Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

Endoscopic Saphenous harvesting with an Open CO2 System (ESOS) trial for coronary artery bypass grafting surgery: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>In coronary artery bypass grafting surgery, arterial conduits are preferred because of more favourable long-term patency and outcome. Anyway <it>the greater saphenous vein </it>continues to be the most commonly used bypass conduit. <it>Minimally invasive endoscopic saphenous vein harvesting </it>is increasingly being investigated in order to reduce the morbidity associated with conventional open vein harvesting, includes postoperative leg wound complications, pain and patient satisfaction. However, to date the short and the long-term benefits of the endoscopic technique remain controversial. This study provides an interesting opportunity to address this gap in the literature.</p> <p>Methods/Design</p> <p><b>Endoscopic Saphenous harvesting with an Open CO₂System </b>trial includes two parallel vein harvesting arms in coronary artery bypass grafting surgery. It is an interventional, single centre, prospective, randomized, safety/efficacy, cost/effectiveness study, in adult patients with elective planned and first isolated coronary artery disease. A simple size of 100 patients for each arm will be required to achieve 80% statistical power, with a significant level of 0.05, for detecting most of the formulated hypotheses. A six-weeks leg wound complications rate was assumed to be 20% in the conventional arm and less of 4% in the endoscopic arm. Previously quoted studies suggest a first-year vein-graft failure rate of about 20% with an annual occlusion rate of 1% to 2% in the first six years, with practically no difference between the endoscopic and conventional approaches. Similarly, the results on event-free survival rates for the two arms have barely a 2-3% gap. Assuming a 10% drop-out rate and a 5% cross-over rate, the goal is to enrol 230 patients from a single Italian cardiac surgery centre.</p> <p>Discussion</p> <p>The goal of this prospective randomized trial is to compare and to test improvement in wound healing, quality of life, safety/efficacy, cost-effectiveness, short and long-term outcomes and vein-graft patency after endoscopic open CO₂harvesting system versus conventional vein harvesting.</p> <p>The expected results are of high clinical relevance and will show the safety/efficacy or non-inferiority of one treatment approach in terms of vein harvesting for coronary artery bypass grafting surgery.</p> <p>Trial registration</p> <p>www.clinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01121341">NCT01121341</a>.</p

Reliability and Diagnostic Performance of CT Imaging Criteria in the Diagnosis of Tuberculous Meningitis

The original publication is available at http:// www.plosone.orgPublication of this article was funded by the Stellenbosch University Open Access Fund.Introduction: Abnormalities on CT imaging may contribute to the diagnosis of tuberculous meningitis (TBM). Recently, an expert consensus case definition (CCD) and set of imaging criteria for diagnosing basal meningeal enhancement (BME) have been proposed. This study aimed to evaluate the sensitivity, specificity and reliability of these in a prospective cohort of adult meningitis patients. Methods: Initial diagnoses were based on the CCD, classifying patients into: ‘Definite TBM’ (microbiological confirmation), ‘Probable TBM’ (diagnostic score $10), ‘Possible TBM’ (diagnostic score 6–9), ‘Not TBM’ (confirmation of an alternative diagnosis) or ‘Uncertain’ (diagnostic score of ,6). CT images were evaluated independently on two occasions by four experienced reviewers. Intra-rater and inter-rater agreement were calculated using the kappa statistic. Sensitivities and specificities were calculated using both ‘Definite TBM’ and either ‘Definite TBM’ or ‘Probable TBM’ as gold standards. Results: CT scan criteria for BME had good intra-rater agreement (k range 0.35–0.78) and fair to moderate inter-rater agreement (k range 0.20–0.52). Intra- and inter-rater agreement on the CCD components were good to fair (k = ranges 0.47–0.81 and 0.21–0.63). Using ‘Definite TBM’ as a gold standard, the criteria for BME were very specific (61.5%–100%), but insensitive (5.9%–29.4%). Similarly, the imaging components of the CCD were highly specific (69.2–100%) but lacked sensitivity (0–56.7%). Similar values were found when using ‘Definite TBM’ or ‘Probable TBM’ as a gold standard. Discussion: The fair to moderate inter-rater agreement and poor sensitivities of the criteria for BME suggest that little reliance should be placed in these features in isolation. While the presence of the CCD criteria of acute infarction or tuberculoma(s) appears useful as rule-in criteria, their absence is of little help in excluding TBM. The CCD and criteria for BME, as well as any new criteria, need to be standardized and validated in prospective cohort studies.Funding: KB received funding from the Discovery Foundation (Academic Fellowship Award; http://www.discovery.co.za/portal/loggedout-individual/discoverycommunity- about), College of Neurology of South Africa (K.M. Browse Award; http://www.collegemedsa.ac.za/Default.aspx ) and the University of Stellenbosch. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Publisher's versio

Medical treatment of pediatric urolithiasis

In recent years the incidence of pediatric stone disease has increased several fold, mostly due to hypercalciuria and hypocitraturia. The goal of medical treatment is to protect the patient from formation of new stones and expansion of existing ones. The non-pharmacological means to address stone disease include high fluid intake and, frequently, modification of nutritional habits. The pharmacological treatment is based on the chemical composition of the stone and the biochemical abnormalities causing its formation; hence, chemical analysis of the stone, urine and blood is of paramount importance and should be done when the first stone is detected. This review discusses the current options of medical treatment of pediatric urolithiasis

Quantification of Circadian Rhythms in Single Cells

Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator. Both models describe the data well and enabled us to quantitatively characterize both wild-type cells and several mutants. It has been suggested that the circadian clock is self-sustained at the single cell level, but we conclude that present data are not sufficient to determine whether the circadian clock of single SCN neurons and fibroblasts is a damped or a self-sustained oscillator. We show how to settle this question, however, by testing the models' predictions of different phases and amplitudes in response to a periodic entrainment signal (zeitgeber)

A Graph Algorithmic Approach to Separate Direct from Indirect Neural Interactions

Network graphs have become a popular tool to represent complex systems composed of many interacting subunits; especially in neuroscience, network graphs are increasingly used to represent and analyze functional interactions between neural sources. Interactions are often reconstructed using pairwise bivariate analyses, overlooking their multivariate nature: it is neglected that investigating the effect of one source on a target necessitates to take all other sources as potential nuisance variables into account; also combinations of sources may act jointly on a given target. Bivariate analyses produce networks that may contain spurious interactions, which reduce the interpretability of the network and its graph metrics. A truly multivariate reconstruction, however, is computationally intractable due to combinatorial explosion in the number of potential interactions. Thus, we have to resort to approximative methods to handle the intractability of multivariate interaction reconstruction, and thereby enable the use of networks in neuroscience. Here, we suggest such an approximative approach in the form of an algorithm that extends fast bivariate interaction reconstruction by identifying potentially spurious interactions post-hoc: the algorithm flags potentially spurious edges, which may then be pruned from the network. This produces a statistically conservative network approximation that is guaranteed to contain non-spurious interactions only. We describe the algorithm and present a reference implementation to test its performance. We discuss the algorithm in relation to other approximative multivariate methods and highlight suitable application scenarios. Our approach is a tractable and data-efficient way of reconstructing approximative networks of multivariate interactions. It is preferable if available data are limited or if fully multivariate approaches are computationally infeasible.Comment: 24 pages, 8 figures, published in PLOS On

Desmoplastic fibroma of the mandible - review of the literature and presentation of a rare case

Desmoplastic fibroma (DF) is a rare, benign but locally aggressive, intraosseous lesion with a high tendency of local recurrence. In this report the actual literature is reviewed regarding epidemiological data, pathology, clinical diagnostic criterias, therapy and prognosis. Moreover, a report of an interesting case is included localized in the mandibular corpus

Imported malaria in a cosmopolitan European city: A mirror image of the world epidemiological situation

© 2008 Millet et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

The Welfare Implications of Using Exotic Tortoises as Ecological Replacements

<div><h3>Background</h3><p>Ecological replacement involves the introduction of non-native species to habitats beyond their historical range, a factor identified as increasing the risk of failure for translocations. Yet the effectiveness and success of ecological replacement rely in part on the ability of translocatees to adapt, survive and potentially reproduce in a novel environment. We discuss the welfare aspects of translocating captive-reared non-native tortoises, <em>Aldabrachelys gigantea</em> and <em>Astrochelys radiata</em>, to two offshore Mauritian islands, and the costs and success of the projects to date.</p> <h3>Methodology/Principal Findings</h3><p>Because tortoises are long-lived, late-maturing reptiles, we assessed the progress of the translocation by monitoring the survival, health, growth, and breeding by the founders. Between 2000 and 2011, a total of 26 <em>A. gigantea</em> were introduced to Ile aux Aigrettes, and in 2007 twelve sexually immature <em>A. gigantea</em> and twelve male <em>A. radiata</em> were introduced to Round Island, Mauritius. Annual mortality rates were low, with most animals either maintaining or gaining weight. A minimum of 529 hatchlings were produced on Ile aux Aigrettes in 11 years; there was no potential for breeding on Round Island. Project costs were low. We attribute the success of these introductions to the tortoises’ generalist diet, habitat requirements, and innate behaviour.</p> <h3>Conclusions/Significance</h3><p>Feasibility analyses for ecological replacement and assisted colonisation projects should consider the candidate species’ welfare during translocation and in its recipient environment. Our study provides a useful model for how this should be done. In addition to serving as ecological replacements for extinct Mauritian tortoises, we found that releasing small numbers of captive-reared <em>A. gigantea</em> and <em>A. radiata</em> is cost-effective and successful in the short term. The ability to release small numbers of animals is a particularly important attribute for ecological replacement projects since it reduces the potential risk and controversy associated with introducing non-native species.</p> </div