Ten years of METEOR (an international rheumatoid arthritis registry): development, research opportunities and future perspectives

OBJECTIVES: Ten years ago, the METEOR tool was developed to simulate treatment-to-target and create an international research database. The development of the METEOR tool and database, research opportunities and future perspectives are described. METHODS: The METEOR tool is a free, online, internationally available tool in which daily practice visits of all rheumatoid arthritis patients visiting a rheumatologist can be registered. In the tool, disease characteristics, patient- and physician-reported outcomes and prescribed treatment could be entered. These can be subsequently displayed in powerful graphics, facilitating treatment decisions and patient-physician interactions. An upload facility is also available, by which data from local electronic health record systems or registries can be integrated into the METEOR database. This is currently being actively used in, among other countries, the Netherlands, Portugal and India. RESULTS: Since an increasing number of hospitals use electronic health record systems, the upload facility is being actively used by an increasing number of sites, enabling them to benefit from the benchmark and research opportunities of METEOR. Enabling a connection between local registries and METEOR is a well established but time-consuming process for which an IT-specialist of METEOR and the local registry are necessary. However, once this process has been finished, data can be uploaded regularly and relatively easily according to a pre-specified format. The METEOR database currently contains data from >39,000 patients and >200,000 visits, from 32 different countries and is ever increasing. Continuous efforts are being undertaken to increase the quality of data in the database. CONCLUSIONS: Since METEOR was founded 10 years ago, many rheumatologists worldwide have used the METEOR tool to follow-up their patients and improve the quality of care they provide to their patients. Combined with uploaded data, this has led to an extensive growth of the database. It now offers a unique opportunity to study daily practice care and to perform research regarding cross-country differences in a large, worldwide setting, which could provide important knowledge about disease and its treatment in different geographic and clinical settings

The Familial Clustering of Age at Menarche in Extended Twin Families

The timing of puberty is complex, possibly involving many genetic factors that may interact with environmental influences. Familial resemblance for age at menarche was studied in a sample of 4,995 female twins, 1,296 sisters, 2,946 mothers and 635 female spouses of male twins. They had indicated their age at menarche as part of a larger longitudinal survey. We assessed assortative mating for age at menarche, gene–environment interaction effects and estimated the heritability of individual differences in pubertal timing. There was significant evidence of gene–environment interaction, accounting for 1.5% of the variance. There was no indication of consistent mate assortment on age at menarche. Individual differences in age at menarche are highly heritable, with additive genetic factors explaining at least 70% of the true variation. An additional 1.5% of the variation can be explained by a genotype–environment interaction effect where environmental factors are more important in individuals genetically predisposed for late menarche

Role of pH in determining the cell-type-specific residual activity of glucocerebrosidase in type 1 Gaucher disease.

The properties of control and 370Asn-->Ser glucocerebrosidase, the frequently encountered mutated form of the enzyme in type 1 Gaucher disease, were studied in vitro as well as in situ. The catalytic properties of purified 370Asn-->Ser glucocerebrosidase were highly dependent on the assay conditions. The enzyme was deficient in activity towards substrate and in reactivity with the irreversible inhibitor conduritol B-epoxide (CBE) when activated by the bile salt taurocholate. In the presence of more physiological activators, the lysosomal activator protein saposin C and phosphatidylserine, the 370Asn-->Ser enzyme was near normal in kinetic properties at pH values approximately 5, but not at higher pH. In intact fibroblasts, the enzymic activity of the 370Asn-->Ser glucocerebrosidase and its reactivity with CBE were found to be clearly deficient. However, in intact lymphoblasts from the same patients, the behavior of the mutant enzyme was near normal. The catalytic efficiency of 370Asn-->Ser glucocerebrosidase in situ was also found to be highly pH dependent. When intact lymphoblasts were cultured in the presence of permeant weak bases, which increase the pH of acidic intracellular compartments, the catalytic efficiency of the mutant enzyme, as assessed by its reactivity with CBE, became markedly impaired. Our findings indicate that the intralysosomal pH in the intact cell can be expected to have a critical influence on the activation state of 370Asn-->Ser glucocerebrosidase and its ability to hydrolyse substrate. This phenomenon may partly underly the marked heterogeneity in clinical manifestation of Gaucher disease among patients with this mutated form of glucocerebrosidase.FWN – Publicaties zonder aanstelling Universiteit Leide

Halfvortices in flat nanomagnets

We discuss a new type of topological defect in XY systems where the O(2) symmetry is broken in the presence of a boundary. Of particular interest is the appearance of such defects in nanomagnets with a planar geometry. They are manifested as kinks of magnetization along the edge and can be viewed as halfvortices with winding numbers \pm 1/2. We argue that halfvortices play a role equally important to that of ordinary vortices in the statics and dynamics of flat nanomagnets. Domain walls found in experiments and numerical simulations are composite objects containing two or more of these elementary defects. We also discuss a closely related system: the two-dimensional smectic liquid crystal films with planar boundary condition.Comment: 7 pages, 8 figures, To appear as a chapter in Les Houches summer school on Quantum Magnetis

The Crystal Structure of OprG from Pseudomonas aeruginosa, a Potential Channel for Transport of Hydrophobic Molecules across the Outer Membrane

Background: The outer membrane (OM) of Gram-negative bacteria provides a barrier to the passage of hydrophobic and hydrophilic compounds into the cell. The OM has embedded proteins that serve important functions in signal transduction and in the transport of molecules into the periplasm. The OmpW family of OM proteins, of which P. aeruginosa OprG is a member, is widespread in Gram-negative bacteria. The biological functions of OprG and other OmpW family members are still unclear. Methodology/Principal Findings: In order to obtain more information about possible functions of OmpW family members we have solved the X-ray crystal structure of P. aeruginosa OprG at 2.4 A ˚ resolution. OprG forms an eightstranded b-barrel with a hydrophobic channel that leads from the extracellular surface to a lateral opening in the barrel wall. The OprG barrel is closed off from the periplasm by interacting polar and charged residues on opposite sides of the barrel wall. Conclusions/Significance: The crystal structure, together with recent biochemical data, suggests that OprG and other OmpW family members form channels that mediate the diffusion of small hydrophobic molecules across the OM by a latera

Endothelial Surface Layer Degradation by Chronic Hyaluronidase Infusion Induces Proteinuria in Apolipoprotein E-Deficient Mice

Functional studies show that disruption of endothelial surface layer (ESL) is accompanied by enhanced sensitivity of the vasculature towards atherogenic stimuli. However, relevance of ESL disruption as causal mechanism for vascular dysfunction remains to be demonstrated. We examined if loss of ESL through enzymatic degradation would affect vascular barrier properties in an atherogenic model. Eight week old male apolipoprotein E deficient mice on Western-type diet for 10 weeks received continuous active or heat-inactivated hyaluronidase (10 U/hr, i.v.) through an osmotic minipump during 4 weeks. Blood chemistry and anatomic changes in both macrovasculature and kidneys were examined. Infusion with active hyaluronidase resulted in decreased ESL (0.32±0.22 mL) and plasma volume (1.03±0.18 mL) compared to inactivated hyaluronidase (0.52±0.29 mL and 1.28±0.08 mL, p<0.05 respectively).Active hyaluronidase increased proteinuria compared to inactive hyaluronidase (0.27±0.02 vs. 0.15±0.01 µg/µg protein/creatinin, p<0.05) without changes in glomerular morphology or development of tubulo-interstitial inflammation. Atherosclerotic lesions in the aortic branches showed increased matrix production (collagen, 32±5 vs. 18±3%; glycosaminoglycans, 11±5 vs. 0.1±0.01%, active vs. inactive hyaluronidase, p<0.05). ESL degradation in apoE deficient mice contributes to reduced increased urinary protein excretion without significant changes in renal morphology. Second, the induction of compositional changes in atherogenic plaques by hyaluronidase point towards increased plaque vulnerability. These findings support further efforts to evaluate whether ESL restoration is a valuable target to prevent (micro) vascular disease progressio

Striking variations in consultation rates with general practice reveal family influence

BACKGROUND: The reasons why patients decide to consult a general practitioner vary enormously. While there may be individual reasons for this variation, the family context has a significant and unique influence upon the frequency of individuals' visits. The objective of this study was to explore which family factors can explain the differences between strikingly high, and correspondingly low, family consultation rates in families with children aged up to 21. METHODS: Data were used from the second Dutch national survey of general practice. This survey extracted from the medical records of 96 practices in the Netherlands, information on all consultations with patients during 2001. We defined, through multilevel analysis, two groups of families. These had respectively, predominantly high, and low, contact frequencies due to a significant family influence upon the frequency of the individual's first contacts. Binomial logistic regression analyses were used to analyse which of the family factors, related to shared circumstances and socialisation conditions, can explain the differences in consultation rates between the two groups of families. RESULTS: In almost 3% of all families, individual consultation rates decrease significantly due to family influence. In 11% of the families, individual consultation rates significantly increase due to family influence. While taking into account the health status of family members, family factors can explain family consultation rates. These factors include circumstances such as their economic status and number of children, as well as socialisation conditions such as specific health knowledge and family beliefs. The chance of significant low frequencies of contact due to family influences increases significantly with factors such as, paid employment of parents in the health care sector, low expectations of general practitioners' care for minor ailments and a western cultural background. CONCLUSION: Family circumstances can easily be identified and will add to the understanding of the health complaints of the individual patient in the consulting room. Family circumstances related to health risks often cannot be changed but they can illuminate the reasons for a visit, and mould strategies for prevention, treatment or recovery. Health beliefs, on the other hand, may be influenced by providing specific knowledge

Genetic Covariance Structure of Reading, Intelligence and Memory in Children

This study investigates the genetic relationship among reading performance, IQ, verbal and visuospatial working memory (WM) and short-term memory (STM) in a sample of 112, 9-year-old twin pairs and their older siblings. The relationship between reading performance and the other traits was explained by a common genetic factor for reading performance, IQ, WM and STM and a genetic factor that only influenced reading performance and verbal memory. Genetic variation explained 83% of the variation in reading performance; most of this genetic variance was explained by variation in IQ and memory performance. We hypothesize, based on these results, that children with reading problems possibly can be divided into three groups: (1) children low in IQ and with reading problems; (2) children with average IQ but a STM deficit and with reading problems; (3) children with low IQ and STM deficits; this group may experience more reading problems than the other two