Genetics of Coronary Artery Disease in Taiwan: A Cardiometabochip Study by the Taichi Consortium

By means of a combination of genome-wide and follow-up studies, recent large-scale association studies of populations of European descent have now identified over 46 loci associated with coronary artery disease (CAD). As part of the TAICHI Consortium, we have collected and genotyped 8556 subjects from Taiwan, comprising 5423 controls and 3133 cases with coronary artery disease, for 9087 CAD SNPs using the CardioMetaboChip. We applied penalized logistic regression to ascertain the top SNPs that contribute together to CAD susceptibility in Taiwan. We observed that the 9p21 locus contributes to CAD at the level of genome-wide significance (rs1537372, with the presence of C, the major allele, the effect estimate is -0.216, standard error 0.033, p value 5.8x10^-10). In contrast to a previous report, we propose that the 9p21 locus is a single genetic contribution to CAD in Taiwan because: 1) the penalized logistic regression and the follow-up conditional analysis suggested that rs1537372 accounts for all of the CAD association in 9p21, and 2) the high linkage disequilibrium observed for all associated SNPs in 9p21. We also observed evidence for the following loci at a false discovery rate >5%: SH2B3, ADAMTS7, PHACTR1, GGCX, HTRA1, COL4A1, and LARP6-LRRC49. We also took advantage of the fact that penalized methods are an efficient approach to search for gene-by-gene interactions, and observed that two-way interactions between the PHACTR1 and ADAMTS7 loci and between the SH2B3 and COL4A1 loci contribute to CAD risk. Both the similarities and differences between the significance of these loci when compared with significance of loci in studies of populations of European descent underscore the fact that further genetic association of studies in additional populations will provide clues to identify the genetic architecture of CAD across all populations worldwide.     

Assessment of Median Nerve Mobility by Ultrasound Dynamic Imaging for Diagnosing Carpal Tunnel Syndrome

Carpal tunnel syndrome (CTS) is the most common peripheral neuropathy and is characterized by median nerve entrapment at the wrist and the resulting median nerve dysfunction. CTS is diagnosed clinically as the gold standard and confirmed with nerve conduction studies (NCS). Complementing NCS, ultrasound imaging could provide additional anatomical information on pathological and motion changes of the median nerve. The purpose of this study was to estimate the transverse sliding patterns of the median nerve during finger movements by analyzing ultrasound dynamic images to distinguish between normal subjects and CTS patients. Transverse ultrasound images were acquired, and a speckle-tracking algorithm was used to determine the lateral displacements of the median nerve in radial-ulnar plane in B-mode images utilizing the multilevel block-sum pyramid algorithm and averaging. All of the averaged lateral displacements at separate acquisition times within a single flexion–extension cycle were accumulated to obtain the cumulative lateral displacements, which were curve-fitted with a second-order polynomial function. The fitted curve was regarded as the transverse sliding pattern of the median nerve. The R² value, curvature, and amplitude of the fitted curves were computed to evaluate the goodness, variation and maximum value of the fit, respectively. Box plots, the receiver operating characteristic (ROC) curve, and a fuzzy c-means clustering algorithm were utilized for statistical analysis. The transverse sliding of the median nerve during finger movements was greater and had a steeper fitted curve in the normal subjects than in the patients with mild or severe CTS. The temporal changes in transverse sliding of the median nerve within the carpal tunnel were found to be correlated with the presence of CTS and its severity. The representative transverse sliding patterns of the median nerve during finger movements were demonstrated to be useful for quantitatively estimating median nerve dysfunction in CTS patients.     

Differentiation of Malignant and Benign Incidental Breast Lesions Detected by Chest Multidetector-Row Computed Tomography: Added Value of Quantitative Enhancement Analysis

To retrospectively determine the association between breast lesion morphology and malignancy and to determine the optimal value of lesion enhancement (HU, Hounsfield units) to improve the diagnostic accuracy of breast cancer in patients with incidental breast lesions (IBLs). A total of 97 patients with 102 IBLs detected from July 2009 to December 2012 were enrolled in this study. Two radiologists analyzed CT images for the presence of malignancy based on the morphology of the lesions alone and in combination with an enhancement value (HU) analysis. There were 36 malignant and 66 benign IBLs. When the morphology and enhancement values were combined, the sensitivity, specificity, and accuracy were 92%, 97%, and 95%, respectively, for reader 1 and 89%, 94%, and 92%, respectively, for reader 2. The addition of HU values led to correct changes in the diagnosis; specifically, the accuracy of the diagnosis of reader 1 and reader 2 improved by 6.9% and 11.8%, respectively. The addition of the enhancement value (HU) to the CT morphology improved the diagnostic accuracy in the differentiation of malignant from benign IBLs by using the region of interest (ROI) to measure the HU within the most suspicious part of the lesion.     

Quality control of an unreliable flexible manufacturing system with scrapping and infinite buffer capacity

Manufacturing multiple part types on a flexible manufacturing system (FMS) is increasingly becoming a rule rather than an exception. In such systems, attention has been drawn to the application of zero-defect technologies. However, in practice, this goal has remained elusive and costly. As a result, even though FMSs may be more reliable, producing fewer defective parts, system complexity and more stringent quality standards are rendering quality control in FMSs potentially useful. The goals of this article are threefold. First, we introduce a procedure for measuring and managing the in-process quality control of an FMS, which is described by an Open Queueing Network (OQN), bridging thereby a gap between queueing theory and quality control. Second, by focusing attention on the potential unreliabilities of FMSs, we provide some managerial insights regarding the role, position, and distribution of the quality control effort in an FMS. Finally, we stress the intricate relations between an FMS's operating characteristics and the manufactured quality and its control. Using numerical analyses, we draw some inferences regarding the design of such FMSs when both quality and quantity issues in the FMSs are considered. These simultaneous considerations of quantity and quality flows in an FMS have not been previously considered in the study of FMSs.     

Monoamine oxidase deficiency in males with an X chromosome deletion

Mapping of the human MAOA gene to chromosomal region Xp21-p11 prompted our study of two affected males in a family previously reported to have Norrie disease resulting from a submicroscopic deletion in this chromosomal region. In this investigation we demonstrate in these cousins deletion of the MAOA gene, undetectable levels of MAO-A and MAO-B activities in their fibroblasts and platelets, respectively, loss of mRNA for MAO-A in fibroblasts, and substantial alterations in urinary catecholamine metabolites. The present study documents that a marked deficiency of MAO activity is compatible with life and that genes for MAO-A and MAO-B are near each other in this Xp chromosomal region. Some of the clinical features of these MAO deletion patients may help to identify X-linked MAO deficiency diseases in humans.     

Replication-defective vectors of reticuloendotheliosis virus transduce exogenous genes into somatic stem cells of the unincubated chicken embryo.

Replication-defective vectors derived from reticuloendotheliosis virus were used to transduce exogenous genes into early somatic stem cells of the chicken embryo. One of these vectors transduced and expressed the chicken growth hormone coding sequence. The helper cell line, C3, was used to generate stocks of vector containing about 10(4) transducing units per ml. Injection of 5- to 20-microliters volumes of vector directly beneath the blastoderm of unincubated chicken embryos led to infection of somatic stem cells. Infected embryos and adults contained unrearranged integrated proviral DNAs. Embryos expressed the transduced chicken growth hormone gene and contained high levels of serum growth hormone. Blood, brain, muscle, testis, and semen contained from individuals injected as embryos contained vector DNA. Replication-defective vectors of the reticuloendotheliosis virus transduced exogenous genes into chicken embryonic stem cells in vivo.     

人体蠕形螨爬行的观察

蠕形螨为一永久性寄生螨类,寄生于人体及家畜、哺乳类动物,种类繁多,目前报道的有120余种,常见的有40余种,寄生人体的有毛囊蠕形螨(Demodex folliculorum)、皮脂蠕形螨(Demodex brevis)、毛囊蠕形螨中华亚种(Demodex folliculorum sinensis)等,分别寄生于毛囊及皮脂腺内。可引起酒渣鼻、痤疮、眼睑炎等皮肤病,在人群中感染甚为普遍,同时也证实了其感染途径是通过直接接触而传播。为此,对蠕形螨活动力的研究是进一步探索其传病机制及防治的重要环节。人体蠕形螨在不同温度、湿度及酸碱度条件下生活能力的观察曾有报道(Spickett,1961;陈国定,1985)。但对其爬行规律及速度至今尚未见报道,为此我们对蠕形螨在不同温度条件下的爬行规律及速度作了系统的观察。今将结果报道如下。     

Neutral red (NR) assay for cell viability and xenobiotic-induced cytotoxicity in primary cultures of human and rat hepatocytes

Neutral red (NR) in medium was absorbed and concentrated in lysosomes of cultured rat and human hepatocytes. NR uptake increased with the time of incubation and reached a plateau in 2 hr. Uptake was proportional to the concentration of the NR solution and the numbers of viable liver cells. Prolonged culture of hepatocytes increased the numbers of lysosomes, and thus, the dye accumulation. The NR can be extracted from lysosomes for quantitative measurement of hepatocyte viability and cytotoxicity of xenobiotics. With this assay, several serum-free media (e.g., Waymouth's, MEM, LHC-8, etc.) were compared for the maintenance of viable hepatocytes in vitro. Interestingly, LHC-8 medium, which is used to grow human bronchial epithelial cells, best preserved viable rat hepatocytes. The cytotoxic effects of dimethylnitrosamine (DMN) and aflatoxin B₁ (AFB₁) were examined by NR assay on rat and human hepatocyte cultures and were found to be dependent on dose and time of the exposures. NR₅₀ was 20 mM for DMN and 0.072 µM for AFB₁ in rat hepatocytes with 24 hr of exposures and reduced to 12.5 mM for DMN and 0.053 µ uM for AFB₁ with 48 fr exposures. Human hepatocytes were more resistant to the toxicity of both chemicals; NR₅₀ values were 100 mM DMN and 1.8 µM AFB₁ respectively, for 24 hr treatments. Compared with lactate dehydrogenase (LDH) leakage test, the NR assay was simpler and more sensitive in determining the viability and cytotoxicity of xenobiotics in primary cultures of hepatocytes.Abbreviations NR Neutral Red - MEM Eagle's Minimum Essential Medium - DMN dimethylnitrosamine - AFB₁ aflatoxin B₁ - LDH lactate dehydrogenase - HBSS Hanks balanced salt solution; - EDTA ethylene bis (oxyethylenenitrilo)-tetraacetic acid - L-15 Leibovitz's 15 - NADH B-nicotinamide adenine dinu - FBS fetal bovine serum - IA immediate autopsy Contribution No. 2816 from Laboratory of Genotoxicology.     

Metabolism of pyrimidine deoxyribonucleosides in Neurospora crassa.

The experiments in this report involve the following series of reactions which were previously demonstrated with purified enzyme preparations from Neurospora crassa: thymidine a yields thymine ribonucleoside b yields thymine c yields 5-hydroxymethyluracil d yields 5-formyluracil e yields uracil-5-carboxylic acid f yields uracil. The evidence for some of the reactions occurring in vivo has been incomplete and for others totally lacking. In this paper intact cells of Neurospora are shown to be capable of converting the substrates of each of the reactions to the corresponding products. Studies are described which were carried out in vivo and in vitro with the pyrimidineless strains pyr-4,uc-1,uc-2 and pyr-4,uc-1,uc-3, developed by Williams and Mitchell. The results reported in the present paper indicate that (reaction a) and the uc-3 mutation affects thymine 7-hydroxylase (reactions c,d, and e). Evidence is presented for the 2'-hydroxylase reaction being the major, if not only, way by which Neurospora can initiate the conversion of thymidine to the pyrimidines of nucleic acids and for the 2'-hydroxylation of thymidine and deoxyuridine being catalyzed by the same enzyme. Deoxycytidine was shown not to be hydroxylated in intact cells but instead deaminated to deoxyuridine, which in turn was converted to uridine. Further studies with the uc-3-carrying strain showed that an enzyme other than thymine 7-hydroxylase can also convert 5-formyluracil to uracil-5-carboxylic acid.