Abnormalities in platelet function and morphology in a case of thrombocythemia. A patient with "life-long" bleeding problems and thrombocythemia had normal results on routine coagulation and fibrinolysis tests, but platelet function tests, including bleeding time, platelet adhesiveness, aggregation, and uptake and release of labeled serotonin were markedly altered. In addition, several types of ultrastructural abnormalities not reported previously were observed in some of the patient's platelets. The relationship between thrombocythemia, platelet dysfunction, and abnormal morphology is discussed.


Cytological diagnosis of malignant pleural effusion in myeloma. The cytological examination of pleural fluid established the malignant etiology of the effusion in two patients with multiple myeloma. In contrast to patients with lymphoma, mediastinal lymph node enlargement in myeloma is an uncommon factor in fluid formation. As in patients with metastatic carcinoma, pleural and underlying lung involvement by myeloma is the main cause of pleural effusion. The two cases in this report, and similar cases in the literature, probably represent distal dissemination from skeletal multiple myeloma.


New neurological findings in trisomy 13. The patient in this report had many of the classic neuropathologic stigmata of trisomy 13, including retinal dysplasia, arrhinencephaly, holoprosencephaly, single external nare and granular cell heterotopias in the cerebellum and microthalmia. In addition, several new findings apparently were present in this case. The neuropathologic entities were as follows: (1) herniation of the cochlear nuclei into the eighth cranial nerve bilaterally to the transition of central to peripheral myelin; (2) gray matter present in eleventh cranial nerve bilaterally; (3) arteriovenous malformations of letpomeningeal and intracerebral vessels; (4) arachnoid cyst at the cauda equina; and (5) retinal pigment epithelium within the optic nerve.


Acute lung lesions due to zirconium and aluminum compounds in hamsters. The lung lesions produced by multiple short-term intratracheal instillations of saline solutions of sodium zirconium lactate (NaZL), zirconium-aluminum-glycine hydroxychloride complex (ZAG), and aluminum chlorhydrate (ACH) in hamsters were studied by light and electron microscopy. These solutions produced lesions beginning with exudative pneumonia followed by pneumonitis (interstitial pneumonia) and foreign body granulomas. Electron microscopic microprobe analysis demonstrated the metallic component of the instilled compounds in membrane-bound cytoplasmic inclusions of macrophages. The lesions produced by NaZL and ZAG were similar to those produced by ACH. These lesions were also similar to those in previous reports of aerosol exposure of animals to zirconium or aluminum, or to other unrelated compounds.


The biologic response to titanium phosphate. A new synthetic mineral fiber. Titanium phosphate, a new manmade fiber, was evaluated by intratracheal and intraperitoneal techniques in rats and hamsters to assess the fibrogenic potential and possible hazard to man. Titanium phosphate fibers structurally resemble asbestos insofar as they are composed of bundles of submicronic fibers. A slight, dose-related fibrogenic response to the fiber was observed subsequent to the intratracheal injection of a 50- and 10-mg/kg but not 2-mg/kg dose in rats or any of these three doses in the hamster. Intraperitoneal administration of 10 or 2 mg/kg of the fibers in rats or hamsters induced no abdominal tumors considered related to treatment. In contrast, approximately 34% of rats given an intraperitoneal injection of 2 mg/kg of asbestos developed abdominal tumors; no tumors developed in hamsters injected with asbestos.


The normal range: a concept in transition. One of the most frequent and perhaps frustrating questions the pathologist is called on to answer regarding laboratory tests is, "What is normal?" In recent years the term "normal range" has been replaced by "reference range." "Upper limit of normal" has been replaced by "referent value," "critical value," or "cut-off point." Our literature now reflects increasing contributions from biostatistics, decision theory, and systems analysis. Yet, for most of us, although the names have changed, the problem has not. Understanding Bayes' Theorum will not help the busy internist when he complains about false-positive elevations in alkaline phosphatase activity on hospital admission profiles. The laboratory director must be able to integrate reference range data and predictive value theory in his own environment if he wishes to provide meaningful information to clinicians. It is the objective of this review to focus on the definition and integration of these areas of emerging concern for the laboratorian.


Ultrastructural observations of the so-called strumal carcinoid of the ovary. A strumal carcinoid arose in a benign cystic teratoma of the ovary. Ultrastructural studies demonstrated that both the solid acinotubular areas as well as the "follicular" components were comprised of light and dark cells that contained numerous secretory granules. These findings indicate that this neoplasm is a pure carcinoid tumor with a follicular pattern. The present study raises the question of whether all strumal carcinoids are indeed pure carcinoid neoplasms.


Multinucleated giant cell neoplasm of pancreas: light and electron microscopy features. The morphological features, as demonstrated by electron microscopy, of a rare pancreatic neoplasm indistinguishable from giant cell tumor of bone by light microscopy is presented. These findings are compared with those of the only other case studied by electron microscopy and reported. Features were noted in both studies that are strongly suggestive of the epithelial origin of this neoplasm. However, there were similarities between the material from the current case and giant cell tumor of bone. Degree of differentiation seems to be the most likely determinant of the degree of similarity of the pancreatic neoplasm to the skeletal lesion.


So-called pseudosarcoma of the esophagus: nodal metastases of the spindle cell element. A polypoid lesion of the esophagus with all the morphological features of a so-called pseudosarcoma produced nodal metastases of the spindle cell element. Ultrastructurally, these spindle cells showed only fibroblastic features. The findings in this case and a review of cases reported as pseudosarcoma of the esophagus lend little support for the contention that they differ from cases categorized as carcinosarcoma of the esophagus.


Early gastric carcinoma: value of combined use of endoscopy, air contrast x-ray films, cytology, and multiple biopsy specimens. Five cases of early gastric carcinoma were diagnosed during a one-year period at the Henderson General Hospital, Hamilton, Ontario, Canada. All five patients were symptomatic and were diagnosed by a combination of endoscopy, roentgenology, brush cytology, and biopsy specimens. No cases of early gastric carcinoma were diagnosed in our hospital in the preceding ten years. A total of 75% of the cytological preparations were positive and all five biopsy specimens showed carcinoma. The ulcerated or type III lesion was present in three cases. No lymph node metastases were present in the gastrectomy specimens. The increasing rate of detection of early gastric carcinoma is attributed to the use of upper gastrointestinal endoscopy, air-contrast barium meal examinations, cytology, and multiple biopsy specimens.


Neurobehavioral and systemic effects of longterm blood lead-elevation in rats. I. Discrimination learning and open field-behavior. In order to assess neurobehavioral deficit subsequent to early low-level lead-exposure, Wistar-rats were prenatally Pb-exposed via their mothers, neonatally via their dams' milk, and later on via their diet containing lead acetate (745 mg Pb/kg diet). Blood-lead levels (PbB) of dams increased from 24.2-31.2 microgram-% during pregnancy and suckling-periods, those of offsprings were 26.6 microgram-% at about 16 days of age and 28.5 microgram-% at about 190 days of age. Between 100 and 200 days of age 40 male offsprings were subjected to behavioral testing, namely an open field-test and a visual discrimination-learning task. Two learning-tasks of different complexity, i.e. orientation- and size-discrimination, were used. Data of 20 lead-treated animals were compared with those of 20 age-matched controls. In the open-field test lead-fed animals were significantly more restless than controls; an increase of ambulation, rearing and grooming was observed. In the difficult learning-task, i.e. size discrimination, only the controls did learn the problem, whereas only one of the lead-group did; there was, however, no difference between lead- and control-animals for the easy task, i.e. orientation-discrimination. The observed effects, namely overreaction in the open field and a deficit of visual discrimination learning, may be interpreted in terms of lead-induced CNS-dysfunction. They clearly suggest that the "no-response level" for neurobehavioral damage in the rat, subsequent to early lead-exposure, must be assumed to be lower than 35 microgram/100 ml.


Kinetic behavior of thallium in the rat. Accelerated elimination of thallium owing to treatment with potent diuretic agents. 1. In acute experiments anesthetized rats were treated with a subthreshold dose of 204Tl+, given intravenously in order to study the elimination kinetics of Tl+. Thallium disappeared from whole blood by means of two different half-lives (5 and 196 min, respectively), whereas VDbeta amounted to 1400 ml. The same kinetic parameters were found after chronic exposure to toxic amounts of Tl+. 2. After chronic exposure to thallium (10 or 30 ppm in the drinking water), the distribution of thallium over various organs proved non-specific. However, a pronounced accumulation was found in the renal medulla. 3. In view of the importance of the renal route in the elimination of Tl+ from the body and also because of the established accumulation of the toxic metal in the kidney, the influence of potent diuretic agents like furosemide and ethacrynic acid on the excretion of Tl+ was studied. The enhanced excretion of water and ions (Na+, K+, Cl-) was accompanied by a significantly accelerated excretion of thallium ions. High doses of ethacrynic acid (25 mg/kg) proved particularly powerful in this respect. Between the enhanced excretion of thallium and potassium ions a significant correlation was obvious, thus supporting the well-known similarity in the behaviour of these ions. The marked increase in renal elimination of thallium upon intensive diuretic treatment may be useful in the management of thallotoxicosis.


Irreversible binding of 14C-labelled trichloroethylene to mice liver constituents in vivo and in vitro. 1. 14C-labelled trichloroethylene was injected i.p. into male mice (10 mumole/g of b.w.). The radioactivity irreversibly bound to hepatic protein reached highest levels after 6 h: 2 nmole/mg in cytosol protein, 4.4 nmole/mg in mitochondrial protein, and 7.6 nmole/mg in microsomal protein. 2. The commercial trichloroethylene contained radioactive impurities binding to proteins without metabolic activation. Purification by various extractions removed 60-70% of those materials. In aerobic incubates of mice hepatic microsomes and NADPH the covalent binding rate of the purified trichloroethylene was 1.4 nmole/mg protein in 60 min. The activity of rat liver microsomes was approximately 40% less. Covalent binding increased 2-fold with microsomes of mice pretreated with phenobarbital.


[Retention indices for gas chromatographic identification of drugs (authors transl)]. The use of the Kovats retention indices for standardization in gas chromatography enables the compilation of gaschromatographic data and the exchange of those data between different laboratories. Factors important for reliable determination of the retention indices, in particular the temperature dependence, are discussed. The gain in information due to the application of the retention indices and their differences on two stationary phases is demonstrated by means of tables with indication of their efficiency in searching for unknown compounds from such files. In the supplement retention indices on OV-1, OV-17 and their differences for 72 compounds frequently encountered in toxicological analyses are given.


Serum concentrations of clozapine determined by nitrogen selective gas chromatography. A simple gas-liquid-chromatographic method employing a nitrogen selective detector for the quantitative determination of clozapine in serum is presented. The method involves after the addition of dibenzepine as internal standard the extraction into diethylether followed by analysis of the extract dissolved in methanol. Detector linearity was established over the range of 100-1000 ng/ml serum. Clozapine levels of 9 manic patients analysed by this method are presented and discussed. A linear relationship between daily intake (mg/kg body weight) and serum levels (ng/ml) was established.


Levels of sulfhydryls and sulfhydryl-containing enzymes in brain, liver and testis of manganese treated rats. The effect of manganese on sulfhydryls and sulfhydryl-containing enzymes in brain, liver and testis of rats was investigated. Manganese produced lowering in the contents of non-protein sulfhydryl groups and inhibited the activity of glucose-6-phosphate dehydrogenase and glutathione reductase in these tissues. The contents of the metal increased significantly in brain, liver and testis of manganese administered rats. The significance of these findings is discussed.


The use of pigment loci for detecting reverse mutations in somatic cells of mice. The retinal pigment epithelium (RPE) consists of a single layer of hexagonal cells, numbering about 10(5) in the 3-day mouse. Examination of the fixed and cleared RPE of mice homozygous for the unstable allele of pink-eye (pun), which shows a relatively high frequency of reversion to wild type, has revealed that the pigmented cells which result from such reversions (mainly arranged singly or in small clonal groups) can be detected with relative ease on the unpigmented RPE background. It is felt, therefore, that this system should provide a suitable way of studying somatic reversions induced by chemical agents in pink-eyed mutations of the mouse and other mammals.


Mutagenicity testing in industry.

Mutagenicity testing in industry. The aims of authorities, university and industrial scientists are outlined. The prime feature remains: How important are the achieved results for estimating the mutagenic risk to humans? The various methods available for the testing of chemical substances for mutagenicity are compared. Their usefulness to estimate the mutagenic risk are considered and the disadvantages and advantages of such methods are discussed. The industrial toxicologist must apply those methods which permit the most accurate conclusions to be made. Further, the toxicologist has to develop new methods which, based on his own experience are more suitable for making more accurate statements. The results of methods carried out on the germ cell of living mammals permit more accurate statements to be made than investigations on isolated cell cultures and somatic cells. Thus, the dominant lethal test on male and female mice and the spermatogenial test on Chinese hamsters are considered suitable methods for estimating the possible dangers to man.


Small numbers in mutagenicity tests.

Small numbers in mutagenicity tests. Experimental control material for statistical analysis of the results of the micronuclei test in the mouse (NMRI strain) and the Chinese hamster and for the host-mediated assay in the mouse (NMRI strain) using auxotrophic bacterial strains are presented. The binomial distribution of the micronuclei makes it possible to analyse the sample size according to the formula of Cochran and Cox (1957). For the host-mediated assay, the experimental principles are given which make it possible to evaluate the results obtained even with a weakly mutagenic, unknown substance. Critical points in comparative tests are not only the methodological questions, but also pharmacokinetic problems of the substance being tested which can only be clarified in the species used for the mutagenicity test. If this is ignored then even experimentally based findings can only be recorded as speculations.


Cyto-enetic investigations of mammals. Comparison of the genetic activity of cytostatics in mammals. Mutagenicity tests have been performed with CP, IP and TP. There is an increase of mutagenic activity from TP to IP to CP 8 h after the second intraperitoneal application. This has been confirmed by analysis of bone marrow chromosomes of mice, rats and Chinese hamsters. The maximum mutagenic activity of all three cytostatics was found 12 h after the second injection. Thereafter the aberration rate induced by CP decreased quickly. The inactivation of IP and TP and the elimination of chromosome aberrations was delayed. Dose-effect-relationships of CP in Chinese hamsters were investigated using the micronucleaus test and analysis of bone marrow chromosomes. Correlations between the two test systems could be demonstrated. Five applications of CP led to a drastic increase of chromosome aberrations in bone marrow of Chinese hamsters. In spermatogonia, on the other hand, no significant increase was detectable. These differences are being discussed.


A biochemical specific locus mutation system in mice. Two mouse strains DBA/2J and C57BL/6J are heteromorphic with respect to the electrophoretic mobility of at least 8 enzymes and the beta-hemoglobin chain. The genotype of DBA/2J for these markers is: Es-1, Es-3, Gpd-1, Gpi-1, Id-1, Mod-1, Pmg-1, Dip-1 and Hbb; and of C57B1/6J: Es-1, Es-3, Gpd-1, Gpi-1, Id-1, Mod-1, Pgm-1, Dip-1 and Hbb. Electrophoresis on tissues of interstrain hybrids will show the two parental bands and additional hybrid bands if the enzyme is a polymeric structure. In specific locus mutations which result in loss of activity (deletions, nonsense mutations), the hybrid resembles the non-mutated parent. In the mutation results in a change in electrophoretic mobility, some of the bands on the gel will either run faster or slower compared to the hybrid bands in a normal F1 animal. Fifty DBA/2J males were irradiated with gamma-rays from a Co60 source with two doses of 500 R at 24-h intervals at a dose rate of 95 R/min. After this irradiation the males were sterile for approximately 3 months. After the males regained their fertility, they were continuously mated to C57BL/6 females. Thus far somewhat over 2600 animals have been tested and four new mutations detected, giving a frequency of approximately 1.7 X 10(-4) mutations per locus per generation. The four mutations are: two independent mutations at Hbb, one at Mod-1 and one at Id-1.


The protein-mapping-method employed to test for chemically induced point mutations in mice. A test system for detecting point mutations chemically induced in the germ cells of mice has been proposed in the past. In the present investigation the effect of the mutagenic substance methylnitrosourea (MNU) in such a test system was studied. Male mice 10-12 weeks of age of the inbred strain BALB/c Han. were treated with MNU. Doses ranging from 40-150 mg/kg were administered over different time periods ranging from 4-14 days. Treatments were scheduled so that spermatogonia in resting or mitotic stages at the time of exposure to MNU would be mature sperm at the time of mating of the males. Proteins of the liver from F1-foetuses were separated by isoelectric focusing followed by electrophoresis (protein-mapping-method). The protein patterns were analysed for new protein spots which should suggest point mutations. The results obtained showed no protein variations in the patterns of 312 control animals (foetuses). However, two individuals with a variant protein were found among a relatively small group of 72 out of 463 treated animals. The animals of this group are offspring of male parents in which the spermatogonia were treated at the mitotic phase with the highest total dose (except the lethal dose) employed in this study. The results suggest that MNU, under these conditions, is capable of inducing point mutations in the germ cells of mice. Furthermore, the mutagenicity test system imployed by this investigation for the first time seems to be a useful system possessing relatively high sensitivity.


Detection of biochemical mutants in mice. Several bioanalytical techniques including electrofocusing, two-dimensional technique comprising electrofocusing and electrophoresis, and chromatography have been evaluated and improved to provide a method for detecting gene mutations in mice. The use of 1 mm gels for both electrofocusing and electrophoresis in the two-dimensional technique resulted in better resolution, shorter separation time, and reduced costs. An electrophoretic apparatus for the second direction electrophoresis has been designed which eliminated cutting of a flat gel into strips prior to electrophoresis. These changes reduced the total time for a two-dimensional separation to 4 h. The scope and application of isoelectric focusing in detecting gene mutations in mice have been improved by the agar contact replica method. This method allows the simultaneous analysis of several genetic loci besides facilitating automation of evaluation, documentation, and storage of zymograms. Preliminary studies on the detection of heritable metabolic disorders of amino acid metabolism in mice show a potential for such studies in estimating mutation rates in mice. Some possible techniques for such studies and their implications are discussed.


Validation of the in vivo somatic mutation method in the mouse as a prescreen for germinal point mutations. The in-vivo somatic mutation method developed by us in an earlier X-ray experiment was tested for its usefulness in chemical mutagenesis work, specifically in the prescreening for germinal point mutations. In order to explore possible parallelisms, the 7 compounds chosen for study, as well as the genetic markers used, were those with which large-scale specific-locus mutation-rate experiments in germcells had been conducted in the past or were in progress. From 1--3 dose levels were tested for each compound. On day 10 1/4 after copulation of C57BL females with T males, a single injection of the test compound was administered, and about 2000 offspring altogether were subsequently scored for survival, morphology, and presence of spots of various types. In accordance with our earlier results we found 3 types of spots: white near midline ventral spots (WMVS) which probably result from killing of melanocyte precursor cells; spots resulting from misdifferentiation; and the remainder, which probably result from expression of the recessive by one of several mechanisms (RS). Induction of teratogenic effects, which were stage-specific rather than agent-specific, generally paralleled induction of WMVS's. Both are interpreted as resulting from cell killing. Induction of RS's did not always parallel induction of WMVS's, but roughly paralleled relative frequencies of specific-locus mutations induced in spermatogonia by the same compounds. Even though the in vivo somatic-mutation method probably detects genetic changes additional to point mutations, the results indicate that it may be a useful prescreen for germinal specific-locus mutations, provided care is taken to distinguish between the 3 types of spots, only one of which (RS) is indicative of expression of the recessive.


The induction of somatic mutations in mouse embryos by benzo(a)pyrene. With the object of establishing a test for specific locus mutations in the somatic cells of mice, the effect of benzo(a)pyrene on the developing pigment cells of mouse embryos was investigated. Embryos were heterozygous for genes affecting coat-colour so that mutations could be scored as spots on the adult mouse. If the pregnant female was treated, with 2 mg/day orally, before day 7 or after day 10 of pregnancy no mutations were seen in the offspring. Treatment at any time from day 7 to day 10 was effective in producing mutations with no day giving a peak response. The effect of treatment on consecutive days appears to be additive. It is suggested that further chemicals be investigated lest differing rates of uptake and metabolism should alter the period in which treatment should be given in order to detect a mutagenic effect.


Hepatic vein thrombosis in mice ingesting chlorinated hydrocarbons. Hepatic vein thrombosis, as well as hepatocellular carcinomas, was induced in inbred C3H male and female mice ingesting 10 ppm of dieldrin, aldrin, heptachlor, or heptachlor epoxide in the diet. Thrombosis was present in 5% of mice ingesting dieldrin or aldrin and in 10.5% of mice ingesting heptachlor or heptachlor epoxide. Occlusion of the hepatic vein often resulted in infarcts of the liver. Females ingesting heptachlor or heptachlor epoxide were slightly more susceptible than males. There was no difference between male and female mice ingesting dieldrin or aldrin. Hepatic vein thrombosis did not appear to be related to the development of carcinoma of the liver because it was present in livers without carcinomas as well. Thrombosis was usually seen only in the liver but also rarely was present in the atria of the heart.


Toluene concentrations in various tissues of rats after inhalation and oral administration. The uptake, distribution, and elimination of 3H-toluene in  various tissues of rats were studied after inhalation or after gastric intubation. The maximum radioactivity was measured 2--3 h after gastric intubation in tissues, except in white adipose tissue, where the peak radioactivity was reached at 5 h. After inhalation exposure, the uptake to various tissues was very rapid. The maximum radioactivity in most tissues was reached in 15--30 min. The accumulation was slowest in white adipose tissue, where it took 1--2 h. The radioactivity in tissues decreased after inhalation exposure more rapidly than after gastric intubation. Brown adipose tissue and white adipose tissue were different from other tissues in their ability to retain toluene. Twenty-four hours after exposures, only 1% or less of the initial radioactivity was found in tissues other than white adipose tissue, in which the corresponding value was 3.5--5%. The results show a very rapid absorption and distribution of toluene after inhalation and a retention of radioactivity in white adipose tissue. After oral ingestion the distribution showed a similar but much slower pattern.


Pharmacokinetics of cyanide in poisoning of dogs, and the effect of 4-dimethylaminophenol or thiosulfate. Cyanide in blood, plasma, and urine of dogs after administration of K14CN was determined with the isotope dilution technique. The addition of large amounts of inactive KCN as soon as possible to a sample to be analyzed inhibited the decrease of the original cyanide concentration. After administration of several lethal doses of cyanide into the stomach or by slow intravenous infusion a concentration of about 40 micron cyanide in plasma was found at the moment of respiratory arrest. Since 60% of the cyanide in plasma was bound to proteins the concentration of free cyanide which stopped respiration was about 16 micron. Quick formation of ferrihemoglobin by i.v. injection of 4-dimethylaminophenol after plasma cyanide had risen to or above 40 micron decreased the cyanide concentration in plasma and restored respiration, while  cyanide  was  accumulated in red cells by formation of ferrihemoglobin cyanide. Equilibrium constants calculated for the reaction between ferrihemoglobin and cyanide in vivo indicated that the reaction approached equilibrium in a few minutes. Up to 60% of the radioactive cyanide absorbed was found as non-cyanide radioactivity in the urine.


Hexachlorobenzene residues and effects on esterase activities in pre-weanling rats after a reciprocal transfer between HCB-treated and control dams. Female Wistar rats were divided into two groups. One group was fed ad libitum powdered rat chow containing 80 ppm hexachlorobenzene (HCB) and the other was fed HCB-free diet 2 weeks before mating until the termination of the experiment. Immediately after parturition, the pups were randomly culled to 10 per litter and 5 pups were reciprocally transferred between HCB and control dams. All pups within same paired litters were sacrificed on the 16th to 17th day and on the 20th to 23rd day after birth. Liver esterase activity toward indophenyl, thiophenyl, and p-nitrophenyl acetates was determined. The liver to body weight ratio, liver esterase activity and HCB residues were significantly higher in pups nursed by HCB-fed dams than in those nursed by control dams. The HCB residue in the liver, kidney, spleen, heart and brain was analyzed by gas-liquid chromatography. At about the weaning time, the HCB residue levels in pups transferred after parturition from HCB fed to control dams were similar to those in pups which remained with the control dams. The results demonstrated that HCB in tissues at about weaning time was obtained largely through milk. In addition, transmission of HCB through milk had greater effects on esterase activities in suckling pups than placental transmission. The pups born to HCB-treated dams and nursed by the control dams were similar to the pups born and nursed by the same control dams.


The effect of selenium on the brain uptake of methylmercury. Twenty-four h after the subcutaneous administration of 0.5 mumoles selenite labelled with 75Se to rats of 200 g body weight, the retention of selenium at the injection site was significantly increased by the presence of equimolar amounts of methylmercury in the injection solution. The retention of Me203HgCl was not affected by the presence of selenite. The most significant shift caused by interaction was a decrease in the blood content and an increase in the brain content of 203Hg. The brain content of 75Se was also increased to a lesser extent. The shift in the distribution--which was the same whether the two metals were injected at the same site or separately--continuously decreased from 6-48 h. The same interaction pattern was observed when methylmercury and selenite were administered by gastric gavage and differences in distribution increased when the dose was increased from 1.25 mumoles/kg to 2.5 mumoles/kg. The increase in the brain content of mercury caused by selenite was not restricted to simultaneous administration and occurred when selenite was given 2-7 days after methylmercury.


[Control of the intensive treatment of thallium intoxications (author's transl)]. A report is given on the control of the thallium level at poisoning during therapy with forced diuresis and extracorporeal hemodialysis. The success of these methods was controlled ty the determination of the thallium level in vomit, blood, urine and dialysate by flameless atomic absorption spectrophotometry. Since the results are obtained within a few minutes, thallium measurements may be helpful for the decision on the therapy to be applied.


Binding of mercury and selenium in subcellular fractions of rat liver and kidneys following separate and joint administration. The distribution of mercury and selenium has been examined in subcellular fractions of rat liver and kidneys in prolonged exposure to HgCl2 and Na2SeO3 administered separately and simultaneously. The molar ratio of mercury and selenium concentrations in subcellular fractions of the organs examined varied considerably. Selenium displaced mercury from the soluble kidney fraction bound mainly with metallothionein to the nonhistone protein fraction of liver nuclei. The Hg-stimulated biosynthesis of metallothionein has been eliminated under the influence of selenium.


Trichloroethylene and 1,1,1-trichloroethane: effects on brain and liver after five days intermittent inhalation. The inhalation exposure of adult male rats to 7.9 mumol/l (200 ppm) of trichloroethylene for 4 days 6 h each day led to an accumulation of the solvent in the perirenal fat 17 h after the last exposure. Exposures to 20 mumol/l (500 ppm) of 1,1,1-trichloroethane caused similar accumulation. The latter rats presented no changes in their behaviour in an open-field test whereas the motor behaviour of the animals exposed to trichloroethylene was more active in comparison to controls 1 h after the exposure on the 4th day. Trace effects of trichloroethylene on emotional behaviour of the same rats could be seen 17 h after the last exposure. Further exposures on the 5th day increased brain, liver, lung and blood contents of trichlorethylene and 1,1,1-trichloroethane. A slight decrease in brain RNA content was found in the 1,1,1-trichloroethane exposed rats while RNA decreased significantly after the fifth day of trichloroethylene inhalation. The exposure to 1,1,1-trichloroethane on the 5th day depressed also the microsomal cytochrome P-450 content in liver of rats whereas trichloroethylene increased the hemochrome content slightly at the same time.


[Submicroscopic changes in the hepatocytes of guinea pigs under the effect of heterologous mitochondrial antibodies]. The electron microscopic examination of livers of guinea pigs treated with heterologous mitochondrial antibody showed that under these circumstances pathological changes developed in hepatocytes entailing various disorders of cell metabolism. These changes consisted in marked disturbance of the circulation of intracellular fluids leading to the general or partial edema of the cell and disorientation of organoids, in different rearrangements of mitochondria with loss of calcium phosphate salts, in degranulation and formation of numerous large cavities of granular endoplasmic reticulum, reduction of the Golgi complex, decrease in the amount or complete lack of glycogen in hepatocytes. The experimental evidence attests to the damaging effect of heterologous mitochondrial antibody on numerous cellular and subcellular structures causing the disorders in the water-salt, protein, and carbohydrate metabolism.


Experimental study of sacculotomy in endolymphatic hydrops. Thirty-nine guinea pigs were used for four groups of experiments: 1. sacculotomy only, 2. sacculotomy and simultaneous obliteration of the endolymphatic duct, 3. sacculotomy followed by obliteration of the endolymphatic duct, and 4. obliteration of the endolymphatic duct followed by sacculotomy. Sacculotomy alone caused only minimal cochlear pathology, whereas sacculotomy on hydropic ears produced severe atrophy of the organ of Corti and cochlear neurons as well as connective cells of the limbus. There was histological evidence that Reissner's membrane in hydropic ears was ruptured by the sacculotomy procedure. The primary cause for the severe atrophic changes is thought to be the toxic effect of intermixing perilymph with a large volume of endolymph. The surgically induced saccular tears appeared to be healed in all ears, and the procedure had no significant effect on the course of endolymphatic hydrops. Although two out of eleven specimens in which sacculotomy was performed on hydropic ears showed tears and collapse of Reissner's membrane, since others with similar tears showed extensive hydrops, the possibility of artifact could not be ruled out. In one specimen with simultaneous sacculotomy and obliteration of the duct, persisting fistulae were noted at the sites of accidental fracture of the osseous spiral lamina; this ear is the only one which failed to develop hydrops following obliteration of the duct. The results of this experiment, namely sacculotomy on hydropic guinea pig ears, suggest that sacculotomy is not a rational procedure for the control of endolymphatic hydrops in Ménière's disease for the following reasons: 1. surgically induced tears in the saccular wall are followed by rapid healing and 2. intermixing of perilymph and a large volume of endolymph causes toxic atrophy of the limbus, organ of Corti and cochlear neurons.


The influence of intravenous injection of lidocaine on optokinetic nystagmus in rabbits. The effects of lidocaine in doses of 2.0--6.0 mg/kg with intravenous injection on optokinetic nystagmus were observed in 21 rabbits. No effect of lidocaine was obtained on the frequency of OKN. On the other hand, the amplitude of OKN in lidocaine groups decreased after the injection. The mode and place of the action of lidocaine on OKN were discussed.


[Concerning the morphology of the supraglottic submucosa and its relation to the growth of cancer (author's transl)]. The histological structure of the supraglottic submucosa consists of a wide-mesh connective net, which builds compartments where glands are included. Somewhere, the walls of compartments are so thick that they may be considered as true ligaments. Some of them are located at the limit between glottis and supraglottis; therefore one may argue that the so-called "biological vallum", which hinders the downward propagation of supraglottic cancers is not only due to the interruption of lymph ways between vestibulum and vocal chords but also to the presence of this thick connective barrier. Two gaps interrupt the continuity of the barrier, the first one at the anterior commissure, the second at the posterior extremity of the ventricle. The situation of the gaps corresponds to the main directions of propagation of the supraglottic cancers, when they spread inferiorly.


[Pharmacokinetical, histological, and histochemical investigation on the ototoxicity of gentamicin, tobramycin, and amikacin (author's transl)]. The pharmacokinetics of gentamicin, tobramycin, and amikacin in the inner ear fluids and serum of the guinea pig were studied. The concentrations of these antibiotics were determined by a microbiological method and could be confirmed by the use of 14C-labeled gentamicin. Retention was clearly demonstrated in perilymph and endolymph, whereas there was no retention in the cerebrospinal fluid and the compartments of the eye. A linear relation between concentrations in the perilymph and dosage of gentamicin was ascertained. There was no difference between the concentration of drug in endolymph and that in perilymph. The concentrations of these antibiotics in the perilymph were symmetrical and many times higher than those in the brain. Long-term treatment did not influence the pharmacokinetics of the three antibiotics in the inner ear. However, increased levels of drug in the inner ears in animals with uremia and in some animals with otitis media explained the increased ototoxicity that was observed in histological investigations of these two conditions. Cisternal puncture and diuretics did not change the concentrations of aminoglycoside antibiotics in the inner ear. In large experimental series the hair cell degeneration pattern of the new aminoglycoside antibiotics was determined by the surface preparation technique as well as the influence of the different factors upon this pattern. A prophylactic effect on the ototoxicity of the aminoglycoside antibiotics could not be found in the 2,3-dimercaptopropanol, but by dividing the daily dosage administered. Young guinea pigs were generally not very sensitive to gentamicin, in some cases however much more. Late ototoxicity could not be found after administration of gentamicin. The pharmacokinetical and especially the histological investigations allowed an evaluation of the ototoxicity of the new aminoglycoside antibiotics. By histochemical investigations no influence of the new aminoglycoside antibiotics upon the amount of unspecific esterases and alkaline phosphatase in the inner ear could be detected, but an increase of the amount of acid phosphatase in slightly damaged outer hair cells.


[Incus, controlled deepfrozen or in cialit conserved, after allogenetic implantation. An animal-experimental study with comparing histology (author's transl)]. The histological reactions to the implantation of allogenetic incus after conservation in Cialit or after controlled deepfreezing are described. After 5 months the incusses of both conservation technics show the same good tendency of revitalisation. Therefore the controlled deep-freezing technic does not offer an advantage compared to the Cialit conservation method at least for the present state of knowledge.


Sacculus laryngis.

Sacculus laryngis. 100 preparations of the larynx from 104 autopsies were examined with reference to the condition of the laryngeal saccule. In 54% of the cases the saccule could not be demonstrated. The examination showed a clear sex difference regarding the existence and size of the laryngeal saccule. In 6% the laryngeal saccules were pathologically enlarged as interne laryngoceles, in all cases in males. The laryngeal saccule must regarded as an atavistic structure.


[Three cases of giant cell fibroma of the vocal cord (author's transl)]. Three cases of giant cell fibroma of the vocal cord are reported. The histological and cytological features of the extirpated tissue confirm the benigne character of these tumors.


The nystagmus and the therapeutic effects on early-diagnosed cases of sudden deafness. We investigated the hearing prognoses of early diagnosed cases of sudden deafness. We tried to find the most reliable factor to determine the prognosis of hearing loss. Of various possibilities that affect the prognosis; the period of onset to first examination, therapeutic manner and vestibular test findings, the findings of caloric test and spontaneous nystagmus showed much better correlation with the hearing prognosis than others. Thus, we presume the vestibular dysfunction in cases of sudden deafness may reflect the extension and severity of inner ear involvement.


Tympanoplasty in Korea (ossiculoplasty). Three hundred and ninety three cases of ossicular reconstruction are presented. In the most favourable cases with both malleus handle and stapes present, this presents a closure of the air-bone gap to within 20 dB better than 80%. With connective tissue, underlay and fixation technique and staging are all important aspects of ossicular chain repair. Preservation of the function of the sound conduction mechanism in most favourable cases (malleus handle and stapes arch present) were improved by the employment of a sculptured, fitted incus prosthesis between the handle of the malleus and the head of the stapes.


[Auditory thresholds in guinea-pig and mouse by the pinna-reflex of Preyer (author's transl)]. Auditory thresholds were obtained by controlling Preyer's pinna-reflex for sound pressure levels quantitatively and selectively for single frequencies. Under the reported test conditions the auditory thresholds are very well reproducible and quickly done.


[Acidosis and clinical condition in asphyctic calves]. In depressed calves (modified APGAR score 4-6) there is at birth an evident combined respiratory-metabolic acidosis (pH = 7.082 +/- 0.175; pCO2 = 73.3 +/- 26.8 mm Hg; BE = -10.6 +/- 7.2 mmol/l). The metabolic adaptation is completed after 6 hours, the respiratory acidosis is present up to 24 hours after delivery. In comparison to normal calves there are significant deviations in pH-values, base excess standard bicarbonate and actual bicarbonate during the whole investigation time. The carbon dioxide tensions of the depressed calves are at birth similar to those of normal calves, but in the following hours they are significantly higher. A definite relationship can be demonstrated between the 1 minute APGAR score and pH-value, base excess, standard bicarbonate and actual bicarbonate. Oxygen tension, oxygen saturation and carbon dioxide do not correlate with the clinical condition.


[Effect of a benzopyrone compound on embryonic tissue and cell cultures (author's transl)]. Embryonic tissues and cells of the chicken were treated with a coumarin-rutin derivative preparation (Venalot). A total of 3000 cultures from embryonic epithelia, skeletal muscle tissue, and connective tissues were tested. At high dosages, never administered in the therapy, the preparation inhibited the cell proliferation strongly. With the diminution to therapeutical concentrations no longer inhibitory but stimulatory effects, viz. to mitosis, were revealed. High cell partition rates in the connective tissue (fibroblasts), in the epithelial cells and in the bony tissue of the embryonic os frontale (osteoblasts) are an indication of the mechanism of the known wound-healing accelerating action of the preparation. The effect of stimulating the proteolytic action in mesenchymal cells, observed on isolated peritoneal macrophages has been confirmed for the mesenchymal cell of the embryonic chicken.


Synthesis of some indole acrylamides. Short communication. The synthesis of some indole acrylamides via the acid chloride is reported. Disubstituted indole acrylamides are successfully prepared by the application of Vilsmeier reaction.


Biological properties and clinical application of propolis. IV. The action of ethanol extract of propolis (EEP) on cells cultured in vitro. An increase of total cell number was shown in the cell culture in vitro under the influence of ethanol extract of propolis (EEP). Addition of EEP to the nutrient medium of the cells caused a strong activation of mitoses. Besides, distinctly intensified metabolism of these cells expressed by a strong activation of NADH2-reductase was also observed.


Chemistry and pharmacology of arginine pyroglutamate. Analysis of its effects on the CNS. By studying the influence of the arginine pyroglutamate on the CNS its variations were evidenced which are clearly identifiable through the analysis of the interaction with molecules having either a depressive or excitatory action. In the case of pentobarbital the antagonistic effect of the compound on the general anaesthesia is very intense and is equally present even when medazepam and flurazepam are associated. Equally obvious is the  antagonism with barbiturate in the case of spontaneous motility but much less so with the two benzodiazepines. As far as the specialized behaviour is concerned, arginine pyroglutamate does not alter the sound discrimination capacity (responses in Sdelta punished) at fixed intervals (F.I.) nor does it influence the learning of a sound discrimination (responses in Sdelta punished) at varied intervals (V.I.). The process of learning is instead moderately accelerated in the case of a temporal discrimination and of a conditioned avoidance response (CAR) in the shuttle-box. No effect was found when the same amino acids were introduced alone or in random association. The hypothesis is proposed that the phenomena described depend on the different pharmacokinetics of arginine pyroglutamate that ensures brain concentrations sufficient to block the activity of depressive compounds but is not capable of influencing in a significant way the spontaneous and specialized behaviour of normal animals.


Action of phenylisopropyl-adenosine (PIA) on the synthesis of corticosterone in rats. The effects of the stereoisomers of phenylisopropyl-adenosine (l- and d-PIA) were studied on the synthesis of corticosterone in rats in vivo and in rat adrenal slices in vitro. In vivo l- and d-PIA elevated plasma corticosterone level in normal but not in dexamethasone-pretreated rats. l-PIA was at least 20 times more active than d-PIA. The ACTH-stimulated steroidogenesis was modified by pretreatment with l-PIA neither in normal nor in dexamethasone-treated rats. Adrenal slices prepared from the l-PIA-pretreated rats were less sensitive in vitro to the stimulatory action of ACTH or N6,2'-O-dibutyryl-3',5'-adenosine monophosphate (DBA) than those from control animals. In vitro l- and d-PIA slightly increased the basal steroidogenesis. On the other hand, both the ACTH- and DBA-stimulated synthesis of corticosterone was inhibited by l- and d-PIA to approximately the same degree. The type of inhibition proved to be competitive in ACTH-stimulated and non-competitive in DBA-stimulated steroidogenesis. l- and d-PIA did not disturb the release process of corticosterone from the adrenal tissue into the incubation medium.


Influence of hypercapnia on the cerebrovascular activities of some drugs used in the treatment of cerebral ischemia. The effects of twelve substances on local cerebral blood flow (LCBF) were studied in the normocapnic and hypercapnic conscious rabbit. In normocapnia, an increase in LCBF was observed after naftidrofuryl (NAF), cinnarizine (CI), viquidil (VI) and heptaminol acefyllinate (HA). The LCBF was only slightly increased or unchanged after hydrogenated ergot alkaloids (HEA), cyclandelate (CY), hexobendine (HE), ifenprodil (IF), piridoxilate (PI), vincamine (VC) and xantinol niacate (XN). It was reduced by theophylline (TH). In hypercapnia, a more pronounced increase in LCBF than in normocapnia was seen with CY, HE, NAF, and VI and a decrease or lesser effect with HA, IF, VC and XN. The decrease in LCBF with TH was enhanced by hypercapnia. The effects of CI, HEA and PI were not modified. The therapeutic implication of these modifications of drug effects by hypercapnia, is discussed.


Effects of metformin on glucose metabolism of isolated perfused rat skeletal muscle. It was investigated whether N,N-dimethylbiguanide hydrochloride (metformin) lowers blood glucose levels by stimulating glucose uptake of skeletal muscle using the isolated perfused rat hindquarter. Osborne-Mendel rats were subjected to a special feeding regimen (food intake only 2 h daily) and were treated orally by metformin (125 mg/kg body weight twice daily) or placebo, respectively. The hypoglycemic effect of metformin could be demonstrated. Thereafter, control rats were perfused in the absence, and metformin-treated rats in the presence of added metformin (0.67 microgram/ml perfusate). Neither the basal nor the insulin-stimulated glucose uptake of skeletal muscle was increased by metformin. Lactate and alanine release, O2 uptake as well as the tissue metabolite levels of glucose, lactate, pyruvate, ATP and creatine-P remained unaffected. On the other hand, metformin caused a significant decline of lactate oxidation as well as an elevated glycogen content of skeletal muscle. It is proposed that the inhibition of lactate oxidation may under certain conditions be instrumental in the development of lactic acidosis associated with biguanide therapy.


Differences in the response to pentobarbital sodium of Roman high- and low-avoidance rats. Wistar-derived, Roman high- and low-avoidance rats (RHA and RLA) have been bred solely for divergent patterns of performance in a behavioral test. In the present study, single and multiple injections were used to investigate the acute and chronic effects of pentobarbital sodium in these 2 strains. The median lethal dose was found to be significantly higher for the male RHA rats than for the RLA males. RHA males also had proportionally larger livers, kidneys and hearts, and lower erythrocyte counts, hematocrits and hemoglobin levels than had RLA males.


Evaluation of a 4% gelatin solution in the treatment of canine haemorrhagic shock. The effects of volume replacement with 4% gelatin containing 1% glycine at pH 5.8 and 6.4 on the changes in mean arterial blood pressure (MABP) and blood levels of glucose, lactate and urea following acute haemorrhage in dogs were studied. Comparison was made with dogs given homologous blood. Dogs bled 30% of blood volume, maintained in shock for 30 min, and infused with gelatin solutions, showed values of MABP, blood glucose, lactate and urea nitrogen insignificantly different from dogs similarly bled and infused with homologous blood. The responses obtained in dogs infused with gelatin at pH 5.8 were better than at pH 6.4.


Comparison of the biological effectiveness of injected testosterone propionate and testosterone released from silastic capsules. The in vitro release and biological effectiveness of silicone rubber implants containing testosterone in orchidectomized male rats was investigated over a period of 20 weeks. A marked reduction in release in 0.9% saline solution could be observed in vitro relative to the incubation time in the medium. The reduction in release was greatest during the first few weeks of the experiment. Rat seminal vesicles and prostates, which were greatly stimulated at the start of the experiment, lost weight corresponding to the release rate in vitro. The implants containing testosterone used here were 4 to 26 times more effective than testosterone propionate injected s.c.


Alcohols-histones metabolic interactions in intact human erythrocytes. Alcohols have a stimulating effect on the intracellular peroxidatic reactions of intact human erythrocytes. This effect depends directly on the molecular weight of alcohol and the H2O2 concentration. The human leukocyte nuclear histones, flavin-adenine-dinucleotide (FAD) and nicotinamide-adenine-dinucleotide (NAD) inhibit the peroxidatic reactions during the metabolism of alcohols in intact human erythrocytes. The participation of erythrocyte catalase, the possible metabolic pathway and the inhibitory effect of human leukocyte nuclear histones, FAD and NAD on the intracellular metabolism of alcohols is discussed.


[Quantitative determination of pemoline in serum and urine after ingestion of therapeutic doses (author's transl)]. Serum and urine 5-phenyl-2-imino-4-oxazolidone (pemoline, Tradon) levels have been determined in normal subjects after therapeutic doses (40 mg). Peak levels in serum were reached within 4-6 h (1.1-1.5 mg/1). The half-life was 16-18 h. After the oral administration of 40 mg of pemoline 35-50% of the dose was excreted in urine within 32 h.


[Iron absorption after oral application of a combination of Fe2+-succinate and multivitamins (author's transl)]. The rate of iron absorption of Fe2+-succinate orally applied with multivitamins, was measured by means of whole-body counter in 45 subjects. The dosage was 330 mg ferrous succinate (115 mg Fe2+). Absorption was generally 4.5% (5.2 mg) in normal subjects, 8.6% (9.9 mg) in subjects with latent iron deficiency, and 29.6% (34 mg) in subjects with manifest iron deficiency. In women taking oral contraceptives and not suffering from iron deficiency, no significant increase in the iron absorption rate was measured.


[On the pharmacokinetics of phenazone in man (author's transl)]. Studies were carried out on the pharmacokinetic behaviour of 5-oxo-2,3-dimethyl-1-phenyl-3-pyrazoline (phenazone) by means of intraindividual comparison following oral and rectal administration in man. A one-compartment model served to describe the course of blood levels, in which the twin peaks of following rectal administration are quite remarkable. The influence of variation in the pharmaceutical dosage form on the pharmacokinetic behaviour patterns of phenazone were studied and intraindividual differences not inconsiderable are obvious.


[Electromyographic studies on the effect of the cinnamamide derivative LCB-29 in spastic syndromes (author's transl)]. In ten patients with para- or tetraspastic syndromes of various etiology 5 different spastic phenomena demonstrating pathologically raised excitability of muscle regulation functions were registered electromyographically before and 1 h after i.v. administration of N-(hydroxy-2-ethyl)-cinnamamide (LCB-29). In the majority of cases a marked decrease of spasticity was registered. The rapid onset of this effect of LCB-29 allowed constant test conditions and therefore eliminated other influences on spasticity. The decrease of raised polysynaptic excitability at spinal level led, at least in part, to the assumption of a spinal site of action of LCB-29. The absence of a sedative effect with oral medication makes a strong central effect seem less probable.


[Modification-possibility of the enterohepatic circulation of digitoxin in man]. Tritiated digitoxin (0.25 mg) was i.v. administered to a control group of 5 patients as well as to 5 patients with a T-tube quantitatively draining the bile fluid. During the initial 24 h after injection, 10% of the dose administered, on the second and third days 5 and 3,5%, respectively, were biliarily excreted. The amount biliarily excreted did not influence the course of the blood level as compared to the controls. Also charcoal given perorally in a sufficient amount (50 g) did not affect the blood level of radioactive digitoxin and/or its metabolites. As obtained from in vitro experiments the absorptive potency of cholestipole and cholestyramine for digitoxin and its metabolites in human bile fluid is similar to that of charcoal.


Spironolactone metabolism in normal subjects and in patients with liver cirrhosis. The dynamic excretion of aldadiene, the principal metabolite of spironolactone with biological activity, was studied in normal subjects and patients with liver cirrhosis following administration of spironolactone. Aldadiene appeared in the three-days urine collection in around 3% of the dose. There was no significant difference in the biological half-life, calculated from the urinary pattern, and in the rate of excretion in patients with hepatopathy and hospitalized controls. Healthy volunteers without hospitalization exhibited the most rapid elimination of the metabolite. An increase of spironolactone dose enhanced the per cent rate of aldadiene excretion, while the biological half-life did not change. Spironolactone decreased the rate of dehydroepiandrosterone and androsterone excretion even after a single dose. Determination of total 17-ketosteroids is of no value on evaluation of adrenal function during spironolactone therapy, due to a Zimmermann-positivity of spironolactone metabolites.


The fate of intravenously infused gelatin. The fate of i.v. infused gelatin was studied by measuring the rise in the level of total hydroxyproline (HP) in some organs of the rat following the infusion of a 5% autoclaved gelatin solution (1 ml/100 g body weight). The results obtained showed that HP levels were consequently increased in all of the organs studied, then the levels were generally normalised during the 3rd day post infusion. Small concentrations of HP were still retained by the kidneys and blood plasma, at the end of the first week after infusion. The rat ratio HP/creatinine (HP/C index), which increased from 0.33 to 3.78 during the first 24 h post infusion, declined gradually to the base-line level after 4 weeks, during which time 94% of the HP infused could be accounted for in the urine. Most of the HP was excreted in the bound form.


[Structure-activity relationships of etozolin, a novel diuretic (author's transl)]. Selection of a structurally confined group of diuretics out of 2-methylenethiazolidones-(4), a new class of compounds, and related heterocycles with partly choleretic properties is described. The physico-chemical parameters of ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (3; etozolin, Gö 687, Elkapin), which has been selected for therapeutic use, are discussed with respect to its close structural relation to the choleretic piprozoline (2). Both the spectroscopic results and the anomalous thermodynamic data of 2, 3 and the homologous compounds 4 and 5 demonstrate a structural specificity of 3 unknown up to now with diuretics.


[On the pharmacology of Etozolin (author's transl)]. Ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)acetate (etozolin, Gö 687, Elkapin) is a diuretic with a new chemical structure. Animal experiments with etozolin showed low toxicity, potent diuretic and saluretic properties with a mild onset of action. A marked antihypertensive effect was found in long-term experiments in hypertensive rats. In investigations concerning general pharmacology etozolin showed no effects which stand against its use as a diuretic.


Effect of Etozolin on whole kidney function and fluid and electrolyte reabsorption in rat proximal convoluted tubules and loops of Henle. The effects of ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (etozolin, Elkapin) on whole kidney function and on fluid, sodium and potassium reabsorption in proximal convoluted tubules and loops of Henle of superficial nephrons were studied in rats using clearance and micropuncture techniques. Etozolin (50 mg/kg i.v. initial dose; 50 mg/kg per hour i.v.) markedly increased urinary fluid and sodium excretion and decreased glomerular filtration rate. Fractional tubular sodium reabsorption fell by 8.7%. Fluid and electrolyte reabsorption in the proximal convolution was not significantly influenced by etozolin. The substance significantly increased flow rate, sodium and potassium concentration and decreased tubular fluid/plasma inulin ratio of the early distal tubular, indicating an inhibitory effect on fluid and electrolyte reabsorption in the loop of Henle. Although etozolin is chemically different its site of diuretic action is the same as that of furosemide and ethacrynic acid.


[Toxicological studies on Etozolin (author's transl)]. The tolerance of ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)acetate (etozolin, Gö 687, Elkapin) has been investigated over 18 months after oral administration in rats and over 1i months after intragastric application in dogs. Further the influence of the compound on pregnant animals and their fetuses after intragastric application has been investigated in rats and rabbits. The investigation of the influence on fertility and breeding capacity as well as on the peri- and postnatal development was carried out in rats after peroral administration. In the course of the chronic experiments a dose related increase of the excretion of fluid and electrolytes was observed. Side-effects, which mainly occurred during the last weeks of the experiment in the highest dosage group, were most probably due to the exhaustion of the fluid and especially of the electrolyte reserves of the animals. The experiments in rats and rabbits did not yield any findings indicating teratogenic properties. Fertility and breeding capacity were likewise not influenced by etozolin. An influence on the peri- and postnatal development could be demonstrated only in the toxic dose range.


[Metabolism of Etozolin in rat, dog and man]. Investigations on the metabolism of the new diuretic ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (Gö 687, etozolin, Elkapin) were carried out with urine of rat, dog and man as well as rat bile after enteral administration of the 14C-labelled substance. Seven metabolites were isolated with either the aid of high-pressure liquid chromatography (HPLC) or extraction and thin-layer chromatography. Mass spectroscopy was applied to determine the structures of the metabolites, partly by use of authentic reference substances. Because of the instability of most of the metabolites, some of them showing strong polarity, the described investigations on the metabolic profiles and the enrichment and purification of some metabolites could only be carried out with the HPLC-radioactivity detector system, which requires no clean-up for the samples. The metabolisation process of etozolin is qualitatively equal in rat, dog and man; it is characterized by 3 steps: 1. enzymatic cleavage of the ester group, which leads to the also diuretically active main metabolite (metabolite I) in the plasma of all 3 species; 2. glucuronidation of the resulting metabolite I, leading to metabolites II and III, which are diastereoisomeric esters of the two enantiomeric forms of metabolite I with beta-D-glucuronic acid. 50--60% of the urinary radioactivity can be described with these two metabolisation steps in all 3 species; 3. Oxidation of the piperidine moiety to metabolites IV--VII.


The distribution of radioactivity in pregnant rats after repeated oral doses of the diuretic agent Etozolin. 1. The distribution of radioactivity has been studied by whole-body autoradiography after administration of daily oral doses of (2-14C)-ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)acetate (etozolin, Gö 687, Elkapin) at a dose level of 100mg/kg to pregnant rats during the 10th to the 17th day of gestation. 2. After the last dose, most of the radioactivity was excreted rapidly and was mainly assoicated with the gastrointestinal and urinary tracts and kidneys of the mothers. 3. Maximal distribution in the mothers occurred at 3--6 h after the last dose, and radioactivity at these times was detectable also in the lungs, muscle mass, fat, mammary and uterine tissue, the reticuloendothelial system, placentae, some ducted and endocrine glands, and in blood, but not in brain or spinal cord. At 4 days, traces of radioactivity had persisted in kidneys, liver, lungs, thyroid and placentae. 4. Radioactivity was present in low and uniform concentrations in most foetal tissues such as the heart, lungs and lens and in even lower concentrations in the brains of the foetuses during 3--6 h after dosing, but was not detected in foetal tissues at 2 days. Concentrations of radioactivity in maternal tissues were at all times much higher compared with those in foetal tissues at corresponding times after dosing.


[Effect of the diuretic Etozolin (Gö 687) on renal elimination of water and solutes in subjects with normal renal function (author's transl)]. The novel diuretic ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)acetate (etozolin, Gö 687, Elkapin) has been investigated on 10 volunteers with intact renal function. Administration of 800 mg of the compound caused a significant increase of the renal elimination of water, sodium, chloride magnesium as well as of the sum of the osmotic constituents while an influence on the creatinine-clearance could not be demonstrated. Potassium elimination was also raised, however, at the same time the sodium-potassium ration increased strongly. Due to its long-lasting action etozolin seems particularly indicated for the treatment of cardiac and renal edema as well as for the treatment of hypertension.


[Effect of the diuretic Etozolin in patients with normal and impaired renal function (author's transl)]. The effect of the novel diuretic ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (etozolin, Gö 687, Elkapin) on renal function and especially on the elimination of solutes has been investigated under clearance conditions on 25 hydrated patients with different glomerular filtration rates (GFR). On normal persons the compound caused a decrease of GFR and of urea elimination while the absolute and the fractional elimination of sodium and chloride as well as the fractional potassium clearance increased significantly. In patients with chronic renal insufficiency (GFR less than 20 ml/min) these values could not be influenced. A significant correlation between initial GFR and decrease of GFR as well as between initial GFR and increase of renal elimination of sodium and chloride could be demonstrated: the lower the initial GFR the weaker the elimination of electrolytes and the decrease of the filtration rate, the latter being neglible at an initial GFR of 80 ml/min or less.


[Comparative studies on the diuretic activities of Etozolin and a reference compound in normal volunteers (author's transl)]. The novel diuretic (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)-acetic acid ethylester (Etozolin; Elkapin) has been investigated against a benzothiazide (Vs) and placebo on 8 volunteers. Etozolin and Vs show a dose dependent diuretic effect: 400 mg etozolin being equipotent to 75 mg Vs and 1200 mg etozolin being 2.8 times more effective than 75 mg Vs. Both substances show maximum effect 2 to 4 h after application, no differences from placebo being demonstrable 10 h after administration. There were no significant differences in potassium excretion between etozolin, Vs and placebo, etozolin and Vs causing, however, a significant excretion of sodium and chloride in contrast to placebo. Etozolin seems to act like a diuretic of the sulfonamide-type in respect to the profile of daily urinary output whereas resembling the loop-diuretic type in respect to urinary volume elimination.


The intrinsic structural asymmetry of highly curved phospholipid bilayer membranes. Phosphorus-31 NMR studies of solutions of small L-alpha-dipalmitoyl phosphatidylcholine bilayer vesicles containing sodium dimethyl phosphate uniformly distributed between the continuous external and the intravesicular aqueous spaces, with the paramagnetic shift reagent Pr3+ present only in the external space, are reported. These studies give the distribution both of dipalmitoyl phosphatidylcholine in the vesicle inner and outer monolayers and of dimethyl phosphate in the aqueous spaces. With the third necessary parameter obtained from the vesicle sedimentation coefficient, the very different packing parameters of dipalmitoyl phosphatidylcholine in inner and outer monolayers can be determined. The vesicle outer radius is 109 A. Although the total bilayer thickness is virtually identical to that of planar bilayers, the outer monolayer is thicker (20 A) and the inner monolayer thinner (15 A). The area per head group at the inner surface, 68 A2, is like the planar value, but the tails are much more folded, so as to decrease the radial lengths and increase the tangential spreat (to 94A2). The reverse is true in the outer layer: the surface per head group is 76 A2, tapering to 51 A2 in the tail region, so that outer layer tails are relatively extended. The difference is equivalent to a shift of about two 2g1 kinks from outer to inner layers; the uneven packing certainly affects fluidity, and may have important biological consequences.


Lateral phase separations in binary mixtures of phospholipids having different charges and different crystalline structures. Synthetic dipalmitoyl phosphatidylserine exhibits a sharp chain-melting transition temperature at 51 degrees C as judged by partitioning of the spin label 2,2,6,6-tetramethylpiperidine-1-oxyl. Phase diagrams representing lateral phase separations in binary mixtures of dipalmitoyl phosphatidylserine with dipalmitoyl phosphatidylcholine as well as with dimyristoyl phosphatidylcholine are derived from paramagnetic resonance determinations of 2,2,6,6,-tetramethylpiperidine-1-oxyl partitioning, freeze-fracture electron microscopic studies and theoretical arguments that limit the general form of acceptable phase diagrams. The reported phase diagrams are the first to describe binary mixtures in which one lipid is charged and the second lipid uncharged. These phase diagrams also are the first to include the problem of solid phases with different crystalline conformations as it relates to the occurrence of a pretransition in phosphatidylcholines and its absence in phosphatidylserines. In addition to the phase diagrams reported here for these two binary mixtures, a brief theoretical discussion is given of other possible phase diagrams that may be appropriate to other lipid mixtures with particular consideration given to the problem of crystalline phases of different structures and the possible occurrence of second-order phase transitions in these mixtures.


Oxygen consumption of the newborn rabbit treated with pulmonary surfactant. A method is described for measuring oxygen consumption of small animals. It was used for 151 newborn rabbits delivered on the 27th, 28th, 29th, and 30th day of gestation. Half of the neonates were given a pharyngeal deposition of a concentrated surfactant (SA) suspension prior to their first breath. The remaining neonates served as controls. The survival rate among the immature rabbits treated with SA was significantly higher. The treatment did not affect oxygen consumption in any age-group. With increasing maturity, the neonates consumed more oxygen, and the controls delivered on the 30th day of gestation consumed 29.6 +/- SEM 4.2 ml oxygen per kilogram and minute.


[Lead content of evaporated milk].

[Lead content of evaporated milk]. In order to determine the concentration of lead in evaporated type of commercially available milks, a study was carried out in 40 cans. Out of them, 20 were of the "vitamin" brand and the other 20 were of "protein" quality. The lead content in either type of milk was not significantly different; "protein" milk showed 38.4 mug/100 ml, while the figure for the "vitamin" grade was 35.0 mug/100 ml. Considering the use of evapored milks in infant feeding, it was deemed wise to carry out an estimation of the amount of lead ingested in case the volume consumed reached from 500 to 1000 ml. As a result of this study, it is stated that somewhat between 150 to 200 mug of lead are ingested daily in the consumption of evapored milk at normal dilution. Based on the tolerance levels, the findings are discussed.


[Changes in the surface-active substance in the lungs of rabbits during endotracheal fluothane anesthesia]. Endotracheal phthorothan anesthesia without any surgical intervention in rabbits for 3.5 hours diminished the surface active properties of the surfactant by increasing the surface tension of the lung washings measured on the Wilhelmy scales. A study of phospholipid fractions in the lung washings by means of the thin-layer chromatography on silicagel showed a decrease of one of the major structures of the surfactant lipoprotein, phosphatidylcholine, with a simultaneous increase of the lysophosphatidylcholine. Determination of the free fatty acid content in the lung washings after the action of phthorothan anesthesia showed their significant increase as compared with control. A possible mechanism of the damaging effect of phthorothan anesthesia on the lung surfactant is discussed.


[Change in the state of surfactant in experimental pneumonia]. The state of pulmonary surfactant in rabbits at different periods (3 to 60 days) of experimental pneumonia was compared with the changes of the redox enzymes in the alveolar epithelium and the cells of the inflammatory infiltrate. At the initial stage (3 to 7 days) of the cellular metabolism activation there occurred a transitory intensification of the synthesis of surfactant lipids with a relative suppression of phospholipid synthesis. Later the progress of dystrophic processes and parenchymal sclerosis was accompanied by reduction of the synthesis of all the surfactant components. Surfactant surface activity became stable at a low level. This is possibly connected with the specific regulation of the surfactant synthesis determined by functional peculiarities of the organ.


Severe disseminated lung disease and bronchiectasis probably due to Mycoplasma pneumoniae. Severe disseminated lung disease causing acute respiratory failure developed in a previously healthy 6 1/2-year-old boy. Mycoplasma pneumoniae was implicated and a complement-fixing antibody titre of 1:1024 against this organism was detected. At autopsy bronchiectasis was found, affecting chiefly the right middle and lower lobes. The unusual radiologic and pathologic findings are discussed.


[Effect of valinomycin on the phase state and passive permeability for calcium ions of membranes from artificial phospholipids]. Effect of valinomycin on passive permeability for calcium ions of liposomes from artificial phospholipids of dimiristoillecithin and dipalmitoillecithin under the conditions of thermotropic structural transitions which were controlled by means of fluorescent probe of 3-metoxibenzantron. It was found that the incorporating of valinomycin into the membrane depends on the density of phospholipid packing. The change of the physical state of phospholipids under the effect of antibiotic was correlated with the change of passive permeability of liposomes for calcium ions.


Familial occurrence of colon and uterine carcinoma and of lymphoproliferative malignancies: clinical description. Carcinoma of the colon occurred in four generations of a family, including two of three siblings of one generation and eight of 19 members of the next generation. In addition, uterine cancer or lymphoproliferative malignancies were found in two family members. Of 41 members of the fourth generation, two were found to have colon cancer and one had malignant lymphoma. Clinical features were similar to those patients with "cancer family syndrome." Although a precise genetic mechanism is uncertain, it appeared to be transmitted as an autosomal dominant character.


The value of Gastrografin in the differential diagnosis of paralytic ileus versus mechanical intestinal obstruction: a critical review and report of two cases. Two cases in which serious intra-abdominal complications were masked by results of the contrast examination using Gastrografin were encountered. This caused the authors to review critically the use of Gastrografin in the differential diagnosis of paralytic ileus versus mechanical intestinal obstruction. In a series of 41 cases in which the diagnostic problem was not solved initially by means of physical examination and plain abdominal roentgenograms, the Gastrografin examination proved reliable in 28 (68 per cent). The reliability of the examination was defined as the relative number of cases in which a correct decision could be made for or against surgical operation. It is concluded that Gastrografin is a valuable diagnostic aid in controversial cases of ileus. A "negative" result of the examination, however, would never be allowed to damp the surgeon's awareness of possible serious intra-abdominal conditions, which the contrast examination has failed to disclose and which require immediate surgical intervention.


[CNS complications and their prevention in malignant non-Hodgkin's lymphoma (author's transl)]. Among 334 patients (aged 15-57 years) with malignant non-Hodgkin's lymphoma there were 14 who developed CNS complications, none in 144 with lymphoma of low malignancy. Lymphoblastic lymphoma predominated amoung those with CNS involvement. In adults with this form treatment should therefore be undertaken to prevent such complications. The study confirms the need for histological subclassification in malignant non-Hodgkins's lymphoma.


Lactose malabsorption among the Pima indians of Arizona. Lactose loading tests and other means were used to determine the pattern of primary "adult" lactose malabsorption (LM) and milk use among 171 subjects, including 122 children and 49 adults, almost all of them Pima Indians of Arizona. LM develops at quite young ages in full-blooded Pima children: already in the 3- to 4-year age group, 40% had LM. Of 62 full-blooded Indians (greater than or equal to 4 years of age), 59 (95%) had LM. Of 41 Indians (greater than or equal to 4 years) who were of mixed Indian-northern European ancestry, however, only 25 (61%) had LM, and, among them, prevalence of LM correlated with degree of northern European admixture. Whereas only 21% of Pima lactose absorbers reported symptoms after the loading test, 72% of malabsorbers did so, with older malabsorbers more likely to experience symptoms. In their everyday lives, only 23% of malabsorbers recognized symptoms brought on by milk consumption, but the percentage of malabsorbers making such an association increased with age. Nevertheless the Pima, adults as well as children, continue to drink reasonable quantities of milk. Family pedigrees are consistent with the hypothesis that adult lactose absorption is inherited as an autosomal dominant trait. Over-all results of this study, moreover, support the geographic hypothesis advanced to explain ethnic or racial differences in prevalence of LM, rather than the induction hypothesis.


[Therapeutic effects on disorders of spermatogenesis in hyperprolactinemia without pituitary adenoma]. As in patients with high pituitary prolactin secretion disturbances of the spermatogenesis are observed, we picked out from our patients with low sperm count those showing hyperprolactinemia without pituitary adenoma. They were treated for 50 days with 2-brom-alpha-ergocryptin (Pravidel, Sandoz AG, Nürnberg), which selectively inhibits prolactin release. Following treatment, in 7 cases an increase in sperm count was observed, while in 2 cases a decrease occurred. 4 cases with azoospermia showed no alteration. No explanation for the possible stimulation of spermatogenesis can be given today.


Examination of the aqueous humor as a diagnostic aid in anterior uveitis. The aqueous humor of 20 cats and 17 dogs was examined to determine its importance as a diagnostic aid in anterior uveitis. Aqueous humor cytology and protein concentration differed in acute and chronic anterior uveitis but was not specific enough to be an aid in the diagnosis of feline infectious peritonitis. Cytologic examination of the aqueous humor was of benefit in determining the cause of anterior uveitis in 2 of 7 cases of lymphosarcoma. Cultures of aqueous humor proved negative in uveitis of more than 3 weeks' duration. Pseudomonas sp was cultured from the aqueous humor of a dog with anterior uveitis secondary to a perforating corneal injury.


Alkaline phosphatase activity in the preimplantation mouse embryo. Alkaline phosphatase (AP) activity has been assayed in frozen sections of preimplantation mouse embryos by an azo-dye cytochemical method. The results indicate that during preimplantation mouse development AP activity is first expressed between the 8- and 16-cell stages and develops in all cells by the late morula stage. During blastocyst formation AP activity is lost or greatly reduced in trophoblast cells while activity is maintained in the inner cell mass.


The ultrastructure of a porcine hereditary lymphoma with some observations on cell cultures and enzyme cytochemistry. Ultrastructural studies have been made on affected tissues and cell cultures established from an hereditary lymphosarcoma of Large White pigs. Certain hydrolytic and lysosomal enzymes have been investigated at light microscope level in tumour cells and in cells established in culture. Morphological, behavioural and enzymatic characteristics indicate that two types of surface-adherent cells persist in primary cultures established from the marrow of affected pigs, namely macrophages and myeloid cells. The latter show an initial tendency to colonial growth which disappears in subsequent passages. In nearly all cases the tumour is considered to be a poorly differentiated lymphocytic lymphosarcoma. There is, however, considerable variation in cellular components and tumour-cell differentiation, and on purely morphological grounds one case might be considered to be an histiocytic i.e. macrophage lymphoma. Intra-nuclear bodies were observed in one case and occasional cytoplasmic virus-like particles were seen in both fresh tissues and cultured cells. In older pigs tumorous lymph nodes often show a cellular depletion associated with an increase of fibroreticular stroma.


The effect of exogenous nucleosides on postimplantation development of mouse embryos. Exogenous nucleosides, either singly or in combination, do not enhance postimplantation development of mouse embryos in vitro, and adenosine, guanosine and thymidine are toxic to the embryos at high concentrations.


A comparison of D.O. and M.D. student performance. The performances of students from two medical colleges, one allopathic (M.D.) and one osteopathic (D.O.), at Michigan State University in a first course in psychiatry are compared. Although the M.D. students had scored significantly higher on the Medical College Admission Test, there was no difference in examination performance in the psychiatry course, which included measures of both basic information and of skill in diagnostic clinical application.


Supplemented fasting as a large-scale outpatient program. Although supplemented fasting is now established as an efficient means of achieving substantial weight reduction in massively obese persons, widespread application of this treatment is contingent on its successful adaptation to a large-scale outpatient regimen. Of 519 patients treated as outpatients, 78% lost a minimum of 18.2 kg during the course of treatment. The overall rate of weight loss was 1.5 kg/wk, with females averaging 1.3 kg/wk and males, 2.1 kg/wk. The majority of patients tolerated the regimen well and were able to continue normal daily activities without experiencing any serious side effects.


Cystic fibrosis. An expanding challenge for internal medicine. The number of adults with cystic fibrosis (CF) receiving care from the US Cystic Fibrosis Centers has been increasing at an average rate of about 200 patients each year. A model based on the continuation of this rate of increase predicts that almost 4,000 adults will be receiving care at the centers by the end of 1985. Four other models developed are based on continuation of a steady state with two variations: a 50% reduction in mortality and universal newborn screening. These models show the boundaries of an equilibrium population to be between 24,000 and 64,000 patients, with 7,000 to 18,000 adults.


Upper airway obstruction in euthyroid goiter. Although it is recognized that an enlarged thyroid may occasionally cause tracheal compression, the incidence in euthyroid goiter is unknown. Twenty patients with nontoxic goiter were investigated for upper airway obstruction. Although none of them had dyspnea as a chief complaint, on direct questioning 9/20 had a history of shortness of breath on exertion and choking sensation. Upper airway obstruction was detected in 7/20 (35%) by roentgenography, 12/20 (60%) by flow volume loop (FVL), and in 16/20 (80%) by combined roentgenography and FVL. After therapy for goiter, there was a reduction in the size of the goiter and an improvement in FVL in the whole group. The statistically significant change occurred in peak expiratory flow (P less than .01) and peak inspiratory flow (P less than .05). These findings and the change in configuration of the curve suggested less upper airway compression. We conclude that goiter often causes unsuspected upper airway obstruction, usually slow in onset and not noticed by the patient.


Tricyclic plasma levels. Effect of age, race, sex, and smoking. Steady-state plasma tricyclic antidepressant levels were determined in 65 patients undergoing treatment for depression with either amitriptyline hydrochloride or nortriptyline hydrochloride to determine if common factors such as age, race, sex, or smoking status were predictors of steady-state drug levels that have been shown to vary up to 36-fold. Evaluation of these factors did not disclose differences in the rate of demethylation of amitriptyline to nortriptyline, or steady-state tricyclic levels in the amitriptyline-treated patients. No differences were found in the nortriptyline-treated patients except regarding race. Black patients had significantly higher (50%) nortriptyline plasma levels than did white patients, which may explain the more rapid response to tricyclic treatment demonstrated in blacks. Decreased rates of nortriptyline metabolism in blacks can result in increased side effects and treatment failure if the therapeutic plasma range is exceeded.


Unusual cause of acute abdomen. Sickle cell trait and nonhypoxic splenic infarction. Splenic infarction under hypoxic conditions is a well-known complication of sickle cell trait (Hgb AS). However, this case illustrates that it may occur without any clinical conditions of circumstances associated with decreased Pao2. In addition, sickle cell trait should be included in the differential diagnoses of splenic infarction even if the patient is not of African ancestry.


Triamcinolone aerosol. Treatment of aspirin-hypersensitive asthmatic patients. The efficacy of triamcinolone acetonide aerosol in the management of asthma in six patients with aspirin hypersensitivity was evaluated during a one-year trial. Five patients were previously chronically dependent on systemic corticosteroids and had undergone unsuccessful trials with cromolyn sodium therapy. Substantial reduction in corticosteroid requirements was observed; in two patients, oral prednisone therapy was completely eliminated. Forced expiratory volume and flow were maintained at levels better than those recorded before triamcinolone therapy throughout the year of follow-up. No substantial side effects due to triamcinolone were observed.


Corticosteroid treatment in systemic lupus erythematosus. Survival studies. Survival rates of two groups of corticosteroid-treated patients with systemic lupus erythematosus (SLE) have been compared using life-table analysis. Group 1 consists of 209 SLE patients studied in New York City between 1957 and 1968; group 2 consists of 156 SLE patients studied in Connecticut between 1968 and 1976. A similar percentage of patients in each group was followed up closely by one of us. The five-year survival rate for group 1 was 70%, compared with 93% for group 2. The improved survival could not be explained by differences in racial composition, incidence of CNS manifestations, or incidence of severe renal disease. The markedly improved survival may be due to several factors, including a generally better understanding of the disease and the recent use of newer antibiotics. The management of the two groups was similar, except that group 2 patient's conditions were managed not only on the basis of clinical evidence of disease activity but also on the basis of the serum complement (C3) level and on the basis of the level of antibody to native DNA. The data suggest that the use of such serologic values may lead to improved survival.


Combination chemotherapy (CISCA) for advanced urinary tract carcinoma. A preliminary report. Twelve patients with metastatic transitional cell carcinoma from the urinary bladder were treated with a combination chemotherapy program consisting of cisplatinum, cyclophosphamide, and doxorubicin hydrochloride (CISCA). Ten patients had conditions for which a response to therapy could be determined, and nine achieved an objective response (one complete response, eight partial responses). Two additional patients with metastatic transitional cell carcinoma from the renal pelvis were also treated, and one achieved a partial response. In our experience, CISCA combination chemotherapy has given the highest response rate of any protocol thus far tested in advanced, metastatic urinary tract carcinoma.


Reversal of central anticholinergic syndrome by galanthamine. Ten volunteers were given 2 mg scopolamine intravenously (IV) to produce substantial drowsiness and sleepiness. Galanthamine, 0.5 mg/kg IV, effectively reversed the central anticholinergic syndrome produced by scopolamine. Electroencephalographic monitoring of two subjects matched the observed changes of consciousness: scopolamine replaced the dominant awake alpha rhythm with a disorganized, slow, 4- to 6-Hz activity. Galanthamine promptly returned to EEG pattern to the control, awake state. Galanthamine produces effective, safe, and long-lasting reversal of the central anticholinergic syndrome in man.


Familial lupus erythematosus.

Familial lupus erythematosus. The child of a woman with discoid lupus erythematosus (DLE) had lesions of DLE develop at the age of 2 months. The original lesions persisted and new lesions continued to develop to date; the child is now 28 months old. In a second child, now 11 months old, a probable lupus erythematosus rash developed at 1 week of age.


Epidemic faintness and syncope in a school marching band. On Sept 21, 1973, during and following a football game at which they had participated, 57 members of an Alabama high school marching band (and one accompanying adult) experienced an illness characterized by headache, nausea, weakness, or dizziness. Six girls fainted. Thirty-six students were treated at a hospital emergency room. Those who had played wind instruments and had worn heavier uniforms including an impermeable plastic jacket overlay were affected earlier and more frequently than the others. Several organic causes were examined in an epidemiologic investigation and considered unlikely to explain the epidemic. Female preponderance, a bimodal epidemic curve, hyperventilation, relapses, and clinical features characterized by subjective complaints in the absence of physical findings suggested a syncopal reaction to heat exacerbated and propagated by mass hysteria.


Participants' reaction to amniocentesis and prenatal genetic studies. Little is known about the effect of amniocentesis and prenatal diagnosis of genetic disease on couples undergoing such studies. A questionnaire was composed to evaluate, among other things, the reason for referral, attitudes and concerns of the pregnant woman and her husband toward prenatal study, and suggestions for improving the experience. Of 315 women referred to this unit for this purpose, 196 have had time to complete their pregnancy and were mailed the questionnaire; 157 (80%) of the latter responded. The majority of the women found the experience reassuring, would recommend it to others, and would seek it again themselves with a subsequent pregnancy.


Severe degenerative joint disease. Mild and moderately severe hemophilia A. Severe degenerative joint disease developed in three adults with mild to moderately severe hemophilia A, as judged by the clinical course and by levels of factor VIII coagulant. Bilateral total hip arthroplasty was required in one patient, unilateral hip arthroplasty in the second, and a recommendation for bilateral knee replacement in the third. The pathogenesis of the arthropathy may be multifactorial and the result of repeated joint hemorrhage that remains unrecognized and inadequately treated. These observations suggest the need for more careful monitoring of patients who have relatively mild hemophilia.


Cooperative study of hospital frequency and character of transient ischemic attacks. V. Symptom analysis. All patients (1,328) suspected of having transient ischemic attacks (TIA) who came to six institutions during a 21-month period were identified. Symptoms and symptom complexes were related to the clinical diagnoses by cross-tabulation, factor analysis, and discriminant analysis. The diagnoses obtained by the discriminant analysis program were comparable to those of reviewing clinical neurologists. Symptoms of importance in the vertebral-basilar system (VBS) were bilateral visual blurring, diplopia, ataxia, and dizziness; In either carotid system (CAS), ipsilateral monocular visual disturbance anc contralateral weakness or sensory complaints; in the left CAS, language disturbances; and in those whose ultimate diagnosis was not TIA, loss of consciousness, confusion, and bilateral leg weakness. Patients with VBS TIAs have symptoms common to conditions that are not TIA and have a greater variety of symptoms and more combinations of symptoms than CAS TIA.


Microcytic polycythemia. Frequency of nonthalassemic causes. A high RBC count combined with a low mean volume generally is attributed to thalassemia minor, either alpha or beta, or to polycythemia vera with iron deficiency. Among 330 patients with a mean corpuscular volume (MCV) less than 70 cumu, 35 had increased RBC counts. Of these, 26 had thalassemia minor and four had polycythemia vera. Five had secondary polycythemia (four from hypoxia, one from hypernephroma) with incidental iron deficiency. In the four of these patients given iron, the RBC count remained above normal and the MCV rose to normal. The RBC size distribution curves reliably distinguished between thalassemia minor and polycythemia with iron deficiency.


Giant cell tumor in the ischium. A therapeutic dilemma. A patient with low back pain was found to have giant cell tumor of the ischium. After initial local radiation therapy, a hemipelvectomy was performed because of tumor progression.


Rheumatoid pericarditis. Rapid deterioration with evidence of local vasculitis. In a patient with classical rheumatoid arthritis and pericardial involvement, accelerated restriction of cardiac filling resulting from pericardial constriction developed. Pericardiectomy was necessary to relieve this condition. Examination of the synovial and pericardial fluid showed noteworthy decreases in total hemolytic complement (CH50) and C3 levels, while these were normal in the serum. Immunofluorescence staining of the pericardium showed plasma cell infiltration and immune deposit staining of pericardial vessels with IgG, IgM, IgA, or C3. These findings suggest that immune complexes deposition plays an important role in the pathogenesis of this condition.


Prognostic implications of the e antigen of hepatitis B virus. The e antigen HBeAg and its antibody anti-HB, have been said to be predictive of chronicity and resolution, respectively, in viral hepatitis. We found, as have others, a specific association with hepatitis B virus-induced disease. In addition, detectability of HBeAg in the acute phase of type B hepatitis was followed by a sixfold higher incidence of chronic hepatitis. Unfortunately, the prediction was erroneous in 65% of positive cases and 6% of negative cases. In chronic hepatitis, HBeAg did not necessarily disappear in advance of resolution, and its disappearance did not necessarily indicate resolution. Two patients with acute hepatitis progressing to chronicity were anti-HBe-positive in both phases, as were seven (5%) with chronic hepatitis. For individual patients, therefore, HBeAg and anti HBe are not prognostically useful indexes.


A survey of the effects of oral contraceptive patient information. A nationwide survey of 1,720 current and 949 former oral contraceptive (OC) users gathered information about receipt, readership, knowledge, opinions, and reported behavioral changes induced by two forms of patient-oriented OC information. A substantial majority of women said they received and read the patient insert dispensed with the drug. However, only about one third of pill users said that they received the longer informational brochure supplied by physicians on patient request. Directions for use and side effects were the most often recalled information. Physician-patient contact patterns were reported as generally unaffected by written patient information. Respondents preferred the longer informational brochure to the insert. Survey results have implications for recently proposed changes in required OC patient information and for the development of patient information on additional prescription drugs.


Syncope in patients with pulmonary embolism. A review of 132 consecutive cases of acute pulmonary embolism (PE) documented by pulmonary angiography indicated that syncope was the initial or predominant clinical feature in 17 (13%). When massive PE causes syncope in a nonhospitalized patient, the diagnosis of PE is frequently overlooked. Hypotension after PE may resolve spontaneously after a short interval. In this circumstance, the syncopal episode might easily be attributed to another cause. The appropriate diagnosis can be established only if other clues, suggestive of PE, are sought. Both arterial blood gas determinations and pulmonary scintigraphy are helpful in making this diagnosis.