About 41% of households globally, mainly in developing countries rely on solid fuels for cooking with consequences for fetal growth and development. Previous reviews were limited in scope, assessing only two outcomes . With important evidence accumulating, there is a need to improve the previous estimates and assess additional outcomes. We conducted a systematic review and meta-analysis to evaluate the quality and strength of available evidence on household air pollution (HAP) and the whole range of adverse pregnancy outcomes.PubMed, Ovid Medline, Scopus and CINAHL were searched from their inception to the end of April 2013. All epidemiological study designs were eligible for inclusion in the review. The random-effects model was applied in computing the summary-effect estimates (EE) and their corresponding 95% confidence interval (CI).Of 1505 studies screened, 19 studies satisfied the inclusion criteria. Household combustion of solid fuels resulted in an 86.43 g  reduction in birth weight, and a 35%  and 29%  increased risk of LBW and stillbirth respectively.Combustion of solid fuels at home increases the risk of a wide range of adverse pregnancy outcomes. Access to clean household energy solutions is the surest way to combat HAP and mitigate their adverse effects. Globally, 41% of households, mainly in developing countries in Asia and sub-Saharan Africa rely on solid fuels  as their primary cooking fuel The subject matter was reviewed previously by Pope et al. We conducted and report the study in accordance with the PRISMA  guidelines We searched PubMed, Ovid Medline, Scopus and CINAHL from their inception to the end of April, 2013 with no language restrictions imposed. Medical Subject Heading (MeSH) terms and free text words were used to identify relevant studies from the databases. The search words applied are provided in Data from eligible studies were extracted independently by two investigators (AKA and RQ) onto a form. Disagreements during synthesis of the data extracted were resolved through discussion with the third investigator (JJKJ) serving as an adjudicator. We contacted authors for clarifications where needed. Methodological quality of the included studies was assessed by using the original Newcastle-Ottawa scale  for case control and cohort designs, and an adapted NOS (maximum of 6 stars) for cross-sectional designs. In evaluating the adequacy of confounding control in the included studies, we put together a shortlist of core confounders that needed to be adjusted for in the analysis. The shortlist included maternal age and obstetric history, maternal nutrition and anthropometry, socioeconomic status, and active and passive smoking.2) test and the 2I statistic with a value>50% deemed to indicate substantial heterogeneity. Forest plots were also visually assessed. We explored possible sources of heterogeneity by conducting subgroup analysis and meta-regression. We conducted sensitivity analysis by limiting the analysis to high quality studies; 7 or more stars on the original NOS for case-control and cohort studies, and 6 stars on the adapted NOS for cross-sectional studies. Publication bias was investigated by visually inspecting funnel plots for asymmetry, and applying the Begg's and Egger's tests. We accounted for publication bias using the trim and fill method. Analyses were conducted using Stata version 9.0 .We anticipated heterogeneity between the studies due to differences in study design, and geographical settings and populations studied. We therefore applied the random-effects model which accounts for both within and between study heterogeneity in computing the summary-effect estimates. With regards to studies providing multiple effect estimates , we first combined the effect estimates using fixed-effects model and applied the single effect estimate in the overall meta-analysis. We quantified heterogeneity using the Cochran Q . Two studies Birth weight was ascertained by 14 studies and was measured at home in four studies that were community-based Selection bias was generally minimized in all the included studies as the studies were largely representative of their source population and reported high response rates. Information bias was a potential problem in all the studies due to the reliance on interview methods in assessing HAP exposure. The prospective cohort studies collected exposure data at baseline but it is unclear whether fuel choices of mothers remained relatively stable throughout pregnancy. The retrospective cohort study Outcomes were objectively measured at home/hospital or ascertained from hospital records for majority of the included studies. There is a strong potential for outcome measurement bias in two studies a priori criteria, of the included studies that adjusted for potential confounders, confounding control was considered inadequate in four studies All but two studies Overall, applying the NOS scale, two studies 2I = 0.0% and EE = 1.49, 95% CI: 1.30, 1.70, 2I = 0.0% respectively).On the relation of solid fuel use with average birth weight, the study conducted in Ghana Regarding the other outcomes investigated, with the exception of miscarriage, we observed no evidence of statistical heterogeneity in the analysis . For PTBResults of the sub-group analysis which was performed for only birth weight and LBW due to the small number of studies investigating the other outcomes are presented in Regarding information collected on solid fuel types used in households, for both outcomes, the combined estimate recorded for studies that grouped the various fuels together was lower than the estimate summarized for studies that assessed one specific fuel or investigated the fuels independently. Evidence of heterogeneity between the studies that grouped the individual solid fuels was noted. For the LBW outcome, the summary-effect estimates increased as the quality of the studies increases . An incoIn the meta-regression models; study design , exposure assessment  and study quality  were the covariates associated with heterogeneity observed in the LBW analysis. None of the covariates was statistically associated with the observed heterogeneity in the birth weight analysis.Our results indicate that household use of solid fuels adversely affects pregnancy outcomes. Solid fuel use leads to an 86.43 g  reduction in birth weight and a 35%  increased risk of LBW. We also found evidence of an increased risk of stillbirth, PTB, IUGR and miscarriage for use of solid fuel at home.Our study is based on much more information (>50%) than the previous reviews and certainly has much higher statistical power. Some of the included studies however had major methodological drawbacks with obvious implications for the quality of the evidence reported. We therefore conducted sensitivity analysis by excluding studies rated as satisfactory and low quality to assess the robustness of our results. The summary-effect estimates from the sensitivity analyses were not markedly different from the overall estimates. We also conducted subgroup analysis and meta-regression to elaborate the observed heterogeneity in the analysis. This was to ensure the inherent differences among the individual studies that were likely to impact on the validity and usefulness of the summary estimates are not ignored. Of the covariates explored, study design, exposure assessment method applied, and the methodological quality appear to be the variables likely to impact on the interpretation of our findings. For these three covariates we observed very consistent results in the stratified analysis. The results obtained from the meta-regression corroborated the findings from the LBW stratified analysis.A major validity concern of meta-analysis is the tendency of overestimating the magnitude of the true effect size due to publication bias. We therefore investigated publication bias and accounted for the bias where evidence of its presence was found . With reWe found household combustion of solid fuels to be associated with an 86 g reduction in birth weight. Accounting for publication bias however reduced the effect size to 54 g suggesting a possible overestimation of the summary estimate in the meta-analysis. Pope et al. We also found household use of solid fuels to be associated with a 29%  increased risk of stillbirth and was quite lower than the effect estimate previously reported by Pope et al. This is the first study to review the available evidence on household solid fuel use and PTB, IUGR and miscarriage. Even though the findings reported are weakened by the small number of studies reviewed, they are consistent with the findings of previous reviews assessing the effects of ambient air pollution Combustion pollutants  exert their effects on fetal growth directly by passing across the placenta or indirectly by reducing maternal lung function and increasing the risk of maternal lung disease CO reduces oxygen-carrying capacity of maternal hemoglobin, which could adversely affect oxygen delivery to fetal circulation Regarding the effects of PAHs, Dejmek et al. Our results show that combustion of solid fuels at home increases the risk of a wide range of adverse pregnancy outcomes. Access to clean household energy solutions is the surest way to combat HAP and mitigate their adverse effects. This requires political will which is often lacking in most developing countries.Even though we noted a high degree of consistency in study findings across the studies reviewed, major methodological limitations of most studies means further quality evidence are needed for causal inferences. All the studies reviewed applied interview methods in the ascertainment of exposure with hardly any consideration for cooking sequence and patterns, relative stability of fuel choices during pregnancy, fuel mixing/stacking, and potency of the individual fuels in causing adverse effects. The inconsistent categorization of kerosene is also a concern. These observations have consequences for the validity of the results reported by the included studies. Future research should therefore incorporate personal exposure monitoring methods and cooking activity diaries, and evaluate biomarkers of exposure. Other sources of HAP such as garbage burning at home should also be explored in future studies as well as considering the relative contribution of outdoor air pollution sources to HAP levels.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.


Vanessa cardui, the species with the widest diet breadth among butterflies and a potential insect pest, by comparing tissue-specific transcriptomes from caterpillars that were reared on different host plants. We tested whether the similarities of gene-expression response reflect the evolutionary history of adaptation to these plants in the Vanessa and related genera, against the null hypothesis of transcriptional profiles reflecting plant phylogenetic relatedness.Although most insect species are specialized on one or few groups of plants, there are phytophagous insects that seem to use virtually any kind of plant as food. Understanding the nature of this ability to feed on a wide repertoire of plants is crucial for the control of pest species and for the elucidation of the macroevolutionary mechanisms of speciation and diversification of insect herbivores. Here we studied Using both unsupervised and supervised methods of data analysis, we found that the tissue-specific patterns of caterpillar gene expression are better explained by the evolutionary history of adaptation of the insects to the plants than by plant phylogeny.V. cardui may use two sets of expressed genes to achieve polyphagy, one associated with the ancestral capability to consume Rosids and Asterids, and another allowing the caterpillar to incorporate a wide range of novel host-plants.Our findings suggest that The online version of this article (doi:10.1186/s12862-016-0627-y) contains supplementary material, which is available to authorized users. Insects and the flowering plants they feed upon comprise the majority of described species and total biodiversity on Earth, yet we know little about why these clades dominate our planet. Although the vast majority of these insect species are specialist feeders, consuming only a few closely related plant species, modern phylogenetic analyses reveal that most specialist clades are millions of years younger than their plant hosts –3. ThereHere, we test a fundamental hypothesis about the origin of a major change in host-plant utilization. Traditionally, molecular genetic studies of host shifts have focused upon key adaptations in species that have specialized on hosts over millions of generations since they initially started using them (e.g. papilionid butterflies using P450s or pierid butterflies using nitrile specifier protein (NSP) for detoxification of hosts) . In contVanessa cardui  is on the threshold of becoming a true generalist and potential agricultural pest ). No specific field work or ethical permission to collect and use the caterpillars and butterflies in this study was necessary. This population was maintained under laboratory conditions  avoiding full-sib mating over the winter and crossed with two new batches of butterflies also obtained commercially (World Wide Butterflies [www.wwb.co.uk] and Heart of England Butterflies [www.heartofenglandbutterflies.com]) in the spring of 2012. The adults of the first generation of this intermixed population were used to assess the female preference of plant for oviposition. The second generation was used to evaluate larval performance on the different plants. Progeny from six females (gene expression) and from four females  were reared on the plants mentioned above  following a split-brood design. That is, ten neonates (gene expression) and thirty neonates  from each family were transferred immediately after hatching to individual plastic cups containing leaves of each different plant. Leaves were kept moist using a wet cotton ball at their base and replaced every day. Larvae fed on their corresponding hosts until the second day after molting into their fifth instar for the gene expression experiment. To assess larval performance, the caterpillars were reared until they reached the adult stage. An additional file describes the methodology followed for the oviposition and larval performance experiments  and summer 2012 . The hosts , has been previously used as a measure of TA quality .The data set supporting the results of this article is available in the ArrayExpress repository, [


Epithelial cancer of the colon and rectum, also known as colorectal cancer (CRC), results from a progressive accumulation of genetic and epigenetic alterations that lead to uncontrolled growth of colonocytes, the cells lining the colon and rectum. CRC is the second leading cause of cancer-related deaths and the third most common cancer in men and in women in the U.S. Of all the patients diagnosed with CRC every year, it is estimated that the vast majority of CRCs are non-hereditary “sporadic cancers” with no apparent evidence of an inherited component. Sporadic CRC results from the cumulative effects of multiple genetic and epigenetic alterations caused by somatic mutations, which may themselves be the indirect result of several environmental factors. This review examines our current understanding of the major genetic alterations leading to colon cancer, options for prevention and early detection of CRC, and the currently available treatment approaches that may target these different genetic alterations. CRC is a common, heterogeneous disease that arises through the aggregate effects of multiple genetic mutations and epigenetic alterations involving genes that regulate cell growth and differentiation. There are approximately 160,000 new cases of CRC every year in the United States and approximately one-third of CRC patients die from the disease . Though CRC presents with a broad spectrum of neoplasms, ranging from benign growths to invasive cancer. CRC starts in the inner lining of the colon and/or rectum as a growth of tissue called a polyp slowly growing through some or all of its layers. A particular type of polyp called the adenomatous polyp or adenoma is a benign tumor that may undergo malignant transformation to cancer. This malignant transformation is the result of mutation or deletion of major regulator genes, resulting first in hyperplasia moving toward adenoma to carcinoma and then metastasis .A present estimate is that between 15–30% of CRCs may have a major hereditary component, given the occurrence of CRC in first- or second-degree relatives . Most ofIt is well established that sporadic CRC is a genetic disease caused by sequential accumulation of mutations in multiple genes. Over the past three decades, molecular genetic studies have identified several crucial gene defects that underlie predisposition to sporadic CRC . As showThe CIN pathway is an adenoma-carcinoma sequence model Fig.  which suAmong the earliest events in sporadic CRC progression pathway is the loss of the APC gene. Genetic disruption of the APC gene or its inactivation by hypermethylation of the APC promoter leads to Wnt/β- catenin signaling activation. This process is hypothesized to be the key event for adenoma initiation , 13. MutAnother important genetic pathway contributing to CIN is KRAS. The KRAS gene belongs to the RAS family of oncogenes and is mutated in 30–50% of CRCs . RAS proStudies have also demonstrated the loss of tumor suppressor TP53 gene and 18q LOH as major contributors to the CIN phenotype . The TP5In addition to CIN pathway, about 10–15% of sporadic CRC are due to the MSI pathway Fig. . MSI is Inactivation of MMR genes occur either through aberrant methylation of promoter CpG of the MutL homolog 1 (MLH1) gene or point mutations in one of the MMR genes, with the former reason accounting for most of the cases of MMR inactivation . As a reClinically, solely based on the extent of MSI, CRCs can be classified as MSI-high, MSI-low, or microsatellite stable (MSS) . As compThe name of this pathway is attributable to the morphologically serrated appearance of the precursor lesions. Different from the CIN Fig. and MSI BRAF, a member of the RAF kinase family is a serine/threonine-specific protein kinase that plays a key role in regulating the MAPKs/ERKs  signaling pathway, which affects cell division, differentiation, and secretion. Point mutation in BRAF (V600E) causes constitutive activation of this kinase as well as its insensitivity to negative feedback mechanisms, leading to enhanced MAPK/ERK signaling . This ovAmong the epigenetically silenced genes in Serrated pathway, p16  is one of the most well- characterized tumor suppressor genes. The p16 tumor suppressor protein functions as an inhibitor of CDK4 and 6 (cyclin-dependent kinase 4 and 6), the D-type cyclin-dependent kinases that initiate the phosphorylation of the retinoblastoma (Rb) tumor suppressor protein. The progression of sporadic CRCs through the Serrated pathway is accelerated by p16 inactivation through promoter hypermethylation.It is possible that no two CRCs are alike and only a few mutations are common to most sporadic CRCs. Therefore, each tumor has its own unique combination of genetic alterations. In addition to the pathways described, the heterogeneity of CRCs is further attributed to the interactions of the described pathways Fig. with othAlthough the incidence and mortality rates from CRC are declining steadily in the United States, health disparities in cancer screening, treatment, and survival still persist . BecauseDepending on the stage and progression state of the disease, treatment regimens for CRCs include: colectomy , postoperative adjuvant chemotherapy (Stage III and some Stage II colon cancers), chemotherapy with multi-drug therapy including 5-fluorouracil and leucovorin and CapeOx  (Stage II) and radiation therapy (recurrent or advanced disease). Another chemotherapeutic agent, imnotecan (CPT- 11) has been shown to improve efficacy in CRCs . Recentlet al [Genetically engineered monoclonal antibodies are used in treating CRCs. Cetuximab and panitumumab are anti-EGFR monoclonal antibodies that block the EGFR signaling pathway. These two drugs are used in the treatment of metastatic CRC in combination with conventional chemotherapy or as single agent. Clinical studies have shown that combination therapy with irinotecan plus cetuximab increases the survival rates and response in metastatic CRC patients as compared to irinotecan alone . Recentlet al  showed tet al .et al [et al [The Genetic Sequencing technique has revolutionized monitoring of disease progression, relapse, and residual disease in CRCs . Bass etet al  reportedl [et al  providedThe pace of recent advances in our understanding of the molecular basis of CRC and expansion in the drugs designed to treat CRC have led to substantial gains in quality of life in CRC patients. However, the significant burden of CRC on public health still remains. Like most other cancer therapeutics, these treatment regimens are associated with side effects and have not yet shown significant efficacy in most instances. Another key factor that limits progress in CRC chemoprevention is the pace of clinical research. There is a significant lack of awareness among people to undergo CRC screening despite established and available techniques. Overcoming these challenges will bring cause for optimism and room for hope in treating CRCs.


The model was first applied to profiles obtained from wild-type C57Bl/6J mice. The results provided insight into the interplay of lipoprotein production, remodelling and catabolism. Moreover, the concentration and metabolism of unmeasured lipoprotein components could be determined. The model was validated through the prediction of lipoprotein profiles of several transgenic mouse models commonly used in cardiovascular research. Finally, the framework was employed for longitudinal analysis of the profiles of C57Bl/6J mice following a pharmaceutical intervention with a liver X receptor (LXR) agonist. The multifaceted regulatory response to the administration of the compound is incompletely understood. The results explain the characteristic changes of the observed lipoprotein profile in terms of the underlying metabolic perturbation and resultant modifications of lipid fluxes in the body. The Murine Lipoprotein Profiler (MuLiP) presented here is thus a valuable tool to assess the metabolic origin of altered murine lipoprotein profiles and can be applied in preclinical research performed in mice for analysis of lipid fluxes and lipoprotein composition.Disturbances of lipoprotein metabolism are recognized as indicators of cardiometabolic disease risk. Lipoprotein size and composition, measured in a lipoprotein profile, are considered to be disease risk markers. However, the measured profile is a collective result of complex metabolic interactions, which complicates the identification of changes in metabolism. In this study we aim to develop a method which quantitatively relates murine lipoprotein size, composition and concentration to the molecular mechanisms underlying lipoprotein metabolism. We introduce a computational framework which incorporates a novel kinetic model of murine lipoprotein metabolism. The model is applied to compute a distribution of plasma lipoproteins, which is then related to experimental lipoprotein profiles through the generation of an  Lipids such as triglycerides and cholesterol are important building blocks and energy suppliers for the body. However, because lipids are hydrophobic they require a matrix to circulate in the bloodstream. This function is fulfilled by lipoproteins. Altered lipoprotein metabolism is known to be associated with disease, for instance there is a well-known association between abnormal lipoprotein-mediated cholesterol transport and atherosclerosis. This change in lipoprotein metabolism is reflected in altered lipoprotein size and lipid composition as illustrated by a lipoprotein profile. We developed a mathematical approach, the Murine Lipoprotein Profiler, that links changes in lipoprotein profiles to alterations in lipoprotein metabolism. The model is developed to provide insight into the mechanisms underlying altered lipoprotein profiles in preclinical research in mice. The model can be used to gain further understanding of how a change in the lipoprotein phenotype can result from changes in lipoprotein metabolism. The transport of lipids between mammalian tissues is largely facilitated by lipoproteins. Lipoproteins are spherically organized protein-lipid compounds that, unlike the individual lipids, are soluble in blood. To achieve this vital property the outer shell of the lipoprotein is a surface layer consisting mainly of phospholipids (PL), free cholesterol (FC) and proteins. The most hydrophobic lipids are stored in the core of the particle which consists largely of triglycerides (TG) and cholesteryl ester (CE).The body produces three classes of lipoproteins Abnormalities of lipoprotein concentration, size and composition are known risk factors for cardiovascular diseases. More specifically, a low concentration of HDL cholesterol and/or a high concentration of low density lipoprotein (LDL) particles, as often observed in the Metabolic Syndrome and Type II Diabetes, is associated with an increased risk of atherosclerosis Lipoprotein size, composition and concentration can be quantified in a lipoprotein profile. In preclinical research, profiles are generated to analyse the impact of genetic, dietary and pharmacological interventions on the lipoprotein phenotype. These profiles are generally generated by means of fast protein liquid chromatography (FPLC), a method for size-based lipoprotein separation from serum or plasma in silico FPLC profile from the model.The application of computational methods provides a powerful tool to retrieve insight into the complex relationship between lipoprotein metabolism and lipoprotein profiles. In recent years, two detailed computational models of human lipoprotein metabolism have been developed that relate lipoprotein distributions to underlying metabolism Due to the common generation of FPLC profiles in preclinical research of cardiometabolic diseases, MuLiP is widely applicable. The availability of lipoprotein production and composition data e.g. in  and FPLCIn this study, the model was first developed for wild-type C57Bl/6J mouse data. Following the successful description of the wild-type profile, model performance was evaluated by prediction of the profiles of several transgenic mouse models commonly used in preclinical cardiovascular research. Finally, the model was applied to analyse phenotype changes in profiles obtained from C57Bl/6J mice that were treated with the anti-atherosclerotic Liver X receptor (LXR) agonist T0901317 Two types of data were incorporated to develop the computational model: the experimentally determined VLDL-TG production, and the FPLC profile of plasma lipoproteins.The FPLC profile was obtained from moderately fasted C57Bl/6J mice on a chow diet. The FPLC profile was collected as part of an extensive dataset, which was previously published in VLDL-TG production was determined following administration of Triton WR-1339 (0.5 g/kg body weight).FPLC profiles of three transgenic mouse models were retrieved from literature for model analysis and validation. The scavenger receptor class B type 1 (SR-B1) knock-out mouse Phospholipid transfer protein (PLTP) knock-out mice display decreased plasma cholesterol levels in silico to qualitatively evaluate the results of simulation of a transgenic mouse model.While the deficiency of both previous mouse models is found in HDL metabolism, the low density lipoprotein receptor (LDLr) knock-out mouse  has a deFor computational analysis of the changes in murine lipoprotein metabolism in response to a pharmaceutical intervention, profiles of C57Bl/6J mice treated with LXR agonist T0901317 were analysed. FPLC profiles of treated mice, as well as the VLDL-TG production, were taken from the dataset described in in silico profile  is based on the number of molecules of core components (denoted by # TG and # CE respectively), the volumes of a TG and a CE molecule .The series of differential equations in the HDL sub-model can be written asi, j), consists of both an increase due to lipoprotein production and an increase due to remodelling of existing lipoproteins. Lipoprotein uptake and lipoprotein remodelling are a function of lipoprotein concentration and can be a function of lipoprotein composition and/or lipoprotein size.The concentration of particles is determined by production, remodelling, and catabolism. The positive term of the differential equation, the increase of lipoproteins with indices . k-th type of HDL particle, and k-th type of particle to the HDL production. In order to preserve the definition of i and j and lipid content and the variability of the grid dimensions in the model.The production of HDL in the framework is determined based on experimental data. The TC content of produced HDL is defined by t change . This isprod, catabolism is represented by upt and the remodelling steps are indicated by lip (lipolysis), sel (selective uptake), chol (accumulation of TC) and trig (accumulation of TG).The general differential equation of the HDL sub-model  was exteHDL selective uptake is dependent on particle size and relative CE content. HDL lipolysis is a function of relative TG content. HDL TG and TC accumulation are a function of the rate of surface remnant entry into the system. HDL catabolism is inversely proportional to HDL size. Thus, HDL production is a function of 2 parameters  the HDL lipolysis equation, which is presumed to be active on VLDL as well as HDL, and (2) a VLDL specific lipolysis equation, which is a function of VLDL size. The function of CE uptake from VLDL is chosen equivalent to HDL, but as the proteins involved are presumed different the parameter of the function is estimated separately for HDL and VLDL. VLDL catabolism is defined by (1) a constant catabolism term and (2) a surface area dependent catabolism function. VLDL production is defined by the single diameter parameter. VLDL lipolysis is described by four parameters. These are divided into the two parameters of the universal lipolysis function which have the same values as in the HDL sub-model and two parameters of the VLDL-specific lipolysis function. VLDL selective uptake is described by one parameter. The catabolism equations contain a total of four parameters. This brings the total model to 2×6 equations defined by 16 parameters, describing the concentration of 2×320 lipoprotein state variables.in silico size with FPLC fraction size range. FPLC fractionated size range is determined by calibrating the location of the VLDL, LDL and HDL peaks with their experimentally determined sizes in FPLC fractions have been separated based on their diameter, according to In this equation, rameter  , and parThe calibration function is described by nm (HDL) .in silico lipoprotein profile, the diameter of the particles in the computational model is first calculated, according to i and j is determined. Finally, numerical integration between the fraction boundaries as expressed in i and j is performed to determine the number of simulated lipoproteins in each fraction. Multiplication by the TG or TC content of the lipoproteins results in in silico TG and TC profiles. The in silico profiles of PL, FC, CE, HDL and Apo B containing lipoproteins are generated through the same procedure. The calculation of the in silico profile is further visualized in To calculate the lsqnonlin. The cost function is composed of a sum of squared residuals weighed with factors based on experimental data from literature  is the global optimum, while the other (to which X1 belongs) is a local optimum. The optima differ mainly in the size of nascent VLDL and the selective uptake parameter, as is illustrated in From analysis of the HDL sub-model parameter values, we concluded that the optimized ratio between five kinetic HDL parameters  involves an extension in HDL remodelling, in particular the HDL TC accumulation equation. The cholesterol uptake equation is elaborated to include additional uptake for large lipoproteins. The equations represent a mechanism whereby Apo E may stimulate the uptake and esterification of cholesterol, e.g. by activation of LCAT activity The second extension (E2) that was tested modifies HDL catabolism by incorporating uptake of large, Apo E-containing HDL by Apo E-binding receptors, such as the the LDL receptor The third extension (E3) expands HDL catabolism to include the additional appearance of larger than normal HDL particles The extended models comprise an addition of two or three to the 15 parameters in the original model. The extensions to the HDL model are visualized in Parameter estimation of the extended models was performed by optimizing the cost function as described in In To identify differences between the three tested models, HDL lipid fluxes are plotted for all accepted parameters sets in The well-established association between plasma lipoprotein concentrations and disease risk underscores the need to quantitatively analyse the factors determining lipoprotein distribution. In preclinical research, mouse models are often used to study the effect of a treatment on lipoprotein metabolism and disease risk. However for mice the computational tools available for human lipoprotein distributions  are abseFor many years, the interpretation of tracer experiments in humans has been aided by compartmental models et al.et al.Two models of human lipoprotein metabolism have been proposed that assume a semi-continuous distribution of lipoprotein components Previous models are inapplicable to murine lipoprotein profiles for several reasons. First of all, to create a complete FPLC profile VLDL, LDL and HDL should all be described by the model. However, the majority of existing models focus on a single major lipoprotein class. Additionally, the models include assumptions of lipoprotein composition which are not suitable to describe the composition of murine lipoproteins. Finally, several differences between human and mouse (fasting) lipoprotein metabolism preclude human lipoprotein metabolism models from application to murine physiology. For instance, in mice HDL contains the majority of cholesterol present in plasma. In humans LDL is the primary cholesterol carrier In contrast to the aforementioned models, our novel computational model was designed specifically for the analysis of profiles obtained from mice. This required a novel model of murine lipoprotein metabolism. Future applications of MuLiP will require the integration of new data, extension of the model and therefore re-optimization of model parameters. Therefore, computational complexity and speed were important design criteria.A coarse-grained non-linear description of the lipoprotein composition space was applied to reduce computation time and distribute the data evenly over the model. Both the relation between fraction number and lipoprotein size and the relation between lipoprotein diameter and lipid content are non linear. In the case of a linear grid, these relations will result in an imbalance in the large amount of states corresponding to a single fraction for fractions on the left-hand side of the profile, which correspond to a relatively large diameter range. The flexibility of the lipoprotein composition is ensured through the inclusion of both CE and TG as variables and inclusion of multiple remodelling processes. The metabolic model has been designed to focus on lipoproteins of which the FPLC profile contains most detail, e.g. spherical HDL as opposed to discoïdal HDL. By including VLDL, LDL and HDL, different aspects of lipoprotein metabolism can be examined simultaneously. The model is capable of providing detailed information on the metabolism of a certain (sub)class of lipoproteins. MuLiP is also capable of describing the large compositional variation observed in murine lipoproteins during genotypical or pharmaceutical interventions, such as the ones described in this study.in silico peripheral lipolysis is “turned off.” In in silico is found to be relatively small. This is in accordance with literature data that quantifies the reduction of the VLDL fractional catabolic rate following injection of a lipolysis inhibitor at 90% et al.: et al.: The framework was developed for analysis of lipoprotein metabolism based on two distinct data types: FPLC profiles (TC and TG) and VLDL-TG production flux. This combination of data provides the types of information necessary for the application of a detailed computational model of lipoprotein metabolism. The FPLC profile contains information on lipoprotein concentration, size and lipid content. The VLDL-TG production provides a VLDL sub-model flux which allows absolute determination of lipoprotein kinetics FPLC is a technique used to separate lipoproteins based on size A second challenge of FPLC profiles reported in the scientific literature is that most studies only report a single measurement of an FPLC profile. FPLC profiles are highly reproducible Murine lipoprotein metabolism in MuLiP is described by the interconnected VLDL and HDL sub-models. The VLDL sub-model describes VLDL and LDL content, composition and metabolism. We note that the lipoproteins in the VLDL sub-model can be computationally separated into VLDL and LDL metabolism. The low concentrations of LDL in mice complicate the analysis of LDL metabolism via an FPLC profile. However, by coupling VLDL and LDL metabolism we increase the information available on LDL metabolism and the associated risk of cardiovascular disease. The HDL sub-model describes the metabolism of spherical HDL. Both metabolic sub-models take into account lipoprotein heterogeneity as they are functions of lipoprotein composition and size. The composition of lipoproteins in the model is based on the TG and CE content of the particles. The remaining lipid constituents of the lipoproteins are calculated from the TG and CE content of the lipoprotein. The interpolation functions for this calculation are obtained from experimental data in silico SR-B1 knock-out profiles  the catabolism or remodelling has been changed. Finally, the extended models can be used to predict the response of an LXR agonist treated mouse when a second intervention or genetic perturbation is applied. In In the future, MuLiP could be used as an additional analysis tool for FPLC profiles. While processes are currently incorporated into the model in a phenomenological manner, isolating the effect of a gene or protein on lipoprotein metabolism will require the inclusion of more (flux) data, model expansion and parameter (re-)optimization. In cases where the VLDL production differs substantially from the assumptions made in this study, the implementation of a case-specific VLDL production distribution may be necessary. We note that with data of nascent VLDL composition and particle size distribution a novel VLDL production type can be derived and implemented without further model adaptation.Another genetic modification commonly used in mouse models is the addition of CETP In conclusion, we developed a computational strategy to analyse FPLC profiles based on mouse lipoprotein metabolism and composition. The model predicts lipoprotein production, remodelling and catabolism fluxes which collectively determine changes in lipoprotein profiles. Following initial application of the model to FPLC profiles of the C57Bl/6J mouse, it was used to successfully predict phenotypes of transgenic mouse models commonly used in cardiovascular research. Furthermore, the model was applied to analyse and elucidate the complex phenotypes resulting from a pharmacological activation of the nuclear receptor LXR. MuLiP can contribute to insight into changes in lipoprotein metabolism underlying observed changes of a lipoprotein profile.Text S1Additional calculations. Extended calculation of CE index j, calculation of the free cholesterol content and phospholipid content and overview of the compositional model.(PDF)Click here for additional data file.Text S2Wild-type model equations. Derivation and equations of the wild-type HDL and VLDL sub-models.(PDF)Click here for additional data file.Text S3FPLC profile calculation. Steps 2 and 3 of the calculation of the FPLC profile. Both the calculation of the concentration FPLC profiles and the calculation of the flux FPLC profiles is explained.(PDF)Click here for additional data file.Text S4Wild-type model parametrisation. In this text the cost function, the parameter transformation, model simulation and the analysis of the results are discussed. Also, the resulting parameter values are reported.(PDF)Click here for additional data file.Text S5Wild-type model analysis. This text describes the performed re-sampling of parameter sets, the profile likelihood, the comparison of parameters with values from literature and additional information on the knock-out phenotypes.(PDF)Click here for additional data file.Text S6LXR model development. Derivation and equations of the adaptations and extensions included in the computational models of the LXR activated mouse.(PDF)Click here for additional data file.Text S7LXR model parametrisation. Parameters of the extended LXR models.(PDF)Click here for additional data file.Text S8Supplemental analyses of the LXR model. Additional visualisations of the parameters and fluxes of the LXR models. Simulations of a knock-out in the LXR activated models.(PDF)Click here for additional data file.Text S9Flux FPLC profiles. Flux FPLC profiles of wild-type, knock-out, and 14 days LXR activated models.(PDF)Click here for additional data file.


Assessing brain activity during complex voluntary motor behaviors that require the recruitment of multiple neural sites is a field of active research. Our current knowledge is primarily based on human brain imaging studies that have clear limitations in terms of temporal and spatial resolution. We developed a physiologically informed non-linear multi-compartment stochastic neural model to simulate functional brain activity coupled with neurotransmitter release during complex voluntary behavior, such as speech production. Due to its state-dependent modulation of neural firing, dopaminergic neurotransmission plays a key role in the organization of functional brain circuits controlling speech and language and thus has been incorporated in our neural population model. A rigorous mathematical proof establishing existence and uniqueness of solutions to the proposed model as well as a computationally efficient strategy to numerically approximate these solutions are presented. Simulated brain activity during the resting state and sentence production was analyzed using functional network connectivity, and graph theoretical techniques were employed to highlight differences between the two conditions. We demonstrate that our model successfully reproduces characteristic changes seen in empirical data between the resting state and speech production, and dopaminergic neurotransmission evokes pronounced changes in modeled functional connectivity by acting on the underlying biological stochastic neural model. Specifically, model and data networks in both speech and rest conditions share task-specific network features: both the simulated and empirical functional connectivity networks show an increase in nodal influence and segregation in speech over the resting state. These commonalities confirm that dopamine is a key neuromodulator of the functional connectome of speech control. Based on reproducible characteristic aspects of empirical data, we suggest a number of extensions of the proposed methodology building upon the current model. Our knowledge of brain activity and network organization during complex motor behaviors in humans relies mainly on neuroimaging studies. However, the majority of available brain imaging methods are not feasible for quantifying the neural processes that occur on very short time-scales at the microscopic level. To address this shortcoming of functional MRI, we designed a mathematical model, which simulates brain activity using local ensembles of neurons and physiologically meaningful variables, such as cellular membrane potentials and ion channel relaxation times. We further incorporated dopaminergic function into our model as a neuromodulator of the dynamic organization of brain networks. We applied our model to examine brain networks controlling human speech and language production. We present a rigorous mathematical proof, which establishes the theoretical validity and solvability of the presented model, and we discuss the influence of dopaminergic transmission on simulated brain activity. We show that our model successfully reproduces characteristic changes seen in empirical data between the resting state and speech production. Our results indicate that the proposed mathematical model may be used as a platform for future studies to investigate the specific impact of certain pathologies within the dopaminergic pathways and their effect on global network dynamics. Indeed, neural simulations did fit well with data from various human imaging modalities, such as magnetoencephalography (MEG) Computational neuroscience takes a grounds-up approach to understand complex neural phenomena by investigating the underlying activity of neurons themselves. Starting from the basic neural model of Hodgkin and Huxley Given that functional activity may be affected by neurotransmitters . The basic model describing current flows across neural membranes in region Following Breakspear et al. Assuming that the ion channel specific opening-thresholds are normally distributed with mean Note that the basic model (1) consists exclusively of uncoupled equations, i.e., the membrane potential of neurons in region The original model (8) uses a scalar parameter We set A second extension to the original model was incorporated to simulate the effects of speech-induced dopamine release, as shown previously in real data We modeled the direct dopaminergic pathway from the substantia nigra, pars compacta (SNc) to the LMC To reflect the positive feedback of neural firing in the SNc on dopamine release we define As mentioned above, dopamine was assumed to affect the firing of the LMC by altering neural ion channel permeability. Thus, the effect of dopamine on potassium channels can be seen as a dependence of the gain in Finally, we modeled the impact of dopamine on calcium and sodium channels in the LMC using the gain In the absence of dopamine we have To establish a closed form representation of the full model, let Similarly, let We used time discrete approximation techniques to simulate sample paths of the SDE system (20). Extensive numerical experiments revealed pronounced non-linear dynamics of the model, which motivated the use of a higher order solution scheme. We encountered numerical instability of the widely used strong order 1.0 Milstein scheme To establish a time discrete approximation of the solution to (20), we started by defining a discretization of the interval The following considerations are based on the family of solution schemes presented in [Rearranging terms, (21) can be simplified to Note that Thus, an approximate solution of (20) was recursively computed following scheme (24) with auxiliary quantities (22) and (26).Note that (24) requires three evaluations of the drift term In order to produce measureable changes in extracellular dopamine levels, which reflect rapid phasic dopamine release during a behavioral task or a pharmacological challenge, the dopaminergic axons must be stimulated at frequencies of 10-20 Hz or greater The simulations shown below have been run on a Mid 2010 Mac Pro  under OS X 10.9.1. All codes have been written in Python The raw model output was converted to a blood oxygen level-dependent (BOLD) signal and compared to functional brain activity data in healthy volunteers. We used fMRI data of 20 right-handed monolingual English speaking subjects with no history of neurological, psychiatric, voice, or respiratory problems . Based on the same 70 ROIs, the DTI data were processed using the FATCAT Toolbox of AFNI software The coupling matrix Below, we start by showing existence and uniqueness of solutions to the model (20) (Theorem 1). Once this fundamental result is established, we present simulations generated by the model and analyze it with respect to empirical fMRI data.The following result guarantees unique solvability of the model (20).Theorem 1.For  and  let . Then the system (20) has a unique -continuous solution .Proof. If we show boundedness and Lipschitz continuity of We start by proving that Next, we show that i-th row of the matrix i-th component Weights connected to region Using (30) we further obtain Finally, we establish Finally, by (12) we have Combining estimates (38), (40) and (42) for This together with the definition (7) of Having established existence and uniqueness of solutions to the model (20), we now present simulations corresponding to the resting state and dopamine modulation and compare them to empirical fMRI data.Using the coupling matrix described above, brain activity was simulated corresponding to the resting state and task-induced dopamine release. A list of all used parameters is provided in In both resting-state and task simulations, complex spatio-temporal patterns of activity emerged. The raw model output was converted to BOLD signals as detailed above. om above , Chap. 2Pairwise interactions in the simulated BOLD signals with and without dopamine modulation were quantified by computing NMI coefficients for each pair of ROI time-series. Analogously, NMI matrices were computed for the group-averaged resting-state and speech production BOLD data. This gave rise to four  speech) . Visual In the following, we discuss simulated and empirical functional connectivity using the framework of graph theory. Interpreting functional connectivity matrices as graphs allowed us to not only reveal the functional topology and connectivity architecture of data and model but to also rigorously quantify the observed differences using well-established network metrics (see Supporting Information). By interpreting the 70 ROIs as nodes The four weighted, undirected networks were analyzed following the concepts of functional integration, segregation, and influence As mentioned above, the local clustering coefficient . Thus,   exhibiteficient  . We founnetworks . This waWe considered functional integration of the NMI networks by evaluating values of local efficiency  . For fulWe presented an extension of a model of neural assemblies proposed by Breakspear et al. In the context of the model, we assumed the difference between the resting state and speech production to be solely given by a modulation of dopamine levels in the LMC via a direct input from the SNc. Thus, the model was oblivious to task-related effects caused by any neurotransmitter other than dopamine. Importantly, we observed pronounced differences between the resting state and task production in simulations. This finding may be interpreted as an indication of the profound physiological impact of dopamine on brain dynamics.It is remarkable that altered neural firing rates within the bilateral LMC only were sufficient for the entire simulated neural population to exhibit changes in its temporal dynamics. We attribute these observed task differences to dopamine driving neural dynamics via the coupling matrix To quantify the impact of dopamine release on the entire neural mass, we used functional connectivity and graph theory analysis and interpreted the results as a stationary synopsis of the global effects of dopamine modulation. The graph theoretical analysis of the functional connectomes revealed a number of similarities between the model and data. Due to the slightly higher variability of NMI coefficients, especially during the rest,  nodal stSimilarly, local efficiency showed good qualitative agreement between simulated and empirical connectomes, thus the model mimicked functional integration patterns seen in the experimental data. However, both model and data failed to show increased network segregation and integration compared to random graphs during rest but showed consistently larger values than null model networks during speech production . Thus, Having tested the model for its efficacy in reproducing essential features of real data from healthy humans during speech production, the next step should be an examination of clinical relevance of the proposed neural population model. This may be achieved by incorporating ‘lesions’ into a simulated network of interest to investigate the extent of inter-regional influences coupled with dopaminergic transmission in a range of neurological and psychiatric disorders, such as Parkinson's disease, dystonia, schizophrenia, etc.Furthermore, the model's use is not limited to human applications Since most parameters used here were taken from literature, some inferences about trajectories of isolated regions can be formulated based on the exhaustive analytical treatment of the original model Given the demonstrated differences in functional connectivity across the entire experimental time in simulations of resting versus speech conditions, the question arises as to what extent dopamine altered function on small versus long time scales within the tasks. Our results indicate that dopamine may influence dynamics on long time scales. This may suggest that rapid temporal release of dopamine, as evidenced by the spontaneous dopamine release incorporated during each time-step in the model, may be involved in slow plastic responses. Thus, it is tempting to speculate that a future adaption of the proposed dopamine model might yield further insight into the learning and adaptation involved in voluntary behaviors, particularly given dopamine's involvement in learning and motivational behavior in other tasks.Finally, models simpler than the one considered in this paper are capable of reproducing empirical functional connectivity. In fact, a recent study showed that a stationary model of resting-sate functional connectivity explains functional connectivity better than more complex models We conclude that a regional model that includes dopamine release, reuptake, and modulation of ion channels significantly alters the behavior of an otherwise unmodulated, resting state neural population model. This work thus combines a small-scale basic cellular biology understanding of dopamine to alter macroscopic behavior of neuronal systems with nontrivial structural circuity, and presents meaningful global simulated fMRI network behavior. Region-specific analysis warrants the identification of specific effects of neuromodulation on task-based networks for speech and other dopamine-modulated voluntary behaviors.Text S1Hemodynamic model and network metrics. Details regarding the hemodynamic model used to convert the raw model output to BOLD signals as well as a short description of the used network metrics and the construction of the random networks.(PDF)Click here for additional data file.


The cyst in mixed dentition stage cause expansion of buccal cortex, displacement of teeth and may present as case of infection. The cyst in periradicular region of deciduous molar are of frequent occurrence. The differential diagnosis of this lesion is radicular cysts of deciduous molar: developmental or infammatory dentigerous cyst of corresponding unerupted premolar. After going through the available literature of radicular cyst of deciduous molars and dentigerous cysts of developing premolars in mixed dentition we studied the five cases of cyst in periradicular region of deciduous molars in mixed dentition retrospectively for the diagnostic dilemma of radicular cyst verses dentigerous cyst. In conclusion, we can set some criteria for the diagnosis which is particularly important for treatment and for conservation of developing premolar.How to cite this article: Manekar VS, Chavan A, Wadde K, Dewalwar V. Cysts in Periradicular Region of Deciduous Molars in Mixed Dentition: Retrospective Study of Five Cases. Int J Clin Pediatr Dent 2014;7(3):229-235. This is particularly important for treatment, prevention of localized malocclusion and conservation of premolar toothbud. Aim – Retrospective study of cases of cyst in periradicular region of deciduous molars in mixed dentition. Objective – To set criteria for diagnosis of radicular cyst vs dentigerous cyst. Inclusive criteria-the cases diagnosed as cyst in posterior jaw of mixed dentition with radiolucency in periradicular region of deciduous molars with corresponding premolar bud in lesion. Cases reported to Department of Oral and Maxillofacial Surgery, at Government Dental College and Hospital, Mumbai were studied. There were five patients with diagnosis of infected cyst with deciduous molar region in mixed dentition; they were comparatively studied for their clinical presentation, radio-graphic presentation, and differential diagnosis, outcome of treatment and for criteria of definitive diagnosis of radicular cyst of deciduous molar or dentigerous cyst of developing premolar.The cyst in periradicular region of deciduous molars in mixed dentition present with the symptoms of swelling, pus discharge, pain and over retained teeth. The expansion of buccal cortex and displacement of corresponding developing premolar is a common presentation. These cysts can be radicular cysts of deciduous molars or; developmental or infammatory dentigerous cysts of corresponding premolar or supernumerary tooth bud. In case of carious or endodontically treated deciduous molar, there is possibility of radicular cyst of deciduous molars or inflammatory dentigerous cyst of corresponding premolars. After going through the available literature of radicular cyst of deciduous molars and dentigerous cysts of premolars we studied the five cases of cyst in periradicular region of deciduous molars in mixed dentition treated in our department for the diagnostic dilemma of radicular cyst Case 3 is cystic lesion with carious 85, around its peri-apical and furcation; 45 tooth engulfied in well corticated lesion . MarsupiCase 5 is cystic lesion with endodontically treated, over retained 85. Out of five cases reported here three were labeled as dentigerous cyst and two were labeled as radicular cyst. The histopathological report of all cases is infected dental cyst. Hence, histopathology was not useful for diagnosis. The diagnosis is done on clinical, radiological and surgical correlation. 1 Cysts associated with deciduous molars are usually in their periapical region and involve the developing premolar teeth and the patients are bellow 12 to 13 years that is before eruption of premolars or in later age group with over retained molars and delayed eruption of premolars. Shear (1994) has estimated that about 9% of dentigerous and 1 % of radicu lar cysts occur in the first decade of life, while according to Donath (1985) about 4% of dentiger-ous and less than 1% of radicular cysts appear in this life period. In the study of Lustmann and Shear (1985), of radicular cysts with deciduous teeth in 23 cases, the mandible was affected more frequently than maxilla, and the deciduous molars were the teeth most often involved. In nine cases buccal expansion was noticed and in eight cases permanent buds were displaced. The caries was the most common etiological factor.1 According to Shear, Radicular cysts of deciduous teeth appear to be rare. Radicular radiolucency related to deciduous teeth tend to be neglected and probably resolve after removal of offending tooth.1Radicular cyst is one which arises from the epithelial residues in the periodontal ligament as a result of infam-mation. The infammation usually follows the death of the dental pulp and cysts arising in this way are found most commonly at the apices of the involved teeth.2 Periradicular cysts that have been described in association with pulpotomized primary molars seem to show specific clinical features: large size, rapid growth, buccal expansion, and displacement of succedaneous teeth.3 Dentigerous cyst or follicular cyst is an odontogenic cyst associated with the crown of an impacted, embedded, unerupted or developing tooth. The cyst which encloses the crown of an unerupted tooth is attached to the cervical region of the tooth. It is the second most common type of odontogenic cysts accounting for 14 to 24% of all jaw cysts.4 The relationship of cyst development to the mandibular second primary molars cariously affected or pulpotomized has been stressed.5 There are two possible explanations: (1) that the mandibular molars have a greater susceptibility to caries and, consequently, are more frequently treated; and (2) that a mandibular second primary molar is more closely associated with its successor's follicle; such association can more easily facilitate the spread of infammation in comparison with other primary teeth.6 Shaw et al noted that distinguishing between dentigerous and radicular cysts on histologic grounds is difficult but that a histologic examination may determine whether the lesion is chronic or acute in nature.6 In our experience all five cases shows histological features of infected dental cyst .9 In the periradicular region of pulpotomized deciduous molars, besides the dentigerous cyst, a glandular odontogenic cyst can develop.2Periapical cysts in the primary dentition are located around the roots and in the inter-radicular area; this is in contrast to the periapical location seen in permanent teeth. Infammation and prolonged irritation are apparent causes of, and the trigger for, proliferation of the epithelial rests. This explains why cysts are found in conjunction with necrotic or pulp-treated teeth in the primary dentition.tal cyst  hence hi10 several differences can been found between the radiological features of periradicular cysts and dentigerous cysts: periradicular cysts are (1) frequently unilocular, although occasionally they are multilocular; (2) they are well-defined radiolucencies, located both periradicularly and inter-radicularly; and (3) the pericoronal space of the underlining permanent tooth appears normal, usually with an intervening total or partially distinct cortical layer of bone. On the contrary, dentigerous cysts: (1)generally have no distinct boundaries between the roots of the primary tooth, and the crown of the underlying succeeding tooth; (2) a single, unilocular, well-defined, radiolucent area encloses each kind of cyst; and (3) a radiolucent area that embraces the permanent tooth bud, ill-defined lesion borders, and arrest of the root development are pathognomonic signs of damaged tooth germs.As mentioned by Asian-Gonzélez et al11 state that, treatment modalities range from enucleation to marsupialization. It is imperative that utilization of a conservative approach to treatment of dentigerous cysts that does not involve, sacrifice of the unerupted permanent tooth whenever possible. However, complete eradication of the cyst should never be compromized for saving the permanent tooth bud. In cases in which the permanent tooth is severely damaged, and hopelessly displaced, complete enucleaton of the cyst to include the permanent tooth bud has been recommended .12Ziccardi et al (1997)Criteria of differentiation as from literature and our study are- radicular cyst- carious or endodonticaly treated deciduous molar; more chances of signs of infection, radiolucency around the roots, involving the furcation as well, complete premolar tooth bud looks engulfied in the lesion on OPG.No carious lesion with deciduous molar; severe displacement of involved developing premolar as well as adjacent premolar; radiographically and after excision lesion looks typically around premolar crown, even if it is displaced.Expansion of buccal cortex, case presenting as infection, displacement of teeth; aspiration of straw colored fuid unless infected, resorption of roots of deciduous molars, well defined cystic radiolucency with cortication.vs dentigerous cyst of corresponding premolar. This is particularly important for treatment purpose, for preservation of developing premolar and the localized malocclusion developed due to delayed development. We studied the five cases retrospectively for this diagnostic dilemma, and we could set some criteria – three cases of dentigerous cysts and two cases of radicular cyst. Though the sample size of this study is very small, the distinction noted in cases of radicular cyst of deciduous cyst and dentigerous cyst of developing premolar are enough to laid down the criteria for their diagnosis. Although, the studies with larger sample sizes are recommended.The differential diagnosis of periradicular cyst of deciduous molars with carious lesion or endodontically treated can be radicular cyst; or Infammatory denti-gerous cyst of corresponding premolar. The periradi-cular cysts of intact deciduous molars are developmental dentigerous cysts of corresponding premolars. It is a diagnostic dilemma of radicular cyst of deciduous molar


There is now abundant evidence that the immune system and the brain have close functional interactions in both directions. This review focuses on the influence of the microbiota (the bacteria resident in the gut) on brain function in major depressive disorder (MDD) and related syndromes.The gut and the central nervous system communicate partly through the autonomic nervous system (ANS), consisting of the sympathetic  and the parasympathetic  nervous system. The brain integrates inputs from the digestive tract by a central autonomic network that includes the hypothalamus, limbic system and cerebral cortex with output to the ANS and hypothalamic-pituitary-adrenal gland (HPA) stress axis Bonaz, . There aAltered immune responses and increased inflammation have been demonstrated in MDD , which is characterized by chronic recurrent abdominal pain, disorder of brain-gut function may be associated with corticotropin-releasing hormone (CRH) and/or serotonin, since administration of CRH exacerbates the visceral sensorimotor response, whereas inhibition of CRH or serotonin with their respective antagonists or antidepressants is protective Fukudo, . MoreoveIn recent papers Berk et al. , Lucas aEvidence supporting this hypothesis includes the following findings. First, chronic mild stress increases the level of bacterial LPS in the circulation of rats, driving activation of the TLR-4 pathway on blood monocytes  by which microbiotic toxins and their effects are transmitted from the gut to the brain and (ii) what specific mechanisms in the brain are affected. Kéri et al.  stipulatWe can now ask what is the mechanism by which bacterial toxins cross the intestinal endothelium. One established mechanism is provided by sub-epithelial intestinal DCs that insert dendrites between epithelial cells to harvest luminal bacteria or soluble products from the gut lumen  subsequently exported from these bacteria and taken up by intestinal DCs. Indeed, olfactory bulbectomy mice demonstrate chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increased c-Fos activity, serotonin levels, and motility in the colon  mRNA in the brain with increases in the cingulate and prelimbic cortices and reductions in the hippocampus, amygdala and locus coeruleus. It also reduced GABA (Aa2) mRNA expression in the prefrontal cortex and amygdala but increased this measure in the hippocampus. Lactobacillus rhamnosus feeding also reduced stress-induced corticosterone levels and anxiety and depression-related behaviors. These findings were abolished following vagotomy. Thus, the vagus must carry this signal from the gut to the brain. The use of psychobiotics (such as Bifidobacterium infantis) in relieving anxiety and depression associated with IBS is reviewed by Dinan and Cryan  infections may affect the mood in addition to the distress caused by the symptoms. The use of antidepressant medications increases the risk of developing CD infection (Rogers et al., The powerful effect on the microbiota during This paper reviews the present status of the “leaky gut” hypothesis relating to MDD and adds some details of the molecular and cellular mechanisms that may be involved. This hypothesis suggests that a key mechanism involved in MDD may be increased gut permeability, abnormal intestinal absorption of gram-negative bacteria, and subsequent activation of the TLR/NF-κ B pathway in innate immune cells of the gut mucosa, or on neurons themselves. This activation induces the release of pro-inflammatory cytokines with a deleterious effect on a number of brain mechanisms involved in stress. We suggest that exosomes may play a prominent part in this process.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The driving mechanism that is responsible for the uplift of intracontinental mountains has puzzled geologists for decades. This study addresses this issue by using receiver function images across the Chinese Tianshan Mountains and available data from both deep seismic profiles and surface structural deformation. The near-surface structural deformation shows that the Tianshan crust experienced strong shortening during the Cenozoic. The receiver function image across the Tianshan Mountains reveals that the lithosphere of the Junggar Basin to the north became uncoupled along the Moho, and the mantle below the Moho subducted southwards beneath the northern part of the Tianshan Mountains, thereby thickening the overlying crust. Similar deep structures, however, are not observed under the Tarim Basin and the adjacent southern Tianshan Mountains. This difference in the deep structures correlates with geomorphological features in the region. Thus, a new model of mantle subduction, herein termed M-type subduction, is proposed for the mountain-building processes in intracontinental compressional settings. The available geomorphological, geological and seismic data in the literatures show that this model is probably suitable for other high, linear mountains within the continent. Mountains and basins are two types of basic tectono-geomorphologic units on the Earth. How and why mountains on continents uplift has challenged geologists since the late 1800s234567This study focuses on the Chinese Tianshan Mountains .


For management of a symptomatic maxillary lateral incisor with dull pain on chewing, suppurative sinus tract, defective metal-ceramic crown and iatrogenic internal root resorption, an interdisciplinary approach was taken. Two-visit nonsurgical treatment with calcium-enriched mixture (CEM) cement, replacement of metal-ceramic crown with all-ceramic crown and corrective periodontal plastic surgery were included in the treatment plan. Six-month and one-year follow-ups revealed complete resolution of signs and symptoms and radiographic healing. This case report highlights the importance of adequate cooling during crown preparation to preserve the pulp vitality and prevent internal resorptive lesions and also the profound sealing ability and biocompatibility of CEM cement. Internal root resorption (IRR) is defined as the loss of dental hard tissues as a consequence of odontoclastic (dentinoclastic) activity, starting from the inner root canal wall. IRR is usually asymptomatic with slow progression and is detectible upon routine radiographic examination . Many etIn addition to the presence of granulation tissue in the pulp, damage to the odontoblastic layer and the predentin layer, lead to the pathologic entity by the adherence of clastic cells related to resorptive process . Both thThere are different materials, in the market to treat the IRR. One of them is calcium-enriched mixture (CEM) cement, which is a water-based tooth-colored biomaterial , 12. SevThis case report describes an interdisciplinary management of a maxillary lateral incisor with perforating IRR including root canal therapy using CEM cement, replacement of the defective metal-ceramic crown by feldspathic porcelain crown, and periodontal plastic surgery for correction of the existing periodontal defect and elimination of the sinus tract related to IRR.A 20-year-old female with her chief complaint being dull pain upon mastication on the left maxillary lateral incisor was referred to an endodontist. On clinical inspection the tooth was slightly tender to percussion and a suppurating sinus tract was obvious on the buccal gingiva of the tooth . PeriodoCone-beam computed tomography (CBCT), was instructed and showed a perforating lesion leading to circular bone resorption with almost 7-8 mm diameter within the radicular bone . The sinAn interdisciplinary treatment strategy was designated. The following complications were decided to be covered; sealing of the perforative IRR, management of periodontal soft and hard tissues, providing coronal seal and esthetic reestablishment.Patient signed the informed consent. Non-surgical root canal treatment was initiated after local administration of 2% lidocaine containing 1:80000 epinephrine . The tooth was isolated with rubber dam. After preparation of the access cavity, the coronal part of the pulp was found to be necrotic, while bleeding was induced on middle part of the pulp. Working length was determined with radiography and canal instrumentation was conducted to master apical file (MAF) set to #40. Hand K-files  were used to thoroughly clean the pulp space and sever the blood supply. Irrigation was done with 1% sodium hypochlorite . At the end of the first session, calcium hydroxide  powder was mixed with saline to prepare the creamy intra-canal dressing. This would control the bleeding and facilitate the removal of remaining pulpal tissues during the second session. Access cavity temporization was done with light-cured glass ionomer (GI) cement .The second appointment was set 10 days later, when under rubber dam isolation, the remnants of pulpal tissue were removed by chemomechanical preparation. Elimination of tenderness on percussion, hemorrhage, discontinuation of suppuration through the sinus tract and decrease in the size of parolis confirmed the right time for obturation . CEM Cement  was used for canal obturation . The whoAfter the completion of RCT, the patient was referred to a specialist of operative dentistry for crown preparation. After 1 month, the patient was asymptomatic, although the fistula was still present and the patient was unhappy with this situation .The patient had no systemic disease affecting tissue healing. The target area was anesthetized using lidocaine. A Luebke-Oschsenbein flap was prepared using a #15 surgical blade  to avoid the gingival margin and gain the benefits of a three-sided flap. The horizontal incision was carried out 3-4 mm away from the gingival margin and across the mid root extending bilaterally to the mesial and distal periodontium. Two diverging vertical releasing incisions were made at the ends of the horizontal incision extending to the alveolar mucosa to encompass the fistula. The flap was reflected using a periosteal elevator  beyond the area of bone destruction. The scar tissue was dissected from the flap with a blunt-tipped dissecting scissor . The granulation tissue, excess of CEM cement and the irregular borders of the perforation site were smoothened with a round bur  attached to an angulated surgical handpiece . When thThe patient remained symptom-free at one- and three-month follow-ups with good looking appearance of the gingiva, without periodontal pockets and sensitivity to percussion. After 6-  and 12-mThis manuscript represented the successful outcome of a multidisciplinary approach for treatment of a maxillary incisor with perforative IRR. Respecting the principles for dentine preparation such as adequate cooling to preserve the pulp, it is postulated that increase of pulp temperature during crown preparation could probably be the reason for internal resorption in this case .Although intraoral radiography is accurate enough, but superior level of accuracy obtained with CBCT increases the likelihood of correct management of internal resorption due to its ideal validity (ability to correctly detect the presence or absence of the lesion and its type) and reliability (ability to regenerate the similar results) -19. In tSuccessful treatment of IRR necessitates complete cleaning of pulpal space, severance of the blood supply, and filling the whole space with biocompatible materials especially when perforation has occurred , 20. In Removal of irritation source should normally ameliorate the resultant parolis, though over extrusion of debris through the perforation site resulted in impairment of soft tissue healing. That is why periodontal intervention became necessary to correct the parolis. Corrective surgery approach allows practitioner to get direct access to the lesion and perform a mechanical cleaning of the target resorbed defect .Complicated IRR is ought to be covered in interdisciplinary modality of treatment, because each part was managed by the most knowledgeable and experienced practitioner of the field.The interdisciplinary approach offered a systematic plan to manage perforating IRR and saved the tooth.


Surgical treatment to restore full range of motion and full weight bearing after extensive femoral bone resection in patients with primary or metastatic femoral tumours is individually challenging. Especially when the remaining distal or proximal bone is very short, a rigid fixation of an implant is difficult to achieve due to the reverse funnel shape of the metaphysis. Herein, we present a novel implant design using a spreading mechanism in the distal part of the prosthesis for rigid, uncemented fixation in the remaining femoral bone after extensive tumour resection of the femur. We present the outcome of 5 female patients who underwent implantation of this spreading stem after extensive proximal or distal femoral bone resection. There was no radiological or clinical loosening or implant-related revision surgery in our follow-up . This uncemented spreading stem may therefore represent an alternative option for fixation of a prosthetic device in the remaining metaphyseal femur. Primary bone tumours or metastatic lesions of the femur may represent a remarkable surgical challenge, particularly in reconstructing the full weight bearing function of the lower limb with a good pain relief. With extensive bone resections, treatment options such as allograft-prostheses composites, rotationplasty, and endoprosthetic reconstruction by custom made devices or modular systems are well established.Although these options offer a wide spectrum of applications, postoperative complications were observed , 2, inclAccordingly, we investigated a novel prosthetic design using a spreading mechanism of the distal/proximal part of the prostheses for rigid, uncemented fixation in the remaining bone after extensive tumour resection of the femur.Between November 2010 and December 2011, 5 female patients underwent extensive proximal, diaphyseal, or distal femoral resections and implantation of an uncemented femoral spreading stem  . Three pAfter resection of the tumour-affected part of the femur, the end of the wide part of the area of the noningrowth region of the prosthesis above the ingrowth rigid fluted stem abuts at the remaining distal femur end cylinder in order to achieve the best possible apposition to the shaft after spreading the distal flat fins. The spreading flat hydroxyapatite coated fins  are fash Postoperative rehabilitation was as follows: toe touch weight bearing for the first six weeks followed by gradual increase of weight bearing for the next six weeks and no rotational forces during the entire three months.In four out of five cases the TESS- and MSTS-Scores were evaluated between 9.5 and up to 46 months postoperatively. One patient died prior to evaluation of these scores due to metastatic disease. Conventional radiographic evaluation was accomplished from 3.5 months to 46 months (mean 21.46 months) for the longest case. The following table shows the detailed patient data . Within With the development of modern chemotherapy, limb salvage surgery in femoral primary or metastatic lesions is well established. Surgical reconstruction remains a challenge when the remaining part of the femur is short, together with the reverse funnel shape and its inherent problems as to biomechanical forces. To anchor the femoral stem in the remaining femoral bone, cement is most often used –12. SeveA further possible option for reconstruction after massive femoral resection was created by Johnson in 1994 by its Compress® prostheses . Here, tLimitations of our study include the paucity of biomechanical studies that prove extrastability resulting from the spreading stem and the absence of data describing the stability against rotational forces to the spreading stem. However, related to our preliminary clinical experience, rotatory instability does not seem to be a problem in our follow-up. Further, the overall follow-up in this series is short, and the clinical scores vary. This is mainly explained by the advanced (metastatic) stage of the diseases of the patients included, which affected the functional score more than the rigid fixation of the device in the bone.Custom-made prostheses for the femur, which are individually designed and manufactured, offer an additional option in reconstruction after extensive resection of the femur. These prostheses are mostly fixed via cortical flanges or interlocking cross-pins , 13. NevBased on our series, the spreading stem may represent an additional alternative option for fixation of a prosthetic device in the remaining femur after extensive tumour resection. Nevertheless, long-term follow-up of a larger series of patients with this novel implant design is needed to stand the test of time.


Localized nasal, conjunctival and corneal amyloidosis was diagnosed in a 15-year-old pony with nasal and conjunctival masses and severe dyspnoea. Multiple swellings had been evident in the nostrils for at least two years and had gradually increased in size before presentation due to dyspnoea and exercise intolerance. Surgical debulking of the masses was performed and histological examination revealed large amounts of extracellular, hyaline, eosinophilic, Congo red positive material in the lamina propria of the nasal mucosa. A tentative diagnosis of localized nasal amyloidosis was made. The treatment relieved the clinical signs, however, the nasal masses recurred and bilateral conjunctival, papillary masses developed. The horse was euthanized. Nodular nasal and papillary conjunctival masses consisting of rubbery, grey to yellow tissue were found at necropsy. At the limbus this tissue infiltrated and expanded the cornea. The masses consisted of amyloid and moderate infiltrates of T lymphocytes and B lymphocytes were present in the tissue. No predominance of either cell type was observed and no distinct neoplastic mass could be identified. Ultrastructural examination of the nasal mucosa and cornea confirmed the presence of abundant extracellular deposits of non-branching fibrils ranging from 9–11 nm in diameter consistent with amyloid. Immunohistochemistry of amyloid revealed no labelling for AA amyloid, and no peptides representing serum amyloid A (SAA) were detected by microscopic laser dissection and subsequent mass spectrometry. Peptides from immunoglobulin kappa-like light chains were detected and are suggestive of AL amyloidosis, however the results were inconclusive and a final identification of the amyloid protein could not be made.Nasal amyloidosis is a clinical entity of localized amyloid deposits in the horse. Localized amyloidosis involving the conjunctiva of the horse is previously described in only seven cases and the present case is the first case of combined, localized nasal and corneal amyloidosis in the horse. In several reported cases surgical excision has provided clinical improvement and return to normal levels of exercise, while medical treatment has had no effect. The present case however, shows that rapid recurrence and progression of nasal amyloidosis to involve ocular tissues can occur and lead to recurrent respiratory obstruction.The online version of this article (doi:10.1186/s13028-014-0050-6) contains supplementary material, which is available to authorized users. Amyloidosis is a group of disorders characterized by extracellular deposits of hyaline, proteinaceous material which shows characteristic green birefringence under polarized light after staining with Congo red. The different amyloid proteins all form fibrils of beta pleated sheet conformation that are resistant to degradation and hence accumulate in tissues. Amyloid deposits are classified according to the type of protein deposited and as localized or systemic based on tissue distribution . SeveralA 15-year-old Norwegian Shetland pony mare was presented to an equine clinic with marked dyspnoea and bilateral nodular and diffuse swelling of the nasal mucosa at the mucocutaneous junction and rostral nasal concha in June 2008. The nodular and diffuse swelling had been present for at least two years and had gradually increased in size and infiltrated the circumference of the nares to cause markedly reduced luminal diameter of both nostrils. Due to the respiratory difficulties surgical debulking of the tissue was performed. Histological examination of the excised tissue revealed large amounts of extracellular, hyaline, eosinophilic, Congo red positive material in the lamina propria of the nasal mucosa and a tentative diagnosis of localized nasal amyloidosis was made. The surgical treatment improved the clinical signs; however the nodular swellings recurred over the next months and multiple, papillary to nodular, conjunctival proliferations also developed bilaterally. In March 2009 the owners elected to euthanize the pony due to the recurrence of the nodular swellings and a reduced general condition of the animal as the swellings rapidly increased in size. The pony was euthanized and immediately necropsied.et al. .FiguMass spectrometry data did not show a clear identification of the amyloid protein in any of the samples. Several immunoglobulin kappa-like peptides were detected among the most abundant proteins, but also albumin and hemoglobin were high on the list, indicating serum contamination of the sample (Additional file The histological and immunohistochemical findings in this case are highly suggestive of localized, nasal and ocular, amyloid light chain amyloidosis. The lack of immunoreactivity to AA amyloid antibodies and the fact that no SAA peptides were detected by mass spectrometry suggests that a SAA protein origin is very unlikely. Lambda chains predominate in normal horse serum  with a ret al. [et al. [Localized, nasal amyloidosis is a rare clinical entity in the horse with only 23 reported cases Table . Equine et al.  developeet al. . In both [et al.  amyloid In humans, only a single case of combined corneal and conjunctival amyloidosis has been reported in the literature. In this case the amyloid deposits were believed to be secondary to previous ocular trauma; however neither the corneal or conjunctival amyloid deposits were subjected to any form of typing . LocalizImmunohistochemistry and mass spectrometry are used to type amyloid in human medicine, and equine amyloid light chain deposits have been shown to cross-react with some anti-human light chain antibodies, however not consistently ,13. Typiet al. [Clinical signs in this case consisted of dyspnoea and epiphora and are most likely related to the space-occupying effect of the nodular amyloid deposits. In other cases of conjunctival and nasal amyloidosis epistaxis, blood tinged tears, respiratory stertor, nasal obstruction and exercise intolerance have been reported ,12,14,16et al.  and may Primary localized conjunctival, as well as localized nasopharyngeal and laryngo-tracheobronchial AL amyloidosis has been described in humans –29,36. ASurgical debulking of the affected nasal mucosa was performed and initially provided clinical relief in the pony mare. Recurrence occurred relatively rapidly and amyloid deposits also developed in the conjunctivae and cornea prompting the owners to euthanize the horse. This contrasts with previous results as surgical treatment in eight equine cases improved the clinical signs and horses successfully returned to previous levels of performance –10,15,16Progression to systemic AL amyloidosis has not been reported in the horse, however the localized nasal amyloidosis in horses seems to be less strictly limited to the respiratory tract, compared to people, where nasal and conjunctival amyloidosis are distinct entities ,28. One aDonated by G. Husby Professor Emeritus of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.


The Cochrane risk of bias (RoB) tool has been widely embraced by the systematic review community, but several studies have reported that its reliability is low. We aim to investigate whether training of raters, including objective and standardized instructions on how to assess risk of bias, can improve the reliability of this tool. We describe the methods that will be used in this investigation and present an intensive standardized training package for risk of bias assessment that could be used by contributors to the Cochrane Collaboration and other reviewers.This is a pilot study. We will first perform a systematic literature review to identify randomized clinical trials (RCTs) that will be used for risk of bias assessment. Using the identified RCTs, we will then do a randomized experiment, where raters will be allocated to two different training schemes: minimal training and intensive standardized training. We will calculate the chance-corrected weighted Kappa with 95% confidence intervals to quantify within- and between-group Kappa agreement for each of the domains of the risk of bias tool. To calculate between-group Kappa agreement, we will use risk of bias assessments from pairs of raters after resolution of disagreements. Between-group Kappa agreement will quantify the agreement between the risk of bias assessment of raters in the training groups and the risk of bias assessment of experienced raters. To compare agreement of raters under different training conditions, we will calculate differences between Kappa values with 95% confidence intervals.This study will investigate whether the reliability of the risk of bias tool can be improved by training raters using standardized instructions for risk of bias assessment. One group of inexperienced raters will receive intensive training on risk of bias assessment and the other will receive minimal training. By including a control group with minimal training, we will attempt to mimic what many review authors commonly have to do, that is—conduct risk of bias assessment in RCTs without much formal training or standardized instructions. If our results indicate that an intense standardized training does improve the reliability of the RoB tool, our study is likely to help improve the quality of risk of bias assessments, which is a central component of evidence synthesis.The online version of this article (doi:10.1186/2046-4053-3-144) contains supplementary material, which is available to authorized users. Systematic reviews and meta-analyses of randomized clinical trials (RCTs) are central to evidence-based clinical decision-making, 2. RCTsIf results of RCTs included in a meta-analysis are biased, so will the results of the meta-analysis, 4. To aIn 2008, the Cochrane Collaboration published a tool and guidelines for the assessment of risk of bias in RCTs, 6. The Several studies reported that the reliability of the risk of bias tool is low–10. ReliWe recently found that the reliability of the risk of bias tool might be improved by intensive standardized training of raters. HoweverThis is a pilot study. The first component is a systematic literature review to identify RCTs that will be used for risk of bias assessment. Using the identified RCTs, the second component of our investigation is a randomized experiment, where raters will be allocated to two different levels of training on risk of bias assessment: minimal training and intensive standardized training.We will search PubMed from inception using database-specific search strategy Figure . We willWe will use standardized, piloted data extraction forms to extract information on publication year, sample size, and type of intervention. We will assess risk of bias for selected items of the risk of bias tool, namely sequence of generation, allocation concealment, blinding , and incomplete outcome data. Although a potentially important source of bias, we will not assess selective outcome reporting in our study due to feasibility issues with such assessment. Within http://www.randomizer.org/form.htm) to allocate two students to minimal training and two to intensive training. Randomization will be performed remotely by one of the authors (SAO), who had no contact with the students. Students will not be informed to which training group they have been randomized, and they will be instructed not to discuss their training with each other to minimize the risk of ‘contamination’[Six raters will assess the risk of bias of every included trial. Four of these raters are doctoral students of physical therapy without previous experience in risk of bias assessment, and two raters are experienced risk of bias assessors. The experienced raters have each been involved in over 15 systematic reviews that included methodological quality assessment. We will use simple randomization , and they will be shown results of empirical investigations that observed the effect of these biases in clinical treatment effects. The raters will be provided with an article, as an optional reading material, that describes the risk of bias tool, which sRaters allocated to intensive training will receive the same lecture for about 60 min. In addition, they will receive standardized instructions on how to assess each of the domains . We will obtain written informed consent from each student rater. This study was not registered in PROSPERO.We will tabulate the characteristics of included trials and the risk of bias assessments of the three groups of raters ; before and after consensus. We will then calculate the chance-corrected weighted Kappa with 95% confidence intervals to quantify agreement within and between the three groups of raters for each of the domains of the risk of bias tool. To calculate between-group Kappa agreement, we will use risk of bias assessments from pairs of raters after resolution of disagreements. Kappa values range from 0 to 1, with higher values indicating higher agreement between raters. To calculate the weighted Kappa agreement, risk of bias classification will be ordered as follows: low, unclear, and high risk of bias. Criteria proposed by Byrt will be P-values[The main outcome of our study is the comparison of the accuracy of assessment across groups, that is, a comparison of the agreement between raters receiving intensive training and experienced raters with the agreement between raters receiving minimal training and experienced raters. To compare agreement of raters under different training conditions, we will calculate the differences between Kappa values for within- and between-group agreement. To address deviations from normal distribution, we will bootstrap the difference in Kappa values using bias correction and acceleration to derive 95% confidence intervals and P-values. Please P-values will be two-sided. Analysis will be conducted in STATA, release 13 .To explore whether quality of reporting influences agreement, we will stratify the analysis according to publication date Additional file 1:Assumptions of the power analysis.(DOCX 13 KB)Additional file 2: