Formant frequency discrimination with a fine structure sound coding strategy for cochlear implants.

Recent sound coding strategies for cochlear implants (CI) have focused on the transmission of temporal fine structure to the CI recipient. To date, knowledge about the effects of fine structure coding in electrical hearing is poorly charactarized. The aim of this study was to examine whether the presence of temporal fine structure coding affects how the CI recipient perceives sound. This was done by comparing two sound coding strategies with different temporal fine structure coverage in a longitudinal cross-over setting. The more recent FS4 coding strategy provides fine structure coding on typically four apical stimulation channels compared to FSP with usually one or two fine structure channels. 34 adult CI patients with a minimum CI experience of one year were included. All subjects were fitted according to clinical routine and used both coding strategies for three months in a randomized sequence. Formant frequency discrimination thresholds (FFDT) were measured to assess the ability to resolve timbre information. Further outcome measures included a monosyllables test in quiet and the speech reception threshold of an adaptive matrix sentence test in noise (Oldenburger sentence test). In addition, the subjective sound quality was assessed using visual analogue scales and a sound quality questionnaire after each three months period. The extended fine structure range of FS4 yields FFDT similar to FSP for formants occurring in the frequency range only covered by FS4. There is a significant interaction (p = 0.048) between the extent of fine structure coverage in FSP and the improvement in FFDT in favour of FS4 for these stimuli. FS4 Speech perception in noise and quiet was similar with both coding strategies. Sound quality was rated heterogeneously showing that both strategies represent valuable options for CI fitting to allow for best possible individual optimization.

Effect of quercetin on traits of the metabolic syndrome, endothelial function and inflammation in men with different APOE isoforms.

BACKGROUND AND AIMS: The polyphenol quercetin may prevent cardiovascular diseases due to its vasorelaxant and anti-oxidative properties. We investigated the effects of quercetin on risk factors of atherosclerosis, biomarkers of inflammation and oxidative stress, depending on the apolipoprotein E (APOE) genotype. METHODS AND RESULTS: In a double-blind crossover study 49 healthy male subjects with APOE genotype 3/3 (n = 19), 3/4 (n = 22) and 4/4 (n = 8) consumed 150 mg/d quercetin or placebo for 8 weeks each, intermitted by a three-week washout phase. After each intervention, endothelial function, anthropometry, metabolic and inflammatory parameters were measured in the fasting and postprandial state following a standardized lipid-rich meal. Endothelial function was not changed. In all subjects combined, quercetin significantly decreased waist circumference (P = 0.004) and postprandial systolic blood pressure (P = 0.044). Postprandial triacylglycerol concentrations were significantly decreased and HDL-cholesterol concentrations increased after quercetin as compared to placebo consumption (P = 0.025). Quercetin also moderately increased levels of TNFα (P = 0.024). There was a significant gene-diet interaction for waist circumference and for body mass index (BMI). CONCLUSIONS: Quercetin supplementation improved some risk factors of cardiovascular disease, yet exerted slightly pro-inflammatory effects. Genotype-dependent effects were seen only on waist circumference and BMI.

A common haplotype of carnitine palmitoyltransferase 1b is associated with the metabolic syndrome.

The carnitine palmitoyltransferase (CPT) enzyme system facilitates the transport of long-chain fatty acids into mitochondria to provide substrates for ß-oxidation. We performed an analysis including three coding SNP in the muscle isoform of the CPT1b gene (rs3213445, rs2269383 and rs470117) and one coding SNP in the CPT2 gene (rs1799821) to find associations with traits of the metabolic syndrome (MetS). Male participants (n 755) from the Metabolic Intervention Cohort Kiel were genotyped and phenotyped for features of the MetS. Participants underwent a glucose tolerance test and a postprandial assessment of metabolic variables after a standardised mixed meal. Carriers of the rare CPT1b 66V (rs3213445) allele had significantly higher γ-glutamyl transpeptidase (GGT), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvate transaminase (GPT) activities (P< 0·0001, P= 0·03 and P= 0·048, respectively) and a higher fatty liver index (FLI, P= 0·026). Fasting and postprandial TAG (P= 0·007 and P= 0·009, respectively) and fasting glucose (P= 0·012) were significantly higher in 66V-allele carriers. The insulin sensitivity index determined after a glucose load was lower in those subjects (P= 0·005). Total cholesterol (P= 0·051) and LDL-cholesterol (P= 0·062) tended to be higher in 66V-allele carriers when compared with I66I homozygotes. Homozygosity of the rare K531E allele presented with lower GGT and GOT activities (P= 0·011 and P= 0·027, respectively). E531E homozygotes tended to have lower GPT and FLI (P= 0·078 and P= 0·052, respectively). CPT2 V368I (rs1799821) genotypic groups did not differ in the investigated anthropometric and metabolic parameters. The present results confirm the association of CPT1b coding polymorphisms with the MetS, with a deleterious effect of the CPT1b I66V and a protective impact of the CPT1b K531E SNP, whereas haplotype analysis indicates a relevance of the E531K polymorphism only.

A promoter polymorphism in the liver-specific fatty acid transport protein 5 is associated with features of the metabolic syndrome and steatosis.

The fatty acid transport protein 5 (FATP5) is exclusively expressed in the liver and is involved in hepatic lipid and bile metabolism. We investigated whether a variation in the FATP5 promoter (rs56225452) is associated with hepatic steatosis and further features of the metabolic syndrome. A total of 716 male subjects from the Metabolic Intervention Cohort Kiel (MICK) and 103 male subjects with histologically proved nonalcoholic fatty liver disease (NAFLD) were genotyped for this FATP5 polymorphism rs56225452 and phenotyped for features of the metabolic syndrome. In the MICK cohort, ALT activities, postprandial insulin, and triglyceride concentrations were higher in subjects carrying the rare A-allele compared to GG homozygotes. Accordingly, the insulin sensitivity index determined after a mixed meal and standardized glucose load was lower in A-allele carriers. NAFLD cases carrying allele A were presented with also higher ALT activities. In NAFLD subjects, the association of BMI with the degree of steatosis and glucose concentration differed across FATP5 promoter polymorphism. The FATP5 promoter polymorphism rs56225452 is associated with higher ALT activity, insulin resistance, and dyslipidemia in the general population. The impact of the BMI on the severity of steatosis in NAFLD cases seems to depend on the FATP5 polymorphism.

Isomer-specific effects of CLA on gene expression in human adipose tissue depending on PPARgamma2 P12A polymorphism: a double blind, randomized, controlled cross-over study.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)gamma is a key regulator in adipose tissue. The rare variant Pro12Ala of PPARgamma2 is associated with a decreased risk of insulin resistance. Being dietary PPARgamma ligands, conjugated linoleic acids (CLAs) received considerable attention because of their effects on body composition, cancer, atherosclerosis, diabetes, obesity and inflammation, although some effects were only demonstrated in animal trials and the results in human studies were not always consistent. In the present study effects of CLA supplementation on genome wide gene expression in adipose tissue biopsies from 11 Ala12Ala and 23 Pro12Pro men were investigated. Subjects underwent four intervention periods (4 wk) in a randomized double blind cross-over design receiving 4.25 g/d of either cis-9, trans-11 CLA, trans-10,cis-12 CLA, 1:1 mixture of both isomers or a reference linoleic acid oil preparation. After each intervention biopsies were taken, whole genome expression microarrays were applied, and genes of interest were verified by realtime PCR. RESULTS: The following genes of lipid metabolism were regulated by CLA: LDLR, FASN, SCD, FADS1 and UCP2 were induced, while ABCA1, CD36 and CA3 were repressed. Transcription factors PPARgamma, NFAT5, CREB5 and EBF1, the adipokine NAMPT, members of the insulin signaling cascade SORBS1 and IGF1 and IL6ST were repressed, while the adipokine THBS1 and GLUT4 involved in insulin signaling were induced. Compared to trans-10,cis-12 CLA and the CLA mixture the cis-9, trans-11 CLA isomer exerted weaker effects. Only CD36 (-1.2 fold) and THBS1 (1.5 fold) were regulated. The CLA effect on expression of PPARgamma and leptin genes depends on the PPARgamma2 genotype. CONCLUSION: The data suggest that the isomer specific influence of CLA on glucose and lipid metabolism is genotype dependent and at least in part mediated by PPARgamma. TRIAL REGISTRATION: http://www.controlled-trials.com: ISRCTN91188075.

[The EWS gene rearrangement in Ewing tumors: key to the disease]. / Das EWS-Genrearrangement in Ewing Tumoren: Schlüssel zur Erkrankung.

The family of Ewing tumors (ET) is characterised by a unique gene rearrangement which is represented by a translocation t(11;22) (q24;q12) or a deletion del 22q12 in most cytogenetically analysable cases. The recent cloning of the underlying gene fusion provides the basis for the diagnostic detection of minimal amounts of residual tumor cells at resection margins, in blood and bone marrow. In addition, the very first steps in ET tumorigenesis can be studied on a functional basis. In this study, a variety of fusion products were identified with a sensitivity of 10(-6) by means of RT-PCR. In 20 of 22 ET, a gene rearrangement was identified which resulted in the substitution of the effector domain of one of the closely related DNA-binding oncogenes, FLI-1 or ERG, by the transactivating domain of a new gene, EWS. Presumably, the oncogene and consequently its target genes are activated by this type of translocation. If the EWS domain was replaced with a transcriptionally irrelevant domain by transfection of a recombinant gene into ET cells, competition with the endogenous chimeric oncogene-product for DNA-binding was observed resulting in a partial growth inhibition. Activation of FLI-1 has been previously shown to occur as a primary event in Friend virus induced mouse erythroleukemia. During progression of this disease, inactivating p53 mutations have been observed frequently. In contrast, such aberrations were found to be extremely rare in ET.

Narrow spectrum of infrequent p53 mutations and absence of MDM2 amplification in Ewing tumours.

The p53 and MDM2 genes are part of a physiological pathway frequently impaired in human cancer. With the exception of tumours occasionally associated with hereditary predisposition, childhood malignancies have not been studied in detail yet. This is the first report on the analysis of p53 and MDM2 in a group of non-hereditary paediatric neoplasms referred to as the Ewing tumours (ETs). Thirty-seven primary tumours and cell lines from 19 patients were screened for the presence of p53 mutations. Only 5% of the primary tumour specimens were found to carry an alteration within this gene. However, p53 mutations were 10-fold enriched in ET cell lines, thus indicating a selective growth advantage in vitro. Strikingly, five out of nine alterations detected were missense mutations within codon 273, which were previously reported to impair only partially the normal p53 function. Two single-base substitutions occurred at codons 277 and 176, and two alterations were loss-of-function mutations. Investigation of the MDM2 gene revealed neither gene amplification in the primary tumours and cell lines nor significant overexpression in any of the cell lines. Our data therefore suggest that impairment of cellular mechanisms involving p53 is rare in a distinct group of childhood malignancies.

p53 mosaicism with an exon 8 germline mutation in the founder of a cancer-prone pedigree.

Changes in the tumor-suppressor gene p53 are frequently acquired during the course of malignant development of human tumors. Recently, constitutional heterozygous mutations in p53 exon 7 have been identified as the primary cause of cancer predisposition in cases of the familial Li-Fraumeni cancer syndrome. These findings underline the need for extensive mutation screening in families with high cancer incidence. This report describes the detection and follow-up by two-dimensional single-strand conformation polymorphism analysis (2DSSCP) of a new germline mutation of p53 exon 8 in a case of suspected Li-Fraumeni syndrome. Although a high cancer incidence had been reported in the family history of the father of siblings suffering from brain tumor and rhabdomyosarcoma, a constitutional heterozygous p53 mutation was identified only in the affected children. Retrospective analysis of archival tissue of a half-sister who died several years ago from a tumor of previously uncertain diagnosis revealed the same mutation. The mutation had therefore occurred in the germ cells of the mother, who thus appears to be a mosaic. The cancer predisposition of the paternal ancestors must have been due to other factors.

[Rhinolithiasis--with special reference to minerology]. / Rhinolithiasis--unter spezieller Berücksichtigung der Mineralogie.

A rhinolith present for 77 years and weighing 18 g. is reported. Special emphasis is given to the problems of establishing the diagnosis of nasal calculi and foreign bodies. Furthermore, the study discusses the mineralogy of the rhinolith on the basis of the results yielded by the electron-ray micro-probe, x-ray diffractometry and infrared-spectroscopy with respect to the mineral Whitlockite.