Effect of metiamide, a histamine H2 - receptor antagonist, on the development of gastric stress ulcers and acid secretion. In normal and stressed rats with chronic gastric fistula small doses of metiamide (0.001-0.01 muM/kg) increased and doses of over 20 muM/kg decreased gastric acid secretion. In both these dose ranges of dosage metiamide suppressed the development of stress ulcers, most markedly in doses of 0.005 and 100 muM/kg. Intermediate doses had no such action. Only the anti-ulcer action of large doses of metiamide ran parallel to a reduction in acid secretion. Small doses of metiamide increased gastric secretion, but like larger doses, had a weak adrenergic action.


Differential sensitivity to apomorphine and clonidine following frontal cortical damage in rats. Rats trained to bar-press on a FI 15 sec schedule for water reinforcement were administered various doses of apomorphine (0.25-10 mg/kg) and clonidine (0.002-0.1 mg/kg) both before and 6-10 weeks after bilateral ablation of frontal cortex. Both drugs monotonically depressed response rates with increasing dose. Frontal cortical lesions increased sensitivity to apomorphine without altering sensitivity to clonidine. The results suggest that the frontal cortex modulates the activity of dopaminergic but not noradrenergic neuronal pathways.


Interaction between lanthanum and calcium in isolated guinea-pig heart. The effect of lanthanum ion on the contraction of the perfused guinea-pig heart has been investigated. Lanthanum caused inhibition of the contractile force. The dose-response curves suggest that there is more than one site with which lanthanum may interact. The high affinity interaction is antagonised by high external calcium. The possibility that a low concentration of lanthanum may block calcium entry into the myocardium is discussed.


Central hypertensive action of histamine in conscious normotensive cats. In conscious normotensive cats intraventricular (i.c.v.) administration of histamine (2.0-50.0 mug) induced dose-related rises in blood pressure, with no increase in heart rate. The hypertensive response elicited by a sub-maximal dose of histamine (10.0 mu i.c.v.) was significantly antagonised by central pretreatment with the H1-receptor antagonist mepyramine maleate (200 mug i.c.v.) but not by the H2-receptor antagonist metiamide hydrochloride (1.0 mg i.c.v.). Behavioural responses were obtained in response to to histamine (10.0 and 50.0 mug i.c.v.), which were not antagonised by these antihistamine pretreatments.


Morphine hyperthermia in the rat: an action on the central thermostats. The mechanism underlying the hyperthermic response to low doses of morphine has been investigated in rats. Doses of morphine sulfate less than 10 mg/kg i.p. caused a rise in body temperature accompanied by vasoconstriction of the cutaneous blood vessels of the tail. This hyperthermia, unlike the hypothermia following higher doses of morphine was not blocked by naloxone nor did tolerance develop to the response. Injections directly into the hypothalamus suggested that, as with the fall in temperature after high doses of morphine, the hyperthermic effect is also due to an action on the preoptic/anterior hypothalamic thermoregulatory centers. Experiments measuring thermoregulatory behavior showed that rats delayed escaping from a heat load after low doses of morphine even though their core temperature was rising. These results suggest that low doses of morphine raise the set point of the central thermostats in rats resulting in a hyperthermia mediated, at least in part, by decreased cutaneous heat loss.


Influence of group selective reagents in tissues containing alpha- and beta-adrenoceptors. N-ethylmaleimide which is known to react irreversibly with free -SH groups of protein when incubated with rabbit aorta (alpha-adrenoreceptor) or atria (beta-adrenoreceptor) markedly depressed the dose-response curves of norepinephrine isomers in the aorta but not in atria. Dithiothreitol, a reagent which reduces S-S linkages caused a parallel shift of the dose-response curves of both isomers to an equal degree in aorta. However, in atria the reagent drastically and selectively reduced the maximal effects of (+)-norepinephrine and dopamine. This selective alteration of the (+)-isomer by the reagent probably reflects the conformational changes at the beta-adrenoreceptor. The concentrations of N-ethylmaleimide and dithiothreitol required to alter the activity of norepinephrine isomers was higher for atria than for aorta. It may be that alpha-adrenoreceptors are more susceptible than the beta-adrenoreceptors on the -SH group selective reagents. In the highest concentration tested, two other reagents 2,4-dimethoxybenzylamine and N-acetylimidazole, did not influence the activity of the steroisomers on aorta. In the presence of dithiothreitol, the pharmacologic effects of a nonadrenoreceptor stimulant drug, histamine was potentiated on aorta (H1) and not on atria (H2). Results are discussed in the light of similarity and dissimilarity of adrenoreceptors as reflected by the group selective reagents and the stereoisomers.


The role of alpha- and beta-adrenergic effects in the action of adrenaline on renal lithium elimination in adrenalectomized rats. Repeated s.c. injections of L-adrenaline (4 X 0.5 mg/kg body weight) increased the urinary clearance of lithium in intact rats and in adrenalectomized animals. Adrenaline also increased the fractional excretion of lithium in adrenalectomized rats; an effect that was prevented by repeated s.c. injections of the alpha-adrenergic blocking agent phentolamine (4 X 1 mg/kg body weight). When administered alone, propranolol and phentolamine decreased the urinary clearance of lithium in adrenalectomized rats. The drug-induced changes in the urinary clearance of lithium were not directly related to the effects of the drugs on the urinary elimination of sodium, potassium, creatine and water. The results suggest that the action of adrenaline on renal lithium elimination in adrenalectomized rats might be mediated by alpha-adrenergic receptors.


Influence of sympathetic nerves on development of responsiveness of the chick smooth muscle to drugs. The role of sympathetic nerves in the development of responsiveness of smooth muscle to drugs was investigated using the expansor secondariorum muscle of 2- to 40-day-old chicks. The normal developmental decrease in the responsiveness of the muscle to acetylcholine was prevented by surgical transection of the nerve or chronic treatment with guanethidine, while it was facilitated by chronic treatment with dimethylphenylpiperazinium. Sensitivity of the muscle to noradrenaline, remaining constant during normal development, was increased by nerve section or guanethidine treatment, while it was slightly decreased by dimethylphenylpipe-azinium treatment. These results suggest that sympathetic nerves regulate the development of the responsiveness of the chick expansor secundariorum muscle to drugs, at least the developmental decrease in responsiveness to acetylcholine.


Changes in the fast component of the rabbit vena cava contraction after repeated stimulation by noradrenaline(NA). The fast component of the rabbit vena cava contraction after repeated stimulation by NA was investigated. Experimental conditions which are known to increase the cellular calcium content led to an increase in contraction amplitude. Transient incubation between stimulations in a solution with high [Ca2+], in a solution with high [K], in a K+-free solution or in a solution containing ouabain is an example of such conditions. When the duration of a singly stimulus in a train of NA stimuli was prolonged the following contraction decreased. With increasing incubation time in Ca2+-free solution the maximum of contraction amplitude decreased far more after repeated stimulation than after a single stimulus. The results allow the interpretation that the fast component of the rabbit vena cava contraction which is induced by NA is related to the cellular calcium content. Moreover the results suggest that only a fraction of the cellular calcium is releasable by NA and that Ca2+-free conditions and/or NA exposure deplete this fraction.


Differential effect of baroreceptor reflexes and clonidine on frequency components of sympathetic discharge. The effects of the baroreceptor reflexes and clonidine on the 3 and 10 Hz components of spontaneously occurring renal sympathetic nervous discharge (SND) were studied in the cat. The proportion of 3 : 10 Hz SND was assessed by selective filtering and integration of activity in the 2-4 Hz and 9-11 Hz frequency bands. Baroreceptor denervation increased activity in both frequency bands while significantly lowering the 3 : 10 Hz ratio. Baroreceptor reflex activation (i.v. phenylephrine) decreased activity in both frequency bands while significantly increasing the 3 : 10 ratio. Clonidine (4-20 mug/kg, i.v.) affected the 3 : 10 Hz ratio of SND in a manner similar to baroreceptor reflex activation. These results indicate that the 3 and 10 Hz components of SND, both of which have been previously shown to be inherent to the central vasomotor system, are differentially affected by the baroreceptor reflexes and clonidine. It is concluded that it is possible to characterize certain cardiovascular states with respect to the 3 : 10 Hz ratio of SND.


Differences in the mode of exucative reaction between early phase and late phase of carrageenin-induced inflammation in rats. Differences in the mode of vascular permeability change induced by some stimulants such as chemical mediators between the early phase and the late phase of the carrageenin-induced granulomatous inflammation were investigated with the aid of 131I-human serum albumin as an indicator for the measurement of vascular permeability. In the early pregranulomatous phase of the inflammation, histamine injection into the inflammation locus markedly elevated local vascular permeability, while prostaglandins E1 and E2 showed no effect. On the other hand, in the late phase of the inflammation, where permanent granuloma tissue had been formed, prostaglandins E1 and E2 significantly enhanced the local vascular permeability, while histamine was inert.


Combinations of selected CNS depressants with d-amphetamine or mazindol on food intake and motor activity of rats. Amobarbital, diazepam, prochlorperazine and thioridazine were tested alone and in combination with d-amphetamine or mazindol on food consumption and spontaneous motor activity in rats. Of the four depressants tested (1) only amobarbital enhanced the anorexic effects of d-amphetamine and (2) amobarbital, diazepam and prochlorperazine enhanced the hypermotility induced by d-amphetamine. None of the depressants altered the anorexic effect of mazindol but amobarbital and diazepam decreased and prochlorperazine increased the hypermotility induced by mazindol. These differential effects of the CNS depressants suggest that d-amphetamine and mazindol might have different mechanisms of anorexiant or stimulatory action. The data also suggest that, to achieve anorexia with diminished CNS stimulation, combinations of d-amphetamine and any of the tested CNS depressants seem to be precluded. In fact, this desired clinical objective might be achieved with combinations of mazindol and either amobarbital or diazepam.


Clonidine-induced increase of renal prostaglandin activity and water diuresis in conscious dogs. I.v. administration of clonidine to conscious dogs induces a water diuresis with hyposmotic urine and minor effect on electrolyte excretion. The diuresis is preceded by an increased urinary PGE excretion, but no change of urinary ADH output is observed. Plasma renin activity decreases. Both ADH infusion and indomethacin pretreatment inhibit the diuretic effect of clonidine. The results support the hypothesis that clonidine-induced water diuresis is mediated via an anti ADH effect due to increased renal prostaglandin activity. Moreover the results suggest that there is no direct stimulation of renin release by PGE.


Production of and response to erythropoietin in the splenectomized mouse. A reliable dose-response curve has been established by exposing  normal mice to graded doses of exogenous erythropoietin (ESF).  In CF1 femal mice, made polycythemic by exposure to reduced air pressure , 59 Fe incorporation in RBC following injections of ESF (ranging from 0.05 to 3.2 IRP-units) varied according to the log of the ESF dose from 2.5 to 29.0 percent.  Experiments with plethorized splenectomized mice showed unequivocally that they were able to respond to ESF, although their responses were very much smaller than that of intact mice, ranging from 1.4 to 12.0 percent.  ESF activity was not detected in plasma from intact mice, but was evident in the plasma of mice that had been splenectomized 4 or 10 days earlier.  Under conditions of hypoxia the plasma ESF level rose rapidly during the first 48 hours and then fell . In the plasma of splenectomized, similarly treated mice, the ESF level at every interval studied was much higher and was maintained for a longer time. Re-exposure to low oxygen tension for brief periods (2-24 h) produced and erythropoietic response in both intact and splenectomized polycythemic mice, its magnitude increasing with increased exposure time.  The response of splenectomized mice, however, was lower than that of intact mice in spite of the fact that the plasma ESF level in the former was higher than in the latter.


Adaptation and dynamics in X-cells and Y-cells of the cat retina. On the basis of the spatial summation properties of their receptive fields, cat retinal ganglion cells were classified as either X-cells (linear) or Y-cells (non-linear). Responses were then obtained to a small, centered spot, square-wave modulated in time and superimposed on various levels of diffuse, steady background illumination. When fully dark-adapted, both X-cells and Y-cells produced responses that were entirely sustained. When well light-adapted but still in the scotopic range, both cell types produced largely transient responses with only a very small sustained component. The sustained or transient nature of responses is, therefore, not an invariant characteristic of X-cells and Y-cells in the scotopic range. We also conclude that the mechanism which controls the center's sensitivity in the scotopic range is similar though not identical in the two types of cells.


Behavioral correlates of focal hippocampal x-irradiation in rats. A study presenting findings of focal hippocampal x-irradiation in early infancy and late behavior at two ages was carried out using Long-Evans hooded rats (Rattus norvegicus). Animals from eleven litters received 150-R irradiation treatments for 5  or 15 consecutive days and were then tested in an open field situation and in a two-way active avoidance apparatus. The results indicated that the behavioral deficits paralleled those seen in animals with classical hippocampal lesions. The results were offered in support of a response suppression model for hippocampal functioning.


Excitatory nature of dopamine in the nigro-caudate pathway. Inputs from the substantia nigra (SN) to the caudate nucleus (Cd) and the effects of electrophoretic dopamine on Cd neurones were studied in cats anaesthetized with pentobarbitone with intracellular techniques. Single shock electrical stimulation of the SN or the medial forebrain bundle (MFB) induced monosynaptic EPSPs in Cd neurones. Dopamine depolarized Cd neurones and chlorpromazine suppressed the SN or MFB induced EPSPs. Appropriate controls indicate that the drug effects were not artifactual. Some recorded neurones were identified by procion yellow dye injection as the medium-size intrinsic Cd neurones.


A comparison of primary afferent and cortical neurone activity coding sinus hair movements in the cat. Responses in the somatosensory cortical area S I to stimulation of facial sinus hairs were recorded in the anaesthetized cat and compared with activity in primary afferent fibres innervating vibrissae follicles. The specific cortical vibrissa area is somatotopically organized; 39% of the cortical units in that area responded to stimulation of only a single sinus hair but in some cases all maxillary vibrissae activated a single cortical neurone. The responses consisted of three major groups; either a phasic discharge in response to the movement part of a stimulus, or an additional tonic discharge related to the steady period of vibrissa deflection, or a tonic discharge. On the basis of a comparison of response and excitability characteristics of primary afferent and cortical neurones it is concluded that all four kinds of peripheral units innervating sinus hair follicles project to the somatosensory cortical area S I. It appears from these findings that some cortical neurones receive a specific input related to a particular component of the complex primary afferent response in fibres innervating sinus hair follicles. The results are discussed with respect to previous reports on the central representation of facial sinus hairs in different species.


Projections from the lateral reticular nucleus to the cerebellar cortex and nuclei in the cat. The fiber projection from the lateral reticular nucleus (LRN) to the cerebellum was examined in the cat. Electrolytic lesions were placed in a confined area of the LRN using a parapharyngeal approach, and the ensuing degeneration was studied in sections stained by the Nauta and the Fink-Heimer methods. Fibers from the LRN ascend the ipsilateral restiform body, terminating bilaterally but chiefly in the ipsilateral cerebellum. In the ipsilateral cortex projections were found to lobules I to V, with denser terminations in sublobules IVb to Ve. The projections are stronger in the intermediate-lateral zones than in the vermis proper. There is also a dense projection to sublobules VId and VIf and to the medialmost part of the simple lobule (HVI). Scanty termination was seen in the medialmost part of crus I. There is a moderate projection to the caudalmost folium of sublobule VIIb and to the rostral folia of sublobule VIIIa and the paramedian lobule. The contralateral projection by fibers crossed within the cerebellum is far less dense but clearcut in the anterior lobe, the rostral folia of lobule VI and the medial part of the simple lobule. In the ipsilateral nuclei strong projections were found to rostral portions of the medial nucleus (M) and the caudal two thirds of the anterior interpositus nucleus (IA) with predominance in the lateral part of the latter. A focal projection was found to rostrodorsal portions of the posterior interpositus nucleus (IP). No projection was found to the lateral nucleus (L). Contralaterally there is a weak projection to the rostral part of M and the medial parts of IA and IP.


[Determination of absolute configuration of amine compounds of pharmaceutical interest by means of measurement of circular dichroism]. The CD curves study of the pyridyl-N-oxide derivatives of some adrenergic and anorexigenic amines showed that the sign of the Cotton effect can be related to their absolute configuration. The obtained results confirm the absolute configuration of fenfluramine and nor-fenfluramine and suggest that the levo isomer of ortoxine has R-configuration.


[Drug-protein interactions: physico-chemical study on the interactions between chlorpromazine and glutamate dehydrogenase]. The molecular basis of inhibition of glutamate dehydrogenase by chlorpromazine was studied by circular dichoroism, differential spectroscopy and fluorescence. Chlorpromazine appears to induce conformational changes of the enzyme at the position of aromatic amino acids, and tryptophan residues in particular are involved. On the other hand the secondary structure of the enzyme is not influenced by binding of the drug.


[Condensation of N-alkyl-o-phenylendiamine with ethyl benzoylacetate]. By reaction in hot xylene of ethyl benzoylacetate with N-methyl-o-phenylenediamine (I a) and N-benzyl-o-phenylenediamine (I b) three five-membered ring compounds and one seven-membered ring compound were obtained. Compounds isolated were: 1-alkyl-2-phenacylbenzimidazoles (III), 1-alkyl-2-phenylbenzimidazoles (V), 1-alkyl-2-methylbenzimidazoles (VI) and 1-alkyl-4-phenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-ones (IV). In the reaction with N-benzyl-o-phenylenediamine we isolated also the N-benzyl-2-benzoylacetamidoaniline (II b), which by further heating in xylene gave (IV b). The structures of compounds were elucidated from their chemical reactivity and their N.M.R. and I.R. spectra.


[Potential anti-inflammatory agents II. 7-Methyl-s-triazo(4,3-a)pyridines]. A synthesis of eight derivatives of 7-methyl-s-triazo-[4,3-a]pyridine substituted in position 3, has been made with a view to studying their possible antiinflammatory and analgesic action. Among the obtained compounds only the 3-(alpha-hydroxyethyl)-7-methyl-s-triazo[4,3-a]pyridine presents an activity similar to aspirin.


[Phthalimide derivatives of pyrimidine and thiazole heterocyclics]. The synthesis of some phthalimido-derivatives of the pyrimidine and thiazole ring systems is described. The functional groups have been suitably selected to enhance structural analogy with the pairs of pyrimidine and purine bases present in nucleic acids. In preliminary tests some of these compounds have shown inhibitory activity towards RNA polymerase reaction in vitro.


Receptor sites of DNA for the photoreaction with psoralen. Biological and pharmacological effects of psoralens are correlated to their capacity to photoreact with pyrimidine bases of native DNA and in particular to form inter-strand cross-linkages. To determine possible prefenrential sites for the photoreaction the Authors have studied the capacity of psoralen to form complexes and to photoreact with various polynucleotides. The Authors have shown that specific sites exist in DNA for the photochemical interaction with psoralen; these sequences which can be considered as specific receptors for photobiological activity of psoralen are represented by alternate sequences in every strand of A and T, corresponding to poly d(A--T) - poly d(A--T). These receptor sites show a high capacity for intercalation and successive photoreaction with psoralen.


Synthesis and neuropharmacology of cyclobutanecarboxylic acid derivatives. Urea, hydrazide and amide derivatives of cyclobutanecarboxylic acid have been examined for central nervous systems depressant properties, potentiation of barbiturate induced sleep, myorelaxant, antitremorine and anticonvulsant activity. The urea derivatives have central nervous system depressant qualities while the hydrazines and heterocyclic amides are either inactive or have central nervous system excitatory properties. N,N'-o-methoxybenzylidenebiscyclobutanecarboxamide and 1,3-dicyclo-butanecarbonyl-2-thiourea are myorelaxant; 1-cyclobutanecarbonyl-3-allylurea antagonizes Metrazol induced convulsions; 1,3-dicyclobutanecarbonyl-2-thiourea and N-cyclobutanecarbonyl morpholine antagonizes tremorine induced tremors.


Synthesis and pharmacological properties of derivatives of pyrrolo(3,4-d)pyrimidines and pyrrolo(3,4-b)pyridines (I). The synthesis of variously substituted pyrrolo[3,4-d]pyrimidines and pyrrolo[3,4-b]pyridines is reported. Some of the compounds act as reducers of the carrageenin edema in the rat and as inhibitors of prostaglandin biosynthesis in a microsomal preparation of bovine seminal vesicles.


[Synthesis of substituted 1-benzyl-1,2,3,4-tetrahydroisoquinolines]. Several derivatives of 1-benzyl-1,2,3,4-tetrahydroisoquinoline have been synthesized in order to evaluate their potential cardiovascular activities. These compounds, which can be related to Trimethoquinol and tetrahydropapaverin, showed no interesting activities in preliminary pharmacological screening.


Environmental and genetic factors affecting the response of laboratory animals to drugs. Only some of the diverse factors that can affect drug disposition and response in laboratory animals have been identified at the present time. These numerous factors contribute to large day-to-day variations that have become a major problem impeding investigation of drug disposition and response in laboratory animals. Although these variations render many experiments difficult to interpret and produce large discrepancies in the literature, few published investigations using laboratory animals provide sufficient details to permit replication of the studies under similar conditions with respect to these variables. Thus, the importance of these variables in affecting results is apparently insufficiently recognized at present. Two commonly overlooked variables affecting the activity of hepatic microsomal enzymes (HME) in rodents and hence the rate at which rodents eliminate from their bodies many foreign compounds are the bedding under the wire mesh cage and the relative cleanliness of the environment. Numerous chemicals present in relatively low concentrations in the environment of the animal room can significantly alter HME activity. Representative of these chemicals are aromatic hydrocarbons in cedarwood bedding, eucalyptol from aerosol sprays, and chlorinated hydrocarbon insecticides, each of which induces HME activity, whereas ammonia generated from feces and urine accumulated in unchanged pans under cages may inhibit HME activity. Chloroform, identified as an environmental contaminant of the water and air of certain cities, exhibits sex and strain differences with respect to toxicity (LD50) in mice. After intraperitoneal injection, twice as much chloroform accumulated in the kidneys of males from the sensitive strain (DBA/2J) as from the resistant (C57BL/6J) strain. First generation offspring were midway between parental strains both with respect to LD50 and renal accumulation of chloroform.


Environmental factors in drug metabolism. Although various kinds of environmental factors may alter the activity of cytochrome P-450 enzymes in liver micromes, their effects on the pharmacokinetics of drugs and other foreign compounds in living animals may not be as great as might be predicted from assays of these enzymes in vitro. Indeed, the effects will depend on the relative importance of excretory and metabolic mechanisms in the elimination of the drug, the relative importance of various metabolic reactions in different tissues, the extraction ratio of the drug by the liver, and in some instances on the route of administration of the drug. Moreover, the effect of the various environmental factors on the pharmacologic and the toxicologic actions of the drug will depend on whether these actions are caused by the parent foreign compounds or by one or more of their metabolites. It may also be important that the environmental factors may alter not only relative activiteis of the cytochrome P-450 in liver microsomes but also the activities of other drug-metabolizing enzymes and that the relative effects of the environmental factors of these enzymes may differ depending on the animal species or the animal strain. Indeed, a given factor may increase the pharmacologic effects of a drug metabolite in one animal species but decrease it in another. For these reasons, it frequently is not possible to predict the effects of environmental factors on drug action in living animals solely from in vitro rates of metabolism of model substrates.


Inherited progressive epilepsy of the dog with comparisons to Lafora's disease of man. A familial progressive form of epilepsy in the beagle dog is clinically characterized by intermittent seizures, often of grand mal type. If not properly treated, the seizures may lead to status epilepticus. The seizures are often elicited by external stimuli, especially a change in noise or light in the surroundings. Histologically, intracytoplasmic inclusions, 2-10 mum in diameter, occur in glial and neuronal cells in the brain, especially the thalamus. The inclusions are strongly positive for carbohydrate stains, weakly metachromatic, and lipid negative. They are spherical with a dense core and an often radiating, less dense periphery. Histologic changes in other organs include basophilic myocardial degeneration, degeneration and variation in diameter size of skeletal muscle fibers, and deposition of periodic acid-Schiff positive material in the cytoplasm of reticuloendothelial cells of the liver, spleen, and lymph nodes. Based on clinical and morphologic manifestations, the beagle disorder resembles Lafora's disease of man. This disorder will provide a useful model for comparative studies with progressive myoclonic epilepsy (Lafora's disease) of man and for defining the pathomechanisms of other forms of epilepsy.


Muscular dystrophy of mink: a new animal model. Muscular dystrophies comprise an important group of inherited disorders of man. Although the disease has been studied extensively, little is known about the underlying primary pathomechanisms. Consequently, treatment of patients is difficult and prognosis is poor. An animal model of muscular dystrophy is a useful research tool for approaching the basic problems of pathogenesis in muscle diseases. An inherited progressive muscular dystrophy of mink which resembles the amyotonic forms of human muscular dystrophy is currently under study. Clinically, the earliest sign is progressive muscular weakness and atrophy. Muscle enzyme activities in serum are usually elevated to pathologic levels. Urinary creatine/creatinine ratio is elevated. Pathologic changes are limited to skeletal muscle and are typical of those seen in amyotonic forms of human muscular dystrophy. These changes include variation in diameter size of muscle fibers, centralized nuclei, floccular and hyaline degeneration of scattered muscle fibers, increase in connective tissue in endomysial and perimysial areas, and regenerative attempts. Both type I and type II muscle fibers are involved in the disease process. Genetic studies indicate an autosomal recessive mode of inheritance. Although the primary defect in muscular dystrophy is traditionally thought to reside in skeletal muscle, recent studies have produced theories of primary involvement of other tissues and organ systems. These theories are presented and relationships to the traditional theory are discussed.


Dietary constituents altering the responses to chemical carcinogens. This paper deals with two categories of compounds having the capacity to inhibit the neoplastic effects of chemical carcinogens on the host. The first are inducers of increased microsomal mixed function oxidase activity. An increasing number of these inducers are being found in natural products. Cruciferous vegetables including brussels sprouts, cabbage, and cauliflower contain such compounds. Recently indole-3-acetonitrile, indole-3-carbinol and 3,3'-diindolylmethane have been identified as inducers in these three plants. Other naturally occurring inducers include flavones, safrole, isosafrole, beta-ionone, and oxidized sterols. Since previous work has shown that synthetic inducers may protect against chemical carcinogens, the composition of the diet could play a role in inhibiting the neoplastic response to these carcinogenic agents. The second category of inhibitors comprises the antioxidants. Several of these compounds have been found to inhibit the carcinogenic effects of a variety of chemical carcinogens. Considerable work of this nature has been done with butylated hydroxyanisole and butylated hydroxytoluene two antioxidants extensively used as food additives. Other antioxidants having carcinogen inhibiting capacities include ethoxyquin, disulfiram, and dimethyldithiocarbamate.


Short-term measurement of D-xylose uptake by isolated rat soleus muscle. The uptake of D-[U-14C]xylose by isolated rat soleus muscle was studied, using D-[1-3H]-sorbitol as an extracellular marker. Xylose uptake was limited by the diffusion of the sugar into and through the extracellular water. This could be overcome in part by allowing the test sugars to pre-equilibrate in the extracellular water at 0 degrees C, before measuring xylose uptake. It was not necessary to fill the extracellular water with the test sugars to obtain maximum rates of xylose uptake. From this it was concluded that the sugar carrier sites were located in a specific region on the plasma membrane, readily accessible to sugar carrier sites were located in a specific region on the plasma membrane, readily accessible to sugars entering the interstitial water. Pre-equilibration was more effective in the absence of insulin than in the presence of the hormone. This suggested that insulin may influence sugar uptake at some site prior to the cell membrane. Pre-incubation at 0 degrees C itself stimulated sugar transport. This effect of cooling was not influenced by insulin, nor did it appear to affect the stimulatory action of insulin on xylose transport.


Immunohistochemical localization of somatostatin in endocrine cells of the rat stomach. Using an immunohistochemical technique involving unlabeled antibody and the peroxidase-anti-peroxidase complex, we have localized somatostatin (or growth hormone-release inhibiting hormone), a hypothalamic hormone which can also inhibit gastrin secretion, in the rat stomach. Somatostatin was found to be present in a few cells in the mucosa of the pyloric antrum. These cells are characterized by the presence of secretory granules of about 150-250 nm in diameter and are probably endocrine cells.


[Serologic diagnosis of bovine and ovine brucellosis by a buffered antigen test]. In the first part the authors compare the results of the test effected by means of a buffered antigen (EAT) whose cellular concentration was about 10%, with those of slow seroagglutination (SAW) and complement fixation (FC). Like the complement fixation, the buffered antigen test is more specific than seroagglutination. On the other hand, with such an antigen concentration the test lacks sensitivity. In the second part the authors compare the results obtained by these three tests--but this time utilizing a buffered brucella antigen of cellular concentration of approximately 5%--on bovines and ovines whose infection had been determined bacteriologically. The authors have established, under these conditions, that the buffered brucella antigen test allows the screening of a greater number of infected animals than does the SAW or even the FC. Both for bovines as well as ovines, the agreement between SAW and EAT equals 89%; betueen FC and EAT it reaches 93%; in case of disagreement it is always the EAT which is positive.


[Lymphoblastic transformation by fractions of Brucella in patients having had brucellosis and subjects vaccinated by the vaccine PI]. Two fractions of brucella, examined elsewhere for their vaccinal properties (P.I. and 4A) have been used in lymphoblastic stimulation tests with lymphocytes of subjects infected by brucellosis and subjects vaccinated with P.I. This investigation attempted to show the importance of cellular immunity in brucellosis and to deduce a valid protection test. The two fractions do not possess non-specific mitogenic activity for human lymphocytes, but they stimulate specifically the sensitized lymphocytes. Subjects formerly or recently infected with brucellosis present constantly positive tests with sometimes a very high stimulation index. Vaccinated subjects have a lower stimulation index which is, however, significant in practically each case. The P.I. fraction gives the most constant results in the two categories of subjects; 4A appears to be much less active. The divergence between the protection rates conferred by 4A to animals and the weak activity of this same fraction in stimulation tests of human lymphocytes raises, on the one hand, the problem of the relation between protection and cellular immunity and, on the other hand, the utilization of animal models for the investigation of human vaccines.


A potency assay for brucella allergens in guinea pigs. In the development of a biological potency assay for brucella allergens by skin testing of guinea pigs, it was observed that the delayed hypersensitivity reactions to a given dose depended upon (1) the method of sensitization of the guinea pigs, (2) the time interval between sensitization and skin test and (3) the total of allergen given per animal. Data illustrating these factors are presented and a method for titrating allergens is recommended.


[A new allergen for the determination of ovine brucellosis]. The authors report on the experimental use of an allergen, prepared by a special method, for the detection of brucellosis in both infected and non-infected sheep. The best method is the intradermal injection into the eyelid of 0.5 ml and the best time for reading the reaction is between 48 and 72 hrs after inoculation. The allergen proved more sensitive than the serum-agglutination test on infected sheep, and extremely specific, since all tests on non-infected sheep were negative and induced neither agglutinin production nor allergic sensitization.


[Antigen therapy in chronic brucellosis]. The different forms of chronic brucellosis have been improved and well stabilized in the proportion of 75% by repeated injections of a vaccine consisting of suspensions of heat-killed B. melitensis. The vaccine should be used in a series of 8 subcutaneous injections, in increasing doses, at the rate of 2 injections a week. To obtain good results it is necessary to give an average of 3 to 4 series of injections, with a two months' interval between each series. After the 2nd series a distinct decrease of the patient's reactions to retarded hypersensitivity tests are generally observed. The most favourable results are obtained in cases of common subjective syndrome with physical and psychical asthenia.


Canine brucellosis: newer knowledge.

Canine brucellosis: newer knowledge. Canine brucellosis is a worldwide disease of dogs characterized prinicpally by abortions in females and epididymitis and infertility in males. It originally was observed in the USA, but recently it has been discovered in Japan, Mexico, Peru, Germany and, possibly, in Brazil. It affects dogs of all breeds and has been diagnosed in breeding kennels and in stray dogs. Several human cases have occurred, with 6 being accidental infections by laboratory personnel. B. canis, like B. ovis, is naturally mucoid, lacking "S" antigens. Serological tests therefore are not appropriate to classification. On the basis of manometric technics, B. canis is similar to B. suis; nevertheless the host range excludes swine. Agreement on its taxonomic status is not universal, although it has been provisionally accepted by the Subcommittee on Taxonomy of Brucella as a new species. A brief review of salient characteristics of B. canis was presented, however the principal discussion focused on recently observed aspects of the immunopathogenesis of male infertility and reported the development of a rapid slide agglutination test, using as antigen a concentrated and stained (Rose Bengal dye) suspension of B. ovis.


[Clinical and epizootiological aspects of bovine, caprine, and ovine brucellosis in Greece]. The author reports on an investigation, in Greece, of the clinical and epizootiological aspects of bovine, caprine and ovine brucellosis. These three types of brucellosis are found in the abortive and latent forms. The abortive form is revealed by contagious abortions whose frequency depends principally on the composition of the animal population of the farm; during its evolution, numerous very high positive serological reactions are observed. It involves many complications, causes heavy economic losses and is passed on to a great number of breeders. The latent form is accompanied by chronic manifestations, but passes unnoticed for the most part and is discovered only by serological tests during a period of suspect abortions of human cases of brucellosis. There are fewer of these cases then when the disease evolves in the region in the abortive form. The latent form contributes to the multiplication of centres of infection (1) when apparently uninfected female animals coming from farms contaminated with the latent form are introduced into healthy herds, (2) when the latent form changes into the abortive form after the introduction of healthy female animals into farms contaminated with this form. Furthermore, because of its inapparent evolution, it is a constant danger to rural populations. Bovine brucellosis has been observed in 16 of the 52 departments in the country, and caprine and ovine brucellosis in 21. The proportion of infection throughout the bovine, caprine and ovine herds of the 38 departments in which the investigation was made is approximately 4.70, 1.29, and 0.33 per thousand, respectively. The usual pathogenic agent of bovine brucellosis is Br. abortus; Br. abortus resistant to thionin is found less frequently and Br. melitensis only occasionally. The usual pathogenic agent of caprine and ovine brucellosis is Br. melitensis; Br. intermedia is less frequent and Br. abortus is found only rarely. Four Tables show the clinical investigation of 150 bovine abortions of brucellic origin and observations on the sanitary conditions of 22 cattle-sheds and herds infected with abortive or latent brucellosis. The author concludes in favour of the necessity of medical prophylactic measures and the strict application of sanitary prophylactic measures. In general, new animals should not be introduced into farms but when this is necessary the animal should not be considered free from brucellosis simply because of negative serological reactions. The best policy, in this case, is to repopulate entire farms negative to serological tests by seronegative animals coming also from entirely negative farms.


[Brucellic mammitis in sows].

[Brucellic mammitis in sows]. In a herd of pigs, 31% presented serological reactions positive or doubtful to brucellic infection; in 15% of the sows the mammary glands were swollen and purulent; the retromammary ganglions were enlarged and hemorrhagic. Bacteriological examination of the pus of mammary lesions showed the presence of Brucella suis, which confirmed the diagnosis of brucellic mammitis in the sows. The purulent discharge of the mammary lesions, diluted with physiological serum, agglutinated with the antibrucellic serum and this fact may constitute, together with other means of investigation, a method of rapid diagnosis.


[Bovine brucellosis in Morocco].

[Bovine brucellosis in Morocco]. A serological investigation was carried out during 1974 on the dairy cattle of Morocco. 20,000 serums from all the different provinces were controlled simultaneously by the slow sero-agglutination test and complement fixation. The centre of brucellic infection, which involves for the most part imported breeds, was found to be in the region of Casablanca (27%), Rabat, Salé, Fès and Meknes.


Recommendations for the description of species and biotypes of the genus Brucella. The properties of the genus Brucella are summarized and recommendations made for the definition of species and biotypes within the genus. In the first instance it is recommended that the classification of an organism as a member of the genus should be based on the following criteria: gramnegative coccobacillary morphology, a G + C content for the DNA of 56-58 moles %, a minimum of 90% homology with the DNA of reference strains in hybridization tests, disk electrophoretograms of acid-phenol soluble proteins of identical pattern to reference strains, a cytochrome C absorption spectrum with absorption maxima between 522-530 nm and 552-560 nm, extensive serological cross-reactions of intra-cellular antigens with those of reference strains. Supporting evidence is obtained from cultural, biochemical and pathogenic properties, although variations in these occur within the genus. Subdivision into species is dependent upon principal natural host, oxidative metabolic pattern and phage sensitivity. Classification into biotypes is dependent upon CO2 requirement, H2S production, dye sensitivity and reaction with monospecific antisera to A and M antigens. It is recommended that any organism proposed as a new member of the genus should have characters which approximate the ranges quoted. In all cases comparisons should be made with the established reference/neotype strains.


[Clinical and epidemiological aspects of bovine brucellosis in tropical Africa]. Bovine brucellosis, in the tropical regions of Africa, is very different, both clinically and epidermiologically, from that observed in temperate zones. From the clinical point of view, abortion is rare and extra-genital lesions (hygromas and abscesses) are frequent. From the epidemiological point of view, the rate of infection is low and the disease has very little tendency to spread. The reason for these differences may be explained by climatic conditions (temperature, insolation, humidity) as well as by breeding conditions (principally nomadic or transhumant breeding). Where climatic and breeding conditions resemble those of intensive breeding in temperate zones the clinical and epidemiological aspects tend towards similarity with the usual form of bovine brucellosis.


[Effect of temperature on preservation of brucella vaccines]. In the case of B.19 vaccine, the test of seven days conservation at 37 degrees C does not provide any indication of the long-term conservation of this type of vaccine. The variable results are difficult to interpret, except in extreme cases where the tested vaccine has deteriorated. If this test permits to disclose the deficiencies of lyophilization, it does not permit the stability of this strain to be foreseen. Heating for 30 days at 37 degrees C gives better results, without showing any satisfactory correlation with the duration of validity of the vaccine. Further trials need to be undertaken to try to establish a correlation between an accelerated ageing test and the duration of validity of B.19 vaccine.


[The place of the principal antibrucellic vaccines in prophylaxis]. This communication is intended to clarify the conditions and methods of the utilization in France of the antibrucellic vaccines in accordance with regulations covering the prevention of brucellosis in animals. It should be noted that it is only within the framework of the prophylaxis of bovine brucellosis that the problem of the utilization of these vaccines will be investigated. Since the objective is the complete eradication of the disease, measure taken within the framework of the regulations are essentially aimed at eliminating contaminated animals; these are for the most part sanitary measures. However, this type of prophylaxis cannot yet be undertaken simply by the application of the regulations because of the lack of financial support accorded by the State. For this reason, as well as because the high rate of infection in certain regions would make the application of these measures very difficult for the farmers, it seemed necessary to utilize vaccines to ensure protection and to attain, in a preparatory phase, a decrease in the rate of infection.


[Control and eradication of ovine and caprine brucellosis in Italy]. The prevention of ovine and caprine brucellosis in Italy is carried out in accordance with Regulation No 33 of 23 January 1968 and with Government Decree of 4 June 1968. The Regulation also provides in addition to sanitary measures, the vaccination of all livestock aged from 3 to 7 months with strain Rev. 1 of Br. melitensis. From the last trimester of 1968 until the end of 1974 3489514 young animals were vaccinated, which corresponds approximately to 50% of the animals today in the zones where the "revisation" was undertaken. An important decrease in the number of abortions was observed, with many epizootical advantages. During the same period a considerable decrease in human cases of brucellosis was observed; from the 19300 cases announced from 1965 to 1968 (yearly average: 4825) the figure fell to 18988 cases for the period 1969-1974 (yearly average: 3164).


[Preparation and testing of different antibrucellic vaccines]. From a highly virulent Brucella melitensis strain of human origin, different vaccines of good antigenic quality are obtained, ranging from the very agglutinogenic oily type vaccine to the totally non-agglutinogenic oily type vaccine. The non-agglutinogenic vaccine is obtained by an original method consisting of submission of the original brucella to several subcultures in the presence of a small quantity of antiserum and clonal selection of a population. The strain finally selected is totally non-agglutinogenic and its biochemical characteristics are hardly different from those of the original strain; it conserves good antigenicity and compares favourably with the other non-agglutinogenic vaccines tested.


Properties of some new Brucella phage isolates; evidence for lysogeny within the genus. A number of phages were isolated from Brucella abortus strains showing atypical phage sensitivity patterns. The phages, designated the Firenze group, were all similar in morphology, host range general properties. They were lytic for smooth Brucella abortus, Br. neotomae and Br. suis, but not for Br. melitensis strains. They were serologically distinct from phages of the Tbilisi and M51-S708-Weybridge groups and also differed from these in plaque morphology and physical and chemical stability. The parent brucella strains although smooth were resistant to lysis by their own phages or by the other available brucella phages. Their general properties suggested a lysogenic state.


[Identification of Brucella of human origin, isolated in France]. 28 strains of human origin, isolated in France, have been examined by the methods recommended by the International Committee on Nomenclature, Sub-Committee on Taxonomy of the genus Brucella including oxidative metabolism and phage typing. Their characteristics correspond to those which allow to define B. melitensis (22 strains) and B. abortus (6 strains). The B. melitensis strains are divided as follows: 11 belong to biotype 1, 6 to biotype 2 and 5 to biotype 3. Among the 6 strains of B. abortus, 4 belong to biotype 1, one to biotype 2 and one to biotype 3. For these two species of brucella, the oxydative spectre established in relation to 12 substrates may be represented graphically by a metabolic profile peculiar to the bacterial species and not to its biotype nor to the nature of the human or animal reservoir.


Studies of Brucella lipopolysaccharide.

Studies of Brucella lipopolysaccharide. Brucella endotoxin differs from other gramnegative endotoxins in that it is recovered in the phenol phase rather than the aqueous phase of the Westphal hot phenol water procedure. This was the first described from this laboratory by Redfearn (1960) with phenol-killed smooth B. abortus and B. melitensis and has since been confirmed by others. Preliminary extraction of brucella cells with acetone, as called for in the original Westphal procedure, was followed by Renoux et al. (1973) who reported that the aqueous phase lacked endotoxic activity and the phenol phase had very low toxicity. In order to test the hypothesis that prior acetone extraction removes lipid A, we have repeated the Redfearn procedure with acetone extracted cells and have confirmed that the major portion of the endotoxic activity resides in the phenol phase. Acetone treatment does not remove the lipid A believed to be responsible for mouse lethality as well as necrotizing activity in guinea pig and rabbit skin. Preparations of brucella endotoxin (lipopolysaccharide) contain varying amounts of polypeptide some of which is tightly bound. The dermal response of sensitized guinea pigs to brucella LPS was shown to be a combination of reactions comprising those due to (1) innate toxicity of lipid A, (2) antibody mediated reactions due to polysaccharide portion of the molecule and (3) delayed hypersensitivity due to polypeptide portion of the molecule.


[Structure and constituents of Brucella. Characterization and biological properties of the fractions]. The analysis of the components of a bacterium may be envisaged from the biological aspect (fractionation), the ultrastructural aspect (staining of the structures examined electron-microscopically), and the biological aspect (measure of an activity). In this report we attempt to examine the components of brucella from all three aspects simultaneously. The brucella envelopes have the same ultrastructure as that of gramnegative bacteria: outer membrane, thick stratum or peptidoglycane, periplasmic space, cytoplasmic membrane. The outer membrane of brucella in phase S contains many types of polysaccharides: (1) the lipopolysaccharide (LPS) (S) and polysaccharide B are solubilized by the phenol-uater and ether-water methods, by trichloracetic acid (TCA), by heated sodium dodecyl-sulfate (SDS). The exact localization of polysaccharide B is not known; by the phenol-water extraction method, the LPS (S) in its toxic form (endotoxin) passes in solution into the phenol phase, unlike the endotoxin of enterobacteria, which passes into the aqueous phase. In addition to its toxicity, this LPS (S) is responsible for reactions of immediate hypersensitivity as well as serological reactions towards the standard antigen. It presents A + M antigenic sites; (2) one or more of the polysaccharides remains unsolubilized by the ether-water method, but solubilized by heated SDS; (3) a polysaccharide is linked to peptidoglycane. The structure of the outer membrane of the brucella in phase R is analogous to that of LPS, carrying antigen R, characteristic of these strains. This antigen may be utilized for the serological diagnosis of infections due to brucella R (B. ovis) or vaccinations by a vaccine in phase R. The peptidoglycane fraction extracted by the heated SDS has a more complex structure than that of E. coli: it consists of a supplementary outer layer containing amino acids and polysaccharides. This fraction has a vaccinal activity. A soluble protein fraction, without organized structure, no doubt of cytoplasmic origin, may be extracted by a cold saline solution. This fraction, known as "brucelline", reveals delayed hypersensitivity when injected intradermally. The biological activity of the other structures (periplasm, cytoplasmic membrane, ribosomes...) is not known. Biological activities have been attributed to fractions, but since these are badly defined from the structural point of view it is difficult to determine the connection between activities and structures.


Brucellosis as a world problem.

Brucellosis as a world problem. Brucellosis is one of the most widespread and economically the most ravaging of zoonoses. The occurrence of the acute, often incapacitating infection in man caused by Brucella melitensis usually coincides with occurrence of the infection in sheep and goats. Well-known foci of this infection have been identified in the Mediterranean basin, Central Asia and Latin America. Recent investigations in parts of Africa and India have shown that the infection is much more widespread than was previously suspected and that more foci remain to be discovered by the application of laboratory methods in epidemiological investigations. Bovine infection has a wider distribution and is more important than infection of sheep and goats as far as economic losses are concerned. Although the infection has been reduced by control measures to a low level of incidence in some countries of Europe and North America, its incidence in other parts of the world has actually increased because of emphasis on increased animal production and aggregation under poor hygienic conditions. This is particularly the case with dairy production units which have developed around rapidly growing urban centres in many developing countries. Although human infection with B. abortus may be mild, it can cause troublesome and intractable illness. The economic ravages of bovine brucellosis are tremendous and the losses in Latin America and the USA alone have been estimated by their respective governments to be 700 million dollars annually. The world figure must be truly staggering. Swine brucellosis is largely a problem of the Americas although a few foci have recently been discovered in other parts of the world, notably in Europe and Southern Asia. In the Americas, swine infection is second only to bovine brucellosis in its economic importance. A large number of human cases of B. suis infection are detected every year in the endemic areas. Other forms of brucellosis, e.g. B. canis in dogs and B. suis, biotype 4 in reindeer, have a limited distribution and are responsible for only sporadic human infections. B. ovis of sheep is more widespread but is generally confined to sheep. Annexes 1 and 2 show the reported incidence of brucellosis in man and animals. However, the officially reported data are generally incomplete and the actual incidence must in most cases be much higher than is shown in these tables. FAO and WHO have been assisting countries in which brucellosis is endemic by organizing control measures, providing training and reference materials, and by focusing coordinated research on problems which arise in these programmes. Some of the highlights of this work are outlined in the following paragraphs.


[Chemical fractionation of Brucella melitensis and the immunizing properties of a new fraction]. A complex phenol-insoluble fraction (fraction P.I.) extracted from Brucella melitensis presents immunizing properties already described by the authors. This fraction contains peptidoglycane whose immuno-adjuvant properties are known in numerous bacterial species. More precise fractionation was carried out to determine if the properties observed after injection of P.I. are in fact specific or on the contrary due to peptidoglycane action. By chemical and enzymatic treatments, 90% of the P.I. are eliminated, leaving a 4A fraction having the same properties as P.I. and having the advantage of providing better protection. This protection specific to genus Brucella and slow in appearing, is not due to peptidoglycane. The 4A fraction consists essentially of peptidoglycane linked covalently with a lipoprotein and proteins of weak molecular weight. All attempts at more precise fractionation have until now led to the loss of biological activity.


Quinidine hypersensitivity and liver involvement. A survey of 32 patients. Thirty-two of 487 patients who received quinidine between the years of 1970 and 1974 in the departments of medicine at Hadassah University Hospital developed hypersensitivity reactions. Ten of the 32 patients had clinical and biochemical manifestations of liver invlovement. In 4 patients liver biopsy showed granulomatous hepatitis. It is therefore concluded that quinidine-induced hepatitis is a relatively common side effect of this drug.


Abnormalities of chemical tests for copper metabolism in chronic active liver disease: differentiation from Wilson's disease. Because identical clinical findings, alterations of hepatic function, and changes in hepatic morphology can occur in Wilson's disease (WD) and chronic active liver disease (CALD), chemical tests that reflect copper metabolism are important in the differential diagnosis of these conditions. The authors therefore measured 24-hr urinary copper excretion, hepatic copper concentration, and serum ceruloplasmin concentration in 54 patients with CALD. Twenty-four hour urinary copper excretion was increased in about 50% of patients, was significantly higher during active disease compared to remission, and was in the WD range in approximately 10% of patients. Hepatic copper concentration was also increased in the majority of patients, generally during active disease, and it sometimes overlapped with values reported in WD. By contrast, serum ceruloplasmin levels were elevated in nearly one-half the Cald patients and were never below normal. It is concluded that the chemical tests routinely used to assess copper metabolism in WD are frequently abnormal in CALD. Because the serum ceruloplasmin concentration never fell in the WD range and often was elevated, it is the most reliable routine chemical screening test to differentiate between CALD and WD.


Esophageal motor dysfunction in idiopathic intestinal pseudoobstruction. Five patients with idiopathic intestinal pseudoobstruction were studied with esophageal manometry and all had abnormalities of esophageal motility. In 2, primary peristalsis was replaced by simultaneous contractions and repetitive spontaneous activity was marked. The lower esophageal sphincter failed to relax and the Mecholyl test was positive in both. In the other 3, primary peristalsis was absent, low amplitude simultaneous waves followed swallows, no spontaneous activity was present, and defects in lower esophageal sphincter relaxation were found in two. The Mecholyl test was negative in the one patient tested. The esophagus appears to be abnormal in idiopathic intestinal pseudoobstruction and could prove useful as an organ for diagnostic study in patients who may have this syndrome.


Inhibition of gastric acid secretion in man by exogenous and endogenous pancreatic glucagon. The interaction of intravenously infused glucagon and pentagastrin on gastric acid secretion was studied in 5 healthy subjects. First a step dose-response study with pentagastrin in doses of 0.01, 0.1,1.0, and 10.0 mug per kg-hr was performed. The dose required for one-half maximal response (D50) was 130 ng per kg-hr. With this dose of pentagastrin as background stimulation a step dose-response study with glucagon in doses of 0.5, 2.0, 8.0, and 16.0 mug per kg-hr was performed. The dose of glucagon required for one-half maximal inhibition was 1.64 mug per kg-hr. In a third experiment the dose-response study with pentagastrin was repeated on a background infusion of glucagon in the dose found to be D50. A significant inhibition of acid secretion was found on all dose levels. The inhibition followed noncompetitive kinetics. Plasma concentrations of pancreatic glucagon in 4 of the 5 subjects in this experiment were comparable concentrations seen after a protein meal. Intravenous infusion of l-arginine on a background stimulation of acid secretion with synthetic human gastrin I in a dose of 250 ng per kg-hr was performed in 7 healthy subjects. Arginine increased serum glucagon concentration to levels seen after a meal and resulted in a significant inhibition of acid secretion. The results favor the hypothesis that pancreatic glucagon may participate in the physiological inhibition of gastric acid secretion.


Pancreatic, gallbladder, and gastric responses to intraduodenal calcium perfusion in man. To determine the effect of intraduodenal calcium on pancreatic, gallbladder, and gastric functions in healthy man, a validated perfusion method was employed to quantify total pancreatic, biliary, and gastric outputs during duodenal perfusion of either 6 mM, 12 mM,or 25 mM of elemental calcium (as isotonic calcium chloride solutions). Intraluminal calcium stimulated pancreatic enzyme secretion and gallbladder contraction in a dose-related fashion, achieving comparable responses to those produced by intravenous cholecystokinin-pancreozymin (CCK-z). Responses to calcium were reproducible when repeated in the same individual. Gastric acid outputs and serum gastrin levels increased significantly only with higher calcium perfusions (25 mM). Although duodenal calcium perfusion (25 mM) slightly increased serum calcium concentrations, induced hypercalcemia (by intravenous calcium infusion) of similar magnitude had no effect on pancreatic or gallbladder function. It is suggested that intraduodenal calcium may induce release of CCK-PZ (and/or other neurohormonal factors) from the gut, causing stimulation of these digestive organs.


Free intrinsic factor in the small intestine in man. Human jejunal and ileal contents and ileostomy effluents were examined for the presence of free intrinsic factor. This was detected in 9 out of 10 jejunal and three out of five ileal aspirates and in one of three ileostomy effluents studied. The intrinsic factor in the ileal effluent was shown to be physiologically active. The presence of free intrinsic factor in the small intestine has considerable physiological significance in maintaining the enterophepatic circulation of vitamin B12. It would also permit the absorption of any free vitamin B12 produced by ileal bacteria.


Ileal crypt cell population kinetics after 40% small bowel resection. Autoradiographic studies in the rat. Ileal crypt cell population kinetics were investigated by autoradiography with tritiated thymidine in rats 60 days after resection of a jejunal segment equivalent to 40% of the length of the small bowel. Controls were subjected to transection and anastomosis. The mean total number of cells and the mean number of labeled cells per crypt cell column were estimated. The distribution of proliferating cells was obtained by determining the percentage of labeled cells at each cell position in the crypt cell columns. The cell cycle was analyzed by the method of percentage-labeled metaphases. The mean total number of cells was increased from 30.5 to 36.6 (P less than 0.002) and the mean number of labeled cells per crypt cell column was increased from 10.2 to 12.4 (P less than 0.001). Labeling index was unaltered. The mean sizes of the proliferative and maturation zones were increased (P less than 0.002). The estimated median duration of the cell cycle was 11.5 hr in the control group and 10.5 hr in the resection group. The duration of DNA synthesis was 6.4 hr in both groups. It is concluded that 40% small bowel resection increases cell renewal by expanding the size of the proliferative zone of the crypt cell population.


Acute hemorrhagic pancreatic necrosis in mice. Intraparenchymal activation of zymogens, and other enzyme changes in pancreas and serum. A new experimental model has been found whereby acute hemorrhagic pancreatic necrosis with fat necrosis is induced in 100% of young female mice fed a choline-deficient diet supplemented with 0.5% DL-ethioine. The onset of the pancreatic necrosis has been shown to follow accumulation, and subsequent activation, of pancreatic zymogens with intraparenchymal formation of significant amounts of elastase, chymotrypsin, and trypsin. Evidence was obtained that the proteolytic enzymes are released also in the circulation and cause a significant drop in the content of the serum protease inhibition alpha 1-antitrypsin and alpha2-macroglobulin. Increased levels of plasma amylase were found to accompany the onset of the pancreatic necrosis.


Effect of hypophysectomy and growth hormone on serum and antral gastrin levels in the rat. The effects of hypophysectomy and subsequent replacement therapy with growth hormone on serum and antral gastrin levels was investigated in both fasted and nonfasted pair-fed rats. Hypophysectomy caused a 57% decrease in serum and 47% decrease in antral gastrin content in 18-hr fasted animals. In nonfasted animals, hypophysectomy resulted in a 42% fall in serum gastrin and a 76% fall in antral gastrin. Animals were given injections of growth hormone over a 10-day period, then fasted 16 to 18 hr before being killed. Doses of 100 to 200 mug per 100 g of body weight were ineffective, but a dose of 500 mug per 100 g was sufficient to restore completely serum gastrin levels to intact control values. In nofasted rats this same dose raised serum gastrin to intact levels and increased antral gastrin significantly over hypophysectomized levels, but did not increase it to control values. When given to pair-fed intact animals, growth hormone caused slight but not significant elevations in serum and antral gastrin. The effect of growth hormone on gastrin secretion and /or synthesis may be a significant physiological factor in the regulation of normal gastrointestinal function and growth.


Stimulation of gastric acid secretion in the dog by the C-terminal penta-, tetra-, and tripeptides of gastrin and their O-methyl esters. Acid secretion from the vagally innervated gastric fistula of conscious dogs was stimulated in a dose-related manner by the C-terminal penta-, tetra-, and tripetide amides of gastrin, the o-methyl esters of the tetra- and tripeptides, and the sulfone derivative of the tetrapeptide amide. The potency and efficacy of Peptavalon and the C-terminal penta- and tetrapeptide amides were about the same on a weight or molar basis. On a molar basis, the pentapeptide amide was about 4300 times as potent as the tripeptide amide. The o-methyl ester and the sulfone derivative of the tetrapeptide were about equipotent; they were, respectively, one-twenty-fifth and one-thirtieth as potent as the tetrapeptide amide. The dipetide amides did not stimulate acid secretion in a dose range of 50 to 1500 mug per kg-hr. The results indicate that (1) the C-terminal tetrapeptide amide cannot be the minimal effective "stump" for biological activity in the gastrin molecule, (2) the C-terminal amide is important but not essential for gastric stimulating power, and (3) oxidation of the sulfur atom of the methionyl residue in the tetrapeptide does not result in total loss of activity.


Effect of growth hormone release-inhibiting hormone on gastric secretion, mucosal blood flow, and serum gastrin. In dogs with gastric fistulae and Heidenhain pouches (HP) growth hormone release-inhibiting hormone (GH-RIH) infused intravenously in a dose of 2.5 mug per kg per hr inhibited almost completely acid and pepsin responses to pentagastrin, Urecholine, and a peptone. Histamine-induced acid secretion was more resistant to the inhibition by GH-RIH, and only acid secretion evoked by the lower doses of histamine was suppressed by this peptide. The inhibition of pentagastrin-induced gastric secretion was associated with a marked reduction in mucosal blood flow. The ratio of aminopyrine concentration in the gastric juice and blood plasma was not significantly changed by GH-RIH, indicating that the reduction in mucosal blood flow was secondary to an inhibition of gastric secretion. Gastric acid and serum gastrin responses to a peptone meal adjusted to pH 5.0 and kept in the main stomach at this same pH by intragastric titration were significantly decreased by GH-RIH, indicating that the observed acid inhibition could be attributed at least in part to the suppression of gastrin release. GH-RIH inhibited acid secretion from HP stimulated by liver extract in HP. The finding that GH-RIH inhibits gastric secretion induced by exogenous stimulants as well as by the direct chemical stimulation of the HP mucosa without changing serum gastrin level suggests that the major action of GH-RIH is a direct suppression of the oxyntic glands.


Cholinergic release of gastrin by feeding in cats. The effect of atropine on acid secretion and serum gastrin level after feeding was studied in 8 cats with denervated fundic pouches (Heidenhain pouch, HP). Serum gastrin concentration was measured by radioimmunoassay. In the control experiments, the mean peak acid response occurred 45 min after feeding and the mean peak gastrin concentration 15 min after feeding. After the 1st postprandial hr, acid secretion declined but the gastrin level remained elevated. Atropine, 0.1 mg per kg intravenously 5 min before feeding, depressed both acid secretion and the increase in serum gastrin concentration during the 1st postprandial hr. In both the control and atropine experiments, acid secretion and serum gastrin level were correlated significantly during the 1st postprandial hr, but no correlation was found later in the experiments. The reduction by atropine of the acid and serum gastrin responses varied among the cats but were correlated significantly. It is concluded that a cholinergic mechanism is implicated in the release of gastrin by feeding in cats during the 1st postprandial hr. Atropine reduces the HP acid response to feeding at least in part by depressing the release of gastrin.


Prevention of secretagogue-induced ulcers in the rat. An inhibitor of gastric secretion, Pfizer UK -9040, a derivative of the antihistamine triprolidine, was given orally 50 to 100 mg per kg 1 hr before and at various times during a 24-hr subcutanwous infusion of ulcerogenic secretagogues. The higher the dose and the more frequent the dosage, the lower was the incidence, severity, number, and perforations of duodenal ulcers. The mechanisms by which UK -9040 prevents these ulcers is probably inhibition of gastric secretion.


Intestinal propulsion in the dog. Its relation to food intake and the migratory myoelectric complex. We studied electrical events and flow in the canine small intestine in vivo. The transit of a small radioactive bolus injected into the jejunum was monitored by counting from a Biebl loop. After feeding, the rate of propulsion of the bolus varied within a narrow range. When food and water were withheld for more than 12 hr, transit of the bolus hecame highly variable. The variability increased at about the same time as the onset of the migratory myoelectric complex associated with fasting. Electrical recordings from the intestinal muscle demonstrated that the bolus was propelled into the loop in advance of the band of intense spike potentials which travels along the small intestine in the fasted state. The bolus was cleared from the loop when the spike potentials reached this segment. Variability of transit after prolonged fasting can be explained by (1) variability in the rate of migration of the phase of intense spike potentials, and (2) the timing of the injection of the bolus in relation to the component phases of the electrical complex. Flow is highly dependent upon the electrical activity and the resulting contraction patterns of the small intestine, which are themselves dependent upon feeding.


Inflammatory bowel disease in all three members of one family. The occurrence of inflammatory bowel disease in all three members of one family is described. Studies of white blood cell chromosomes, histocompatibility antigens, and cellular and humoral immunity failed to explain this unusual phenomenon. However, the appearance of inflammatory bowel disease in an entire family reemphasizes the potential role of genetic and environmental influences in the pathogenesis of some cases of ulcerative colitis and Crohn's disease.


Bilirubin secretion and conjujation in the Crigler-Najjar syndrome type II. Features characteristic of the Crigler-Najjar syndrome (type II) are described in an adolescent boy with severe congenital unconjugated hyperbilirubinemia. Bilirubin encephalopathy developed only in early puberty after surgery and fasting, coincident with a dramatic rise in serum bilirubin, which responded to intensive therapy. Fasting was later shown to increase markedly the serum bilirubin levels and probably was a major factor in precipitating the initial acute event. One year later, while the patient was in a metabolic steady state, the secretion rate of bilirubin was measured by aduodenal marker-perfusion technique, and the nature of the secreted bilirubin conjugates was characterized. Total bilirubin secretion rates were low, 4.39 mg per hr and 4.44 mg per hr on two separate studies. The major pigment detected in bile was bilirubin monoglucuronide. Bilirubin diglucuronide comprised only a minor fraction of the pigments, and other conjugates were not detected. The present study documents a reduced biliary bilirubin secretion and suggests that the addition of the second glucuronic acid moiety to the bilirubin molecule may be defective in Crigler-Najjar syndrome (type II).


Fulminant hepatitis and lymphocyte sensitization due to propylthiouracil. Fulminant hepatic failure developed in a 24-year-old black woman who had been treated with propylthiouracil and propranolol for hyperthyroidism. Clinical and biochemical recovery followed discontinuation of drug therapy. Liver biopsy disclosed submassive hepatic necrosis. During the acute phase of the disease, lymphocyte transformation  studies revealed sensitization of the patient's lymphocytes to propylthiouracil but not to propranolol. Sensitization remained demonstrable 2 months after cessation of the former drug. Lymphocytes obtained from a hyperthyroid patient treated with propylthiouracil without complications failed to show evidence of sensitization. These observations indicate that submassive hepatic necrosis may result from treatment with propylthiouracil and are consistent with the notion that sensitization mechanisms may be responsible for the hepatic injury induced by this drug.


Adenocarcinoma in biliary papillomatosis. A patient with multicentric biliary papillomatosis associated with invasive adenocarcinoma of the bile duct is reported. This case documents the progression to malignancy of a lesion generally thought to be benign. It serves to alert clinicians to a rare but important cause of recurrent biliary obstruction. The literature on this entity is reviewed.


The mechanism of action of gastrin on the lower esophageal sphincter. Gastrin I or pentagastrin caused contraction of the lowe esophageal sphincter in anesthetized oppossums. The contraction was not modified, either qualitatively or quantitatively, by 30 or 1000 mug per kg atropine pretreatment. Moreover, neural block with tetrodotoxin did not influence the effect of gastrin on the sphincter pressure. H2 receptor antagonist, metiamide, did not modify the magnitude of the contractile response of the lower esophageal sphincter to gastrin I. These studies show: a) gastrin does not cause sphincter contraction by stimulating cholinergic neurons: and b) gastrin does not exert an inhibitory effect on the sponcter pressure by stimulating H2 receptors. We suggest that gastrin may contract the lower esophageal sphincter by a direct action on the sphincter muscle.


[Operative procedures for male sterilization (author's transl)]. The sterilization of the male by vasectomy receives increasing acceptance in this country as part of family planning in general. Current laws and bylaws are lacking. The present procedures, indications and methods for vasectomy for fertility are described and discussed. This type of vasectomy differs in some points from vasectomy for other therapeutic indications. Noticeable complications, especially immunologic complications were not observed and were not detectable by immunologic testing of 23 men. Since all attempts to achieve a temporary occlusion of the vas have failed, vasectomy for the control of fertility is irreversible, in the majority of the cases. It is therefore advisable to deposit semen in sperm banks in these cases. The success rate of re-anastomosis of the vas to the vas or the vas to the epididimus varies between 10 and 30%.


[Does oral contraception cause cancer? (author's transl)]. A complete answer to the question of the relationship between malignant tumors in man and the administration of contraceptive steroids is at present not possible. Difficulties of the investigation are caused by the multiplicity of compounds used for contraception, the generally slow development of malignant tumors and the difficulty of the epidemiologic and statistical investigations on the multi-factorial etiology of cancer. Nevertheless, it can be stated with a high degree of certainty that "cancer due to the pill" does not exist in man and that a direct hormonal induction of malignant tumors in  man cannot be proved. The question whether oral contraceptives may favor the development of cancer indirectly is explored in this paper regarding cancer of the female genital tract and the breast. No correlation between oral contraception and squamous cell carcinomas of the vulva and vagina and tumors of the ovary is known. As yet no statistics are available on the incidence of carcinoma of the endometrium in women who took oral contraceptives during their reproductive life span. Because of the direct hormonal suppression of the endometrial growth by oral contraception, a protective effect against endometrial hyperplasia and endometrial cancer must be expected. For cancer of the female breast no protective and no enhancing cancer risk due to progestational agents can be postulated. The known fragmentary data suggest a more protective value. Regarding dysplasia and carcinoma in situ of the uterine cervix large investigations in high numbers of patients are available. An increase of the risk to develop cancer of the cervix by using oral contraception cannot be shown with sufficient accuracy at our present state of knowledge by statistical means. Some observations suggest that oral contraception increases the relevant exogenous factors for carcinogenesis of the uterine cervix such as sexual behavior and hygiene.


[Advantages and disadvantages of deliveries after induction of labour by convenience (author's transl)]. The development of 601 deliveries after induction of labour by convenience, 92 births after induced labour following pregnancies at risk and 1829 births after spontaneous onset of labour were examined and compared. The data were recorded retrospectively and submitted to an electronic data processing. Patients with whom the labour was induced had the shortest birth times, the difference amounted on average to 2 hours. In the comparison collective with spontaneous setting in of labour a hypotonic uterus motility was found to be the most frequent pathological labour activity. Pathological pattern of heart frequency, especially late decelerations were most frequently registered with fetuses of the risk group. The frequency of the operative deliveries amounted to 13% in the case of the collective of the induced labour, 35,9% in the case of patients in the risk group, and 10% in the case of the comparison collective. Threatening fetal asphyxia and protracted extrusion period were in the case of primiparas after induced labour equally often the indication for a vaginal-operative delivery, whereas with the comparison collective, in the risk group and also with multiparas after induced labour, the threatening fetal asphyxia was primarily for the carrying out of a forceps delivery or a vacuum extraction. Concerning the birth weight and size the new-borns of the collectives examined showed no significant differences. The best Apgar-score was achieved by the new-born induced labour babies. Only 0,5% of these babies showed pronounced signs of placental dysfunction, in the risk group 9,6%, and in the comparison collective 1,6% of the babies were born with a pronounced Clifford-syndrome. Induced labour babies did not need any pediatric treatment. There were no perinatal deaths. In the case of comparison collective, long term pediatric treatment was necessary for 8 babies, 1 baby died subpartual, another one in the pediatric clinic, that means a perinatal mortality of 0,1%. In the risk group 3 babies needed pediatric treatment, 1 baby died of the consequences of a serious erythroblastosis, the perinatal mortality amounted to 1,1%. In a critical evaluation of the without exception favourable obstetrical results after induced labour, the technical, personal and organisational efforts should not be overlooked. This stands in the way of a widespread use of the process in the near future. The results hitherto permit the temporary inference that 1) psychologically positive prerequisites for the birth are created if the pregnant woman knows a firm date for the delivery, 2) the whole partus can be continuously supervised and the maternal and infantile emergencies prevented in good time and 3) through the calculability of risks during pregnancy and birth, perinatal mortality and morbidity can be reduced considerably.


[Progress and change in geriatric gynecological surgery (author's transl)]. Two periods of geriatric gynecological surgery (1947-1959 and 1960-1972) at the University Women's Hospital in Hamburg-Eppendorf were compared in regard to the age of the patient, surgical indications, surgical procedure, anesthetic technique, preoperative and postoperative morbidity, length of hospitalization and mortality rate. During a period of 26 years, 1514 women over the age of 60 were treated surgically. During the first period, 489 women were treated, and in the second period, 1,025. This 109.6% increase has been confirmed statistically. The increase in geriatric surgical cases stems basically from the increase in the number of surgical patients over the age of 70. The increase in breast carcinoma during the second period (from 43 to 348 operations) is most conspicuous. This is an increase of 809.3%. On the basis of this disproportionately large increase in breast surgery, more women were treated surgically in the University Women's Hospital in Hamburg-Eppendorf for breast carcinoma during the second period, than for carcinoma of the reproductive organs. Vulva carcinoma and craurosis vulvae were also more frequently considered to be an indication for surgical treatment. The total number of women who were surgically treated for prolapsed uterus and vagina remained more or less constant. In the analyzing the surgical records, it should be emphasized that, in the second observation period, two-thirds of these cases were treated by performing a vaginal hysterectomy with anterior and posterior vaginoplasty. For older patients, palliative surgical measures for prolapsed uterus and vagina were abandoned in favor of more definitive methods. The postoperative morbidity and mortality rate remained more or less constant for both periods. The postoperative period of hospitalization was slightly longer while the preoperative period was slightly shorter. The statistically confirmed increase in geriatric surgery during the last 13 years at the University Women's Hospital in Hamburg-Eppendorf clearly shows how important geriatric surgery has become. The immediate consequences are an increased workload for physicians, nursing staff and physical therapists.


[Frequency of obstetrical operations and perinatal mortality before and after admission of continuous fetal monitoring (author's transl)]. Two groups of obstetrical patients were statistically analyzed with a computer. The first group A (2339 deliveries, January 1967-June 1968) was controlled by conservative obstetrical methods, the second group B (2512 deliveries, January 1973-June 1974) was controlled by continuous monitoring of fetal heart rate and by analysis of fetal blood during labour. The results of the statistical analysis can be summarized: 1. The frequency of obstetrical operations (vacuum, obstetrical forceps, Caesarean section) increases from 12.8% (group A) to 22.5% (group B). 2. The percentage of Caesarean sections decided on for the sake of the child rose from 45.7% (group A) to 54.7% (group B). 3. Vital indications fell due to increasingly preventive obstetrics from 54.3% to 45.3%. 4. The frequency of Caesarean sections rose due to increasing indication "absolute or relative pelvic disproportion" of the mediterranean patients. 5. However the analysis of fetal blood during labour and the continuous monitoring of fetal heart rate has prevented a further increase of Caesarean sections. 6. The increasing percentage of obstetric forceps was due to our intention of preventing prolonged labour. 7. Maternal mortality after operative delivery reached 0.04% in group A and 0% in group B. 8. Perinatal mortality of children, delivered by operation, has decreased from 3.0% (group A) to 0,7% (group B). 9. The Apgar scores after operative deliveries were much better in group B (continuous fetal monitoring) than in group A (without fetal monitoring).


[The monitoring of high risk pregnancies by determination of the estriol-16-glucoronide excretion. I. Methods and normal values (author's transl)]. A thin layer chromatographic method for the specific determination of estriol-16-glucoronide as azo dye is described. With this simple method the estriol excretion during pregnancy can be determined with omission of several steps in the determination such as the hydrolysis or evaporation of solvents. A single determination including the thin layer chromatography takes approximately 40 minutes. Based on 210 single determinations from the urine of pregnant women the normal range of excretion between the 28-42 week of pregnancy is determined. The mean excretion rises from 10.8 mg/24 hours at 28 weeks gestation to 25.8 mg/24 hours at 41 weeks gestation. The excretion of estriol-16-glucoronide is a measure of the estriol synthesis in the fetal-placental unit.


[Hypersensitivity reaction associated with the use of Dextran 70 (Hiscon) in Hysteroscopy (author's transl)]. A hypersensitivity reaction to Dextran 70 during hysteroscopy for removal of an implanted Dalkon Shield is reported. The patient had not been exposed to Dextran previously and the hypersensitivity reaction was controlled by the administration of Benadryl, Solu-cortef and Phenergan. Since Dextran 70 is especially useful for hysteroscopy when bleeding is anticipated the possibility of enought Dextran uptake in the blood stream to cause a hypersensitivity reaction must be kept in mind during hysteroscopies with Dextran 70.


[Mature intraligamentary pregnancy with florid salpingitis tuberculosa (author's transl)]. Reported is a case of a 32 year old para II where an intraligamentary extrauterine pregnancy was terminated by caesarean section at term following spontaneous rupture of the amniotic sack. The newborn male weighed 3600 g, there were no malformations. There was a transient phase of asphyxia. Histologic examination of the placenta, that had developed in the mesosalpinx, the Fallopian tube and the uterus that had been amputated supracervically, showed to our surprise a florid caseating tuberculosis of the mucosa of uterus and Fallopian tube and also in a circumscribed area of the basal plate. After an initial uneventful course the newborn developed clinical manifestations of connatal tuberculosis on the 16th day of life. Whereas the mother died a few days after delivery, the baby survived the infection, this certainly was due in large part to the prophylactic tuberculostatic treatment that had been initiated immediately after the diagnosis of tuberculosis was made on account of histology. The case of an extrauterine pregnancy at term reported here differs from most of the previous reports by a) the site of the pregnancy, b) the development of a mature living newborn without malformations and in respect to b) it differs from all previous publications by the existing active caseating tuberculous salpingitis and endometritis of the mother, and the connatal tuberculosis of the newborn with its successful treatment.


[The decrease in the number of marriages (author's transl)]. Demographers adhere to the thesis that the increasing or decreasing incidence of marriage shows a statistical link to the existing number of males and females in the age group for marriage. For several years now it can be observed that this thesis requires revision. The number of marriages especially the number of marriages in those age groups in which the highest number of men and women absolutely and relatively get married decreases continually. At the same time the number of males and females in these groups increases. This development is a sign of an incipient disconnection of marriage from demographic data such as the number of persons in the age group for marriage and a disconnection for social and economic factors. Causes of this development are primarily the improvement of general education and the liberalization of sexual behavior. The traditional philosophy that all sexual intercourse should serve potential procreation is fading. The low rate of marriages and the low birth rate are signs of this development. Modern contraceptive methods facilitate this development of mature and autonomous persons but also opens a new complex area of new material and philosophical difficulties apart from  the legal position of marriage for the protection of the partners and their offspring and for the social stability of their relationships.


[Ifosfamide in comparison with cyclophosphamide in advanced ovarian carcinomas (author's transl)]. Ifosfamide or cyclophosphamide was employed in an alternating series in 49 advanced ovarian carcinomas. The two cytostatic drugs were given in single massive doses. In primary inoperable ovarian carcinomas at stage III and IV a partial remission occurred in 8 of 19 cases (42%) after treatment with cyclophosphamide. Ifosfamide produced a partial or complete remission in 9 of 11 cases (82%). However, 3 patients treated by ifosfamide died within 3 weeks after the administration of the first massive dose. Regarding these cases as failures there was a remission in 9 of 14 cases (64%). Cyclophosphamide enabled a secondary radical operation in 7 of 19 (37%), ifosfamide in 6 of 14 cases (43%). The intervals between an exploratory laparotomy and the secondary radical operation were 5 months on the average for the two cytostatic drugs.


Isolation and genetic analysis of mutant strains of Chlamydomonas reinhardi defective in gametic differentiation. Impotent mutant strains of Chlamydomonas reinhardi, mating-type (mt) plus, are described that have normal growth and motility but fail to differentiate into normal gametes. Procedures for their isolation and their genetic analysis are described. Five of the imp strains (imp-2, imp-5, imp-l, imp-7, and imp-8) exhibit no flagellar agglutination when mixed with mt- or mt+ gametes and the mutations are shown to be unlinked to the mt locus (with the possible exception of imp-7). Two of the strains (imp-3 and imp-4) carry leaky mutations that affect cell fusion; neither mutation is found by tetrad analysis to be linked to mt or to the other. Cells of the imp-1 strain agglutinate well with mt- gametes and active agglutination continues for up to 48 hours, but cell fusion occurs only very rarely. Analysis of these rare zygotes indicates that imp-1 is closely linked to the mt+ locus, and fine-structural studies reveal that imp-1 gametes produce a mutant mating structure involved in zygotic cell fusion. The development of sexuality in C. reinhardi therefore appears amenable to genetic dissection.


The unit of selection in Drosophila mercatorum. I. The interation of selection and meiosis in parthenogenetic strains. An important problem in population genetics is the determination of the level of genetic organization to which fitness measures can be ascribed that yield an adequate description or prediction of the outcome of selection in populations. To study this problem, we used two strains of Drosophila merca torum (S-1-Im and O-3-Im) that are capable of both sexual and parthenogenetic reproduction, a feature that allows us to experimentally control many factors which affect genetic variability. Both S and O reproduce parthenogenetically by "pronuclear duplication," a mechanism that retains normal meiosis (and hence crossing over and assortment) but results in homozygosity for all loci in a single generation. Since an isozyme survey indicated that S and O differ at a third of their loci, we hypothesized that S and O have adapted in genetically distinct fashions to the genetic environment of total homozygosity. This is tested by breeding females that are S-O hybrids for 100%, 60% and 40% of their genetic backgrounds, and scoring their respective pathenogenetic progenies for four isozyme and two visible markers. The data collected gave evidence for a coadaptation to total homozygosity involving non-additive and non-multiplicative interactions between non-alleles. As the perturbation of the parental coadapted genotypes by meiosis increases (i.e., the greater the degree of S-O hybridity), the level of genetic material which behaves as an additive/multiplicative fitness unit becomes larger. Selective neutrality of genetic variation may be an artifact of our failure to measure the proper genetic unit of selection.


A computer model allowing maintenance of large amounts of genetic variability in Mendelian populations. II. The balance of forces between linkage and random assortment. It is shown, through theory and computer simulations of outbreeding Mendelian populations, that there may be conditions under which a balance is struck between two facotrs. The first is the advantage of random assortment, which will, when multilocus selection is for intermediate equilibrium values, lead to higher average heterozygosity than when linkage is introduced. There is some indication that random assortment is also advantageous when selection is toward a uniform distribution of  equilibrium values. The second factor is the advantage of linkage between loci having positive epistatic interactions. When multilocus selection is for a bimodal distribution of equilibrium values  an early advantage of random assortment is replaced by a later disadvantage. Linkage disequilibrium, which in finite populations is increased only by random or selective sampling, may hinder the movement of alleles to their selective equilibria, thus leading to the advantage of random assortment.-Some consequences of this approach to the structure of natural populations are discussed.


Total arthroplasty of the wrist to relieve pain and increase motion. Total joint arthroplasty of the wrist is a feasible and satisfactory solution to the problems of patients who have significant wrist pain or severe limitation of motion, or both. It is particularly useful in patients with rheumatoid arthritis or with post-traumatic or degenerative arthritis of the wrist. In geriatric patients, this procedure appears to be a satisfactory alternative to wrist joint arthrodesis. Proper placement of the device and proper surgical technique to simulate the normal balance and motion of the wrist are necessary.


Prevention of wound sepsis in joint replacement surgery. Prevention of infection in the newer orthopedic procedures that involve implantation of large foreign bodies requires the establishment of routines and a policy of meticulous attention to detail. A careful preoperative examination, including identification of occult infections, is crucial. Then, uninfected patients who are selected for such surgery should receive prophylactic antimicrobial agents. The operating room technique includes rigid traffic control, strict aseptic precautions, protection of instruments from airborne contamination until the procedure is begun, and use of impermeable hoods and large masks by members of the surgical team. An iodophor skin preparation appears to achieve satisfactory skin asepsis. Although the use of unidirectional airflow or ultraviolet light reduces the level of airborne bacteria, these procedures have not been proved to be more effective than meticulous, carefully performed surgery in lowering rates of postoperative wound infection.