Electrophysiologic properties of a new antiarrhythmic drug--tocainide

Tocainide (Astra W36095) is an orally active antiarrhythmic drug that is structurally related to lidocaine. This paper describes in vivo and in vitro studies undertaken to assay the electrophysiologic properties of this compound. Ouabain-induced ventricular ectopic activity was abolished by this drug in both isolated canine Purkinje fibers and in intact dogs. Similarly, the ventricular ectopic activity that occurs 24 hours after the two stage Harris coronary arterial ligation procedure also was abolished by tocainide. The amount of current necessary to evoke an action potential by intracell stimulation during diastole was Increased in direct relation to drug concentration. Similarly, in dogs anesthetized with pentobarbital sodium, tocainide increased the ventricular fibrillation threshold up to 150 percent above control values during normal supraventricular rhythm and up to 285 percent after premature ventricular beats. The transmembrane action potential duration and effective refractory period of isolated canine Purkinje fibers were shortened by tocainide. Tocainide depressed atrioventricular nodal conduction in anesthetized dogs, an effect that was magnified in the presence of premature atrial beats but had no effect on His, Purkinje or ventricular muscle conduction. These results Indicate that tocainide is a potentially effective antiarrhythmic agent and deserves further investigation in patients.     

Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability

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Hereditary defects of the conotruncal septum in Keeshond dogs: pathologic and genetic studies

Pathologic studies of a hereditary cardiovascular defect in Keeshond dogs demonstrated a spectrum of malformations, primarily involving the ventricular outflow tracts. Lesions ranged from subclinicai defects of the crista supraventricularis to end-stage tetralogy of Fallot and included isolated ventricular septal defects and pulmonic stenosis. The spectrum can be explained by assuming that the anatomic variations represent different thresholds along a continuum of maldevelopment producing hypoplasia and malpositioning of the conotruncal septum. The results of breeding experiments conducted in a colony of Keeshond dogs with conotruncal septal defects confirmed the hereditary nature of the abnormality but were not consistent with any simple genetic hypothesis. Both the incidence and the severity of the conotruncal lesions increased with the severity of the parental defect. The results are shown to fit a polygenic model with three developmental thresholds, in which multiple genes act additively to produce a continuous distribution of maldevelopment involving the conotruncal septum. Lesions of increasing severity occur with an increasing “dose” of genes predisposing to conotruncal septal defects.     

Hereditary dysplasia of the pulmonary valve in beagle dogs: Pathologic and genetic studies

Pathologic and genetic studies were conducted in a colony of beagle dogs with pulmonary stenosis. The pulmonary valve lesions were shown in 70 affected dogs to consist of thickening, fusion and hypoplasia of valve leaflets, which occurred in varying degrees of severity and in various combinations. The gross anatomic structure of the pulmonary valve in some affected dogs resembled that seen in “typical” pulmonary stenosis in human beings; in others it was similar to what has been called pulmonary valve dysplasia. Both types, and intermediate forms, occurred in members of the same litter, indicating that these two types of pulmonary valve deformity are not separate etiologic or developmental entities in the beagle. Pulmonary valve atresia was present in two pups. Light and electron microscopic examination of affected and normal valves indicated that valve thickening, the most prominent feature of the valve abnormality, was due to an increase in the thickness of the valve spongiosa. Blood vessels and sinuses lined with endothelium were common in affected leaflets. We propose that the term hereditary pulmonary valve dysplasia be used to describe the entire range of pulmonary valve abnormalities in this hereditary defect of beagles.Genetic studies, including matings of affected to affected, outcrosses, F₁ crosses and repeated backcrosses showed that pulmonary valve dysplasia is not inherited as a simple Mendelian trait. Genes at more than one locus predispose to abnormal development of the pulmonary valve. The risk of pulmonary valve dysplasia increased with inbreeding, indicating that homozygosity for specific alleles at these loci increases the probability of abnormal development. There is no evidence in affected beagles that other body systems are involved. The genetic data in beagles are consistent with available evidence concerning genetic factors involved in isolated pulmonary stenosis in human beings.     

Pathogenesis of persistent truncus arteriosus in light of observations made in a dog embryo with the anomaly

Among 36 embryos obtained from a strain of Keeshond dogs in which there is a large incidence of spontaneously occurring conotruncal anomalies, a specimen with persistent truncus arteriosus, type 1 was found. The embryo had a crown-rump length of 20 mm. The specimen was serially sectioned and a wax plate reconstruction was made of the heart and proximal great vessels at a magnification of X100. The truncal valve was quadricuspid and dysplastic; associated anomalies were a right subclavian artery arising anomalously from the descending aorta, a single coronary artery, an absent ductus arteriosus and a small persistent left cranial (superior) vena cava. The truncus cushions were hypoplastic, had failed to fuse and each had simply produced an arterial cusp. The observations made on this embryo support the view that in persistent truncus arteriosus there is failure of septation of the truncus arteriosus. No evidence was found in favor of the concept that persistent truncus arteriosus represents a form of tetralogy of Fallot with atresia of the subpulmonary infundibulum and partial or complete absence of the aorticopulmonary septum.     

Comparative genodermatoses

Hereditary skin diseases constitute a large group of syndromes that is diverse both in range of symptoms and in range of severity. Some of these diseases are debilitating or even life-threatening, and others are of little more than academic or historical interest. Of the long list of diseases reported to affect dogs and cats (Table 1), a limited number of syndromes will be presented in this article. The diseases to be discussed were chosen on the strength of evidence of their heritability or on the expected frequency of their occurrence.Some of the hereditary skin diseases presented should probably not be considered diseases at all; for example, in the case of the hairless breeds, the syndromes in question are desirable, at least to the owners. In some cases, the defects are evident at birth (congenital); others appear after a variable amount of time, usually by young adulthood (tardive). Some of the syndromes involve factors other than heritable ones that determine their final outcome.     

Elevation rate of glycosylated hemoglobins in dogs after induction of experimental diabetes mellitus

The glycosylated hemoglobin, hemoglobin A_1c (HbA_1c), which reflects average plasma glucose of the previous few weeks, has recently been used to monitor humans with diabetes mellitus. Further understanding of the HbA_1c elevation rate would improve interpretation of HbA_1c. We determined glycosylated hemoglobin elevation rates in 5 dogs with induced diabetes. Hemoglobin A_1c was determined by an established column chromatographic technique; plasma glucose by glucose oxidase. Values were determined on 13 normal dogs and compared with values obtained weekly from surgically or chemically-induced diabetic dogs. Hemoglobin A_1c increased in a fashion that could be predicted by modelling. The model predicts that large changes in Hb A_1c will occur within the first few weeks of a sudden change in glucose and that a new plateau will be reached at a time equal to the erythrocyte life span. In the present experiment abnormally elevated HbA_1c occurred after 2 wk of hyperglycemia. The results should approximate the elevation rate after acute onset and sustained severe hyperglycemia in humans, because humans and canines are hematologically similar and thus extend previously reported studies on human out-patient diabetics.     

Human papillomaviruses biochemical and biologic properties

The viral origin of warts and condylomas was established at the beginning of this century by experiments on the transmission of warts by means of cell-free tissue extracts.¹ For a long time, a single virus—the human wart virus—was considered responsible for these lesions,¹ although the multiplicity of human papillomaviruses (HPVs) was suspected on the basis of epidemiologic,² serologie,³ and histologic^4,5 data. It was, thus, generally thought that “the clinical type is determined by the local conditions at the site of infection and not by the virus”¹ and that the clinical evolution of the lesions—in particular, the rare malignant transformation^6,7 of genital condylomas and that of the cutaneous lesions of patients suffering from epidermodysplasia verruciformis (EV)—depended on immunologic, genetic, or extrinsic factors.^1,6,8

The characterization of HPVs and the study of their pathogenic properties have long been hindered by the absence of a cellular system permitting the in vitro replication of these viruses.⁹ During the last few years, new methods of analysis of the viral DNA—in particular, the molecular cloning of viral genomes in a plasmid or in the DNA of a bacteriophage—have permitted considerable improvement in our knowledge of HPVs.^10–12 At least 28 HPV types now are recognized^13–29 (Ostrow, R. personal communication). It seems likely that the different clinical types of lesions classically associated with an HPV are, in fact, distinct diseases caused by specific viruses.^23,30–34 Finally, the discovery of the high frequency of infection of the uterine cervix by an HPV,^36,36 as well as the frequent detection of HPV DNA sequences in neoplasias of the skin,^{16,32,37–39} the external genitalia,^40–46 and the uterine cervix^24,25 have broadened the spectrum of the pathogenicity of PVs for human beings and imposed the idea that infection by specific HPV types is a risk factor for the development of these neoplasias.

After reviewing the physicochemical and biologic characteristics of HPVs and the methods used for their study, we will present recent data on the nomenclature, the pathogenicity, and the oncogenic potential of HPVs.