Comparison of two normative paediatric gait databases

The availability of age-matched normative data is an essential component of clinical gait analyses. Comparison of normative gait databases is difficult due to the high-dimensionality and temporal nature of the various gait waveforms. The purpose of this study was to provide a method of comparing the sagittal joint angle data between two normative databases. We compared a modern gait database to the historical San Diego database using statistical classifiers developed by Tingley et al. (2002). Gait data were recorded from 60 children aged 1–13 years. A six-camera Vicon 512 motion analysis system and two force plates were utilized to obtain temporal-spatial, kinematic, and kinetic parameters during walking. Differences between the two normative data sets were explored using the classifier index scores, and the mean and covariance structure of the joint angle data from each lab. Significant differences in sagittal angle data between the two databases were identified and attributed to technological advances and data processing techniques (data smoothing, sampling, and joint angle approximations). This work provides a simple method of database comparison using trainable statistical classifiers

The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load

<p>Abstract</p> <p>Background</p> <p>A genome-wide association study (GWAS) using metabolite concentrations as proxies for enzymatic activity, suggested that two variants: rs2014355 in the gene encoding short-chain acyl-coenzyme A dehydrogenase (<it>ACADS</it>) and rs11161510 in the gene encoding medium-chain acyl-coenzyme A dehydrogenase (<it>ACADM</it>) impair fatty acid β-oxidation. Chronic exposure to fatty acids due to an impaired β-oxidation may down-regulate the glucose-stimulated insulin release and result in an increased risk of type 2 diabetes (T2D). We aimed to investigate whether the two variants associate with altered insulin release following an oral glucose load or with T2D.</p> <p>Methods</p> <p>The variants were genotyped using KASPar^®PCR SNP genotyping system and investigated for associations with estimates of insulin release and insulin sensitivity following an oral glucose tolerance test (OGTT) in a random sample of middle-aged Danish individuals (<it>n</it>_{<it>ACADS </it>}= 4,324; <it>n</it>_{<it>ACADM </it>}= 4,337). The T2D-case-control study involved a total of ~8,300 Danish individuals (<it>n</it>_{<it>ACADS </it>}= 8,313; <it>n</it>_{<it>ACADM </it>}= 8,344).</p> <p>Results</p> <p>In glucose-tolerant individuals the minor C-allele of rs2014355 of <it>ACADS </it>associated with reduced measures of serum insulin at 30 min following an oral glucose load (per allele effect (β) = -3.8% (-6.3%;-1.3%), <it>P </it>= 0.003), reduced incremental area under the insulin curve (β = -3.6% (-6.3%;-0.9%), <it>P </it>= 0.009), reduced acute insulin response (β = -2.2% (-4.2%;0.2%), <it>P </it>= 0.03), and with increased insulin sensitivity ISI_Matsuda(β = 2.9% (0.5%;5.2%), <it>P </it>= 0.02). The C-allele did not associate with two other measures of insulin sensitivity or with a derived disposition index. The C-allele was not associated with T2D in the case-control analysis (OR 1.07, 95% CI 0.96-1.18, <it>P </it>= 0.21). rs11161510 of <it>ACADM </it>did not associate with any indices of glucose-stimulated insulin release or with T2D.</p> <p>Conclusions</p> <p>In glucose-tolerant individuals the minor C-allele of rs2014355 of <it>ACADS </it>was associated with reduced measures of glucose-stimulated insulin release during an OGTT, a finding which in part may be mediated through an impaired β-oxidation of fatty acids.</p

Role of endoplasmic reticulum stress induction by the plant toxin, persin, in overcoming resistance to the apoptotic effects of tamoxifen in human breast cancer cells

Background: Persin is a plant toxin that displays synergistic cytotoxicity with tamoxifen in human breast cancer cell lines. Here, we examined the ability of persin to circumvent tamoxifen resistance and delineated the intracellular signalling pathways involved. Methods: The induction of apoptosis in tamoxifen-resistant and -sensitive breast cancer cells was measured by flow cytometry following treatment with persin±tamoxifen. Markers of endoplasmic reticulum stress (ERS) were analysed following treatment, and their causal role in mediating persin-induced apoptosis was determined using chemical inhibitors and RNA interference. Results: Cells that were resistant to an apoptotic concentration of tamoxifen maintained an apoptotic response to persin. Persin-induced apoptosis was associated with an increase in markers of ERS, that is, CHOP expression and XBP-1 splicing and was decreased by CHOP siRNA. The CASP-4 inhibitor Z-YVAD-FMK markedly inhibited persin-induced apoptosis in both tamoxifen-sensitive and -resistant cells. Conclusion: The cytotoxic effects of persin are CASP-4 dependent and mediated by CHOP-dependent and -independent ERS signalling cascades. Increased ERS signalling contributes to persin-induced reversal of tamoxifen resistance