Effects of general anesthesia on myoelectric activity of the intestine in horses.

Myoelectric activity was monitored from the terminal ileum, cecum, and colonic pelvic flexure by use of AgpAgCl bipolar electrodes in 4 adult horses before, during, and after general anesthesia. Horses were anesthetized by way of 3 commonly used regimens, including xylazine (1.1 mg/kg of body weight) and ketamine hydrochloride (2.2 mg/kg); thiopental sodium (7.7 mg/kg), followed by halothane vaporized in oxygen; and thiopental sodium (2.5 g) in guaifenesin (100 mg/ml) solution given to effect, followed by halothane in oxygen. All 3 anesthetic regimens decreased intestinal spike-burst activity in the areas monitored. The slowest return to preanesthetic myoelectric activity was observed after xylazine and ketamine administration. After both of the barbiturate/halothane anesthetic regimens, there was a rebound increase in spike-burst frequency, without alteration in the proportion of propagative myoelectric events. All 3 anesthetic regimens appeared to reset the timing of the small and large intestinal migrating myoelectric complexes. By 9 hours after recovery from anesthesia, the effects of anesthesia, irrespective of regimen, had disappeared. Although anesthesia significantly (P less than 0.05) altered intestinal myoelectric activity, no particular anesthetic regimen had a prolonged effect. Results of our study indicate that the particular chosen regimen of general anesthesia is unimportant in development of motility disturbances in horses after anesthesia.


Effect of xylazine on cerebrospinal fluid pressure in conscious horses.

Lumbosacral CSF pressure was measured in 6 horses via a catheter inserted through the lumbosacral space. Heart rate, facial artery pressure, central venous pressure, and CSF pressure were measured before IV injection of a saline solution control, for 15 minutes after saline solution injection, and for 60 minutes after the IV injection of 1.1 mg of xylazine/kg of body weight. Arterial pH and blood gases were analyzed before saline solution injection, 15 minutes after saline solution injection, and at 15, 30, and 60 minutes after xylazine injection. Constant craniocervical posture was maintained during sedation. Lumbosacral CSF pressure was significantly decreased for 15 minutes after xylazine injection. Diastolic arterial pressure was significantly increased 4 minutes after xylazine administration and diastolic and mean arterial pressure were increased at 6 and 8 minutes after xylazine administration. Small increases in systolic arterial blood pressure and central venous pressure, and a small decrease in heart rate were observed. There were no significant differences in the arterial blood gas values. It was concluded that IV injection of xylazine causes a decrease in intracranial pressure in healthy conscious horses. The effects may be different in horses with neurologic disease or cerebral trauma.


Influence of cyclooxygenase inhibitors on furosemide-induced hemodynamic effects during exercise in horses.

Furosemide, which commonly is used as a prophylactic treatment for exercise-induced pulmonary hemorrhage in horses, may mediate hemodynamic changes during exercise by altering prostaglandin metabolism. To determine if furosemide's hemodynamic effects during exercise in horses could be reversed, cyclooxygenase inhibitors were administered with furosemide. Four treatments were administered 4 hours prior to treadmill exercise at 9 and 13 m/s. They included a control treatment (10 ml of 0.9% NaCl solution, IV), furosemide (1 mg/kg of body weight, IV) administered alone, and furosemide in combination with phenylbutazone (4 mg/kg, IV, q 12 h for 2 days) or with flunixin meglumine (1.1 mg/kg, IV, on the day of experiment). Five horses were randomly assigned to complete all treatments. Physiologic variables at rest prior to exercise were not influenced by treatments. Furosemide, administered alone, reduced mean right atrial pressure and mean pulmonary artery pressure during exercise. The combinations of furosemide and flunixin meglumine or furosemide and phenylbutazone, at both levels of exercise intensity, returned mean right atrial pressure and mean pulmonary artery pressure to the value of the control treatment. During rest and exercise, plasma lactate concentration, PCV, heart rate, mean carotid artery pressure, oxygen consumption, carbon dioxide elimination, and cardiac output were not altered by any of the treatments. At 5 minutes after exercise, the administration of furosemide, alone or with phenylbutazone, reduced mean right atrial pressure. Other measured variables were not significantly influenced by treatments during recovery from exercise. These results suggested that cyclooxygenase inhibition partially reverses the decrease in mean right atrial pressure or pulmonary artery pressure induced by furosemide during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)


Kinetics of healing of grafted and nongrafted wounds on the distal portion of the forelimbs of horses.

Full-thickness, circular, cutaneous wounds (5 cm in diameter) were created on the distal portion of the forelimbs of 6 horses. One wound on each horse was treated with 6 full-thickness punch grafts that were obtained from the horse's neck with a 6-mm skin biopsy punch and inserted in the graft sites on day 14 after wounding. The wound on the contralateral limb was not grafted. A combination of ticarcillin disodium and clavulanate potassium was applied to the wounds when bandages were changed to control bacterial infection. Areas of each wound were measured on days 1, 7, 9, 11, 13 through 15, 17 through 22, 24, 26, 29, and 32 after wounding. Three distinguishable phases of healing were observed (expansion, contraction, and epithelialization), and the time course of each phase was evaluated, using formulas of first-order processes. Rate constants of each phase were not significantly (P less than 0.05) affected by punch grafts.


Effects of split-thickness and full-thickness skin grafts on secondary graft contraction in horses.

Full-thickness, circular (4-cm diameter) cutaneous wounds were created on the metacarpi and metatarsi of 6 horses. Immediately after wounding, 1 wound on each horse received a meshed, split-thickness skin graft (0.64 mm) obtained from the ventrolateral aspect of the horse's thorax by use of a pneumatic dermatome, whereas a second wound received a meshed, full-thickness skin graft obtained from the pectoral area. In addition, sections of split-thickness and full-thickness grafts were refrigerated in a solution of McCoy's 5A medium, to which equine serum (10%) and gentamicin sulfate solution (16 mg/dl) were added. Ten days after wounding, 1 granulating wound on each horse was grafted with a stored, meshed, split-thickness graft, and 1 granulating wound on each horse was grafted with a stored, meshed, full-thickness graft. Areas of wounds were calculated from photographs taken of wounds on days 1, 5, 10, 15, 20, 25, and 30 after wounding. Time course of contraction was determined by use of a first-order mathematic model of changes in area through time. Rate constants of contraction for fresh or granulating wounds receiving full-thickness grafts did not differ significantly from those for fresh or granulating wounds receiving split-thickness grafts. Rate constants of contraction for grafted fresh wounds, however, were significantly less than those of grafted granulating wounds, regardless of whether a split-thickness or full-thickness graft was applied.


Influence of wound shape on wound contraction in horses.

Three sets of paired circular and square full-thickness skin wounds were made on the dorsum of the metacarpus (n = 48) of 8 horses. Each wound was 6.25 cm2 in area. The wounds were treated topically with an ointment, nonadherent dressing, and bandaged with a snug elastic wrap. Wounds were photographed every other day until healing was complete. Wound areas were measured and exponential and linear wound healing models were applied to the wound healing data generated. Wound healing variables measured for each wound were: number of days to healing, maximal size attained, rate of wound contraction (calculated by use of first-order and linear models), final wound size, and percentage of wound that healed by contraction. The exponential model fit the data significantly better than the linear model. The maximal size attained by circular wounds was significantly smaller than the maximal size attained by square wounds. Wound shape did not influence the rate of wound healing. On the basis of our findings, conversion of circular defects to square defects would not speed wound healing.


Fate and effect of autogenous osteochondral fragments implanted in the middle carpal joint of horses.

Four autogenous osteochondral fragments removed from the lateral trochlear ridge of the talus were arthroscopically placed as loose bodies in a randomly selected middle carpal joint in each of 10 horses. The contralateral middle carpal joint, subjected to a sham procedure, served as control. Postoperative treatment was consistent with that for clinical arthroscopic patients. Lameness evaluation, radiographic examination, carpal circumference measurement, and synovial fluid analysis were performed before and at scheduled intervals after surgery. After a 2-month confinement, horses were subjected to an increasing level of exercise. Horses were euthanatized at intervals through 6 months. Gross and microscopic evaluations were performed on remaining fragments, articular cartilage, and synovial membrane of each middle carpal joint. Increased joint circumference, effusion, lameness, and degenerative joint disease distinguished implanted from control joints over the 6-month period. Implanted joints were characterized by grooved, excoriated cartilage surfaces, and synovium that was thick, erythematous, and irregular. At 4 weeks, implants were found to have adhered to synovium at their subchondral bone surface. The bone within fragments was undergoing necrosis, while cartilage was preserved. At 8 weeks, fragments were radiographically inapparent, grossly evident as pale plaques on the synovial surface, and composed of dense fibrous connective tissue. Synovial membrane specimens from implanted joints had inflammatory change characterized by mononuclear cell infiltration 2 months after implantation. Physical damage was apparent within articular cartilage of implanted joints at 2 months, and was significant (P less than 0.05) at 6 months after surgery. Chondrocyte degenerative change was significant (P less than 0.05) at 6 months after surgery. Focal reduction in safranin-O uptake was observed in cartilage layers adjacent to physical defects. Osteochondral loose bodies of the size implanted in the middle carpal joint of horses in this study were resorbed by the synovium within 2 months. Synovitis and significant articular cartilage damage were associated with the implanted fragments. Regardless of origin, free osteochondral fragments within the middle carpal joint should be removed, and methods to prevent residual postoperative debris should be implemented to reduce potential for articular pathologic change.


Long-term cannulation of the ovarian vein in mares.

A cannulation technique was developed to collect blood samples from the ovarian vein of mares over an extended period. Ovarian venous cannulae placed in 4 mares remained patent for a mean (+/- SEM) duration of 36.8 (+/- 6.2) days. During mid-diestrus, concentrations of progesterone in the ovarian vein ipsilateral to the corpus luteum (1,663.8 +/- 238.8 ng/ml) were significantly (P less than 0.001) higher than concentrations measured in paired samples from the jugular vein (6.1 +/- 0.3 ng/ml). Concentration of estradiol in the ovarian vein ranged from a mean of 1,053.2 +/- 303.1 pg/ml during diestrus to 3,353.8 +/- 1,052.8 pg/ml during estrus, whereas values for 74% of samples collected concurrently from the jugular vein were near or below the sensitivity of the assay (10 pg/ml). Results of the study indicate that patent long-term ovarian vein cannulation can be achieved in mares. The cannulation technique provides access to important fundamental information on equine reproductive endocrinology, which to our knowledge, has not been available.


Treatment of reperfusion injury in dogs with experimentally induced gastric dilatation-volvulus.

In dogs, gastric dilatation-volvulus (GDV) is characterized by cardiogenic shock, with resulting hypoperfusion. Treatment goals include reperfusion of transiently ischemic tissues, which indicates that reperfusion injury may be a factor in the physiopathogenesis of GDV. Recently, we obtained data that indicate that reperfusion injury may be involved in experimentally induced GDV. Using this GDV model, we evaluated mortality in 24 dogs of 4 equal groups, treated with deferoxamine (an iron chelator), dimethylsulfoxide (a free radical scavenger), a combination of the 2 drugs, or isotonic saline solution. All 6 dogs that were given deferoxamine survived; however, 3 dogs of the dimethylsulfoxide-treated group, 2 dogs of the combination-treated group, and 4 dogs of the saline-treated group died. Results of the study indicate that mortality associated with experimentally induced GDV is reduced by appropriate and timely pharmacologic intervention to prevent or attenuate reperfusion injury, and that deferoxamine may be more effective than dimethylsulfoxide.


Evaluation of the proximal portion of the femur as an autogenous cancellous bone donor site in dogs.

The proximal portion of the femur was evaluated as a source of autogenous cancellous bone in dogs. Bilateral oval cortical defects were created in the lateral subtrochanteric area of the femur in 16 dogs. Cancellous bone was removed and the weight recorded. Cancellous bone was similarly harvested from the proximal portion of the humerus in 7 of these dogs. Subtrochanteric femoral defects in 11 dogs were randomly assigned to receive cancellous bone graft obtained from the femur (n = 4) or the humerus (n = 7). Subtrochanteric defects in 5 dogs were not grafted. Radiographic assessment of subtrochanteric defects was performed at 4-week intervals, and histologic assessment at 4, 8, 16, and 24 weeks after surgery. Nongrafted donor sites healed by ingrowth of trabecular bone during the first 12 weeks after surgery. By week 24, the lateral cortical wall had reformed, but remodeling was incomplete. Donor sites grafted with cancellous bone healed similarly, but with more rapid healing and more complete remodeling evident by week 24. Although the mean weight of cancellous bone harvested from the proximal portion of the femur (0.82 +/- 0.22 g) was significantly (P less than 0.05) less than that harvested from the proximal portion of the humerus (1.38 +/- 0.29 g), there was no qualitative histologic or radiographic difference in bony healing of grafted defects. We determined that the proximal portion of the femur can be safely used to provide moderate amounts of cancellous bone, and that a second bone graft can be collected from the same subtrochanteric donor site after 12 weeks.


Radiographic/morphologic investigation of a radiolucent crescent within the flexor central eminence of the navicular bone in thoroughbreds.

The source of a previously described radiolucent crescent in the flexor cortex of the distal sesamoid (navicular) bone on the palmaro45 degrees proximal-palmarodistal oblique (Pa45 degrees Pr-PaDio) clinical radiographic projection was investigated in 48 forelimb navicular bones from 24 Thoroughbreds by use of high-detail radiography and x-ray computed tomography (CT). Twenty-five of these bones also were evaluated, using microradiography and histologic examinations. Of these 25 bones, 5 had been labeled in vivo with fluorochrome markers. Tetrachrome-stained 100-microns-thick nondecalcified sections of these 5 bones were examined, using epifluorescence microscopy. A reinforcement line of compacted cancellous bone, parallel and several millimeters deep to the flexor cortex in the region of the flexor central eminence, was visualized by CT in 42 of 48 navicular bones and by microradiography in 23 of 25 navicular bones investigated. Variable degrees of compaction were observed in the cancellous bone between the flexor cortex and the reinforcement line. High-detail skyline radiographic projections and reconstructed CT images indicated a crescent-shaped lucency within the flexor central eminence of the flexor cortex in the bones in which the reinforcement line was identified, but the cancellous bone between the reinforcement line and the flexor cortex had not been compacted. The radiolucent crescent seen in the flexor central eminence of the navicular bone on the Pa45 degrees Pr-PaDiO projection was not caused by the concave defect or synovial fossa of the flexor central eminence overlying the flexor cortex, as was described.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of standard and radionuclide methods for measurement of glomerular filtration rate and effective renal blood flow in female horses.

Comparison of standard and radionuclide methods for measuring glomerular filtration rate (GFR) and effective renal blood flow (ERBF) was performed in 8 healthy female horses. Inulin and p-aminohippurate solutions were administered IV as a bolus, followed by sustained administration. Urine and plasma inulin and p-aminohippurate concentrations and urine volume were measured. Glomerular filtration rate and ERBF were calculated on the basis of these measurements. Glomerular filtration rate and ERBF were measured on the basis of plasma clearance of the radiopharmaceuticals, 99mTc-labeled diethylene-triaminepentaacetic acid (99mTc-DTPA) and [131I]-o-iodohippuric acid (131I-OIH), respectively. Mean +/- SEM GFR, using inulin, was 1.83 +/- 0.21 ml/min/kg of body weight. Mean GFR, using 99mTc-DTPA was 1.79 +/- 0.18 ml/min/kg. Mean ERBF, using p-aminohippurate, was 15.13 +/- 1.28 ml/min/kg. Mean ERBF, using 131I-OIH, was 18.42 +/- 1.57 ml/min/kg. Analysis of variance indicated no significant difference between mean values for GFR and ERBF. Radionuclide measurement of GFR and ERBF compared well with standard methods and is an alternative technique to the cumbersome standard methods for determination of GFR and ERBF in horses.


Use of end-tidal CO2 tension to predict arterial CO2 values in isoflurane-anesthetized equine neonates.

End-tidal carbon dioxide tension (PetCO2) and arterial carbon dioxide tension (PaCO2) were determined and compared in isoflurane-anesthetized spontaneously breathing equine neonates. End-tidal carbon dioxide and PaCO2 values increased with respect to time. Difference between values of PetCO2 and PaCO2 increased over time. End-tidal carbon dioxide tension was useful to predict changes in and was more closely correlated with PaCO2 early in the anesthetic period (T less than or equal to 60 minutes). The dead space volume to tidal volume (Vd/Vt) ratio increased with respect to time, indicating increase in physiologic dead space in isoflurane-anesthetized foals. The data indicate that the increased difference between widening of the PetCO2 and PaCO2 values over time may have been attributable to hypoventilation and decreased pulmonary capillary perfusion of alveoli.


Comparison of the nonionic contrast agents, iopromide and iotrolan, for positive-contrast arthrography of the scapulohumeral joint in dogs.

Arthrographic quality and synovial inflammatory response were examined to compare the use of iopromide with that of iotrolan for arthrography of the scapulohumeral joint in 6 dogs. Radiographs obtained 1 and 3 minutes after injection of either nonionic compound were of similar quality, but radiographs obtained 5 minutes after injection of iotrolan were significantly (P less than 0.05) better than those obtained after injection of iopromide. Results of analysis of synovial fluid samples obtained at 1, 3, 7, and 14 days after injection of contrast media were not significantly different between the 2 groups. Histologic examination of synovium and articular cartilage 2 weeks after injection of iopromide or iotrolan revealed minimal inflammatory response for both contrast agents. Injection of iopromide and iotrolan into the scapulohumeral joints of dogs had less effect on synovial fluid than that reported after injection of ionic compounds.


Cortical somatosensory evoked potentials in cows.

A method was developed to record cortical somatosensory evoked potentials (SEP) from thoracic and pelvic limb stimulation in cows. Recordings were similar in latency and amplitude to those reported for horses. Correction for conduction pathway length did not alter the average latency values because the cows of the study were uniform in size; however, the data provided will enable use of this normative data with smaller or larger individual animals. Although latency variability for the SEP peaks was low, variability of the amplitude measurements was high. This observed variability was similar to that seen in other species. Validity of the recorded responses was indicated by lack of a tibial nerve SEP in 1 cow that had been given a tibial nerve conduction block, using lidocaine, and by repeatability of the response in 2 recordings taken 1 year apart in the same cow.


Effects of low-dose aspirin and specific thromboxane synthetase inhibition on whole blood platelet aggregation and adenosine triphosphate secretion in healthy dogs.

Platelet aggregation and adenosine triphosphate (ATP) secretion in response to arachidonic acid (10 microM) or collagen (5 micrograms/ml) were compared in healthy, adult female Beagles treated with low-dosage aspirin (3.5 mg/kg of body weight, PO, q 12 h for 7 treatments) or with CGS 12970, a specific thromboxane synthetase inhibitor (10 mg/kg, PO, q 8 h for 10 treatments). Platelet aggregation was assessed in whole blood by use of an electrical impedance method. Baseline values obtained prior to treatment served as controls. Addition of arachidonic acid to blood from nontreated dogs resulted in significantly (P less than 0.001) increased impedance, but had no effect in blood from dogs treated with either aspirin or CGS 12970. Treatment with CGS 12970 or aspirin significantly (P less than 0.001) decreased platelet ATP secretion in response to arachidonic acid, compared with baseline values; however ATP secretion in aspirin-treated dogs was significantly (P less than 0.01) less than ATP secretion in CGS 12970-treated dogs. Differences in platelet aggregation were not observed between control dogs and aspirin- or CGS 12970-treated dogs in response to collagen as an aggregant, however, collagen-induced platelet ATP secretion was significantly (P less than 0.001) decreased in dogs treated with aspirin, compared with control values and values from dogs treated with CGS 12970. In dogs treated orally with 0.1, 0.2, 1.0, or 10 mg of CGS 12970/kg, dose-dependent inhibition of arachidonic acid-induced platelet aggregation was observed, with impedance changes not observed at the 10-mg/kg dosage and normal platelet aggregation associated with the 0.1-mg/kg dosage.(ABSTRACT TRUNCATED AT 250 WORDS)


Serum free and total iodothyronine concentrations in dogs with hyperadrenocorticism.

Serum concentrations of total and free thyroxine (T4 and FT4, respectively), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (reverse T3) were measured in 42 dogs with hyperadrenocorticism, and were compared with values determined in clinically normal dogs. Mean total T4 concentration in dogs with hyperadrenocorticism (14.3 nmol/L) was significantly (P less than 0.001) lower than the normal value (25.7 nmol/L), with 38% of the dogs having low serum T4 concentration. Although 16 (38%) of the 42 dogs with hyperadrenocorticism had a high FT4 fraction, indicative of diminished serum T4 binding, normal FT4 concentration was found in only 6 of the 16 dogs (38%) with low total T4 values. Mean serum T3 concentration in dogs with hyperadrenocorticism (0.79 nmol/L) was also significantly (P less than 0.001) lower than the normal value (1.16 nmol/L), with 39% of the dogs having T3 values below the normal range. Individual T3-to-T4 and T3-to-FT4 ratios, indices of T3 production and/or clearance, were above the normal range in 29 and 24% of dogs with hyperadrenocorticism, respectively. Mean reverse T3 concentration in dogs with hyperadrenocorticism (0.17 nmol/L) was also significantly (P less than 0.001) lower than the normal mean value (0.39 nmol/L), with 48% of the dogs having reverse T3 values below the normal range. Of the 21 dogs in which all iodothyronines were measured, 6 (29%) had undetectable values for all hormones.(ABSTRACT TRUNCATED AT 250 WORDS)


Measurement of total volume and protein concentration of intrauterine secretion after intrauterine inoculation of bacteria in mares that were either resistant or susceptible to chronic uterine infection.

Undiluted uterine secretion was used to determine the concentration of total protein and the accumulated volume of uterine secretion after a bacterial inoculation in mares susceptible and resistant to chronic uterine infection (CUI). The uterus of 6 susceptible and 5 resistant mares was inoculated with 5 x 10(6) Streptococcus zooepidemicus on the third day of estrus. Using a tampon inserted in the uterus, secretions were sampled at 5, 12, 24, and 36 hours after inoculation, followed by intrauterine lavage with phosphate buffered saline solution. The concentration of protein was determined in the undiluted secretion as well as in the uterine washing and the total amount of accumulated uterine secretion was calculated. Protein concentrations in plasma were compared before and after absorption by the tampon. Protein concentration of plasma before and after absorption by the tampon did not differ. Mares susceptible to CUI accumulated significantly (P less than 0.001) more fluid in the uterus than mares resistant to CUI, and uterine washings from the resistant mares were significantly (P less than 0.05) more dilute than those from the susceptible mares. Significant differences in protein concentrations between susceptible and resistant mares were not found. It was concluded from this study that the described method to sample undiluted uterine secretion was practical and reliable for the analysis of protein concentration. Various concentrations of uterine secretions in washings from susceptible and resistant mares emphasizes the importance in using undiluted uterine secretions or dilution markers in washings when intrauterine products are analyzed.


Effect of head and neck position on respiratory mechanics in horses sedated with xylazine.

We studied the temporal changes in respiratory mechanics associated with xylazine administration (1.1 mg/kg of body weight, IV) in standing horses (experiment 1), and determined the effects of head and neck position (experiment 2) and atropine administration (experiment 3) on the observed changes. Thoroughbred geldings, 3 to 5 years old (5 in experiment 1, 4 in experiments 2 and 3) were used. Flow rates were obtained from a pneumotachograph and a differential transducer attached to a tight-fitting mask. Electronic integration of the flow signal gave tidal volume. Total pulmonary pressure (PL) was defined as the difference between esophageal pressure, measured with a balloon sealed to the end of a polyethylene catheter, and mask pressure. In experiment 3, a blunt cannula positioned in the dorsal third of the eighth or tenth intercostal space was used to estimate transpulmonary pressure. Lateral tracheal pressure was measured, using a polypropylene catheter inserted percutaneously in the midextrathoracic tracheal lumen. Upper and lower airway pressures were defined as the difference between mask pressure or transpulmonary pressure and lateral tracheal pressure, respectively. Five observations were made: (1) There was a significant (P less than 0.05) increase in PL from 10 to 40 minutes after administration of xylazine. (2) Although an overall agreement between head and neck position and PL was detected, the maximal PL value was not always obtained with lowest head and neck position. (3) Lower and upper airway resistance increased with low head carriage, with a greater increase in upper airway resistance resulting in a decrease in lower to total airway resistance ratio.(ABSTRACT TRUNCATED AT 250 WORDS)


Pharmacokinetics and local tolerance of a long-acting oxytetracycline formulation in camels.

Disposition and local tolerance of a new oxytetracycline (OTC) long-acting formulation were evaluated in camels by measuring the dynamics of creatine kinase. Six camels (Camelus dromedarius) were administered OTC by IV and IM routes according to a 2-period cross-over, study design. Serum OTC concentration was measured, using a microbiological assay procedure. After IV administration (5 mg/kg of body weight), mean residence time was 7.7 +/- 2.8 hours, steady-state volume distribution was 706.1 +/- 168.6 ml.kg-1 and serum clearance was 75.3 +/- 23.2 ml.kg-1.h-1. After IM administration of the long-acting OTC formulation (10 mg/kg), maximal OTC concentration (3.49 +/- 0.44 micrograms.ml-1) was observed after 7.3 +/- 3.5 hours; the mean systemic availability was near 100%, and serum concentration greater than 0.5 micrograms.ml-1 was maintained for about 72 hours. After IM administration, mean control serum activity of creatine kinase was multiplied by a factor of 3.36 +/- 1.55; at 72 hours after OTC administration, the serum creatine kinase activity returned to control values. It was concluded that OTC is an antibiotic of potential interest in camels and that a dosage regimen of 10 mg.kg-1 deserves attention when using a long-acting formulation that has good local tolerance and near total systemic availability.


Effect of repeated doses of albendazole on enantiomerism of its sulfoxide metabolite in goats.

Five adult Saanen goats were dosed orally 3 times with albendazole (2.5 mg/kg of body weight) at 24-hour intervals, and blood samples were taken by jugular venapuncture at standardized intervals. Plasma was analyzed to determine concentrations of S-oxidation metabolites, and a chiral column was used for enantiomeric discrimination of the sulfoxide metabolite of albendazole. Marked changes were evident between the first and subsequent plasma profiles concerning, on one hand, the proportions of sulfoxide and sulfone metabolites concentrations and, on the other hand, the enantiomeric balance of sulfoxide metabolite. These correlated phenomena may be explained by the following arguments: the enzyme responsible for sulfoxidation is mainly a flavine-containing monooxygenase, whereas the enzyme responsible for sulfonation is a cytochrome-dependent monooxygenase; the latter, but not the former, is induced by albendazole; the enantioselectivities of both enzymic systems are opposite, the flavine produces the (+) sulfoxide, whereas the cytochromes can use as a substrate, specifically, the (-) sulfoxide.


Evaluation of a one-hour saline diuresis protocol for administration of cisplatin to dogs.

A study was undertaken to determine the toxic effects of cisplatin, an antineoplastic agent, when administered immediately after a 1-hour saline diuresis. Four treatments with cisplatin (70 mg/m2 of body surface, q 3 wk) were administered IV to 6 healthy dogs over a 20-minute period after 0.9% NaCl (saline) solution was administered IV for 1 hour at a volume of 132 ml (kg)0.75. Each dog vomited at least once within 8 hours after each treatment was administered. Clinical status, body weight, and food consumption were normal throughout the 12-week study for 5 of the 6 dogs. The sixth dog developed acute renal failure and became acutely blind and deaf within 3 days after the fourth treatment with cisplatin. Serum electrolyte, creatinine, and urea nitrogen values remained within established normal limits in all dogs immediately prior to each treatment, and in 5 of 6 dogs evaluated 3 weeks after the final treatment. The serum creatinine value (3.3 mg/dl) obtained from the Beagle euthanatized 2 weeks after the fourth treatment was above established normal values. Despite normalcy for all but 1 of the creatinine values, serum creatinine concentration obtained 3 weeks after the final treatment with cisplatin was significantly (P = 0.0001) higher than pretreatment values. When compared with data from all other evaluation periods, significant decreases in glomerular filtration rate, as determined by exogenous (P less than or equal to 0.0001) and endogenous (P less than or equal to 0.0001) creatinine clearance testing, were identified 3 weeks after the fourth treatment with cisplatin.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of allergen challenge on plasma concentrations of prostaglandins, thromboxane B2, and histamine in calves infected with bovine respiratory syncytial virus.

To examine the influence of allergen-induced type-1 hypersensitivity on the pathogenesis of bovine respiratory syncytial virus (BRSV) infection, we sensitized calves by aerosol to Micropolyspora faeni (MF) and challenge exposed them during infection with BRSV. The development of MF-specific IgE serum concentrations was confirmed by ELISA. The dynamics of arachidonic acid metabolism and histamine release during a type-1 hypersensitivity reaction in the bovine lung were studied by quantitating the concentrations of prostaglandin (PG)E2, PGF2 alpha, PGI2 as 6-keto-PGF1 alpha, thromboxane (TX) A2 as TXB2, and histamine in plasma of BRSV-infected and/or MF-sensitized/challenge-exposed calves. Four treatment groups were established: (1) BRSV infection only, (2) aerosol sensitization to MF followed by BRSV infection and aerosol challenge exposure to MF, (3) MF aerosol sensitization and challenge exposure without BRSV infection, and (4) aerosol sensitization to MF followed by BRSV infection without MF challenge exposure. Significantly increased concentrations of PGI2 were associated with MF aerosol exposure, particularly when combined with BRSV infection in group 2. After MF challenge exposure, TXB2 concentrations were significantly greater in the virus and MF challenge-exposed group 2. Individual calf data for the change in MF-specific IgE concentration between the first and second MF challenge exposures and the change in PGE2 concentration 30 minutes after the second MF challenge exposure had a highly significant direct correlation. Histamine concentrations were significantly greater in calves infected with BRSV than in uninfected controls regardless of MF exposure. These data further substantiate the thesis that implicates type-1 hypersensitivity as a pathogenic mechanism in BRSV-related disease.


Protein kinase-C activity in phorbol myristate acetate-stimulated neutrophils from newborn and adult cattle.

Neutrophils from newborn calves have been shown to be deficient in ability to generate superoxide anion (O2-) after stimulation of the respiratory burst enzyme with the phorbol ester, phorbol 12-myristate 13-acetate (PMA). This compound activates the O(2-)-generating enzyme of bovine neutrophils through a pathway involving protein kinase C (PKC). To investigate the biochemical basis underlying this functional difference between neutrophils from newborn and adult cattle, we measured and compared the activity of the enzyme PKC in nonstimulated and PMA-stimulated bovine neutrophils. Neutrophils from newborn calves (n = 5) and adult cows (n = 5) were stimulated with various concentrations of PMA (0, 10, 100, and 500 ng/ml) for 3 minutes, and PKC activity was assayed in the cytosolic and the membrane fractions. In nonstimulated cells, most PKC activity was detected in the cytosolic fraction of neutrophils from newborn and adult cattle. Activity of PKC in the cytosol was dependent on the presence of added calcium and phospholipids, whereas membrane-associated PKC in nonstimulated cells did not have such dependence. Significant differences in PKC activity were not observed between newborn and adult cattle in either the cytosolic or the membrane fractions from nonstimulated cells. Stimulation with PMA caused redistribution of PKC activity in the cell (translocation) in newborns and adults, consisting of decrease in cytosolic PKC activity and increase in membrane-associated PKC activity. Similar to that in nonstimulated cells, PKC activity in cytosolic fractions from PMA-stimulated neutrophils was dependent on the presence of cofactors (calcium and phospholipids), whereas PKC activity in the membrane did not have such requirement.(ABSTRACT TRUNCATED AT 250 WORDS)


Immunolocalization of epidermal growth factor (EGF) and EGF receptors in the porcine upper gastrointestinal tract.

The factors controlling growth and maturation in the porcine gastrointestinal tract are not well understood. Epidermal growth factor (EGF) is a polypeptide that has been implicated in the control of gastrointestinal tract growth, maturation, and protection in other species. Immunoreactive EGF (IR-EGF) and EGF receptors (EGF-R) were histochemically identified in formalin-fixed tissues of the upper digestive tract of 1-, 3-, 7-, 14-, 21-, and 28-day-old pigs. The ductal epithelium consistently contained IR-EGF in the parotid salivary gland of pigs of all ages and in the mandibular salivary gland in pigs greater than or equal to 7 days old. Immunoreactive EGF was detected in the mucosal epithelium of the esophagus and nonglandular portion of the stomach, and in the pancreas and liver in all pigs. Gastric gland IR-EGF was inconsistently detected in pigs less than 14 days old and was consistently observed in all older pigs. Enterocyte EGF immunoreactivity was usually weak and was variably detected in the duodenum of pigs less than or equal to 7 days old and in the jejunum of pigs less than or equal to 14 days old, but was consistently observed in older pigs. Ileal immunoreactivity was erratic. Immunoreactive EGF-R were identified in the esophageal epithelium of all pigs, and in the nonglandular gastric and glandular gastric mucosa of all pigs, except for two 7-day-old pigs and one 7-day-old pig, respectively. Immunoreactive EGF-R were detected in the duodenal, jejunal, and ileal enterocytes of pigs of all ages examined.


Cytogenetic characterization of the Madin-Darby bovine kidney cell line.

The permanent bovine cell line, Madin-Darby bovine kidney, was cytogenetically analyzed. Chromosomal staining indicated 52 metaphase chromosomes with variations from 49 to 54. The isochromosomes 5, 12, and 13, and centric fusions between chromosomes 1 and 26, 9 and 11, 9 and 24, 17 and 25, 18 and 23, 20 and 24, and 24 and 27 were considered marker chromosomes.


Lymphocyte reactivity to antigens of Haemonchus contortus in antigen-inoculated and H contortus-naive lambs.

Lambs were inoculated during either fetal or early neonatal life with antigens of Haemonchus contortus (HcAg) third-stage larvae, or ovalbumin (OVA), or were left untreated. By the time lambs were 4 weeks old, blood lymphocytes from all of them responded to HcAg. This was evident in all lambs, regardless of the previous inoculation regimen, although higher response was seen in HcAg-inoculated lambs, compared with naive lambs. Only lambs inoculated with OVA had OVA-specific lymphocyte activity. In HcAg-naive lambs, the maximal HcAg lymphocyte response was observed between the ages of 5 and 25 weeks, with gradual decrease thereafter. In vitro detection of HcAg-reactive lymphocytes was affected by antigen concentration and presence of plasma. Plasma inhibited HcAg-reactive lymphocytes from all lambs at high in vitro antigen concentration and completely abrogated the response in H contortus antigen-naive lambs.


Histochemical and morphologic changes of porcine airway epithelial cells in response to infection with Mycoplasma hyopneumoniae.

Mycoplasma hyopneumoniae causes pneumonia in pigs. The effect of infection by this organism on histochemical characteristics of airway mucin within epithelial cells was studied. Seven- to 10-week-old pigs were inoculated intratracheally with M hyopneumoniae or culture broth, and lung tissues were collected from inoculated and control pigs at 2, 4, and 6 weeks after inoculation. Tissue sections were stained with periodic acid-Schiff/Alcian blue, pH 2.5 or high iron diamine/Alcian blue. Histologic features of randomly selected bronchi, bronchioles, and submucosal glands were compared in sections stained with periodic acid-Schiff/Alcian blue. Bronchial goblet cell sulfomucin and sialomucin were quantitated by image analysis of sections stained with high iron diamine/Alcian blue. Bronchi and bronchioles of infected pigs contained proportionately fewer goblet cells with mucin at all stages of infection than age-matched control pigs. Goblet cells in bronchi of infected pigs contained significantly less total mucin and sialomucin, and significantly more sulfomucin than goblet cells of control pigs. Increased sulfated mucin in bronchial goblet cells may reflect altered glycoprotein production or secretion in response to infection with M hyopneumoniae.


Identification of halothane gene carriers by use of in vivo 31P nuclear magnetic resonance spectroscopy in pigs.

In vivo muscle 31P nuclear magnetic resonance spectroscopy was performed on 12 homozygous halothane-nonsensitive female pigs and 13 female pigs heterozygous with respect to the halothane gene. Fifteen female pigs of a third line, consisting of heterozygotes and halothane-nonsensitive homozygotes, were also available. Body weight ranged from 12 to 18 kg. Mean decrease in phosphocreatine concentration in the biceps femoris of anesthetized pigs was significantly lower for heterozygous vs homozygous pigs (3.46% vs 5.94%, P less than 0.01) after 40 minutes of halothane exposure (3%; oxygen flow, 3 L/min). Also, a statistically significant difference, with respect to the initial (7.21 vs 7.11, P less than 0.008) and end muscle pH values (7.18 vs 7.06, P less than 0.0002), was observed for homozygous vs heterozygous pigs. By means of canonical discriminant analysis, it was possible to distinguish nonsensitive homozygotes from heterozygotes (P less than 0.0001). When applying this classification method to pigs of the same strain, 2 populations (nonsensitive homozygotes, heterozygotes) emerged, with a proportion of pigs corresponding to the expected value on the basis of breeding records. In contrast to the phenotypic expression of muscular rigidity related to the malignant hyperthermia syndrome, the expression of metabolic variables (phosphocreatine, pH) was shown to be dominant.


Managerial risk factors of intramammary infection with Streptococcus agalactiae in dairy herds in Ohio.

Dairy herds in Ohio were selected by stratified random sampling for participation in a disease-monitoring study to relate Streptococcus agalactiae intramammary prevalence to herd management and environmental conditions. Of 48 herds studied, 27 herds had at least 1 cow infected with this pathogen. Management and environmental conditions were assessed by direct observation as well as by an interview with the dairy producers. One-way ANOVA or chi 2 analysis, with presence or absence of Streptococcus agalactiae as the dependent variable, was used to test each of 70 independent variables. Variables found significant at P less than 0.20 were further evaluated by use of logistic regression. Our sample size permitted only 4 independent variables to be simultaneously evaluated by logistic regression. The most predictive risk factors were identified as poor teat and udder hygiene, poor environmental sanitation, large herd population, and use of a shared washcloth for premilking cleaning of teats and udders.


U.S. mental health policy. Doomed to fail.

Changes in the de facto system of mental health care in the last decade reflect organizational and entrepreneurial responsiveness to changes in health policy, not mental health policy. Various other actions described here reduced statutory or institutional leadership roles in mental health and increased the pace at which mental health policy was becoming dependent on health policy. In turn, U.S. health policy in the 20th century has been inherently flawed. The short-term general hospital--the "doctors' workshop"--emphasizing acute care and surgery, has been the cornerstone of U.S. health policy throughout the 20th century. The mimicry of health services by mental health leads to demonstrably more expensive and less effective mental health care and dooms mental health policy to failure.


The debt of neuropsychology to the epilepsies.

Both neuropsychology and psychology in general have been enhanced markedly by brain-behavior models derived from the study of the epilepsies. A significant body of neuropsychological concepts originated or were confirmed through epilepsy-based treatment and research. These concepts include the peri-Rolandic homunculus, the role of the hippocampal-temporal lobe complex in cognitive memory, hemisphere plasticity for speech in childhood, the intracarotid amytal procedure for determining hemisphere memory patency, and hemisphere-based models of cognition confirmed through human commissurotomy. Personality and social-emotional research in epilepsy are additional areas in which new conceptual models grounded in psychological science can both repay our debt to the epilepsies and provide much needed psychological research and treatment.


Childhood epilepsy and the role of psychology.

The relatively long history of psychology's involvement in the field of epilepsy is discussed. The view of epilepsy is that of a chronic disorder with onset in childhood, at a time when normal development is at risk for interference from the direct and secondary aspects of repetitive seizures, the neurological abnormalities from which they arise, and the clinical interventions that attempt to control them. The objective and scientifically based methods of psychology are viewed as particularly well suited to these topics. Past efforts by psychologists have increased understanding of the syndrome that is epilepsy, and have paved the way for opportunities to further contribute to the theoretically and practically important problems associated with epilepsy.


Psychopathology in epilepsy. The role of psychology in altering paradigms of research, treatment, and prevention.

This article offers a brief review of the literature examining epilepsy and abnormal behavior. The generally accepted concept of epilepsy as a high psychiatric risk disorder is reexamined in light of research that has investigated the influence of selection bias. A conceptual model that organizes the known or postulated risk variables (neurological, psychosocial, and medication) is presented, with emphasis on psychology's potential contribution.


The role of neuropsychology in the assessment and treatment of persons with epilepsy.

Several areas of current interest in the neuropsychology of epilepsy are briefly reviewed in this article. These include variables pertaining to seizures, seizure history, antiepileptic drugs, and methods of neuropsychological evaluation. It is apparent that epilepsy is a multifaceted area: Psychologists not only can be of great assistance to patients with this condition, but may also learn a great deal from this complex disorder.


Inhaled platelet-activating factor causes pulmonary neutrophil sequestration in normal humans.

Inhaled platelet-activating factor (PAF) causes bronchoconstriction and transient peripheral neutropenia in humans. We studied eight normal subjects to investigate whether inhaled PAF caused pulmonary neutrophil sequestration. All subjects received autologous 99mTc-red cells as a blood pool marker, seven received 111In-neutrophils, and one received 111In-platelets. Six subjects inhaled 48 micrograms of PAF. There was immediate pulmonary sequestration of 111In-neutrophils, maximal (218% baseline) at 6 min (p less than 0.001), returning to normal by 3 h. There was no change in circulating platelet count or pulmonary 111In-platelet transit. Methacholine inhalation caused equivalent bronchoconstriction to PAF, but it had no effect on neutrophil count or pulmonary 111In-neutrophil activity. We have demonstrated pulmonary neutrophil, but not platelet, sequestration after PAF. This supports a role for PAF as an inflammatory mediator in humans. This may be a useful model for exploring pulmonary neutrophil kinetics and preinflammatory processes.


Tachykinins increase respiratory clearance of 99mTc-DTPA. Mechanisms of action.

We investigated the effects of tachykinins on the respiratory clearance of 99mTc-DTPA (RC-DTPA) in anesthetized and ventilated guinea pigs. We measured the change in RC-DTPA and in maximal pulmonary insufflation pressure (PIPmax) induced by substance P, neurokinin A, and capsaicin. Substance P, neurokinin A, and capsaicin increased both PIPmax and RC-DTPA in a concentration-dependent fashion. Substance-P- and capsaicin-induced increases in RC-DTPA were unaffected by pretreatment with atropine. Bilateral vagotomy attenuated substance-P-induced change in both RC-DTPA and PIPmax by approximately 70 and 50%, respectively. Capsaicin-induced change in RC-DTPA and PIPmax were slightly but not significantly reduced by bilateral vagotomy. The bronchodilator, salbutamol, dramatically reduced increase in RC-DTPA and in PIPmax induced by substance P, neurokinin A, and capsaicin, but it had no effect on increases in RC-DTPA and PIPmax generated by application of a positive end-expiratory pressure. We conclude that (1) tachykinins increase respiratory clearance to the solute, and (2) tachykinin-induced increase in RC-DTPA is not mediated by cholinergic neurotransmission but rather by the bronchoconstrictor effect of neuropeptides.


31P-NMR study of skeletal muscle metabolism in patients with chronic respiratory impairment.

To evaluate the energy metabolism of peripheral skeletal muscle during exercise in patients with chronic respiratory impairment, the 31P-nuclear magnetic resonance (NMR) spectra of forearm muscle were investigated in nine patients and nine age-matched control subjects. We calculated the phosphocreatine (PCr) to PCr + inorganic phosphate (PI) ratio, the time constant of PCr recovery and the intracellular pH. The exercise consisted of repetitive hand grips against a 2-kg load every 3 s for 6 min (0.33 W). The patients showed a marked decrease in the PCr/(PCr + PI) ratio and pH in the muscle during exercise in contrast to the control subjects whose PCr/(PCr + PI) showed a minor decrease without any change in pH. The relationship between PCr utilization and pH demonstrated that anaerobic glycolysis switched on earlier in patients with chronic respiratory impairment. A split PI peak was observed in five of nine patients during exercise. The PCr/(PCr + PI) ratio during the last minute of exercise correlated significantly with the vital capacity (% predicted), with the FEV1/FVC, with the body weight, with the maximum strength of hand grip, and with the muscle mass. The results indicate impaired oxidative phosphorylation and the early activation of anaerobic glycolysis in the muscles of patients with chronic respiratory impairment. Several factors related to chronic respiratory impairment, such as disuse, malnutrition and dysoxia, would contribute to the metabolic changes observed in the muscles examined.


Respiratory muscle strength in hyperthyroidism before and after treatment.

We undertook this study to investigate respiratory muscle strength in relation to thyroid function in 20 thyrotoxic patients and in a group of 20 normal subjects matched for age and sex. Global respiratory muscle strength was assessed by measuring mouth pressure during maximal static inspiratory (PImax) and expiratory (PEmax) efforts. We also measured VC, FVC, and FEV1 as well as thyroid-related hormones (T3, T4, TSH). Measurements were made once in normal subjects and twice in thyrotoxic patients, before and 3 months after medical treatment. Our results showed that both maximal pressures were significantly reduced (p less than 0.0001) before treatment in thyrotoxic patients in relation to the mean values of the normal subjects (p less than 0.0001), and they increased significantly (p less than 0.0003) after treatment. Lung volumes were significantly reduced (p less than 0.0001) before and increased significantly (p less than 0.008) after treatment. The ratio FEV1/FVC did not change. A statistically significant linear relationship was found when PImax of patients with thyrotoxicosis before treatment and of normal subjects were plotted against thyroid hormones (T3, T4) (r = -0.746 and r = -0.745, respectively, p less than 0.001). Similarly, a statistically significant linear relationship was found between PEmax and T3 and T4 (r = -0.837 and r = -0.838, respectively, p less than 0.001). No relationship was found between maximal pressures and TSH. Finally, a significant linear relationship was found between PImax and PEmax (r = 0.872, p less than 0.001). Our results confirm that in thyrotoxicosis respiratory muscle weakness occurs that affects both inspiratory and expiratory muscles.(ABSTRACT TRUNCATED AT 250 WORDS)


The effects of transcutaneous electrical stimulation during wakefulness and sleep in patients with obstructive sleep apnea.

Upper airway (UA) collapse in obstructive sleep apnea (OSA) is considered in part to result from the decrease in UA dilator muscle tone that occurs during sleep. We hypothesized that augmentation of UA muscle function by transcutaneous electrical stimulation (TES) might function to enlarge UA size during wakefulness and/or prevent UA collapse during sleep in patients with OSA. Eight male patients with OSA were studied both awake and asleep, with TES administered to the submental region in two patients and to both the submental and subhyoid regions in six patients. Fast-CT scans obtained at FRC and end-inspiration (VTei) demonstrated increased UA size with tidal breathing, p less than or equal to 0.05. The active generation of -10 cm H2O pressure at FRC substantially decreased UA size, p less than or equal to 0.001. However, no changes in UA size were detected at either FRC or VTei with TES applied at 50 and 100% of the maximal tolerated intensity. The collapsibility of the UA in response to the generation of -10 cm H2O pressure was also unchanged by TES. In contrast to the lack of effect of TES on UA size, voluntary protrusion of the tongue increased cross-sectional area (CSA) of the orohypopharyngeal (OHP) segment of the UA, p less than 0.05, and to a lesser extent the CSA of the distal velopharyngeal segment, p = 0.06. When applied during sleep, TES failed to prevent or improve either sleep-disordered breathing or sleep architecture.(ABSTRACT TRUNCATED AT 250 WORDS)


Morphometric changes during the early airway response to allergen challenge in the rat.

The purpose of this study was to determine the relative contributions of airway wall edema and smooth muscle contraction to the early response (ER) of allergic bronchoconstriction. Brown Norway rats, 6 to 7 wk old, were sensitized with ovalbumin (OA). Anesthetized rats were challenged with either OA or saline 2 wk later. Pulmonary resistance (RL) was measured every minute until either it increased to 150% of the baseline, defined as a significant ER, or until 15 min elapsed. Eight OA-challenged test rats with a significant ER and eight saline-challenged control rats were used for morphometric studies. The lungs were quick-frozen with liquid nitrogen, processed with freeze substitution, and sagittal sections (5 microns) were stained with hematoxylin and eosin. The airway lumen subtended by the epithelial basement membrane (LuB) and cross sectional airway wall area (AW) of all airways were measured by camera lucida and digitization. The LuB and AW of each airway was standardized for size by dividing by the ideal airway lumen (LuBideal), which was calculated from the length of basement membrane, assuming a perfect circle in the unconstricted state. The cumulative frequency distribution of the LuB/LuBideal for the airways from test rats was shifted to the left compared with the control rats (p less than 0.01), indicating airway narrowing after challenge. Airway narrowing increased as a function of airway size. Cumulative frequency distributions of AW/LuBideal showed that there was a significant increase in the wall thickness of only the small airways of test animals.(ABSTRACT TRUNCATED AT 250 WORDS)


Idiopathic pulmonary fibrosis. Quantitative assessment of lung pathology. Comparison of a semiquantitative and a morphometric histopathologic scoring system.

The objective of this study was to determine the accuracy of a semiquantitative method of assessing the relative degree of cellularity and fibrosis compared with a morphometric analysis of specific histopathologic features in idiopathic pulmonary fibrosis (IPF). Morphometric analysis was performed on biopsy tissue from 20 patients. Morphometry showed that approximately 70% of parenchymal tissue was abnormal: 35% cellular consolidation and fibrosis, 20% honeycomb changes, 10% thick alveolar septa, and 5% small airways within abnormal parenchymal tissue. The prominent components of the abnormal parenchymal tissue were extracellular fibers, an abundance of interstitial cells, and epithelial cell hyperplasia. Correlation between four groupings of pathologic features, identified by a semiquantitative analysis, and each of the components of the parenchymal lesions showed significant correlations between (1) the fibrotic or reparative factor (alveolar wall metaplasia, fibrosis, honeycombing, and smooth muscle and vascular changes) and components of honeycomb lesions (extracellular fibers, interstitial cells, and epithelial injury and repair), and (2) the inflammatory and exudative factor and extracellular fibers in the lesions. These results support that the scoring system used by the pathology panel provides an accurate assessment of pathologic features useful in the assessment of the extent and severity of the histopathologic lesions of IPF.


Reperfusion after a two-hour period of pulmonary artery occlusion causes pulmonary necrosis.

The role of reperfusion injury in the progression to necrosis in pulmonary embolism was evaluated. To simulate this condition, we used a technique that enables occlusion and reopening of the pulmonary arterial branch supplying the right upper lobe in conscious rats. The rats were divided into five groups: the occlusion group (n = 12), in which the pulmonary artery (PA) branch was occluded without reperfusion; the reperfusion group (n = 12), in which the PA branch was reopened after a 2-h period of occlusion; and the reperfusion-SOD (n = 9), reperfusion-IM (n = 8), or reperfusion-IA-SOD (n = 6) groups, in which superoxide dismutase (SOD), indomethacin (IM), or inactivated SOD (IA-SOD), respectively, was administered during reperfusion. The lungs were removed 24 h after the PA occlusion, and histologic examination was performed. In the occlusion group, the alveolar structure of the right upper lobe was well preserved, and there was no erythrocyte or leukocyte accumulation. The only significant changes compared with the control lobe was the appearance of wavy internal elastic lamina of the PA and slight neutrophil adherence to the endothelial cells. In contrast, the right upper lobe of the reperfusion group disclosed numerous foci of hemorrhagic necrosis, with disrupted alveoli and leukocyte accumulation in all cases. With SOD treatment, the changes compatible with hemorrhagic necrosis were attenuated to the level of the control lobes. However, neither IM nor IA-SOD decreased these changes.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of cirrhosis on the production and efficacy of pneumococcal capsular antibody in a rat model.

We sought to study the immunogenicity of Type 3 pneumococcal capsular polysaccharide (PCP) antigen and the protective efficacy of Type 3 PCP antibodies in a rat model of cirrhosis. Cirrhosis with ascites was induced in male Sprague-Dawley rats by weekly gavage with CCl4. Cirrhotic and age-matched control rats were vaccinated with 25 micrograms of Type 3 PCP. Serum antibodies against Type 3 PCP were determined before vaccination and on postvaccination Days 5, 7, 10, 14, 21, 28, and 42 by radioimmunoassay. Maximum concentrations occurred at 7 days in cirrhotic rats and 10 to 14 days in control rats. Geometric mean Type 3 PCP antibody levels (ng AbN/ml) were higher in cirrhotic versus control rats before vaccination (75.9 versus 33.8; p = 0.011) and on post-vaccination Day 5 (626 versus 158; p = 0.008) and Day 7 (1,755 versus 493; p = 0.002). Postvaccination antibody from immunized control and cirrhotic animals provided passive immunity to Type 3 Streptococcus pneumoniae infection in mouse protection studies. Sham-immunized and PCP-immunized control and cirrhotic rats were challenged with 10(7) cfu Type 3 S. pneumoniae. Immunization was associated with a greater reduction in postchallenge mortality in control rats (91% reduced to 36%; p = 0.02) compared with cirrhotic rats (100% reduced to 83%; p = 1.0). Thus, the increased serum concentrations of functional, type-specific anticapsular antibody in vaccinated cirrhotic rats does not reverse their impaired resistance to Type 3 pneumococcal pneumonia.


Nosocomial bronchopneumonia in the critically ill. Histologic and bacteriologic aspects.

To provide a comprehensive description of the histologic and bacteriologic characteristics of human nosocomial bronchopneumonia (BPN), the lungs of 83 critically ill patients decreased after a period of mechanical ventilation were examined in the immediate postmortem period. In addition, the accuracy of the protected minibronchoalveolar lavage (BAL) technique in the diagnosis of nosocomial BPN was evaluated. In each patient, a surgical pneumonectomy was performed at the bedside within 30 min following death. Each pulmonary lobe was sampled and bacteriologically analyzed using semiquantitative cultures in 50 patients and quantitative cultures in 33 patients. The entire lung was histologically analyzed using 5 to 10 slices per lung segment. In 69 patients, the bacteriologic result of a protected mini-BAL performed within 48 h preceding death was compared with histologic and bacteriologic results of study of the lung tissue itself. Histologic lesions of BPN were found in 43 of the 83 lungs examined. These lesions were (1) severe in the majority of patients (confluent BPN, n = 23; lung abscess, n = 6), (2) preferentially found in dependent lung segments, (3) often associated with nonspecific alveolar damage, (4) associated with positive lung cultures in 65% of patients (53% with gram-negative bacteria), (5) polymicrobial in 28% of patients, (6) characterized by a lobar bacterial burden greater than 10(3) cfu/g in 32% of cases. Using semiquantitative bacteriologic analysis, the sensitivity and the specificity of the protected mini-BAL in the diagnosis of nosocomial BPN were found to be 70 and 69%, respectively. Protected mini-BAL identified 77% of causative microorganisms of BPN.(ABSTRACT TRUNCATED AT 250 WORDS)


Chest radiography and high resolution computed tomography of the lungs in asthma.

CT scans have been studied only in asthmatics who were smokers, and no such study has been performed in patients with chronic uncomplicated asthma where a permanent bronchial destruction is likely to occur after a long course of the disease. The object of the study was to characterize CT-scan abnormalities and determine whether bronchial destructive lesions may be observed. Fifty-seven adults with chronic asthma of variable severity and etiology and 10 normal subjects were studied. None of the subjects smoked. Chest radiographs and HR-CT scans were performed in all patients. To discriminate between reversible and irreversible CT-scan abnormalities, two examinations were made in 10 patients with acute asthma both before and 2 wk after parenteral high dose corticosteroid treatment. The chest radiographs showed the expected abnormalities of asthma in 37.8% of the asthmatics. CT scans were abnormal in 71.9% of the asthmatics. Reversible abnormalities included mucoid impactions, acinar pattern, and lobar collapse. Irreversible abnormalities included bronchiectasis, bronchial wall-thickening, sequellar line shadows, and emphysema. Most of these abnormalities are likely to be related to bronchial destruction.


Physiologic studies of tracheobronchial stents in airway obstruction.

When airway obstruction is due to extraluminal compression and/or dynamic collapse, metal and silicone rubber prosthetic stents may stabilize the affected airway. Through a rigid bronchoscope, we inserted three metal stents in two patients and 18 silicone stents in 15 adult patients with symptomatic tracheobronchial compression and dynamic airway collapse. The underlying cause was malignancy in three patients; benign tracheobronchial malacia in three patients, two of whom refused surgical resection; and tracheobronchial stenosis that developed at the anastomotic site following lung transplantation in 11 patients. Clinical status and lung function studies were analyzed before and after stent insertion. Following stent insertion, airway diameter at least doubled and near normal patency of the affected tracheobronchial tree was achieved in every patient using stents of axial length 4 to 5 cm. The stents were well tolerated clinically, and all patients noted immediate relief of dyspnea. Following stent insertion, the forced vital capacity (FVC) increased from 64 +/- 21% predicted (mean +/- 1 SD) to 73 +/- 19% predicted, p less than 0.1; the forced expiratory volume in 1 s (FEV1) from 49 +/- 25% predicted to 72 +/- 26% predicted, p less than 0.02; the ratio of the FEV1/FVC from 59 +/- 16% to 78 +/- 15%, p less than 0.01; and the maximum flow at 50% expired FVC from 38 +/- 26% predicted to 72 +/- 31% predicted, p less than 0.01.


Interleukin-8 is a major neutrophil chemotactic factor in pleural liquid of patients with empyema.

Interleukin-8 (IL-8), a potent neutrophil chemotactic peptide, has been found in association with human disease, but its contribution to chemotactic activity in humans is not yet known. We asked whether IL-8 is present in inflammatory human pleural effusions, and to what extent it contributes to pleural liquid neutrophil chemotactic activity. Because tumor necrosis factor alpha (TNF-alpha) is a strong inducer of IL-8, we also asked whether TNF-alpha was present. For this prospective study, we collected pleural liquid from 51 patients (empyema, 14; parapneumonic, four; tuberculous, eight; malignant, nine; miscellaneous exudative, seven; and transudative, nine), counted pleural neutrophils, and measured IL-8 and TNF-alpha concentrations in the supernatant. To determine the contribution of IL-8 to chemotactic activity in empyema, we measured the neutrophil migration induced by empyemic liquids before and after addition of anti-IL-8 F(ab')2 antibody fragments or control anti-IL-6 F(ab')2. We found that IL-8 concentrations were higher in empyema (61.3 +/- 21.0 ng/ml [SEM]) than in all other effusions (1.1 +/- 0.5 ng/ml) (p = 0.0001). All empyema liquids had IL-8 concentrations above 2.5 ng/ml, which was true for only three of the other 37 effusions (two parapneumonic, one tuberculous). IL-8 levels correlated with the pleural neutrophil count (r = 0.46; p = 0.007) and the neutrophil chemotactic activity of pleural liquid (r = 0.43; p = 0.008). Anti-IL-8 antibodies decreased chemotactic activity in empyema liquids by 65 +/- 5%, whereas the control antibody had no effect (0 +/- 5% decrease) (p = 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)


Heterogeneity of phagocytosis for inhaled versus instilled material.

Animal experiments involving lung exposure to particles and toxins often use intratracheal instillation, although inhalation is more physiologically relevant to human respiratory tract exposures. Using nontoxic magnetic particles, we examined the particle content distribution within the macrophage population lavaged from the lungs of Syrian golden hamsters exposed either by inhalation or by intratracheal instillation. One to 3 days after iron oxide particle delivery to the lungs, lung macrophages were harvested from animals in pairs, one exposed by inhalation and one exposed by instillation. The macrophages were then magnetically fractionated according to magnetic iron oxide content by flowing the cell suspension through tubing placed within the magnetic field gradient of an electromagnet. Macrophages that had ingested the largest quantity of magnetic iron oxide preferentially collected adjacent to the tubing wall when the electromagnet was at its lowest current; those with fewer particulates collected at correspondingly higher amperages; those cells that were never pulled out of the flowing stream had little or no magnetic iron oxide content. Our results showed that 80% of the lavaged cell population from animals exposed by inhalation had measurable particle content, whereas by instillation, many cells (70%) received no dose at all. Exposure by inhalation produced a more even distribution of dose among lung macrophages. Macrophage intracellular motions showed a decrease when cell content exceeded 7 to 8% of cell volume. We conclude that the method of particle delivery to lungs can influence the dose distribution among lung macrophages.


Diagnosis of Pneumocystis carinii pneumonia by multiple lobe, site-directed bronchoalveolar lavage with immunofluorescent monoclonal antibody staining in human immunodeficiency virus-infected patients receiving aerosolized pentamidine chemoprophylaxis.

The yields of both induced sputum examination and bronchoalveolar lavage (BAL) have been reported to be decreased for breakthrough episodes of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients receiving aerosolized pentamidine chemoprophylaxis. This study assessed whether the yield of a single middle or lower lobe BAL could be increased by the utilization of two techniques: (1) indirect immunofluorescent staining with a combination of two murine monoclonal anti-Pneumocystis antibodies in addition to routine toluidine blue O and cytopathologic staining, and (2) the performance of multiple lobe, site-directed BAL (i.e., both upper lobe and middle or lower lobe lavage, including the lobe with the greatest radiographic abnormality). Results of 252 fiberoptic bronchoscopies performed at the National Institutes of Health and the Los Angeles County-University of Southern California Medical Center were analyzed. P. carinii pneumonia was documented in 21 episodes in patients who did not receive prior anti-Pneumocystis chemoprophylaxis and in 41 episodes in patients who received aerosolized pentamidine. Monoclonal antibody staining and multiple lobe, site-directed BAL resulted in similar diagnostic yields for P. carinii in the nonprophylaxis (100%) and aerosolized pentamidine (98%) groups. If BAL had been performed without monoclonal antibody staining and multiple lobe, site-directed lavage, then the yield would have decreased to 95% in the nonprophylaxis group and to 80% in the aerosolized pentamidine group.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of aerosolized pentamidine prophylaxis on the clinical severity and diagnosis of Pneumocystis carinii pneumonia.

To determine if the use of aerosolized pentamidine prophylaxis decreases the clinical severity or the sensitivity of diagnostic tests for Pneumocystis carinii pneumonia (PCP), we conducted a retrospective matched cohort comparison study of patients admitted to San Francisco General Hospital with PCP from August 1, 1989, to June 30, 1990. Patients who had received pentamidine prophylaxis during at least the 2 months prior to the diagnosis of PCP were matched with patients who had not received the drug. Matching was based on the number of prior episodes of PCP, sex, age, and risk factors for human immunodeficiency virus infection. As markers of clinical severity, we chose alveolar-arterial oxygen difference, serum lactate dehydrogenase levels, outpatient versus inpatient treatment, length of hospitalization, length of intravenous anti-pneumocystis treatment, development of respiratory failure, in-hospital mortality, and chest radiographic appearance. Although, of the 27 matched pairs identified, significantly fewer of the pentamidine cohort were treated as inpatients, and significantly more of this cohort had upper lobe dominant disease on chest radiograph, we found no other significant differences between markers of clinical severity for the two cohorts. In addition, we found no significant differences in the rate of sputum or bronchoalveolar lavage positivity for P. carinii between the two cohorts. We conclude that, although hospitalization is less common in patients with a history of prophylactic pentamidine use, aerosolized pentamidine prophylaxis does not decrease the clinical severity or the sensitivities of sputum induction or bronchoalveolar lavage as diagnostic tests for PCP.


Cohort study of human immunodeficiency virus infection in patients with tuberculosis in Nairobi, Kenya. Analysis of early (6-month) mortality.

Retrospective studies suggest that the mortality rate from HIV-1-associated tuberculosis is greater than that from tuberculosis alone, but it is not clear if this is due to failure of antituberculosis treatment or to the complications of HIV-1 infection. We have carried out a prospective cohort study of patients with tuberculosis in Nairobi, Kenya, to compare mortality rates, risk factors, and causes of death in HIV-1 positive and HIV-1 negative patients. One hundred seven HIV-1 positive and 174 HIV-1 negative patients with tuberculosis attending two tuberculosis treatment centers in Nairobi were enrolled and followed monthly. Mortality was significantly higher in HIV-1 positive than in HIV-1 negative patients within 6 months of the start of antituberculosis treatment after adjustment for age, sex, and education (rate ratio = 3.8; 95% confidence interval, 1.7 to 8.1; p less than 0.001). Most of the excess mortality occurred after the first month of treatment and was due to nontuberculous infections. Predictors for mortality differed greatly between HIV-1 positive and HIV-1 negative patients. Mortality was greater in HIV-1 positive patients treated with a "standard" regimen for tuberculosis than in HIV-1 positive patients receiving a "short-course" regimen (p = 0.08 when adjusted for all independent risk factors). Tuberculosis control programs in developing countries need to implement "short-course" regimens and train health workers to recognize and treat nontuberculous infections to maintain their effectiveness in the face of the HIV epidemic.


Longitudinal lung function decline in subjects with respiratory symptoms.

The relation of respiratory symptoms and lung function has not been extensively investigated. To determine better the rate of FEV1 decline in subjects reporting persistent wheeze, chronic cough, chronic phlegm, and/or dyspnea, longitudinal data from an adult population sample of 3,948 subjects (1,757 men; 2,191 women) followed for 12 yr were analyzed. At the initial and subsequent follow-up visits, subjects completed a standardized respiratory questionnaire and performed spirometry using the same methods and spirometers. Subjects were categorized based on the presence or absence of self-reported respiratory symptoms (persistent wheeze, chronic cough, chronic phlegm, or shortness of breath) at the initial visit. Six-specific linear regression models were fitted to determine the effect of these respiratory symptoms on lung function. In both men and women, reporting of any respiratory symptoms was associated with both a reduction in initial lung function and more rapid decline in height-adjusted FEV1. Furthermore, after adjustment for height, age, and cigarette smoking, men with cough or phlegm and women with cough alone showed accelerated loss in FEV1. Clinicians should be aware of the predictive value of these respiratory symptoms, because therapeutic intervention may modify the associated decline in lung function.


Relation of dose-response slope to respiratory symptoms and lung function in a population study of adults living in Busselton, Western Australia.

For describing bronchial responsiveness, it has been suggested that the dose-response slope (DRS), which is the linear slope of the dose-response curve, is a more useful measure of severity than the provoking dose that causes a 20% fall in FEV1 (PD20FEV1). To determine the distribution of DRS measurements and their relation to respiratory illness in adults, we have reanalyzed data collected in 1981 from a random sample of the population of Busselton, Western Australia. We measured bronchial responsiveness to histamine by the rapid method and atopy by skin prick tests to 15 common allergens. Satisfactory bronchial challenge data were recorded for 858 subjects. Subjects were classified as having asthma symptoms by self-reported history or as having chronic airflow limitation by abnormality of lung function. In normal subjects, DRS values were symmetrically distributed on a logarithmic scale so that a value that represented abnormal responsiveness could be calculated. The dose-response slope had a significant independent association with past and current asthma symptoms, smoking history, sex, atopy, and FEV1/FVC ratio but not with chronic airflow limitation. In subjects in whom a PD20FEV1 could not be measured, the DRS had a significant relation to asthma symptoms, smoking history, and FEV1/FVC. Thus, DRS values, which could be obtained for most subjects, contributed additional information to PD20FEV1 values and discriminated more accurately between groups classified according to respiratory history. These data confirm that DRS values should be used in preference to PD20FEV1 values for describing the severity of bronchial responsiveness in populations.


The predictive relationship between serum IgE levels at birth and subsequent incidences of lower respiratory illnesses and eczema in infants.

Cord serum IgE levels are predictive of subsequent atopic diseases early in life. Lower respiratory illnesses (LRI) have often been included with atopic diseases in infancy but have not been examined as a separate entity for a relation to cord IgE levels. Among 767 healthy newborns in Tucson, Arizona studied longitudinally, cord serum IgE levels were directly related to the subsequent incidence of eczema. In contrast, the incidence of LRI not only failed to show a direct relationship to IgE levels but actually decreased with increasing cord IgE levels from 34.8% in the lowest cord IgE group to 22.2% in the highest IgE group (greater than 1.0 IU/ml IgE; p for trend chi-square less than 0.03). Limiting LRI to those with wheeze did not alter the inverse relationship with IgE levels. The inverse LRI-IgE relationship was strong for non-RSV LRI, whereas RSV LRI had neither a direct nor an inverse relationship. These inverse LRI-IgE relationships were significant for LRI occurring in infants before but not after 6 months of age. Maternal (but not paternal) allergic history was associated with higher cord IgE levels and with an increased incidence of LRI, the latter effect being independent of IgE. This study suggests that most LRI in the first year of life are not early manifestations of an allergic predisposition.


Methacholine responsiveness, smoking, and atopy as risk factors for accelerated FEV1 decline in male working populations.

Longitudinal lung function data from four occupational health surveys was used to explore the relationship between nonspecific bronchial responsiveness (NSBR) and the rate of decline of FEV1 (RDFEV) and to address other factors that may predict or influence RDFEV. Of the 1,203 subjects with baseline methacholine and lung function data, follow-up data were available for 733 individuals (61%). The data-available and data-unavailable groups were well matched with respect to baseline lung function, atopy, and smoking status. Compared with the unavailable group, those available for follow-up were younger (42.5 versus 37.7 yr; p less than 0.0001) and slightly less responsive to methacholine (p less than 0.01). Somewhat unexpectedly, RDFEV was lower in the 30 asthmatic subjects than in the nonasthmatics. Among the nonasthmatic subgroup (96% of those available for follow-up), age, occupational group, and baseline FEV1 (% predicted) were independent predictive factors for RDFEV. When these factors were included in the model, RDFEV was found to be increased among current smokers compared with never-smokers or ex-smokers. In the final regression model, a relationship was found between methacholine sensitivity (calculated as a dose-response slope) and RDFEV in nonasthmatics (p less than 0.05). Stratification by smoking status revealed that the relationship between RDFEV and bronchial responsiveness was confined to current smokers and that atopy was an additional risk factor in this subgroup only. This relationship was valid among current smokers in each of the three occupational groups studies. However, reinclusion of the 30 asthmatic subjects in the study population obscured the relationship between NSBR and RDFEV.(ABSTRACT TRUNCATED AT 250 WORDS)


Association of asthma with use of pesticides. Results of a cross-sectional survey of farmers.

We investigated the association of self-reported asthma and pesticide use in 1,939 male farmers. Regardless of age, smoking pack-years, and nasal allergic reactions, the prevalence of asthma was significantly associated with the use of carbamate insecticides (prevalence odds ratio = 1.8, 95% confidence interval: 1.1 to 3.1, p = 0.02). Self-reported asthmatics, in comparison with nonasthmatics, had significantly lower mean values for lung function test variables after adjusting for age and height and a higher prevalence of respiratory symptoms. These findings raise the possibility that exposure to agriculture chemicals could be related to lung dysfunction in exposed farmers.


A community-based study of the epidemiology of asthma. Incidence rates, 1964-1983.

To determine whether the incidence of asthma had increased in Rochester, Minnesota, from January 1, 1964 through December 31, 1983, we used a population-based computer-linked medical diagnosis system to identify individual medical records with diagnosis of asthma or other conditions mimicking asthma. All records were reviewed using explicit predetermined diagnostic criteria; we identified 3,622 incident cases of asthma, including definite asthma (n = 1,547), probable asthma (n = 952), and single wheezing episodes (n = 1,123). The annual age- and sex-adjusted incidence of definite + probable asthma rose from 183 per 100,000 in 1964 to 284 per 100,000 in 1983. This rise was entirely accounted for by increased incidence rates in children and adolescents (age range, 1 to 14 yr); incidence rates for infants younger than 1 yr of age and for adults remained constant. For definite + probable asthma cases, the incidence rates for males were higher than for females from infancy through 9 yr of age and for persons older than 50; incidence rates for females were higher than for males from 15 through 49 yr of age. The median age at onset was 3 yr for males and 8 yr for females. We conclude that asthma begins in early childhood, with a higher incidence and earlier onset in males, and that the increase in incidence rates seen from 1964 to 1983 occurred only in children and in adolescents.


Maximal airway narrowing in a general population.

To characterize airway responses in a population sample, respiratory symptoms, smoking habits, and changes in FEV1 (delta FEV1) to inhaled methacholine (maximal cumulative dose of 196 mumol or maximal decrease in FEV1 of 50%) were recorded in 201 subjects. From each dose-response curve the plateau (delta FEV1 less than or equal to 5% over two or more dose steps) response, the maximal response (average of responses on the plateau or maximal delta FEV1 when no plateau was present), slope, and PD20 (dose required to cause delta FEV1 greater than 20%) were derived. The pattern of dose-response curves was a continuous change from being flat (maximal delta FEV1 less than or equal to 5%), becoming steeper with a plateau that occurred at a greater change in FEV1 as the curves were shifted more to the left, to being the steepest without a plateau response. Maximal delta FEV1 was significantly related to the PD20 (r = -0.64, p less than 0.001) and the slope (r = 0.63, p less than 0.001). A history of doctor-diagnosed asthma or wheeze in the last 12 months was related to the level of the maximal delta FEV1 and to PD20. Likelihood ratios [LR = sensitivity/(1-specificity)] for asthma or wheeze were higher for a maximal delta FEV1 of 50% plus a PD20 of 4 mumol (LR = 6.5) or 1 mumol (LR = 7) than for either alone. Subjects without reported asthma or wheeze more often had a plateau on the dose-response curve (76%) than those with a positive history (49%, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Alveolar macrophage accessory cell function in bronchial asthma.

The capacity of peripheral blood monocytes and alveolar macrophages (AM) obtained by bronchoalveolar lavage (BAL) to present recall antigens, namely, tuberculin purified protein derivative (PPD) or streptokinase-streptodornase (SKSD), to highly purified autologous T-cells has been studied in 11 asthmatic and 11 healthy, nonatopic normal subjects. In the asthmatic group, AM accessory cell function was variable, and most subjects were unable to present either recall antigen as effectively as blood monocytes, although one asthmatic subject demonstrated larger proliferative responses than blood monocytes for both antigens. AM accessory cell activity was not antigen-specific, and there was a correlation between accessory cell efficacy for the two antigens (r = 0.92; confidence interval, 0.53 to 0.98). Furthermore, a correlation existed between the percentage lymphocyte count in the BAL fluid and the ratio of macrophage to monocyte antigen-presenting capability for both PPD (r = 0.92; 95% confidence interval, 0.83 to 0.99) and SKSD (r = 0.90; 95% confidence interval, 0.45 to 0.98). In the normal subjects, AM were also unable to act effectively as accessory cells for the presentation of PPD and SKSD in the majority of subjects. No correlation existed between the percentage lymphocytes in BAL fluid and the ratio of AM to monocyte accessory cell function. These results suggest an association between AM accessory function and the presence of BAL lymphocytes in bronchial asthma.


Effect of atrial natriuretic peptide given by intravenous infusion on bronchoconstriction induced by ultrasonically nebulized distilled water (fog).

Atrial natriuretic peptide (ANP) is secreted by cardiac atria and lung tissue; it has a bronchodilator action in normal subjects and patients with asthma and has been shown to protect against histamine-induced bronchoconstriction in patients with asthma. Bronchoconstriction caused by inhalation of ultrasonically nebulized distilled water (fog), in contrast to histamine-induced bronchoconstriction, has features in common with exercise-induced asthma but can be given more easily in a dose-response fashion. The present study aimed to determine the effect of elevated plasma ANP concentrations on the bronchoconstrictor response to inhalation of fog. Eight patients with atopic asthma were studied, mean baseline FEV1 3.00 1, equivalent to 89% (range 76-103%) predicted. The provocation dose of fog producing a 25% fall in FEV1 (PD25) was determined for each subject. On 4 study days, subjects received an intravenous infusion of placebo or ANP at a rate of 1.25, 3.0, or 10.0 pmol/kg/min in randomized, double-blind manner for 30 min to allow steady-state plasma concentrations to be achieved; the PD25 fog was then administered and FEV1 recorded over 30 min. Mean (SEM) baseline plasma ANP concentration was 19.3 (4.1) pg/ml and increased to 39.4 (6.6), 106.4 (11.1), and 445.9 (105.4) with the three rates of ANP infusion. The highest rate of infusion increased prechallenge FEV1 by 8.7 (2.4)% (p less than 0.01), but the lower rates of infusion had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of platelet activating factor antagonist on ozone-induced airway inflammation and bronchial hyperresponsiveness in guinea pigs.

We investigated the role of platelet-activating factor (PAF) in ozone-induced airway responses by examining the effects of L659,989, a potent PAF antagonist, on bronchial hyperresponsiveness and airway inflammation. Twenty-four male guinea pigs were studied in four equal groups. Total lung resistance (RL) in intubated and spontaneously breathing animals was measured in a constant-volume body plethysmograph. Dose-response curves to methacholine were determined in all animals at the start of the experiment. These were repeated on a separate day after the following types of treatments: air exposure in Group 1, intraperitoneally administered alcohol and air exposure in Group 2; intraperitoneally administered alcohol and ozone exposure in Group 3, and intraperitoneally administered L659,989 (a specific PAF antagonist), 5 mg/kg dissolved in alcohol, and ozone exposure in Group 4. Bronchoalveolar lavage (BAL) was performed after the second methacholine challenge, and the bronchial mucosa was also examined for inflammatory cells. Exposure to 3 ppm ozone for 2 h resulted in a three-doubling concentration increase in bronchial responsiveness, which was not significantly inhibited by prior treatment with L659,989. Ozone induced a 1.8-fold increase in BAL total cell count, increased eosinophilic influx into the airways, and increased eosinophilic infiltration in the bronchial mucosa, which were all not inhibited by L659,989 pretreatment. The results suggest that PAF may not have an essential role in ozone-induced airway hyperresponsiveness and nonallergic airway inflammation.


A novel leukotriene antagonist, ONO-1078, inhibits and reverses human bronchial contraction induced by leukotrienes C4 and D4 and antigen in vitro.

ONO-1078, 4-oxo-8(-)[p-(4-phenylbutyloxy)benzoylamino]-2-(tetrazol-5-y l)-4H-1-benzopyran hemihydrate, is a novel compound that has been shown to be a leukotrienes C4 and D4 (LTC4, LTD4) antagonist in the guinea pig airways. We studied the ability of ONO-1078 to inhibit and reverse the contraction of isolated human bronchus induced by LTC4, LTD4, and antigen. The human bronchial tissues were prepared from patients undergoing surgery for lung cancer, and they were placed in organ baths. ONO-1078 (10(-8) to 10(-6) M) produced a concentration-dependent inhibition of LTC4 and LTD4 concentration-response curves. In the presence of l-serine borate complex, which inhibits the conversion of LTC4 to LTD4 by gamma-glutamyl transpeptidase, ONO-1078 significantly inhibited the LTC4-induced contraction, suggesting that ONO-1078 is an antagonist of both LTC4 and LTD4. ONO-1078 (10(-6) M) also significantly reversed an ongoing contraction induced by LTC4 (10(-7) M). The inhibitory effect of ONO-1078 on LTC4-induced contraction was at least 100 times more potent than that of FPL 55712, the first discovered LTC4 and LTD4 antagonist. To study the effect of ONO-1078 on the contraction induced by antigen challenge, bronchial tissues were incubated for 2 h with serum of high specific IgE against house dust from an asthmatic patient. House dust antigen was added to the sensitized bronchial tissues after incubation with ONO-1078 (10(-6) M) or histamine H1 antagonist pyrilamine (10(-6) M), either alone or in combination.(ABSTRACT TRUNCATED AT 250 WORDS)


Exercise capacity and ventilatory, circulatory, and symptom limitation in patients with chronic airflow limitation.

Dyspnea, leg effort (Borg 0 to 10 scale), ventilation, and heart rate (VEmax/VEcap; HRmax/HRcap expressed as a percentage of capacity) were measured at maximal exercise (cycle ergometer) in 97 patients with chronic airflow limitation (CAL) (FEV, 46.6 +/- 14.23% of predicted) and compared with 320 matched control subjects. Patients with CAL achieved a maximum power output of 86 +/- 39.5 W (60 +/- 23.2% of predicted) compared with 140 +/- 37.5 W (98 +/- 14.5% of predicted) in controls (p less than 0.0001), VEmax/VEcap was 72 +/- 19.3% compared with 53 +/- 18.6% (p less than 0.0001), and HRmax/HRcap was 76 +/- 13.5% compared with 82 +/- 13% (p less than 0.001). These findings were expected. The median intensity of dyspnea was 6 (severe to very severe) and leg effort was 7 (very severe) in both groups, and these findings were unexpected. The patients with CAL were handicapped by an increase in both dyspnea and peripheral muscular effort relative to the actual power output. The rating of dyspnea exceeded leg effort in 25 (26%) of CAL versus 69 (22%) control subjects: the rating of leg effort exceeded dyspnea in 42 (43%) CAL and 117 (36%) control subjects; both were rated equally in 30 (31%) CAL and 134 (42%) control subjects, respectively (NS). VEmax/VEcap and HRmax/HRcap were not significantly different in those limited by dyspnea, leg fatigue, or a combination of both. All values are expressed +/- SD.


Oxygen may improve dyspnea and endurance in patients with chronic obstructive pulmonary disease and only mild hypoxemia.

Oxygen (O2) has been reported to improve exercise tolerance in some patients with chronic obstructive pulmonary disease (COPD) despite only mild resting hypoxemia (PaO2 greater than 60 mm Hg). To confirm these prior studies and evaluate potential mechanisms of benefit, we measured dyspnea scores by numeric rating scale during cycle ergometry endurance testing and correlated the severity of dyspnea with right ventricular systolic pressure (RVSP) measured by Doppler echocardiography during a separate supine incremental exercise test. Both sets of exercise were performed according to a randomized double-blind crossover protocol in which patients breathed compressed air or 40% O2. We studied 12 patients with severe COPD (FEV1 0.89 +/- 0.09 L [mean +/- SEM], FEV1/FVC 37 +/- 2%, DLCO 9.8 +/- 1.5 ml/min/mm Hg[47% of predicted], PaO2 71 +/- 2.6 mm Hg). With endurance testing on compressed air, PaO2 did not change significantly in the group as whole (postexercise PaO2 63 +/- 5.1 mm Hg, p = NS), but did fall to less than 55 mm Hg in four patients from this group. Duration of exercise increased on 40% O2 from 10.3 +/- 1.6 to 14.2 +/- 1.5 min (p = 0.005), and the rise in dyspnea scores was delayed. Oxygen delayed the rise in RVSP with incremental exercise in all patients and lowered the mean RVSP at maximum exercise from 71 +/- 8 to 64 +/- 7 mm Hg (p less than 0.03). Improvement in duration of exercise correlated with decrease in dyspnea (r2 = 0.66, p = 0.001) but not with decreases in heart rate, minute ventilation, or RVSP.(ABSTRACT TRUNCATED AT 250 WORDS)


Real-time gas analysis improves the measurement of single-breath diffusing capacity.

The measurement of single-breath diffusing capacity of the lung for carbon monoxide (DLCOsb) has traditionally used slow-responding analyzers that require large sample volumes for gas analysis. In addition, these measurement systems must use only assumed values of washout volume (Vwash) since gases are not measured continuously. More recently, a rapid analyzer was developed to continuously measure CO and methane (CH4, an inert tracer gas), which offers advantages, including accurate determination of Vwash and utilization of small sample volume (Vsamp) for gas analysis. We used this analyzer on 135 consecutive measurements of DLCOsb obtained from 70 patients and compared two analysis methods. (1) American Thoracic Society (ATS) guideline method: a standard Vwash (ATS-Vwash) of 0.75 L and a Vsamp of 0.75 L (for vital capacities [VC] less than 2.0 L, ATS-Vwash of 0.5 L and a Vsamp of 0.5 L); (2) VIS method: a Vwash visually just adequate to clear phases I and II of the CH4 washout curve (VIS-Vwash) and a Vsamp of 0.75 L (0.5 L for VC less than 2.0 L). We found that in four patients with VC less than 1.2 L, DLCOsb was attainable despite the small Vsamp (less than 500 ml). Of the other 66 patients whose tests were analyzed by both methods, 33 (50.0%) had Vis-Vwash less than or equal to ATS-Vwash such that phases I and II were actually cleared using ATS criteria. The other 33 patients (50.0%) had VIS-Vwash greater than ATS-Vwash such that phases I and II could not be cleared using ATS criteria.(ABSTRACT TRUNCATED AT 250 WORDS)


Acute effect of cigarette smoking on the carbon monoxide diffusing capacity of the lung.

To determine the acute effect of smoking on DLCO, we studied 12 smokers (mean age, 36 yr; range, 19 to 52 yr, six men and six women) before and after they had smoked as many cigarettes as they could (mean, 6.0; SD, 1.9) over a period of 1 h. Blood COHb was estimated using a rebreathing-breathholding technique after a vital capacity inhalation of O2. Capillary blood volume (VC) was determined from DLCO performed at inspired O2 concentrations of 25 and 90%. DLCO (in ml/min/mm Hg) corrected for COHb back pressure decreased from 22.5 (SD, 6.6) before smoking to 21.0 (SD, 6.6) after smoking (p = 0.003). After correction for the "anemia effect" of COHb, DLCO still significantly decreased, from 22.8 (SD, 6.3) before smoking to 21.8 (SD, 6.4) after smoking p = 0.01). VC (corrected for the reduction in hemoglobin by COHb) was 52.0 (SD, 20.1) ml before smoking and 46.4 (SD, 22.7) ml after smoking; this difference did not achieve statistical significance (p = 0.056). There was no significant change in DLCO or VC in six control subjects tested before and after 1 h of sham smoking of an unlit cigarette. In 12 control subjects studied before and after inhalation of 0.1% CO to result in mean COHb levels of 10.6% (SD, 1.4%), there was a slight but significant decrease in VC (mean change, 21%) and in DLCO (mean change, 4%) after correction for COHb back pressure and reduction in available hemoglobin, suggesting that CO inhalation may have a direct effect on DLCO by reducing VC.(ABSTRACT TRUNCATED AT 250 WORDS)