Suppression of calpain expression by NSAIDs is associated with inhibition of cell migration in rat duodenum.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the alleviation of pain and inflammation, but these drugs are also associated with a suite of negative side effects. Gastrointestinal (GI) toxicity is particularly concerning since it affects an estimated 70% of individuals taking NSAIDs routinely, and evidence suggests the majority of toxicity is occurring in the small intestine. Traditionally, NSAID-induced GI toxicity has been associated with indiscriminate inhibition of cyclooxygenase isoforms, but other mechanisms, including inhibition of cell migration, intestinal restitution, and wound healing, are likely to contribute to toxicity. Previous efforts demonstrated that treatment of cultured intestinal epithelial cells (IEC) with NSAIDs inhibits expression and activity of calpain proteases, but the effects of specific inhibition of calpain expression in vitro or the effects of NSAIDs on intestinal cell migration in vivo remain to be determined. Accordingly, we examined the effect of suppression of calpain protease expression with siRNA on cell migration in cultured IECs and evaluated the effects of NSAID treatment on epithelial cell migration and calpain protease expression in rat duodenum. Our results show that calpain siRNA inhibits protease expression and slows migration in cultured IECs. Additionally, NSAID treatment of rats slowed migration up the villus axis and suppressed calpain expression in duodenal epithelial cells. Our results are supportive of the hypothesis that suppression of calpain expression leading to slowing of cell migration is a potential mechanism through which NSAIDs cause GI toxicity.

Blood and tissue content of the iso-enzymes of lactate dehydrogenase in the thoroughbred.

The occasions, position and relative concentration of LDH iso-enzymes in the blood tissues of the thoroughbred horse were determined. Locomotor muscles possess a high concentration of LDH 5 whereas non-locomotor muscles have a low concentration of this iso-enzyme.

Exercise studies in horses: 2. The cardiac response to exercise in normal horses and in horses with chronic obstructive pulmonary disease.

The relationship of velocity (v) to heart rate (HR)and of kinetic energy (KE) to heart rate, were investigated in 6 normal horses and in 6 horses with chronic obstructive pulmonary, disease (COPD). Radiotelemetry was used to determine the heart rate while subjects were ridden on a 400m track. Velocity was measured by stop-watch between 2 markers 50 m apart at the end of the track. Kinetic energy was calculated from the formula KE =1/2 Mv2, where M = mass of horse, rider, saddle and bridle (KG) and V = velocity (metres per second). In all subjects, the relationship of velocity to heart rate was a linear one at each individual pace (i.e. walk, trot and gallop). There were however significant differences between the v/HR regression curves of each pace. These differences indicated that the increase in velocity per unit increase in heart rate was greater at the trot than at the walk, and greater at the gallop than at the trot. When data for all paces were combined, the relationship log v/log HR was a linear one. The above findings were also true of the relationship of kinetic energy to the heart rate. In horses, which reached maximal heart rate at a relatively low velocity, the v/HR curve became asymptotic. At comparable submaximal velocities, the heart rate of COPD subjects was approximately 20 beats per minute higher than that of normal subjects. This was also true when the term "kinetic energy per units mass" was substituted for velocity.

Exercise studies in horses: 1. A simple telemetry system for recording excercise ECGs in horses.

A robust low cost portable radiotelemetry system is described for the horse and its method of operation and advantages briefly discussed. The equipment consisted of 2 electrodes forming a bipolar lead, a transmitter, a receiver and a writing device. The sitting, application and immobilising of the electrodes was a most important factor in obtaining good quality recordings. ECGs were recorded at all paces and also while jumping and the results proved satisfactory.

Studies on the physiopathology of chronic obstructive pulmonary disease in horses. I. Clinical signs.

Twenty cases of chronic cough originating in the lung and associated with loss of performance were clinically examined. The physical signs observed were compared with those observed in a control series of 38 clinically normal horses. Reduced work tolerance, coughing for more than 3 months and abnormal pulmonary sounds (râles) were primary signs of chronic obstructive pulmonary disease (COPD). Forced abdominal expiratory efforts and pumping of the anus were regarded as confirmatory signs. Neither nasal discharge nor increased marginal distance was found to be a reliable sign of COPD. The mean respiratory frequency of the COPD subjects, namely 25,4 per minute, was significantly higher than the 16,7 per minute (P less than 0,001) of the 38 normal subjects.

Studies on the physiopathology of chronic obstructive pulmonary disease in the horse. III. The intrathoracic pressure.

The intrathoracic pressure was determined by direct intrapleural cannulation in 17 clinically normal horses and 14 horses with chronic obstructive pulmonary disease (COPD). There were significant differences between the normal and COPD horses with regard to max. Ppl and max. delta Ppl. The mean values for minimum Ppl of the 2 groups of subjects were not significantly different. The results were discussed in relation to those of other workers.

Studies on the physiopathology of chronic obstructive pulmonary disease in the horse. II. Right heart haemodynamics.

Pressure curves obtained by cardiac catheterization of the pulmonary artery, right ventricle and right atrium of 9 horses and ponies with chronic obstructive pulmonary disease (COPD) were compared with those similarly recorded from 6 clinically normal control subjects. The mean pulmonary peak systolic, pulmonary minimum diastolic and ventricular peak systolic pressures of the COPD subjects were significantly higher (P less than 0,01) than the corresponding mean pressures of the clinically normal control subjects. The mean pressure calculated from pressure curves obtained from 8 Thoroughbreds in training did not differ significantly from those of the clinically normal subjects not in training.

Studies on the physiopathology of chronic obstructive pulmonary disease in the horse. V. Blood gas and acid-base values during exercise.

The haemoglobin concentration, the partial pressures of oxygen and carbon dioxide, the oxygen content and the pH were determined in the arterial and mixed venous blood of 5 normal and 3 horses with chronic obstructive pulmonary disease (COPD) at 3 stages of an exercise distance of 1200 m. Arterial and mixed venous samples were collected simultaneously by means of an automatic technique during the walk, trot and gallop at 0-100 m, at 500-600 m and at 1100-1200 m. The standard bicarbonate and the lactic and pyruvic acid concentrations were also determined in arterial and mixed venous blood. Highly significant changes in the mean values of PvO2. O2 content and delta a-vO2 content occurred during exercise in COPD subjects, and significant changes in PvO2 and delta a-vO2 content occurred during exercise in normal subjects. We concluded that COPD subjects compensated for respiratory dysfunction during exercise by extracting more oxygen from the blood than did normal horses. There was a highly significant correlation between the changes in standard bicarbonate and the changes in lactic acid concentration during exercise in both normal and COPD subjects. This led to the conclusion that lactic acid production was primarily, but not completely, responsible for the metabolic acidosis of exercise in horses.

Studies on the physiopathology of chronic obstructive pulmonary disease in the horse. IV. Blood gas and acid-base values at rest.

Radiometer Blood Micro-system 2 was used in studies designed to, (a) compare the mean blood gas and acid-base values of 38 normal horses and 20 horses with chronic obstructive pulmonary disease (COPD), (b) determine the means and standard deviations of blood gas and acid-base values of Thoroughbred horses in training, and (c) investigate the relationships between clinical data, blood gas values, intracardiac and pulmonary arterial pressures in subjects with COPD. There were significant differences between the mean values for partial pressure of arterial oxygen (PaO2), arterial carbon dioxide (PaCO2) and mixed venous carbon dioxide (PvCO2) in normal and COPD subjects. The mean values and standard deviations for determinations of blood gases and acid-base status in Thoroughbred horses in training were as follows: PaO2 = 77,4 +/- 4,3 mm Hg; PvO2 (mixed venous oxygen partial pressure) = 36,2 +/- 4,1 mm Hg; PaCO2 = 40,9 +/- 5,8 mm Hg; PvCO2 = 49,4 +/- 5,0 mm Hg; pHa (arterial) = 7,358 +/- 0,051; pHv (venous) = 7,343 +/- 0,027; standard bicarbonate = 22,7 mM/l. The PaO2, the PaCO2 and the arterial pH were significantly correlated to the respiratory frequency in COPD subjects. The correlations of pulmonary diastolic pressure to both PaO2 and pHa were of probable significance (P less than 0,05) in COPD subjects. PaCO2 was highly significantly correlated to PaO2 and pHa in COPD subjects.

Studies on the physiopathology of chronic obstructive pulmonary disease in the horse. VII. Percentage venous admixture.

The percentage venous admixture was calculated in 21 clinically normal horses and ponies and in 13 horses and ponies with chronic obstructure pulmonary disease (COPD). The oxygen contents of pulmonary end-capillary blood, arterial and mixed venous blood were calculated from blood and respiratory gas values and substituted in the shunt equation. The mean percentage venous admixture of the COPD subjects was significantly greater than that of the normal subjects. It was concluded that a larger proportion of alveoli in the lungs of COPD subjects were hypoventilated than that of alveoli of the normal lungs.

Studies on the physiopathology of chronic obstructive pulmonary disease in the horse. VIII. Mean modal vectors of the P wave and the QRS complex.

Mean modal vectors of P1, P2 and QRS were determined in the 3 planes of a semi-orthogonal EKG lead system in 17 horses and ponies with chronic obstructive pulmonary disease (COPD) and in 17 clinically normal horses and ponies. Subjects were paired so that the heart rates of each pair were not dissimilar by more than 2 cycles per minute. Probably significant differences were observed between the mean angles of P1 vectors in the transverse and sagittal planes (T plane, normal = 324 degrees +/- 24,6 degrees, COPD = 342 degrees +/- 21,0 degrees, t = 2,0, P less than 0,05; S plane, normal = 331 degrees +/- 22,6 degrees, COPD = 348 degrees +/- 16,2 degrees, t = 2,52, P less than 0,02). There were no significant differences between the mean angles of planar modal QRS vectors of normal subjects and those of COPD subjects.

Pulmonary arterial haemodynamics and blood gas values of Thoroughbred racehorses with a history of epistaxis during a race.

In ten Thoroughbred racehorses which suffered epistaxis during a race, the mean pulmonary arterial diastolic pressure (PADP) was significantly higher, and the mean pulmonary arterial oxygen tension (PaO2) was significantly lower, than the corresponding mean values of a sample of fourteen clinically normal Thoroughbreds in training. The authors conclude that in horses with epistaxis during a race, pulmonary dysfunction may persist for up to two months after the episode, and that the results indicate a need for pulmonary function studies before and after racing, in order to resolve problems concerning exercise-induced pulmonary haemorrhage.

The ratio of cardiopulmonary blood volume to stroke volume as an index of cardiac function in horses.

A method was developed for determining the ratio of cardiopulmonary blood volume to stroke volume, in horses. The radioisotope 99 Tc (technetium 99m pertechnetate) was injected into the jugular vein as a bolus, which was then detected in the right and left ventricles consecutively by a scanning device consisting of a Na I crystal, a collimator, an amplifier and a discriminator. The radiocardiogram (RCG) and the ECG were recorded simultaneously by a two-channel writing device. The ratio of cardiopulmonary blood volume to stroke volume (cardiopulmonary flow index = CPFI) was then determined from the RCG and ECG tracings. Five categories of horses were examined, viz. Thoroughbreds in training, showjumpers in training, horses not in training, horses with cardiovascular disease and horses with chronic lung disease. The mean CPFI of the above categories were respectively 7.0 +/- 0.39, 7.3 +/- 0.45, 6.7 +/- 0.61, 9.8 +/- 1.30 and 6.2 +/- 0.47. The mean CPFI of the subjects with heart disease was significantly greater than the mean values of the other four categories (P less than 0.001). It was concluded that the CPFI was a reproducible physiological parameter in horses and that the value was significantly increased in our series of subjects with heart disease.

An apparatus for collecting blood samples by radiotelemetry from horses during exercise.

An apparatus was designed to collect four consecutive blood samples from exercising horses. The collection of each sample was controlled by valves activated by radiotelemetry signals transmitted by an observer. Using the device, venous blood samples were collected from ten thoroughbred racehorses before, during and after a 400 m training gallop. Blood glucose increased markedly post-exercise. Both phosphorus and potassium concentrations increased during exercise, decreased post-exercise and recovered to pre-exercise levels within 120 minutes. The system was modified to collect anaerobic samples of arterial and venous blood, and the efficiency of the modified system was investigated in a standing conscious horse. Blood gas values of samples collected by means of the apparatus were compared with those collected manually and simultaneously, directly from the neck of the intravascular catheter. For eight pairs of arterial and venous samples, the coefficients "r" were 0.998 and 0.997 for PO2 and PCO2 respectively. It was concluded that the system worked efficiently and that the anaerobic sealing of the modified version was adequate.

The effect of lateral and dorsal recumbency on cardiopulmonary function in the anaesthetised horse.

The effect of lateral and dorsal recumbency on cardiopulmonary function in six anaesthetised horses were compared. Cardiac output/kg, stroke volume/kg, alveolar ventilation, venous admixture, pulmonary shunt and blood-gas values were determined. From lateral to dorsal recumbency cardiac output/kg decreased non-significantly. A significant increase in pulmonary shunt occurred. A positive correlation between body mass and pulmonary shunt in dorsal recumbency was found. Alveolar ventilation increased significantly in dorsal recumbency when breathing air compared to oxygen.

Some aspects of the epidemiology of equine babesiosis.

The sex, coat colour, age, province and month of occurrence of every case of babesiosis was recorded in a horse population of 5856 in South Africa and Rhodesia. A total of 115 cases were recorded during the period 1973-01-01 to 1973-12-31. Chisquared tests were used to evaluate the significance of frequencies. Significant biases in the distribution of cases of babesiosis were found with regard to season (P < 0,05), sex (P < 0,001) and coat colour (P < 0.01).