GABAergic Interneurons at Supraspinal and Spinal Levels Differentially Modulate the Antinociceptive Effect of Nitrous Oxide in Fischer Rats

Background: The study hypothesizes that nitrous oxide (N2O) releases opioid peptide in the brain stem, which results in inhibition of [gamma]-aminobutyric acid-mediated (GABAergic) neurons that tonically inhibit the descending noradrenergic inhibitory neurons (DNIN), resulting in activation of DNIN. In the spinal cord, activation of DNIN leads to the release of norepinephrine, which inhibits nociceptive processing through direct activation of [alpha]2 adrenoceptor and indirect activation of GABAergic neurons through [alpha]1 adrenoceptor. Arising from this hypothesis, it follows that GABAergic neurons will modulate the antinociceptive effect of N2O in diametrically opposite directions at supraspinal and spinal levels. The authors have tested this tenet and further examined the effect of midazolam, a GABA-mimetic agent, on N2O-induced antinociceptive effect.

Methods: Adult male Fischer rats were administered muscimol (GABAA receptor agonist) intracerebroventricularly (icv), gabazine (GABAA receptor antagonist) intrathecally (intrathecal), or midazolam intraperitoneally (intraperitoneal). Fifteen minutes later, they were exposed to air or 75% N2O and were subjected to the plantar test after 30 min of gas exposure. In some animals administered with midazolam, gas exposure was continued for 90 min, and the brain and spinal cord were examined immunohistochemically.

Results: The N2O-induced antinociceptive effect, which was attenuated by icv muscimol, intrathecal gabazine, and intraperitoneal midazolam. Midazolam inhibited N2O-induced c-Fos expression (a marker of neuronal activation) in the pontine A7 and spinal cord.     

Modulating role of dopamine on anesthetic requirements

The influence of dopamine on halothane anesthetic requirements was determined in mice. Halothane anesthetic requirement was defined as the minimum anesthetic concentration (MAC) that prevented 50% animals from moving in response to a supramaximal stimulus. Levodopa (L-DOPA) dose-dependently decreased halothane MAC to a maximum of 49% of control; over the same dose range L-DOPA increased striatal dopamine nearly 4-fold. The MAC-reducing effect of L-DOPA was attenuated by selective antagonism of the D2 dopamine receptor with YM-09151-2 while selective blockade of the D1 dopamine receptor with SCH-23390 did not alter L-DOPA's effect on the MAC for halothane. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreased striatal dopamine by 82% and increased the MAC for halothane by 27%. Repletion of striatal dopamine with L-DOPA, in MPTP-treated mice, restored the MAC for halothane back to the control state. The regression line derived from the plot of halothane MAC versus striatal dopamine content shows a highly significant correlation between the two variables (r2 = 0.94). These are the first results to suggest that anesthetic requirements can be modulated directly and precisely by increasing or decreasing the content of a single neurotransmitter in the central nervous system.     

Silicone-Coated Polypropylene Hollow-Fiber Oxygenator: Experimental Evaluation and Preliminary Clinical Use

Background. A membrane oxygenator consisting of a microporous polypropylene hollow fiber with a 0.2-μm ultrathin silicone layer (cyclosiloxane) was developed. Animal experimental and preliminary clinical studies evaluated its reliability in bypass procedures.

Methods. Five 24-hour venoarterial bypass periods were conducted on dogs using the oxygenator (group A). In 5 controls, bypass periods were conducted using the same oxygenator without silicone coating (group B). As a preliminary clinical study, 14 patients underwent cardiopulmonary bypass with the silicone-coated oxygenator.

Results. Eight to 16 hours (mean, 12.2 hours) after initiation of bypass, plasma leakage occurred in all group B animals, but none in group A. The O₂ and CO₂ transfer rates after 24 hours in group A were significantly higher than at termination of bypass in group B (p < 0.005 and p < 0.03, respectively). Scanning electron microscopy of silicone-coated fibers after 24 hours of bypass revealed no damage to the silicone coating of the polypropylene hollow fibers. In the clinical study, the oxygenator showed good gas transfer, acceptable pressure loss, low hemolysis, and good durability.

Conclusions. This oxygenator is more durable and offers greater gas transfer capabilities than the previous generation of oxygenators.     

Role of the sympathetic nervous system in the maintenance of hypertension in rats harboring pheochromocytoma

Hypertension due to pheochromocytoma is generally considered to be a straightforward, direct consequence of the elevated concentrations of circulating catecholamines. However, clonidine, a centrally acting antihypertensive drug, has been reported to lower blood pressure in patients with pheochromocytoma, suggesting the possibility that the sympathetic nervous system is involved in the maintenance of hypertension in this disease. We have investigated this possibility in New England Deaconess Hospital rats harboring a transplantable pheochromocytoma that secretes norepinephrine and dopamine. Both clonidine and chlorisondamine, a ganglionic blocker, markedly decreased blood pressure in tumor-bearing rats. However, in other rats made acutely hypertensive with a norepinephrine infusion, neither clonidine nor chlorisondamine decreased blood pressure. This result indicates that in an acute model of hypertension, where baroreflex mechanisms have likely withdrawn sympathetic tone, neither clonidine nor chlorisondamine had nonspecific antihypertensive effects. A central nervous system site of action for the antihypertensive effect of clonidine in the rats harboring pheochromocytoma was suggested by the observation that the opiate antagonist naloxone both reversed and prevented clonidine's effect on blood pressure. Prazosin and yohimbine were utilized to determine the respective contributions of alpha-1 and alpha-2 adrenergic receptors in the maintenance of hypertension in rats harboring pheochromocytoma. Both drugs markedly lowered blood pressure in these rats. Our data suggest that both the sympathetic nervous system and circulating catecholamines are involved in the maintenance of hypertension due to pheochromocytoma.     

Myocarditis: unresolved issues in diagnosis and treatment

Myocarditis is an enigmatic disease. Lymphocytic myocarditis is most commonly viral in origin. Considerable evidence suggests that myocardial damage is due to an immune-mediated mechanism rather than to direct effects of the virus itself. The presentation is variable, ranging from a clinically inapparent or relatively benign illness to acute progressive heart failure and death. Although examination of the endomyocardial biopsy specimen is the "gold standard" for the diagnosis of myocarditis there are problems with this technique, relating particularly to sampling error and histologic interpretation. Considerable evidence, both animal and human, suggests that a link between viral myocarditis and dilated cardiomyopathy does exist. There is a rational basis for the use of immunosuppressive therapy in myocarditis. Although many favorable responses have been reported with the use of these agents, the results of more definitive studies are awaited to determine the role of immunosuppressive therapy in myocarditis more clearly. Recommendations for the practical management of patients with myocarditis are made. Whenever possible, patients with this diagnosis should be entered into the ongoing NIH trial.     

Dexmedetomidine synergism with midazolam in the elevated plus-maze test in rats

The anxiolytic profile of dexmedetomidine, a novel, highly-selective ₂-adrenergic agonist, was examined in rats in the elevated plus-maze test when administered either alone or in combination with the benzodiazepine agonist midazolam. Dexmedetomidine, 0.1–10 µg/kg, was inactive in modifying the rats' behavioral response in this test. Midazolam, 0.1–10 mg/kg, dose-dependently produced an anxiolytic-like profile characterized by an increased time spent in the open arms of the elevated plus-maze. A combination of dexmedetomidine 0.5 µg/kg and midazolam 0.5 mg/kg produced a synergistic interaction. This heterergic interaction of dexmedetomidine on midazolam's anxiolytic-like profile was dose-dependently blocked by pretreatment with an ₂-adrenergic antagonist, atipamezole, 10–50 µg/kg, and a benzodiazepine antagonist flumazenil, 1.0 and 10 mg/kg, but not by the ₁-adrenergic antagonist, prazosin, 0.1–10 mg/kg. While the transmembrane signal transduction pathways for benzodiazepine- and ₂-agonist responses do not share any molecular component, there does appear to be crosstalk between these two systems. These may involve GABA or noradrenergic downstream effects of either dexmedetomidine or midazolam, respectively.     

A case of malignant fibrous histiocytoma of the chest wall

A case of malignant fibrous histiocytoma of the chest wall. A 56-year old man was admitted to the hospital with a complaint of showing abnormal shadow on chest X-ray. Chest X-ray and chest CT scan showed a calcified tumor of the chest wall. Histological diagnosis could not be made prior to the operation. Wide resection of the right chest wall containing the tumor and partial resection of the right lung were done. Malignant fibrous histiocytoma (MFH) showing a striform-pleomorfic pattern was recognized histologically with resected specimen. MFH commonly arises in the soft tissues of the extremities, but rarely in those of the chest. This paper also presents a review of 38 reported cases of MFH originated from the chest wall.     

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

ΔFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to several stimuli including antipsychotic drugs such as haloperidol. However, the functional consequences of increased ΔFosB expression following antipsychotic treatment have not been explored. Here, we assessed whether ΔFosB induction by haloperidol mediates the positive or negative consequences or clinical-related actions of antipsychotic treatment. We show that individuals with schizophrenia who were medicated with antipsychotic drugs at their time of death display increased ΔFosB levels in the PFC, an effect that is replicated in rats treated chronically with haloperidol. In contrast, individuals with schizophrenia who were medication-free did not exhibit this effect. Viral-mediated overexpression of ΔFosB in the PFC of rodents induced cognitive deficits as measured by inhibitory avoidance, increased startle responses in prepulse inhibition tasks, and increased MK-801-induced anxiety-like behaviors. Together, these results suggest that ΔFosB induction in the PFC by antipsychotic treatment contributes to the deleterious effects of these drugs and not to their therapeutic actions.