Altered enzyme activities of xenobiotic biotransformation in kidneys after subchronic administration of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) to rats

Activities of the xenobiotic metabolizing enzymes were measured in the liver, kidney, duodenum and lung microsomes and cytosol fractions of Wistar rats after subchronic administration of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a potent bacterial mutagen in chlorinated drinking water. MX was administered by gavage at the dose level of 30 mg/kg for 18 weeks (low dose), or at the dose level which was raised gradually from 45 mg/kg for 7 weeks via 60 mg/kg for 2 weeks to a clearly toxic dose of 75 mg/kg for 5 weeks (high dose). Microsomal and cytosolic preparations were made and the activities of 7-ethoxyresorufin-O-deethylase (EROD), pentoxyresorufin-O-dealkylase (PROD), NADPH-cytochrome-c-reductase, UDP-glucuronosyltransferase (UDPGT) and glutathione-S-transferase (GST) were measured. Kidneys were affected most. A dose-dependent decrease was observed in EROD (90% in males, 80% in females at the high dose) and in PROD (58% in females, at the high dose) in kidneys. An increase was, however, detected in kidney NADPH-cytochrome-c-reductase (66% in females at high dose), UDPGT (89% in males and 97% in females at high dose) and GST activities (56% in males and 50% in females at high dose). MX caused only a few changes in the enzyme activities of the liver. The EROD activity was decreased 25% to 37%, both in the livers of males and females, but the total content of P450s was not altered. Hepatic GST activity was elevated in females in a dose-dependent manner (31% and 44%). GST activity was elevated in duodenum in females (59%) at the high dose. There were no marked changes in the enzyme activities in the lungs. MX was a weak inhibitor of EROD activity both in the liver and kidney microsomes in vitro, decreasing the EROD activity by 53% and 43%, respectively at the concentration of 0.9 mM. The results indicate that MX decreases the activity of phase I metabolism enzymes, but induces phase II conjugation enzyme activities, particularly in kidneys in vivo. It is possible that these changes contribute to metabolism of MX in kidneys and renders them susceptible to MX in the course of repeated exposure.     

EEG reactivity correlates with neuropsychological test scores in Down's syndrome

Introduction – Down's syndrome patients express a neurodegenerative disorder and mental retardation. We studied the reactivity of EEG and its correlation with neuropsychological test score in Down's syndrome. Material and methods – We studied 32 patients with Down's syndrome and 31 controls for blocking of occipital EEG activity. The temporo-occipital EEG with eyes open (EO) was compared with resting EEG with eyes closed (EC), (EC/EO ratio). Results – Both Down patients and controls showed significant diminution of alpha, beta and theta activity and decrease of EEG frequency with EO. However, there was a significant impairment in Down patients in the EC/EO ratio in alpha band, compared to controls. The controls had no correlation of the alpha EC/EO ratio with age or gender. The Down patients showed a significant correlation of this variable with age which is in accordance with a gradually progressing disease. They had also significant correlations of the alpha EC/EO ratio and neuropsychological test scores which indicates that this ratio may be a more general measure of cerebral or hemispherical dysfunction than a mere impairment of visual activation. Down patients also showed significant differences in resting EEG variables, compared to the controls, even if the conventional EEG showed normal or mildly slowed dominant occipital rhythm in most of the patients. The correlation analysis between resting EEG and EC/EO ratio variables pointed out that they are relatively independent, representing different factors in the regulation of EEG. Conclusions – We believe that the alpha EC/EO ratio of EEG add a new domain in the assessment of cerebral dysfunction in Down's syndrome.     

Effect of linoleic acid, linoleic acid anilide, and arachidonic acid on the expression of adhesion molecules on human neutrophils

The effects of linoleic acid, linoleic acid anilide, and arachidonic acid on the expression of CD11b/CD18, CD11c/CD18 integrins and l-selectin on human neutrophils were studied by flow cytometry in a whole blood assay. None of these compounds had any effect on the basal expression of CD11b, CD11c, or l-selectin in the concentration range of 20–100 μM. However, linoleic acid at a concentration of 1000 μM slightly up-regulated CD11b and CD11c by a factor of 2.1 and 1.7, respectively. Linoleic acid, linoleic acid anilide, and arachidonic acid did not affect the formyl-methionyl-leucyl-phenylalanine induced up-regulation of CD11b or CD11c. However, linoleic acid and linoleic acid anilide slightly inhibited the phorbol myristate acetate (PMA)-induced expression of CD11b, which was decreased by 27 and 21% at concentrations of 100 and 1000 μM, respectively. Likewise, arachidonic acid at 40 μM inhibited the PMA-induced expression of CD11b by 19%. Our results suggest that linoleic acid, linoleic acid anilide, and arachidonic acid do not dramatically affect the expression of leukocyte adhesion molecules in a whole blood assay. Received: 17 February 1997  / Accepted: 5 May 1997     

CSF beta-endorphin-like immunoreactivity in delirium

Cerebrospinal fluid beta-endorphin-like immunoreactivity (CSF BLI) was determined for 69 patients who met DSM-III criteria for delirium and for 8 controls. The CSF BLI was significantly lower in the delirious patient group than in the controls (12.5 +/- 3.0 pg/ml versus 15.0 +/- 3.4 pg/ml, p less than 0.05). CSF BLI had no correlation with age or neuroleptic drug dosage, but did have a significant positive correlation with cognitive functioning as evaluated by the Mini-Mental State. Our findings suggest a role for beta-endorphinergic dysfunction in the development of delirium.     

Reelin-immunoreactivity in the hippocampal formation of 9-month-old wildtype mouse: effects of APP/PS1 genotype and ovariectomy

Reelin, an extracellular matrix protein has an important role in the migration, correct positioning and maturation of neurons during development. Though it is generally down-regulated in the postnatal period, expression of this large glycoprotein continues in the adult brain in some cell populations. In the present study, we examined the distribution of reelin-immunoreactivity (-ir) in the hippocampal formation of 9-month-old wildtype mice (WT). Then, reelin-ir in normal mice was compared to that of transgenic mice (APP/PS1) carrying mutated human APP and PS1 genes, which are linked to the familial form of Alzheimer's disease (AD). The APP/PS1 mice were additionally burdened with a second risk factor for AD, namely depletion of circulating gonadal hormones by ovariectomy (APP/PS1 + OVX). The analyses revealed that in adult WT reelin-ir is expressed by Cajal-Retzius cells and a subgroup of interneurons throughout the hippocampal formation. In addition, layer II projection neurons in the lateral entorhinal subfields are reelin-ir. Interestingly, ovariectomy decreases the number of reelin-ir cells in the hilus in WT mice, whereas AD-related genotype alone induces only a non-significant reduction. Unexpectedly, additional stress, e.g., depletion of gonadal hormones, does not aggravate the slight reduction in the reelin cell number in the APP/PS1 mice. We propose that the changes in normal reelin-ir are linked to disturbances in repair mechanisms in which APP/PS1 and gonadal hormones are involved and which are perturbed in neurodegenerative conditions, namely AD.     

Cerebrospinal fluid somatostatin correlates with spectral EEG variables and with parietotemporal cognitive dysfunction in Alzheimer patients

Somatostatin levels of the cerebrospinal fluid (CSF) were correlated with variables of quantitative EEG and with neuropsychological performance in patients with probable Alzheimer's disease. Low somatostatin levels of CSF correlated with decreased beta activity and with decreased mean frequency in the combined alpha and theta EEG range. In the subgroup of mild Alzheimer cases CSF somatostatin correlated positively also with alpha power, and the peak and the mean frequency, and negatively with theta power but not with delta activity. Furthermore, low somatostatin of the CSF correlated with neuropsychological tests assessing temporoparietal dysfunction. To our knowledge, this is the first study to indicate the correlation between spectral analysis results of the EEG and CSF somatostatin suggesting that the relationship between somatostatin and EEG variables is worthy of further studies.     

Specificities and Opsonophagocytic Activities of Antibodies to Pneumococcal Capsular Polysaccharides in Sera of Unimmunized Young Children

An enzyme immunoassay (EIA) for antibodies to pneumococcal capsular polysaccharides (Pnc PSs) detects in some cases antibodies that are cross-reactive within different Pnc PSs. Recently, it has been suggested that for detection of only serotype-specific antibodies, EIA can be modified by removing cross-reactive antibodies by absorption with an irrelevant PS, e.g., the type 22F PS. The opsonophagocytosis assay measures the functional activities of antibodies in vitro, and the results of that assay correlate with in vivo protection better than measurement of the antibody concentration by EIA. We compared these different methods for measuring antibodies to type 1, 6B, 11A, 14, 19F, and 23F Pnc PSs in the sera of unimmunized young children who had been monitored for pneumococcal carriage, acute otitis media, and acquisition of antibodies to Pnc PSs from 2 to 24 months of age. Serum samples with antibody increases after contact with a pneumococcus of a homologous serotype contained specific antibodies and often had opsonophagocytic activity (OPA) (20 of 46). In samples with antibody increases from children who had not had contact with a pneumococcus of a homologous serotype, the antibodies found to be type specific by conventional EIA were usually cross-reactive and infrequently had OPA (10 of 68). When type 22F PS absorption was used in the EIA, most of the false antibody increases were eliminated, but most of the true antibody increases were still detected and the association between the antibody concentration detected by EIA and OPA was improved. However, there were serotype-dependent differences in the frequency of OPA. Use of absorption with a heterologous PS in EIA should be encouraged, and both the specificity of EIA and the sensitivity of opsonophagocytic assays should be further evaluated and improved.     

Neurotransmitter markers in the cerebrospinal fluid of normal subjects effects of aging and other confounding factors

Summary We have investigated neurotransmitter-related markers of the cerebrospinal fluid (CSF) in a carefully screened series of normally aging subjects in standardized conditions in order to find out the influence of age and other confounding factors on CSF measures. The levels of 3-methoxy-4-hydroxyglycol (MHPG) and the activity of acetylcholinesterase (AChE) also increased with age, while homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5 HIAA) and immunoreactivities of somatostatin (SLI), beta-endorphin (BLI) and adrenocorticotropic hormone (ACTH) were unrelated to age. The gender of subjects had no significant effect on the levels of neurotransmitter markers, while seasonal changes, as well as height and weight of the subjects seemed to cause some variations in the levels of HVA, dopamine--hydroxylase (DBH) and ACTH. The study underscores the importance of standardized conditions and matched patient groups in the CSF studies.