Acute neurologic decompression illness in pigs: lesions of the spinal cord and brain.

A detailed histopathologic description of central nervous system lesions from a porcine model of neurologic decompression illness is presented. Pigs were dived in a dry chamber to 200 feet of seawater for 24 min before the start of decompression. Of 120 pigs, 40 (33.3%) were functionally unaffected and 80 (66.6%) developed neurologic decompression illness; 16 died, 64 survived. Petechial hemorrhages were grossly visible in the spinal cord of 73% of the survivors, 63% of the fatalities, and 3% of the clinically unaffected pigs. The thoracic part of the cord was most commonly involved. Histologic cord lesions were found in 75 (63%) pigs: 83% of decompression illness survivors, 81% of the fatalities, and 23% of those clinically unaffected. Morphologically, hemorrhagic lesions were the most common (54%). Other common findings included spongiosis (48%), axonal swelling and loss (39%), and myelin degeneration (35%). White matter hemorrhages in the spinal cord were generally more numerous and extensive than those affecting the gray matter; however, gray matter hemorrhage was associated with increasing disease severity. Brain lesions were present in 23% of pigs and were most frequent in fatalities. Cerebellar and brain stem hemorrhages were the most common brain lesions; the molecular layer of the cerebellum appeared particularly susceptible. Pigs were chosen because of their cardiovascular and gas exchange similarities to humans. The clinical and histopathologic features of the pig model were compared with previous accounts in animals and humans; the model was judged analogous to severe human decompression illness. The finding of occult brain and cord lesions in clinically unaffected pigs is discussed. The model provides a useful tool for the study of dysbaric lesions of the central nervous system. Its noninvasive nature may facilitate the study of nervous system injury and repair processes.

Flow cytometry of fine needle aspirations of the Sprague-Dawley rat testis: defining normal maturation and the effects of multiple biopsies.

Quantitative assessment of spermatogenesis by flow cytometry reproducibly correlates with histological examination. Flow cytometry of fine needle aspirates from the testis was used to analyze normal spermatogenesis of Sprague-Dawley rats. Aged matched male weanlings were divided into 3 groups: group 1-5 rats underwent bilateral percutaneous aspiration of the testes with a 22 gauge Chiba needle on postpartum days 19, 24, 30 and 40; group 2-5 rats aspirated on days 24, 30 and 40, and group 3-4 rats aspirated on days 30 and 40. This sequential approach allowed for evaluation of normal spermatogenesis and the effects of repeated fine needle aspiration on spermatogenesis. Deoxyribonucleic acid distribution analysis by flow cytometry correlates with haploid (1N), diploid (2N), tetraploid (4N) and S phase cell populations. These cell populations were evaluated and comparisons among each group were made at all biopsy times. No significant differences in mean 2N, 4N or S phase cell populations in single versus repeat biopsied testes were detected. However, there was a significant increase in the 1N population at 30 days post partum in the repeat biopsy group (p = 0.037), which normalized by day 40. This increase in 1N corresponds to the beginning of meiosis, which is maximal between postpartum days 30 and 40, and occurs earlier in the repeat biopsied testis. Repeat fine needle aspiration of the testis can be performed without significantly affecting spermatogenesis in the "weanling" rat. This provides a useful technique in the future investigations of the time related effects of varicocele, chemotherapy and toxicologic drugs on spermatogenesis.

HI-6 and 2-PAM in sheep: pharmacokinetics and effects on muscle tissue following intramuscular injection.

The pharmacokinetics of 2-PAM, a component of the current nerve agent antidote therapy for U.S. military forces was compared to the pharmacokinetics of another acetylcholinesterase reactivator HI-6. Additionally, the effects of these compounds on muscle tissue following intramuscular injection was examined. Plasma concentrations of the oximes were determined by HPLC. Plasma concentration-time profiles for both oximes fit a one-compartment open model with first-order absorption and elimination. The results demonstrate that the half-time of absorption of HI-6 was significantly higher than that for 2-PAM. Musculoirritancy was assessed on the basis of quantitative histological examinations of the injection sites and by the measurement of serum creatinine phosphokinase. Comparison of the scores from the histological sections demonstrate no difference between the two oximes. Serum creatinine phosphokinase values were elevated following injections of HI-6, but were not consistently elevated following the 2-PAM injections.

Pharmacokinetics and pharmacodynamics of oximes in unanesthetized pigs.

The pharmacokinetics and cardiovascular pharmacodynamics of two oximes were studied in unanesthetized pigs. Effects of 2-[(hydroxyimino)methyl]-1-methylpyridinium chloride (pralidoxime chloride; 2-PAM Cl; 50 mumol/kg) were compared with those of 1,1-methylene bis[4(hydroxyiminomethyl) pyridinium] dichloride (methoxime; MMB-4; 100 mumol/kg). Cardiopulmonary parameters were monitored and plasma concentrations of oximes were determined from arterial blood samples taken at intervals over a period of 5 hr postinjection. Plasma concentrations for both oximes were fitted to standard pharmacokinetic models using the computer program PCNONLIN. Average pharmacokinetic parameters were determined for each oxime. Only mild to moderate physiological side effects were detected following intramuscular administration. 2-PAM Cl was more rapidly absorbed and distributed in the blood than MMB-4. Although the latter had a slight lag time to attain detectable levels in the blood, retention time was longer than that of 2-PAM Cl.

Decreased brain pathology in organophosphate-exposed rhesus monkeys following benzodiazepine therapy.

Two benzodiazepine compounds, midazolam and diazepam, were administered as adjunctive treatment to soman-exposed rhesus monkeys to evaluate their effects on acute soman intoxication. Monkeys were pretreated orally with pyridostigmine, exposed to soman, and treated i.m. with atropine, pralidoxime chloride (2-PAM), and with midazolam, diazepam or sterile water (control). All monkeys that received the benzodiazepines recovered sooner and exhibited no convulsions. Neuronal degenerative and necrotic lesions were decreased or eliminated in the entorhinal cortex, caudate nucleus, and hippocampus of those animals that received benzodiazepine therapy. These findings support the continued evaluation of drugs with anticonvulsant activity as standard adjunct therapy for soman intoxication.

Intramuscular administration of atropine in the rat: jet spray versus conventional needle injection.

The characteristics of atropine plasma levels after jet spray injection were compared to those after conventional needle injection (i.m.) in 12 male rats, six per group. Blood samples were sequentially collected from the tip of the tail over a 7h period. Injection of atropine sulfate (8.0 mg kg-1) using the jet spray resulted in mean peak plasma levels of 650 ng ml-1 (95 per cent C.I. = 90) compared to 488 ng mg-1 (95 per cent C.I. = 64) using a conventional needle. Times to reach maximum concentration were 30 min (95 per cent C.I. = 12) and 58 min (95 per cent C.I. = 6) for the jet spray and needle, respectively. Histopathologic examination (5 days post-injection) of target muscle showed that minimal fiber damage resulted from using the low pressure setting on the jet spray. The results suggest that the jet spray may offer a means of increasing the antidotal benefit over that achieved with conventional techniques using presently available therapeutic formulations for acetylcholinesterase poisoning.