The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury

Soft Matrices Suppress Cooperative Behaviors among Receptor-Ligand Bonds in Cell Adhesion

The fact that biological tissues are stable over prolonged periods of time while individual receptor-ligand bonds only have limited lifetime underscores the critical importance of cooperative behaviors of multiple molecular bonds, in particular the competition between the rate of rupture of closed bonds (death rate) and the rate of rebinding of open bonds (birth rate) in a bond cluster. We have recently shown that soft matrices can greatly increase the death rate in a bond cluster by inducing severe stress concentration near the adhesion edges. In the present paper, we report a more striking effect that, irrespective of stress concentration, soft matrices also suppress the birth rate in a bond cluster by increasing the local separation distance between open bonds. This is shown by theoretical analysis as well as Monte Carlo simulations based on a stochastic-elasticity model in which stochastic descriptions of molecular bonds and elastic descriptions of interfacial force/separation are unified in a single modeling framework. Our findings not only are important for understanding the role of elastic matrices in cell adhesion, but also have general implications on adhesion between soft materials

Everolimus and long acting octreotide as a volume reducing treatment of polycystic livers (ELATE): study protocol for a randomized controlled trial

Contains fulltext : 97893.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Polycystic liver disease (PLD) is defined as having more than 20 liver cysts and can present as a severe and disabling condition. Most symptoms are caused by the mass effect of the liver size and include abdominal pain and distension. The somatostatin analogues octreotide and lanreotide have proven to reduce polycystic liver volume. mTOR inhibitors such as everolimus inhibit cell proliferation and might thereby reduce growth of liver cysts. This trial aims to assess the benefit of combination therapy of everolimus and octreotide compared to octreotide monotherapy. In this study we present the structure of the trial and the characteristics of the included patients. METHODS/DESIGN: This is a randomized open-label clinical trial comparing the effect of 12 months of everolimus and octreotide to octreotide monotherapy in PLD patients. Primary outcome is change in liver volume determined by CT-volumetry. Secondary outcomes are changes in abdominal symptoms and quality of life. Moreover, safety and tolerability of the drugs will be assessed. DISCUSSION: This trial will compare the relative efficacy of combination therapy with octreotide and everolimus to octreotide monotherapy. Since they apply to different pathways of cystogenesis we expect that combining octreotide and everolimus will result in a cumulative reduction of polycystic liver volume. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01157858

Intertwining relations for one-dimensional diffusions and application to functional inequalities

International audienceFollowing the recent work [13] fulfilled in the discrete case, we pro- vide in this paper new intertwining relations for semigroups of one-dimensional diffusions. Various applications of these results are investigated, among them the famous variational formula of the spectral gap derived by Chen and Wang [15] together with a new criterion ensuring that the logarithmic Sobolev inequality holds. We complete this work by revisiting some classical examples, for which new estimates on the optimal constants are derived

Haplotype association analyses in resources of mixed structure using Monte Carlo testing

<p>Abstract</p> <p>Background</p> <p>Genomewide association studies have resulted in a great many genomic regions that are likely to harbor disease genes. Thorough interrogation of these specific regions is the logical next step, including regional haplotype studies to identify risk haplotypes upon which the underlying critical variants lie. Pedigrees ascertained for disease can be powerful for genetic analysis due to the cases being enriched for genetic disease. Here we present a Monte Carlo based method to perform haplotype association analysis. Our method, hapMC, allows for the analysis of full-length and sub-haplotypes, including imputation of missing data, in resources of nuclear families, general pedigrees, case-control data or mixtures thereof. Both traditional association statistics and transmission/disequilibrium statistics can be performed. The method includes a phasing algorithm that can be used in large pedigrees and optional use of pseudocontrols.</p> <p>Results</p> <p>Our new phasing algorithm substantially outperformed the standard expectation-maximization algorithm that is ignorant of pedigree structure, and hence is preferable for resources that include pedigree structure. Through simulation we show that our Monte Carlo procedure maintains the correct type 1 error rates for all resource types. Power comparisons suggest that transmission-disequilibrium statistics are superior for performing association in resources of only nuclear families. For mixed structure resources, however, the newly implemented pseudocontrol approach appears to be the best choice. Results also indicated the value of large high-risk pedigrees for association analysis, which, in the simulations considered, were comparable in power to case-control resources of the same sample size.</p> <p>Conclusions</p> <p>We propose hapMC as a valuable new tool to perform haplotype association analyses, particularly for resources of mixed structure. The availability of meta-association and haplotype-mining modules in our suite of Monte Carlo haplotype procedures adds further value to the approach.</p

Dispersion of carbon nanotubes in polyamide 6 for microinjection moulding

The focus of this study was to investigate the dispersion state of pure and functionalized carbon nanotubes in polyamide 6, on composites prepared by twin-screw extrusion and then processed by microinjection moulding. Nanocomposites were prepared with different carbonvnanotube compositions, with and without functionalization. The nanotubes were functionalized by the 1,3-dipolar cycloaddition reaction. The dispersion of the carbon nanotube agglomerates was quantified using optical microscopy and image analysis. The effect of functionalization on the polyamide 6/carbon nanotube interface, the nanocomposite morphology and the mechanical and electrical properties were studied. It was observed that the microinjected composites with functionalized carbon nanotubes presented improved dispersion, with smaller carbon nanotube agglomerate area ratio compared to the composites with pure nanotubes. The functionalized nanotubes showed better adhesion to polyamide 6 compared to pure nanotubes, as observed by scanning electron microscopy. The incorporation of carbon nanotubes considerably improved the mechanical properties. The effect of high polymer shear rate on carbon nanotube alignment during microinjection moulding was assessed by comparing the electrical resistivity of the composite after extrusion and after microinjection moulding, through the thickness and along the flow direction. The experiments showed that the mould design and processing conditions significantly affected electrical resistivity.Fundação para a Ciência e Tecnologia (project PEst-C/CTM/LA0025/2013

Decision Forest Analysis of 61 Single Nucleotide Polymorphisms in a Case-Control Study of Esophageal Cancer; a novel method

BACKGROUND: Systematic evaluation and study of single nucleotide polymorphisms (SNPs) made possible by high throughput genotyping technologies and bioinformatics promises to provide breakthroughs in the understanding of complex diseases. Understanding how the millions of SNPs in the human genome are involved in conferring susceptibility or resistance to disease, or in rendering a drug efficacious or toxic in the individual is a major goal of the relatively new fields of pharmacogenomics. Esophageal squamous cell carcinoma is a high-mortality cancer with complex etiology and progression involving both genetic and environmental factors. We examined the association between esophageal cancer risk and patterns of 61 SNPs in a case-control study for a population from Shanxi Province in North Central China that has among the highest rates of esophageal squamous cell carcinoma in the world. METHODS: High-throughput Masscode mass spectrometry genotyping was done on genomic DNA from 574 individuals (394 cases and 180 age-frequency matched controls). SNPs were chosen from among genes involving DNA repair enzymes, and Phase I and Phase II enzymes. We developed a novel adaptation of the Decision Forest pattern recognition method named Decision Forest for SNPs (DF-SNPs). The method was designated to analyze the SNP data. RESULTS: The classifier in separating the cases from the controls developed with DF-SNPs gave concordance, sensitivity and specificity, of 94.7%, 99.0% and 85.1%, respectively; suggesting its usefulness for hypothesizing what SNPs or combinations of SNPs could be involved in susceptibility to esophageal cancer. Importantly, the DF-SNPs algorithm incorporated a randomization test for assessing the relevance (or importance) of individual SNPs, SNP types (Homozygous common, heterozygous and homozygous variant) and patterns of SNP types (SNP patterns) that differentiate cases from controls. For example, we found that the different genotypes of SNP GADD45B E1122 are all associated with cancer risk. CONCLUSION: The DF-SNPs method can be used to differentiate esophageal squamous cell carcinoma cases from controls based on individual SNPs, SNP types and SNP patterns. The method could be useful to identify potential biomarkers from the SNP data and complement existing methods for genotype analyses

Expression of Msx1 and Dlx1 during Dumbo rat head development: Correlation with morphological features

The Dumbo rat possesses some characteristics that evoke several human syndromes, such as Treacher-Collins: shortness of the maxillary, zygomatic and mandibular bones, and low position of the ears. Knowing that many homeobox genes are candidates in craniofacial development, we investigated the involvement of the Msx1 and Dlx1 genes in the Dumbo phenotype with the aim of understanding their possible role in abnormal craniofacial morphogenesis and examining the possibility of using Dumbo rat as an experimental model for understanding abnormal craniofacial development. We studied the expression of these genes during craniofacial morphogenesis by RT-PCR method. We used Dumbo embryos at E12 and E14 and included the Wistar strain as a control. Semi-quantitative PCR analysis demonstrated that Msx1 and Dlx1 are expressed differently between Dumbo and Wistar rats, indicating that their low expression may underly the Dumbo phenotype

Evidence-informed obstetric practice during normal birth in China: trends and influences in four hospitals

BACKGROUND: A variety of international organizations, professional groups and individuals are promoting evidence-informed obstetric care in China. We measured change in obstetric practice during vaginal delivery that could be attributed to the diffusion of evidence-based messages, and explored influences on practice change. METHODS: Sample surveys of women at postnatal discharge in three government hospitals in Shanghai and one in neighbouring Jiangsu province carried out in 1999, repeated in 2003, and compared. Main outcome measures were changes in obstetric practice and influences on provider behaviour. "Routine practice" was defined as more than 65% of vaginal births. Semi-structured interviews with doctors explored influences on practice. RESULTS: In 1999, episiotomy was routine at all four hospitals; pubic shaving, rectal examination (to monitor labour) and electronic fetal heart monitoring were routine at three hospitals; and enema on admission was common at one hospital. In 2003, episiotomy rates remained high at all hospitals, and actually significantly increased at one; pubic shaving was less common at one hospital; one hospital stopped rectal examination for monitoring labour, and the one hospital where enemas were common stopped this practice. Mobility during labour increased in three hospitals. Continuous support was variable between hospitals at baseline and showed no change with the 2003 survey. Provider behaviour was mainly influenced by international best practice standards promoted by hospital directors, and national legislation about clinical practice. CONCLUSION: Obstetric practice became more evidence-informed in this selected group of hospitals in China. Change was not directly related to the promotion of evidence-based practice in the region. Hospital directors and national legislation seem to be particularly important influences on provider behaviour at the hospital level

Single Mode Lasing from Hybrid Hemispherical Microresonators

Enormous attention has been paid to optical microresonators which hold a great promise for microlasers as well as fundamental studies in cavity quantum electrodynamics. Here we demonstrate a three-dimensional (3D) hybrid microresonator combining self-assembled hemispherical structure with a planar reflector. By incorporating dye molecules into the hemisphere, optically pumped lasing phenomenon is observed at room temperature. We have studied the lasing behaviors with different cavity sizes, and particularly single longitudinal mode lasing from hemispheres with diameter ∼15 μm is achieved. Detailed characterizations indicate that the lasing modes shift under varying pump densities, which can be well-explained by frequency shift and mode hopping. This work provides a versatile approach for 3D confined microresonators and opens an opportunity to realize tunable single mode microlasers