Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach

Aims/hypothesis In the present study we investigated potential associations of a set of 45 single nucleotide polymorphisms (SNP) in 20 candidate genes on eight chromosomes with diabetic nephropathy (DN) in type 2 diabetes mellitus. We aimed to compare two methodological approaches suitable for analysing susceptibility to complex traits: single- and multi-locus analyses. Materials and methods The study comprised a total of 647 subjects in one of three groups: diabetes with or without DN, or no diabetes. Genotypes were detected by PCR-based methodology (PCR only, PCR plus RFLP, or allele-specific PCR). Haplotypes were inferred in silico. Set association (tested using SUMSTAT software) was used for multilocus analysis. Results After correction for multiple comparisons, only one SNP, in the gene encoding the receptor of advanced glycation end products, AGER 2184A/G (gene symbol formerly known as RAGE) showed a significant association with DN (p = 0.0006) in single-locus analysis. In multi-locus analysis, six SNPs exhibited a significant association with DN: four SNPs on chromosome 6p (AGER 2184A/G, LTA 252A/G, EDN1 8002G/A and AGER -429T/C) and two SNPs on chromosome 7q (NOS3 774C/T and NOS3 E298D), omnibus p = 0.033. Haplotype analysis revealed significant differences between DN and control groups in haplotype frequencies on chromosome 6 (p = 0.0002); however, there were no significant difference in the frequencies of the NOS3 haplotypes on chromosome 7. Logistic regression analysis identified SNPs AGER 2184A/G and NOS3 774C/T, together with diabetes duration and HbA_1c, as significant predictors of DN. Testing for interactions between SNPs on chromosomes 6 and 7 did not provide significant evidence for epistatic interaction. Conclusions/interpretation Using the set-association approach we identified significant associations of several SNPs on chromosomes 6 and 7 with DN. The single- and multi-locus analyses represent complementary methods. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

New iron chelators in anthracycline-induced cardiotoxicity

The use of anthracycline anticancer drugs is limited by a cumulative, dose-dependent cardiac toxicity. Iron chelation has long been considered as a promising strategy to limit this unfavorable side effect, either by restoring the disturbed cellular iron homeostasis or by removing redox-active iron, which may promote anthracycline-induced oxidative stress. Aroylhydrazone lipophilic iron chelators have shown promising results in the rabbit model of daunorubicin-induced cardiomyopathy as well as in cellular models. The lack of interference with the antiproliferative effects of the anthracyclines also favors their use in clinical settings. The dose, however, should be carefully titrated to prevent iron depletion, which apparently also applies for other strong iron chelators. We have shown that a mere ability of a compound to chelate iron is not the sole determinant of a good cardioprotector and the protective potential does not directly correlate with the ability of the chelators to prevent hydroxyl radical formation. These findings, however, do not weaken the role of iron in doxorubicin cardiotoxicity as such, they rather appeal for further investigations into the molecular mechanisms how anthracyclines interact with iron and how iron chelation may interfere with these processes.     

Determination of dimethindene enantiomers in pharmaceuticals by capillary electrophoresis with carboxyethyl-beta-cyclodextrin

Cyclodextrin-mediated capillary zone electrophoresis in a hydrodynamically closed separation system with suppressed electroosmotic flow and UV absorbance photometric detection was developed for a high effective separation and quantitation of dimethindene enantiomers in various pharmaceutical formulations (solution, gel, capsules). The running buffer consisted of epsilon-aminocaproic acid (20 mmol/l) adjusted to pH 4.5 with acetic acid, negatively charged carboxyethyl-beta-cyclodextrin (2.5 mg/ml), serving as chiral selector, and 0.1% (w/v) methylhydroxyethylcellulose, serving as an electroosmotic flow suppressor. The proposed method was successfully validated appraising parameters of sensitivity, linearity, precision, accuracy/recovery and robustness and it is useful for routine use.     

Model-Based Evaluation of Drying Kinetics and Solvent Diffusion in Pharmaceutical Thin Film Coatings

Pharmaceutical Research - Fluid-bed coating processes make it possible to manufacture pharmaceutical products with tuneable properties. The choice of polymer type and coating thickness provides...     

Sacrococcygeal teratoma in Sweden between 1978 and 1989: long-term functional results.

Thirty-four patients operated with sacrococcygeal teratoma in Sweden between 1978 and 1989 were reviewed. Twenty-five children were available for functional follow-up. The patients and their parents were interviewed for bowel and micturition habits. Fourteen patients from this number were subjected to anorectal manometry (56%). Fifteen children reported normal bowel habits (60%). In 10 patients (40%) soiling was observed. However, four of them were under 3 years of age and wearing diapers, which made the functional evaluation difficult. The manometries showed normal and resting tone and squeezing pressures in 10 patients and subnormal values in four patients who also had soiling problems. All investigated children showed normal rectoanal inhibition reflex. Twenty-one patients reported normal micturition, in four (16%) urinary incontinence was recorded. Two of the latter children required intermittent clean catheterization, one was on medication and the last one lives without any treatment. No difference in functional outcome was noted between patients with intrapelvic or extrapelvic tumor location. Retrospectively, it is not possible to know whether the observed functional outcome is due to tumor growth or the result of surgery. Preoperative clinical investigation and in some cases anorectal manometry and cystometry could theoretically resolve this problem.     

Effect of the combination of laser excision and interstitial hyperthermia in palliative therapy of head and neck tumours in the advanced stage of the disease

BACKGROUND AND OBJECTIVES: We evaluated the potential of combining laser excision with laser interstitial hyperthermia in order to improve the quality of life of patients with 3rd or 4th stage malignant head and neck tumours. STUDY DESIGN/MATERIALS AND METHODS: To evaluate the quality of life, we used the 4th version of the University of Washington Quality of Life assessment score modified for head and neck tumours. The study group of 20 patients assessed their condition in a questionnaire, examining 12 aspects of their quality of life before the laser treatment, the second day after, and 6 weeks after the treatment. RESULTS: We observed a gain of 16.41 points, which subjectively represents a 70.32% improvement in the quality of life. CONCLUSIONS: Following this therapy the quality of life significantly improved in patients with primarily low quality of life, whereas the group of patients with less affected quality of life reported a temporary decline in the quality of life after the treatment. To obtain a proper objective indication, we suggest a mathematical modelling of possible gains for the individual patient using the University of Washington Quality of Life classification.