Strong Inter-individual Variation Research Articles

Therapeutic drug monitoring of SSRI's in adolescents

Selective-serotonin-reuptake-inhibitors (SSRI) are found to be effective in the treatment of depression, obsessive compulsive disorder, and anxiety. In this study the serum levels of SSRI were correlated to the therapeutic window suggested by the tiaft (The International Association of Forensic Toxicologists) for adults.Serum levels of the SSRI´s fluvoxamine, citalopram, paroxetine, sertraline, and its metabolite norsertraline, have been studied using HPLC with UV-detection. At doses of citalopram between 10 and 40mg/day serum levels between 8 and 144 ng/ml serum have been found. Most often used was fluvoxamine, with serum levels between 14 and 275 ng/ml serum with doses between 25 and 250mg/day. Especially in the case of fluvoxamine, but also for citalopram, strong interindividual variations of the serum levels, up to tenfold, could be observed, indicating that monitoring of the serum levels is helpful in dose adjustment. In adolescents the serum levels of sertraline and norsertraline are found to be significantly lower as compared to adults. For Paroxetine serum levels seem to be no good indicator for therapeutic response. In summary it seems to be useful to establish therapeutic windows for SSRI´s for adolescents.

Thyroid Hormone Receptor Expression in the Human Hypothalamus and Anterior Pituitary

In the present study, we describe for the first time the distribution of thyroid hormone receptor (TR) isoforms in the human postmortem hypothalamus and anterior pituitary using immunocytochemistry. We used a set of polyclonal antisera raised against the specific isoforms of the human TR. The distribution of TR alpha 1, alpha 2, beta 1, and beta 2 was studied in consecutive sections of six hypothalami and pituitaries. Staining intensity showed strong interindividual variation but was consistently present in the infundibular nucleus, paraventricular nucleus, and supraoptic nucleus. In addition, strong TR immunoreactivity was observed in the anterior pituitary. Neuropeptide Y and proopiomelanocortin mRNA-positive cells in the infundibular nucleus, which were studied in three other hypothalami, appeared not to express TRs, and thus, the neurons expressing TRs in the human mediobasal hypothalamus remain to be characterized.

A Common 936 C/T Mutation in the Gene for Vascular Endothelial Growth Factor Is Associated with Vascular Endothelial Growth Factor Plasma Levels

Background: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. Strong interindividual variations of VEGF plasma levels have been reported previously. Aim of the present study was to search for mutations in the 3′ untranslated region (3′-UTR) of the VEGF gene and to analyze their relation to VEGF plasma levels. Methods: The complete 3′-UTR (nucleotide 700–2622) of the VEGF gene was screened for sequence variations by single-strand conformation polymorphism (SSCP) analysis. Frequencies of mutated alleles were determined in 119 healthy subjects; VEGF plasma levels were analyzed in a subgroup of 23 healthy men aged 18–36 years. Results: Three novel mutations (702 C/T, 936 C/T, 1612 G/A) were found, allele frequencies of 702T, 936T and 1612A were of 0.017, 0.160 and 0.471, respectively. VEGF plasma levels were significantly lower in carriers of the 936T allele (9.1 ± 2.7 pg/ml, mean ± SEM) than in noncarriers (28.0 ± 5.5 pg/ml, p = 0.033), whereas the 702 C/T and the 1612 G/A mutations showed no association with VEGF plasma levels. The 936 C/T exchange led to the loss of a potential binding site for transcription factor AP-4, although the functionality of this binding site remains unclear. Conclusion: We have found three common mutations in the VEGF gene; one of them, a 936 C/T exchange, may be an important determinant of VEGF plasma levels.

STAGGERED CLINES IN A HYBRID ZONE BETWEEN TWO CHROMOSOME RACES OF THE HARVESTMAN GAGRELLOPSIS NODULIFERA (ARACHNIDA: OPILIONES)

We analyzed a hybrid zone between two chromosome races (2n = 16 and 2n = 22) of a Japanese harvestman, Gagrellopsis nodulifera Sato and Suzuki (Arachnida: Opiliones: Phalangiidae). The hybrid zone is located in the eastern part of Tottori Prefecture, western Honshu. The width of the zone is approximately 5 to 15 km. Three independent tandem fusions/fissions seem to be the main cause of the karyotypic differences between the parental races. Ten karyotypic variants were found in the hybrid zone. They differed by numbers of diploid chromosomes and trivalents detected in meiosis. In most of the collecting sites, karyotypic heterozygotes were less common than expected. A positive correlation was found between number of trivalents in a karyotype and its deficiency rate. In some sites, the deficit of heterozygous individuals was accompanied by an excess of the intermediate homozygotes. One of the three transects across the zone was studied in detail. We found that three types of single heterozygotes (2n = 17, 2n = 19 and 2n = 21) formed a series of successive, spatially separated peaks along the transect. Two types of intermediate homozygotes (2n = 18 and 2n = 20) were also spatially separated. The most parsimonious explanation of such a structure is the staggering of clines of three tandem (or Robertsonian) fusion/fission variants that differentiate the parental races caused by selection against multiple heterozygotes. Analysis of nondisjunction in single heterozygotes demonstrated that there was a strong interindividual variation in nondisjunction rate. The mean frequency of aneuploid MII in single heterozygotes was 0.10 ± 0.03. Crossover exchanges in some critical regions of trivalents result in abnormal chromosomal configurations: chromosomes with unequal chromatids and dicentric chromosomes. Frequency of crossover-induced chromosomal abnormalities was low in single heterozygotes (≃ 4%), and was unexpectedly high in the double heterozygotes (≃ 15%). Selection against karyotypic heterozygotes is considered as a main evolutionary force responsible for the structuring of the hybrid zone. A positive association between diploid chromosome number and altitude was found. The race 2n = 16 tended to occupy lower altitudes than the 2n = 22 parental race. Differences in ecological preferences may be a result of previous adaptations to different environments in allopatry. A hypothesis concerning the origin and evolution of the hybrid zone is proposed.Corresponding Editor: J. Mallet

DNA adducts in human placenta in relation to tobacco smoke exposure and plasma antioxidant status.

The DNA adduct 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been widely used as a biomarker for oxidative stress. Bulky DNA adducts, which are detectable by the 32P-postlabelling method, provide evidence for exposure to and metabolic activation of large, mainly apolar compounds, e.g. polycyclic aromatic hydrocarbons. We determined both types of adducts in placental tissues of 30 term pregnancies and related the adduct levels to the exposure to tobacco smoke and the plasma antioxidant status. Urine and plasma continine concentrations were used to select 10 nonsmokers, 9 nonsmokers exposed to environmental tobacco smoke (ETS) and 11 smoking women. Placental levels of 8-OHdG were 0.84 +/- 0.11, 0.90 +/- 0.21 and 0.83 +/- 0.20/10(5) deoxyguanosine bases (dG) for nonsmokers, nonsmokers exposed to ETS and smokers, respectively. The differences between the groups were not significant. Smoking women had significantly lower plasma vitamin C and beta-carotene concentrations than nonsmoking women or nonsmoking women exposed to environmental tobacco smoke. The 8-OHdG adduct level in placental DNA was inversely correlated with the plasma vitamin E concentration (r = -0.47, P < 0.05). There was no association between placental 8-OHdG adducts and vitamin A, C and beta-carotene in plasma. In total, 15 different adducts could be identified in the 30 placenta samples by the 32P-postlabelling method. There was a strong inter-individual variation in both the number of adducts and adduct intensities. No smoking-related or vitamin-related effects on adduct patterns or intensities were found. Our findings suggests that, within the limits of the methods used, tobacco smoke exposure during pregnancy does not lead to a measurable increase in placental DNA adduct levels and that vitamin E appears to have a protective effect on placental 8-OHdG formation.

Significance of Autofluorescence for the Optical Demarcation of Field Cancerisation in the Upper Aerodigestive Tract

Background: Second primaries in the upper aerodigestive tract (UADT) are increasingly related to bad prognosis. So early detection of small cancer foci is required to improve the survival rate. Here, autofluorescence (AF) might become useful as in vivo biochemical changes of cancer metabolism can be shown by fluorescence.Material: For more exact data on AF in cancerous lesions 32 cancer specimens of the UADT and 57 specimens of normal oral mucosa as a control group were examined by using autofluorescent microscopy and spectroscopy, the tissue being activated with light at 365 ran wavelength. Video-controlled in vivo fluorescence examinations in field cancerisation of the UADT were also investigated and compared with pathohistological findings.Results: The intensity of AF of the connective tissue was observed to increase at the tumour border. Contrary to results in the literature, no homogeneous fluorescence gradient could be proved between marginal epithelium and the tumour itself. The brightly shining submucosal elastic fibres allowed fluorescent spectroscopic detection of the tumour margins in vitro in 71%. Even small precancerous lesions were traced in vivo mainly by keratinization when using the autofluorescence diagnostic imaging system.Contusions: Our examination proved a multi-factorial genesis of autofluorescence with strong inter-individual variations. Preliminary clinical examination showed that this method can be applied as an additional tool for early detection of cancerous lesions in the UADT.

Cotinine, a major metabolite of nicotine, is detectable in follicular fluids of passive smokers in in vitro fertilization therapy

To assess cotinine, a metabolite of nicotine, in follicular fluids (FF) of women who smoke either actively or passively or not all. Controlled clinical study. Infertile patients in a hospital IVF-ET program. One hundred eleven women classified by smoking habits: active smokers (n = 44), passive smokers (n = 17), or nonsmokers (n = 50). Ovarian hyperstimulation. Cotinine levels in FF. A strong correlation between number of cigarettes smoked and levels of FF cotinine was found. The levels of FF cotinine were: active smokers 710.4 +/- 128.2, passive smokers 76.3 +/- 56.5, and nonsmokers 4.2 +/- 2.0 ng/mL (mean +/- SEM). The level in active smokers was significantly greater than in other groups. The levels of FF cotinine in passive smokers differed significantly from nonsmokers. Eighty-four percent of nonsmokers actually were exposed to nicotine, with a mean value of 5.0 ng/mL. Cotinine was detectable in a dose-dependent manner in active and passive smokers. It was detected in all active smokers and in a majority of passive smokers and self-reported nonsmokers. A strong interindividual variation suggests differences in metabolism and smoking habits. Follicular fluid cotinine assessments are useful for infertility studies.

Altered expression of ABO (H) carbohydrate antigens is seen in pleomorphic adenomas.

Cell surface carbohydrate antigens show changes in relation to differentiation, maturation and malignant transformation. The expression of type 2 chain ABH carbohydrate structures of the ABO histo-blood group system was investigated in 28 pleomorphic adenomas (PA) and normal parotid glands in order to study possible changes in the glycosylation pattern. The distribution of carbohydrate structures was investigated by immunohistological stainings of formalin-fixed paraffin-embedded material using monoclonal antibodies (MAbs) with well-defined specificity. A strong interindividual variation was found in the normal tissue as well as in the tumors. In normal tissue, acinus and duct cells all expressed elongated carbohydrate structures. The yoepithelial cells did not stain with any of the MAbs investigated. In the PAs, staining was seen in the ductular structures and myoepithelial cells. In contrast to normal tissue, the tumors expressed the short precursor molecule sialylated N-acetyllactosamine. Furthermore, the PAs showed loss of H and A antigens, and a reduced expression of Le(y) compared to normal tissue. The ductular structures as well as the modified myoepithelial cells expressed binary N-acetyllactosamine, which in the normal tissue could only be found in the striated and excretory ducts. Thus our study has shown that aberrant glycosylation is not only a feature of malignant neoplasms but also occurs in pleomorphic adenomas.

Vanadium induced impairment of haem synthesis.

Biochemical and haematological profiles of workers exposed to vanadium were compared with those of non-exposed age matched subjects. A significantly positive and dose related correlation between serum vanadium and zinc protoporphyrin (ZPP) was observed. Normal lead concentrations excluded this heavy metal as a possible cause. Inhibition of the reduction of Fe to Fe++ by vanadium is discussed as the possible cause of interference of vanadium with haem synthesis. Iron and iron binding capacity were found to be significantly lower and ferritin significantly higher in the population exposed to vanadium. Strong inter-individual variations do not allow an explanation of this interference with iron metabolism.