A comparative ex vivo study of plasminogen activators and proteases for fibrinolytic activity and side effects in rabbits.

Urokinase, streptokinase, Brinase, trypsin, and SN 687, a bacterial exoprotease, have been evaluated in an ex vivo assay system. These enzymes were injected into rabbits and the fibrinolytic activity as well as other coagulation parameters were measured by in vitro techniques. Dose-response correlations have been made using the euglobulin lysis time as a measure of fibrinolytic activity and the 50% effective dose has been determined for each enzyme. Loading doses, equal to four times the 50% effective dose were administered to monitor potential toxicity revealing that Brinase, trypsin and SN 687 were very toxic at this concentration. Having established the 50% effective dose for each enzyme, further testing was conducted where relevant fibrinolytic and coagulation parameters were measured for up to two days following a 50% effective dose bolus injection of each enzyme. Our results have demonstrated that urokinase and streptokinase are plasminogen activators specifically activating the rabbit fibrinolytic system while Brinase, trypsin and SN 687 increase the general proteolytic activity in vivo. The advantages of this ex vivo assay system for evaluating relative fibrinolytic potencies and side effects for plasminogen activators and fibrinolytic proteases have been discussed.


Oxygen-induced consumptive coagulopathy and its enhancement by lead acetate.

The exposure of rats to 100% oxygen at 1 atmosphere leads to a prolongation of prothrombin times and activated partial thromboplastin times. This development is associated with a consumption of factor XII, VIII, and VII activities and with the appearance of fibrin monomers and fibrinogen degradation products. Lead acetate enhances all oxygen-induced changes of the coagulation systems drastically. The O2 survival time of chicks which are naturally deficient in factor XII is greatly increased over that of rats and is not affected by lead acetate. Oxygen survival times of rats suffering from chronic respiratory disease (CRD) are also significantly increased when compared with normal rats. It appears that consumptive coagulopathy and disseminated intravascular coagulation are early events in oxygen exposure, and that their development is accelerated by lead ions.


The effect of phospholipase C on platelet factor 3 in human blood platelets.

Intact human platelets isolated by gel filtration have been treated with purified phospholipase C. The effect of the enzyme on available and total platelet factor 3 has been tested. The available procoagulant platelet factor 3 was very low. A further small reduction was observed after incubation with phospholipase C when the enzyme was washed away before testing. External attack on platelets by phospholipase C led to a marked inactivation of total platelet factor 3.


In vivo labeling of platelets with 75Se -- selenomethionine in patients with hepatic cirrhosis and thrombocytopenia.

Labeling of platelets in vivo by 75Se -- Selenomethionine (75Se-M) was performed in nine cases of hepatic cirrhosis and thrombocytopenia for evaluation of the kinetics of platelet maturation. Folic acid and vitamin B12 deficiency was excluded by pretreatment of the patients with these agents. The platelet maturation time -- time between the injection of the isotope and maximum radioactivity of separated blood platelets -- was shortened to 7.7 +/- 1.1 days (mean +/- SD) compared to the normal 9.1 +/- 1.4 days. For explanation a disturbance of megakaryocyte maturation and/or platelet release from the bone marrow is suggested.


Influence of cytotoxic drugs on platelet functions and coagulation in vitro. IV. Melphalan.

Influence of melphalan on some platelet functions, plasmatic coagulation and fibrinolysis "in vitro" was investigated, using different concentrations of the drug (25, 50 and 250 mug/ml). The lowest concentration slightly inhibited adrenaline and/or collagen-induced platelet aggregation. Following the highest concentration of the drug, strong inhibition of aggregation was recorded, regardless of the inducer used. Melphalan was also shown to inhibit release of aggregating activity and release of platelet factor 4, as well as availability of platelet factor 3 and platelet acid phosphatase. The intensity of inhibition depended on both, melphalan concentration and the time of preincubation. In contrast to this, adhesion of platelets to glass slide was not found to be influenced by melphalan. Similarly, melphalan did not induce (in any concentration) loss of LDH from platelet cytoplasma, while triton X-100 or freezing and thawing of platelets caused significant increase of LDH activity. From coagulation tests studied, only thrombin time and reptilase time was found to be moderately prolonged in the presence of melphalan. Authors assumed that melphalan acts as a specific inhibitor of release reaction and can induce an acquired thrombocytopathy. The platelet membrane is not damaged by the drug, as was confirmed by the investigation of LDH activity. Influence on coagulation indicates some antithrombin effect of the drug. Although presented results were obtained in vitro, analogous changes in vivo could be suspected. Thus, impairement of platelet functions might play a part in haemorrhagic complications accompanying, in some cases, melphalan therapy.


Induction of the platelet release reaction by 1.3-dimethyl-5-aminoadamantane, a new adamantane derivative.

The amantadine derivative 1.3-dimethyl-5-aminoadamantane, D 145, induces in high concentrations of 2-10 mM the release reaction. Adenine nucleotides and 5-hydroxytryptamine (5-HT) are liberated to the same extent and in the same ratio as found after thrombin-induced release. The time course of release is very slow; maximal release is reached in 15-20 min. The process is temperature-dependent and dependent on energy derived from glycolysis and oxidative phosphorylation. Extracellular Ca++ does not promote the release process. D 145, in accordance with the mother-substance amantadine, inhibits 5-HT uptake non-competitively, KI = 0.15mM. In concentrations of 0.1-1 mM D 145 triggers only the liberation of 5-HT, adenine nucleotides are not liberated. The ADP induced platelet aggregation is completely inhibited after preincubation with a 1 mM solution of D 145.


Kinetic aspects of the interaction of blood clotting enzymes. VII. The relation between clotting time and prothrombin concentration.

The relation between clotting time and the inverse of prothrombin concentration is shown to be rectilinear.


Localization of tissue thromboplastin in the human brain.

Monospecific antisera against the purified protein component of tissue thromboplastin (apoprotein-III) from human brain have been raised in goats and rabbits. The antisera neutralized tissue thromboplastin prepared from brain, thyroid gland and pulmonary tissue, indicating that apoproteins in the various preparations cross-reacted immunologically and therefore were similar or identical. Comparison of the activities of tissue thromboplastin preparations from 34 different areas of the brain demonstrated a characteristic distribution pattern and a wide range of activities. White and grey matter from the same areas had similar activities. Bulbus and tractus olfactorius, medulla oblongata, corpus pineale, hippocampus and hypothalamus contained 160-270% of the average activity, whereas cerebellum globus pallidus, nucleus ruber and substantia nigra contained 30-60%. The distinct distribution pattern was unrelated to tissue vascularization, and may suggest that apoprotein-III could serve other functions, apart from the coagulation of blood. The predominance in phylogenetically older brain regions would suggest that it represents a primitive or fundamental feature.


[Treatment of chronic leptomeningitis (arachnoiditis) by administration of ozone into the subarachnoid space].

The authors report of ozone administration into the subarachnoid space for the treatment of chronic scarring--adhesive processes in the pial membrane. Among the 104 studied patients, 62 had convexital leptomeningitis, 7--basal, 3--of the posterior cavity and 28 diffuse forms. In patients with leptomeningitis of the posterior cavity in the absence of an engorged papilla of the eyeground, ozone was introduced by occipital punctures, in convexital and basal leptomeningitis--by lumbar puncture. An introduction of ozone into the subarachnoid space was conducted in combination with resorptive and general therapy.


The size of growth hormone granules in pituitary adenomas producing acromegaly.

Measurements of the diameters of large numbers of granules in electron micrographs of pituitary adenomas in cases of acromegaly do not show that a typical size exists which allows of the retrospective diagnosis of the hormone secreted by the tumour. The granule diameters found in single cases show a normal distribution. The average values determined in 19 unselected cases of acromegaly range between 160 and 342 nm. They are also normally distributed about the mean for the entire group which is 238 nm. With histo-immunological electron microscopic techniques h GH can be demonstrated in small, medium and large granules. The size of hormone granules is determined by functional factors such as the speed of hormone synthesis and hormone release but not by the type of hormone secreted.


Effect of administration frequency of growth hormone on longitudinal bone growth in the hypophysectomized rat.

The effect of the administration frequency of growth hormone on longitudinal bone growth was investigated with tetracycline as intravital marker of the bone growth of the proximal tibia in hypophysectomized rats. The total dose of growth hormone (NIH-GH-B16) and the administration period were the same in all compared experiments. It was possible to achieve an optimum growth response for a certain total dose of growth hormone by increasing the injection frequency. The period of hormone administration was 10 or 5 days followed by a 10 days withdrawal period. When the growth hormone was administered alone or in association with L-thyroxine for 10 days, the optimum injection frequency for growth hormone was found to be 1 inj./day in hypophysectomized rats and 2 inj./day in thyroxine-treated hypophysectomized rats. When the administration period was 5 days for growth hormone given in association with L-thyroxine, the growth stimulation induced by one daily growth hormone injection was the same as that induced by two or four daily injections of the same total dose. An increase in the administration frequency for a total daily dose of thyroxine from 1 to 2 inj./day did not increase the longitudinal bone growth either when thyroxine was given alone or in association with growth hormone.


Diurnal rhythm of vasotocin in the pineal of the male rat.

The pineal content of arginine vasotocin in the male rat is subject to diurnal changes, having a high value around noon and a low value around midnight. Since in rats exposed to 24 h constant light the pineal content in arginine vasotocin decreases, and in the rats exposed to 24 h constant darkness the pineal content in arginine vasotocin increases, it appears that during the night both the synthesis and release of arginine vasotocin is enhanced.


Five cases of absence of iodide concentrating mechanism.

Five cases, 2 males and 3 females, with absence of iodide concentrating mechanism are reported. Three of the five subjects are siblings and the eldest sister has no symptom to account for the cretinism. All 5 cases have improved clinically following the administration of potassium iodide and 4 cases are still in a euthyroid state without any adverse effects during a half to more than 4 years. This study suggests that the absence of iodide concentrating mechanism might be erroneously diagnosed as athyroidal cretinism or adolescent non-toxic diffuse goitre, and may at times not show any clinical symptoms.


Outcome of long-term antithyroid treatment of graves' disease in relation to iodine intake.

Seventy-seven patients with Graves' disease, with an average of 56 years of age were treated with carbimazole in the period 1968-1975. The duration of therapy was on an average, 17.9 months and the follow-up on an average, 28.5 months. Remission was found only in 32% of the patients. Data on the urinary iodine excretion from a total of 127 euthyroid controls and 15 patients with Graves' disease living in the same area were collected during the periods: 1962-1964, 1965-1968, 1971-1973 and 1972-1974. No significant difference was found in the urinary iodine excretion in the period 1962-1973 and no significant difference was found in the urinary iodine excretion between the patients with Graves' disease and the euthyroid controls. Our data demonstrate a high relapse rate following long-term treatment with anti-thyroid drugs in an area with relative low iodine intake.


The interrelationships between serum 25-hydroxycholecalciferol, serum parathyroid hormone and bone changes in anticonvulsant osteomalacia.

Serum 25-hydroxycholecalciferol (25-HCC) and serum parathyroid hormone (iPTH) were measured in 59 randomly selected adult epileptic outpatients receiving chronic anticonvulsant therapy. Quantitative morphometric analysis of iliac crest biopsies was performed. A mild degree of osteomalacia was found which was inversely correlated to dietary vitamin D intake. Serum 25-HCC was reduced in the epileptic patients compared to a control group, although dietary intake of vitamin D was higher than the mean daily intake in the Danish population. Serum 25-HCC was positively correlated to dietary vitamin D intake, but not correlated to the severity of bone changes, indicating that other factors than circulating 25-HCC are responsible for the development of anticonvulsant osteomalacia. Serum 25-HCG was inversely correlated to serum iPTH in patients with a low dietary calcium intake. The mean value of serum iPTH was not increased, and there was no correlation between serum iPTH and bone morphometry.


Decreased parathyroid function in hyperthyroidism: interrelationships between serum parathyroid hormone, calcium-phosphorus metabolism and thyroid function.

Serum immunoreactive parathyroid hormone (S-iPTH) was measured together with serum and urinary calcium and phosphorus in 45 hyperthyroid patients in order to assess parathyroid fe of hyperthyroidism. The prevalence of hypercalcaemia was 51.1% using serum calcium values corrected for individual variations in serum albumin concentration compared to 15.6% using the uncorrected calcium values. S-iPTH was decreased and inversely correlated to serum calcium values. S-iPTH was decreased and inversely correlated to serum calcium (corrected). Subnormal levels of S-iPTH were found in 28.9% of the patients. The urinary excretion of calcium and phosphorus was increased and positively correlated to the degree of hyperthyroidism. The tubular reabsorption of calcium (TRCa%) was decreased, positively correlated to S-iPTH and inversely correlated to serum calcium. Increased mobilisation of bone mineral in hyperthyroidism is suggested mainly to be responsible for the elevated serarathyroid function.


Vasoactive intestinal peptide (VIP): variation of the jejuno-ileal content in the developing rat as measured by radioreceptorassay.

This study was undertaken to investigate the variations of the Vasoactive Intestinal Peptide (VIP) content of rat jejuno-ileum (JI) with age. VIP was measured by its ability to inhibit competitively the binding of [125I]pork VIP (pVIP) to rat liver plasma membranes. The radio receptor assay was sensitive to 0.5 ng/ml. VIP fragments 1-6, 14-28 and 18-28 exhibited no cross reaction with [125I]pVIP. Glucagon had no effect and secretin was about 100 times less effective than pVIP. Rat VIP was extracted from JI by 0.5 M acetic acid and partially purified by adsorption on silicate. The effect of JI extracts in inhibiting the binding of [125I]pVIP paralleled that of pVIP used as standard. The VIP content of JI showed a 340-fold increase between day 21 post coitum (p.c.): 41 +/- 4 ng/JI and day 63 post partum (p. p.): 14 110 +/- 954 ng/JI. On a gut weight basis, VIP increased slightly from day 21 p. c. (591 +/- 51 ng/g of JI) to day 14 p. p. (906 +/- 109 ng/g of JI) and then increased more sharply (day 21 p. p.: 1508 +/- 222 ng/g of JI) until day 63 p. p. (2672 +/- 207 ng/g of JI). The VIP content seemed to reach a plateau after 2 months. A similar pattern was observed when the results were expressed per mg of JI protein. It is speculated that the rise in VIP content is related to the role of this peptide in the regulation of the gastro-intestinal function and/or the distribution of fuels in the organism.


Serum cortisol appearance-disappearance in adrenal insufficiency after oral cortisone acetate.

Six patients with long-standing idiopathic primary adrenal insufficiency were given 25 mg of cortisone acetate orally on two occasions. Circulating serum cortisol levels were determined hourly for five hours after ingestion. Two patients were additionally studied with an oral dose of 20 mg of cortisol. Marked patient to patient variation in peak hormone and in fifth hour hormone levels was observed. Both values were lowest in the two chronically symptomatic patients who had been maintained on empiric glucocorticoid replacement. Specific information on blood cortisol levels in treated Addisonian individuals has not been previously reported.


Familial adrenocortical hypoplasia with early clinical and biochemical signs of mineralocorticoid deficiency (hypoaldosteronism).

Biochemical investigations in a boy with a salt losing syndrome revealed a very low secretion of aldosterone which did not rise during salt deprivation, in spite of a normal rise in plasma renin activity. Cortisol secretion was normal - but subsequently decreased, while the corticosterone secretion was high. The patient was studied at the age of 5 weeks, 3 months and also at the age of 8 months. He survived until the age of 18 months on treatment with sodium chloride and DOCA, but did not receive glucocorticoids. At autopsy the adrenal glands were absent, but in fat tissue from the upper renal poles foetal adrenal cortex tissue was found. The histological picture agrees well with other cases which could be designated as "foetal-cortex-only" adrenal hypoplasia. The same histological changes were demonstrated in the boy's brother who died suddenly at the age of 6 weeks. The boy's testes were advanced in maturation to a stage of about ten years: spermatocytes and Leydig cells were present.


Foetal and maternal hormonal changes preceding normal bovine parturition.

Successful chronic cannulation of the foetal posterior vena cava and maternal utero-ovarian and jugular veins in five Jersey cows between days 240 and 260 of gestation enabled changes in plasma hormone levels preceding calving to be monitored. All cows delivered live calves within the expected range of gestation for the breed. Corticosteroids were assayed by competitive protein-binding and prostaglandin F, progesterone, oestrone and oestradiol-17beta by radioimmunoassay. Foetal corticosteroids rose slowly from 5.0 +/- 0.7 ng/ml at 20 days to 9.3 +/- 3.0 ng/ml at 10 days before term, then progressively increased to a mean of 74 ng/ml, though higher concentrations occurred following surgery. Foetal oestrone and oestradiol-17beta concentrations were both less than 50 pg/ml and showed little change toward term. The maternal utero-ovarian oestrogens increased slowly from 20 to 10 days pre-partum and then rose more rapidly reaching peak levels (2.9 +/- 0.6 ng/ml for oestrone and 1.4 +/- 0.3 ng/ml for oestradiol-17beta) 1 to 4 days before delivery. Maternal progesterone concentrations fell towards term, with a rapid decrease over the last 36-48 h before calving when they gradually increased until the last 24 h where was a dramatic rise, reaching peak levels (5.7 +/- 0.6 ng/ml) during labour.


Macrophage disappearance reaction induced by lymphokines.

Macrophage disappearance reaction was induced in normal (non-sensitized) guinea pigs by human lymphokines deriving from Con A-stimulated lymphocytes, by ellagic acid (an activator of intrinsic coagulation) and by thromboplastin (an activator of extrinisic coagulation). The results are discussed from the aspect of the pathomechanism of macrophage disappearance reaction.


A multi-centre trial of pollen-tyrosine adsorbate.

We report the results of a multi-centre trial involving 433 hay fever patients treated in 1975 with a 3-injection tyrosine-adsorbed vaccine containing glutaraldehyde-modified grass pollens and cultivated rye. Despite the high pollen counts recorded in Germany in 1975, treatment was considered to be effective in 73 per cent of the patients, irrespective of their age, sex or past history. Side effects were normally mild although the incidence of local reactions was relatively high. Only six patients discontinued treatment due to untoward reactions and there were no cases of anaphylactic shock. This paper adds further evidence to support the view that this vaccine offers a safe, effective and convenient method of treatment for grass pollen allergy.


Cellular immunity to penicillin in newborns.

A leukocyte migration micromethod has been used to study the cellular immunity to penicillin (CIP) in newborns. No detectable CIP has been found in newborns who had not been treated with penicillin. Fifteen per cent of the newborns treated with pencillin were found to have a CIP as early as the 12th day of life.


Ocular function in cirrhosis of the liver.

The ocular state of 28 ascertained non-alcoholic females with cirrhosis of the liver was assessed. Only twenty were able to go through the complete colour vision test, and among these, three patients (one without, and two with increased level of serum bilirubin) with acquired colour vision defects were observed. Visual acuity, visual field, intraocular pressure, binocular function, slit lamp microscopy, ophthalmoscopy and tear production were normal in all cases. It is concluded that the frequency of colour vision defects in the present sample is increased, and that alcohol abuse is not a prerequisite for colour vision defects in patients with cirrhosis.


Vertical steps in isopters at hemiopic border - in normal and glaucomatous eyes.

Careful perimetry disclosed small steps in peripheral isopters corresponding to the vertical meridan in about 50% of normal eyes as well as eyes with glaucomatous field defects. Most steps were found inferiorly. The contraction of the isopter was always found on the nasal side of the field apart from a few of the glaucomatous eyes, all of which also showed central field defects. The findings suggest that no significance with regard to pathology can be attached to small peripheral steps at the vertical meridan provided that the temporal hemifield is the greater. Steps showing preponderance of the nasal half of the field, however, should arouse suspicion of an existing pathology. The reported observation as well as findings in the literature concerning function, anatomy and pathology suggest that the nasal hemiretina is dominant over the temporal one.


Some essential optical features of the Zeiss fundus camera.

The imaging system of the Zeiss fundus camera comprises a front lens and a mirror with a central opening in the anterior focus of a camera objective. Focusing is achieved by changing the distance between the film and the camera objective. The principal point of the examined eye is imaged in the central opening of the mirror when the camera is correctly positioned. By applying reasoning current in elementary geometrical optics it was found 1) that both the absolute and the relative magnification depend on the "reduzierte Axenlängenkonvergenz" only, 2) that it is possible to correct the influence of refraction on magnification and 3) that the relation between the camera extension needed to provide sharp pictures and the principal point refraction of the examined eye is linear. The validity and practical importance of those findings as well as transcleral illumination and theoretical resolving power are briefly discussed.


Microscopically and chemically detected haemolacria.

Two methods have been developed for the detection of occult haemolacria (occult blood in tears): 1) Microscopy of conjunctival fluid aspirated by means of the quantitative pipette method. 2) Chemical stix method employed on a sample of conjunctival fluid transferred to cotton-wool plug. Double samples from 306 eyes were subjected to microscopy, and chemical tests were performed on samples from303 other eyes. Microscopy has been found to disclose occult blood in 13 per cent of normals (greater than or equal to 100 erythrocytes/3.1 mm2 in 3 per cent of normals), while blood is detected chemically in 3 percent. Occult blood is most frequently found in cases of acute infectious conjunctivitis (65 per cent microscopically and 21 per cent chemically), less frequently in subacute and chronic infectious conjunctivitis (26 and 20 per cent respectively). Haemolacria is most feequently seen in relation to neutrophilia (45 per cent), less frequently with lymphocytosis (35 per cent), and even more rarely in the absence of both neutrophilia and lymphocytosis (11 per cent). Ciliary congestion is an unlikely cause of haemolacria. Postoperatively blood is present for two or three days, wheras blood instilled into the conjunctival sac of a normal eye disappears in less than one hour. The protein concentration in tears is raised in association with haemolacria.


Lenticonus in Alport's syndrome. A family study.

A South Indian family with three well documented cases of Alport's syndrome with anterior lenticonus are reported. Clinical features of the syndrome including ocular and laboratory findings have been presented and discussed. Macular pigmentation, 5 cases, subcapsular opacity and nephrotic syndrome, one case each, observed in the present series are of great interest and are quite rare in patients with Alport's syndrome. Critical analysis of the family pedigree revealed autosomal dominance with incomplete penetrance as the possible mode of genetic transmission of the disease.


Cluster headache syndrome and migrain. Ophthalmological support for a two-entity theory.

Patients suffering from migraine, cluster headache and atypical cluster headache, including patients with chronic paroxysmal hemicrania, were studied with respect to corneal temperature, intraocular pressure and corneal indentation pulse amplitude changes during pain attacks. Significant rises in these three parameters were deomonstrated during attacks of cluster headache and atypical cluster headache, indicating that intraocular vasodilation with increased ocular blood flow occurs during attacks. No definite changes were found in migraine. The results strongly suggest that significant pathophysiological differences exist between migraine and cluster headache. The point is stressed that these disorders probably represent separate pathogenetic entities and should be classified as such, and not be grouped together within an ill-defined group of "vascular headache".


330 trabeculectomies--a follow-up study through 1/2-3 years.

In 1967 a new microsurgical procedure for glaucoma known as trabeculectomy was introduced. This method is reported to have few early complications and a good pressure-reducing effect. Our material presents the results of 330 consecutive trabeculectomies with a follow-up period of 1/2-3 years. The following items are discussed: IOP, visual acuity, visual fields, surgical complications, and need of re-operation and medical postoperative therapy. We conclude that trabeculectomy is a safe and efficient antiglaucoma operation, recommended as an attractive alternative to heavy medication.


Relationship between perimetric eccentricity and retinal locus in a human eye. Comparison with theoretical calculations.

A blind but grossly normal eye was removed because of severe pain. With the patient's consent, photo-coagulation markers were placed along the horizontal meridian of the retina prior to surgery. The angular coordinates in visual space of the markers were determined by an ophthalmoscopic procedure. The loci of the markers were also determined in a flat preparation following enucleation. The relationship between retinal arc and perimetric eccentricity was found to be approximately linear up to at least 50 degrees. Our findings validate earlier theoretical calculations within this range.


Photography of the nerve fiber layer in retinal disturbances.

The diagnostic value of nerve fiber layer photography is assessed. The series comprised 39 patients with various neuro-ophthalmological diseases. Photography of the nerve fibers in the retina is time consuming and requires skill on the part of the photographer. Differences in the papillomacular nerve fiber layer are difficult to distinguish using the present methods. The wasting of nerve fibers could be documented by photography in advanced cases with bitemporal hemianopia, but not in small relative scotomas. Cases with homonymous hemianopia are interesting because lesions in the optic tract can be differentiated from affections of the second neuron on the basis of retinal nerve fiber atrophy. In demyelinating diseases inspection of the retinal nerve fiber layer is of clinical importance and diagnostic changes appear,


Aseptic thrombosis of orbital veins and cavernous sinus. Clinical symptomatology.

Occlusion or thrombosis of the superior ophthalmic vein or of the cavernous sinus is an unspecific finding that may be secondary to different disorders such as tumours of the skull base or nasopharynx. Sometimes, however, no underlying disorder is found in spite of an extensive clinical and radiological evaluation. Eight such cases are here presented. Similar cases have previously been described, both as examples of the Tolosa-Hunt syndrome and as aseptic cavernous sinus thrombosis. The literature on these two disorders is reviewed and different diagnostic criteria discussed.


The metabolism of biphenyl. IV. Phenolic metabolites in the guinea pig and the rabbit.

The phenolic metabolites of biphenyl in guinea pigs and rabbits were qualitatively and quantitatively analysed as trimethylsilyl (TMS) ethers by combined gas chromatography/mass spectrometry and gas chromatography, respectively. The parent compound was hydroxylated to monohydroxylated biphenyls and minor amounts of dihydroxylated derivatives, and the main route of body clearance appeared to be by the urine in both species. Thus, in the urine of guinea pigs 32.9% of the dose was detected 96 hrs after dosing, while the major part (29.5%) was eliminated during the first day as conjugates. The main metabolite was 4-hydroxybiphenyl (25.5%). During the first 24 hrs faecal recovery was 20.3% of the dose, and most of this (14.3%) consisted of biphenyl itself. Biliary excretion of the metabolites of biphenyl origin amounted to 3.3% of the dose during the first day, and 4-hydroxybiphenyl was the major metabolite. In the urine of rabbits 49.1% of the dose was recovered 96 hrs after dosing, and most of this (25.4 and 15.9%, respectively) was eliminated during the first two days as conjugates. The major metabolite was 4-hydroxybiphenyl (35.3%). On the first day faecal recovery was 1.6%, of which 1.4% was detected as biphenyl itself. Less than 1% of the dose was found in the 7 hrs rabbit bile, and exclusively as 4-hydroxybiphenyl. The experiments thus show that both qualitative and quantitative differences in the metabolism of biphenyl exist between the guinea pig and the rabbit even though 4-hydroxybiphenyl was the most prominent metabolite of biphenyl in both species.


The metabolism of biphenyl. V. Phenolic metabolites in some marine organisms.

The phenolic metabolites of biphenyl in the crustacean Cirolana borealis LILJEBORG (ISOPODA), the gastropod Buccinum undatum L and the ophiuroid Ophiocomina nigra ABILDGAARD have been analysed qualitatively and semi-quantitatively as trimethylsilyl (TMS) ethers by combined gas chromatography/mass spectrometry and gas chromatography, respectively. The findings demonstrate the in vivo metabolic capacity of these organisms to convert biphenyl into its hydroxylated derivatives. Thus, 2-hydroxybiphenyl is the most prominent metabolite detected in all these experiments, which also showed that minor amounts of the 4-hydroxy and 4,4'-dihydroxy metabolites are formed. Metabolites of biphenyl origin are found both in the sea water from the aquaria and in the tissue of the respective marine organisms. The experiments, moreover, indicate a slow metabolism of biphenyl in C. borealis, B. undatum and O. nigra, between which no qualitative metabolic differences are found.


Effects of the hexahydroxyhexane myoinositol on bone uptake of radiocalcium in rats: Effect of inositol and vitamin D2 on bone uptake of 45Ca in rats.

The objective of this study was to investigate the effects of inositol and vitamin D2 on bone uptake of 45Ca in rats. The radioactive calcium was administered to young rats by orogastric intubation (2 muci/100 g body weight (b. wt)) with inositol (20 mg/100 g b. wt.) and/or vitamin D2 (5OO IU/100 g b. wt.) to normal rats. Bone uptake of 45Ca was measured after 24 hours by standard technique. Inositol alone produced a 48% increase in calcium uptake. It is concluded that inositol significantly increases bone uptake of radioactive calcium (P greater than 0.005). Simultaneous administration of vitamin D2 decreases the effect of inositol considerably, while vitamin D2 has no significant effect.


Effect of acetyl derivatives of some sympathomimetic amines on the blood pressure of the rat.

The effect of five sympathomimetic amines and some of their acetyl derivatives on the blood pressure of the rat was determined on the left carotid artery. After pretreatment with chlorisondamine (1 mg/kg subcutaneously) the blood pressure rise by sympathomimetic amines and their acetyl derivatives was compared with that of adrenaline. If the potency of adrenaline is specified as 100, the potencies of the other drugs are phenylephrine (metaoxedrinum, NFN) 37, tyramine 1.1, O-acetyltyramine 0.52, amphetamine 0.50, O-diacetylphenylephrine 0.25, ephedrine 0.23, O-acetylephedrine 0.02, N-acetylphenylephrine 0.01. The effects of N-acetyltyramine, N-acetylephedrine and N-acetylamphetamine are even weaker. Reserpine 5.0 or 0.05 mg/kg intraperitoneally 24 hours before the experiment increased the blood pressure rise by the directly acting sympathomimetic amines and their acetyl derivatives, but decreased the effects of the indirectly acting drugs. After treatment with phenoxybenzamine (2 mg/kg intraperitoneally), adrenaline exhibited the greatest blood pressure decrease and the effects of the other drugs in descending order: orciprenaline, O-acetyltyramine, phenylephrine, ephedrine, amphetamine, O-diacetylphenylephrine and O-acetylephedrine. Tyramine did not show any blood pressure decrease. The blood pressure decrease by sympathomimetic amines and by their acetyl derivatives was probably due to beta-receptor stimulation because it was prevented by propranolol. The N-acetyl derivatives recembled their parent drugs with regard to the immediate onset and short duration of their effects. The O-acetyl derivatives exhibited slower onset and longer duration of effect than their parent drugs. Physostigmine-pretreatment diminished the rise in blood pressure by O-acetyltyramine, but the effect of tyramine remained unchanged.


A comparison of the effects of ouabain, noradrenaline and nifedipine on the contractile force of the isolated rat atrium at different calcium levels.

The effects of ouabain 5 x 10-5 M, noradrenaline 10-7 M and nifedipine 100 mug/1 on the contractile force of the isolated rat left atrium were tested and compared at varying concentrations of calcium in the Ringer solution. The effect of ouabain was small, developed slowly and almost independently of the calcium concentration. Noradrenaline, which increases Ca++ influx during excitation, caused an increase in the contractile force which was complete within 2 min. The percentage as well as the absolute increase in contractile force was pronounced at lower, but small at higher calcium concentrations. Nifedipine, which reduces Ca++ influx during excitation, caused a decrease in contractile force which was complete within 2-4 min. The nifedipine-induced depression in contractile force decreased with a rise in the calcium concentration. It is assumed that the ouabain-induced increase in contractile force in the rat, is not mediated by an increase in the magnitude of the inward calcium current, and other modes of action for the inotropic effect of glycosides are discussed.


Effects on rat urinary kallikrein excretion of bumetanide, bendroflumethiazide and hydralazine.

Single and/or repeated administrations of bumetanide, bendroflumethiazide and hydralazine to normotensive and spontaneously hypertensive rats resulted in an increase of urinary kallikrein excretion. No correlation was found with sodium output. The role of the increased plasma renin activity is discussed and it is suggested that the activation of the renal kallikrein-kinin system is related to the increase in renal blood flow.


Guanethidine-induced acute hypersensitivity to noradrenaline in anaesthetized rats.

The changes in mean arterial blood pressure, heart rate and the respective noradrenaline dose-response curves after guanethidine sulphate (0.25, 1.25, 5, 20, and 40 mg/kg given intravenously) were studied in chloralose-urethane anesthetized adult rats. After transient changes a dose-dependent maximum fall of the blood pressure was observed 15 minutes after the administration of guanethidine. A fall in heart rate was observed after guanethidine sulphate 0.25 mg/kg, whereas 1,25, 5, 20, and 40 mg/kg initially increased the heart rate followed by a decrease to subnormal levels with minimum values 6-24 hours after guanethidine. Normalization of blood pressure and heart rate occurred within 24 hours and 96 hours, respcetively. Maximum dose-dependent enhancement of changes in blood pressure by noradrenaline 0.5 mug/kg was obtained approximately 15 minutes after guanethidine. Following guanethidine 40 mg/kg the response was increased by a factor 2, and normalization occurred within 96 hours. Fifteen minutes after guanethidine, significant changes in the response of the heart rate to noradrenaline 0.5 mug/kg were obtained with guanethidine 1.25, 5, and 20 mg/kg, whereas fully developed hypersensitivity after 20 and 40 mg/kg did not occur until 6-24 hours later. Following guanethidine 40 mg/kg the response was increased by a factor of 3, and normalization was observed after 96 hours. The present investigation has demonstrated different time-dependent patterns of the effect of guanethidine on blood pressure and heart rate responses to noradrenaline.


Activities of proscillaridin A in thoracic duct lymph after single oral doses in man.

In order to study the possibility that orally administered proscillaridin after absorption is transported by the lymph to the systemic circulation, the concentrations of the glycoside in thoracic duct lymph were analyzed in two patients with thoracic duct drainage. They received the drug as a single oral dose; plasma and lymph concentrations were measured by 86Rb-technique. Lymph was collected at various intervals for 24 hrs. The proscillaridin activity in thoracic duct lymph was low and followed closely that the plasma. During the sampling period, a total of 300 ng and 240 ng, respectively, was recovered in the lymph, corresponding to less than 0.03% of the administered dose. The results indicate that proscillaridin is not transported by the thoracic duct lymph.


Determination of dextropropoxyphene and norpropoxyphene in autopsy material.

A method for the simultaneous determination of dextropropoxyphene (DP) and its major metabolite norpropoxyphene (NP) in autopsy material, has been developed. By the extraction procedure used, NP is completely converted to its more stable amide form, which like DP, produces well-defined peaks, in the subsequent gas-liquid chromatographic determination. Thin-layer chromatography is used for additional identification of the two compounds. In 20 g of autopsy material, the detection limit is 0.3 mug/g of tissue or body fluid. The recovery of standards added to control blood samples (1.25 mug/g) was 65 +/- 10% (S.D.) for DP and 59 +/- 9% (S.D.) for NP (n = 54). The method is routinely used for determinations in blood, muscle, liver and urine.


Dextropropoxyphene and norpropoxyphene in blood, muscle, liver and urine in fatal poisoning.

Post-mortem concentrations of dextropropoxyphene (DP) and its major metabolite norpropoxyphene (NP) were determined by combined gas-liquid chromatography and thin-layer chromatography in autopsy material from 53 cases of fatal DP poisoning collected over a 1-year period. Among 11 oral cases without simultaneous ethanol ingestion, the minimal lethal dose was less than 1.5 g DP chloride. The ranges of total drug concentrations (DP + NP) were 1.1-15 mug/g in blood, 1.3-23 mug/g in muscle, and 27-261 mug/g in liver. Among 21 oral cases were ethanol was detected in the blood, the minimal lethal dose was 0.7 g DP chloride (ethanol 2.41 mg/g) and the total drug concentrations was 0.7-12 mug/g in the blood, 1.3-8.4 mug/g in the muscle and 19-285 mug/g in the liver. The minimal lethal blood concentrations tended to decrease with increasing ethanol concentration. NP constituted roughly half of the total drug levels, somewhat less in muscle and more in the urine, and this pattern was not changed in connexion with ethanol ingestion. Other metabolites were not detected.


Biochemical effects of baclofen (beta-parachlorophenyl-GABA) on the dopamine and the noradrenaline in the rat brain.

Baclofen (beta-parachlorophenyl-GABA) caused an increase in the concentration of dopamine in the rat brain with a maximum of about 170% of the control value after 1 hr and after doses of 50 mg/kg or more intraperitoneally. The alpha-methyltyrosine-induced disappearance of dopamine was inhibited to about the same extent in the corpus striatum and in the limbic system by baclofen. The accumulation of DOPA following decarboxylase inhibition was stimulated more in the corpus striatum than in the limbic system by baclofen, thus accounting for the fact that the concentration of dopamine was elevated about three times as much in the corpus striatum as in the limbic system. Amphetamine almost completely inhibited the rise in dopamine produced by baclofen. Baclofen did not cause any consistent changes in the concentration, the synthesis and the utilization of noradrenaline. These effects of baclofen are similar to those described following gammahydroxybutyric acid or axotomy. Hence, baclofen might also interrupt the nerve impulse flow in central dopamine neurones, perhaps by stimulating a central GABA mechanism.


Effect of methysergide and indomethacin on the anaphylactic contraction of the rat isolated uterus (Schultz-Dale response).

The anaphylactic contraction (Schultz-Dale response) of the isolated uterus from actively sensitized rats was partially suppressed by methysergide, 1.5 mug/ml. Although the inhibitory effect of indomethacin, 3.5 mug/ml, was only slight, the combination of indomethacin and methysergide abolished the response almost completely. These observations indicate that, although serotonin must be the primary mediator of tha anaphylactic uterine response, prostaglandin is also involved. Metiamide, a histamine H2-receptor antagonist, 10 mug/ml, did not affect the anaphylactic response, suggesting that histamine was not released in amounts sufficient to counteract the uterine contracting mediators.


Extraction and metabolism of lidocaine in rat liver.

The use of lidocaine as an oral antiarrhythmic drug is limited by its rapid disposition in the liver. In accordance with this we found that the drug was completely extracted during one passage through the perfused rat liver. The drug binds to rat liver microsomes with a type I spectral change of unusually high affinity. It is rapidly de-ethylated by the microsomes with an apparent Vmax of about 15 nmol per mg protein x min. The apparent Km for this reaction is about 250 muM. The reaction occures at about the same rate in isolated rat liver cells. We believe that the high affinity of lidocaine for the cytochrome P-450 system, as indicated by its type I spectral change, as well as the rapid oxidation of the drug are the two main determinants for the marked liver extraction and first pass effect of the drug.


Cyclophosphamide effect on collagen metabolism in granulation tissue, skin, and aorta of rats.

Granulation tissue was produced in rats by subcutaneous implantation of viscose cellulose sponges. Cyclophosphamide 10 mg/kg was given daily intraperitoneally to 15 rats from the day of sponge implantation. Fifteen rats served as pair-fed controls, and 15 rats served as non-starved controls. After 14 days of treatment the animals were decapitated. Groups of 3 rats were given 50 muci 14C-proline intraperitoneally 1, 3, 6, 12, or 24 hours before death. The aorta, skin, and granulation tissue were examined. Cyclophosphamide caused no effect on collagen of the aorta, while in skin, the only detectable effect was a decrease in 14C-OH-proline biosynthesis. In granulation tissue, cyclophosphamide caused a fall in the dry weight, a decrease in 14C-proline uptake and 14C-OH-proline synthesis, as well as an increase in the alpha-amino nitrogen to OH-proline ratio in purified collagen. These results indicate that cyclophosphamide inhibits the synthesis of proteins, including collagen, and inhibits the hydroxylation of proline in collagen. No effect of cyclophosphamide could be detected on the amount of salt soluble OH-proline or on collagen cross-linking. The registered effects of cyclophosphamide on granulation tissue is probably of importance with regard to the anti-inflammatory action of cyclophosphamide. This action as well as the tissue differences in the sensitivity of cyclophosphamide may be of relevance to the clinical application of cytostatics in rheumatological diseases.


Effect of a vasopressin analogue (Nalpha-glycyl-glycyl-glycyl-[8-lysine]-vasopressin) on organ blood flow in the pregnant guinea pig.

Nalpha-triglycyl-(8-lysine)-vasopressin (TGLVP) was administered intravenously to pregnant guinea pigs and the effect on regional blood flow examined by the radioactive microsphere technique. A dose of 10 mug/kg TGLVP caused an elevation of the mean arterial blood pressure, from 6.4 to 11.1 kPa, a significant reduction in blood flow to the gut, skin and skeletal muscle and a significant increase in blood flow to the spleen. The number of 15 +/- 5 mum microspheres reaching the lungs diminished significantly after 10 mug/kg TGLVP, indicating that this dose constricted arterio-venous short circuits in the systemic circulation. There was also a decrease in blood flow to the urogenital tract, including the placentae. When 3 mug/kg TGLVP was injected, the mean arterial blood pressure rose from 6.5 to 8.7 kPa and there was no longer any consistent effect on maternal placental blood flow. It is suggested that pregnancy constitutes a contraindication for TGLVP, since a reduction in uterine and maternal placental blood flow might occur with clinically relevant doses.


Inhibition of apomorphine-induced hypermotility in rats by chlorpromazine, perphenazine, thioridazine and melperone.

Hypermotility in rats produced by various subcutaneous doses of apomorphine (ap) was studied. The neuroleptics chlorpromazine, perphenazine, thioridazine and melperone were administered subcutaneously 30 minutes before ap. The four neuroleptics were found to inhibit ap-induced hypermotility. When the dose of ap was increased, higher doses of the neuroleptics were required to inhibit the hypermotility. By varying the dose of chlorpromazine, thioridazine and melperone partial ap-antagonism was found, but increase of the perphenazine-dose resulted in complete ap-inhibition. Hypermotility produced by ap is presumably dependent on direct stimulation of dopamine (DA)-receptors. Neuroleptics blocking some, but not all, DA-receptors may cause no, or weak parkinsonian side effects.


Prostaglandin/kinin activity related to changed renal compliance after bumetanide in dogs.

Bumetanide (0.25 mg/kg intravenously) increases kidney volume by 20% at maximal diuresis in anaesthetized dogs. The kidney expansion is initially accompanied by a 2-4 fold increase in the subcapsular pressure, which is normalized at a time when kidney volume is still considerably increased. Renal blood flow and urinary kinin excretion are enhanced parallel to kidney volume. Renal prostaglandin E activity decreases. The increase in renal blood flow and urinary kinin excretion are inhibited by indomethacin pretreatment. The results leads to the conclusion that the kinins mediate the vascular response of bumetanide. The results also suggest that the subcapsular/interstitial pressure might affect the prostaglandin level of activity after bumetanide while factors related to tubular volume activate the kallikrein-kinin system.


Hypercalcaemia in elderly hospital in-patients: value of discriminant analysis in differential diagnosis.

Plasma calcium was measured routinely as a part of profile screening of patients admitted to a geriatric department. Pathological hypercalcaemia was found in 1.33% of those screened, the cause being bone metastases (29%), hyperparathyroidism (21%), bronchial carcinoma without bone metastasis (18.5%), lymphosarcoma without bone metastasis (8%) and multiple myeloma (2.5%). There remained a further group of patients with hypercalcaemia and renal failure (21%) in whom diagnosis was often obscure. Where renal function was normal, discriminant analysis showed that the four main diagnostic groups were biochemically distinguishable. Discriminant analysis thus seems likely to be of practical value in the differential diagnosis of hypercalcaemia in elderly patients with normal renal function, but requires prospective validation.


Immunoblastic sarcoma.

A systemic, malignant disorder of immunoblasts has been reported to occur as a late transition phase of immunoblastic lymphadenopathy in an older population. With a background of polyclonal gammopathy, drug sensitivity, lupus erythematosus or rheumatoid arthritis, there may develop a progressive "cloning out" of monomorphous immunoblasts to form immunoblastic sarcoma. Recently, a 17-year-old, postpartum girl without these bizarre hypersensitivity phenomena developed a rapidly fatal, systemically malignant process with severe clinical complications. No historical incitent was identified. The pregnancy had been uneventful and birth had produced a thriving, viable infant. This case may represent the youngest patient with primary, malignant immunoblastic disease occurring in the absence of a "hypersensitivity" state. A brief discussion of the clinical situation, management, and autopsy findings, is presented. Basic morphologic criteria for proper differentiation of malignant immunoblastic problems, lymphoma, and Hodgkin's disease are discussed.


Characteristics of pulmonary surfactant in adult respiratory distress syndrome associated with trauma and shock.

Broncho-alveolar lavage fluid was obtained from a 24-year-old man who developed the adult respiratory distress syndrome one day after massive trauma and hemorrhagic shock. The lungs were available 3 days later when organ transplantation was performed. When the various fractions of the lavage material obtained by centrifugation, including the purified surface-active lipid-protein aggregates, were examined on the film balance, they revealed the usual minimal surface tension of 16 to 18 dyne per cm at 37 degrees C, but the compressibility of the films from the lungs with adult respiratory distress syndrome was 5 to 10 times higher than the normal range. This suggests that surfactant films in the adult respiratory distress syndrome are less responsive to stress, and that as a result, a loss of film elasticity may contribute to the abnormal pressure-volume relationships observed with the intact lung. Changes in the lipid-to-protein ratios of the purified lipid-protein aggregates were also found, as indicated by the recovery of 3 lipid-protein aggregates with different isopycnic densities from the lung with adult respiratory distress syndrome; only one major aggregate could be recovered from the lavages of normal lungs.


[New antibiotic no. 792 formed by Actinomyces bottropensis].

An actinomycetes strain 792 producing a new antibiotic was isolated under the programme of antitumor antibiotic screening. By its morphological and cultural properties strain 792 was classified as belonging to species Actinomyces bottropensis. Antibiotic 792 was recovered from the culture fluid of the strain by the extraction method in the form of a crystalline orange substances. lambda max 235, 305, 410 nm (E 1% 1cm 705, 105, 168), m. p. 232-255 degrees (dec), molecular weight 340, C 67 per cent, H 4.8 per cent, no nitrogen, sulphur or halogens. The antibiotic was inactivated in alkaline solutions forming a hardly soluble compound crystallizing in the form of red needles, lambda max 256, 485 nm (E 1% 1ct 800, 195), m. p. 202-204 degrees (dec), molecular weight 320, C 69.5 per cent, H 4.7 per cent. Antibiotic 792 had antitumor and antimicrobial activity.


[Antitumor activity of the components of a carminomycin complex].

The antiblastomic activity of the carminomycin complex components was studied with respect to 8 strains of transplantable tumors of mice: lymphosarcoma L10-1, prestomach cancer OZh-5, sarcoma 180, lymphoid leucosis L 1210, lung bronchogenic cancer RL, lymphodenosis NK/LI, Ehrlich carcinoma and Garding-Passy melanoma. It was shown that components I, II and III possessed almost the same high antiblastomic activity and the same optimal administration schemes should be used for them. The scheme consisted of two-fold administration of the drug at intervals of 96-120 hours. Component I had broader therapeutic ranges and was more active against the lung bronchogenic cancer as compared to component II. All 3 components had no selective antiblastomic effect on the ascitic form of Ehrlich carcinoma. A comparative study of the component toxicity and pharmacology is required for final conclusion as to the recommendation of one of the components for clinical trials.


Mesangiolytic glomerulonephritis in an infant with immune deficiency and echovirus infection.

An unusual glomerulonephritis characterized by diffuse mesangial cell necrosis and lysis of mesangial areas was observed in a male infant who had a combined immune deficiency and systemic echovirus type 6 infection. The occurrence of glomerular disease in a patient with combined immune deficiency indicates that the glomerular injury can be inflicted without mediation of immune mechanisms, presumably by direct cytopathic effect of echovirus 6.


Fatal desquamative interstitial pneumonia in an infant: case report with transmission and scanning electron microscopical studies.

Desquamative interstitial pneumonia in a young infant followed a rapidly fatal course and developed morphologic features of honey-combing, giant cell pneumonia, and pulmonary alveolar proteinosis. The rapid and fatal progression of the disease in spite of steroid therapy and the polymorphous histologic appearance of the lungs at autopsy raise doubt that the disease is a relatively benign and uniform entity and invalidate the classical initial histologic features as prognostic indicators.


Electron microscopy in the diagnosis of giardiasis.

Biopsy specimens of intestinal mucosa from two patients with malabsorption syndrome were examined with routine light and electron microscopy. Both showed intact intestinal mucosa, but by electron microscopy, the presence of Giardia lamblia in the intervillar spaces was identified. Electron microscopy is useful for the identification of this parasite, since the stool examinations in up to 50% may be negative. The parasites appear in light microscopy as cellular debris and can be easily overlooked, while by electron microscopy the typical morphologic features of the parasite are diagnostic.


Benign developmental cysts of the mediastinum.

The examination of 40 benign developmental cysts of the mediastinum from the surgical pathology files supports the previous conclusions in the literature about these lesions. In distinguishing bronchogenic from esophageal cysts, the lining epithelium is not helpful, but the presence of two muscle layers in esophageal cysts and bronchial glands or bronchial cartilage in bronchogenic cysts enables categorization in the majority of cases. Gastroenteric cysts are lined by intestinal epithelium and are further distinguished by their location in the posterior mediastinum and association with other developmental anomalies. Pericardial cysts are histologically characterized by their simple, thin-walled structure, and they are usually closely associated with the pericardium and the diaphragm. A small group of cysts, usually bronchogenic or esophageal in type, cannot be readily classified because they are detached and do not contain helpful identifiable structures. An awareness of the developmental anatomy of the tracheo-bronchial tree and esophagus clarifies the relationships in location and structure that are seen in cysts of this region. All the benign developmental cysts in this series were easily removed at surgery, and there were no known postoperative complications.


Electron microscopy of clear cell thyroid carcinoma.

Three thyroid carcinomas composed in part or entirely of clear cells were studied by light and electron microscopy, and thyroglobulin content was determined by biochemical methods. Clear cells have been found in follicular and papillary thyroid carcinomas and in undifferentiated carcinomas. The clear (wasserhelle) appearance of the cytoplasm was due to the accumulation of glycogen. The major ultramicroscopic features of the clear cells were the presence of glycogen granules, the decreased amounts of rough endoplasmic reticulum, the increased amounts of free ribosomes arranged in polysomes, a hypertrophic Golgi apparatus, and a sparsity of dense bodies of lysosomal character. It is hypothesized that the intracellular accumulation of glycogen may be a result of a selective loss of the peptide portion of thyroglobulin, and may influence the degree of biochemical differentiation and the natural course of the tumors.


Mucoepidermoid carcinoma of the subglottis. An ultrastructural study.

A well-differentiated mucoepidermoid carcinoma of the subglottis of a 77-year-old man was studied by light and electron microscopy. The tumor consisted of mucous cells, epidermoid cells, and intermediate cells of both differentiation. Mucous cells formed glands and cystic spaces filled with mucin. Abundant tonofibrils in aggregates were observed in tumor cell cytoplasms when they were differentiated into epidermoid cells. Epidermoid cells varied in differentiation.


Benign chondrolipomatous tumor of the human female breast.

A benign chondrolipomatous breast tumor occurred in a 66-year-old woman. The preoperative diagnosis, based on mammography and xeroradiography, was fibroadenoma. Grossly, the demarcated lesion resembled a fibroadenoma with islands of cartilage projecting from its cut surface. Histologically, it was composed of benign mature fibrous stroma, fat, breast ducts, and islands of mature cartilage. Most cartilage-containing tumors of the human breast are associated with primary mammary malignant neoplasms. A few of the benign cartilage-containing tumors reported in the literature are discussed. The last case was published in 1909.


The regional lymph node in cancer. Relationship of nodal histologic findings to cytotoxicity and immunity.

Although regional lymph nodes showed increased numbers of pyroninophilic cells for at least six weeks after the implantation of a C3H mammary tumor, a decrease in the number of these cells was noted four weeks after amputation of a tumor-bearing limb. These observations appear paradoxical, since such animals have repeatedly demonstrated so-called sinecomitant tumor immunity. However, the lack of pyroninophilia coincided with prior observations that cells obtained from the regional nodes after amputation of a tumor-bearing limb-showed decreased in vitro cytotoxicity. This suggested that the pyroninophilic elements, vis a vis immunoblasts, may have been more closely related to cytotoxicity rather than to tumor immunity per se. The possible importance of nodal lymph follicle formation in the latter was suggested by their increased presence in such regional nodes.


Serum prolactin levels and the value of bromocriptine in the treatment of anovulatory infertility.

Basal serum levels of prolactin were measured in 37 infertile anovulatory patients who had failed to conceive on therapy with clomiphene citrate. Twenty of these patients, 16 of whom had galactorrhoea, had elevated basal serum prolactin values which were suppressed to normal or subnormal values during therapy with bromocriptine, the most commonly effective dose being 2.5 mg twice daily. Ovulation, as assessed by urinary oestrogen and pregnanediol measurements, was induced in 17 of these patients with pregnancy in 14. Ovarian responses short of defined criteria for ovulation were induced initially in eight patients, but these progressed to full ovulatory responses in five patients, either on the same or increased doses of bromocriptine. In all the patients who ovaulated, the prolactin levels had been reduced below the mean value for normal women (10.6 ng-ml). The three patients who failed to ovulate all had values higher than this at a dose of bromocriptine reaching 5.0 mg thrice daily. There seemed to be no value in increasing the dose of bromocriptine once ovulation had been achieved. Of the 17 patients with normal basal prolactin values, only one had an unequivocal response to bromocriptine with ovulation and conception, even though the prolactin values in the majority were suppressed to below normal.


[Mycotic aneurysm of the internal carotid artery after an orbital cellulitis caused by Staphylococcus aureus. Report of 2 cases].

Two cases are reported of severe type of S. aureus cellulitis which led to the production of mycotic aneurysms of the internal carotid artery. This situation has not been previously described in the literature. Analysis is made of the infectious pathogenesis of mycotic aneurysms.


Venereal disease education and a selected group of American college students.

Education is considered to be an important factor in the control and possible eradication of venereal diseases. A study was undertaken to discover what effect education had had on a selected group of university students so as to determine suitable avenues for future educational programmes. Many of the schools attended by the students had issued information on venereal diseases; most students considered that this information was useful. The study did not generally show a significant relationship between previous health education, current attitude and behaviour, and the contraction of venereal disease. However, the data did appear to reveal a correlation between the lack of education at junior high school and the acquisition of venereal disease. The university student health service, together with books and pamphlets made available outside the school of classroom, were regarded as being important in venereal disease education. These findings can help those planning venereal disease education for young adults.


[Normal nutrition--malnutrition during malassimilation?].

Intestinal resorption can be disturbed in its intraluminal, intracellular or postcellular phase. Any such dysfunction may lead to an isolated or global malabsorption syndrome. An exact elucidation of the underlying pathophysiology is a prerequisite for a rational diet prescription. Only when this is completed, the diet can be adapted in a quantitative and qualitative sense to the residual intact function of the diseased digestion or absorption organ. The dietetic measures in an isolated or global malabsorption syndrome have been discussed.


[Comparative bioavailability of three pharmaceutical forms of digoxin].

The bioavailability single doses (0.5 mg) from three preparations of digoxin is compared in a crossover study in nine normal volunteers. Plasma digoxin concentrations from 0 to 72 hr and urinary glycoside excretion for 96 hr are measured by radioimmunoassay. Areas under the plasma concentration-time curves are assessed according to two different statistical methods, one comparing preparations, the other comparing subjects. With the first, bioavailabilities are similar; with the second, they significantly differ. On the other hand, urinary excretions do not differ. This discrepancy is probably related to different kinetics of digoxin release from the pharmaceutical preparations, the total amount absorbed being equivalent.


A second conponent of atropine mydriasis.

A patient with Waardenburg syndrome had, in addition to the classical findings, a semidilated fixed pupil which did not react to changes of illumination, to convergence, or to pilocarpine of phospholine iodide. However, it responded normally to locally applied drugs acting on the sympathetic system. The pupil dilated after application of atropine, homatropine, or cocaine. The effect of cocaine, but not of atropine and homatropine, was prevented by pretreatment with guanethidine. It is concluded that the mydriasis caused by atropine and homatropine is partly dependent upon a direct action on the radial smooth muscle.


Chemoimmunotherapy for canine lymphosarcoma.

A total of 157 dogs with lymphosarcoma were available for study; 67 were treated. All of the treated dogs were given 4 drug combinations and 20 of them also were given autogenous vaccine. Sixty (90%) of the dogs treated with multiple drugs improved clinically. Of the dogs with clinical improvement, 48 (80%) had either complete or partial remission; of these, 32 (67%) had complete remission. Clinical staging proved useful in increasing the accuracy of prognosis, whereby dogs in less advanced stages of disease responded better to therapy, with a higher percentage of complete clinical remissions and longer survival. The mean survival time of the 47 dogs treated with drugs alone was 138 days, which compared with a mean survival time of 30 days for 34 nontreated dogs. Dogs subjected to chemotherapy and immunotherapy had a mean survival time of 341 days. Dogs in complete remission at time of vaccination survived significantly (P less than 0.01) longer than did dogs treated with drugs and vaccinated while not incomplete remission.


A dermatoglyphic study of autistic patients.

Dermatolglyphic patterns of autistic children were compared to those of control subjects matched socioeconomically and by age and sex. Analysis of dermal ridge patterns and ridge counts resulted in significant differences between the 78 autistic and 78 normal children. Differences from normal expectation in the autistic children were most apparent in the reduced number of whorls and increased number of arches, in lowered ridge counts, and in less distinctness in formation of ridge line. The number of dermal ridges on autistic hands was much lower for each finger as well as for the total hand. Moreover, covariance of the contribution of increased numbers of arches failed to alter the significance of findings of general reduction of ridge count in the autistic sample. Other abnormalities of ridge structure among the autistics were noted and described. Complete absence of transverse crease in this sample was combined with other dermatoglyphic evidence to argue for the separateness of autism from other pathological syndromes. It was concluded that evidence was sufficient to indicate the existence of congenital factors in the etiology of autism.


Sign language and multisensory input training of children with communication and related developmental disorders.

This report deals with the preliminary findings of a research project on simultaneous communication and multisensory input in the treatment of six autistic and communication disordered children. The children, aged 5 to 12, were taught manually signed English and speech using a multisensory-intrusion approach. The hypothesis was that such a technique would serve to alleviate the children's difficulties in information processing, organization of experience, and affect. The dependent measures were behavioral ratings derived from both structured (teaching) and unstructured (free play) sessions. The results indicate that the children manifested a consistent acquisition of sign lanuage, which in some cases transferred into verbal communication skills. Moreover, statistical analyses of some of the observed socioaffective behaviors (i.e., nonsolitary play, interaction with peers and adults, exploration, and detachment) revealed tendencies supportive of the hypothesis. The variability of the data preclude any categorical statement in relation to the hypothesis. However, the preliminary results strongly support the continuation of the study.


Handedness in autistic children.

A test of handedness in a sample of 20 autistic children and 25 normal children revealed marked differences. The frequency of non-right-handedness in normal children was 12%, whereas it was 65% in autistic children. The significance of this difference for the etiology of autism is discussed.


Compliance and resistance in autistic children.

The study was designed to explore factors related to negativism in autistic children, where negativism was defined as the consistent avoidance of a correct response in a multiple choice discrimination task. A design employed in an earlier study of autistic children (Cowan, Hodinott, & Wright, 1965) was modified to allow a more detailed examination of patterning of the child's responses. A positive relationship was found between use of spoken language and successful performance of the task. However, no child was negativistic. Of the 27 children tested, 18 had a near perfect performance and 9 scored at chance level. A subsequent exact replication of the Cowan et al. method still failed to produce any negativism. A further study using a more difficult discrimination task produced a higher rate of errors but still no negativism. Possible reasons for the failure to replicate are discussed.


A relationship between motor control and language development in an autistic child.

Recent work in both experimental and clinical psychology indicates an important link exists between the development of motor control and language development. Diagnostic and therapeutic work with autistic children reveals a high incidence of gross motor dysfunction along with language deficits. A study to evaluate the effectiveness of behavior modification techniques in eliciting speech from nursery-age autistic children yielded new data to confirm the importance of the relationship. Results from a case study of one autistic child demonstrated that the child most frequently vocalized when motorically quiet, and engaged in motor activity when not speaking and especially prior to speech. Data from 30 half-hour behavior modification sessions and an intensive clinical interview indicated that limiting the child's gross motor activity was effective in increasing the frequency of vocalization. Several theoretical interpretations of this phenomenon as well as implications for treatment and further research are offered.


Follow-up report on autism in congenital rubella.

A longitudinal study was conducted of 243 children with congenital rubella. In this sample a high rate of autism and a high rate of recovery were observed. Examination of the data suggested that the rubella virus was the primary etiologic agent. It is hypothesized that the course of autism was that of a chronic infection in which recovery, chronicity, improvement, worsening, and delayed appearance of the autistic syndrome all were found. Other rubella consequences such as blindness, deafness, and cardiac and neuromuscular defects remained present except as modified by operations and prostheses. Degree of mental retardation initially was related to the outcome of autism but shifts in mental retardation over time did not correlate significantly for the group with shift in the autistic symptoms.


The late repair of torn cruciate ligaments using menisci.

An operation using either the medial or the lateral meniscus to effect the late repair of torn cruciate ligaments is described. Forty-three patients under fifty years of age who were unable to return to their work because of severe joint laxity have been treated in this way and reviewed after one to thirty years. Sagittal stability was measured by a special apparatus, and a comparison was made between normal knees and affected knees before and after operation. The review of forty-five knees showed normal stability in thirty-one, slight instability in twelve and no improvement in two. Forty-one patients had returned to their former work: twenty-two complained of instability when tired; all had pain-free joints. The use of a meniscus for the reconstruction of either cruciate ligament is considered to be simple, safe and effective.


An experimental model of osteoarthritis; early morphological and biochemical changes.

An experimental model of osteoarthritis resulting from laxity of the joint was induced in eighteen mature dogs (at least two years old) by sectioning the anterior cruciate ligament of the right knee (stifle) with a stab incision, the left knee providing a control. A sham operation was also performed in three other dogs, in which a stab incision was made but the ligament left intact. The dogs were killed at various intervals from one to forty-eight weeks later. Morphological changes in bone, cartilage, synovial membrane and joint capsule were examined in all the joints and biochemical changes in the cartilage of three dogs killed after two, eight, and sixteen weeks. All the changes resulting from the operation progressed with time and became indistinguishable from those found in three dogs with natural osteoarthritis of the knee. There were no changes in the joints which had sham operations. As the time of onset is known, this experimental model in a larger species enables a study to be made of the biochemical as well as the morphological changes in the early stages of osteoarthritis.


The inhibitory effect of dopamine agonists on LH release in women.

Our demonstration of an inhibitory effect of dopamine on LH release prompted us to examine whether a similar action exists for dopamine agonists, such as L-dopa and 2-bromo-alpha-ergocryptine (CB-154). Following the administration of L-dopa (0.5 g, orally) to 6 normal women in the early follicular phase, a significant fall in mean LH levels after 1 h which lasted for 5 h was observed (P less than 0.00005). This was followed by a significant rebound above basal levels between the 7th and 10th h (P less than 0.00005). The expected fall in mean PRL levels which lasted for 4 h (P less than 0.00001) was followed by a significant rebound above basal levels after the  6th h (P less than 0.00001)). There was no significant change in mean FSH levels. Following the administration of CB-154 (2.5 mg. orally) to 6 women with hyperprolactinemic amenorrhea, there was also a significant fall in LH levels (P less than 0.00001) and in FSH levels (P less than 0.00001) from 5 h until the study ended at 10 h. The anticipated PRL suppression was also observed and persisted for the duration of the 10 h study. The demonstration of an inhibitory effect of L-dopa and CB-154 on LH release adds further support to the role of dopaminergic control of pituitary LH secretion.


Lack of indomethacin effect on thyroid function in man.

Administration of indomethacin 200 mg daily for 2 days to four euthyroid volunteers was without significant effect on serum triiodothyronine or thyroxine and caused no cinsistent alteration of serum TSH. There were minor and variable changes in the pattern of thyroidal iodine release (TIR) in these euthyroid subjects. In one subject both the TIR pattern and serum TSH concentration were altered in the same direction, suggesting that these minor changes were of central origin. Indomethacin also had no effect on the stimulated pattern of TIR in one euthyroid subject receiving daily exogenous TSH injections, or in a patient with untreated hyperthyroid Graves' disease. Prostaglandin A1 infusion in one subject did not alter serum TSH or thyroidal iodine release. It is concluded that prostaglandins probably have no obligatory physiological role in modulating TSH or thyroid hormone secretion in man.


Iodinating activity of thyroid tissue in toxic diffuse goiter.

Thyroid tissue obtained from 12 patients with Graves' disease and treated with thionamide drugs for 3-7 mo before subtotal thyroidectomy, from 12 patients with Graves' disease, similarly treated, and given 50 mug of triiodothyronine (T3) for 10 days before surgery, and from 12 euthyroid patients with solitary cold nodules was investigated to compare in vitro iodination of thyroglobulin in toxic diffuse goiter and in normal thyroid tissue. The supernates of the homogenates (105,000g) were subjected to sucrose density gradient centrifugation (5--28%) to separate the thyroglobulin fraction. The precipitates were treated with 1% digitonin and centrifuged to collect the supernate (particulate fraction). When thyroglobulin and particulate fractions obtained from the same patient were incubated with 125I-, iodide, glucose, and glucose oxidase, the amount of iodine bound to thyroglobulin was several times greater in toxic diffuse goiter than in normal thyroid tissue; administration of T3 did not affect iodination in toxic diffuse goiter. When the thyroglobulin fraction from each patient was incubated with a standardized quantity of peroxidase instead of the individual particulate fraction, the amount of iodine bound to thyroglobulin was the same among the three groups of patients. Finally, when bovine serum albumin was substituted for thyroglobulin from each of the patients, iodination of bovine serum albumin was several times greater with the particulate fraction obtained from toxic diffuse goiter tissue than with that obtained from normal tissue. The guaiacol-oxidizing activity oty. These results suggest that in vitro iodination of thyroglobulin is increased in toxic diffuse goiter even when patients are made euthyroid by treatment with thionamide drugs as well as when they are given additional T3 for 10 days before operation. The increase in iodination of thyroglobulin appears to be due to an increase in peroxidase activity in the particulate fraction.


Treatment of mycotic intracranial aneurysms.

Two patients with mycotic intracranial aneurysms were successfully treated with only antibiotic therapy. One patient, who had subacute bacterial endocarditis, rheumatic valvular disease, and an abscessed tooth, sustained a subarachnoid hemorrhage from a ruptured right middle cerebral artery trifurcation aneurysm. The other patient, who had Turner's syndrome and probable congenital aortic stenosis, developed multiple neurological findings during an ipisode of acute bacterial endocarditis precipitated by an infected ingrown toenail; a false aneurysm of the distal left middle cerebral artery and two lesions involving the left superior cerebellar artery were found. A study of the literature shows that only 45 patients with mycotic intracranial aneurysms have received adequate antibiotic therapy and angiographic documentation. Statistically, there does not appear to be a clear-cut advantage to antibiotic plus surgical therpy over antibiotic alone. In fact, in 21 patients who underwent serial angiography, lesions were smaller in six and not visualized in 11. In four patients the aneurysms increased in size; in two others fresh lesions formed. The author proposes the following diagnostic and therapeutic regimen: 1) earliest possible diagnosis of the underlying disorder; 2) appropriate antibiotic therapy; 3) early four-vessel cerebral angiography and follow-up studies every 2 to 3 weeks; study; 5) definitive operation upon completion of antibiotic therapy if the lesion is larger or the same size; and 6) postoperative angiography to evaluate the effectiveness of treatment and to search for interim lesions.


Selenosis, hepatic selenium accumulation, and plasma glutathione peroxidase activity in chicks as affected by a factor in linseed meal.

Linseed meal has previously been reported to contain an organic factor that reduces toxicity of selenium in animals. The purpose of the studies reported here was to obtain information on the mechanism of action of the linseed meal factor in counteracting selenosis in chicks. Feeding a diet containing 20% linseed meal to chicks partially counteracted the growth depression caused by including high levels of selenium (10-40 ppm) in the diet. In contrast to the rat, chicks fed diets containing selenium did not accumulate significantly more of the element per unit of liver dry matter when the diet contained linseed meal, and at two selenium levels accumulated significantly less. Linseed meal did not interfere with the absorption of an oral dose of 75Se as measured by tissue retention 24 hours later. A methanol extract of linseed meal did not interfere with the normal increase in plasma glutathione peroxidase activity in chicks fed diets supplemented with low levels of selenium even though the extract counteracted the growth depression obtained by adding 20 ppm selenium. Linseed meal contains a factor that interacts with selenium in the tissues in some unknown way to reduce the toxic effects of the element, but does not prevent normal synthesis of glutathione peroxidase.


Alkaloids of Vinca rosea L. (Catharanthus roseus G. Don). 38. 4'-Dehydrated derivatives.

A series of 4'-dehydrated derivatives of various dimeric Vinca alkaloids has been synthesized to further define the structure-activity relationships of Vinca alkaloids with onolytic potency. The concentrated sulfuric acid dehydration in most cases gave mixtures of the 3',4'-and two isomeric 4',20'-alkenes, which were isolated and characterized primarily by proton and 13C NMR. Compound tested for antitumor activity include the three dehydro isomers of 4'-deacetylvinblastine, 4-deacetylvincristine, and 4-deacetylvinblastine-23-amide and some4'-dehydrated derivatives epimeric at C-18'. Generally, the decrease in toxicity imparted by the new double bond was accompained by a decrease in potency. An exception was 3',4'-dehydro-4-deacetylvincristine, which showed a decrease in toxicity and increase in potency against at least one tumor in which vincristine itself has little effect.


Quantitative correlations between albumin binding constants and chromatographic Rm values of phenothiazine derivatives.

The binding constants of 15 phenothiazine derivatives to bovine serum albumin were obtained by a circular dichroic probe technique; The lipophilicity of the drugs, measured by a reversed-phase thin-layer technique using oleyl alcohol and methanol-water mixtures as the solvents, is expressed as RMw. The binding constants were of the same order of magnitude as the literature values, and the RMw values correlated well with log P octanol values from the literature. Correlations of log K with RMw were found to be more satisfactory when corrections for the state of ionization of the phenothiazines were made, the nonprotonated species accounting for the bulk of the binding. A better correlation was obtained when contributions from both species were taken into account. Similar correlations were attempted between RMw values and enzyme inhibitory activities of these phenothiazines taken from the literature.


Anticoccidial derivatives of 6-azauracil. 1. Enhancement of activity by benzylation of nitrogen-1. Observations on the design of nucleotide analogues in chemotherapy.

Benzylation of 6-azauracil at N-1 (which corresponds to the point of attachment of the ribose phosphate unit in pyrimidine nucleotides) has been found to augment its anticoccidial activity fourfold. The high potency of 1-benzyl-6-azauracil is ascribed to a combination of intrinsic activity, efficient oral absorption, and a moderate rate of excretion. Metabolism experiments using 1-benzyl-6-azauracil labeled with 14C in the heterocycle and (separately) in the side chain showed that, in the drug accounted for, no cleavage had occurred. Additional activity increases were achieved by introducing small, electron-withdrawing substituents in the meta and/or para position(s) of the benzyl group. One of the most active derivaties, 1-(3-cyanobenzyl)-6-azauracil, is about 16 times as potent as 6-azauracil.


Tumor formation in preneoplastic mammary nodule lines in mice treated with nafoxidine, testosterone, and 2-bromo-alpha-ergocryptine.

The tumor potentials of five preneoplastic mammary nodule lines were examined in BALB/cCrgl mice treated with either nafoxidine, an estrogen antagonist; 2-bromo-alpha-ergocryptine, a prolactin suppressant; or testosterone. The inhibitory effect of any of the three agents was dependent on the individual nodule line and was not correlated with the effects of ovariectomy. Nafoxidine inhibited tumor formation only in nodule line D2; testosterone inhibited tumor formation in lines C3 and C4; and 2-bromo-alpha-ergocryptine failed to inhibit tumor formation in any of the nodule lines. These results provided information on the range of responses of mouse preneoplastic mammary tissues to a variety of antihormone treatments and suggested that responses to ovariectomy need not be correlated with responses to specific antihormone treatments.


Suppression of mammary tumorigenesis in C3H/He mice by ovariectomy or treatment with 2-bromo-alpha-ergocryptine: a comparison.

We compared the effects of chronic treatment with 2-Br-alpha-ergocryptine (CB-154) and of ovariectomy on the genesis of mammary hyperplastic nodules (HN) and mammary tumors in the C3H/He mouse. CB-154 is an established potent suppressor of pituitary prolactin. Eighty-five 21- to 25-day-old female mice were divided into three groups. Group I received daily sc injections of 0.1 mg CB-154. Group II was ovariectomized and group III served as controls. Mice were examined weekly for mammary tumors. Fifteen months from onset of treatment all surviving mice were killed. The mean number of HN per inguinal mammary gland, total number of mammary tumors, and number (percent) of mice with mammary tumors in each group were, respectively: controls--4.6 +/- 1.1, 41, 24/29 (83%); ovariectomized--1.2 +/- 0.6, 20, 14/28 (50%); and CB-154-treated--0.2 +/- 0.1, 16, 13/28 (46%). A significant (P less than 0.001) and equally comparable inhibition of mammary tumor incidence was observed in the ovariectomized and CB-154-treated mice. Thus early ovariectomy and CB-154 treatment (specific inhibition of prolactin secretion) appeared equally effective in the prophylaxis of mammary tumorigenesis in the C3H/He female mouse.


Description of a permeable eukaryotic cell system to study agents affecting DNA synthesis: demonstration that cytembena is a direct inhibitor of replicative DNA synthesis.

Cells were made permeable to DNTP's by a 15-minute treatment with 0.01 M Tris/HCl (pH 7.8), 0.25 M sucrose, 1 mM EDTA, 30 mM 2-mercaptoethanol, and 4 mM MgCl2 at 4 degrees C. These cells used exogenously supplied dNTP's to carry out semiconservative, replicative DNA synthesis. This system could be used to identify inhibitors of DNA synthesis and to determine whether chemotherapeutic agents affect precursor synthesis or whether they have a direct effect on the DNA replication complex. Thus DNA synthesis in the permeable cells was not inhibited by hydroxyurea or by the nucleoside analogue arabinofuranosyl cytosine. In contrast, the active form of the nucleoside analogue, arabinofuranosyl cytosine triphosphate, and daunorubicin promptly inhibited DNA synthesis in the permeable cells. Cytembena, sodium cis-beta-4-methoxybenzoyl-beta-bromoacrylate, also inhibited DNA synthesis in the permeable cells; this demonstrated that this agent functioned as a direct inhibitor of the DNA replication complex.


Evaluation of possible sites of action of rubratoxin B-induced polyribosomal disaggregation in mouse liver.

The disaggregation of liver polyribosomes (disruption of the site of protein synthesis) into single ribosomal units has been observed after treatment of mice with rubratoxin B, a toxic metabolite of Penicillium rubrum. Several mechanisms for the polysomal alteration were evaluated. A generalized decrease in mouse liver RNA following administration of rubratoxin B was noted. RNAase activity in the postmicrosomal fraction was increased after similar treatment; however, this increase was too small to account for the observed polysomal breakdown. Incubation of rubratoxin B with isolated polysome fractions indicated no direct interaction between the toxin and the polyribosomal complex, apparently eliminating such a complex as the cause of the in vivo disaggregation. Rubratoxin caused shifts in the ultraviolet absorption spectra of DNA and RNA in vitro, a preliminary indication of binding of the toxin to nucleic acid. Such preliminary observations lend support to the hypothesis that rubratoxin-induced polyribosomal disaggregation may result from an alteration in the critical informational macromolecules such as nucleic acids, or protein, or both in that both are involved in the control of cell growth. This alteration in the DNA-protein complex may then result in a malfunction of the DNA-dependent RNA polymerase activity and subsequent polysomal disaggregation.


Thyroid supplementation for hypothyroidism. An latrogenic cause of breast cancer?

In four subpopulations grouped by varying durations of thyroid supplementation (none, one to five years, six to 15 years, and 15 years of more), breast cancer frequency correlated positively with attained age. The cancer experience of persons in the same age-group was relatively stable regardless of how long women took thyroid supplements. The present data support the provisional inference that breast cancer and duration of thyroid therapy are both age-dependent and question the belief that pretreatment with thyroid supplements increases the risk of breast cancer development. Relationship of these two variables can only be determined by prospective studies.


Myoglobinemia in inflammatory myopathies.

Myoglobin was detected in the sera of patients with dermatomyositis, polymyositis, scleroderma, and systemic lupus erythematosus (LE) with active myopathy. Overall, myoglobinemia was detected in 74.1% of sera taken from patients with active myositis before therapy, with slightly greater frequency in the groups with dermatomyositis and polymositis. With steroid therapy, this frequency fell to 43.4% and to 9.5% in patients in clinical remission not requiring therapy. Serum enzyme (creatine phosphokinase, lactic dehydrogenase, and SGOT) activity was higher in samples containing myoglobin, but there was considerable overlap between those with and without myoglobinemia. Sequential serum determinations in six patients demonstrated rapid reduction in the levels of serum myoglobin with therapy, usually before enzyme values had returned to normal. In one patient followed up for 30 months, myoglobinemia correlated with clinically observed exacerbations of rash and weakness to a greater degree than did enzyme determinations.


Oral aminophylline therapy. Increased dosage requirements in children.

While monitoring oral aminophylline (theophylline ethylenediamine) therapy, larger doses (milligrams per kilogram) were necessary for children than for adults to achieve similar therapeutic serum levels. The mean apparent theophylline clearance (ATC) determined in 59 children was significantly higher (P less than .001) than determined in 114 adults (84.8 versus 51.4 ml/hr/kg). Additionally, the younger children (1 to 9 years) eliminated theophylline more rapidly than the older children (0 to 18 years) (93.8 versus 77.3 ml/hr/kd). When initiating continuous oral aminophylline therapy, dosage guidelines, based on the mean ATC calculated for each group, were predicted, and trough theophylline serum levels of 10mug/ml were obtained. The guidelines for aminophylline were 28.0, 23.2, and 15.6 mg/kg/day administered in four divided doses for the younger children, older children, and adults, respectively. Monitoring of serum levels is suggested to further individualize the patient's aminophyline therapy.


Bronchopancreatic fistula following traumatic rupture of the diaphragm.

A bronchopancreatic fistula developed in a 14-year-old boy two weeks following transabdominal splenectomy and repair of a ruptured diaphragm. This unusual entity should be suspected when a patient with pancreatitis or pancreatic trauma has pleural complications associated with profuse, frothy sputum. The diagnosis is established by the presence of high levels of amylase in the sputum or by the appearance in the sputum or the bronchi of dye or contrast material injected into the external fistula. The primary goal of treatment, in addition to the management of the thoracic complications, is subdiaphragmatic control of the pancreatic fistula. A brief summary of seven previously reported cases is presented.


Hypertension crisis. Recognition and management.

Situations requiring immediate lowering of systemic blood pressure are infrequent. Certain clinical syndromes resulting from or complicated by severe hypertension demand vigorous, usually parenteral, antihypertensive therapy. Such syndromes include (1) diastolic hypertension accompanied by sudden disruption of cerebral function, (2) dissecting or leaking aortic aneurysm; (3) accelerated or malignant hypertension, (4) toxemia of pregnancy when either the fetus' or the mother's life is immediately threatened, (5) some instances of diastolic hypertension and acute left ventricular failure, (6) uncontrolled hypertension in the patient who requires emergency surgery, (7) refractory elevation of the diastolic pressure in the kidney transplant patient, and (8) refractory hypertension complicating myocardial infarction or angina. Drugs useful in acutely lowering blood pressure include diazoxide, sodium nitroprusside, methyldopa intravenously, reserpine intramuscularly, and trimethaphan camsylate intravenously. Use of furosemide reinforces the hypotensive effect of these agents. Theoretical advantages and disadvantages of these agents are not always encountered in clinical use.


Pseudo-Sjögren syndrome with hyperlipoproteinemia.

Eight patients with parotid enlargement were seen because of varying musculoskeletal complaints. All were overweight and hypertensive; six had diabetes mellitus, four had palpable hepatomegaly, and six were 49 years or older. One patient had arthritis type IIB hyperlipoproteinemia. Four patients had varying degrees of fibrositis, and two of these also had osteoarthritis. Of the others, one each had gout, Reiter syndrome, and restless legs syndrome. All had hyperlipoproteinemia type IV or IIB, and none abused alcohol. None of these patients have true Sjögren syndrome.


Paraben allergy.

A hydrocortisone preparation containing methylparaben and propylparaben provoked bronchospasm and pruritus when given intravenously to an asthmatic patient, whereas another hydrocortisone preparation without paraben preservative did not. Direct and passive transfer (Prausnitz-Küstner) skin tests for immediate hypersensitivity to parabens were positive. Parabens, frequently employed as bacteriostatic agents, are capable of producing immunologically mediated, immmediate systemic hypersensitivity reactions.


Retrognathia and sleep apnea. A life-threatening condition masquerading as narcolepsy.

The association of sleep apnea with daytime hypersomnolence without obesity, and its potentially lethal cardiopulmonary sequelae, make it crucial that this condition be distinguished from narcolepsy. A patient with retrognathia who had been diagnosed as a narcoleptic for 15 years had the primary complaint of excessive daytime sleepiness. Sleep laboratory evaluation showed severe hypoxemia and a mean of 366 upper airway obstructions per night. The patient was treated with a tracheotomy; this resulted in relief of the sleep-related upper airway obstructions, hypoxemia, and hypersomnolence.


Myocarditis associated with methyldopa therapy.

Five patients with hypertension died as a result of myocarditis. Three were treated with methyldopa and hydrochlorothiazide, two with methyldopa alone. Their ages ranged from 30 to 71 years. In all instances death occurred suddenly, and myocarditis was not suspected clinically. The inflammatory changes in the hearts of these patients were most consistent with a hypersensitivity reaction. Additionally, there was hepatitis consistent with hypersensitivity in four of the cases.


Cooperative study of radiologic aspects of renovascular hypertension. Bilateral renovascular disease.

Abnormal urographic features were present in 60.7% of 250 patients with bilateral diseases. The urogram was relatively insensitive in the minority of patients whose lesions were of approximately equivalent severity bilaterally. In bilateral renovascular disease, the urogram demonstrated some surgical prognostic value that was not evident in unilateral renovascular disease. Furthermore, in patients with bilateral disease, the urogram was helpful in deciding between unilateral or bilateral operation.


Eight-day survival without adrenal steroids.

A patient with advanced breast cancer who had undergone a total bilateral adrenalectomy in the past refused adrenal steroid replacement therapy with the idea that this would be the easiest and quickest way to end her life. However, she continued to live for more than eight days. Survival under these circumstances is unusual, and the terminal course of her illness is described.


Edema associated with ibuprofen therapy.

A 15-kg weight gain developed in a patient during the third week of ibuprofen therapy. The edema disappeared with discontinuation of the drug regimen and did not reappear during a subsequent six-month observation period. It should be recognized that ibuprofen may be associated with salt and water retention in the same fashion as previously described with phenylbutazone and indomethacin.