Synthesis of radiolabelled 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a neurotoxic chloral-derived mammalian alkaloid, and its biodistribution in rats.

Chloral hydrate, the oldest synthetic hypnotic, is still among the most common agents used for conscious sedation of infants and children. Chloral (Clo) spontaneously condenses with the biogenic amine tryptamine (Ta) giving rise to the endogenous formation of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo). TaClo constitutes a mammalian alkaloid and a potent neurotoxin, which is capable of inducing a slowly developing degeneration of the dopaminergic system in rats. Due to the late onset of parkinsonian-type symptoms after TaClo administration, this agent has been postulated to be a potential natural inducer of Parkinson's disease. In order to elucidate its pharmacokinetics, its tissue distribution and excretion profile, radiolabelled [3-14C]-TaClo was prepared in a convenient four-step synthetic pathway. Studies on rats intraperitoneally treated with a single dose of 2.1 mg/kg (0.6 microCi/kg) of [3-14C]-TaClo.HCl (specific activity: 0.28 microCi/mg) revealed the radioactivity to be rapidly incorporated with the highest concentrations of 14C found in the excretory organs. [3-14C]-TaClo was poorly absorbed systemically, as indicated by the very low plasma radioactivity levels. Maximum levels of 14C were reached between 2 and 6 h postdose, with the exception of large intestine peaking at 12 h after dosing. Total mean percent recovery of the radioactive dose was about 96% within the 48-h period examined. Urinary excretion accounted for ca. 34.5%, with the majority of the applied dose being eliminated by the hepatobiliary pathway.

Platelet sialic acid as a potential pathogenic factor in coronary heart disease.

It was previously reported that, compared to healthy individuals, patients with coronary heart disease (CHD) exhibit a higher proportion of platelets with lower densities and higher propensity to aggregate. Reasons for this increased tendency to aggregate were unknown but appeared to be independent of the patient's age, gender, or smoking habits. Sialic acid (N-acetyl-neuraminic acid), a negatively charged sugar and constituent of many glycoproteins and gangliosides, is known to confer the bulk of negative charges to mammalian cell surfaces. These negatively charged surfaces can help cells of the bloodstream to maintain a relative distance from each other due to repulsion of the same (negative) charges. In this study, we examined whether differences in platelet sialic acid are a potential pathogenic factor in patients with coronary heart disease. Upon isolating platelets, we found a significantly higher (p < 0.05) proportion of low density platelets in patients compared to healthy controls, which is in accordance with previously published data. We found significantly less (p < 0.05) sialic acid in platelets from patients compared to the control. Most of the platelet total sialic acid was susceptible to cleavage by neuraminidase, demonstrating sialic acid to be preferably localized at the outer platelet surface. We conclude that the lower sialic acid content found in platelets from CHD patients could represent a contributing factor for the observed higher aggregability of platelets from these patients. Due to the lower sialic acid content and resulting lower negative surface charge, less repulsion between the platelets could facilitate aggregation.

Clinical evaluation of refraction using a handheld wavefront autorefractor in young and adult patients.

PURPOSE: To determine the accuracy of measurement by the SureSight autorefractor (software version 2.0) and the influence of accommodation. SETTING: Pediatric Section, Department of Ophthalmology, University of Hamburg, Hamburg, Germany. METHODS: In a series of comparative measurements, autorefractor readings were compared with cycloplegic retinoscopy in 195 eyes of 108 patients (1 to 81 years) measured under cycloplegia. Ninety-six eyes were also measured without cycloplegia. RESULTS: The wavefront autorefractor was able to refract human eyes from a distance of 0.35 m. The accuracy was lower than that with conventional tabletop autorefractors. A difference of less than 0.51 diopter (D) was found in 68% of the spherical equivalents under cycloplegia. Many emmetropic and hyperopic children accommodated during the noncycloplegic measurements and were minus-overcorrected up to -6.13 D. In our group of young patients (2 to 17 years), 47% were minus-overcorrected by more than -2.00 D. CONCLUSIONS: The wavefront autorefractor uses a new method to determine the refractive state of the eye from a distance. It was less accurate than other conventional autorefractors. A benefit is its application in infants and disabled and uncooperative subjects. Cycloplegia is necessary in young hyperopic patients.

Serotonergic effects of clozapine and its metabolites in hippocampal HT22 cells.

In the hippocampal neuronal in vitro system of HT22 cells, we studied the effects of clozapine (Cloz) and its metabolites clozapine-N-oxide (Cloz-N-oxide) and norclozapine (Norcloz) on 5-HT transporter affinity (K(M)) and uptake (V(max)), MAO-B affinity (K(M)) and maximal velocity (V(max)), as well as on 5-HT(2) receptor affinity and density. Clinically relevant concentrations of Cloz (200 and 400 ng/ml) and its metabolites (100 and 200 ng/ml) were used for the examination of the effects after short-term (4 h) and long-term (24 h) incubation. Statistical evaluation revealed that a significantly lowered 5-HT transporter affinity (higher K(M)) was related to higher concentrations of Cloz and its metabolites. A significantly higher 5-HT transporter uptake was dependent on both high concentrations of drugs and an increased time of incubation. No significant influence of the investigated independent variables on MAO-B affinity could be demonstrated, whereas a significant drug-related increase of MAO-B velocity was detectable. Additionally, low and high concentrations of Cloz and its metabolites induced a higher 5-HT(2) receptor affinity (lower K(D)). No significant influences of the investigated independent variables on 5-HT(2) receptor density were detectable. The results of the present study show that Cloz and its metabolites induce significant alterations in serotoninergic parameters of hippocampal HT22 cells, validating the system of hippocampal HT22 cells for further examinations of the mechanisms of action of atypical neuroleptics.

Factors influencing the reliability of autorefractometry after LASIK for myopia and myopic astigmatism.

PURPOSE: To study the factors influencing the reliability (accuracy) of autorefractometry before and after laser in situ keratomileusis (LASIK) for myopia and myopic astigmatism. DESIGN: Retrospective case series. METHODS: A total of 250 consecutive eyes (132 patients, mean age 37 years) were included from the Department of Ophthalmology, J.W. Goethe University, Frankfurt, Germany. The mean preoperative spherical equivalent of the subjective refraction (SR) was -6.59 diopters (D) (-1.38 to -15.13). The patient data were reviewed before and 1 month after LASIK, including SR, objective automated refraction (AR), and visual acuity. Subgroup analysis was performed with regard to the preoperative myopia and the excimer laser optical zone (OZ). The Holm-Sidak and Wilcoxon matched-pairs tests were used for statistical analysis. RESULTS: The correlation coefficient between AR und SR is r = 0.98 before LASIK versus r = 0.79 afterwards (P < .001). The mean difference between the spherical equivalents (DSE) is +0.13 ± 0.51 D preoperatively versus -0.30 ± 0.58 D after LASIK (P < .001). With a small optical zone size (5.0-5.5 mm) the postoperative difference is -0.61 D, versus -0.36 D for OZ 5.6-6.0, versus -0.16 for OZ 6.1-7.0 mm. With a rising preoperative amount of myopia, the postoperative AR results become increasingly more myopic than the SR. CONCLUSIONS: Following LASIK, autorefractometry is less accurate than in nonoperated eyes. The reliability of the AR is influenced by the OZ and the preoperative amount of myopia, with a small OZ and high myopia resulting in a greater difference between AR and SR and with the AR determining more myopic results.

Measuring contrast sensitivity under different lighting conditions: comparison of three tests.

PURPOSE: The purpose of this study was to evaluate three psychophysical tests for the measurement of contrast sensitivity (CS) and disability glare (DG) at different luminance levels. METHODS: In 60 eyes of 60 individuals (group 1: 20 healthy eyes of young individuals; group 2: 20 healthy eyes of elderly subjects; group 3: 20 eyes with nuclear cataract), CS with best correction was measured twice with the Frankfurt-Freiburg Contrast and Acuity Test System (FF-CATS) and the Functional Acuity Contrast Test (FACT, 1.5 cycles per degree [cpd]) at 167 cd/m2 and 0.167 cd/m2, and with the Pelli-Robson Chart (PRC) at 100 cd/m2 with and without glare. Repeatability of test and retest, and discriminative ability between the different subgroups, were assessed for CS values. RESULTS: Maximum CS values varied across tests. In all groups, highest CS values were obtained with the photopic FF-CATS. For FACT scores at 1.5 cpd, there was a ceiling effect for young subjects. CS scores obtained with the PRC were the lowest. The PRC had the best test-retest repeatability of all tests. Under mesopic conditions with glare, reliability was generally lower; the FF-CATS had the highest repeatability of the mesopic tests. The FF-CATS discriminated best between the different groups for all conditions. CONCLUSIONS: There are large discrepancies in the test results between CS testing methods, especially under different lighting conditions. Results from different CS tests are not interchangeable.

[Visual acuity measured via the Freiburg visual acuity test (FVT), Bailey Lovie chart and Landolt Ring chart]. / Sehschärfebestimmung mit Freiburger Visustest, Bailey-Lovie-Tafel und Landoltring-Tafel.

INTRODUCTION: If different ways for correcting refractive errors of the human eye have to be compared, accurate and reproducible measurement procedures are necessary. METHODS: Binocular visual acuity of 130 students without pathologies was measured with the Freiburg Visual Acuity Test, the Bailey-Lovie chart and a Landolt ring chart (4 orientations). The reproducibility of the FVT was determined by repeated measurements. RESULTS: The average visual acuity was 1.93 +/- 0.03 (= 20/10.4) with the FVT, 1.82 +/- 0.03 (= 20/11) with the Landolt ring chart, and 1.48 +/- 0.02 (= 20/13.5) with the Bailey-Lovie chart. 50 % of all repeated measurements with the FVT were within an interval of +/- 0.035 logMAR from the mean value. 95 % were within +/- 0.1 logMAR. Results of earlier studies are discussed. CONCLUSION: On average, visual acuity values found with the Freiburg Visual Acuity Test were slightly larger as compared to the Landolt ring chart (difference = 0.025 logMAR). Taking the maximal difference of 0.05 logMAR tolerated by the international standard DIN EN ISO 8597 into account, both tests are equivalent. The results found with the Bailey-Lovie chart were substantially lower as compared to the Landolt ring chart (difference = 0.09 logMAR). The Freiburg Visual Acuity Test has a high reproducibility and measures visual acuity on a continuous scale that is not limited to the traditional visual acuity steps. Thus, it can be recommended as a reference procedure for comparative visual acuity studies.