Conversion of Ouabain-Induced Ventricular Tachycardia in Dogs with Epicardial Lidocaine: Pharmacodynamics and Functional Effects

Epicardial antiarrhythmic drug administration was studied as a therapeutic approach for experimental ventricular tachycardia (VT) in an open-chest dog model. Lidocaine-polyurethane matrices (28%, w/w) were formulated as a model system. Matrices were placed on the left ventricular epicardium in each of 23 anesthetized open-chest dogs with ouabain-induced VT, to evaluate effectiveness in restoring sinus rhythm. Conversion occurred in all animals treated with matrices containing 300 mg or more of lidocaine after 1.5 to 7.0 min. The matrix lidocaine content correlated linearly with the time required for conversion to sinus rhythm (r = 0.75, P = 0.0002); irrespective of matrix size the myocardial/plasma lidocaine ratio was 20.1 ± 4.2 (mean ± SD) at the time of conversion. In a separate series of five dogs without ventricular tachycardia, systolic wall thickening measured with sonomicrometers after 5 min of controlled-release lidocaine administration (500- to 1000-mg matrix lidocaine content, 7.48 ± 3.49-mg/kg dose) was only minimally diminished (–14.1%) and this effect was observed only at the site of matrix placement on the anterior-apical epicardium. In contrast, intracoronary injection of 0.3 or 1.0 mg/kg of lidocaine-HCl resulted in complete elimination of wall thickening or replacement by systolic thinning. Thus epicardial administration of lidocaine from polyurethane matrices was an effective means of treating ouabain-induced ventricular tachycardia. Regional myocardial function in the vicinity of the matrices was modified to a very limited degree, supporting the view that the matrices can be used safely, without serious risk to ventricular contractile performance.     

Definition of Mycobacterium tuberculosis culture filtrate proteins by two-dimensional polyacrylamide gel electrophoresis, N-terminal amino acid sequencing, and electrospray mass spectrometry.

A number of the culture filtrate proteins secreted by Mycobacterium tuberculosis are known to contribute to the immunology of tuberculosis and to possess enzymatic activities associated with pathogenicity. However, a complete analysis of the protein composition of this fraction has been lacking. By using two-dimensional polyacrylamide gel electrophoresis, detailed maps of the culture filtrate proteins of M. tuberculosis H37Rv were generated. In total, 205 protein spots were observed. The coupling of this electrophoretic technique with Western blot analysis allowed the identification and mapping of 32 proteins. Further molecular characterization of abundant proteins within this fraction was achieved by N-terminal amino acid sequencing and liquid chromatography-mass spectrometry. Eighteen proteins were subjected to N-group analysis; of these, only 10 could be sequenced by Edman degradation. Among the most interesting were a novel 52-kDa protein demonstrating significant homology to an alpha-hydroxysteroid dehydrogenase of Eubacterium sp. strain VPI 12708, a 25-kDa protein corresponding to open reading frame 28 of the M. tuberculosis cosmid MTCY1A11, and a 31-kDa protein exhibiting an amino acid sequence identical to that of antigen 85A and 85B. This latter product migrated with an isoelectric point between those of antigen 85A and 85C but did not react with the antibody specific for this complex, suggesting that there is a fourth member of the antigen 85 complex. Novel N-terminal amino acid sequences were obtained for three additional culture filtrate proteins; however, these did not yield significant homology to known protein sequences. A protein cluster of 85 to 88 kDa, recognized by the monoclonal antibodies IT-57 and IT-42 and known to react with sera from a large proportion of tuberculosis patients, was refractory to N-group analysis. Nevertheless, mass spectrometry of peptides obtained from one member of this complex identified it as the M. tuberculosis KatG catalase/peroxidase. Thus, the detailed mapping of M. tuberculosis proteins, combined with state-of-the-art analytical techniques such as mass spectrometry, provides a basis for further analysis and rapid identification of biologically relevant molecules.     

Occupational mortality from gastric and duodenal ulcer.

The pronounced geographical and temporal variations in gastric and duodenal ulcer suggest that important environmental factors must play a part in their aetiology. To determine the nature of possible factors, the Registrar General's decennial supplement and the vital statistics special reports of the United States Department of Health, Education, and Welfare on occupational mortality were analysed for occupation-specific mortality from peptic ulcer. The data disclose a high mortality from both types of ulcer among manual workers and a low mortality among sedentary occupations. This general pattern runs parallel to a low mortality from gastric and duodenal ulcer among the high social classes and a high mortality in the low social classes. Married women displayed a gradient of gastric ulcer mortality increasing from social class 1 to social class 5 but gave no evidence of social class correlation with respect to duodenal ulcer. The significant correlation between mortality from gastric and duodenal ulcer among different occupations could suggest that both types of ulcer hold some of the precipitating environmental risks in common. In duodenal ulcer the varying extent of energy expenditure among different occupations may be responsible for the different risk of contracting duodenal ulcer and dying from it. The association between energy expenditure and peptic ulcer mortality seems to be less important for gastric ulcer where additional factors associated with social class may also be operating.     

Renal regulation of salt balance: a primer for non-purists

The greater than 40-fold range of voluntary salt intake in humans requires corresponding adjustments in renal excretion to maintain balance. Although many mechanisms have been implicated in the regulation of salt output by the kidney, surprisingly little consideration has been given to their quantitative significance and possible interaction. This survey summarizes the effects of changes in glomerular filtration rate, proximal peritubular physical factors, and plasma concentrations of aldosterone and atrial natriuretic factor (ANF), singly and in combination, on the level of salt excretion. Contrary to expectation, even large increases in filtration or decreases in proximal reabsorption have only minor natriuretic effects, due to constancy of fractional reabsorption in downstream nephron segments. Lack of aldosterone release increases salt excretion as much or more than the upstream mechanisms, whereas ANF-induced inhibition of reabsorption in the medullary collccting duct has the largest effect. It may be concluded, therefore, that the potency of these natriuretic factors increases with distance along the nephron, even though each is operating on a progressively small tubular load. However, none of the mechanisms, in isolation, is sufficient to explain salt balance over the range of voluntary intake. Combination of factors demonstrates synergism rather than simple additivity, resulting in more than enough reserve capacity for salt excretion.     

Associations of peptic ulcer and gastric cancer with other diseases in US veterans.

OBJECTIVES: The purpose of this study was to examine, through the database of the Department of Veterans Affairs, the joint occurrence of different diseases in individual patients. METHODS: Patients with a diagnosis of gastric cancer, gastric ulcer, or duodenal ulcer were extracted from the 1987 through 1990 computer files. A random sample of patients from each annual file served as a control population. All previous discharges of each case or control patient between 1970 and 1990 were searched for the occurrence of hypertensive diseases or chronic diseases of the joints, lungs, pancreas, and liver. The relative frequencies of such diagnoses in case and control patients were compared by multivariate logistic regression. RESULTS: Gastric ulcer and duodenal ulcer, but not gastric cancer, were significantly associated with chronic diseases of the joints, lungs, pancreas, and liver. None of the three diagnoses showed any significant association with hypertensive diseases. CONCLUSIONS: These relationships may reflect the influence of nonsteroidal anti-inflammatory drugs, smoking, and alcohol. They stress the importance of environmental risk factors other than Helicobacter pylori in terms of damage to the upper gastrointestinal mucosa.     

Iatrogenic diaphragmatic hernia due to laparoscopic gastric banding

A patient developed a huge diaphragmatic hernia following laparoscopic gastric banding. Almost the entire stomach was incarcerated within the left chest. Segmental necrosis of the greater curvature of the stomach necessitated partial gastrectomy. The postoperative course was uneventful. The etiology, diagnosis and treatment of this previously undescribed complication of laparoscopic gastric banding are addressed in relation to the present case.     

The relationship between receptor-effector unit heterogeneity and the shape of the concentration-effect profile: Pharmacodynamic implications

The apparent concentration-effect relationship is the ensemble of many effector units (such as individual cells or channels) that do not always exhibit a uniform stimulus-effect relationship. This concept is substantiated by many observations of heterogeneity in receptor-effector populations including hormone secreting cells, response to hormonal stimuli, activity pattern of second messengers, stimulus-evoked synaptic currents, and single ion channels. The relationship between drug concentration and magnitude of pharmacologic response is commonly described by the sigmoidalE _max model which was derived from the Hill equation. The sigmoidicity factor (N) in this model is assumed to be a pure mathematical parameter without physiological connotations. This work demonstrates that the numerical value ofN (measured empirically) is the product of two factors: (i) the degree of heterogeneity of the effector subunits, i.e., the elemental component that upon drug stimulus contributes its pharmacological effect independently and does not interact with other subunits (it could range from a single receptor up to a whole tissue), and (ii) value ofN ^*—the shape factor of the subunits' concentration-effect relationship. A special case of this approach occurs whenN ^*>5, which is an on-off case. HereN is determined by the distribution (density equation) of the subunit values. In case of heterogeneity of the microparameters of the effector subunits the apparentN will always have a lower value thanN ^*. According to this theory it can be concluded that without knowledge of the distribution of the microparameters no mechanistic interpretation can be deduced from the apparentN value. If in the futureN ^* can be determined by theoretical or experimental methods, the distribution function relatingN ^* toN can be calculated. The relevance of this theory is increased in view of the progress being made in advanced research techniques which may enable us to determine the concentration-effect relationship at the level of the individual effector unit.     

Was belastet in der Feuerwehr?

Background: Previous studies investigated extreme stress of ambulance personnel, where post-traumatic stress disorder dominated as far as the consequences were concerned. Recent studies are being led by the assumption that daily stress can increase the vulnerability with regard to psychological and health impairments. Aim: In the study, the main focus is placed on which daily stress exposures are of importance in the fire brigade and how they correlate with the personal health of the fire fighters. Burnout and the reduced habitual physical well-being are being examined as potential impairments. Method: Data was gathered from fire fighting personnel working in Berlin and Saxony-Anhalt by means of a questionnaire. Responses of 364 (response rate 40%) fire fighting personnel were analyzed by performing univariate, bivariate and multivariate analyses. A frame model “stress — burnout — physical well-being” is examined by using structural equation modelling (Lisrel). Results: Work-related obstacles in every-day life are of the greatest importance in the fire brigade’s daily work; extreme stress is being experienced rather seldom in comparison. Unfavorable general conditions of work organization correlate with higher burnout levels. The analyzed frame model — work-related stress influences burnout, burnout as an predictor for impairments of well-being — exhibits a satisfactory level of model fit. Conclusions: The results support the assumption that burnout has an intermediating effect on the relation of work-related stress and health. Therefore, the possibility of achieving a reduction of work organizational stress in order to lower the probability of long-term health impairments exists in the fire brigade.     

Colonic Drug Delivery: Enhanced Release of Indomethacin from Cross-Linked Chondroitin Matrix in Rat Cecal Content

Pharmaceutical Research -