Functional cortical effects of novel allelic variants of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in humans.

INTRODUCTION: Genetic variations of the serotonin transporter-linked polymorphic region (5-HTTLPR) have been implicated in the pathogenesis of several psychiatric disorders. Recent evidence indicates that the biallelic polymorphic region (S and L allele) contains additional variations affecting the mRNA expression. METHODS: According to recent preclinical and clinical studies, the loudness dependence of auditory evoked potentials (LD) was investigated as surrogate parameter for the central serotonergic activity in 185 healthy subjects subdivided according to newly identified 5-HTTLPR genotypes. RESULTS: Individuals homozygous for the L (A) allele showed the lowest LD of all genotypes suggesting a high serotonergic neurotransmission. The other observed genotypes (L (A)/L (G), S/L (A), S/L (G), S/S) had an LD which was similar to each other but higher compared to the L (A)/L (A) genotype. DISCUSSION: The data provide a rationale to subdivide the L allele of the 5-HTTLPR into L (A) and L (G) alleles in terms of their serotonin activity as indicated by the LD. The present IN VIVO measurements provide a basis for grouping the L (G) and S alleles for further investigations.

Attentive and preattentive processing in narcolepsy as revealed by event-related potentials (ERPs).

Narcolepsy is a neurological disorder, characterised by excessive daytime sleepiness, sleep attacks, cataplexy and abnormal manifestations of rapid eye movement sleep. Recent studies suggest that neuropsychological impairments in narcolepsy may include memory and attention deficits due to a monoaminergic or cholinergic transmitter dysfunction. To explore the nature of cognitive problems, the P300 and mismatch negativity (MMN) event-related potentials were investigated in narcoleptic patients and matched controls. Narcoleptics showed significantly increased P300 amplitudes relative to controls, especially at frontal recording sites. While control subjects exhibited typically larger MMN over the right than the left hemisphere, in particular at frontal and central electrodes, narcoleptics did not show this asymmetry. These results are interpreted as possible alterations in cognitive preattentive and attentive processing associated with altered functioning of the prefrontal cortex in narcolepsy.

Increased prevalence of obesity in narcoleptic patients and relatives.

Increased Body Mass Indices (BMIs), increased prevalences of non insulin-dependent diabetes and sleep apnoe syndrome have been reported to be associated with narcolepsy. Our objective was to explore and possibly confirm the association of narcolepsy and increased BMI. In addition, we addressed the question whether increased BMIs also occur in relatives of narcoleptic patients. Together with narcolepsy-related clinical parameters we measured body weight and height of 132 narcoleptic patients who agreed to participate in our narcolepsy research program. In addition, 52 first degree relatives of 22 index patients, mostly from multiplex families, were included in the study. Data were compared to published general population surveys, recently conducted in Germany and Switzerland as well as to collective of 104 psychiatric inpatients. Narcoleptic patients had significantly increased BMIs in comparison to general populations or psychiatric controls. BMIs of first degree relatives were lower than those of index patients but significantly higher than those found in the general population. BMIs were not related to symptom severity or to medication status. Thus, the elevated BMIs appeared not to be secondary to behavioral consequences of narcolepsy but may reflect a trait at least partially common to index patients and relatives.

A prepro-orexin gene polymorphism is associated with narcolepsy.

The orexin (hypocretin) neurotransmitter system was recently shown to be directly involved in the pathogenesis of narcolepsy in two animal models. Furthermore, decreased levels of orexin A in the CSF were shown in narcoleptic patients. To define any genetic contribution of orexin to the etiology of narcolepsy, the authors screened the entire prepro-orexin gene for mutations or polymorphisms in 133 patients suffering from narcolepsy. They report an association of a rare polymorphism in the prepro-orexin gene with narcolepsy in a cohort of 178 patients.

[Narcolepsy. An illness in transition]. / Narkolepsie. Eine Erkrankung im Aufbruch.

The signs of narcolepsy have been known since the last century and the tetrad of symptoms was described 50 years ago: excessive sleepiness, cataplexy, sleep paralysis, and hallucinations. Polysomnography typically shows decreased sleep and REM sleep latency, and laboratory testing reveals a high association with the human leucocyte antigens (HLA) DQB1*0602 and DQA1*102. Actual studies suggest disturbances in the orexin (hypocretin) neurotransmitter system. However, the exact pathophysiology is still unclear. In Germany, about 1500 patients diagnosed with narcolepsy are known. The prevalence in Caucasian populations is estimated at 50/100,000. Thus, the number of undiagnosed patients is likely to be high.

Increased frequency of migraine in narcoleptic patients.

We explored the relationship between narcolepsy and different types of headaches. We interviewed 68 patients with idiopathic narcolepsy for the presence of headache symptoms based on the criteria of the International Headache Society (IHS). Eighty-one percent of the patients reported headaches that warranted an IHS headache diagnosis. Fifty-four percent of the patients (64% women, 35% men) had migraine with all IHS criteria fulfilled.

Automated determination of clozapine and major metabolites in serum and urine.

Clozapine is an atypical neuroleptic that is increasingly used for the treatment of schizophrenia. An automated method was developed for the routine quantification of clozapine and its major metabolites, N-desmethylclozapine and clozapine N-oxide, in human serum and urine by column switching and online high-performance liquid chromatography with ultraviolet detection. The method included adsorption of clozapine and its metabolites on a cyanopropyl-coated clean-up column (10 microns; 10 mm x 4.0 mm ID), washing interfering serum constituents to waste by deionized water, and, after column switching, separation on C18 ODS Hypersil reversed-phase material (5 microns; 250 mm x 4.6 mm ID). The compounds of interest were separated and eluted in fewer than 20 minutes, using a mobile phase consisting of 37.5 acetonitril:62.5 water, containing 0.4% (vol/vol) tetramethylethylenediamine and adjusted to pH 6.5 with concentrated acetic acid. Ultraviolet-detection was performed at 254 nm. The determinations exhibited linearity between detector signal and drug concentrations in a range from 5 ng/ml to 50 micrograms/ml. As little as 10 ng/ml of clozapine and 20 or 30 ng/ml of the metabolites was quantifiable. Interferences with other psychotropic drugs, serum, or urine constituents were negligible. The automated procedure enables the analysis of clozapine and metabolites in serum or urine in less than 1 hour.

Visual memory in Alzheimer patients: effects of practice, retention interval and severity of cognitive decline.

The study was aimed at estimating the effect size of practice, retention interval and dementia severity on free recall performance in Alzheimer patients. Patients met DSM-III-R criteria for dementia of Alzheimer type. Different picture sets were presented on 4 days. The forgetting curves on different days were compared using ANOVA for repeated measurements. Practice had a minor, but significant negative effect on recall performance explaining 1% of the variance in recall performance. The retention interval varied between zero and 24 h explaining 23% of the total variance. Dementia severity explained 52% of the variance. For the development of memory improvement strategies in Alzheimer patients, the repeated measurement design using intraindividual comparisons seems more powerful than group comparisons.

[Cell loss after combined thermo-radiotherapy. Determination in vivo of the cell-loss rate of euoxic and hypoxic cells of experimental tumors (author's transl)]. / Der Zellverlust nach kombinierter Thermo-Radio-Therapie--Bestimmung der Zellverlustrate bei euoxischen und hypoxischen Tumorzellen an Experimentaltumoren in vivo.

Solid Ehrlich cancers with a volume of one millilitre, situated on the necks of mice, were treated with X-rays (150 kV), a low dose of hyperthermia (high frequency), a high dose of hyperthermia and a combined therapy of mild hyperthermia and X-ray irradiation. As labeling method, the technique of 125-I-deoxyuridine was employed. At the time of the therapy, there uas either a majority of hypoxic tumor cells or a majority of euoxic tumor cells, both in labeled form. The loss of cells was measured externally as a decrease of activity between the 96th and the 192th hour after the injection of 125-I. Xray irradiation tends above all to destroy euoxic cells while hypoxic cells are preponderantly destroyed by high doses of hyperthermia. Mild hyperthermia does not influence the cell loss in a significant manner. Mild hyperthermia in combination with X-ray irradiation, however, increases the loss of hypoxic cells up to the rate of euoxic cells.