EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta

Osteogenesis imperfecta (OI) comprises a group of inherited disorders characterized by bone fragility and increased susceptibility to fractures. Historically, the laboratory confirmation of the diagnosis OI rested on cultured dermal fibroblasts to identify decreased or abnormal production of abnormal type I (pro)collagen molecules, measured by gel electrophoresis. With the discovery of COL1A1 and COL1A2 gene variants as a cause of OI, sequence analysis of these genes was added to the diagnostic process. Nowadays, OI is known to be genetically heterogeneous. About 90% of individuals with OI are heterozygous for causative variants in the COL1A1 and COL1A2 genes. The majority of remaining affected individuals have recessively inherited forms of OI with the causative variants in the more recently discovered genes CRTAP, FKBP10, LEPRE1,PLOD2, PPIB, SERPINF1, SERPINH1 and SP7, or in other yet undiscovered genes. These advances in the molecular genetic diagnosis of OI prompted us to develop new guidelines for molecular testing and reporting of results in which we take into account that testing is also used to ‘exclude' OI when there is suspicion of non-accidental injury. Diagnostic flow, methods and reporting scenarios were discussed during an international workshop with 17 clinicians and scientists from 11 countries and converged in these best practice guidelines for the laboratory diagnosis of OI

From Nonspecific DNA–Protein Encounter Complexes to the Prediction of DNA–Protein Interactions

©2009 Gao, Skolnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.doi:10.1371/journal.pcbi.1000341DNA–protein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNA–protein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNA–protein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNA–protein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNA–protein interaction modes exhibit some similarity to specific DNA–protein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Ca deviation from native is up to 5 Å from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNA–protein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein

‘1L=10L for Africa’: Corporate social responsibility and the transformation of bottled water into a ‘consumer activist’ commodity

In recent years, it has become an increasingly common marketing practice to connect the sale of consumer products to corporate social responsibility (CSR) initiatives, such as aid and development projects in so-called ‘developing’ countries. One example is Volvic’s pioneering ‘1L=10L for Africa’ campaign (2005–2010), which linked the sale of each liter of bottled water in ‘developed’ countries with the promise by Danone, Volvic’s owner, to provide 10 liters of drinking water in Africa. In this article, we engage with this ‘cause-related marketing’ campaign, using critical discourse analysis (CDA) to uncover its mechanisms and ideological functioning. We show how Volvic was able to transform an ordinary commodity, bottled water, into a consumer activist brand through which consumers could take part in solving global social problems, such as the access to safe drinking water in ‘developing’ countries. Our analysis of this exemplary case shows the ways that CSR often operates to deflect ethical critiques, consolidate brand loyalty and corporate profits, and defuse political struggles around consumption. By doing so, we suggest that CSR forms part of a complex strategy deployed to legitimize particular brands and commodities. In this way CSR can be seen as playing an important role in the ideological makeup of contemporary consumer capitalism. </jats:p

The flying buttress construct for posterior spinopelvic fixation: a technical note

<p>Abstract</p> <p>Background</p> <p>Posterior fusion of the spine to the pelvis in paediatric and adult spinal deformity is still challenging. Especially assembling of the posterior rod construct to the iliac screw is considered technically difficult. A variety of spinopelvic fixation techniques have been developed. However, extreme bending of the longitudinal rods or the use of 90-degree lateral offset connectors proved to be difficult, because the angle between the rod and the iliac screw varies from patient to patient.</p> <p>Methods</p> <p>We adopted a new spinopelvic fixation system, in which iliac screws are side-to-side connected to the posterior thoracolumbar rod construct, independent of the angle between the rod and the iliac screw. Open angled parallel connectors are used to connect short iliac rods from the posterior rod construct to the iliac screws at both sides. The construct resembles in form and function an architectural Flying Buttress, or lateral support arches, used in Gothic cathedrals.</p> <p>Results and discussion</p> <p>Three different cases that illustrate the Flying Buttress construct for spinopelvic fixation are reported here with the clinical details, radiographic findings and surgical technique used.</p> <p>Conclusion</p> <p>The Flying Buttress construct may offer an alternative surgical option for spinopelvic fixation in circumstances wherein coronal or sagittal balance cannot be achieved, for example in cases with significant residual pelvic obliquity, or in revision spinal surgery for failed lumbosacral fusion.</p

Ethnic minorities and prescription medication; concordance between self-reports and medical records

BACKGROUND: Ethnic differences in health care utilisation are frequently reported in research. Little is known about the concordance between different methods of data collection among ethnic minorities. The aim of this study was to examine to which extent ethnic differences between self-reported data and data based on electronic medical records (EMR) from general practitioners (GPs) might be a validity issue or reflect a lower compliance among minority groups. METHODS: A cross-sectional, national representative general practice study, using EMR data from 195 GPs. The study population consisted of Dutch, Turks, Surinamese, Antilleans and Morrocans. Self-reported data were collected through face-to-face interviews and could be linked to the EMR of GPs. The main outcome measures were the level of agreement between annual prescribing rate based on the EMRs of GPs and the self-reported receipt and use of prescriptions during the preceding 14 days. RESULTS: The pattern of ethnic differences in receipt and use of prescription medication depended on whether self-reported data or EMR data were used. Ethnic differences based on self-reports were not consistently reflected in EMR data. The percentage of agreement above chance between EMR data and self-reported receipt was in general relative low. CONCLUSION: Ethnic differences between self-reported data and EMR data might not be fully perceived as a cross-cultural validity issue. At least for Moroccans and Turks, compliance with the prescribed medication by the GP is suggested not to be optimal

Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study

<p>Abstract</p> <p>Background</p> <p>In the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn resuscitation occurs in at least 200 of the 180–185.000 newly born infants per year. International randomized controlled trials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia neonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ failure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are lacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences the distribution, metabolism and elimination of commonly used drugs in neonatal intensive care.</p> <p>Methods/Design</p> <p>Multicenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic Encephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be eligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to investigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual drug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated how clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into account. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to pharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance.</p> <p>Discussion</p> <p>On basis of the derived population PK-PD models dosing guidelines will be developed for the application of drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug treatment of hypothermic neonatal patients. Results will be published in a national web based evidence based paediatric formulary, peer reviewed journals and international paediatric drug references.</p> <p>Trial registration</p> <p>NTR2529.</p

Errors in Judicial Decisions

In criminal cases the task of the judge is to transform the uncertainty about the facts into the certainty of the verdict. In this experiment we examine the relationship between evidence of which the strength is known, subjective probability of guilt and verdict for abstract cases. We look at two situations: (1) all evidence is given and (2) evidence can be acquired. Roughly half of the participants do not base their decision on a subjective belief of the probability of guilt. The others underestimate in general the probability of guilt, but this is more than compensated by a tendency to convict at too low probability of guilt. In the situation where evidence can be acquired, participants do not acquire enough evidence

Model-independent search for CP violation in D0→K−K+π−π+ and D0→π−π+π+π− decays

A search for CP violation in the phase-space structures of D0 and View the MathML source decays to the final states K−K+π−π+ and π−π+π+π− is presented. The search is carried out with a data set corresponding to an integrated luminosity of 1.0 fb−1 collected in 2011 by the LHCb experiment in pp collisions at a centre-of-mass energy of 7 TeV. For the K−K+π−π+ final state, the four-body phase space is divided into 32 bins, each bin with approximately 1800 decays. The p-value under the hypothesis of no CP violation is 9.1%, and in no bin is a CP asymmetry greater than 6.5% observed. The phase space of the π−π+π+π− final state is partitioned into 128 bins, each bin with approximately 2500 decays. The p-value under the hypothesis of no CP violation is 41%, and in no bin is a CP asymmetry greater than 5.5% observed. All results are consistent with the hypothesis of no CP violation at the current sensitivity

Rib Cage Deformities Alter Respiratory Muscle Action and Chest Wall Function in Patients with Severe Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder characterized by bone fragility, multiple fractures and significant chest wall deformities. Cardiopulmonary insufficiency is the leading cause of death in these patients.Seven patients with severe OI type III, 15 with moderate OI type IV and 26 healthy subjects were studied. In addition to standard spirometry, rib cage geometry, breathing pattern and regional chest wall volume changes at rest in seated and supine position were assessed by opto-electronic plethysmography to investigate if structural modifications of the rib cage in OI have consequences on ventilatory pattern. One-way or two-way analysis of variance was performed to compare the results between the three groups and the two postures. compared to predicted values, on condition that updated reference equations are considered. In both positions, ventilation was lower in OI patients than control because of lower tidal volume (p<0.01). In contrast to OI type IV patients, whose chest wall geometry and function was normal, OI type III patients were characterized by reduced (p<0.01) angle at the sternum (pectus carinatum), paradoxical inspiratory inward motion of the pulmonary rib cage, significant thoraco-abdominal asynchronies and rib cage distortions in supine position (p<0.001).In conclusion, the restrictive respiratory pattern of Osteogenesis Imperfecta is closely related to the severity of the disease and to the sternal deformities. Pectus carinatum characterizes OI type III patients and alters respiratory muscles coordination, leading to chest wall and rib cage distortions and an inefficient ventilator pattern. OI type IV is characterized by lower alterations in the respiratory function. These findings suggest that functional assessment and treatment of OI should be differentiated in these two forms of the disease

Study of DJ meson decays to D+π−, D0π+ and D∗+π− final states in pp collisions

A study of D+π−, D0π+ and D∗+π− final states is performed using pp collision data, corresponding to an integrated luminosity of 1.0 fb−1, collected at a centre-of-mass energy of 7 TeV with the LHCb detector. The D1(2420)0 resonance is observed in the D∗+π− final state and the D∗2(2460) resonance is observed in the D+π−, D0π+ and D∗+π− final states. For both resonances, their properties and spin-parity assignments are obtained. In addition, two natural parity and two unnatural parity resonances are observed in the mass region between 2500 and 2800 MeV. Further structures in the region around 3000 MeV are observed in all the D∗+π−, D+π− and D0π+ final states