Pregnancy in patients with implantable cardiac defibrillators

The number of patients of reproductive age with inherited and congenital heart disease receiving implantable cardiac defibrillators (ICD) is steadily increasing. Safely and effectively coordinating pregnancy in this high-risk cohort is important to optimise maternal-foetal outcomes. As members of the multidisciplinary team caring for pregnant patients with indications for ICD, cardiologists and electrophysiologists should be aware of the considerations and nuances involved in managing these patients. This article reviews the pathophysiology of arrhythmias, ICD implantation considerations, novel minimal fluoroscopy techniques and subcutaneous ICD. In addition, antenatal and device management during pregnancy and delivery are discussed

Hospitalized poisonings after renal transplantation in the United States

BACKGROUND: The national incidence of and risk factors for hospitalized poisonings in renal transplant recipients has not been reported. METHODS: Historical cohort study of 39,628 renal transplant recipients in the United States Renal Data System between 1 July 1994 and 30 June 1998. Associations with time to hospitalizations for a primary diagnosis of poisonings (ICD-9 codes 960.x-989.x) within three years after renal transplant were assessed by Cox Regression. RESULTS: The incidence of hospitalized poisonings was 2.3 patients per 1000 person years. The most frequent causes of poisonings were immunosuppressive agents (25.3%), analgesics/antipyretics (14.1%), psychotropic agents (10.0%), and insulin/antidiabetic agents (7.1%). In Cox Regression analysis, low body mass index (BMI, <21.6 vs. >28.3 kg/m(2), adjusted hazard ratio (AHR), 3.02, 95% CI, 1.45–6.28, and allograft rejection, AHR 1.83, 95% CI, 1.15–2.89, were the only factors independently associated with hospitalized poisonings. Hospitalized poisonings were independently associated with increased mortality (AHR, 1.54, 95% CI 1.22–1.92, p = 0.002). CONCLUSIONS: Hospitalized poisonings were associated with increased mortality after renal transplantation. However, almost all reported poisonings in renal transplant recipients were due to the use of prescribed medications. Allograft rejection and low BMI were the only independent risk factors for poisonings identified in this population

Combined novel approaches to the microscopic study of the dental implant site

Poster presentation to ICOI Summer Implant Symposium Knowledge Above Opinion, 14-16 Aug 2015, San Francisco, CA, USA which won the poster prize.Poster presentation to ICOI Summer Implant Symposium Knowledge Above Opinion, 14-16 Aug 2015, San Francisco, CA, USA which won the poster prize.Poster presentation to ICOI Summer Implant Symposium Knowledge Above Opinion, 14-16 Aug 2015, San Francisco, CA, USA which won the poster prize.Poster presentation to ICOI Summer Implant Symposium Knowledge Above Opinion, 14-16 Aug 2015, San Francisco, CA, USA which won the poster prize.Poster from ICOI Summer Implant Symposium Knowledge Above Opinion. 14 Aug 2015. MATERIAL: We studied trephine core samples taken from 252 sites where implants were to be placed in a series of 35 patients from KW's practice: all material was obtained with patient consent and local ethical committee approval. The sites were both 'native cores' - where implants were placed at the first operation - and grafted sites, where a sinus graft procedure had been performed approximately six months before the second operation to place the implant. The initial studies were performed in 1996-1999 while both KW & AB were at UCL [1]. [1] Wong K. Studies of the quality of the intraosseous dental implant bed and of thermal effects in implant pathology. PhD Thesis, 2000, University College London, 190pp. METHODS (1): Samples were fixed in 70% ethanol, dehydrated in ethanol and embedded in PMMA. Resulting blocks were finished to produce polished longitudinal sections through the cores. Real time direct view 3D fluorescence light microscopy was used to study tissue morphology before carbon coating for study by qualitative and by quantitative backscattered electron (qBSE) scanning electron microscopy (SEM) imaging using brominated and iodinated dimethacrylate standards to calibrate backscattering (mineralisation density) [2]. For further correlative light microscopy (LM) for cell and uncalcified matrix histology, blocks were lightly repolished to remove the carbon coat, surface stained with toluidine blue and ethidium bromide, and studied using transmitted light and/or the background fluorescence of the sample to illuminate the stained surface layer. [2] Boyde A, Travers R, Glorieux FH, Jones SJ (1999) The mineralisation density of iliac crest bone from children with osteogenesis imperfecta. Calcified Tissue International 64:185-190. METHODS (2): Later (in 2000 and 2001), several cores were studied by x-ray microtomography (XMT/μCT) using the QMUL MuCAT scanner. This enabled us to make direct correlations between the current block face imaged with qBSE SEM and rendered XMT data. We revisited the same blocks (2011-2015) after evolving iodine staining methods for BSE SEM of PMMA block surfaces at 50Pa chamber pressure [3,4]. This enabled us to read the soft tissue and cellular histology directly in the SEM image of uncoated blocks and represents an important advance in the utilisation of archival resin embedded histological material in implant related research. Summary and conclusions •Valuable information can be retrieved from the study of the bone core removed to make the space for the dental implant. •The bone core can be studied asap, or stored for later analysis, eg in 70% ethanol. •Derived data could be used for research or medico-legal or forensic evidence. •Do not give the core to the ‘histology lab’, since they will hardly be able to constrain themselves from demineralising the sample, when half the evidence goes down the sink. •μCT can be done on the wet retrieval core with no further processing. •the moderate spatial resolution available with standard lab μCT systems will suffice both to study the connectivity and volumetric density of native bone, and the interconnectedness of graft bone with patient’s new bone. •The main function of the live osteocyte is to prevent or down-regulate bone mineralisation: dead bone, including all grafted bone accumulates mineral and will be recognised as a denser phase. •Block face methods are strongly preferred for this kind of sample: it should be embedded in a resin: we have found PMMA to be satisfactory: sections as such contain only damaged tissue: the intact tissue remains in the block face, which can be finished by diamond micromilling (expensive) or polishing (cheap). •Microscopic methods for studying the block face include reflection and fluorescence conventional and confocal optical microscopy, but VIP BSE SEM: iodine or tri-iodide staining permits the study of soft tissue elements including cells and matrix. •A variety of bone types are found in the retrieval core samples, in various mixtures, and it is not satisfactory to say that there is, or is not, bone there. •Bone varies widely in its mineral content (concentration) and this is best studied by qBSE SEM since μCT does not have sufficient spatial resolution; LM, qBSE SEM, Iodine contrasted BSE SEM and μCT are easily correlated. •Most bone in the jaw bone wound site – which is what is studied in the graft retrieval cores – contains a high proportion of large diameter collagen fibre bundles (Sharpey fibres) which are also extensively present in the surrounding marrow spaces: these are only incorporated in normal bone at periosteal sites and in the bundle bone of the socket, where PDL Sharpey fibres are inserted. •Direct lining of internal bone surfaces with adipocytes is only sometimes found in native cores, whereas post-cranial bone sites usually have adipocytes as the lining cells in older mature bone. •Sinus graft cores sometimes include respiratory epithelium and associated glandular epithelium: we are not aware that this has been reported previously, though it is an obvious risk. •A high frequency of arterioles may be found in the ‘marrow’ space in sinus graft retrieval cores: small blood vessels may be in extremely close proximity to - or in contact with - bone. •Bone mineral content and osteomalacia: more research needed. •Substantial regions of non-mineralised bone matrix (osteoid) are found in some retrieval cores, easily spotted in iodine contrasted SEM: some such contain no mineral, and others small unfused mineral patches. •Recognition of osteoid is simple in iodine contrasted SEM

CCancer: a bird’s eye view on gene lists reported in cancer-related studies

CCancer is an automatically collected database of gene lists, which were reported mostly by experimental studies in various biological and clinical contexts. At the moment, the database covers 3369 gene lists extracted from 2644 papers published in ∼80 peer-reviewed journals. As input, CCancer accepts a gene list. An enrichment analyses is implemented to generate, as output, a highly informative survey over recently published studies that report gene lists, which significantly intersect with the query gene list. A report on gene pairs from the input list which were frequently reported together by other biological studies is also provided. CCancer is freely available at http://mips.helmholtz-muenchen.de/proj/ccancer

Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

Power grip, pinch grip, manual muscle testing or thenar atrophy - which should be assessed as a motor outcome after carpal tunnel decompression? A systematic review

<p>Abstract</p> <p>Background</p> <p>Objective assessment of motor function is frequently used to evaluate outcome after surgical treatment of carpal tunnel syndrome (CTS). However a range of outcome measures are used and there appears to be no consensus on which measure of motor function effectively captures change. The purpose of this systematic review was to identify the methods used to assess motor function in randomized controlled trials of surgical interventions for CTS. A secondary aim was to evaluate which instruments reflect clinical change and are psychometrically robust.</p> <p>Methods</p> <p>The bibliographic databases Medline, AMED and CINAHL were searched for randomized controlled trials of surgical interventions for CTS. Data on instruments used, methods of assessment and results of tests of motor function was extracted by two independent reviewers.</p> <p>Results</p> <p>Twenty-two studies were retrieved which included performance based assessments of motor function. Nineteen studies assessed power grip dynamometry, fourteen studies used both power and pinch grip dynamometry, eight used manual muscle testing and five assessed the presence or absence of thenar atrophy. Several studies used multiple tests of motor function. Two studies included both power and pinch strength and reported descriptive statistics enabling calculation of effect sizes to compare the relative responsiveness of grip and pinch strength within study samples. The study findings suggest that tip pinch is more responsive than lateral pinch or power grip up to 12 weeks following surgery for CTS.</p> <p>Conclusion</p> <p>Although used most frequently and known to be reliable, power and key pinch dynamometry are not the most valid or responsive tools for assessing motor outcome up to 12 weeks following surgery for CTS. Tip pinch dynamometry more specifically targets the thenar musculature and appears to be more responsive. Manual muscle testing, which in theory is most specific to the thenar musculature, may be more sensitive if assessed using a hand held dynamometer – the Rotterdam Intrinsic Handheld Myometer. However further research is needed to evaluate its reliability and responsiveness and establish the most efficient and psychometrically robust method of evaluating motor function following surgery for CTS.</p

Mutational analysis of Peroxiredoxin IV: exclusion of a positional candidate for multinodular goitre

BACKGROUND: Multinodular goitre (MNG) is a common disorder characterised by an enlargement of the thyroid, occurring as a compensatory response to hormonogenesis impairment. The incidence of MNG is dependent on sex (female:male ratio 5:1) and several reports have documented a genetic basis for the disease. Last year we mapped a MNG locus to chromosome Xp22 in a region containing the peroxiredoxin IV (Prx-IV) gene. Since Prx-IV is involved in the removal of H(2)O(2) in thyroid cells, we hypothesize that mutations in Prx-IV gene are involved in pathogenesis of MNG. METHODS: Four individuals (2 affected, 2 unrelated unaffected) were sequenced using automated methods. All individuals were originated from the original three-generation Italian family described in previous studies. A Southern blot analysis using a Prx-IV full-length cDNA as a probe was performed in order to exclude genomic rearrangements and/or intronic mutations. In addition a RT-PCR of PRX-IV was performed in order to investigate expression alterations. RESULTS: No causative mutations were found. Two adjacent nucleotide substitutions were detected within introns 1 and 4. These changes were also detected in unaffected individuals, suggesting that they were innocuous polymorphisms. No gross genomic rearrangements and/or restriction fragment alterations were observed on Southern analysis. Finally, using RT-PCR from tissue-specific RNA, no differences of PRX-IV expression-levels were detected between affected and unaffected samples. CONCLUSIONS: Based on sequence and genomic analysis, Prx-IV is very unlikely to be the MNG2 gene

Enhanced stochastic optimization algorithm for finding effective multi-target therapeutics

<p>Abstract</p> <p>Background</p> <p>For treating a complex disease such as cancer, we need effective means to control the biological network that underlies the disease. However, biological networks are typically robust to external perturbations, making it difficult to beneficially alter the network dynamics by controlling a single target. In fact, multi-target therapeutics is often more effective compared to monotherapies, and combinatory drugs are commonly used these days for treating various diseases. A practical challenge in combination therapy is that the number of possible drug combinations increases exponentially, which makes the prediction of the optimal drug combination a difficult combinatorial optimization problem. Recently, a stochastic optimization algorithm called the Gur Game algorithm was proposed for drug optimization, which was shown to be very efficient in finding potent drug combinations.</p> <p>Results</p> <p>In this paper, we propose a novel stochastic optimization algorithm that can be used for effective optimization of combinatory drugs. The proposed algorithm analyzes how the concentration change of a specific drug affects the overall drug response, thereby making an informed guess on how the concentration should be updated to improve the drug response. We evaluated the performance of the proposed algorithm based on various drug response functions, and compared it with the Gur Game algorithm.</p> <p>Conclusions</p> <p>Numerical experiments clearly show that the proposed algorithm significantly outperforms the original Gur Game algorithm, in terms of reliability and efficiency. This enhanced optimization algorithm can provide an effective framework for identifying potent drug combinations that lead to optimal drug response.</p

Simultaneous chronic rupture of quadriceps tendon and contra-lateral patellar tendon in a patient affected by tertiary hyperparatiroidism

Spontaneous ruptures of the extensor mechanism of the knee are very rare. They tend to increase considerably in patients with metabolic diseases such as chronic renal failure, hyperparathyroidism, diabetes, gout, and systemic lupus erythematosus. The reported case regards a 48-year-old man with chronic, spontaneous and simultaneous quadriceps, and contra-lateral patellar tendon rupture. The patient suffered from chronic renal failure and for the past year from tertiary hyperparathyroidism. Ruptured tendons were repaired and both knee were evaluated monthly for the next 12 months. Good functional recovery was achieved on both knees without relapse. This case emphasizes the importance of long-term high parathyroid hormone level in the etiology of tendons ruptures

A general and efficient method for estimating continuous IBD functions for use in genome scans for QTL

<p>Abstract</p> <p>Background</p> <p>Identity by descent (IBD) matrix estimation is a central component in mapping of Quantitative Trait Loci (QTL) using variance component models. A large number of algorithms have been developed for estimation of IBD between individuals in populations at discrete locations in the genome for use in genome scans to detect QTL affecting various traits of interest in experimental animal, human and agricultural pedigrees. Here, we propose a new approach to estimate IBD as continuous functions rather than as discrete values.</p> <p>Results</p> <p>Estimation of IBD functions improved the computational efficiency and memory usage in genome scanning for QTL. We have explored two approaches to obtain continuous marker-bracket IBD-functions. By re-implementing an existing and fast deterministic IBD-estimation method, we show that this approach results in IBD functions that produces the exact same IBD as the original algorithm, but with a greater than 2-fold improvement of the computational efficiency and a considerably lower memory requirement for storing the resulting genome-wide IBD. By developing a general IBD function approximation algorithm, we show that it is possible to estimate marker-bracket IBD functions from IBD matrices estimated at marker locations by any existing IBD estimation algorithm. The general algorithm provides approximations that lead to QTL variance component estimates that even in worst-case scenarios are very similar to the true values. The approach of storing IBD as polynomial IBD-function was also shown to reduce the amount of memory required in genome scans for QTL.</p> <p>Conclusion</p> <p>In addition to direct improvements in computational and memory efficiency, estimation of IBD-functions is a fundamental step needed to develop and implement new efficient optimization algorithms for high precision localization of QTL. Here, we discuss and test two approaches for estimating IBD functions based on existing IBD estimation algorithms. Our approaches provide immediately useful techniques for use in single QTL analyses in the variance component QTL mapping framework. They will, however, be particularly useful in genome scans for multiple interacting QTL, where the improvements in both computational and memory efficiency are the key for successful development of efficient optimization algorithms to allow widespread use of this methodology.</p