skin were not altered. The effect of thermal injury was to elevate serum acid protease activity and to depress neutral protease activity. Additional treatment with the benzopyrones further enhanced the former and depressed the latter. Acid and neutral protease activity of the skin was depressed by burn, but enhanced by benzopyrone treatment. The enhancement of proteolytic activities by the bezopyrones is indicative of increased phagocytosis and digestion. The resulting small protein fragments can rapidly leave the injured region thus freeing the osmotically attracted fluid, which is the cause of oedema.


Vasotropic drugs--a survey based on a unifying concept of their mechanism of action.

A group of vasotropic drugs was surveyed using a new assay method based on the inhibition of endothelaemia increases after a standard vascular lesion in rats. The new test is considerably more sensitive than all previous ones. It provides a common link between all tested vasotropic drugs and points also to their common mechanism of action. All of them have a protective effect on endotherlium based, in some of them at least, on the preservation of the consistency of endothelial cement. The effect is probably mediated by their influence on calcium availability.


[Biopharmaceutic investigations with D-norpseudoephedrine. 2nd communication: Bioavaliability of a depot preparation (author's transl)].

The concentrations of D-norpseudoephedrine in the plasma of five healthy male subjects were measured after oral administration of either two Fugoa depot aragees or of a standard of 60 mg D-norpseudoephedrinehydrochloride in a hard gelatin capsule. Areas under curves (AUC) were calculated with the trapezoidal-rule for blood levels to compare bioavailability. The medium bioavailability of Fugoa depot dragees was 95% compared to the standard. With the paired t-test no significant difference in the bioavailability occurred.


[Experimental investigation of psychophysiological effect of a new antidepressant (lofepramine) as compared to imipramine and placebo (author's transl)].

Using 24 non-selected healthy male students the effects of imipramine (single dose of 100 mg orally) and 4'-chloro-2-[3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-propyl]-methylamino]-acetophenone-hydrochloride (lofepramine, Gamonil) (single dose of 140 mg orally) in comparison to placebo (doubleblind) on subjective, physiological and performance variables were examined. All subjects (Ss) received the three drugs in a completely counterbalanced sequence. On the basis of their scores on the Depression Scale of the Freiburger Personality Inventory (FPI, Fahrenberg) Ss were divided into two groups of 12 Ss each, "high depression" and "low depression" group. Two-way analyses of variance were computed. Imipramine and Lofepramine elevate scores in the mood scale, but only for the "high depression" group. For the Ss scoring lower in depression no such effect can be demonstrated. The physiological effects are similar. Reported side effects are less for lofepramine than for imipramine.


Laser photolysis and fluorescence studies on pyrene-thiazide and pyrene-diazoxide systems.

The laser photolysis studies on pyrene, pyrene-thiazides and pyrene-diazoxide systems in acetonitrile revealed that thiazides and diazoxide can scavenge the photoejected electron. It was found that the pyrene fluorescence is quenched by the present diuretics and related compounds and both static and dynamic quenching constants were obtained. Thiazides quench the fluorescence through both static and dynamic mechanism, while the small static quenching constant and no lifetime shortening of pyrene were observed in the case of diazoxide quencher. This difference may correspond to the difference of their diuretic activity.


[Antiviral agents / 9th communication: virustatically active N-(1-adamantyl)-thiourea derivatives based on cyclic secondary amines (author's transl)].

By nucleophilic addition of pyrrolidine (2a), piperidine (2b), 3-hydroxypiperidine (2c), and 4-hydroxypiperidine (2d) on 1-adamantyl-isothiocyanate (1), the N',N'-disubstituted N-(1-adamantyl)-thiourea derivatives 3a, 3b, 3c, and 3d are accessible. Particularly 3d exhibits remarkable antiviral activity vaccinia and herpes virus.


[Anticoagulant activity of triiodinated x-ray opaque media (author's transl)].

The anticoagulant activity of the triiodinated X-ray opaque media iodipamide, iothalamate and diatrizoate on standardized normal human pool plasma was investigated in vitro. We found a dose dependent lengthening of the thrombin time, the reptilase time and the partial thromboplastin time together with a dose dependent drop of the calcium thromboplastin and factor V activity. Iodipamide proved to exert the most pronounced anticoagulant activity of the 3 contrast media tested. The results are interpreted as latent disseminated intravascular coagulation with hyperfibrinolysis following the direct interaction of contrast media with the coagulation enzymes.


[Phytopharmacological study on proadiphene, amiphenazole and bemegride in association with phenobarbitone (author's transl)].

The capacity of 2-diethylaminoethyl-alpha, alpha-diphenylvalerate (proadiphene), 2,4-diamino-5-phenyl-thiazole (amiphenazole) and 2,6-dioxo-4-methyl-4-ethyl-piperidine (bemegride) of stimulating or stopping the growth of seedlings of Lepidium sativum L. was tested. Only bemegride shows a weak stimulating effect between 10(-3) and 10(-2) moles/l. In combination with phenobarbital these compounds counteract the stimulating effect and increase the inhibiting one of this barbiturate on the growth of the seedlings.


[Exchange of aromatically bound halogen for OH- and SCH3-groups in metabolising clozapine in the human organism (author's transl)].

8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo-(b,e)(1,4)-diazepine (clozapine, 1) is metabolized in humans by exchange of the aromatic halogen for a hydroxy- or a methylthio-group (compounds 2 and 3). Further metabolites are the N-demethyl derivatives of 2 and 3, the compounds 4 and 5. In addition a clozapine metabolite with the structure 6 with an oxidized piperazine ring was found. The presence of a metabolite with an oxidized sulfur atom is suggested. Possible ways for the formation of these metabolites are discussed.


[Biotransformation and pharmacokinetics of grandiflorenic acid [kauradiene-9(11),16-oic acid-18] / 1st communication (author's transl)].

Grandiflorenic acid is oxidized by several partial-synthetic ways. The spectroscopic properties of the resulting compounds are compared in mass-, IR- and 1H-NMR-spectrometer.


Isolation of apoprotein from bovine lung surfactant material by sodium deoxycholate.

Aqueous solutions of bovine lung surfactant material were solubilized with a high concentration of sodium deoxycholate and the protein moiety could then be separated from the mixed lipid-sodium deoxycholate micelles by gel filtration in the presence of a micellar concentration of sodium deoxycholate of 10 mM. The lipid-free protein showed only one detectable peak in the gel filtrate and the sedimentation rate of this protein was 12.1 S. Sodium dodecyl sulfate disc gel electrophoresis showed essentially the same pattern as did the protein extracted directly from the bovine lung surfactant material with organic solvents, of which the major component has a molecular weight of 36 000. This protein should be the main apoprotein of lung surfactant material, and the main band in the sodium dodecyl sulfate disc gel electrophoresis, with a molecular weight of 36 000, would constitute the major protein subunit.


On enzymatic clotting processes. I. Kinetics of enzyme-triggered coagulation reactions.

The kinetics of enzymatic clotting reactions such as the clotting of blood or milk, is analyzed. The appearance of a lag phase in the clotting is shown to be due to the difference in reaction order of enzymatic production and flocculation. The weight-average particle weight of the product formed is found to be a quadratic function of the reaction time. The condition for the clotting time is t square root of ksV/2 = C, where t is the clotting time, ks the flocculation rate constant, V the maximum rate of enzymatic product formation and C a constant. In agreement with this result double-logarithmic plots of t versus enzyme dilution are always observed to be linear over a wide range of enzyme concentrations. No statistical evidence could be produced for the widely held belief that the clotting time should be inversely proportional to the enzyme concentration. Varying exponents of the latter in its relation to the clotting time are discussed in terms of von Smoluchowski's theory of the slow coagulation of colloidal particles.


Combination intrathecal therapy for meningeal leukemia: two versus three drugs.

The comparative effectiveness of intrathecal (IT) combination chemotherapy using two agents, methotrexate (MTX) and hydrocortisone (HDC), and three agents, MTX, HDC, and cytosine arabinoside (CA), in treating meningeal leukemia was determined in a randomized Southwest Oncology Group study. Following central nervous system (CNS) remission induction the same regimen was used for periodic maintenance until CNS relapse supervened. Complete CNS remission was achieved in 100% of 43 children given two-agent therapy and in 96% of 48 children given three-agent therapy. Length of CNS remission for two-agent therapy was 1-150+ wk, median 47.2 wk; for three-agent therapy, remissions were 1-190+ wk, median 64.6 wk. Differences in length of remission curves were not of statistical significance (p=0.71). Toxicity of combination IT chemotherapy in the two- and three-agent regimens was reduced compared to that of IT MTX alone for CNS remission induction and maintenance. The additive effects of the IT drug combinations have been less than expected. The cytocidal activity of these agents when administered simultaneously of sequentially is not fully understood. Further studies are clearly indicated to determine optimum doses, schedules, and sequences for the chemotherapeutic agents which can be given intrathecally in combination.


Is milk a coronary health hazard?

Epidemiological and clinical evidence is presented on an association between the quantity of milk consumed and the incidence of ischaemic heart disease. It is suggested that the daily intake of liquid milk for adults should be at most one-third of a pint (less than 0-21).


Antitumor effects of RNA isolated from murine tumors and embryos.

We describe the antitumor effects of a certain RNA(s) isolated from murine tumors and embryos. A single i.v. injected of 10 to 30 microgram of this RNA(s) induces necrosis, hemorrhages, and regression of solid tumors in the strain of origin; in pregnant mice it is embryotoxic, causing resorption of the embryos, but has no toxic effect upon the tumor-bearing or pregnant host. Its action is highly specific, and its presence in both tumors and embryos suggests that it may result from reexpression of embryonic genes in tumor cells.


Perilymph penetration of methotrexate in cats.

The perilymph of the inner ear has recently been suggested as a site of frequent leukemic or lymphomatous infiltrates. Experimental evidence supports the existence of barrier mechanisms and explains the attenuated entry of several substances, including chemotherapeutic agents, from either the cerebrospinal fluid or blood into theperilymph. The present study describes the attenuated entry of methotrexate into the perilymph compartment of experimental animals following intrathecal or iv administration.


Clinical pharmacology of intrathecal methotrexate. I. Pharmacokinetics in nontoxic patients after lumbar injection.

Cerebrospinal fluid (CSF) and plasma methotrexate (MTX) concentrations were measured in 76 children and adults who received intrathecal MTX, 12 mg/m2 body surface area, without developing symptoms of lumbar puncture syndrome or drug-induced neurotoxicity. After an initial rapid redistribution of the injected drug, the mean antifolate value in the lumbar CSF declined in a biphasic manner with half-lives of 4.5 and 14 hours. In the plasma the mean MTX concentration reached a peak of 2 X 10(-7) M between 3 and 12 hours after injection and decreased biexponentially thereafter with half-lives of 5.5 and 24 hours. Pharmacokinetic analysis suggested that the predominant mode of MTX transfer from the central nervous system to the systemic circulation is bulk flow absorption of CSF with entrained drug. The two phases of disappearance from the lumbar CSF appear to result from interaction of the convective transport and diffusion between the CSF and brain extracellular fluid (and perhaps some intracellular sites).


Reduction of plasma triiodothyronine (T3) induced by propranolol.

The effect of propranolol on plasma triiodothyronine (T3), thyroxine (T4) and triiodothyronine uptake by Sephadex G-25 (RT3U%) was studied in fourteen thyrotoxic patients and eight normal volunteers. 40 mg of propranolol as a single oral dose caused significant reduction in total serum T3 which began 60 min after administration. No significant changes were observed in T4 and RT3U% values. Plasma T3 levels remained suppressed during a 5 day course of treatment with propranolol. These results suggest that propranolol has a direct effect on peripheral metabolism of T3 rather than on thyroid hormone secretion.


Development of a lymphocytic lymphoma during immunosuppressive therapy with azathioprine for systemic lupus erythematosus with renal involvement induced by phenylbutazone.

A case of systemic lupus erythematosis (SLE) with renal involvement after the administration of phenylbutazone is described. The patient subsequently developed a lymphocytic lymphoma following two years treatment with azathioprine and prednisone. Although the association between SLE, immunosuppressive therapy and the development of lymphomas is well documented, the increased incidence of malignant disease in uremic patients is less well recognized. The varied factors that may have contributed to the development of the lymphoma in this case are discussed, together with a review of the literature.


Genital herpes: the newest venereal disease. Report of a case associated with aseptic meningitis.

A case of genital herpes associated with aseptic meningitis is presented. The current concepts regarding epidemiology and pathogenesis, with special attention to involvement of the central nervous system, are discussed. The various clinical and laboratory aspects of the disease are briefly discussed. A review of the literature revealed only forty-four cases of proved herpetic infection of the cerebrospinal fluid in patients other than neonates. The concept of genital herpes as a new and serious public health problem is presented. With the present state of our knowledge and technology, genital herpetic infections will be a major problem for some time to come.


[Intraamnial application of 14C-labeled lecithine at man 13 hrs. ante partum (author's transl)].

It was examined, whether by intraamnial applicated lecithine an approaching respiratory distress syndrome could be prevented. This possibility of therapy was tested on a fetus unviable of life. It was shown by examining the lavage-fluid of the fetal lung, as well as the organ homogenates of lung; liver and gut, that the intraamnial applicated lecithine was metabolised and resynthesised in the organism. In the lung the lecithine was present as a complete molecule.


[Studies on the relationship of maturity to the tolerance of ischemia].

In newborn rabbits during asphyxia caused by ligature of the trachea circulation was maintained 2-3 times as long as in adult rabbits because in contrast to the adults myocardial energy loss in asphyxia is rather low caused by a small energy consumption for circulatory work. In the cerebral cortex of newborn rabbits glycolysis is able to meet a good part of energy demand, with the energetic situation predominantly depending on glucose supply by maintenance of circulation. Thus in addition sufficient blood glucose levels deliberated from glycogen stores in liver and lung are an important factor for the central nervous revivability. Kidney and skeletal muscle tolerate anaerobic periods for rather long time because of their high glycogen stores and low metabolic activity but do not contribute to glucose supply of other tissues.


Pharmacokinetics of carfecillin and carindacillin.

The pharmacokinetics of carfecillin and carindacillin was compared in 10 volunteers. The pharmacokinetic parameters of both antibiotics were also determined using an analog computer. From the pharmacokinetic point of view, no significant differences between the two carbenicillin esters were found.


Factors affecting the bioavailability of phenytoin.

The bioavailability of seven phenytoin (DPH) formulations, five brands of tablets and two suspensions, was measured in a cross-over study with six healthy volunteers. Single doses of 600 mg of DPH were used and the bioavailability was determined as the area under the serum DPH concentration-time curve (AUC). Highly significant differences between the bioavailability of various products were found. The highest bioavailability was obtained with suspension prepared from the micronized raw material of DPH and the lowest bioavailability (26% of that of the former suspension) with the tablets having the largest particle size of DPH. The in vitro dissolution rate of the products in borate buffer at pH 9 showed a significant (p less than 0.01; r=0.93) correlation with the in vivo bioavailability of the DPH products. In addition to the particle size, several other formulation factors are important for dissolution rate and absorption characteristics of DPH products. The properly performed measurement of the in vitro dissolution rate can be used as a preliminary screening test in predicting the bioavailability of DPH products.


Pulmonary surfactants in pulmonary oedema induced by head injury in mice.

A study has been carried out to examine the role of pulmonary surfactants in pulmonary oedema induced by head injury. Pulmonary oedema was induced by head injury in mice by the method of Mackay (5). There was no change in surface tension as well as total phospholipid concentration of the lung between control and test groups suggesting that there was no involvement of lung surfactant sytem in pulmonary oedema induced by head injury. Since the animals in the test group died within a few minutes, possibly there may not have been sufficient time for alteration of lung surfactant system.


Photography of peripheral pulmonary airway expansion as affected by surfactant.

Edges of excised lungs from twenty 27-day-old rabbit fetuses were photographed as tracheal pressure was raised and air entered alveoli. Lungs from two littermates were expanded simultaneously with pressure up to 50 cmH2O. The effect of surfactant (SA) on peripheal airway expansion was assessed by depositing 25 mul of SA suspension in the trachea of one pair of lungs. The suspension was obtained by washing the lungs of young adult rabbits and concentrating the SA by centrifugation. In 9 of the 10 experiments, the SA-treated lung was the first to become expanded. When pressure was lowered to 10 or 0 cmH2O, peripheral airways of treated lungs usually maintained expansion; air in control lung alveoli disappeared, or was trapped. High surface tension tended to collapse the cylindrical respiratory bronchiole rather than the spherical alveolus, causing air trapping, if the radius of the cylinder was less than half of the sphere. SA lessened collapsing tendency in the respiratory bronchiole.


Dysthyroid ophthalmopathy: orbital evaluation with B-scan ultrasonography.

B-Scan ultrasonography was used to show muscle enlargement in all patients with Graves' disease and positive eye signs even when the clinical signs were minimal (lid lag and stare only). In addition, in cases of Graves' disease without clinical eye signs, 63% of orbital examinations showed ultrasonic evidence of muscle enlargement, often to a marked degree. This occurred more frequently in euthyroid patients after ablation of the thyroid by surgery or radiation, than in frankly thyrotoxic patients. The presence of subclinical ophthalmopathy in the fellow eye is a useful diagnostic aid in cases of uniocular proptosis.


Use of litmus milk agar for presumptive identification of cutaneous propionibacteria.

Presumptive identification of cutaneous propionibacteria can be achieved with litmus milk agar as medium.


Aortic mycotic abdominal aneurysm involving all visceral branches: excision and dacron graft replacement.

A 41 year-old patient with an aortic mycotic abdominal aneurysm involving all visceral branches is presented. Excision and dacron graft replacement involving limbs to the coeliac axis, superior mesenteric, and both renal arteries was accomplished successfully. The rationale for employing dacron material in infected tissue is reviewed. In our opinion, an integral aspect of its usage includes the debridement or removal of the aneurysm in conjunction with prolonged antibiotic coverage postoperatively. The patient is alive and free of apparent infection one year following surgery.


Milk consumption by black and by white pupils in two primary schools.

It is heartening to note that relatively well nourished black children in the United States, a number of whom are, in all probability, lactose intolerant and most of whom are destined to become lactose intolerant adults, are able to consume nutritionally valuable quantities of milk with meals and, on the whole, do not report suffering from any abdominal pain or discomfort. It is also encouraging that this population of over two hundred primary school children consumed, on the average, 75 per cent of the 1/2 pt. milk served with lunch, reported drinking an average of three glasses of milk daily, and the vast majority reported liking milk and a number of other dairy products which are important nutrient sources in their diets.


The management of infected arterial aneurysms.

Infected aneurysms involve the aorta, visceral and peripheral arteries and are associated with a high morbidity and mortality. Prompt confirmation of the suspicion of infection, resection of all infected tissue, and prolonged antibiotic therapy based on appropriate sensitivity studies are crucial to successful management. Patients whose aortic aneurysms grew Gram negative organisms were more likely to suffer early rupture of an aortic aneurysm, and had a higher mortality. Superior mesenteric aneurysms are preferably treated by resection. Upper extremity aneurysms can often be excised without distal ischemia. Lower extremity aneurysms were more likely to require reconstruction which can be accomplished through non-infected tissue planes, preferably with autogenous tissue.


Studies on the ecology of the tick Amblyomma hebraeum Koch in the Eastern Cape Province of South Africa. II. Survival and development.

Quantitative data are given on the survival and rate of development of Amblyomma hebraeum Koch in relation to temperature and humidity, in laboratory and field conditions. By comparison with other ixodid species the developmental periods of A. hebraeum are extremely long. Development is most rapid at 30 C, and the duration of the developmental periods increases exponentially with decreasing temperature. Oviposition occurs successfully at 15 and 30 C, egg incubation at 20 to 30 C, and larval and nymphal molting at 15 to 35 C. The ability of the developing stages to survive in dry conditions increases with increasing size, i.e. from egg to engorged larva. Mortality in the developing stages increases at low humidities as temperature decreases, due to the longer periods over which water is lost. The conversion efficiency of ovipositing females is influenced by both temperature and atmospheric humidity. Longevity of unfed larvae is correlated directly with saturation deficit. Longevity of unfed nymphs and adults is dependent on both temperature and saturation deficit.


Interaction of hydrocortisone with model membranes containing phospholipid and cholesterol.

Pure and mixed monolayers of lecithin and cholesterol were spread on substrates of dissolved hydrocortisone at 25 and 37 degrees. The presence of hydrocortisone increased the surface pressure of dipalmitoyl and egg lecithin films that were in head contact. The increase in surface pressure was dependent on steroid concentration. There were no significant interactions with coherent cholesterol monolayers. Penetration of hydrocortisone was decreased by the addition of cholesterol to the monolayer system. These model membrane systems indicate that hydrocortisone interacts with the hydrated polar head group of the phospholipid and not with films whose molecules are in hydrocarbon tail contact.


Selection of breast cancer patients for adjuvant chemotherapy. Another look at the prognostic importance of involved lymph nodes.

To aid in the selection of breast cancer patients for adjuvant chemotherapy, 263 patients with primary breast carcinoma undergoing curative surgery at the Yale-New Haven Medical Center were examined with respect to axillary lymph node involvement and prognosis. Thirty-five percent of patients with one to three axillary nodes histologically involved with cancer relapsed within five years, as did 61% of patients with four or more cancer-positive nodes. Equally important was the clinical stage. Stage III patients had a poor prognosis (71% relapse rate) regardless of their axillary status. Stage I patients with metastasis to one to three axillary nodes did just as well as stage I patients with no nodal involvement (13% relapse rate). Relapse rates within the nodal categories are significnatly less (P less than .05) than those reported by the National Surgical Adjuvant Breast Project.


Gray-scale ultrasonography and thin-needle cholangiography. Evaluation in the jaundiced patient.

Gray-scale ultrasonography (GSU) and thin-needle cholangiography (TNC) were performed in 35 consecutive patients with unexplained jaundice. The status of the biliary tree was correctly assessed by GSU in 33 of 35 cases (94%); in two patients technical difficulty prevented definitive assessment. Neither false-positive nor false-negative results were encountered. There were no discrepancies between the results of GSU and TNC. We conclude that GSU provides a safe, highly reliable method of assessing the jaundiced patient and should be the preferred initial procedure in the diagnostic evaluation of patients with jaundice when the major differential lies between the medical and surgical types. If GSU does not demonstrate a dilated biliary system, TNC is unnecessary, and other diagnostic studies should be undertaken.


Lightning-strike disaster among children.

A lightning strike involving 47 children is described. Four cases demonstrate the most common and serious resulting pathology: burns, myocardial infarction, and neurological symptoms varying from feelings of fear and nightmares to brain death. The pathophysiology of lightning injury is described. The importance of immediate resuscitation of the victim who appears dead after a lightning strike is emphasized, and procedures to prevent lighting injury are presented.


Insulin-dependent diabetes mellitus. Sudden onset following hypophysectomy in an acromegalic patient.

A euglycemic woman with acromegaly contracted conspicuous hyperglycemia two hours following transphenoidal hypophysectomy. Insulin therapy was initiated and has by necessity been continued. The development in the immediate postoperative period of blood glucose levels ranging from 300 to 500 mg/dl was totally unexpected, as the levels on the preoperative oral glucose tolerance test were normal. No explanation for this sudden development of hyperglycemia is apparent. Therefore, frequent monitoring of the blood glucose level is necessary in all acromegalic patients following hypophysectomy, even if they are euglycemic prior to surgery.


Pop bottle explosions.

To our knowledge, there are only two brief reports in the medical literature of injury sustained as a result of a carbonated soft-drink (pop) bottle explosion. We report three such cases and review pertinent data on this hazard.


Serum ferritin level. Determinant of iron requirement in hemodialysis patients.

Seventeen patients without renal failure and 14 patients receiving long-term hemodialysis were studied. Serum and bone marrow ferritin determinations were made at the time of bone marrow aspiration. A good correlation was found between serum ferritin levels and bone marrow iron stores, as well as between bone marrow ferritin levels and iron stores. Serum ferritin determinations appear to give an accurate estimation of bone marrow iron stores, thereby providing a reliable guide for iron replacement therapy and reducing the need for repeated bone marrow aspirations. Serum ferritin levels of less than 105 ng/ml suggest decreased iron stores, and values greater than 120 ng/ml indicate adequate or increased iron stores. Preliminary data also suggest that bone marrow ferritin determinations may be useful in quantitating bone marrow iron stores.


Salt substitutes as a source of potassium.

Chemical analysis of commercially obtained potassium-containing salt substitutes was performed. The potassium content was remarkably uniform from sample to sample of each brand and even among different brands. When hypertensive outpatients ranked these products, several were shown to differ considerably in taste characteristics and in overall preference. A cost comparison showed salt substitutes to be less costly than prescription (pharmaceutical) potassium supplements.


Sudden catatonic stupor with disastrous outcome.

Catatonic stupor occurred in two psychiatric inpatients, predisposing them to staphylococcal pneumonia, venous thrombosis, and pulmonary embolism. Disastrous outcomes ensued. Catatonic stupor can lead to fatal complications, and aggressive medical and psychiatric therapy is indicated.


Diabetes insipidus following cardiorespiratory arrest.

Diabetes insipidus following cardiac arrest and hypoxemic encephalopathy occurred in two patients. In both, severe hypoxemic brain damage was followed within three days by clinical and laboratory features of diabetes insipidus, which were corrected by administration of exogenous vasopressin. Hypothalamic injury resulting in diabetes insipidus should be considered in the differential diagnosis of polyuria and dehydration occurring in critically ill patients who have suffered cardiorespiratory arrest.


Patterns of blood pressure in Milwaukee.

Blood pressure measurements were obtained among 92,074 persons in Milwaukee between 1974 and 1976 by the Milwaukee Blood Pressure Program. Systolic hypertension was more prevalent in young white men than blacks below 25 years of age, was more common in middle-aged blacks than whites, and was equally prevalent among all persons past 65 years. Diastolic hypertension was more prevalent in blacks than whites of all ages. Whereas the prevalence of systolic hypertension in the population increased with age and was present in a majority or near majority of persons past 65 years, the prevalence of diastolic hypertension rose until the sixth decade, after which it declined. Hypertension was primarily of a diastolic variety in young blacks, whereas systolic hypertension was a prominent feature in young whites.


Treatment of Bechçet's syndrome with transfer factor.

Six patients with Behçet's syndrome were treated with transfer factor (TF) from randomly selected donors. Mucocutaneous symptoms and signs were predominant at the time that TF injections were started. Three patients showed great improvement, one moderate improvement, and one was unresponsive to multiple injections of TF from different donors. One case was uninterpretable because of concomitant administration of high doses of prednisone and chlorambucil and brief treatment with TF. These results indicate that TF therapy may be beneficial in some patients with Behçet's syndrome and that a trial of TF is warranted at least in the absence of severe ocular or neurologic manifestations.


Mammographic screening. Value in diagnosis of early breast cancer.

Analysis of the two-year results of a project screening asymptomatic women for breast cancer is presented. There were 10,008 women examined and 490 biopsies completed. There were 97 cancers found, of which 55 were nonpalpable; 36 of the 97 cancers were in women under 50 years of age. The incidence of axillary metastasis was 7% in the nonpalpable lesions. We suggest that mammography is useful in discovering curable breast cancer, even among younger women at least down to the age of 40. The potential benefit seems to greatly outweigh the theoretical carcinogenic hazard. Selection of candidates for mammography should be based on all risk factors, not just age. An attempt is made to correlate the results with the theoretical risks as proposed by others.


A planned system of patient education.

A planned system of patient education is now used in more than 70 group clinics, hospitals, and other health care institutions. Essential features of this system are (1) a patient education center, (2) a patient educator, and (3) patient education programs. Structured programs are especially useful in the management of chronically ill patients. Patients have responded enthusiastically to this planned system. The response of physicians has ranged from enthusiastic to resistant.


Angiotensin II inhibition. Treatment of congestive cardiac failure in a high-renin hypertension.

A patient with intractable congestive cardiac failure secondary to renovascular hypertension and severe coronary artery disease was infused with the competitive antagonist of angiotensin II, saralasin acetate. The infusion produced an impressive increase in cardiac output and left ventricular stroke work index in parallel with a striking decrease in the systemic and pulmonary vascular resistance, the coronary resistance, and the myocardial oxygen consumption. It is suggested that angiotensin inhibition may present advantages over other forms of treatment of congestive cardiac failure in selected cases.


Quinidine-induced agranulocytosis.

In a 75-year-old man, agranulocytosis and septicemia developed after eight weeks of quinidine sulfate therapy. An IgG antibody requiring the presence of quinidine was shown by complement-dependent leukocytotoxicity and leukoagglutination reactions. The antibody did not cross-react with quinine and was active against WBCs obtained from normal subjects and from the patient himself.


Adaptive coping mechanisms in adult acute leukemia patients in remission.

The adult leukemia patient in a drug-induced remission possesses a unique set of emotional responses as he adjusts to an altered life-style and a life-threatening disease. Six patients, ranging in age from 24 to 62 years and being treated with monthly maintenance chemotherapy, were interviewed over a six-month period. The adaptive coping mechanisms most frequently identified were denial of being sick, identification with fellow patients to form a "hospital family," and anticipatory grief of one's own losses by participation in grieving another patient's death. The means of adjustment was to adapt to the "hospital family" and benefit from the therapeutic milieu established on the ward. The patient's total response to remission in acute leukemia can be influenced positively by appropriate intervention based on an assessment of his previous and present patterns of coping.


Occupational hazards for operating room-based physicians. Analysis of data from the United States and the United Kingdom.

Comparative analysis of data from three large retrospective surveys in the United States and the United Kingdom reaffirms an increased incidence of spontaneous abortion among female physicians working in the operating room. The live-born children of female physicians exposed in the operating room also had substantially more congenital abnormalities. Male anesthetists, compared with nonanesthetist physicians, had an increased incidence of hepatic disease; there was also an increased frequency of congenital abnormality in their children. The incidence of spontaneous abortion in wives of male anesthetists and in the rate of cancer among exposed male anesthetists was similar to control. Despite differences in survey methods and analysis, there was remarkable agreement in conclusions to be drawn from the independent studies.


The Minnesota Rural Physician Redistribution Plan, 1971 to 1976.

The Rural Physician Associate Program was developed by the University of Minnesota Medical School faculty in an attempt to meet the demands of the citizens of Minnesota to improve the distribution of primary physicians to rural areas. The program is offered to students who have completed 2 2/3 academic years of medical school. There were no regulations requiring the students' return to rural areas after completion of training. Thus far, 163 students have completed the program. Forty-three have continued in medical school and another 27 are in residency-training programs. Primary care residencies have been chosen by 68; another 31 have completed their medical education and are in rural practice. Of the 22 practicing in Minnesota, 21 have returned to rural communities.


Confirmation of brain death at bedside by isotope angiography.

Documentation of the absence of cerebral circulation is useful as a confirmatory test of brain death. Intravenous isotope angiography performed at the bedside with a mobile gamma camera is a safe, convenient, rapid, reliable, and easily understood method of proving the absence of cerebral blood flow that occurs in brain death.


Comparative study of bowel lymphosarcoma in childhood.

Five cases of lymphosarcoma of the bowel in Nigerian Igbo children are presented. They were found to be similar to an Australian series in the following respects: boys were more commonly affected than girls; affected children were all aged over two years; and the two main modes of presentation were intussusception and a localized abdominal mass. Unlike Australian children, Nigerian Igbos did not present with features suggestive of acute appendicitis.


[Etiopathogenesis of mycotic aneurysms].

In a patient after operation for metastatic bronchogenic brain abscess presence of aneurysm was demonstrated during control carotid angiography. In previous angiography the aneurysm had not been seen. During further observation the size of the aneurysm decreased. The patient died 5 weeks after the operation due to rupture of lung abscess into the pleural cavity. Microscopic examination showed that the lesion was in fact pseudoaneurysm. The authors discuss the mechanism of development of mycotic aneurysms and their possible role in the pathogenensis of metastatic brain abscesses.


Renal cell carcinoma with erythrocytosis and elevated erythropoietic stimulatory activity.

A case study is presented of a 55-year-old man who had clear cell renal carcinoma with pulmonary metastases and erythrocytosis. The increase in red blood cell mass was associated with an elevation in erythropoietic stimulatory activity in serum, pleural fluid, and tumor-cyst fluid as determined by the exhypoxic polycythemic mouse assay. It is postulated that the increased erythropoietic stimulatory activity represents autonomous tumor secretion of erythropoietin or an erythropoietin-like material. Electron microscopic studies confirmed the proximal tubular origin of this tumor.


Neurosurgical complications of heroin addiction: brain abscess and mycotic aneurysm.

Few neurosurgical complications occur as the result of heroin addiction. One case of brain abscess and another of brain abscess associated with mycotic aneurysm caused by such addiction are presented.


[Electrolyte metabolism in toxic goiter].

The author presents the results of parallel studies of potassium, sodium and calcium in the blood plasma and the 24-hour urine of 146 patients suffering from toxic goiter of different severity (mild course in 43 patients, of moderate severity in 59, and severe in 44). Investigations were carried out before and after the treatment with thyrotoxic preparation and in some of the patients (24) after strumectomy. Before the treatment patients with mild and moderately severe forms of the disease showed a tendency to increase of potassium and calcium and a fall of sodium level in the blood. Patients with a severe course of thyrotoxicosis displayed an opposite tendency in the changes of plasma electrolyte composition--the majority of the patients showed hypokaliemia, hypocalciemia and hypernatriemia. A tendency to normalization of plasma ionic composition was noted after the treatment with thyrotoxic preparations during the euthyroid state. Sodium and calcium plasma level became normal after strumectomy; potassium content remained lowered. Correction of electrolyte metabolism should be carried out in the patients with a severe form of toxic goiter; potassium and calcium administration is recommended.


Respiratory health and dust levels in cottonseed mills.

Four cottonseed mills in the southern United States contained high levels of total and respirable dust. A survey of 172 workers showed low prevalences of byssinosis (2-3%) and chronic bronchitis (4%). Mean baseline (out of dust) lung function values were normal. Mean functional declines over the working shift were present on Monday and absent on Friday, indicating an acute bronchoconstrictor response. Despite limitations in translating measured dust levels into estimates of individual exposures, the overall dose-response relationship seems to differ from that found in the cotton textile industry.


Calcium electrode--a method for the continuous monitoring of the platelet release reaction.

The calcium electrode is a convenient, inexpensive, and non-traumatic method for measuring changes in the extracellular calcium which accompanies a platelet release reaction. With this instrument, the temporal pattern of release by platelets in a buffered-saline medium following thrombin stimulation was observed as follows: an initial time lag phase, followed by a maximum release phase, and finally a slow release phase.


Potentiation by alpha and inhibition by beta-adrenergic stimulations of rat platelet aggregation. A comparative study with human and rabbit platelets.

Epinephrine, known to potentiate and elicit aggregation of human platelets, was shown to inhibit thrombin-induced aggregation of rat platelets, delaying the onset of aggregation from 2 to 12 times. Incubation of rat platelet suspensions with propranolol (1.25--30 micrometer), inactive by itself, totally prevented the inhibitory effect of epinephrine and also permitted a potentiation effect to show up. On the contrary, phentolamine (1.25--30 micrometer) potentiated the inhibitory effect of epinephrine on rat platelets and unmasked an inhibitory effect on human platelets. Finally, isoproterenol (0.25--9 micrometer) produced a marked inhibition of aggregation induced by thrombin, ADP and collagen in the three species studied, but most particularly in the rat. From these results, we conclude that stimulation of the platelet adrenergic receptors may either result in promotion (alpha-stimulation) or inhibition (beta-stimulation) of platelet aggregation. Furthermore, differences in the ratios or responses of alpha/beta receptors may account for species variations in the platelet aggregation response to catecholamine challenge.


Cigarette-smoking effect on platelet function.

The immediate effect of cigarette-smoking on ADP-induced platelet aggregation and on platelet adhesiveness was investigated in 12 normal subjects aged 20 to 40, in 10 normal subjects aged 43 to 72 and in 10 patients with cerebrovascular disease aged 45 to 75. All the subjects were heavy smokers (more than 20 cigarettes a day). After smoking 2 cigarettes a significant increase in ADP aggregation and platelet adhesiveness was found in the group of young heavy smokers, while in the old subjects with or without cerebrovascular disease the increase in platelet activity was never significant. These data were discussed and some hypotheses for this higher reactivity of platelets from young people were suggested.


The plasminogen activator of the arterial wall.

The plasminogen activator in 645 specimens of various human arteries--thoracic, abdominal aorta, carotic, pulmonary, renal, basilar, coronary - was studied using Todd's histochemical method. 92 cadavers were used, 1--18 hours post mortem from subjects aged from 272 days to 83 years. 45 specimens of pulmonary, renal and splenic arteries were obtained during surgery. The greatest fibrinolytic activity was within the adventitia. Intima occasionally showed very little fibrinolytic activity, or none at all. No statistically significant differences in plasminogen activator activity were found between the various arteries examined. A statistically significant increase in fibrinolysis in adventitia of atherosclerotic arteries was established. No correlation was found between the fibrinolytic activity of the arteries and their alkaline phosphatase content. Some properties of the plasminogen activator of the arterial vessel wall were evaluated. Influence of storage, inactivation with epsilonaminocaproic acid and extracted with potassium thiocyanate was studied.


Marathon run I: effects on blood coagulation and fibrinolysis.

Blood coagulation and fibrinolysis were assessed in 13 Finnish amateur runners aged 31 to 48, and one 65-year old taking part in a non-competitive marathon (42.2 km). After the run the mean values of partial thromboplastin time showed a very significant shortening, whereas the mean values of the prothrombin time and of plasma fibrinogen were not significantly altered. The mean values of euglobulin lysis time were significantly shorter and the mean values of fibrin degradation products increased highly significantly. After the run, protamine sulphate was positive or strongly positive in all subjects, whereas the ethanol gelation test was negative in all runners; no cryofibrinogen was detected in any participant. Thus, running a marathon race affects the haemostatic balance and activates the fibrinolytic mechanism. The effects of training and physical fitness on the above parameters are discussed.


Marathon run II: Effects on platelet aggregation.

Platelet count and aggregation were assessed in 9 Finnish amateur runners aged 34 to 48, and one 65-year old taking part in a non-competitive marathon race (42.2 km). After the run the mean value of platelet count showed a very significant rise (p less than 0.001). The platelets were markedly more sensitive to both ADP and collagen-induced aggregation. A highly significant increase (p less than 0.001) was noted for both the intensity and velocity of platelet aggregation. The finding of platelet by hyperaggregability after prolonged strenous exercise even in trained subjects is discussed. It is concluded that a through medical examination of the haemostatic balance is recommended before a marathon race.


A method for the measurement of fibrinolytic activity based on one dimensional diffusion using small glass tubes. II. With special reference to the differences between the use of plasminogen-rich fibrinogen and that of plasminogen-free fibrinogen as the substrates.

The optimal conditions for the measurement of the fibrinolytic factors of plasma were examined using human and bovine plasminogen-rich fibrinogen or plasminogen-free fibrinogen as the substrates using the one dimensional diffusion method. The results were as follows: 1. There was no essential difference found between using human or bovine fibrinogen. 2. The levels of proactivator-plasminogen and plasminogen could be measured while using either plasminogen-rich or plasminogen-free fibrinogen. But, in using the latter, the proactivator-plasminogen level could not be measured, if a final concentration of more than 2,000 Christensen units of streptokinase were employed. 3. When using plasminogen-rich fibrinogen, anti-plasmin(s) and anti-activator(s) could be measured while using urokinase and plasmin, but not while using streptokinase. However, further study should be given to the measurement of the inhibitors, when using plasminogen-free fibrinogen.


Characterisation of serum fibrinogen degradation products using gel chromatography and radioimmunoassay.

Fibrin(ogen) degradation products (FDP) are detected by radioimmunoassay in the serum of all subjects. Some of these FDPs have considerable biological activity in vivo, and hence may play a significant part in the process of coagulation. Chromatography of serum samples from patients including those with pulmonary emboli and deep venous thrombosis indicates that the majority of non-clottable fibrin(ogen)-related antigen present is of high molecular weight--greater than that of fibrinogen--and that in pathological situations there is a quantitative increase not a qualitative alteration in the molecular species present.


Early venous thrombosis: A scanning electron microscopic study.

The passage of a minimal electric charge was used to initiate thrombosis in rabbit femoral veins, and the events occurring during formation of the thrombus were observed using scanning electron microscopy. Thrombosis began to occur within ten minutes after passage of the charge, upon an apparently unaltered endothelium. The first event was the laying down of a fibrin meshwork and this was shortly followed by the appearance of regularly arranged platelet clumps.


Use of 125I-fibrinogen kinetic data to detect disseminated intravascular coagulation and deposition of fibrin in patients with metastatic cancer.

A technique using computerized data handling for following the fate of 125I-fibrinogen through various physiological compartments is presented. Its use in detecting fibrin build up in patients with metastatic tumors and cancer-caused DIC is explained. An increase in j3u (fractional catabolic rate as seen in the urine data) throughout the course of a study was found to be an important indicator of extravascular fibrin build up.


Interlaboratory oral anticoagulant quality assessment by the Netherlands Federation of Thrombosis Services.

The 50 laboratories of the Netherlands Federation of Thrombosis Services, covering a population of 9 million and responsible for the laboratory control of approximately 150,000 patients under oral anticoagulation, have participated since 1974 in a voluntary external and internal quality control program. The external program comprises a monthly distribution to the member laboratories of a series of artificially prepared control blood samples, two of which are identical. The overall variation of the coagulation times found were 10% (CV) in 1974 and 8% (CV) in 1975. Performance improved rather abruptly at the beginning of 1975, after the application of a tight methodological standardization and improvement by the manufacturer of the thromboplastin preparation (Thrombotest) used by the great majority of the laboratories involved. The main source of variation was found to be random error in the Thrombotest determination, approximately 6%. Interbatch variation of Thrombotest and inter-aliquot variation of control blood samples both do amount to approximately 3%(CV). In terms of rabbit tissue thromboplastins, which have a lower sensitivity than Thrombotest (i.e., a flatter slope of the correlation between the PT and the anticoagulant effect), the total variation in the performance of the Dutch laboratories is 2.2--5.6% (CV), which is unusually low. The main reason for this is the fact that the laboratories can rely not only on the services of the manufacturer but also on a central information office and a reference laboratory responsible for the preparation of the control blood as well as the standardization (calibration) of thromboplastin.


Factor VIII inhibition associated with chlorpromazine-induced hepatic injury.

A 90-year-old man was given chlorpromazine for sedation and 2 weeks later developed cholestatic jaundice and subsequently a factor VIII inhibitor. His death 4 weeks after institution of chlorpromazine, from massive bleeding, coupled with the autopsy finding of intrahepatic cholestatic jaundice, suggests that both adverse reactions were due to the drug.


Fibrinolytic, factor VIII and pulse rate responses to repeated adrenaline infusion followed by haemorrhage.

The role of catecholamines in the activation of coagulation and fibrinolysis following surgery remains controversial. In this study 5 dogs were infused with 1,2,3,6,9 and 12 microgram kg-1 min-1 of adrenaline at twice weekly intervals and were then reexposed to 3 microgram kg-1 min-1. Pulse rate and factor VIII increased after infusion of 1,2 and 3 microgram kg-1 min-1 but thereafter there was a diminished response and no response on reexposure to 3 microgram kg-1 min-1 although this was not significant in the case of pulse rate. Euglobulin lysis time shortened after each infusion of adrenaline and showed no development of tolerance. A control series of dogs infused with saline showed no similar changes. Both groups of animals were then bled to a blood pressure of 60 mm Hg for 60 minutes. Pulse rate and factor VIII did not change but euglobulin lysis time shortened in both groups. The results suggest that the activation pathways for changes in factor VIII and euglobulin lysis time induced by adrenaline are separate.


Spectrophotometric determination of factor Xa generation in factor IX concentrates.

Previous work from this department, concerned with testing the potential thrombogenicity of therapeutic factor IX concentrates, demonstrated that following recalcification of factor IX concentrates thrombin was generated within 3--30 minutes of incubation (Sas el al. 1975). The test developed (known as the TGt 50 test) is a two-stage assay and was thus found to be time consuming, tedious and tended to become inaccurate with long incubation periods and a large number of samples. A semiautomatic version of the test is reported in which the synthetic peptide Bz-ILE-GLU-GLY-ARG-pNA (S-2222) is added to recalcified, diluted factor IX concentrate in the micro-cuvette of a multiple sample recording spectrophotometer. Information can be obtained on (a) the amount of Xa (if any) present prior to recalcification (b) the initial amount of Xa formed and (c) the time taken to activate all factor =X to Xa. Direct graphical interpretation shows a number of qualitative differences between commercial preparations, but by either of the criteria (b) or (c) above, it is possible to place the different products into "activated" and "non activated" groups such that both the Xa generation times and TGt 50 tests identify the same two groups of products. This aggreement also indicates that the TGt 50 test is independent of the intrinsic factor V levels in the various concentrates.


Studies on the tissue thromboplastin during the coagulation-fibrinolytic process--ultrastructural changes.

An electron-microscopical study was made on morphological changes in which T-Tbp would undergo during clotting and fibrinolytic process. Morphological appearance of concentrically arranged membrane structure in T-Tbp remained nearly intact during blood coagulation process. T-Tbp, which existed in the sediments following dissolution of fibrin clot by the application of UK, showed an appearance of fine granules adhering to the surface of aggregates of particles through SEM. Through TEM, T-Tbp in the sediments was found to have retained its concentrically arranged membrane structures in most places, while, in some other places the appearance of fused membranes, smaller single vesicles and long sheets of membranes, and the formation of "blebs" etc. were observed. Various morphological changes caused by fibrinolytic substances accompanied the loss in coagulation activities. Our results showed that coagulation activities of T-Tbp must be completely dependent upon the presence of the membrane structures.


Specific vector control methods for prevention and eradication of malaria in Israel.

Wide-scale antimalaria activities have been continuously carried out in Israel since 1918. Regular checking and tracing of Anopheles provided important information on the seasonal appearance, life habits, flight range and population density of the malaria vectors. This method enabled us at any time to assess the degree of malaria risk and the effectiveness of the control measures taken. Specific methods of vector control were applied in accordance with the bionomy of the various Anophelines transmitting malaria. No resistance of local malaria vectors to DDT was found in 1961, probably due to the general use of larvicides not containing residual insecticides (including DDT) and the mode of indoor DDT application; spraying in selected localities and special timing in accordance with the bionomy of the local vectors. The relation between the changed status of the various Anopheles vectors and changes in the epidemiology of primary malaria cases in the course of time is also described. Malaria eradication in Israel was practically achieved in 1962.


Benin City mothers: their beliefs concerning infant feeding and child care.

One hundred and forty-three mothers residing in a representative area of Benin City were interviewed concerning their beliefs about child care, nutrition, and sources of information related to child care. Although all the mothers believed that breast-feeding was a natural procedure which should start from birth, they were not aware of the importance of breast milk to the baby. 58.7 per cent of the mothers would introduce artificial milk within the first month of life, and only 19.6 per cent would give breast milk alone for the first three months. Kwashiorkor was not widely believed to be related to protein-calorie deficiency, although some other food-related causes were given. The food taboos mentioned were not thought by the investigators to have any significant adverse effect on the sample children's health. Most of the information on health was obtained from friends and relatives and from infant welfare clinics. Recommendations are made for improvement of mothers' knowledge in total child care and use of health facilities.


Growth and morphological characteristics of canine venereal tumor cells in vitro.

Canine venereal tumor cells were grown in monolayer and tumor tissue fragments were maintained in vitro for 56 days in medium-199. Attachment and cell replication were evident within 17 hours and monolayer was obtained by the tenth day. Growth at first comprised mainly round cells with abundance of cytoplasm and vesicular nuclei, and a few spindle-shaped cells. Later cells became more elongated and like fibroblasts. Cell degeneration started by the 17th day and most were degenerated by the 24th day. Necrosis and depletion of cell population were prominent in tumor explants during the first 2 weeks. Distinct cell multiplication was evident by the 21st day and tumor fragments were repopulated with cells resembling the original tumor by the 56th day. Two distinct morphological cell types were seen: small cells with vesicular, round to oval nuclei and acidophilic cytoplasm; and the large cells with large hyperchromatic nuclei and acidophilic cytoplasm.


Exudative retinal detachment in retrolental fibroplasia.

Four cases of exudative retinal detachment associated with retrolental fibroplasia are presented. The exudation appears to be secondary to leakage from neovascularization as well as vitreous traction on normal retinal vessels. The range in age of onset was between 13 and 17 years, with three of the four cases occurring in patients 23 years of age or younger. Treatment is directed at eliminating the abnormal vasculature which, in our experience, has been accomplished best by an encircling scleral-buckling procedure. One patient, however, required vitrectomy because of the severe vitreous membranes and traction which were present.


[Distribution of aflatoxin M1 in whey and curd during cheese processing (author's transl)].

In model experiments on the distribution of aflatoxin M1 in whey and curd, the influence of the different processing steps was investigated. Taking the same weight ratio between whey and curd, the following results were obtained: a) The aflatoxin M1-distribution in whey and curd was not changed with increasing amounts of rennet, thus decreasing the renneting time at constant renneting temperatures. b) With increasing renneting temperatures, however, the toxin's percentage in the curd decreased at constant amounts of rennet, whereas the whey's content remained stable. For the commonly used temperature variations between 28 and 35 degrees C, the toxin content of the cheese varied in the range of about 12%. c) Processing of curd by acidification with different organic acids at constant temperatures did not show any change in the aflatoxin M1 distribution as compared to rennet coagulation. d) Curd processing by means of starter cultures led to a decrease in the aflatoxin M1 in curd only at higher temperatures; the toxin's percentage in whey remained practically the same. e) Washing of the curd with the 2 1/2 volumes of water decreased the aflatoxin M1 content of cheese by 22%.


Spontaneous regression of enlargement of the sella turcica and of associated panhypopituitary symptoms.

The case history of a woman born in 1946 is given. In 1968 she developed a syndrome of headache, fever. elevated antistreptolysin titer, enlarged and ballooned sella turcica, hypothyroidism secondary to TSH deficiency, secondary amenorrhoea of pituitary genesis, probable growth hormone deficiency, and secondary adrenocortical insufficiency. From 1972 all the mentioned pituitary defects of function disappeared, and the sella turcica gradually became normal in size as shown by X-ray examination.


The stimulation of prolactin secretion by sulpiride in "adolescent gynaecomastia".

In order to evaluate the function of the hypothalamic-pituitary-prolactin axis in "adolescent gynaecomastia" (AG), sulpiride was administered to 7 normal boys and 7 boys with AG. The maximum increase in serum prolactin (PRL) above the mean baseline level (deltamax) was used as index of response. The sulpiride induced a greater PRL release in boys with gynaecomastia than in the controls. Our data indicate that boys with gynaecomastia may have a greater pituitary prolactin pool. The results also illustrate the usefulness of specific neurotrophic agents such as sulpiride as important tools for evaluating the function of the hypothalamic-pituitary-PRL axis.


Pituitary luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin from birth to puberty in female and male rats.

Pituitary content and concentration of LH, FSH and prolactin were measured by radioimmunoassay (RIA) at 2-day intervals from birth to puberty in female and male rats. During the first 2 to 3 weeks of life all hormones were low in pituitary content and concentration in both sexes. They all increased in females during the third and fourth week, but decreased sharply during the days before vaginal opening. During the first ovulatory cycle pituitary content and concentration of LH and prolactin increased again, FSH, however, remained low. In males, pituitary LH, FSH and prolactin content reached peak levels during puberty. Our results show a distinct sexual dimorphism for pituitary FSH. Pituitary LH and prolactin content and concentration patterns show similar tendencies in both sexes with a delay of several days in males. The dramatic changes in female pituitary hormone concentrations just before the first ovulation were not detected in males before the first occurrence of mature spermatozoa in the tubuli of the testes.


Development of stress-induced pituitary prolactin and TSH release in male rats.

Blood was collected from male rats of various ages under control conditions and after introduction of two stress factors. All animals were sacrificed between 15.00 and 16.00 h. Serum prolactin levels in immature male rats were found to be very low between birth and day 15 after birth. Neither exposure to a new environment, for example removal from the animal rooms for the duration of 10 min, nor exposure to concentrated ether vapour resulted in increased serum prolactin levels. Between day 20 and 35 basal serum prolactin levels were increased, they then fell at adult values. During this period of increasing serum prolactin levels pituitary prolactin release became stress-susceptable; i.e. elevated serum prolactin levels were observed after introduction of stress factors as in adult male rats. Serum TSH levels were found to be high between birth and day 10. Low TSH levels measured between day 15 and 40 and adult values were detected after day 40. Neither ether nor removal of the animals from their normal environment changed serum TSH levels at any age tested. The results indicate that the hypothalamo-pituitary in immature rats reacts in a similar way as that in adult animals from day 16-20 onwards. Serum TSH levels in these animals, however, are reduced, indicating that an increase in serum TSH is not necessary for normal processes of maturation.


Iodopeptides from human thyroglobulin.

Human thyroglubulin labelled in vivo by 125I was purified from eight different thyroid glands including normal thyroid tissue, thyrotoxic goitre and euthyroid multinodular goitre. The purified protein was cleaved with cyanogen bromide (CNBr) and the resulting peptides were separated by column chromatography and ion exchange chromatography. Reproducible elution profiles of both protein and iodine were obtained. However, the distribution of iodine depended on the iodine content of the intact thyroglobulin. Small CNBr peptides seemed to be preferentially iodinated, but with a limited capacity. With higher degrees of iodination, larger peptides became richer in iodine. This suggests sequential iodination of the thyroglobulin molecule. The mixture of small peptides was digested by trypsin. Two iodopeptides were identified in this material by peptide mapping and they had identical migration in thyroglobulins of different origin. One of them was purified by ion exchange chromatography and high voltage electrophoresis. Analogous amino acid composition was obtained for the iodopeptide purified from two different thyroglobulins. The data indicates that thyroglobulin iodination occurs in specific portions of the polypeptide chain and probably in a sequential manner.


Effects of amiodarone on thyroid iodine metabolism in vitro.

Since alterations of thyroid function have been reported in patients treated with amiodarone, 2-butyl,3-(4-diethylaminoethoxy-3,4-diiodo, benzoyl) benzufuran, the effects of this drug on the active iodide transport, organic iodine formation, thyroid peroxidase and the enzymatic iodotyrosine deiodination, were studied. In pig thyroid slices the iodide transport was affected by amiodarone at concentrations of 10(-4) M and 10(-5) M, showing a decrease of T/M (tissue/medium) ratios of 20% and 23%, respectively. Lower concentrations produced no significant differences from the controls. Iodotyrosine synthesis was only, but poorly, affected by 10(-4) M and 10(-5) M amiodarone. Inhibition of the DIT formation was greater than that produced for MIT. Thyroid peroxidase activity, as measured by the tyrosine-iodinase assay, showed a 20% decrease at 10(-3) M amiodarone. None of the other concentrations have affected the activity of the enzyme, except for 7% at a concentrations of 10(-4) M. The iodotyrosine deiodination was affected by amiodarone only at a concentration of 10(-3) M and 10(-4) M. The inhibitions were of 22.5% and 16.8%, respectively. We have concluded that, under the conditions of our study, amiodarone per se does not affect the intrathyroidal iodine metabolism in concentrations which are usually present in the sera of patients treated with this drug. However, it is not possible to rule out an in vivo direct action, if amiodarone is substantially concentrated in the human thyroid gland.


Distribution of LATS activity in immunoglobulin G subclass.

The immunological character of LATS was examined by affinity chromatography on Anti-IgG, Anti-Fab, Anti-Fc and Staphylococcal Protein A bound Sepharose. By affinity chromatography on Anti-IgG, Anti-Fab and Anti-Fc bound Sepharose, it is possible to separate LATS-immunoglobulin from LATS positive serum without loss of activity. Affinity chromatography on Protein A bound Sepharose is useful for obtaining further purified LATS-immunoglobulin. By this method, it is possible to separate IgG molecules of the subclasses IgG(1), IgG(2) and IgG(4) with high LATS activity. LATS activity was not found in the IgG(3) fraction. When IgG(1) fraction was purified from the fraction containing the 3 subclasses of IgG(1), IgG(2) and IgG(4), about 85% of total protein was found in IgG(1). However, specific activity per protein of LATS in IgG(1) fraction did not change remarkably. After papain hydrolysis the thyroid stimulating activity of LATS-immunoglobulin was located in Fab fraction of these 3 subclasses of IgG(1), IgG(2) and IgG(4), and especially in IgG(1). The Fab fraction presents a short acting type of thyroid stimulating activity. These data indicate that LATS activity is mainly distributed in the Fab fragment of IgG(1).


Secretin: high plasma levels in diabetes mellitus.

Plasma immunoreactive secretin levels were measured in 22 newly diagnosed non-ketotic, maturity-onset diabetics and 10 healthy control subjects during 50 gram oral glucose tolerance test (OGTT). The test was repeated in the diabetic group after 6 months' dietary treatment. At diagnosis the fasting secretin levels in the diabetics were higher than in control subjects but fell within the normal range following dietary treatment. In the diabetics there was a significant positive correlation between the fasting glucose and fasting secretin levels at the time of diagnosis. Suppression of secretin levels occurred during the OGTT, both in diabetic and control subjects.


Decrease of non-suppressible insulin-like activity after pancreatectomy and normalization by insulin therapy.

Non-suppressible insulin-like activity (NSILA-S) was determined in 5 dogs before and after pancreatectomy and again during insulin therapy. All NSILA-S determinations were carried out on serum samples which were passed over Sephadex G-50 columns equilibrated with 1 M acetic acid. The levels of NSILA-S decreased drastically shortly after pancreatectomy and rose slowly after institution of insulin therapy, to normal levels. During the period of severe diabetes after pancreatectomy the concentration of growth hormone was elevated. These findings indicate that 1) the pancreas cannot be the site of synthesis and release of NSILA-S, 2) NSILA-S levels do not always parallel growth hormone levels and 3) the synthesis and secretion of NSILA-S among other factors is under the control of insulin.


A case of adrenogenital syndrome with aberrant 11beta-hydroxylation.

A 17 year old female patient with hypertension, amenorrhoea and hirsutism was found to have subnormal levels of plasma and urinary cortisol, significant plasma levels of Reichstein's compound S and 21-deoxycortisol, high urinary levels of THS and pregnanetriolone as well as elevated levels of plasma and urinary testosterone. Treatment with 0.5 mg/day of dexamethasone or 25 mg/day cortisone reduced her hypertension and restored her menstrual cycles, but also resulted in the development of moon face, body striae and a gain in weight. Lower doses of cortisone were without effect. The deficient cortisol production coupled with the presence of unusual intermediates such as Reichstein's compound S and 21-deoxycortisol can be explained by a shift in the substrate specificity of 11beta-hydroxylase from C-21-hydroxylated substrates (i.e. compound S) to C-21-deoxy substrates (i.e. 17-hydroxyprogesterone).


A new assay method for the determination of oestrogen receptors.

A new assay method was developed to determine the quantity of oestrogen cytoplasmic receptors which are capable of associating with acceptor sites on chromatin. The quantity of oestrogen receptor complexes associated with chromatin is of paramount importance in the mechanism of action of oestrogen. This method is based on the specific binding properties of oestrogen to the receptor and on the binding of the complex to chromatin. Cytosol was pre-incubated with [3H]oestradiol-17 beta ([3H]Oe2) to form a complex, and further incubated with a constant amount of chromatin. After this the quantity of [3H]Oe2 cytosol receptor complexes specifically associated with the chromatin was determined. The binding activity of the chromatin to the [3H]Oe2 receptor complex was stable for at least six months in 0.15 M NaCl at -20 degrees C. This method enables us to determine the quantity of the biologically active oestrogen receptors more specifically than with other methods.


Statistical inference as applied to bioavailability data--a guide for the practicing pharmacist.

Descriptive statistics and statistical tests used in reporting bioavailability data are reviewed in order to give the practicing pharmacist the fundamental knowledge needed to evaluate such data. Using acetaminophen bioavailability data as a model the following concepts are explained: mean, median, mode, standard deviation, range, 95% confidence limit, Student's t-test, analysis of variance, and the Wilcoxon rank sum test.