Physico-chemical and analytical studies on Halopredone acetate. Physico-chemical, spectroscopic (UV, CD, ORD, IR-1H-DMR, 19F-NMR, PFT13C-NMR, MS), and chromatographic (TLC, HPLC) properties of 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione (halopredone acetate; Topicon) are reported. Densitometric and high-pressure liquid chromatographic quantitative analytical methods are described. The usual descriptive data, purity tests, potential impurities arising from the synthesis and stability tests are given.


Syntheses and primary pharmacological screening of tandamine and related tetrahydrothiopyranoindoles with potential antidepressant properties. A series of novel 1,3,4,9-tetrahydro-1-methyl-thiopyrano-[3,4-b]indole-1-ethanamines has been synthesized and examined for effects on reserpine-induced ptosis and reserpine-induced hypothermia in mice. One member of the series, the 9-ethyl-N,N-dimethyl derivative V (tandamine), was selected for further studies in regard to its possible use as an antidepressant agent. Tandamine has been resolved, and the levorotatory enantiomer was found to be more active than the racemic compound. The N-desmethyl derivative XIII, a metabolite of tandamine, has been prepared. The 5-ethyl-1,3,4,5-tetrahydro-N,N,1-trimethylthiopyrano[4,3-b]indole-1-ethanamine XXI, an analog of tandamine with the isomeric ring system, has also been synthesized and evaluated. In the primary pharmacological screening and in the drug-interaction studies with reserpine, tetrabenazine, and tremorine, tandamine was compared to the clinically effective tricyclic antidepressants--desipramine, imipramine, and amitriptyline. Tandamine was more effective than these agents in several screening procedures indicative of potential antidepressant activity.


Synthesis and antitussive activity of 3-azabicyclo[3.2.2]nonane derivatives. Mannich bases derived from a number of substituted acetophenones and propiophenones and 3-azabicyclo[3.2.2]nonane have been evaluated for antitussive activity. One of these compounds was as potent as codeine and dextromethorphan in its antitussive activity. The most potent compound of the series, 3-(3-azabicyclo[2.2.2]nonan-3-yl)-4'-benzyloxy-2-methyl propiophenone, also exhibited antimorphine activity. There was no direct correlation between the antitussive effect and antimorphine activity.


Synthesis and pharmacological properties of some 4-amino-5-substituted thiazole-2(3H)-thiones and thiazolo(4,5-d)pyrimidin-7(6H)-one-2(3H)-thiones. 4-Amino-5-substituted thiazole-2(3H)-thiones and thiazolo(4,5-d)-pyrimidin-7(6H)-one-2(3H)-thiones have been synthesized and screened for antimicrobial and pharmacological activities. Significant analgesic, antiinflammatory, anticonvulsant and antimicrobial properties have been found in some of the compounds synthesized. Analgesic and antiinflammatory activities are reported for the first time in thiazole-2(3H)-thiones.


[Modification by drugs of cellular and humoral resistance mechanisms in animal experiments. I. In-vitro studies of peritoneal leukocytes and serums in rats]. 44 rats were fed p.o. with 3.1 ml/kg of Esberitox over a period of 5 days once daily, for increasing their non-specific resistance against injections. It could be shown that peritoneal leucocytes exhibited an increased phagocytosis of staphylococcus aureus. Besides the direct influence on the ingestion of this pathogenic microorganism, the leucocytes of the Esberitox group showed a stimulated uptake of oxygen when tested in vitro. The humoral defence seems also to be improved due to the elevated bactericidal activity of sera from Esberitox treated rats.


Comparison of the hypotensive and diuretic effects of 1,4-dimorpholino-7-phenylpyrido[3,4]pyridazine (DS-511) and hydrochlorothiazide in Doca, renal and spontaneously hypertensive rats. The hypotensive and diuretic activities of a new diuretic, 1,4-dimorpholino-7-phenylpyrido[3,4-d] pyridazine (DS-511), were compared with those of hydrochlorothiazide (HC) in DOCA, renal and spontaneously hypertensive rats. The results obtained were: 1. During the developing stage of DOCA-hypertension the daily treatment of rats with DS-511 and HC showed significant hypotensive action. During this period the diuretic activity of both agents was clear. 2. During the equilibrium stage of DOCA-hypertension the hypotensive action of DS-511 was indistinct despite its diuretic activity. The hypotensive and diuretic action of HC was not clear. 3. In renal-hypertensive rats the daily treatment of DS-511 and HC caused significant, but weaker hypotension than that in the developing stage of DOCA-hypertension. In these animals the diuretic activity of both agents was clear. 4. In spontaneously hypertensive rats the daily treatment with DS-511 and HC exhibited a similar hypotensive and diuretic action. 5. In all three kinds of hypertensive rats the diuretic activity of DS-511 was similar to that of HC in the excretion of urine and sodium, but the former was less kaliuretic than the latter.


Effect of diltiazem on coronary blood flow of the heart with experimental coronary sclerosis and on regional myocardial blood flow of the heart with acute myocardial ischemia. Effects of 3-acetoxy-2,3-dihydro-5[2-(dimethyl-amino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one hydrochloride (diltiazem) on coronary circulation of the heart with experimental coronary sclerosis induced by i.v. allylamine (Group A), and on regional myocardial blood flow in acutely-induced ischemic myocardium (Group S) were studied in anesthetized open-chest dogs. Regional myocardial blood flow was continuously measured with heated cross thermocouple method and following results were obtained: 1. In Group A coronary blood flow and coronary flow resistance remained unchanged essentially after the injection of diltiazem, whereas coronary blood flow markedly rose and coronary flow resistance decreased in the normal heart. 2. Local blood flow in both of the inner and outer thirds of the ischemic myocardium was not affected by diltiazem in Group S. In the normal myocardium, however, it increased definitely. 3. From these findings it is concluded that the clinical effectiveness of diltiazem is independent of its vasodilator properties.


Antagonizing effect of aspartic acid on the development of physical dependence on and tolerance to morphine in the rat. As free amino acids in the brain have a role in the development of physical dependence on and tolerance to morphine, and in the mechanism of action of some drugs, the effects of aspartic acid which antagonizes some effects of the single dose of morphine were studied during the development of the physical dependence on morphine and after the withdrawal of morphine. 108 rats were given morphine and aspartic acid in different combinations in drinking water for 30 days. Every tenth day the dose of morphine was increased: At the end of this period some of them in each group continued or began to receive aspartic acid depending on the experimental conditions after the withdrawal of morphine. During the experiments body weight, spontaneous motor activity and analgesic threshold were determined. Aspartic acid prevented the alterations induced by morphine during the development of physical dependence and tolerance. Furthermore the rats that received aspartic acid after the withdrawal showed no body weight loss.


Distribution of S-adenosyl-L-(methyl-14C)methionine in animals. The distribution of i.v. injected S-adenosyl-L-(methyl-14C) methionine was studied in the whole body of mice and in the cat brain using an autoradiographic technique. The drug was concentrated, at shorter survival times, mainly in the blood stream and in highly vascularized organs. Low concentration of radioactivity was found at longer times in the central nervous system (CNS). The quantitative analysis by means of organ radioassay was carried out in rats and confirmed the autoradiographic data.


A comparison between the morphologic changes in the livers of hamsters and rats after galactosamine treatment and their correlation with altered serum transaminase levels. Galactosamine caused changes in the livers of rats that were similar to those seen in human viral hepatitis. In hamsters the changes were characteristic of a typical toxic hepatitis. The response by the liver to galactosamine was very variable in both the rat and the hamster and there was a degree of correlation between the raised transaminase levels and the liver cell damage.


A pharmacokinetic study of 3H-diosmine.

A pharmacokinetic study of 3H-diosmine. A pharmacokinetic study of 3H-labelled 7-rhamnoglycoside of 5,7,3'-trihydroxy-4'-methoxyflavone (3H-diosmine) administered both i.v. and orally, shows the great ease with which it is absorbed in digestion. A very sharp difference in elimination between the two modes of treatment must be associated with a difference in metabolism. A study of fixation confirms this conclusion. In particular the fixation on the tunica vascularis, perhaps due to a metabolite, appears relatively late. Furthermore the existence of an enterohepatic cycle assures a permanent hepatic binding.


[The effect of silybin dihemisuccinate on cholesterol biosynthesis in rat liver homogenates (author's transl)]. The effect of silybin dihemisuccinate on the hepatic biosynthesis of cholesterol was studied by measuring the incorporation of [1-14C]-acetate and [2-14C]-mevalonate in the postmitochondrial supernatant of liver homogenates. 2. Under absolute in vitro conditions, silybin dihemisuccinate inhibits the biosynthesis of cholesterol in dependence on its concentration. With [1-14C]-acetate or [2-14C]-mevalonate the concentrations of silybin for 50% inhibition are 0.37 mM or 0.40 mM, resp. 3. 30 min after i.v. injection of 150.6 mg silybin dihemisuccinate/kg with both precursors the biosynthesis of cholesterol studied in vitro is diminished in comparison to controls. 60 min or 24 h after i.v. injection of silybin no effects on in vitro biosynthesis of cholesterol can be observed.


Antagonism of non-steroidal anti-inflammatory drugs and narcotic analgesics against ethacrynic acid induced writhing. Thiol-group reactive agents [alloxan, N-ethyimaleimide (NEM), ethacrynic acid, p-chlormercuribenzoate (PCMB)] were shown to induce a writhing syndrome in mice and rats when injected i.p. in appropriate dosage. Non-steroidal anti-inflammatory agents, narcotic analgesics and also psychotropic drugs inhibit the syndrome elicited in rats by ethacrynic acid. Rats pretreated with cysteine i.p. show a greatly reduced nociceptive response to ethacrynic acid or alloxan.


[Collected findings of long-lasting chemical stimulation of the immune system by N-(2-cyanethylene)-urea derivatives (author's transl)]. The present paper describes our findings so far on the long-lasting chemical stimulation of the immune system by means of various batches from the synthesis of N-(2-cyanethylene)-urea (BA 1). These findings were also supported by results of other authors. Furthermore some recent findings have demonstrated that 2-cyanaziridine, 2-cyanethyl-urea and a bicyclic isomer represent examples for immunologically effective BA 1-derivatives or BA 1-isomers, respectively.


[On the determination of azapropazone from plasma by direct quantitative thin-layer chromatography (author's transl)]. For the purpose of investigating drug interactions, a new selective method for determination of 5-dimethylamino-9-methyl-2-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dione-dihydrate (azapropazone, Prolixan 300) was developed. The method is based upon the direct quantitation of the drug by thin-layer chromatography using remission measurement. The method is well suited for routine analysis of numerous samples, because of its simplicity and rapidity. The standar deviation of the method is about +/-4% at therapeutic plasma concentrations.


Oversaturation of urine with sulphadiazine during treatment with a small therapeutic dose. The urinary crystallization of N1-pyrimid-2-yl-sulfanilamide (sulphadiazine, Sulfolex) during treatment with a small therapeutic dose (600 mg/day p.o.) for 6 days was evaluated in seven voluntary female subjects. In 5/7 and 3/7, respectively, of the urine supernatants obtained from samples collected 6 and 24 h after the last dose of sulphadiazine, the sulphonamide concentration exceeded the experimental solubility of the drug in 37 degrees C urine at the same pH. However, only in 3 sediments of the 6-h urine samples could a few sulphadiazine crystals be found. The findings suggest that the urine often can be oversaturated in respect to sulphadiazine, without any marked crystallization.


[Indications for determining serum levels of antiepileptic drugs (author's transl)]. Measurement of the serum levels of antiepileptic drugs is an important progress in managing the patients with epilepsy. The determination of serum levels has become indispensable in special indications such as assessing the compliance in taking medication and identifying the responsible agent in intoxicated patients on multiple drug therapy. The long-term prognostic value of the routine determination of anticonvulsant drugs is related to the validity of the concept "therapeutic serum level".


[The role of cytochrome P450 in the activation of drugs (author's transl)]. Unspecific microsomal monooxygenases have been found in many organisms of different developmental stages. In higher organisms liver is the main organ of drug metabolism but smaller intestine, lung and skin also show this activity. The corresponding membrane-bound enzyme system could be isolated by modern chromatographic techniques and was found to consist of a reductase and a series of cytochrome P450 enzymes. Each of these cytochromes has a different, but with other forms overlapping substrate specificity. The steady-state concentrations of the various forms is regulated by induction with drugs and foreign compounds. The unspecificity of the systems is also reflected in the varying pattern of metabolites. In general stable and more polar metabolites are formed by the monooxygenation reaction, but reactive and unstable products may also appear, e.g. N-hydroxy compounds, 1,2-diphenols, epoxides and a new class of compounds which have been characterized as carbenes.


[Activation mechanisms in chlorinated aliphatic compounds/experimental possibilities and clinical significance (author's transl)]. Chemical reactivity, biotransformation and toxic effects of chlorinated aliphatic compounds are decisively determined by type and number of chlorine substitutions. In saturated compounds, chlorine substitution exerts a destabilization; metabolic reactions are free radical formation and dechlorination or dehydrochlorination, respectively, under formation of olefins. In saturated alkenes, Cl-substitution leads to a stabilization of the olefinic double bond. Biotransformation of this class of compounds starts with epoxidation. The epoxides are prone, among other reactions, to intramolecular rearrangement; more stable aldehydes or acid chlorides are formed. In the series of chlorinated ethylenes, the rearrangement mechanisms have been studied systematically in vitro and in vivo. As judged from the identified metabolites there is accordance in vitro and in vivo, with one important exception: trichloroethylene. The only formation of chloral in vivo may be due to a catalysis by the iron in P450. In a modified Ames test system the unsymmetrically substituted chlorinated ethylenes are found mutagenic (tri-,1,1-dichloroethylene and vinyl chloride), whereas symmetrically substituted molecules are inactive. The reason for this is seen in the high instability of the unsymmetric molecules caused by the electron withdrawal effect of chlorine.


[Mechanisms in inactivating reactive metabolic products of drugs (author's transl)]. An in vitro test system was used to study the relative contribution of epoxides metabolically produced from aromatic or olefinic drugs to the total of mutagenically reactive metabolites. As an epoxide-specific tool the enzyme epoxide hydratase was purified to homogeneity. Using several aromatic and olefinic hydrocarbons as model substrates the following was observed, exceptions being discussed in the main text: 1. Epoxides represent the most important and generally the almost exclusive metabolites responsible for the observed toxic endpoint. 2. These epoxides generally are efficiently inactivated by epoxide hydratase. The rather narrow limitations of exceptions are outlined in detail. 3. Amongst the enzymes metabolizing epoxides, for the substrates investigated epoxide hydratase represents the system which is most critical for the control of tissue levels of epoxides. 4. Several practical consequences following from these facts are outlined in the last paragraph of this paper. 5. A generalization from these model experiments will be justified only after further experimental validation.


[Polymorphisms and deficient drug metabolism as triggers of toxic reactions (author's transl)]. The influences of polymorphisms and pharmacokinetic defects of drug metabolism as causes of toxic drug reactions are presented. The different mechanisms of toxic side effects mediated by alterations of the metabolism and excretion of drugs are discussed.


[Capacity limited pharmacokinetics, a mechanism of drug toxicity (author's transl)]. In the past drug elimination was described mainly by two different laws. Zero-order kinetics postulates that the speed of elimination be constant and independent of drug concentration; in first-order kinetics which describes satisfactorily the elimination of all drugs except ethyl alcohol it is assumed that the speed of the elimination is proportional to the plasma drug concentration. This can only be interpreted biologically in the case of polar drugs eliminated by diffusion or filtration. Non-polar drugs, however, bind reversibly to macromolecules such as albumin and enzymes. This means that elimination should be saturable as predicted by the law of mass-action. Saturation phenomena have clearly been demonstrated with several drugs eliminated by tubular and biliary secretion, or by enzymatic transformation. It is shown that zero-order and first-order kinetics are consequences of the validity of the mass-action law in two extremely different drug concentration ranges. When the affinity between drug and biological macromolecules is high the possible clinically relevant consequences are abnormal drug accumulation and drug interactions such as mutual displacement from the plasma albumin binding sites, inhibition of active drug transport and metabolism, or enzyme induction.


[Drug-induced disorders of lupus erythematosus type (author's transl)]. Drug induced Lupus erythematosus (LE)-like syndromes are generally observed after long-term and/or high-dose therapy with so called "principal inducers" procainamide, hydralazine, isoniazide, chlorpromazine, anticonvulsives and possibly with D-penicillamine, too, and even so in some cases after some additional 26 drugs. The rare pseudo LE syndrome appears after combined drugs which usually contain pyrazolone derivatives used especially against venous diseases. The mechanism of induction of autoimmune reactions in these disorders varies and is after all still unknown. There are individual differences in drug metabolism, genetic disposition for increased autoantibody formation and sometimes humoral and cellular immune reactions against the drug itself. Essentially involved in the indication of autoimmune reactions is often the production of hapten carrier complexes between drugs and body constituents and drug induced changes of autoantigen elimination as well as drug mediated immunologic imbalance.


[Mechanisms of photoallergies (author's transl)]. Photoallergic reactions represent a special form of allergic contact dermatitis. The immunological aspects of the delayed-type sensitivity are fairely well known, whereas information on the photochemical antigen formation is still scarce. This is illustrated by two examples.


Pathology of intracerebral hemorrhage.

Pathology of intracerebral hemorrhage. Spontaneous intracerebral haemorrhages are dealt with on the basis of a great number of clinical and neuropathological cases. They amounted to 4.9 per cent of the patients admitted to the hospital and 5.2 per cent of the autopsies. In two thirds hypertension was found about 20 per cent were ruptured aneurysms. In 3 per cent of the respective autopsies no cause was found. The clinical courses are dealt with in greater detail. Eighty per cent of the hypertensive haemorrhages are located in the cerebral hemisphere; among these, 60 to 80 per cent show ventricular perforations. This percentage is still higher in thalamus--brain stem haemorrhages. Two theories on the aetiology are discussed. Traumatic haemorrhages are especially dealt with in connection with late apoplexy. Deformations of the cerebral vessels, too, are described in detail. Among the aneurysms, 82 per cent belong to the circulus willisi. Angiomas were found in 15.2 per cent of the autopsies in case of cerebral haemorrhages, but in 58 per cent of the surgically treated intracerebral haemorrhages. These figures are higher than those given in the relevant literature. Among 1600 cerebral tumours, there were 2.2 per cent massive cerebral haemorrhages. The cases are compiled in a table.


[Role of serum fibrinogen penetrating the subarachnoid space in the pathogenesis of brief cerebral arteriospasm]. A mixture of fibrinogen (4 ml in a 1 per cent solutions) and thrombin (10 I.U.) were instilled into the cisterma magna of 18 dogs which led to the formation of a fibrin clot in the subarachnoid space. This fibrin clot produced a spasm of the large cerebral arteries, which resulted in a narrowing to 84.8 +/- 1.8 per cent of the initial value. The subsequent administration of 400 units of fibrinolysin into the cisterna magna led to the dissolution of the fibrin clot and the dilatation of the arterie to 116.3 +/- 2.5 per cent of the initial value. Experiments carried out in 15 cats showed that, after being brought in the subarachnoid space, the spasmogenic factor of the clot, which consisted of all blood components, passes through the arachnoid into the subdural space. The penetration of the spasmogenic factor from the blood clot located on the surface of the arachnoid from the subdural to the subrarachnoid space was not observed. The arachnoid proves to be a membrane which can only be passed in one direction by the spasmogenic blood factor.


Optimum humidification of air administered to a tracheostomy in dogs. Scanning electron microscopy and surfactant studies. The effect of the inhalation of dried (less than 40% water-saturation) or humidified air (100% water-saturation at 25, 30, 35 and 40 degrees C) was studied in dogs in which a tracheostomy had been performed to determine the optimal humidity. After inhalation for various periods, the dogs were killed and pieces of lung tissue were excised for analysis of surfactant. Sections of the trachea and the primary to tertiary bronchi were taken for scanning electron microscopic examination. Structural changes were observed in the trachea of dogs inhaling dried at and in the tertiary bronchi of dogs inhaling 100% water-saturated air at 35 degrees C. No changes was observed after 24 h in dogs which had inhaled 100% water-saturated air at 25 degrees C under anaesthesia or at 30 degrees C without anaesthesia. Consequently, the optimal range of humidity was determined to be 100% water-saturation between 25 and 30 degrees C.


Canine transmissible venereal sarcoma: electron microscopic changes with time after transplantation. The structure of canine transmissible venereal sarcoma (CTVS) has been examined from 14 to 71 days after implantation. During early growth, the tumour appears to be composed primarily of loosely arranged, round cells and a few fibroblast-like cells. As the tumour mass increases, the round cells become tightly packed with highly interdigitating plasma membranes. The number of irregularly shaped round cells and fibroblast-like cells increases with increasing tumour mass. Collagen and reticular fibres can be found in early tumours, frequently in association with the round cells, and in regions devoid of fibroblast-like cells. During tumour regression, cellular degradation is evident in fibroblast-like and irregularly shaped cells as well as round cells. The data suggest that transformation may occur in the course of tumour growth, causing morphological change from round to fibroblast-like cells, and that CTVS is an undifferentiated round-cell sarcoma capable of differentiation in a fibroblastic direction. Also present, primarily in tumour cells from newborn dogs, are cytoplasmic lamellar arrays and crystalline virus-like structures, both previously described in other forms of tumor cells.


Raman spectra and vibrational assignments for deuterated membrane lipids. 1,2-Dipalmitoyl phosphatidylcholine-d9 and -d62. Vibrational Raman spectra of polycrystalline 1,2-dipalmitoyl phosphatidylcholine-d9 (fully deuterated choline methyl groups) and 1,2-dipalmitoyl phosphatidylcholine-d62 (fully deuterated acyl chains) were recorded in the 3050- 2800, 2250-2050 and 1800-700 cm-1 regions. The fundamental vibrational modes were assigned primarily on the basis of isotopic frequency shift ratios, group frequency correlations and comparisons with specific model compounds. Since deuterium-substituted lipids provide well-isolated spectral probes, particularly in the carbon-deuterium stretching region, the dependence of the 2250-2050 cm-1 region on lipid phase was examined for the dipalmitoyl phosphatidylcholine-d62 species. The methylene CD2 deformation and twisting modes at 984 and 919 cm-1, respectively, also exhibit intense, isolated vibrational transitions which should prove useful for monitoring molecular order in mixed dueterated and undeuterated lipid systems. Except for the relatively weak choline methyl C-D and C-H stretching modes, the spectrum of 1,2-dipalmitoyl phosphatidylcholine-d9 is not distinguishable from that of the undeuterated system. For both the d9 and undeuterated species, the vibrational modes associated with the lipid head group region are sensitive to slight hydration.


Biochemical studies on muscarinic receptors. Muscarinic receptors have been characterized in smooth muscle and brain by the binding of reversible (e.g. atropine, quinuclidinylbenzylate) or irreversible (benzilylcholine or propylbenzilylcholine mustards) ligands. There is a close correlation between affinity constants derived from binding experiments and the affinities of muscarinic ligands for these sites obtained in pharmacological experiments on smooth muscle. Whereas atropine shows a single high affinity binding component (in subcellular preparations) several other ligands (QNB, ACh, oxotremorine) show multiple affinity binding. This indicated the existence of several types of binding sides which show selectivity toward certain cholinergic effectors. Most detergents inhibit the binding of ligands to the receptor site and therefore cannot be used to solubilize the receptor protein from the membrane. Treatment of brain subcellular membrane preparations with high salt concentrations (2M NaI) solubilize proteins which possess the muscarinic ligand binding properties observed in the membrane preparation. The affinities for muscarinic antagonists however are decreased, which suggests that a conformational change occurs in the protein upon solubilization.


Venereal disease: its place in health education in schools. The paper reports the findings concerning venereal diseases and contraception in several surveys conducted into health education in Northern Ireland. The evidence shows that there is little instruction and discussion of these subjects, either at home or at school, but that teenagers are divided in their attitudes, some desiring information while others are apathetic. The need for well informed teenagers willing to make responsible decisions is stressed and reference is made to one curriculum development project producing materials in this field.


In which hospital departments may sexually transmitted diseases be seen? The views of 56 medical students. Fifty-six medical students were asked to list the hospital departments where sexually transmitted diseases (STDs) might be seen and to name the conditions that might occur. The students mentioned 37 departments altogether. Forthy-seven students listed six or more departments and 43 described 11 or more conditions that might be seen. The departments mentioned were placed in ranking order. Over half the students stated that patients with STDs might present in departments of dermatology, neurology, gynaecology, ophthalmology, general medicine, urology, and rheumatology. Writing the lists did not encroach on the time available for clinical teaching and it helped stude-nts to visualise the ways and places in which STDs may present. This form of teaching could be used in other branches of medicine.


Chemoimmunotherapy for canine lymphosarcoma. Thirty-two dogs with naturally occurring multicentric lymphosarcoma were randomly assigned to one of two treatment groups. One half of the animals received combination chemotherapy plus vitamin injections (controls) while the other half received indentical chemotherapy plus injections of chemically-modified tumor cell extract in Freund's complete adjuvant (vaccinates). Clinical staging revealed no bias between groups but showed that prognosis could be closely correlated with the severity of disease at initial presentation. Twenty dogs (62%), including 11 vaccinates and 9 controls, responded favorably to chemotherapy and were evaluated for length of first remission and total survival time. Both parameters were significantly longer in vaccinated dogs than in controls. These data suggest that immunological stimulation may be a helpful adjunct to conventional therapy in selected types of cancer when immunological principles are observed.


Nuclear binding of steroid-receptor complex to lymphosarcoma P1798 resistant and sensitive cells and effect of concanavalin A on receptor levels. Glucocorticoid-resistant P1798 cell lines have been found to contain levels of glucocorticoid receptor comparable to receptor levels in glucocorticoid-sensitive P1798 cells. Previously, most of the P1798 resistant cells examined were found to contain low levels of glucocorticoid receptor, and this was thought to account for the resistance of these cells to glucocorticoid treatment. Resistant cells with high receptor levels exhibited 10 to 50 percent lower levels of nuclear binding than did sensitive cells. In addition, 90 percent of the glucocorticoid-receptor complex could be extracted from resistant nuclei with 0.2 M NaCl, while only 55 percent of the complex could be extracted from sensitive nuclei, indicating that the affinity of the hormone-receptor complex for resistant nuclei may be weaker than the affinity of the hormone-receptor complex for sensitive nuclei. The effect of concanavalin A was also examined in P1798 sensitive and resistant cells. Concanavalin A effectively lowered glucocorticoid receptor levels in the sensitive cells by 45 percent, while receptor levels of the resistant cells were only slightly lowered. The effect of concanavalin A was both temperature dependent (effective at 37 degrees but not 0 degrees) and time dependent. Thus glucocorticoid resistance of P1798 cells appears to have a more complex mechanism than previously proposed.


Clinical pharmacology of intrathecal methotrexate. II. An improved dosage regimen derived from age-related pharmacokinetics. Cerebrospinal fluid (CSF)-antifolate concentration was analyzed in 100 specimens from 47 patients treated with intrathecal methotrexate (MTX) (12 mg/m2 of body surface area [BSA]). The drug concentrations varied 100-fold, with high levels associated with neurotoxicity and low levels with a poor response to therapy. CSF-MTX concentration was correlated directly with patient age, suggesting that a constant dose, regardless of age or BSA, should provide more consistent CSF-drug concentrations. In a subsequent study 25 patients treated with a conventional-dose schedule of 12 mg/m2 of BSA were compared with a matched group of 24 patients administered a constant dose of 12 mg. There was significantly less variability of drug levels in the CSF with the constant-dose method than with the dosage derived from BSA. It is recommended that patients between 3 and 40 years of age receive the same intrathecal dose rather than varying doses adjusted for patient BSA.


[Retrobulbular tissue changes following TSH administration and influence of various drugs in rats]. Our results demonstrate that the thyreotropin induced exophthalmus is a useful model for testing the efficacy of drugs in animal experiments. Concerning the exophthalmus producing tissue factors till now only qualitative results could be offered. Measuring the incorporation of 3H methionine the statements could be improved quantitatively. Hyaloronidase markedly reduced the thyreotropin induced exophthalmus. L-triiodothyronine, D-triiodothyronine. L-thyroxine, D-thyroxine and hydrocortisone had no certain influence on the TSH induced alterations.


Behavioral nutrition: consumption of foods of the future by toddlers. Behavioral measures of food consumption and tasting were combined with nutrient analysis of foods served at a toddler day-care center to determine whether children at the stage of initial exposure to adult diets would accept textured vegetable protein (TVP) and nonfat dry milk as well as they ate other sources of protein and calcium. Main dishes were prepared alternately with TVP, meat, or neither; others were prepared with or without nonfat dry milk. The variation in ingredients appeared not to affect the amount children ate, the percentage sampling the foods, or the percentage eating half a portion or more. Dishes made with TVP increased protein intake comparable to the amount obtained with meat supplements, and calcium intake increased with nonfat dry-milk supplements. In light of these findings, it appears that TVP and nonfat dry-milk are practical alternative sources of protein and calcium in menus for young children.


Factors influencing comparative bioavailability of spironolactone tablets. The bioavailability of spironolactone from 10 tablet formulations, selected to provide a wide range of specifications and in vitro dissolution rates, was assessed from the plasma and urinary levels of its major unconjugated metabolite, canrenone, in a study of balanced incomplete block design using 11 healthy subjects. Significant but weak correlations existed between the amount of spironolactone in solution at 40 min in vitro and the area under the plasma concentration-time curve for canrenone and urinary canrenone excretion. The correlations between in vitro dissolution and bioavailability parameters appeared to be weakened by two tablet formulations, one with dibasic calcium phosphate as the principal excipient and the other formulated from micronized spironolactone bulk drug. Measurement of in vitro dissolution of spironolactone tablets is of value for quality control purposes, provided no major alteration is made in the formulation.


Generic propoxyphene: need for clinical bioavailability evaluation. Plasma level data on two investigational capsule formulations of propoxyphene with similar physicochemical parameters demonstrate that the formulations have different in vivo bioavailabilities. The potential bioavailability problems with water-soluble drugs and the lack of correlation of in vitro and in vivo parameters for equivalent drug formulations are discussed.


Phase II evaluation of cytembena (NSC-104801) in patients with advanced ovarian carcinoma resistant to alkylating agents: brief communication. Seventeen patients with stages III and IV alkylating agent-resistant ovarian carcinomas were treated with cytembena, which was given in doses of 200 mg/m2 twice daily for 5 consecutive days every 5 weeks. Sixteen patients completed at least one course of treatment; 11 of them experienced objective progression of disease or failed to continue treatment because of a continuing symptomatic deterioration within the first two treatment cycles. Three patients remained objectively stable after two courses of treatment, but were symptomatically worse and stopped treatment for that reason. Another patient experienced progression after three courses, and the final patient voluntarily withdrew after three courses. No objective regression of disease occurred during treatment with cytembena. Nausea and vomiting occurred at some time in all except 1 patient, and 3 patients experienced mild diarrhea. Two patients had alopecia.


Predictive value of renin determinations in renal artery stenosis. The prognostic value of renal vein and peripheral renin levels was analyzed in 66 patients with unilateral renal artery stenosis who underwent corrective surgery. Patient selection for operation was independent of renin results. Fifty-three percent of those with confirmed renovascular hypertension had renal vein renin ratios less than 2.0, ie, within the 95% confidence limit for the control group of 82 patients with essential hypertension. Thirty-four patients with clearly lateralizing renin data (ipsilateral:contralateral greater than or equal to 1.5 and contralateral:peripheral less than or equal to 1.3) were benefited by operation, but 23 additional patients with nonlateralizing data also benefited. No proposed scheme for renin data analysis detected more than 75% of those with renovascular hypertension. Although lateralizing renin data are highly predictive of operative benefit, nonlateralizing data do not necessarily herald operative failure and should not be dogmatically used to exclude surgical intervention.


Long-term antiarrhythmic therapy in survivors of prehospital cardiac arrest. Initial 18 months' experience. Ambulatory rhythm monitoring and chronic arrhythmia management were studied in 16 patients resuscitated from prehospital cardiac arrest. Asymptomatic complex ventricular arrhythmias (ACVA) occurred in 12 patients (75%) entering long-term follow-up during the first 12 months (average follow-up, 13.25 months). The patients' therapy consisted of a dose-adjusted, membrane-active antiarrhythmic drug regimen monitored by blood levels. While there has been little change in the frequency of ACVAs despite carefully controlled antiarrhythmic management, only one death has occurred during 212 patient-months of postarrest follow-up, a 6% one-year mortality. This compares favorably to our previous experience in survivors of prehospital cardiac arrest not receiving a controlled antiarrhythmic program. Despite the failure to suppress ACVAs, the drug-monitored population is showing a trend toward a decreased frequency of recurrent cardiac arrest.


Hepatitis B surface antigen (HBsAg) and antibody to HBsAg. Prevalence in homosexual and heterosexual men. The prevalence rates of serum hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs) were 5.6% and 34% in 144 homosexual men in Seattle. Prevalence rates were only 0.9% and 3.6% in 111 heterosexual male venereal disease clinic patients with nongonococcal urethritis, and also 0.9% and 3.6% in 111 healthy men undergoing routine physical examinations. Thus, previous exposure to hepatitis B virus (HBV) was estimated to be 8.8 times greater for homosexual men than for heterosexual men. Four of four HBsAg positive sera from homosexual men were subtyped as "ad," whereas subtype "ay" is preponderant in intravenous drug abusers. Future public health measures to control HBV infection should address the prevention of sexually transmitted HBV infection among homosexual men.


Ventricular fibrillation in a medically supervised cardiac exercise program. Clinical, angiographic, and surgical correlations. Five patients with ischemic heart disease were resuscitated after experiencing ventricular fibrillation in a medically supervised exercise program. Four subsequently had successful myocardial revascularization (three prior to hospital discharge), and three have returned to an exercise prescription of reduced intensity. Multivessel operative coronary disease is common in patients experiencing ventricular fibrillation. Ventricular fibrillation may occur unpredictably (two to 48 months) in duration of exercise. Exercise fitness centers for such patients should be medically supervised and equipped with a defibrillator and appropriate drugs.


Disseminated North American blastomycosis. Occurrence with clinical manifestations of adrenal insufficiency. Adrenal involvement in cases of disseminated North American blastomycosis occurs frequently, but clinically substantive adrenal insufficiency is rare. An unusual case of disseminated blastomycosis with clinical manifestations of adrenal insufficiency was found. One should be alert to the symptoms of adrenal insufficiency that may develop in patients with disseminated mycoses.


Brain-stem compression in rheumatoid arthritis. A woman had cervical C-1 to C-2 subluxation with dysphagia. Initial improvement with halo cast and posterior fusion was followed by recurrence of symptoms, but transpharyngeal resection of the odontoid process had continued to alleviate symptoms at 18-month follow-up examination. The importance of vertical C-1 to C-2 subluxation in rheumatoid cervical arthritis is emphasized.


Scintigraphy of sacroiliac pyarthrosis in children. Eight children with low back, hip, or lower limb pain who were subsequently shown to have pyogenic infections of their sacroiliac joints were examined by a combination of plain roentgenography and radionuclide bone scintigraphy. In all cases, the scintigraphic examination was diagnostic, while the roentgenograms were initially abnormal in only two cases. In the other six cases, one to six weeks passed before changes compatible with sacroiliac pyarthrosis were seen on roentgenographic examination. Radionuclide scintigraphy is recommended as part of the initial workup of children with appropriate symptoms.


Allergic alveolitis caused by home humidifiers. Unusual clinical features and electron microscopic findings. Allergic alveolitis (hypersensitivity pneumonitis) developed in two patients who were exposed to home humidifiers contaminated by thermophilic actinomycetes. Diagnosis was difficult because severe dyspnea was chronic and not easily associated with specific environmental exposure. Furthermore, chest roentgenograms were normal for long periods despite severe physiologic abnormalities. After several years of disabling symptoms, open lung biopsy findings suggested allergic alveolitis rather than sarcoidosis because a mononuclear interstitial infiltrate overshadowed the granulomas. Also, plasma cells were prominent and there was an intense bronchiolitis. Cultures of the humidifier water grew thermophilic organisms to which the patient's sera formed precipitins. Both patients experienced notable subjective and objective improvement following removal of the contaminated appliances. The ultrastructure of alveolar macrophages and basement membranes was similar to that described in animal models, suggesting cell-mediated hypersensitivity in the patients.


Clinical laboratory use in the evaluation of anemia. Follow-up tests ordered on 258 consecutively examined inpatients with low hemoglobin values on admission were analyzed. The appropriateness of the follow-up tests was evaluated by chart review after preselection by an algorithm. When the cause of the anemia was known or was irrelevant in view of the patient's clinical status, the laboratory use was judged to be adequate. Seventy-one percent of patients studied had an adequate follow-up, though 11% had nonindicated tests performed, scored as laboratory overuse. Twenty-four percent had no follow-up, scored as laboratory underuse. Five percent did not have all indicated tests done and had nonindicated tests done, scored as a mixture of underuse and overuse. Potential remedies to correct misuse are discussed.


Myocardial rupture. Major left ventricular infarct rupture treated by infarctectomy. A myocardial rupture that occurred during anesthesia induction for infarctectomy was successfully repaired, and the patient is well and free of symptoms 10 1/2 months later.


Peritoneovenous (LeVeen) shunt. Control of renin-aldosterone system in cirrhotic ascites. Because of the unusual clinical course of a patient with hepatic cirrhosis, refractory ascites, and hepatorenal syndrome, we were able to examine the complex interrelationships between massive ascites, renin-aldosterone activity, and renal and hepatic function before and after placement of a peritoneojugular vein (LeVeen) shunt. Measurements indicated that when the shunt was functioning, renin-aldosterone production was suppressed, the hepatorenal syndrome was reversed, and ascites remitted. These data suggest that hyperreninemia, hyperaldosteronism, and functional renal abnormalities of this disorder are potentially reversible and arise primarily from the imbalance between formation and drainage of hepatosplanchnic lymph rather than from hepatocellular dysfunction, lowered plasma oncotic pressure, or portal hypertension.


Ibuprofen in the treatment of acute gouty arthritis. Ibuprofen is a nonsteroidal anti-inflammatory drug used in the treatment of rheumatoid arthritis and osteoarthritis. Ten patients with acute gouty arthritis were treated with daily doses of 2,400 mg of ibuprofen. All patients had rapid improvement and complete resolution within 72 hours; no adverse reactions were reported. Ibuprofen therapy may be an effective alternative in the treatment of acute gouty arthritis.


Needle aspiration biopsy: a critical appraisal. Eight years and 3,267 specimens later. Fine-needle aspiration biopsy was used to diagnose lesions from the breast, subcutaneous nodules and lymph nodes, prostate, deep masses, lung, and pancreas. Over an eight-year period, 3,267 specimens were examined. The biopsy specimens were taken with 18- to 22-gauge disposable needles with attached syringes, were fixed immediately, and were stained according to the method of Papanicolaou. Frequently, the aspiration was done as an office procedure. The method was essentially complication-free. The biopsy specimen was easy to interpret, and the procedure had an overall accuracy of approximately 90%. It should be used by all clinicians, especially on the initial visit of the patient.


Thiazide-induced hypokalemia. Association with acute myocardial infarction and ventricular fibrillation. Ten of 59 patients (17%) were receiving a thiazide preparation at the time of an acute myocardial infarction and ventricular fibrillation. Hypokalemia was present in seven of eight patients (87%) receiving thiazides, whereas it was observed in only one of 38 patients (2.6%) not receiving these medications. If hypokalemia is present in patients receiving thiazides who have had an acute myocardial infarction, it should be corrected so as to remove this predisposing cause of ventricular fibrillation.


Disseminated varicella complicating ulcerative colitis. Disseminated varicella is an uncommon complication of ulcerative colitis, despite the frequent use of steroid therapy in this disorder. Fatal varicella infection occurred in a patient with ulcerative colitis who was receiving steroid therapy. This observation suggests that zoster-immunoglobulin should be administered to patients exposed to varicella with ulcerative colitis who are receiving steroid therapy.


Splinter hemorrhages in patients receiving regular hemodialysis. Typical subungual splinter hemorrhages were found on routine medical examination in four of 20 patients receiving regular hemodialysis, with no apparent clinical cause.


Antifungal agents used for deep-seated mycotic infections. The main emphasis in this paper is on the broad-spectrum antifungal agent amphotericin B and the narrow-spectrum agent flucytosine. Amphotericin B remains the cornerstone of antifungal therapy. For the treatment of cryptococcal meningitis, the current recommendation is for the combined use of amphotericin B and flucytosine. 2-Hydrostilbamidine is used only in indolent cases of blastomycosis; this condition is usually treated with amphotericin B. A number of newer agents and combinations of drugs also warrant mention, but clinical experience is limited and these agents or combinations have not been approved for clinical use. Not all patients from whom fungal agents are isolated require treatment and the extent of the fungal infection should be determined when possible for evaluation of the need for treatment.


[Radiographic differential diagnosis of benign and malignant space occupying lesions in the facial area (author's transl)]. Radiological signs of clinically and microscopically verified space occupying lesions in the facial region are demonstrated, particularly referring to tomography. The possibilities to distinguish between benign and malignant lesions are pointed out.


[Reflex excitability of the spinal centers in patients with diffuse toxic goiter (concerning the pathogenesis of motor disorders)]. Reflex activity of the spinal cord motor centres was studied in patients with diffuse toxic goiter and in healthy persons. Methods of recording N- and M-responses of the soleus muscle were used. It was revealed that the number of motor neurons participating in the reflex reaction was changed; the restoratory cycle of the motor neuron pool was disturbed in double stimulation; inhibition of the H-reflex during the voluntary contraction of the antagonist muscle was diminished. The occuring disturbances were connected with the functional changes both of the segmental spinal cord apparatus and of the supersegmental formations. The extent and the direction of the detected disturbances are determined by the presence or the absence of affection of the mesodiencephalic formations on the patients under study and failed to depend on the severity of the disease.


[Biological significance of fibrinopeptide A elevation in the blood]. In 13 patients with effusions of varying etiology, considerably higher fibrinopeptide A (FPA) immunoreactivity were found in the effusions than in the corresponding plasmas. After instillation of heparin into the effusion the FPA concentration diminished significantly but very slowly. The difference in concentration between plasma and effusion therefore represents a relative FPA accumulation in the effusion. In view of its extremely short half-life in plasma, the FPA produced in the effusions is thought not to contribute to the increased plasma FPA levels. In addition, injection of amounts of FPA into the effusion such as to produce an acute increase of the local FPA level did not lead to a significant change in the FPA level in plasma.


Onco-embryonic antigens on murine normal adult cells. Normal adult C57BL/6J fibroblasts, cultured to saturation density and therefore in resting phase, were harvested by EDTA, treated with trypsin at various concentrations for different lengths of time and then tested for absorbing capacity of a C57BL/He anti-embryo serum, the residual cytotoxic activity being measured by a 51Cr release assay on a C57BL/He lymphosarcoma known to carry embryonic antigens. A weak proteolytic treatment (0.05-0.25% trypsin for 5-10 min) uncovered structures which absorbed over 40% activity of the anti-embryo serum. The treated fibroblasts partially retained the absorbing capacity for an antihistocompatibility serum. Higher doses or longer exposure to trypsin progressively inactivated the absorbing capacity of fibroblasts for both antisera. Trypsin treatment of fibrosarcoma cells, which when untreated completely absorbed the anti-embryo serum, decreased their absorbing capacity. Additionally, normal untreated fibroblasts in growing phase were found to absorb the anti-embryo serum.


A morphometric examination of type II alveolar epithelial cells in normal and isolated-perfused dog lungs. The volume densities of type II alveolar cell cytoplasmic organelles and alveolar surface densities were estimated by established stereologic procedures. The morphometric measurements were obtained from normal dog lungs (in situ) and isolated dog lungs perfused for 30-minute, 1-hour, and 2-hour periods. The type II cell lamellar body volume densities and the alveolar surface densities progressively decreased as the times of perfusion were increased. The volume densities of the granular and agranular endoplasmic reticulum progressively increased during the periods of perfusion. These morphometric parameters from lungs in situ and isolated lungs suggest that changes occur in pulmonary surfactant synthesis and activity during perfusion. It is further postulated that progressive increases in the rates of surfactant removal and/or inactivation during perfusion may contribute to spontaneous edema in lungs isolated for periods exceeding two hours. The morphologic and physiologic integrity of isolated perfused lung preparations, widely used as models of lungs in vivo, in situ requires further evaluation.


Gastric emptying of lactose and milk in subjects with lactose malabsorption. Six lactose absorbers (LA) and 5 lactose malabsorbers (LM) had tests of gastric emptying with 750-ml meals of glucose in water, lactose in water, plain milk, and chocolate milk. The glucose and lactose meals emptied in a similar fashion in LA and LM subjects with a significant decrease in gastric emptying as the osmolarity of the meals was doubled. If the data are normalized by dividing lactose emptying by the emptying of glucose meals of twice the osmolality in each individual, the lactose malabsorbers empty significantly more lactose. Both LA and LM subjects emptied comparable amounts of milk meals having similar osmolarity. Chocolate milk, which had a higher osmolality than plain milk, emptied more slowly than plain milk in both groups, and this difference was significant in the LM group.


[Pulmonary oedema ex vacuo (author's transl)]. Spontaneous respiration in the presence of upper airway obstruction causes considerable negative intra alveolar pressure which may lead to pulmonary oedema "ex vacuo". Four cases are presented of spontaneously breathing patients who sustained upper airway obstruction lastin from one to several hours, leading to manifest pulmonary oedema. The pathogenesis of pulmonary oedema ex vacuo is discussed on the basis of alteration of physiological parameters such as capillary, alveolar and pleural pressures, as well as the properties of lung liquid exchange. In contrast, pulmonary oedema occurring after re-expansion of a collapsed lung is reported in one patient. No negative intraalveolar pressure could be incriminated in this case since the patient was ventilated using intermittent positive pressure from the beginning of lung expansion. We tend to attribute the evolution of this second kind of pulmonary oedema to capillary damage, resulting from hypoperfusion of the atelectatic areas, altered alveolar surface lining layer, infection and other cases. The therapeutic measures used in pulmonary oedema "exvacuo" are briefly mentioned.


Cerebrospinal fluid cytology in canine neurologic disease. Samples of cerebrospinal fluid (CSF) of 93 dogs with neurologic diseases were examined by cytomorphologic technique, and the changes in the CSF were correlated with histopathologic examinations of the central nervous system (CNS). It was concluded that CSF examination is a significant aid in obtaining a neurologic diagnosis and that good correlation exists between the CSF changes and the pathologic changes in the CNS. The CSF examination allows making a diagnosis of encephalitis and differentiation between viral and other causes (although in mycotic infection the cell membrane preparation can be used to identify the cause directly), could allow making differentiation between congenital malformations and congenital degenerative disease, and helps in identifying physical spinal cord damage, differentiating it from muscular, neurogenic, or functional disorders clinically presented as spinal ataxia. The CSF cytologic examination can indicate the presence of hemorrhage in the CNS. There is not enough experience available in the diagnosis of brain tumors by means of CSF examination; however, in dogs with lymphosarcoma in the CNS, CSF cytologic changes can be diagnostic.


[Utilization of gossypol-free cottonseed and its by-products as human food]. Trials  have principally turned on a glandless cottonseed flour, with 56 p. 100 of proteins. It is possible to blend it with millet or sorghum flour, and  so to prepare the main meals of the local cooking. Trial of acceptability and long-dated consumption have shown that this flour is rather well appreciated especially in sauces. The growth of young children has been better thanks to the consumption of a cottonseed flour pap during six months. Trials to manufacture biscuits and noodles have been attempted. Kernels of cottonseed with 32 p. 100 of proteins and 33 p. 100 of lipids have been consumed with success. Four tons of kernels have been sold at the same price as sorghum in the area where the glandless cotton plant is under cultivation.


Retrolental fibroplasia--res ipsa non loquitur. The misconception that retrolental fibroplasia (RLF) occurs only in premature infants who have been exposed to excessive concentrations of oxygen is discussed. The fact that RLF occurs without exposure to oxygen is documented. Basic principles of jurisprudence regarding medical malpractice relating to RLF are discussed. Since RLF can occur without exposure to oxygen the doctrine of res ipsa loquitur should not apply. The burden of proof should still rest with the plaintiff.


Prolactin oversuppression.

Prolactin oversuppression. Patients with primary infertility due to hyperprolactinemic corpus luteum insufficiency and oligomenorrhea were treated with Bromocriptin. Suppression of serum prolactin for up to four menstrual cycles resulted in a normalisation of the length of the cycle(32 vs 28 days) as well as of luteal progesterone secretion. In addition, ovulation occurred earlier after than before treatment (on day 14 vs day 18). When, however, prolactin concentrations reached levels of less than 120 muU/ml (3 ng/ml), which were observed during the 5th and 6th treatment course, reappearance of shortened luteal phase occurred probably due to oversuppression of prolactin. Premenstrual spottings were observed too. The data presented indicate that minimal prolactin is required for normal follicular maturation and luteal development. On the other hand, the gonadostat may be susceptable to the dopaminergic stimulus of Bromocriptin to a different extent as oversuppression of prolactin is not observed in hyperprolactinemic anovulatory syndromes. Thus, treatment with Bromocriptin requires a continuous monitoring of serum prolactin as well as individual treatment regimens.


[Isolation and characterization of the placental protein pp5 (author's transl)]. The isolation and characterization of placemental protein PP5 is described. The purification was achieved by use of immunoadsorbents. From the tissue of one human term placenta an average amount of 15 mg PP5 can be extracted. PP5 apparently is specific for the placenta; it could not be detected in extracts from other human tissues. In sera from pregnant women PP5 is not present or only in trace amounts (less than 0.1 mg%). In the ultracentrifuge PP5 was found to have a sedimentation coefficient of 2.8 S and a molecular weight of 36,600 daltons. Electrophoretically the protein migrates as a fast beta1-globulin. The isoelectric point was determined to be 4.6. PP5 is a glycoprotein and contains 19.8% carbohydrates (hexoses 10.0%, hexosamine 4.4%, fucose 0.4%, sialic acid 5.0%). The amino acid composition of the protein is reported, too. PP5 was found to inhibit the activity of trypsin and plasmin; the biological role of this protein therefore may be the inhibition of proteases.


[Results of in vitro sperm penetration tests in cervical mucus under takings of the sequential oral contraceptive ovanon and sequilar (author's transl)]. The in vitro penetrability of cervical mucus by sperm was investigated in women who were taking Ovanon or Sequilar. Measurements were made under constant experimental conditions on every day of the cycle. The depth of penetration differed strikingly between women with normal menstrual cycles and women taking the sequential hormonal contraceptives. The penetration depth was substantially less when Sequilar or Ovanon was used. The Sequilar induced cervical sperm barrier during the entire cycle was almost as strong as that observed when combined preparations are used. During the proliferative phase of the cycle the penetration depth allowed by Ovanon was less than that observed during normal cycles but greater than that seen with Sequilar. During the secretion phase no appreciable differences in the penetrability of cervical mucus between the two contraceptives was observed. The hypothetical relationship between these data and the problem of cervical carcinoma was described.


[Ultrastructural investigations on the nuclear channel system in the human endometrium (author's transl)]. The Nuclear Channel System (NCS) is a distinct endometrial pattern as observed by transmission electron microscopy. The NCS was identified in the present study in cell nuclei of endometrial glands during mid and late proliferation. These observations do not support the concept that the NCS develops at the ovulation, and is therefore not a typical post ovulatory structure. It is suggested that there are relations between hormonal factors and the development of the NCS which are as yet not clarified.


[Hormonal pattern in premenopauseal cycles (author's transl)]. By serial determinations of plasma LH, FSH, progesterone and estradiol-17beta as well as total gonadotropines, total estrogens and pregnanediol in 24 h urine samples it was possible to classify 19 cycles of premenopauseal women, aged 44-50 years, into two groups. The first group showed ovulatory cycles with partially shortened hyperthermic phases in the basal body temperature curves, slightly elevated levels of FSH and diminuished estradiol-17beta, pregnanediol and progesterone concentration, indicating the beginning insufficiency of the ovarian function. The second group was characterized by several times above normal elevated FSH and somewhat less elevated LH levels significantly lowered estradiol-17beta and only basal progesterone and pregnanediol concentrations. The ovulatory transitional cycles explicated a nearly normal fluctuation pattern which was completely abolished in the anovulatory cycles.


[Purification of the peptide hormone relaxin (author's transl)]. A simple procedure for the purification of the peptide hormone relaxin is described. It allows prepare with good yield highly purified relaxin of an activity of 700 GPU/mg protein. For the first time ion-exchange chromatography by Amberlite IRA-410 and subsequent gel filtration on sephadex G-25 fine were used as purifications steps.


[Pseudohermaphroditism due to XY gonadal absence syndrome (author's transl)]. A case about a 16 year old individual is presented, in whom no internal genitals and vagina were found; no signs of breast development, axillary and pubic hair growth could be detected. The external genitals were hypoplastic. A sinus urogenitalis was present. The sex chromosome pattern was normal male (XY). On both sides of the pelvic wall rudiments of the Fallopian tube were observed by laparoscopy. Testosterone, estradiol, 17 alpha-OH-progesterone as well as androstendione-secretion could not be stimulated by HCG. Basal and LH-RH stimulated gonadotropins indicated a hypergonadotropic state. Height and bodyweight were in the range of a 12-year old boy, the bone age correlated with 14 years.


Correlation of quantitative asbestos body counts and occupation in urban patients. Asbestos bodies were quantified in digests of lung from 252 urban patients who were over 40 years of age. Patients were assigned to six occupational categories that had been determined without knowledge of asbestos body counts. Asbestos bodies were present in the lungs of 96% of the total population. Fewer than 12% of the white-collar men and the blue- and white-collar women had more than 100 asbestos bodies per gram of lung, whereas 32% of the blue-collar men not working in steel mills or construction, 45% of steelworkers, and 65% of construction workers had more than 100 asbestos bodies per gram lung. This distribution suggests that almost everyone in our population has some exposure to asbestos, and certain persons are subject to an additional occupational exposure. Whether asbestos bodies in low concentration are related to disease remains to be determined.


Early embryonic development in lead-intoxicated mice. The development of the embryo until day 7 was studied in histologic sections of the uterus, oviduct, and ovary from normal and lead-treated mice (0.5% of lead in the diet). Such lead treatment causes a substantial reduction in pregnancies in successfully mated female mice. After lead treatment, the blastocyst is formed normally, although it has a slightly reduced size. Differentiation of giant cells in the trophoblast and of decidua cells in the uterus is, however, impaired. Moreover, the corpora lutea are underdeveloped. Since earlier normal estradiol secretion on day 4 and a diminished progesterone secretion from day 5 on had been found, activation of the embryo and/or development of decidua cells fall due to the absence of this hormone.


Asymptomatic liver disease in alcoholics. Several types of histologic changes of the liver have been found in 116 of 154 chronic alcoholics who showed no symptoms of organic liver disease and were admitted to a department of psychiatry for treatment of their addiction. No relation was found either between the nature of the hepatic damage and the duration of alcoholism or with the presence of degree of clinical and biochemical disturbances. Results of clinical and biochemical examination of 55 patients with histologic abnormalities were normal, and these patients were considered as apparently healthy alcoholics. Liver biopsy specimens from 61 to 69 asymptomatic alcoholics, who had abnormalities on clinical and/or biochemical investigation, showed hepatic damage under light microscopy, but specimens from the other eight were histologically normal. Conventional liver function tests have limited value in detecting the existence and severity of liver injury, while liver biopsy specimens may reveal a large range of abnormalities in asymptomatic alcoholics.


Hepatic pathologic condition in asymptomatic Australia antigen carriers. A light microscopical study of 26 cases and a review of the literature. Liver biopsies were performed on 26 Australia antigen carriers who were asymptomatic with normal liver function tests. The carriers are part of a prospective and long-term study designed to analyze the clinical and pathological consequences of persistent, though asymptomatic antigenemia. The liver abnormalities that were indicated on biopsy included fifteen specimens with "inflammatory changes" that were characterized by intralobular foci of mononuclear cells and/or portal tract infiltrates. Fifteen biopsy specimens demonstrated "ground-glass" cells. Nine biopsy specimens showed fatty change, and three specimens were normal. The results of our study in conjunction with cases that were reviewed in the literature indicate a narrow and mild spectrum of liver biopsy specimen abnormalities in the asymptomatic carrier with normal liver function tests. Prognostic inference from this liver biopsy data is premature and clinical follow-up of carriers is advocated.


Multiple bone marrow necrosis and disseminated intravascular coagulation. Pancytopenia and disseminated intravascular coagulation (DIC) developed in a 62-year-old woman. Scattered granulomatous nodules in the bone marrow, composed of numerous eosinophilic concentric spherules with amorphous eosinophilic deposits and reticulin fibrosis between them, resulted in the destruction of the bone marrow architecture. These rare morphologic appearances in the bone marrow may have been caused by lipogranulomatosis and multiple bone marrow infarctions, which were subsequent developments to DIC. Such a process is believed to have induced a lethal secondary hypoplastic anemia.


Thrombotic thrombocytopenic purpura in a child with Alexander's disease. Thrombocytopenic purpura developed in a 14-year-old boy with Alexander's disease; he died. The proximity of Rosenthal fibers to small vessels in the brain, the presence of perivascular lymphocytes in the brain, and the presence of complement in renal arterioles suggest that the Rosenthal fibers could have injured the endothelium-basement membrane resulting in an immune response triggering the thrombotic thrombocytopenic purpura.


Histochemical changes in striated muscle in patients with intermittent claudication. Biopsy specimens from the gastrocnemius or rectus femoris muscle of 20 patients with intermittent claudication were studied using fresh frozen cryostat sections and histochemical reactions for adenosine triphosphatase, nicotinamide adenine nucleotide dehydrogenase reductase and phosphorylase and modified Gomori trichrome staining. Neuropathic changes, such as fibertype grouping and small group atrophy, were present to some extent in all of the biopsy specimens. Myogenic muscle changes such as necrosis and phagocytosis were seen in approximately one third and various forms of myofibrillar disorganization in approximately two thirds of the specimens. The amount and size of the type I aerobic fibers increased with the increasing severity of the ischemic disease.


An exploration method of the Eustachian tube for intact and perforated drums: tubal-impedance-manometry. The author describes an exploratory method of the Eustachian tube: tubal-impedance-manometry. This method comprises two types of techniques, the one applicable to patients whose eardrum is intact, the other to cases of tympanic perforation. The instrumentation and the examination techniques are described. The discussion allows the results to be incorporated into a clinical perspective: T.I.M. with closed eardrums will deal principally with localizing an eventual tubal problem. On the other hand, T.I.M. with open eardrums will be more specifically viewed as a pre-surgical examination (tympanoplasty).


Protein and isoamylase content of rat-submaxillary gland under the influence of alpha- and beta-sympathicolysis. In order to study the function of adrenergic receptors in the submaxillary gland in vivo, rats were treated with the alpha-sympathicolytic, phentolamine (Regitin) and with the beta-sympathicolytic, propranolol (Dociton) and the protein, amylase, and isoamylase content of their submaxillary glands were investigated. The protein concentration rises after 3 weeks of alpha- as well as combined alpha- and beta-sympathicolysis while the amylase concentrations remain, on the whole, unchanged. The pharmacologically induced secretory inhibitions are being discussed in connection with the generally accepted receptor functions.


[On the effect of hyperbaric oxygen (OHP) at the guinea pig's cochlea insulted by hypoxia (author's transl)]. The effect of OHP (oxygen under high pressure) by examining 17 CO-intoxicated guinea pigs. The following effects have been observed: The microphonics recovered significantly faster after hypoxia caused by CO than under air. Hyperbaric oxygen has a protecting effect on the inner ear. If OHP is applicated before CO, the microphonics decrease less than under normal breathing. The postmortal microphonics increased to a level above the known postmortal slope, suggesting a diffusion of oxygen through the round window.


[The trigemino-facial reflexes: a methodological approach to the evaluation of facial nerve function (author's transl)]. Since 1952 electromyographic registration of the trigemino-facial reflexes have been repeatedly described to evaluate facial nerve function. Comparable to peripheral nerve conduction velocity studies, this method enables us to detect intratemporal lesions. In order to obtain optimal results, we modified the registration technique of the trigemino-facial reflexes as regard to the following items: 1. Because of great interindividual variability of latencies and amplitudes this method should be used only by comparing the right and the left side. For a reliable assessment of both, recovery and detoriation of the facial nerve a standardized stimulation and recording technique is necessary. Stimulus strength should be defined by the applied current rather than voltage. 2. Since, in many cases, only certain neurones of the facial nerve are affected with different degree, important information is gained by recording not only from the M. orbicularis oculi but also from M. levator labii, M. zygomaticus and M. orbicularis oris. 3. In order to detect small reflex responses in severe and advanced cases, averaging technique should be applied. Thus, minute potentials hidden in the amplifier noise can be detected and clearly defined as either a stimulus dependent reflex response or unvoluntary muscle activity.


[A comparative ultrastructural-morphometric study of the cochlear spiral ganglion in rats and guinea pigs (author's transl)]. The cochlear spiral ganglion of rats consists of 61.8% granular ganglion cells, 22.4% satellite cells and Schwann cells, 9.3% extracellular space, 4.8% myelinated nerve fibers and 1.4% filamentous ganglion cells. The granular ganglion cells consist of 76% cytoplasmic components and 24% nuclei. Their cytoplasm contains 66.3% hyaloplasm, 11.4% mitochondria, 11% free ribosomes, 7.8% rough endoplasmic reticulum, 2.7% Golgi apparatus and 0.8% lysosomes. Comparing with morphometric data in guinea pigs, granular spiral ganglion cells in rats show some species dependent differences in their quantitative cytoarchitecture. They don't differ in their principal architectural pattern, especially in regard to the metabolism for energy and cell performance. The spiral ganglion cells of rats in contrast to those of guinea pigs do not show viral particles. Since it is impossible to evaluate with certainty the influence of viruses on the metabolism of infected cells, in our opinon rats are more suitable experimental animals for morphometric investigations of spiral ganglions.


[ERA-findings by "cortical hearing disorder" (author's transl)]. Since about the last 2 years the late potential's component N1 (90--110 ms) as well as the early acoustically evoked potentials, appearing in a latency range of 1--8 ms and consisting of the nerve action potential (Pot. I) and the brain-stem potentials (Pot. II-V), were registered at some hearing impaired patients. This procedure enabled us to diagnose a "cortical hearing defect" at five patients: a) three children at an age of 2--3 years; they all have a slight cerebral damage, a hearing impairment and no speech-development; b) a 15 year old girl with a hearing impairment which is on the right side more severe than on the left side, as consequence of an encephalitis; and c) a 50 year old man suffering on both sides from a loss of temporal brain's substance and from a total deafness after an insult of both arteriae meningeae mediae. At all these patients the ERA-findings result in an almost normal behaviour of the bioelectrical transfer of the acoustic stimuli in the region of the brain-stem, whereas the late potential's component N1 showed a pathologic distortion. The ERA-results together with the anammesis make a "cortical hearing disorder" probable at these five patients. The audiograms and the ERA-characteristic lines are shown and discussed.


Comparative morphological investigation on the rabbit's auricle after exposure to CO2- and Nd:YAG-laser radiation. By comparing the effects of CO2- and Nd:YAG-laser radiation (mainly differing in wave-length by a factor of 10), a surgical instrument suitable for Otorhinolaryngology had to be found. The studies were performed on the rabbit's auricle in order to examine the effect of the laser irradiation mainly on the cartilage. The CO2-laser was found to be more efficient in cutting and caused less extended tissue damage than the Nd:YAG-laser. The latter seems to be more suitable for soft tissue surgery.


Diseases of the thyroid: some practical considerations from a surgical view point. The physiology of the thyroid gland and the basic principles underlying diagnostic tests have been outlined, and need to be understood if diseases of the thyroid are to be managed efficiently. In the choice of therapy for the thyrotoxic patient, consideration should be given to such features as safety, convenience, age, available skill and economics as well as the more obvious factors fo gland size, pressure effects and potential malignancy. Non toxic goitre is often a physiological process, and early institution of thyroxine replacement therapy may prevent the development of changes in the gland requiring surgery. However, the diffusely enlarged gland may be the site of a variety of disease processes, such as anaplastic malignancy or autoimmune thyroiditis. The singly throid nodule is potentially neoplastic, and surgical exploration is mandatory without clear evidence to the contrary. Free Thyroxine Index and Serum TSH levels are the best guide to thyroxine replacement therapy, and TSH release should be blocked in the long term after removal of hormone dependent thyroid tumours. Lifelong follow-up is essential after treatment of any thyroid disease, with the particular aim of determining thyroid function in the long term.


Deuteron nuclear magnetic resonance studies of phase equilibria in a lecithin-water system. Water deuteron NMR spectra have been studied for the system dipalmitoyllecithin (DPL)-heavy water (D2O) at different compositions and temperatures. From an analysis of the spectra in terms of quadrupole splittings, a phase diagram has been constructed for the temperature range 25-60 degrees C and the composition range 4-15 mol of D2O/mol of DPL. Evidence is given that the "pretransition" observed by differential scanning calorimetry is caused by a crossing of a three-phase line. Strong support for a specific hydration of about 11 water molecules per lecithin molecule in the phase between the pretransition and main transition is also found.


Decreased tuftsin concentrations in patients who have undergone splenectomy. Serum tuftsin concentrations were measured, using a radioimmunoassay developed in Israel, in normal subjects and in patients who had undergone splenectomy. Concentrations in those who had undergone traumatic and elective splenectomy were much lower. The tuftsin concentration in 38 patients with Hodgkin's disease who had undergone splenectomy during staging laparotomy was not significantly different from the mean concentration in other patients who had had elective splenectomy. In four patients who underwent splenectomy for non-malignant haematological disorders measurements made before and after operation showed that tuftsin concentrations fell significantly in the days after operation. The increased susceptibility to overwhelming infections of patients with Hodgkin's disease and others who have undergone splenectomy may be related to the low tuftsin concentrations. As pre-splenectomy tuftsin concentrations in patients with Hodgkin's disease were normal, the practice of performing staging laparotomy and splenectomy in patients with Hodgkin's disease should perhaps be reconsidered.


Observations on syphilis in Addis Ababa. 1. General considerations. The socioeconomic picture of Addis Ababa, the capital of Ethiopia, is briefly described and the provision of general medical care is outlined. Control of venereal disease is centred on one clinic. Here two doctors attend to nearly 1000 outpatients daily. It is perhaps not surprising that self-diagnosis and self-medication are common and follow-up attendance is erratic.


[Treponemal serology in a Bi-Aka pygmy population of Central Africa]. A serologic survey on 196 blood samples (20% of the present population) in a Bi-Aka pygmean population in Central African Republic. The survey demonstrated the frequency of the unquestionably positive sera: 79.4% of the studied sera. The existence of 78.5% positive sera in children and the observation of yaws lesions suggest a massive and very probably endemic infestation with Treponema pertenue.


[Detection of Australia antigen in blood donors from Saigon (Vietnam)]. An electro-immunodiffusion's study on blood donnors in Grall Hospital (Saïgon, Vietnam) is analysed. In a population of 514 subjects, 39 carriers of antigen HbS are detected: i.e. 7.6%. Interfering factors are observed, necessiting for an epidemiological study the specification of each sample.


Serum glycylproline p-nitroanilidase activity in blood cancers. Glycylproline p-nitroanilidase activity in serum of patients with acute lymphatic leukemia, lymphosarcoma and Hodgkin's disease, and of normal neonates (umbilical blood) was significantly lower than that of normal adult controls. In contrast, the enzyme activity of patients with myelocytic leukemias did not differ significantly from that of normal controls.


Immunological status of mycetoma patients. Mycetoma patients were investigated for cell-mediate immunity by means of the tuberculin test, DNCB sensitization and lymphocyte transformation induced by phytohaemagglutinin. Levels of immunoglobulins, IgG, IgM and IgA were also determined. Results seem to point towards deficiency in cell-mediated immunity at least partial if not whole. There was a definite rise in the IgM and IgA class of immunoglobulins and a decrease in IgG. These antibodies are of diagnostic value in the precipitin and complement fixation tests but have no protective value.


[Evaluation of intestinal parasitoses found in Algerians (1971-1975)]. A high incidence of intestinal parasitism was found in and around Algiers: out of 4,334 cases tested, 1,387 (about one third) were positive. The authors consider this to be a conservative estimate. The figures quoted will be revised, if necessary, on the results of a systematic survey at present under way.


[The use in current practice in the French Antilles (FWI) of a unique standard for the identification of hemoglobins]. The use of a standard with Several hemoglobic fractions allows and easy identification when are done electrophoretic runs. This standard may be adapted in terms of the area where it is utilized, in using others hemoglobins than those ones proposed, availables for the Caribbean Zone. At all events there is to bring together hemoglobins outright different by their electrophoretic mobility in acid or alkaline media and with a definite voltage.


The hippocampal slice: a system for studying the pharmacology of seizures and for screening anticonvulsant drugs. Interictal spikes with a configuration similar to that occurring in grand mal epilepsy were generated by the application of penicillin to a hippocampal slice preparation. This slice preparation has potential value for screening anticonvulsant drugs and for studying epileptic activity. The effect of anticonvulsant drugs on seizure activity was tested at concentrations comparable to reported clinical serum concentrations. Phenytoin and diazepam were maximally effective at concentrations of 20 microgram/ml and 3-4 microgram/ml, respectively, in good agreement with their effective concentrations in clinical practice. Phenobarbital was more potent (5 microgram/ml) and mesuximide (50% potent at 80 microgram/ml) was least effective.


Pharmacokinetics of tolamolol in the treatment of hypertension. Tolamolol was administered in a "double-blind" study to fifteen hypertensive patients by dose-titration against arterial blood pressure. Mean steady-state plasma tolamolol concentrations (Css) were determined for each patient from the area under the plasma concentration--time curve during a dosage interval whilst patients were receiving optimal tolamolol doses. No significant correlation was observed between daily tolamolol dose and Css; the relationship between fall in lying mean arterial pressure and Css also failed to reach conventional levels of statistical significance, but Css was observed to be correlated with the fall in standing pressure. The results suggest that plasma concentrations in excess of 200 ng/ml may be required to achieve an effective hypothensive response with the drug.


Comparative bioavailability of a sustained release preparation of amitriptyline and conventional tablets. A sustained release preparation of amitriptyline has been compared with conventional tablets in eight healthy human volunteers. The tablet produced a distinct peak in serum concentration shortly after administration, whereas the sustained release preparation caused a slow rise to a plateau. The maximum serum concentration and the time of its occurrence differed significantly between the two preparations. The differences between the serum concentration curves of the two preparations can be explained on the basis of a two compartment model of amitriptyline pharmacokinetics and from a difference in the absorption rate. The similar clinical effect obtained with a lower daily dose of the sustained release preparation than of the tablet cannot be accounted for in terms of pharmacokinetics. It is possible that a single evening dose of sustained release amitriptyline gives a more appropriate serum concentration profile of amitriptyline and its active metabolite nortriptyline than a conventional tablet taken three times a day.


[Neurologic complications of ciguatera]. The authors report a case of severe two phases fish poisoning, treated at hospital and ruled by a complex neurological picture with both central and peripheric manifestations. The detailed data, they have got about the disease, are an opportunity to discuss the various pathogenic procedures of human ciguatera.


Bioavailability of three phenytoin preparations in healthy subjects and in epileptics. Serum phenytoin concentrations have been studied in epileptic patients and healthy subjects taking tablets of phenytoin calcium (Desitin), A, phenytoin acid (Desitin), B, and phenytoin acid (Nordmark), C. Retrospective data and prospective investigation of hospitalized patients on long-term phenytoin treatment showed that significantly higher serum concentrations of phenytoin were produced by the phenytoin acid preparations B and C than by the phenytoin calcium preparation A. In a cross over study six volunteers received 200 mg/day of preparations A, B, and C for three weeks. In this study, too, higher phenytoin serum concentrations were produced by B and C than by A, although the differences were not statistically significant. The reasons for the discrepancies between the studies in healthy and epileptic subjects are discussed.


[Alcyonidium gelatinosum (L.) (Bryozoa) and cutaneous hypersensitivity reactions. Preliminary results of an experimental study]. The appearance of acute eczematous dermatitis in fishermen from the estuary of the Seine, about which the responsibility of Alcyonidium gelatinosum (L.) is still under discussion, led us to estimate the ability of this Bryozoa to induce cutaneous responses of delayed hypersensitivity. Intradermal tests carried out in guinea-pigs after subcutaneous, respiratory or percutaneous sensitization, gave evidence of a clear allergenic ability of this alcyonelline. The deposit of the biological product on normal skin during four consecutive days is enough to induce strong responses of delayed hypersensitivity. This experimental study needs further investigations in which the possible existence of anaphylactic reactions should be confirmed.


Antitumor activity of new anthracycline antibiotics, aclacinomycin-A and its analogs, and their toxicity. New anthracycline antibiotics have been isolated from the culture of Streptomyces galilaeus MA144-M1. Among 14 anthracycline compounds, aclacinomycin-A showed the strongest activity in inhibiting leukemia L-1210 and had lower toxicity than others. Antitumor activity of aclacinomycin-A against leukemia L-1210 and P-388, solid sarcoma-180, and lymphosarcoma 6C3HED was examined in comparison with adriamycin and daunomycin. Aclacinomycin-A showed the same degree of activity against leukemia L-1210 and P-388, when administered intraperitoneally, as daunomycin and somewhat less than adriamycin. In oral administration, aclacinomycin-A also exhibited a significant activity on leukemia L-1210. The degree of inhibition of the growth of sarcoma-180 and 6C3HED lymphosarcoma transplanted subcutaneously by aclacinomycin-A was almost the same as that of adriamycin and daunomycin, although the optimal dose was about twice more than adriamycin. Acute cardiotoxicity of aclacinomycin-A by a test using hamsters was more than 10 times lower than that of adriamycin.


Thyroid autoimmune disease in a large Newfoundland family: the influence of HLA. Ninety-eight members of a large Newfoundland family, seven of whose members over three generations suffered from Graves' disease, were studied with respect to the mode of transmission of the disease and its association with HLA. Compared to Newfoundland communities of similar size and geographical location, very little consanguinity was documented in this family. The susceptibility to Graves' disease appeared to be inherited as a dominant with a variable degree of expressivity; the degree of expressivity being determined by the female sex. In part of the pedigree, the susceptibility to Graves' disease entered the family with a wife. Three of her offspring who subsequently developed Graves' disease shared with her the haplotype A9, Bw16. Of the three remaining affected family members, two shared the haplotype A1, B8, whereas the third carried the haplotypes Aw32,b8; a9,bw16. Graves' disease could be associated with either of these two haplotypes in the last individual. This study shows that the susceptibility to Graves' disease is inherited associated with HLA and that whereas the disease susceptibility gene for Graves' disease is in linkage disequilibrium with HLA-B8 in Caucasians, it can be randomly associated with other HLA-B antigens.


Surgery of the thyroid gland.

Surgery of the thyroid gland. Records of 92 patients operated on for thyroid diseases were reviewed. There were four histologic groups: adenoma-56 (61%), thyrotoxicosis-22 (24%), cancer-10 (11%) and Hashimoto's thyroiditis-4 (4%). Among the cold nodules, 9% were malignant. Routine frozen section examination revealed three cases of cancer and three other cases were missed but were discovered on permanent section examination. The type of operations were lobectomy with or without isthmusectomy, subtotal thyroidectomy and modified radical neck dissection. Postoperative complications included two thyroid crises, two recurrent laryngeal nerve injuries, one laryngeal obstruction and hypothyroidism, and one wound infection. There was no surgical mortality.


Thyroid disease in children and adolescents. Thyroid diseases in children and adolescents are not common. The present paper describes 73 patients, aged 5 to 18 years, who had thyroid disease which was treated by surgery. Of these, 18 had diffuse simple goiter, 11 had diffuse toxic goiter and 44 had nodular goiter. Of those patients with nodular goiter, 34 had adenomatous goiter, one had lymphocytic thyroiditis, one had lymphosarcoma and eight had cancer. In the patients with nodular goiter under the age of ten years, 40% had cancer, and of those aged 11 to 18 years, 14.7% had cancer. Thyroid nodules were more frequent in girls than in boys, but the incidence of cancer in nodular goiter was higher in boys than in girls.


Rare tumors of the intestines and rectum. Some rare tumors of the intestines and rectum (eight cases) have been presented and discussed. All were successfully managed without operative mortality. I have presented some observations deduced from these cases which might aid in the diagnosis of such rare tumors--the importance of palpating the terminal ileum in any abdominal operation and the necessity for a frozen section biopsy from suspicious schistosomal masses of the sigmoid colon or the rectum before deciding to resect them. I have discussed cases of carcinoma of the rectum where microscopic schistosomal deposits were spotted and stressed that in such cases it is a mere coincidental association.


Direct current cardioversion. Effect on creatine kinase, lactic dehydrogenase and myocardial isoenzymes. Creatine kinase (CK), lactic dehydrogenase (LDH), and more recently their isoenzyme determinations (CK-MB and LDH1) have been useful adjuncts in verification of myocardial injury. To determine whether DC cardioversion affects these serum enzyme levels, we recorded total CK, total LDH, CK-MB, and LDH1 levels serially during 24 hours following elective DC cardioversion in 18 patients without cardiac ischemia. New postcardioversion elevations in total CK and total LDH levels were small and occasional: CK (one of 18 patients), LDH (four of 18 patients). Elevations of CK-MB or LDH1 following cardioversion did not develop in any of the patients. Therefore, new CK-MB or LDH1 elevations associated with arrhythmias must result from myocardial damage to DC cardioversion.


Acute renal failure. Association with administration of radiographic contrast material. Fourteen cases of acute renal failure secondary to administration of radiographic contrast media were observed, eight within a 15-month period. No patient had multiple myeloma, and only three were diabetic. Predisposing factors included renal hypoperfusion, preexisting renal insufficiency, hyperuricemia, age of more than 60 years, solitary functioning kidney, and exposure to several contrast studies at closely spaced intervals. Control of blood volume and serum uric acid, appropriate spacing of radiographic studies, and possibly urinary alkalinization and hypouricosuric drugs in high-risk patients are recommended to decrease the incidence and morbidity of contrast-mediated nephropathy.


Aeromonas hydrophila sepsis in a patient undergoing hemodialysis therapy. Aeromonas hydrophila septicemia complicated by a generalized cutaneous vasculitis developed in a patient receiving home hemodialysis therapy. Because the Aeromonas organism is found in many natural water sources, the possibility that this patient's hemodialysis system became contaminated was explored. Although cultures from the patient's home environment showed no Aeromonas sp, the possibility still exists that the site of contamination was in the dialysis system.


Enterovenous fistulization in Crohn's disease. A case of Crohn's disease was complicated by enterovenous fistulization (ileum to superior mesenteric vein) with septic manifestations. The fistulization was diagnosed by the observation of gas in the liver and by the opacification of mesenteric veins following a barium meal.


Migration of physicians from one specialty to another. A longitudinal study of US medical school graduates. To demonstrate the extent to which physicians change their specialty, randomized samples of the graduating classes of 1960, 1964, and 1968 were studied with respect to their self-designated specialties in 1971 and 1976. Of the 2,046 physicians in the three samples, 333 (16%) changed their specialty between 1971 and 1976. It was 8% for the 1960 cohort, 11% for 1964, and 29% for 1968. Of all the changes, 78% were from one specialty practice to another or back to a formal residency in a different specialty; 22% changed from one specialty residency to either practice or another residency in a different specialty. Between 1971 and 1976, a total of 127 (16%) of 783 primary care physicians changed their specialty. The magnitude of this change must be considered in planning for distribution of physicians by specialty.


Hepatitis B infection in physicians. Results of a nationwide seroepidemiologic survey. To define the epidemiologic features of occupationally acquired hepatitis B infection among physicians, we conducted a seroepidemiologic survey of physicians attending three American Medical Association conventions in 1975 and 1976. Of 1,192 participating physicians, 220 (18.5%) had serologic evidence of prior hepatitis B virus infection (positive hepatitis B surface antibody). The infection rate was higher among those practicing in urban communities; it increased with the number of years in practice; and among specialties, it was highest in pathologists (27%) and surgeons (28%). The serologic data demonstrated a changing pattern of viral hepatitis related to entry into the medical profession, with hepatitis B accounting for a majority of clinical hepatitis experienced after beginning medical practice.


Cardiovascular effects of tricyclic and tetracyclic antidepressants. Cardiovascular effects of therapeutic doses of tricyclic or tetracyclic antidepressants (TCA) were examined in 66 patients. After three weeks of therapy, heart rate and PR interval were increased (P less than .02, P less than .05), while prolongation of the QTc time and the QRS interval did not reach significant levels. We observed significant flattening of T waves (P less than .05), which was not associated with changes in the serum potassium level. These changes were reversible after treatment was discontinued. When therapy was maintained for 13 months, only the heart rate continued to be increased, whereas all other ECG values had returned to normal. The TCA therapy led to a significant prolongation of the preejection period (P less than .01) and slight shortening of the left ventricular ejection time, indicating a decrease in myocardial contractility. There was no difference of effects on the values studied between tricyclic and tetracyclic antidepressants.


The role of H-Y antigen in primary sex determination. The basic embryonic plan of mammals is inherently feminine. Male development is due to two-step interventions of this basic plan: the Y chromosome directs the embryonic indifferent gonad to organize a testis instead of an ovary; the Y-organized testis synthesizes and secretes testosterone, which induces all the extragonadal masculine development. The Y chromosome plays no direct and appreciable role in extragonadal masculine development. Testicular organization, normally under the direction of the Y, is the function of the evolutionary conserved plasma membrane protein serologically detectable as H-Y antigen. Under specific circumstances, H-Y antigen may be expressed in the absence of the Y chromosome, thus producing XO and XX males. If H-Y antigen is not expressed, XY individuals develop as females. H-Y antigen is the first plasma membrane or cell surface protein to which a specific organogenesis function has been assigned.