Impact of diagenesis on carbonate mound formation

Weering, T.C.E. van [Promotor]Reijmer, J.J.G. [Promotor]Mienis, F. [Copromotor

Follow-up study of sensory-motor polyneuropathy in Type 1 (insulin-dependent) diabetic subjects after simultaneous pancreas and kidney transplantation and after graft rejection

The influence of successful simultaneous pancreas and kidney transplantation on peripheral polyneuropathy was investigated in 53 patients for a mean observation period of 40.3 months. Seventeen patients were followed-up for more than 3 years. Symptoms and signs were assessed every 6 months using a standard questionnaire, neurological examination and measurement of sensory and motor nerve conduction velocities. While symptoms of polyneuropathy improved (pain, paraesthesia, cramps, restless-legs) and nerve conduction velocity increased, there was no change of clinical signs (sensation, muscle-force, tendon-reflexes). Following kidney-graft-rejection there was a slight decrease of nerve conduction verlocity during the first year, which was not statistically significant. Following pancreas-graft rejection there was no change of nerve conduction velocity during the first year. Comparing the maximum nerve conduction velocity of the patients with pancreas-graft-rejection to the nerve conduction velocities of these patients at the end of the study, there was a statistically significant decrease of 6.5 m/s. In conclusion, we believe that strict normalization of glucose metabolism alters the progressive course of diabetic polyneuropathy. It may be stabilized or partly reversed after successful grafting even in long-term diabetic patients

Regulation of vascular signalling by nuclear Sprouty2 in fetal lung epithelial cells:Implications for co-ordinated airway and vascular branching in lung development

This work was supported by a Wellcome Trust project grant 088032/Z/08/Z to SCL.Sprouty2 (Spry2) acts as a central regulator of tubular growth and branch patterning in the developing mammalian lung by controlling both magnitude and duration of growth factor signalling. To determine if this protein coordinates airway and vascular growth factor signalling, we tested the hypothesis that Spry2 links the primary cue for airway outgrowth, fibroblast growth factor-10 (FGF-10), to genomic events underpinning the expression and release of vascular endothelial growth factor-A (VEGF-A). Using primary fetal distal lung epithelial cells (FDLE) from rat, and immortalised human bronchial epithelial cells (16HBE14o-), we identified a nuclear sub-population of Spry2 which interacted with regions of the rat and human VEGF-A promoter spanning the hypoxia response element (HRE) and adjacent 3′ sites. In FDLE cultured at the PO2 of the fetal lung, FGF-10 relieved the Spry2 interaction at the HRE region by promoting clearance of a 39 kDa form and this was accompanied by histone-3 S10K14 phosphoacetylation, promoter de-methylation, hypoxia inducible factor-1α activation and VEGF-A expression. This repressive characteristic of nuclear Spry2 was relieved in 16HBE14o- by shRNA knockdown, and stable expression of mutants (C218A; C221A) that do not interact with the VEGF-A promoter HRE region. We conclude that nuclear Spry2 acts as a molecular link which co-ordinates airway and vascular growth of the cardiopulmonary system. This identifies Spry2 as a contributing determinant of design optimality in the mammalian lung.Publisher PDFPeer reviewe

Galaxy Zoo: the dependence of morphology and colour on environment

We analyse the relationships between galaxy morphology, colour, environment and stellar mass using data for over 100,000 objects from Galaxy Zoo, the largest sample of visually classified morphologies yet compiled. We conclusively show that colour and morphology fractions are very different functions of environment. Both are sensitive to stellar mass; however, at fixed stellar mass, while colour is also highly sensitive to environment, morphology displays much weaker environmental trends. Only a small part of both relations can be attributed to variation in the stellar mass function with environment. Galaxies with high stellar masses are mostly red, in all environments and irrespective of their morphology. Low stellar-mass galaxies are mostly blue in low-density environments, but mostly red in high-density environments, again irrespective of their morphology. The colour-density relation is primarily driven by variations in colour fractions at fixed morphology, in particular the fraction of spiral galaxies that have red colours, and especially at low stellar masses. We demonstrate that our red spirals primarily include galaxies with true spiral morphology. We clearly show there is an environmental dependence for colour beyond that for morphology. Before using the Galaxy Zoo morphologies to produce the above results, we first quantify a luminosity-, size- and redshift-dependent classification bias that affects this dataset, and probably most other studies of galaxy population morphology. A correction for this bias is derived and applied to produce a sample of galaxies with reliable morphological type likelihoods, on which we base our analysis.Comment: 25 pages, 20 figures (+ 6 pages, 11 figures in appendices); moderately revised following referee's comments; accepted by MNRA

Usefulness of primary care electronic networks to assess the incidence of chlamydia, diagnosed by general practitioners

Background: Chlamydia is the most common curable sexually transmitted infection (STI) in the Netherlands. The majority of chlamydia diagnoses are made by general practitioners (GPs). Baseline data from primary care will facilitate the future evaluation of the ongoing large population-based screening in the Netherlands. The aim of this study was to assess the usefulness of electronic medical records for monitoring the incidence of chlamydia cases diagnosed in primary care in the Netherlands. Methods. In the electronic records of two regional and two national networks, we identified chlamydia diagnoses by means of ICPC codes (International Classification of Primary Care), laboratory results in free text and the prescription of antibiotics. The year of study was 2007 for the two regional networks and one national network, for the other national network the year of study was 2005. We calculated the incidence of diagnosed chlamydia cases per sex, age group and degree of urbanization. Results: A large diversity was observed in the way chlamydia episodes were coded in the four different GP networks and how easily information concerning chlamydia diagnoses could be extracted. The overall incidence ranged from 103.2/100,000 to 590.2/100,000. Differences were partly related to differences between patient populations. Nevertheless, we observed similar trends in the incidence of chlamydia diagnoses in all networks and findings were in line with earlier reports. Conclusions: Electronic patient records, originally intended for individual patient care in general practice, can be an additional source of data for monitoring chlamydia incidence in primary care and can be of use in assessing the future impact of population-based chlamydia screening programs. To increase the usefulness of data we recommend more efforts to standardize registration by (specific) ICPC code and laboratory results across the existing GP networks

Looking to Score: The Dissociation of Goal Influence on Eye Movement and Meta-Attentional Allocation in a Complex Dynamic Natural Scene

Several studies have reported that task instructions influence eye-movement behavior during static image observation. In contrast, during dynamic scene observation we show that while the specificity of the goal of a task influences observers’ beliefs about where they look, the goal does not in turn influence eye-movement patterns. In our study observers watched short video clips of a single tennis match and were asked to make subjective judgments about the allocation of visual attention to the items presented in the clip (e.g., ball, players, court lines, and umpire). However, before attending to the clips, observers were either told to simply watch clips (non-specific goal), or they were told to watch the clips with a view to judging which of the two tennis players was awarded the point (specific goal). The results of subjective reports suggest that observers believed that they allocated their attention more to goal-related items (e.g. court lines) if they performed the goal-specific task. However, we did not find the effect of goal specificity on major eye-movement parameters (i.e., saccadic amplitudes, inter-saccadic intervals, and gaze coherence). We conclude that the specificity of a task goal can alter observer’s beliefs about their attention allocation strategy, but such task-driven meta-attentional modulation does not necessarily correlate with eye-movement behavior

The CD14 functional gene polymorphism -260 C>T is not involved in either the susceptibility to Chlamydia trachomatis infection or the development of tubal pathology

BACKGROUND: The functional polymorphism -260 C>T in the LPS sensing TLR4 co-receptor CD14 gene enhances the transcriptional activity and results in a higher CD14 receptor density. Individuals carrying the T/T genotype also have significantly higher serum levels of soluble CD14. The T allele of this polymorphism has recently been linked to Chlamydia pneumoniae infection. We investigated the role of the CD14 -260 C>T polymorphism in the susceptibility to and severity (defined as subfertility and/or tubal pathology) of C. trachomatis infection in Dutch Caucasian women. METHODS: The different CD14 -260 C>T genotypes were assessed by PCR-based RFLP analysis in three cohorts: 1) A cohort (n = 576) of women attending a STD clinic, 2) a cohort (n = 253) of women with subfertility, and 3) an ethnically matched control cohort (n = 170). The following variables were used in the analysis: In cohort 1 the CT-DNA status, CT IgG serology status, self-reported symptoms and in cohort 2, the CT IgG serology status and the tubal status at laparoscopy. RESULTS: In the control cohort the CC, CT and TT genotype distribution was: 28.2%, 48.2%, and 23.5% respectively. No differences were found in the overall prevalence of CD14 -260 genotypes (28.1%, 50.7%, and 21.2%) in cohort 1 when compared to the control cohort. Also no differences were observed in women with or without CT-DNA, with or without serological CT responses, with or without symptoms, or in combinations of these three variables. In subfertile women with tubal pathology (cohort 2, n = 50) the genotype distribution was 28.0%, 48.0%, and 24.0% and in subfertile women without tubal pathology (n = 203), 27.6%, 49.3% and 23.2%. The genotype distribution was unchanged when CT IgG status was introduced in the analyses. CONCLUSION: The CD14 -260 C>T genotype distributions were identical in all three cohorts, showing that this polymorphism is not involved in the susceptibility to or severity of sequelae of C. trachomatis infection

Bone Marrow Stromal Cell Regeneration Profile in Treated B-Cell Precursor Acute Lymphoblastic Leukemia Patients:Association with MRD Status and Patient Outcome

SIMPLE SUMMARY: For the last 20 years, measurable residual disease (MRD) has proven to be a strong prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the effects of therapy on the bone marrow (BM) microenvironment and their potential relationship with MRD and patient outcome still remain to be evaluated. Here, we show that mesenchymal stem cells (MSC) and endothelial cells (EC) are constantly present at relatively low frequencies in normal BM and in most follow-up BM samples from treated BCP-ALL patients. Of note, their levels are independent of the MRD status. From the prognostic point of view, an increased percentage of EC among stromal cells (EC plus MSC) at day +78 of therapy was associated with shorter disease free survival (DFS), independently of the MRD status both in childhood and in adult BCP-ALL. Thus, an abnormally high EC/MSC distribution at day +78 of therapy emerges as an adverse prognostic factor, independent of MRD in BCP-ALL. ABSTRACT: For the last two decades, measurable residual disease (MRD) has become one of the most powerful independent prognostic factors in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the effect of therapy on the bone marrow (BM) microenvironment and its potential relationship with the MRD status and disease free survival (DFS) still remain to be investigated. Here we analyzed the distribution of mesenchymal stem cells (MSC) and endothelial cells (EC) in the BM of treated BCP-ALL patients, and its relationship with the BM MRD status and patient outcome. For this purpose, the BM MRD status and EC/MSC regeneration profile were analyzed by multiparameter flow cytometry (MFC) in 16 control BM (10 children; 6 adults) and 1204 BM samples from 347 children and 100 adult BCP-ALL patients studied at diagnosis (129 children; 100 adults) and follow-up (824 childhood samples; 151 adult samples). Patients were grouped into a discovery cohort (116 pediatric BCP-ALL patients; 338 samples) and two validation cohorts (74 pediatric BCP-ALL, 211 samples; and 74 adult BCP-ALL patients; 134 samples). Stromal cells (i.e., EC and MSC) were detected at relatively low frequencies in all control BM (16/16; 100%) and in most BCP-ALL follow-up samples (874/975; 90%), while they were undetected in BCP-ALL BM at diagnosis. In control BM samples, the overall percentage of EC plus MSC was higher in children than adults (p = 0.011), but with a similar EC/MSC ratio in both groups. According to the MRD status similar frequencies of both types of BM stromal cells were detected in BCP-ALL BM studied at different time points during the follow-up. Univariate analysis (including all relevant prognostic factors together with the percentage of stromal cells) performed in the discovery cohort was used to select covariates for a multivariate Cox regression model for predicting patient DFS. Of note, an increased percentage of EC (>32%) within the BCP-ALL BM stromal cell compartment at day +78 of therapy emerged as an independent unfavorable prognostic factor for DFS in childhood BCP-ALL in the discovery cohort—hazard ratio (95% confidence interval) of 2.50 (1–9.66); p = 0.05—together with the BM MRD status (p = 0.031). Further investigation of the predictive value of the combination of these two variables (%EC within stromal cells and MRD status at day +78) allowed classification of BCP-ALL into three risk groups with median DFS of: 3.9, 3.1 and 1.1 years, respectively (p = 0.001). These results were confirmed in two validation cohorts of childhood BCP-ALL (n = 74) (p = 0.001) and adult BCP-ALL (n = 40) (p = 0.004) treated at different centers. In summary, our findings suggest that an imbalanced EC/MSC ratio in BM at day +78 of therapy is associated with a shorter DFS of BCP-ALL patients, independently of their MRD status. Further prospective studies are needed to better understand the pathogenic mechanisms involved

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10−3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10−4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10−3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10−7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia