Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia

Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.

Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population

Background - Recent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry. Methods - We genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects. Results - The minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7). Conclusion - Our results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups.

Parameter optimization for noise and vibration reduction associated with position and speed sensorless control of permanent magnet machines at low speed

With the advantages and popularity of Permanent Magnet (PM) motors due to their high power density, there is an increasing incentive to use them in variety of applications including electric actuation. These applications have strict noise emission standards. The generation of audible noise and associated vibration modes are characteristics of all electric motors, it is especially problematic in low speed sensorless control rotary actuation applications using high frequency voltage injection technique. This dissertation is aimed at solving the problem of optimizing the sensorless control algorithm for low noise and vibration while achieving at least 12 bit absolute accuracy for speed and position control. The low speed sensorless algorithm is simulated using an improved Phase Variable Model, developed and implemented in a hardware-in-the-loop prototyping environment. Two experimental testbeds were developed and built to test and verify the algorithm in real time.^ A neural network based modeling approach was used to predict the audible noise due to the high frequency injected carrier signal. This model was created based on noise measurements in an especially built chamber. The developed noise model is then integrated into the high frequency based sensorless control scheme so that appropriate tradeoffs and mitigation techniques can be devised. This will improve the position estimation and control performance while keeping the noise below a certain level. Genetic algorithms were used for including the noise optimization parameters into the developed control algorithm.^ A novel wavelet based filtering approach was proposed in this dissertation for the sensorless control algorithm at low speed. This novel filter was capable of extracting the position information at low values of injection voltage where conventional filters fail. This filtering approach can be used in practice to reduce the injected voltage in sensorless control algorithm resulting in significant reduction of noise and vibration.^ Online optimization of sensorless position estimation algorithm was performed to reduce vibration and to improve the position estimation performance. The results obtained are important and represent original contributions that can be helpful in choosing optimal parameters for sensorless control algorithm in many practical applications.^

Sediment and Nutrient Deposition Associated with Hurricane Wilma in Mangroves of the Florida Coastal Everglades

The distribution of mangrove biomass and forest structure along Shark River estuary in the Florida Coastal Everglades (FCE) has been correlated with elevated total phosphorus concentration in soils thought to be associated with storm events. The passage of Hurricane Wilma across Shark River estuary in 2005 allowed us to quantify sediment deposition and nutrient inputs in FCE mangrove forests associated with this storm event and to evaluate whether these pulsing events are sufficient to regulate nutrient biogeochemistry in mangrove forests of south Florida. We sampled the spatial pattern of sediment deposits and their chemical properties in mangrove forests along FCE sites in December 2005 and October 2006. The thickness (0.5 to 4.5 cm) of hurricane sediment deposits decreased with distance inland at each site. Bulk density, organic matter content, total nitrogen (N) and phosphorus (P) concentrations, and inorganic and organic P pools of hurricane sediment deposits differed from surface (0–10 cm) mangrove soils at each site. Vertical accretion resulting from this hurricane event was eight to 17 times greater than the annual accretion rate (0.30± 0.03 cm year−1) averaged over the last 50 years. Total P inputs from storm-derived sediments were equivalent to twice the average surface soil nutrient P density (0.19 mg cm−3). In contrast, total N inputs contributed 0.8 times the average soil nutrient N density (2.8 mg cm−3). Allochthonous mineral inputs from Hurricane Wilma represent a significant source of sediment to soil vertical accretion rates and nutrient resources in mangroves of southwestern Everglades. The gradient in total P deposition to mangrove soils from west to east direction across the FCE associated with this storm event is particularly significant to forest development due to the P-limited condition of this carbonate ecosystem. This source of P may be an important adaptation of mangrove forests in the Caribbean region to projected impacts of sea-level rise.

The Genetics of Success: How Single-Nucleotide Polymorphisms Associated With Educational Attainment Relate to Life-Course Development.

A previous genome-wide association study (GWAS) of more than 100,000 individuals identified molecular-genetic predictors of educational attainment. We undertook in-depth life-course investigation of the polygenic score derived from this GWAS using the four-decade Dunedin Study (N = 918). There were five main findings. First, polygenic scores predicted adult economic outcomes even after accounting for educational attainments. Second, genes and environments were correlated: Children with higher polygenic scores were born into better-off homes. Third, children's polygenic scores predicted their adult outcomes even when analyses accounted for their social-class origins; social-mobility analysis showed that children with higher polygenic scores were more upwardly mobile than children with lower scores. Fourth, polygenic scores predicted behavior across the life course, from early acquisition of speech and reading skills through geographic mobility and mate choice and on to financial planning for retirement. Fifth, polygenic-score associations were mediated by psychological characteristics, including intelligence, self-control, and interpersonal skill. Effect sizes were small. Factors connecting DNA sequence with life outcomes may provide targets for interventions to promote population-wide positive development.

An Exploration of the challenges associated with software logging in large systems

Over the past few years, logging has evolved from from simple printf statements to more complex and widely used logging libraries. Today logging information is used to support various development activities such as fixing bugs, analyzing the results of load tests, monitoring performance and transferring knowledge. Recent research has examined how to improve logging practices by informing developers what to log and where to log. Furthermore, the strong dependence on logging has led to the development of logging libraries that have reduced the intricacies of logging, which has resulted in an abundance of log information. Two recent challenges have emerged as modern software systems start to treat logging as a core aspect of their software. In particular, 1) infrastructural challenges have emerged due to the plethora of logging libraries available today and 2) processing challenges have emerged due to the large number of log processing tools that ingest logs and produce useful information from them. In this thesis, we explore these two challenges. We first explore the infrastructural challenges that arise due to the plethora of logging libraries available today. As systems evolve, their logging infrastructure has to evolve (commonly this is done by migrating to new logging libraries). We explore logging library migrations within Apache Software Foundation (ASF) projects. We i find that close to 14% of the pro jects within the ASF migrate their logging libraries at least once. For processing challenges, we explore the different factors which can affect the likelihood of a logging statement changing in the future in four open source systems namely ActiveMQ, Camel, Cloudstack and Liferay. Such changes are likely to negatively impact the log processing tools that must be updated to accommodate such changes. We find that 20%-45% of the logging statements within the four systems are changed at least once. We construct random forest classifiers and Cox models to determine the likelihood of both just-introduced and long-lived logging statements changing in the future. We find that file ownership, developer experience, log density and SLOC are important factors in determining the stability of logging statements.

Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype

BACKGROUND: Pulmonary fibrosis is a debilitating and lethal disease with no effective treatment options. Understanding the pathological processes at play will direct the application of novel therapeutic avenues. Hypoxia has been implicated in the pathogenesis of pulmonary fibrosis yet the precise mechanism by which it contributes to disease progression remains to be fully elucidated. It has been shown that chronic hypoxia can alter DNA methylation patterns in tumour-derived cell lines. This epigenetic alteration can induce changes in cellular phenotype with promoter methylation being associated with gene silencing. Of particular relevance to idiopathic pulmonary fibrosis (IPF) is the observation that Thy-1 promoter methylation is associated with a myofibroblast phenotype where loss of Thy-1 occurs alongside increased alpha smooth muscle actin (α-SMA) expression. The initial aim of this study was to determine whether hypoxia regulates DNA methylation in normal human lung fibroblasts (CCD19Lu). As it has been reported that hypoxia suppresses Thy-1 expression during lung development we also studied the effect of hypoxia on Thy-1 promoter methylation and gene expression.

METHODS: CCD19Lu were grown for up to 8 days in hypoxia and assessed for global changes in DNA methylation using flow cytometry. Real-time PCR was used to quantify expression of Thy-1, α-SMA, collagen I and III. Genomic DNA was bisulphite treated and methylation specific PCR (MSPCR) was used to examine the methylation status of the Thy-1 promoter.

RESULTS: Significant global hypermethylation was detected in hypoxic fibroblasts relative to normoxic controls and was accompanied by increased expression of myofibroblast markers. Thy-1 mRNA expression was suppressed in hypoxic cells, which was restored with the demethylating agent 5-aza-2'-deoxycytidine. MSPCR revealed that Thy-1 became methylated following fibroblast exposure to 1% O2.

CONCLUSION: These data suggest that global and gene-specific changes in DNA methylation may play an important role in fibroblast function in hypoxia.

ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma.

BACKGROUND: ALK rearrangement is particularly observed in signet-ring sub-type adenocarcinoma. Since fluorescence in situ hybridization (FISH) is not suitable for mass screening, we aimed to characterize the predictive utility of tumour morphology and ALK immunoreactivity to identify ALK rearrangement, in a primary lung adenocarcinoma dataset enriched for signet-ring morphology, compared with that of other morphology. METHODS: 7 adenocarcinomas from diagnostic archives reported with signet-ring morphology were assessed and compared with 11 adenocarcinomas without signet-ring features over the same time period. Growth patterns were reviewed, ALK expression was assessed by standard immunohistochemistry using ALK1 clone and Envision detection (Dako), and ALK rearrangement was assessed by FISH (Abbott Molecular). Associations between groups and predictive utility of tumour morphology and ALK expression using FISH as gold standard were calculated. RESULTS: 2 excision lung biopsy cases with pure (100%) signet-ring morphology and solid patterns demonstrated diffuse moderate cytoplasmic ALK immunoreactivity (2+) and harboured ALK rearrangements (p=0.007), unlike 5 mixed-signet-ring and 11 non-signet-ring adenocarcinomas, which showed negative or 1+ immunoreactivity; and did not harbour ALK rearrangements (p>0.1). ALK expression was not associated with ALK copy number. 6 of 7 cases with signet ring morphology stained for TTF-1. Pure signet-ring morphology and moderate ALK expression were both associated with ALK rearranged tumours. CONCLUSION: ALK rearrangement is strongly associated with ALK immunoreactivity, and was seen only in tumours with pure signet-ring morphology and solid growth pattern. Tumour morphology, growth pattern and ALK immunoreactivity appear to be good indicators of ALK rearrangement, with TTF-1 positivity aiding in proving primary pulmonary origin.

Abnormalities on 1q and 7q are associated with poor outcome in sporadic Burkitt's lymphoma. A cytogenetic and comparative genomic hybridization study.

Comparative genomic hybridization (CGH) studies have demonstrated a high incidence of chromosomal imbalances in non-Hodgkin's lymphoma. However, the information on the genomic imbalances in Burkitt's Lymphoma (BL) is scanty. Conventional cytogenetics was performed in 34 cases, and long-distance PCR for t(8;14) was performed in 18 cases. A total of 170 changes were present with a median of four changes per case (range 1-22). Gains of chromosomal material (143) were more frequent than amplifications (5) or losses (22). The most frequent aberrations were gains on chromosomes 12q (26%), Xq (22%), 22q (20%), 20q (17%) and 9q (15%). Losses predominantly involved chromosomes 13q (17%) and 4q (9%). High-level amplifications were present in the regions 1q23-31 (three cases), 6p12-p25 and 8p22-p23. Upon comparing BL vs Burkitt's cell leukemia (BCL), the latter had more changes (mean 4.3 +/- 2.2) than BL (mean 2.7 +/- 3.2). In addition, BCL cases showed more frequently gains on 8q, 9q, 14q, 20q, and 20q, 9q, 8q and 14q, as well as losses on 13q and 4q. Concerning outcome, the presence of abnormalities on 1q (ascertained either by cytogenetics or by CGH), and imbalances on 7q (P=0.01) were associated with a short survival.

Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease

Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.

Physician choice making and characteristics associated with using physician-rating websites: cross-sectional study

BACKGROUND: Over the past decade, physician-rating websites have been gaining attention in scientific literature and in the media. However, little knowledge is available about the awareness and the impact of using such sites on health care professionals. It also remains unclear what key predictors are associated with the knowledge and the use of physician-rating websites. OBJECTIVE: To estimate the current level of awareness and use of physician-rating websites in Germany and to determine their impact on physician choice making and the key predictors which are associated with the knowledge and the use of physician-rating websites. METHODS: This study was designed as a cross-sectional survey. An online panel was consulted in January 2013. A questionnaire was developed containing 28 questions; a pretest was carried out to assess the comprehension of the questionnaire. Several sociodemographic (eg, age, gender, health insurance status, Internet use) and 2 health-related independent variables (ie, health status and health care utilization) were included. Data were analyzed using descriptive statistics, chi-square tests, and t tests. Binary multivariate logistic regression models were performed for elaborating the characteristics of physician-rating website users. Results from the logistic regression are presented for both the observed and weighted sample. RESULTS: In total, 1505 respondents (mean age 43.73 years, SD 14.39; 857/1505, 57.25% female) completed our survey. Of all respondents, 32.09% (483/1505) heard of physician-rating websites and 25.32% (381/1505) already had used a website when searching for a physician. Furthermore, 11.03% (166/1505) had already posted a rating on a physician-rating website. Approximately 65.35% (249/381) consulted a particular physician based on the ratings shown on the websites; in contrast, 52.23% (199/381) had not consulted a particular physician because of the publicly reported ratings. Significantly higher likelihoods for being aware of the websites could be demonstrated for female participants (P<.001), those who were widowed (P=.01), covered by statutory health insurance (P=.02), and with higher health care utilization (P<.001). Health care utilization was significantly associated with all dependent variables in our multivariate logistic regression models (P<.001). Furthermore, significantly higher scores could be shown for health insurance status in the unweighted and Internet use in the weighted models. CONCLUSIONS: Neither health policy makers nor physicians should underestimate the influence of physician-rating websites. They already play an important role in providing information to help patients decide on an appropriate physician. Assuming there will be a rising level of public awareness, the influence of their use will increase well into the future. Future studies should assess the impact of physician-rating websites under experimental conditions and investigate whether physician-rating websites have the potential to reflect the quality of care offered by health care providers.

Wet litter – factors associated with the shed micro-environment and litter properties

Wet litter in meat chicken sheds occurs as the result of multiple, interrelated causes. This paper discusses some of the sources of water in meat chicken sheds, the properties of litter and the contribution of the shed micro-environment. By increasing awareness of the factors associated with wet litter, it will empower the chicken meat industry with knowledge to identify causes and address local incidences through improved litter management. In general, wet litter will be caused by excess water going into the litter, insufficient evaporation and/or limited water holding capability of the litter. Some strategies to improve the effectiveness of ventilation to maintain litter dryness are discussed

Nurse Rostering with Genetic Algorithms

In recent years genetic algorithms have emerged as a useful tool for the heuristic solution of complex discrete optimisation problems. In particular there has been considerable interest in their use in tackling problems arising in the areas of scheduling and timetabling. However, the classical genetic algorithm paradigm is not well equipped to handle constraints and successful implementations usually require some sort of modification to enable the search to exploit problem specific knowledge in order to overcome this shortcoming. This paper is concerned with the development of a family of genetic algorithms for the solution of a nurse rostering problem at a major UK hospital. The hospital is made up of wards of up to 30 nurses. Each ward has its own group of nurses whose shifts have to be scheduled on a weekly basis. In addition to fulfilling the minimum demand for staff over three daily shifts, nurses’ wishes and qualifications have to be taken into account. The schedules must also be seen to be fair, in that unpopular shifts have to be spread evenly amongst all nurses, and other restrictions, such as team nursing and special conditions for senior staff, have to be satisfied. The basis of the family of genetic algorithms is a classical genetic algorithm consisting of n-point crossover, single-bit mutation and a rank-based selection. The solution space consists of all schedules in which each nurse works the required number of shifts, but the remaining constraints, both hard and soft, are relaxed and penalised in the fitness function. The talk will start with a detailed description of the problem and the initial implementation and will go on to highlight the shortcomings of such an approach, in terms of the key element of balancing feasibility, i.e. covering the demand and work regulations, and quality, as measured by the nurses’ preferences. A series of experiments involving parameter adaptation, niching, intelligent weights, delta coding, local hill climbing, migration and special selection rules will then be outlined and it will be shown how a series of these enhancements were able to eradicate these difficulties. Results based on several months’ real data will be used to measure the impact of each modification, and to show that the final algorithm is able to compete with a tabu search approach currently employed at the hospital. The talk will conclude with some observations as to the overall quality of this approach to this and similar problems.

Factors associated with institutional delivery in Dangila district, North West Ethiopia: a cross-sectional study.

Introduction: Childbirth in a health institution has been shown to be associated with lower rates of maternal and neonatal mortality. However, about 85% of mothers in Ethiopia deliver at home. Objective: To assess factors associated with institutional delivery service utilization among women who gave birth within one year prior to the study in Dangila district. Methods: A cross-sectional study was conducted from February 01-28, 2015. A total of 763 mothers were interviewed using structured questionnaire. SPSS version 20 was used for analysis. Crude and adjusted Odds ratios were computed for selected variables. A P-value less than 0.05 was considered statistical significant. Results: Only 18.3% of mothers gave birth at health facilities. Knowledge on danger signs [AOR=2.0, 95% CI: (1.1, 3.4)], plan to give birth at health institution [AOR=5.4, 95% CI: (3.0, 9.6)], having ANC follow up during pregnancy [AOR=12.9, 95% CI: (5.0, 33.3)] and time taken to get to a nearby health institution [AOR=5.1, 95% CI: (2.9, 9.1)] were associated with institutional delivery service utilization. Conclusion: Institutional delivery was very low. Knowledge about danger signs, having ANC visits, and time were factors associated with institutional delivery service utilization. Thus,the findings recommend repeated re-enforcement of institutional delivery service utilization through professionals. And also, the findings recommend promotion of institutional delivery service utilization through mass media.

PCR-Internal Transcribed Spacer (ITS) genes sequencing and phylogenetic analysis of clinical and environmental Aspergillus species associated with HIV-TB co infected patients in a hospital in Abeokuta, southwestern Nigeria.

Background: Aspergillosis has been identified as one of the hospital acquired infections but the contribution of water and inhouse air as possible sources of Aspergillus infection in immunocompromised individuals like HIV-TB patients have not been studied in any hospital setting in Nigeria. Objective: To identify and investigate genetic relationship between clinical and environmental Aspergillus species associated with HIV-TB co infected patients. Methods: DNA extraction, purification, amplification and sequencing of Internal Transcribed Spacer (ITS) genes were performed using standard protocols. Similarity search using BLAST on NCBI was used for species identification and MEGA 5.0 was used for phylogenetic analysis. Results: Analyses of sequenced ITS genes of selected fourteen (14) Aspergillus isolates identified in the GenBank database revealed Aspergillus niger (28.57%), Aspergillus tubingensis (7.14%), Aspergillus flavus (7.14%) and Aspergillus fumigatus (57.14%). Aspergillus in sputum of HIV patients were Aspergillus niger, A. fumigatus, A. tubingensis and A. flavus. Also, A. niger and A. fumigatus were identified from water and open-air. Phylogenetic analysis of sequences yielded genetic relatedness between clinical and environmental isolates. Conclusion: Water and air in health care settings in Nigeria are important sources of Aspergillus sp. for HIV-TB patients.