Nerve growth factor facilitates conditioned taste aversion learning in normal rats

Chronic intracerebroventricular (i.c.v.) infusion of 3.2 μg/day of nerve growth factor (NGF) in normal rats elevated choline acetyltransferase (ChAT) activity of the striatum, medial septum, and basal forebrain and improved performance of a conditioned taste aversion (CTA) task. Relative to bovine serum albumin (BSA) or Cytochrome C treatments, NGF treatment facilitated acquisition and prolonged extinction of a lithium chloride (LiCl)-induced saccharin aversion. This facilitation was evident at saccharin/LiCl intervals ranging up to 1 h. Also, NGF treatment did not increase reactivity to LiCl-induced illness and neither shifted detection thresholds nor altered hedonic reactions to taste stimuli, indicating that NGF did not produce simple changes in sensory function. NGF treatments that elevate ChAT also facilitate memory of CTA in normal, adult rats.     

Hydantoin bioisosteres. In vivo active spiro hydroxy acetic acid aldose reductase inhibitors.

The hypothesis that clinical side effects of the aldose reductase inhibitor (ARI) sorbinil were related to its hydantoin ring led to a bioisosteric analysis and replacement of the hydantoin by a spiro hydroxy acetic acid moiety as in 40. These hydroxy acids, compared to hydantoins, showed a similar potency increase on chroman 2-methyl substitution, a similar orthogonal relationship of acidic to aromatic moieties, and similar ARI enantioselectivity. In this series the six-membered spiro hydroxy acetic acid anion array is a bioisostere for a spiro hydantoin anion and leads to ARIs with excellent in vivo activity. In vitro and in vivo activity was improved over 40 by chroman cis 2-methylation as in 4 and by aromatic 6,7-halogen substitution. Compounds with the best acute in vivo activity in rats were compared for chronic in vivo activity. The highest tissue levels and best chronic in vivo activities were found in the racemic 6,7-dichloro and 6-fluoro-7-chloro analogues 18 and 23. ARI activity was enantioselective for 58 and 60, the 2R,4R-enantiomers of 18 and 23. 7-Chloro-6-fluoro-cis-4-hydroxy-2(R)-methyl-chroman-4-acetic acid (60) was selected for phase 1 clinical trials and did not exhibit sorbinil-like hypersensitivity side effects.     

Study of the distribution of HLA antigens within a population and a comparison between 2 populations

HLA complex is made up of numerous loci whose alleles are codominant. Several associations between HLA antigens and diseases have been identified. Analysis of these associations require statistical methods taking into account the number of tests and the existence of alleles which have not yet been identified. Statistical methods for the estimation and the comparison of alleles frequencies are presented for genotypic, phenotypic and marginal data. An example concerning patients with medullary thyroid carcinoma illustrates these methods.     

Development of tolerance to the therapeutic effect of amantadine on akathisia

Four patients with akathisia as a result of neuroleptic administration were treated with amantadine. Although substantial improvement occurred initially, all four patients developed tolerance to this therapeutic effect within 1 week. An increase in dosage also had only a transient effect. The rapid development of tolerance significantly limits the usefulness of amantadine in the treatment of akathisia. One patient who suffered from akathisia and drug-induced parkinsonism experienced significant attenuation of both movement disorders in response to treatment with amantadine. Although she became tolerant to the effect of amantadine on her akathisia within the first week of treatment, her parkinsonism did not recur. The possibility that these two neuroleptic-induced extrapyramidal syndromes are pharmacologically separable is discussed.     

EEG-results in early-treated children with phenylketonuria 4 through 10 years under treatment (author's transl)]

EEG-results in 21 children with Phenylketonuria (PKU), put on a diet at least since their 3rd month of life, now aged 4 through 10 years, with normal psychomotor development, lacking abnormal neurological signs, are compared with the results in 796 healthy children of the same age. Visual evaluation and frequency analysis of the background activity of the EEGs reveal no differences between children with PKU and controls. Generally, there is no close correlation between mean plasma levels of phenylalanine (phe-means) during treatment, and the composition of the EEG when combined age groups are compared. But a trend can be demonstrated: In the small group of 8 years old children phe-means up to 6 mg-% can be associated with a faster (alpha), and phe-means above 6 mg-% with a slower (theta) background activity. The frequency of metabolic derailment (single phe-values above 10 mg-%) does not correlate with the EEG. Focal and generalized hypersynchronous activity (HSA) is observed significantly more often even in early treated, normally developing children with PKU. In children aged 4--8 years, HSA is associated with a high proportion of slow waves compared with those who do not display HSA. In children 9 and 10 years old, however, no such differences can be seen. It is hypothesised that even early treated children with PKU, in their first years show a retardation in the development of their background activity but catch up by 9--10 years. It still remains uncertain whether further age-appropiate development of the EEG can be observed after liberating or discontinuing the dietary regimen at this age.     

Electroencephalographic sleep in mania

Electroencephalographic (EEG) sleep patterns were examined in nine unmedicated patients meeting DSM-III-R criteria for a current manic episode (four men and five women) for two to four consecutive nights. Compared with age- and sex-matched normal control subjects, manic patients exhibited significantly decreased total recording period, decreased time spent asleep, increased time awake in the last two hours of recording, shortened rapid eye movement (REM) latency, increased REM activity, and increased REM density. These results suggest that mania is associated with marked disturbances of sleep continuity and REM measures. Sleep continuity and REM sleep abnormalities of a similar nature and degree have been reported in major depression and psychotic depression. Thus, it is possible that various forms of affective disorders and psychotic disorders have pathophysiologic mechanisms in common.