Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.

Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3+CD4-CD8- lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each child had defective Fas-mediated T lymphocyte apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when coexpressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this recently recognized disorder of lymphocyte homeostasis and peripheral self-tolerance.

[Animal production and animal health and their relationship with veterinary public health in Latin America and the Caribbean]. / La producción y la salud animal y sus interrelaciones con la salud pública veterinaria en América Latina y el Caribe.

The authors analyse the relationships which exist, in terms of programmes, sectors and institutions, between animal health, animal production and veterinary public health on the one hand, and between each of these three sectors and public health in general on the other. The most important common factor is food safety. Undernutrition, which affects some 60 million inhabitants of Latin America and the Caribbean, is still the most important public health problem in this part of the world. While it is known that the major cause of undernutrition is the low gross domestic product and uneven distribution of wealth, increased animal production and productivity would provide the key to an improvement in the situation. The concept of animal health, in its broadest sense, implies optimum animal production in a given region and during a specified period of time. Veterinary public health has functions and objectives which are crucial for food safety: protection and hygiene of foods, and control of the use in animal production of substances toxic to human beings (such as heavy metals, hormones and insecticides). Within the area of transmissible diseases, the authors discuss control measures for zoonoses. Besides the specific subject of interdisciplinary relationships in regard to zoonoses, the authors stress the importance of joint work conducted in the research, development and implementation of laboratory diagnostic activities and the production and quality control of antigens and vaccines. The production of laboratory animals is another sphere of common activity and research, and it cannot be said that such work is specific to any one of the three disciplines. Moreover, the fields of health, animal health and veterinary public health share the same methods and strategies, and reciprocal benefits could be more significant than the objectives of individual programmes. Reference is made to the organisation of state services and their adaptation to administrative de-centralisation, particularly at the local level.

Consideraçöes sobre a saúde animal na América Latina / Animal health in Latin America

Tradicionalmente a saúde animal está vinculada exclusivamente aos modelos biomédicos das enfermidades dos animais, principalmente as transmissíveis. A influência microbiologicista, sempre associada à técnica de diangóstico e a procedimentos imunoprofiláticos, apesar de produzir avanços notórios, também produz metodologicamente uma visäo reducional, parcial e desintegradora da saúde animal. As alternativas de soluçäo dos problemas de saúde animal na América Latina têm que levar em consideraçäo as características destas sociedades, considerando que nestas há grupos de atores sociais com distintas visöes, objetivos e interesses

Social structure and veterinary epidemiology in Latin América / Estructura social y epidemiologica veterinaria en América Latina

The objective of veterinaty epidemiology is established as the definition, analysis and solution of specific animal-health profiles. In turn, those profiles are understood as the synthesis at a given time and place of the production and sanitary problems with the actions organized by society to resolve them. The reference framework is the economic, political and social structure in which the livestock activity is developed. Determined by the role played by the livestock activity in the development of Latin América from colonial times to the present, the structure of production assumes specific forms to livestock organization. These forms are conceived as the principal epidemiological categories: pre-industrial beef cattle breeding, industrial forms of breeding and of fattening-finishing, industrial forms of milk production and peasant subfamily simple mercantile and associative forms. A methodology is proposed for the objetive characterization of these productions forms, based on indicators of productivity ,indirect indicators of the organization of the animal hered, and economic indicators, some of which are readily available from existing census information. A short epidemiological analysis attemps to outline the formal and ideological content of the various categories of epidemiology. Within an overall view of the concrete reality, these categories are not exclusive if they are taken as.

Estructura social y epidemiológica veterinaria en América Latina

Se establece como objetivo de la epidemiología veterinaria el definir, conocer y resolver perfiles específicos de salud animal, los que por su vez son entendidos como la síntesis en un espacio y tiempo concretos entre problemas productivo-sanitarios y acciones organizadas por la sociedad para resolverlos. El marco de referencia es la estructura económica, política y social en que se desarrolla la ganadería. Determinada por el papel que jugó la ganadería en el desarrollo de América Latina desde la época de las colonias hastas nuestos días, la estructura de producción asume formas específicas de organización ganadera que son concebidas como las categorías epidemiológicas principales. Se distinguen formas preempresariales de cría de ganado de carne; formas empresariales de cría, de producción de leche y de engorde y formas campesinas subfamiliares, mercantiles y asociativas. Se propone una metología para la caracterización objetiva de estas formas de producción basada en indicadores de productividad, indicadores indirectos de la organización del rebaño animal e indicadores económicos, algunos de los cuales fácilmente asequibles a través de información censal existente.

The objective of veterinary epidemiology is established as the definition, analysis and solution of specific animal-health profiles. In turn, those profiles are understood as the synthesis at a given time and place of the production and sanitary problems with the actions organized by society to resolve them. The reference framework is the economic, political and social structure in which the livestock ativity is developed. Determined by the role played by the livestock activity in the development of Latin America from colonial times to the present, the structures of production assumes specific forms of livestock organization. These forms are conceived as the principal epidemiological categories: pre-industrial beef cattle breeding, industial forms of breeding and of fattening-finishing, industrial, industrial forms of milk production, and peasant subfamily simple mercantile and associative forms. A methodology is proposed for the objective characterization of these production forms, based on indicators of productivity, idirect indicators of the organization of the animal herd, and economic indicators, some of which are readily avaiable from existing census information.

Estudio epidemiológico de la estomatitis vesicular en América del Sur

[Introducción] En este trabajo se presenta un estudio general del comportamiento de la incidencia de la estomatitis vesicular (EV) en la población animal en la dimensión espacio-temporal de los cuatro países de América del Sur donde ella se presenta con frecuencia.

[Introduction] This paper presents a general study of the bhavoir of the incidence of vesicular stomatitis (VS) in the animal population in the space-time dimension of the four South American countries in which the isease frequently occurs.

Estructura social y epidemiologica veterinaria en America Latina / Social structure and veterinary epidemiology in Latin America

The objective of veterinaty epidemiology is established as the definition, analysis and solution of specific animal-health profiles. In turn, those profiles are understood as the synthesis at a given time and place of the production and sanitary problems with the actions organized by society to resolve them. The reference framework is the economic, political and social structure in which the livestock activity is developed. Determined by the role played by the livestock activity in the development of Latin America from colonial times to the present, the structure of production assumes specific forms to livestock organization. These forms are conceived as the principal epidemiological categories: pre-industrial beef cattle breeding, industrial forms of breeding and of fattening-finishing, industrial forms of milk production and peasant subfamily simple mercantile and associative forms. A methodology is proposed for the objetive characterization of these productions forms, based on indicators of productivity ,indirect indicators of the organization of the animal hered, and economic indicators, some of which are readily available from existing census information. A short epidemiological analysis attemps to outline the formal and ideological content of the various categories of epidemiology. Within an overall view of the concrete reality, these categories are not exclusive if they are taken as

Iosulamide: a new intravenous cholangiocholecystographic medium.

Iosulamide is a bis-benzoic analogue of metrizoate that shows clear advantages in animal tests over meglumine iodipamide. The intravenous toxicity of iosulamide meglumine is considerably lower than that of iodipamide (Cholografin) in the mouse and rat. The LD50 in mice for iosulamide meglumine is 11,500 +/- 844 mg free acid/kg and for iodipamide is 2380 +/- 290 mg free acid/kg. A threefold difference in toxicity was seen in rats; the LD50 for iosulamide meglumine is 13,600 +/- 1710 mg free acid kg and for iodipamide is 4430 +/- 310 mg free acid/kg. Iosulamide is a highly effective contrast agent for cholangiocholecystographic visualization in cats and monkeys. speed and degree of opacification are equivalent to that of iodipamide at equimolar doses. Studies of biliary and urinary excretion patterns indicate iosulamide is rapidly excreted compared to iodipamide, while at the same time providing equal concentrations in bile on an mg/ml bile basis. A more efficient blood to bile clearance rate and a shorter blood half-life for iosulamide may account for the lower circulating blood levels and rapid total excretion compared to iodipamide. Iosulamide's rapid blood-bile clearance coupled with its extremely low toxicity may allow rapid administration of high doses, affording superior visualization and safety compared to iodipamide. It may also provide visualization of the liver parenchyma with computerized axial tomography, due to the pharmacokinetic profile that provides for high liver clearance but low blood levels. The emetic potential of iosulamide meglumine is quite low compared to iodipamide. Iosulamide meglumine also lacks hypotensive activity. Little or no effect on blood pressure was seen with iosulamide meglumine in cats or monkeys, whereas iodipamide caused marked transient, or sustained, reductions. Iosulamide meglumine did not produce significant toxic effects when administered as single daily intravenous injections to albino rats for three weeks, or in 10-minute intravenous infusions to rhesus monkeys 10 times in 14 days. Clinical trials with iosulamide are under way.

Metrizamide, iothalamate, and metrizoate: effects of internal carotid arterial injections on the blood-brain barrier of the rabbit.

Experiments were conducted on anesthetized rabbits to determine the effect of internal carotid artery injection of various contrast media on permeability changes in the blood-brain barrier. Changes in respiratory pattern, neuromuscular effects, and trypan blue extravasation were recorded after 3-ml injections of ionic and nonionic contrast media. Metrizamide and iothalamate meglumine were compared at iodine doses of 300, 400, and 500 mg I/ml. Metrizoate at 280 and 440 mg I/ml and diatrizoate meglumine at 385 mg I/ml were also included for comparison. The results demonstrated that metrizamide at all three iodine concentrations used caused minimal disruption of the blood-brain barrier, the effect being no greater, statistically, than saline controls. Iothalamate was benign at the lowest iodine concentration, but caused significant barrier breakdown at the two higher concentrations. These results suggest that alterations in blood-brain barrier permeability following angiography are mediated by both hyperosmolality of the contrast medium and the chemotoxicity of the contrast molecule.

(2,6-Methano-3-benzazocin-11 beta-yl)alkanones. 1. Alkylalkanones: a new series of N-methyl derivatives with novel opiate activity profiles.

A general stereospecific synthesis of (N-methyl-2,6-methano-3-benzazocin-11 beta-yl)alkanones is described and applied to the preparation of a series of alkyl ketones wherein the alkyl group is a straight or terminally branched chain containing from one to six carbon atoms. Several compounds with methoxy groups in the aromatic ring are in the morphine range of potency; they are uniformly inactive as phenazocine antagonists. Phenolic analogues range up to 100 times as potent as morphine. Those containing five or six carbon atoms in the alkyl group exhibit phenazocine antagonist activity, in one case equivalent to naloxone. This compound (3e) is selective for phenazocine in its antagonist action.

Microencapsulation of bitolterol for controlled release and its effect on bronchodilator and heart rate activities in dogs.

Spheronized cores produced by extrusion and marumerization were microencapsulated with ethylcellulose by organic phase separation to produce beads exhibiting controlled-release characteristics. In vitro dissolution studies indicated that the drug was released as a first-order model and that the release rates were proportional to the amount of film on the bead. The bronchodilator activity in the anesthetized dog and the heart rate effect in the unanesthetized trained dog were evaluated. Microencapsulated beads were prepared which produced controlled release as assayed by bronchodilation. The heart rate increases induced by the controlled-release formulations were gradual in onset, and the total increase in heart rate over a 6-hr period was less than that associated with the plain drug powder.

Dual effects of aspirin in guinea-pig lungs.

Dual effects of aspirin were demonstrated in guinea-pig lungs: (a) aspirin (3.3 mg/kg i.v.) antagonized bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A); (b) aspirin produced bronchoconstriction when injected in the presence of propranolol into guinea-pigs in vivo at 330 mg/kg, or into guinea-pig isolated lungs in vitro as a 4% solution (40 mg/ml). 2 The severity of bronchoconstriction following administration of aspirin was directly related to the degree of beta-adrenoceptor blockade and to the age of the guinea-pigs. Aspirin-induced bronchoconstriction was prevented in vivo and in vitro by atropine and it could be reversed in vivo by atropine. Aspirin-induced bronchoconstriction was not inhibited by vagotomy or phenoxybenzamine. 3 These data suggest that the mechanism involved in aspirin-induced bronchoconstriction may be local cholinergic stimulation and that reduced beta-adrenergic drive may be a predisposing factor.

Intrathecal tolerance of metrizamide in chloralose anesthetized cats.

The water soluble radiopaque medium, metrizamide (Amipaque) was introduced into the lumbar subarachnoid space in chloralose anesthetized cats at a standard volume of 0.35 cc/kg in concentrations of 300 mgI/cc to 500 mgI/cc during EMG recording. These animals did not differ from controls which received cerebrospinal fluid under otherwise identical conditions; both groups usually showed some mild and occasional muscle fasciculations or mild spasms. Treatment with metrizamide appeared to be a less deleterious procedure than that using hyperosmotic sucrose (1.32 M) as judged from EMG records. In contrast, equivalent amounts of neglumine iothalamate produced frank convulsions in 7 of 15 cases and a range of hyperirritability in the remaining 8.

Drugs derived from cannabinoids. 1. Nitrogen analogs, benzopyranopyridines and benzopyranopyrroles.

Various nitrogen analogs of delta6a,10a-tetrahydrocannabinol were synthesized by a general procedure described in an earlier communication. Minimum effective doses (MED50's) and lethal doses (LD50's) were determined by a modified Irwin mouse screen after iv administration of compounds in PEG 200. The most potent compounds were the propargyl (5t), allyl (5m), and chloroallyl (5o-q) derivatives. Overt behavioral effects (CNS depression, static ataxia, and hypersensitivity) of 5t and Roger Adams' carbocyclic analog (III) were found to be similar in the mouse, cat, dog, and monkey. Dichloroisoproterenol prevented and reversed many of the depressant effects of both III and 5t but had no effect on the ataxia produced by these compounds. In antinociceptive tests, 5t was active in the phenylquinone and Eddy hot-plate tests but was inactive in the tail-flick test.

Emetic activity of N-substituted norapomorphines.

Norapomorphine and ten of its N-substituted derivatives were prepared by modifications of procedures described earlier. In a dog emesis test the N-ethyl and N-n-propyl compounds had minimum effective doses of 0.00025 and 0.0005 mg/kg, respectively, when administered iv, sc, or im. In a modified Irwin mouse profile screen the minimum effective iv dose was 0.013 mg/kg for the N-ethyl and 0.0024 mg/kg for the N-n-propyl compound; percutaneous absorption was also observed in mice. All compounds examined caused the stereotyped apomorphine behavior syndrome but hypotensive effects were not serious.

El conocimiento de la epidemiología de la fiebre aftosa con particular referencia a Sudamerica

[Introducción] Este trabajo pretende integrar en un enfoque global los resultados de aplicación a los programas que se pueden extraer de las publicaciones sobre fiebre aftosa, recalcando en particular aquellos eslabones de su cadena epidemiológica que aún están por ser encontrados y que son críticos para la planificación racional de su combate. Este método deberá permitir una mejor prioritación de las investigaciones en materia de fiebre aftosa.