Pharmacological modulation of neuropeptides in peripheral mononuclear cells.

The concentrations of beta-endorphin and cholecystokinin were measured in fresh resting peripheral mononuclear cells obtained from rats and human subjects in basal conditions and after different pharmacological treatments. Both in the human and the rat, beta-endorphin concentrations in mononuclear cells, increased after treatment with serotoninergic agonists, decreased after dopaminergic or GABAergic drugs, while the respective antagonists exerted the opposite effect. In vitro, serotoninergic and GABAergic compounds confirmed their roles in the modulation of beta-endorphin in mononuclear cells. Cholecystokinin was never affected by the pharmacological treatments.     

Familial association of intracranial aneurysms and cervical artery dissections.

BACKGROUND AND PURPOSE: The familial occurrence of intracranial aneurysms and cervical artery dissections has been described in different families and supports the hypothesis that a primary arteriopathy may play a role in the pathogenesis of these disorders. Although the basis for this arteriopathy is generally not believed to be similar among cases of intracranial aneurysms and cervical artery dissections, several similarities exist in the epidemiology of these disorders and a common underlying arterial abnormality may be suspected. SUMMARY OF REPORTS: The medical records of all 175 patients with spontaneous dissections of the cervical arteries who were seen at the Mayo Clinic between 1970 and 1989 were reviewed to identify families in which intracranial aneurysms and cervical dissections coexisted. Three families were identified in which intracranial aneurysms and cervical artery dissections were observed among siblings. These families are described in detail. CONCLUSIONS: The familial occurrence of intracranial aneurysms and cervical artery dissections within the same families provides support to the importance of a common underlying arteriopathy in the pathogenesis of both these disorders. The underlying vascular defect may, at least in some cases, be inherited.     

Interaction between free radicals and excitatory amino acids in the formation of ischemic brain edema in rats

Both oxygen free radicals and excitatory amino acids have been implicated as important cellular toxins in ischemic brain. Recent in vitro studies suggest that there may be a mutual interaction between these two mediators. We explored the relation between oxygen free radicals and excitatory amino acids in the development of ischemic brain edema in vivo. Male Sprague-Dawley rats were treated with the free radical scavenger dimethylthiourea 1 hour before ischemia or with the excitotoxin antagonist MK-801 30 minutes before ischemia produced by occlusion of the middle cerebral artery. Groups of seven or eight animals were treated with vehicle, low-dose (375 mg/kg) dimethylthiourea, high-dose (750 mg/kg) dimethylthiourea, low-dose (0.5 mg/kg) MK-801, high-dose (2.0 mg/kg) MK-801, or both high-dose dimethylthiourea and low-dose MK-801. After 4 hours of ischemia, brain water content was determined. In eight vehicle-treated controls, mean +/- SEM water content of tissue in the center of the ischemic zone was 83.29 +/- 0.18%. A significant reduction of brain edema was observed in all drug-treated groups: for example, 50.2% (p less than 0.001) in the high-dose dimethylthiourea group, 53.7% (p less than 0.001) in the low-dose MK-801 group, and 66.4% (p less than 0.001) in the combined dimethylthiourea and MK-801 group. Combined treatment with dimethylthiourea and MK-801 provided no significant additive effect over that resulting from treatment with MK-801 alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Simulated home treatment of depression with nortriptyline

1. Twenty-two patients hospitalized for treatment of depression were treated under conditions simulating those of home treatment. 2. Full doses of nortriptyline, from 100 to 150 mg/day, were started after baseline observations were made. 3. Two patients were dropped from the study, one for orthostatic hypotension, one for an aberrant response to nortriptyline. Two additional patients developed orthostasis which was easily managed. Otherwise no unusual side effects were noted. 4. After six days of treatment, 9 of 20 patients showed significant improvement with an overall reduction in scores on the Hamilton Depression Scale of 49% for the entire group. 5. Using the weight-adjusted dosage schedule, 18 of the 21 patients attained plasma concentrations of nortriptyline within the presumed therapeutic range; however, no clear relationship could be established between plasma concentrations and clinical response. 6. With proper selection of patients, it should be possible to treat at home some patients who currently are considered to require hospitalization.     

Crossed innervation of the superior rectus.

We studied two patients which showed a paralysis of the oculomotor nerve on one side and isolated paralysis of the superior rectus on the other side. On the side of oculomotor nerve paralysis, midbrain infarct extending from the paramedian tegmentum to crus cerebri was demonstrated in one case who showed no recovery, and a small lacuna in midbrain tegmentum in another one who showed complete recovery. On the side of isolated paralysis of the superior rectus, no lesion was demonstrated by CT and MRI, and no clinical signs of the involvement of fiber tracts or nuclei were evident in both cases. A unilateral lesion of oculomotor nerve nucleus caused a paralysis of the contralateral superior rectus.     

Glutamate receptor antagonists block cocaine-induced convulsions and death.

The involvement of excitatory amino acid (EAA) receptors in mediation of the toxic effects of cocaine was studied in male ICR mice. Cocaine HCl (90 mg/kg, IP) induced seizures in 95% and death within 24 h in 68% (n = 135) of the animals. There was a significant correlation (r = .54) between the time to onset of convulsions and the time to death in mice which died within 30 min of injection (n = 84). Pretreatment with selected EAA receptor antagonists 15 min prior to cocaine differentially blocked cocaine toxicity. Selective N-methyl-D-aspartic acid (NMDA) receptor antagonists (MK-801, dextrorphan, CPP) decreased both the incidence of seizures and mortality. A nonselective EAA antagonist, kynurenic acid, decreased lethality in doses which did not reduce convulsions. A similar action was observed following pretreatment with the selective kainic acid/AMPA receptor antagonist, GDEE. Antagonists at EAA receptors can provide significant protection against cocaine-induced toxicity. Moreover, the data provide evidence for the involvement of both NMDA and non-NMDA receptor subtypes in aspects of cocaine toxicity.     

Genetic factors for the span of apprehension test: a study of normal twins.

The Partial Report Span of Apprehension test has been found to detect cognitive deficits in some first degree relatives of schizophrenic patients. To assess the relative contribution of genetic vs. environmental factors on this measure, 19 monozygotic and 14 dizygotic female twin pairs, selected from a normal population, were tested on the Span of Apprehension test and an IQ test. Both Span of Apprehension test performance and IQ score had high heritabilities: 0.65 and 0.71, respectively. The mode of transmission for performance on the Span of Apprehension test appears to operate in a nonadditive manner. A multivariate behavioral-genetic model applied to the Span of Apprehension and IQ measures indicated that slightly less than half of the genetic effects important for the Span of Apprehension test are found in common with the genetic factors important for IQ. The phenotypic correlation between the Span of Apprehension and IQ measures can be attributed entirely to genetic factors. The influence of unique genetic components in the performance of the Span of Apprehension test in the general population heightens the promise of this measure as a genetic marker for schizophrenia.     

Studies on the contact system of coagulation during therapy with high doses of recombinant IL-2: implications for septic shock

Patients treated with high doses of interleukin-2 (IL-2) because of cancer, develop hemodynamic and vasopermeability changes, that resemble those observed in sepsis. These patients thus provide a unique opportunity to study the early events in the development of septic shock. We analysed the changes that occurred in the contact system of coagulation in plasma from 4 patients, who together received seven 12-day cycles of high doses of IL-2. Levels of factor XII and prekallikrein during the cycles progressively fell to 50 and 30% of their initial levels, respectively, whereas significant increases in plasma factor XIIa- and kallikrein-C1-inhibitor complexes were not observed (in 3 out of 211 samples slightly increased levels of both complexes were found). The reductions in factor XII and prekallikrein were only in part due to protein leakage, since levels were still significantly lower, i.e., 80 and 50%, respectively, when corrected for albumin decreases. Levels of high molecular weight kininogen (HMWK) also decreased during IL-2 therapy, however, this decrease paralleled that of albumin. SDS-PAGE analysis of plasma HMWK did not reveal increased cleavage of this protein. The reduction of factor XII and prekallikrein, corrected for protein leakage, significantly correlated with albumin levels and inversely with daily cumulative weight gain in the patients. Thus, we demonstrate that factor XII and prekallikrein decrease during IL-2 therapy. As these decreases, already observed after 1 day treatment, were disproportional to that of albumin, a negative acute phase reactant, and correlated with signs of the vascular leak syndrome, we favor the explanation that they reflected activation rather than a decreased synthesis of the contact system proteins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of 2,3,5-triphenyltetrazolium chloride staining to delineate rat brain infarcts.

BACKGROUND AND PURPOSE: Accurate and reproducible determination of the size and location of cerebral infarcts is critical for the evaluation of experimental focal cerebral ischemia. The purpose of this study was to compare intracardiac perfusion of 2,3,5-triphenyltetrazolium chloride with immersion of brain tissue in 2,3,5-triphenyltetrazolium chloride to delineate brain infarcts in rats. METHODS: After 6, 24, or 48 hours of ischemia induced by permanent middle cerebral artery occlusion, some rats were perfused with 2,3,5-triphenyltetrazolium chloride; other rats were given an overdose of barbiturates, after which brain sections were immersed in 2,3,5-triphenyltetrazolium chloride. Coronal sections were taken 4, 6, and 8 mm from the frontal pole, and infarct areas in perfused and immersed sections were compared; subsequently, the same sections were stained with hematoxylin and eosin. RESULTS: In rats subjected to 24 or 48 hours of occlusion, areas of infarction were clearly defined with both 2,3,5-triphenyltetrazolium chloride staining techniques, and the infarct sizes correlated well with the results of hematoxylin and eosin staining (r = 0.85-0.94). CONCLUSIONS: These results demonstrate that intracardiac perfusion of 2,3,5-triphenyltetrazolium chloride is an accurate, inexpensive, and efficient staining method to detect infarcted tissue 24 and 48 hours after the onset of ischemia in rats.