Exploratory factor analysis of MRI brain structure measures in schizophrenia

Much of the literature shows various regional structural brain abnormalities in schizophrenia, but the complexity and variability of brain makes it difficult to determine how these regions are related. Statistical methods which estimate factors underlying patterns of covariance have not been widely used, but could be useful for analyzing such complex data. We applied exploratory and confirmatory factor analysis procedures to specific cortical and subcortical regional brain volume measures from MRI data in 60 normal and 44 schizophrenic subjects. Basal ganglia, heteromodal cortical gray, and medial temporal lobe factors were present in both the normal and the schizophrenia groups. The factor structure observed in the normal group showed a high degree of bilateral symmetry which is present but disrupted in the schizophrenia group. In the bilateral data, the disruption is most pronounced with medial and lateral temporal lobe structures including entorhinal cortex and anterior and posterior superior temporal gyri. There was a significant correlation between the basal ganglia factor and the heteromodal cortical gray factor in the normal group that was not present in the schizophrenia group. In the unilateral data, left posterior superior temporal gyrus did not load onto any factor in the schizophrenia group. Confirmatory factor analyses showed significant differences between the two groups in factor structure. A number of specific brain regions are affected in schizophrenia, and structural relationships between groups of regions also are abnormal. The results suggest that heteromodal dorsolateral prefrontal and superior temporal cortical gray regions are structurally related, whereas inferior parietal cortical gray is less so. These results should be viewed as preliminary as the ratio of parameters to subjects was relatively low, and replication is needed. However, the results demonstrate the potential utility of latent structure methods such as factor analysis in study of complex relationships in neuropsychiatric data.     

HIV protease inhibitory bis-benzamide cyclic ureas: a quantitative structure-activity relationship analysis

A series of N,N'-disubstituted cyclic urea 3-benzamides has been synthesized and evaluated for HIV protease inhibition and antiviral activity. Some of these benzamides have been shown to be potent inhibitors of HIV protease with Ki < 0.050 nM and IC90 < 20 nM for viral replication and, as such, may be useful in the treatment of AIDS. The synthesis and quantitative structure-activity relationship for this benzamide series will be discussed.     

Cardiovascular responses to intracerebroventricular injection of GABA in renovascular hypertensive rats

Effects of central GABAergic stimulation on cardiovascular function were evaluated in 2-kidney, 1-clip (2K1C) renovascular hypertensive rats (RVHR). Intracerebroventricular injection (icv) of GABA (100 and 200 micrograms) reduced blood pressure (BP) to a greater degree in RVHR as compared with sham-operated controls, and the greatest response was seen in RVHR 4 wk after operation (4 wk-RVHR). In addition, a decreased sensitivity of baroreflex was observed in 4 wk-RVHR, and was improved by icv GABA. Pretreatment with icv captopril (200 micrograms) only reduced BP moderately in 4 wk-RVHR, but attenuated remarkably the depressor effect of GABA. On the contrary, pretreatment with ip captopril was less effective in attenuating the depressor effect of GABA. Our results indicated that RVHR was deficient in central GABAergic inhibition on BP control, for GABAergic stimulation reduced BP to a greater degree and improves the decreased sensitivity of baroreflex in RVHR; the depressor effect of GABA is mediated, at least in part, by inhibiting brain angiotensin system.     

Myelodysplastic syndrome with myelofibrosis and basophilia: detection of trisomy 8 in basophils by fluorescence in-situ hybridization

We report a case of myelodysplastic syndrome (MDS) with myelofibrosis and pulmonary tuberculosis who had marked basophilia in the peripheral blood. A clonal karyotypic abnormality characterized by trisomy 8 was demonstrated by cytogenetic analysis. By correlation of cell morphology with results of fluorescence in situ hybridization using a chromosome 8 probe, we demonstrated that the basophils were not reactive but belonged to the neoplastic MDS clone.     

Phospholipid pool, lipid peroxidation, and superoxide dismutase activity under various types of oxidative stress of the brain and the effect of low-energy infrared laser irradiation

The effect of low-energy infrared laser irradiation on the phospholipid pool, lipid peroxidation, and superoxide dismutase activity in the brain of white rats was studied in experimental ischemia, reperfusion, and acute edema. These models are characterized by oxidative stress; the contents of tri- and diphosphoinositides and sphingomyelins were lowered, whereas the levels of phosphatidylserine and phosphatidylethanolamine did not change, and the amount of phosphatidylcholine was increased. In acute brain edema, the contents of hydroperoxides and malonic dialdehyde in enzymatic and nonenzymic lipid peroxidation systems were increased in mitochondrial and microsomal fractions and the level of arachidonic acid was significantly elevated. Infrared laser irradiation contributes to the correction of the changes in the phospholipid pool; laser irradiation lowered the increased levels of hydroperoxides and malonic dialdehyde and elevated superoxide dismutase activity in the brain during ischemia, reperfusion, and acute edema of the brain. The data suggest that low-energy infrared laser irradiation has certain neuroprotective activity in various types of oxidative stress including ischemia, reperfusion, and acute edema of the brain.     

Preparation, isolation, analysis, and characterization of 3-benzo[a]pyrenyl-beta-D-glucopyranosiduronic acid: a metabolite of 3-hydroxybenzo[a]pyrene with potentially high carcinogenic activity

The aglycone, 3-hydroxybenzo[a]pyrene, was metabolized to 3-benzo[a]pyrenyl-beta-D-glucopyranosiduronic acid in the presence of uridine 5'-diphosphoglucuronic acid and rabbit liver microsomes. The course of the biosynthetic reaction was followed by fluorimetry and reverse-phase, paired-ion high pressure liquid chromatography (HPLC). Also, the HPLC system was used to analyze for glucuronide and 3-hydroxybenzo[a]pyrene during the isolation procedure. The existence of a glucuronide of 3-hydroxybenzo[a]pyrene was determined by radiotracer and enzymic techniques, utilizing the HPLC system. Field desorption and direct inlet mass spectral techniques were used to characterize the 3-hydroxybenzo[a]pyrene glucuronide.     

Digitalis-like and vasoconstrictor effects of endogenous digoxin-like factor(s) from the venom of Bufo marinus toad

Digitalis glycoside-like properties of the Bufo marinus toad crude venom and one of its constituents, bufalin, were studied in various assay systems. In concentrations 0.3-30 micrograms/ml crude venom increased the contractility of isolated electrically driven rat atria, constricted rat aortic rings, inhibited ouabain-sensitive Na+,K(+)-ATPase in rat erythrocytes and the Na+,K(+)-pump in rat aorta, and cross-reacted with antidigoxin antibody from the dissociation enhanced lanthanide fluoroimmunoassay (DELFIA). These effects were unaffected by adrenoceptor blockers and the 5-HT antagonist, deseril, but were blocked by antidigoxin antibody. Bufalin (10-30 microM) increased myocardial contractility and inhibited Na+,K(+)-ATPase in rat erythrocytes similarly to crude Bufo marinus venom. In rat aorta bufalin showed weak and delayed vasoconstrictor activity which was antagonized by 2 microM phentolamine, and had a biphasic effect on the Na+,K(+)-pump; 0.5-1.0 microM bufalin stimulated the pump, while higher concentrations inhibited its activity. Although the effects of bufalin were blocked by antidigoxin antibody, bufalin showed very low digoxin-like immunoreactivity in the DELFIA. These observations suggest that, in addition to bufalin, Bufo marinus venom contains at least one more digitalis-like steroid with significant intrinsic vasoconstrictor activity which, unlike bufalin, constricts the blood vessels acting directly via inhibition of the sodium pump in the vascular smooth muscle membrane.