Mindfulness: top-down or bottom-up emotion regulation strategy?
The beneficial clinical effects of mindfulness practices are receiving increasing support from empirical studies. However, the functional neural mechanisms underlying these benefits have not been thoroughly investigated. Some authors suggest that mindfulness should be described as a 'top-down' emotion regulation strategy, while others suggest that mindfulness should be described as a 'bottom-up' emotion regulation strategy. Current discrepancies might derive from the many different descriptions and applications of mindfulness. The present review aims to discuss current descriptions of mindfulness and the relationship existing between mindfulness practice and most commonly investigated emotion regulation strategies. Recent results from functional neuro-imaging studies investigating mindfulness training within the context of emotion regulation are presented. We suggest that mindfulness training is associated with 'top-down' emotion regulation in short-term practitioners and with 'bottom-up' emotion regulation in long-term practitioners. Limitations of current evidence and suggestions for future research on this topic are discussed.


Composite resin layering and placement techniques: case presentation and scientific evaluation.
Composite resin technology has evolved, providing clinicians with the ability to deliver more natural-looking restorations for their dental patients. The evolution of layering techniques and internal staining procedures has further improved composite resins' potential for optimal results. This article discusses difficulties associated with traditional composite layering and staining, and it presents in vitro research that supports a novel layering approach. Specifically, the cut-back, etch, bond, and layer technique (CEBL) is introduced as an alternative to freehand layering. This article presents current concepts for composite resin layering and bonding technology. Upon reading this article, the reader should: Understand the clinical protocol for resin layering and bonding. Recognize the scientific advantages associated with composite layering with the CEBL technique.


A graphical tool for locating inconsistency in network meta-analyses.
In network meta-analyses, several treatments can be compared by connecting evidence from clinical trials that have investigated two or more treatments. The resulting trial network allows estimating the relative effects of all pairs of treatments taking indirect evidence into account. For a valid analysis of the network, consistent information from different pathways is assumed. Consistency can be checked by contrasting effect estimates from direct comparisons with the evidence of the remaining network. Unfortunately, one deviating direct comparison may have side effects on the network estimates of others, thus producing hot spots of inconsistency. We provide a tool, the net heat plot, to render transparent which direct comparisons drive each network estimate and to display hot spots of inconsistency: this permits singling out which of the suspicious direct comparisons are sufficient to explain the presence of inconsistency. We base our methods on fixed-effects models. For disclosure of potential drivers, the plot comprises the contribution of each direct estimate to network estimates resulting from regression diagnostics. In combination, we show heat colors corresponding to the change in agreement between direct and indirect estimate when relaxing the assumption of consistency for one direct comparison. A clustering procedure is applied to the heat matrix in order to find hot spots of inconsistency. The method is shown to work with several examples, which are constructed by perturbing the effect of single study designs, and with two published network meta-analyses. Once the possible sources of inconsistencies are identified, our method also reveals which network estimates they affect. Our proposal is seen to be useful for identifying sources of inconsistencies in the network together with the interrelatedness of effect estimates. It opens the way for a further analysis based on subject matter considerations.


DNA adducts and cancer risk in prospective studies: a pooled analysis and a meta-analysis.
Bulky DNA adducts are biomarkers of exposure to aromatic compounds and of the ability of the individual to metabolically activate carcinogens and to repair DNA damage. Their ability to predict cancer onset is uncertain. We have performed a pooled analysis of three prospective studies on cancer risk in which bulky DNA adducts have been measured in blood samples collected from healthy subjects (N = 1947; average follow-up 51-137 months). In addition, we have performed a meta-analysis by identifying all articles on the same subject published up to the end of 2006, including case-control studies. In the pooled analysis, a weakly statistically significant increase in the risk of lung cancer was apparent (14% per unit standard deviation change in adduct levels, 95% confidence interval 1-28%; using the weighted mean difference method, 0.15 SD, units higher adducts in cases than in controls). The association was evident only in current smokers and was absent in former smokers. Also the meta-analysis, which included both lung and bladder cancers, showed a statistically significant association in current smokers, whereas the results in never smokers were equivocal; in former smokers, no association was detected. The results of our pooled and meta-analyses suggest that bulky DNA adducts are associated with lung cancer arising in current smokers after a follow-up of several years.


Application of a Poisson deep neural network model for the prediction of count data in genome-based prediction.
Genomic selection (GS) is revolutionizing conventional ways of developing new plants and animals. However, because it is a predictive methodology, GS strongly depends on statistical and machine learning to perform these predictions. For continuous outcomes, more models are available for GS. Unfortunately, for count data outcomes, there are few efficient statistical machine learning models for large datasets or for datasets with fewer observations than independent variables. For this reason, in this paper, we applied the univariate version of the Poisson deep neural network (PDNN) proposed earlier for genomic predictions of count data. The model was implemented with (a) the negative log-likelihood of Poisson distribution as the loss function, (b) the rectified linear activation unit as the activation function in hidden layers, and (c) the exponential activation function in the output layer. The advantage of the PDNN model is that it captures complex patterns in the data by implementing many nonlinear transformations in the hidden layers. Moreover, since it was implemented in Tensorflow as the back-end, and in Keras as the front-end, the model can be applied to moderate and large datasets, which is a significant advantage over previous GS models for count data. The PDNN model was compared with deep learning models with continuous outcomes, conventional generalized Poisson regression models, and conventional Bayesian regression methods. We found that the PDNN model outperformed the Bayesian regression and generalized Poisson regression methods in terms of prediction accuracy, although it was not better than the conventional deep neural network with continuous outcomes.


Molecular cloning, gene structure, and expression analyses of NKD1 and NKD2.
Mouse Nkd is a Dishevelled-binding protein, functioning as a negative regulator of WNT - beta-catenin - TCF signaling pathway. Here, human NKD1 and NKD2 were cloned and characterized. NKD1 and NKD2 were predicted to encode 470- and 451-amino-acid polypeptide, respectively. NKD1 and NKD2, showing 43.8% total amino-acid identity, were more homologous in the NH1, NH2, NH3, and NH4 domains. The NH2 domain of NKD1 and NKD2 contained the EF-hand motif. Exon-intron structures of NKD1 and NKD2 genes, consisting of 10 exons, were well conserved. NKD1 was highly expressed in fetal kidney, while NKD2 was moderately expressed in fetal kidney, lung, and adult lung. NKD1 was up-regulated in colorectal cancer cell line SW480, gastric cancer cell line TMK1, and pancreatic cancer cell line Hs700T. NKD2 was up-regulated in gastric cancer cell line MKN45, pancreatic cancer cell line BxPC-3, and esophageal cancer cell lines TE6, and TE13. NKD1 and NKD2 were up-regulated together in 1 case of primary gastric cancer out of 10 cases, and were down-regulated together in 2 cases. Up-regulation of NKD1 or NKD2 might be due to a negative feed-back mechanism. Alternatively, genetic alteration of NKD1 or NKD2 might lead to activation of the WNT - beta-catenin - TCF signaling pathway.


Outcome measurement instruments for peripheral vascular malformations and an assessment of the measurement properties: a systematic review.
The Outcome measures for vascular malformation (OVAMA) group reached consensus on the core outcome domains for the core outcome set (COS) for peripheral vascular malformations (venous, lymphatic and arteriovenous malformations). However, it is unclear which instruments should be used to measure these domains. Therefore, our aims were to identify all outcome measurement instruments available for vascular malformations, and to evaluate their measurement properties. With the first literature search, we identified outcomes and instruments previously used in prospective studies on vascular malformations. A second search yielded studies on measurement properties of patient- and physician-reported instruments that were either developed for vascular malformations, or used in prospective studies. If the latter instruments were not specifically validated for vascular malformations, we performed a third search for studies on measurement properties in clinically similar diseases (vascular or lymphatic diseases and benign tumors). We assessed the methodological quality of these studies following the Consensus-based Standards for the selection of health Measurement Instruments methodology, and evaluated the quality of the measurement properties. The first search yielded 27 studies, none using disease-specific instruments. The second and third search included 22 development and/or validation studies, concerning six instruments. Only the Lymphatic Malformation Function Instrument was developed specifically for vascular malformations. Other instruments were generic QoL instruments developed and/or partly validated for clinically similar diseases. Additional research on measurement properties is needed to assess which instruments may be included in the COS. This review informs the instrument selection and/or the development of new instruments. PROSPERO, 42017056242.


Japan's advanced medicine.
Like health care systems in other developed countries, Japan's health care system faces significant challenges due to aging of the population and economic stagnation. Advanced medicine (Senshin Iryou) is a unique system of medical care in Japan offering highly technology-driven medical care that is not covered by public health insurance. Advanced medicine has recently developed and expanded as part of health care reform. Will it work? To answer this question, we briefly trace the historical development of advanced medicine and describe the characteristics and current state of advanced medical care in Japan. We then offer our opinions on the future of advanced medicine with careful consideration of its pros and cons. We believe that developing advanced medicine is an attempt to bring health care reform in line rather than the goal of health care reform.


The Incidence of Dental Fracturing in Electroconvulsive Therapy in Sweden.
One adverse effect of electroconvulsive therapy (ECT) is dental fracture; thus, a bite guard and muscle relaxants are used to prevent it. Earlier research reported varying rates of dental fracture, but there is no large-scale study on the incidence of dental fracture during ECT. This study aimed to examine the incidence of dental fracture during ECT and to investigate whether the incidence differs between different sexes, age groups, diagnosis groups, electrode placements, or number of treatment sessions. This register-based study used data from the Swedish national quality register for ECT. All hospitals offering ECT report to this register, and the coverage ratio is about 90%. All registered patients who started an ECT series between January 2012 and January 2019 were included in this study, with the data representing 16,681 individuals, 38,862 series, and 254,906 sessions. Forty-six dental fractures were identified, giving an incidence of dental fracture of 0.2% per series, 0.02% per session, and 0.3% per individual. We did not find any significant associations between dental fracture rates and male or female populations, age, or different diagnosis groups, nor was there any significant difference between dental fracture rates and electrode placement. The mean number of treatments was significantly higher in the dental fracture group than in patients without dental fracture. There is a minimal risk of dental fracture during ECT. Our findings, together with those of other studies, provide further motivation for the use of a bite guard and muscle relaxant.


IL7 receptor signaling in T cells: A mathematical modeling perspective.
Interleukin-7 (IL7) plays a nonredundant role in T cell survival and homeostasis, which is illustrated in the severe T cell lymphopenia of IL7-deficient mice, or demonstrated in animals or humans that lack expression of either the IL7Rα or γ c chain, the two subunits that constitute the functional IL7 receptor. Remarkably, IL7 is not expressed by T cells themselves, but produced in limited amounts by radio-resistant stromal cells. Thus, T cells need to constantly compete for IL7 to survive. How T cells maintain homeostasis and further maximize the size of the peripheral T cell pool in face of such competition are important questions that have fascinated both immunologists and mathematicians for a long time. Exceptionally, IL7 downregulates expression of its own receptor, so that IL7-signaled T cells do not consume extracellular IL7, and thus, the remaining extracellular IL7 can be shared among unsignaled T cells. Such an altruistic behavior of the IL7Rα chain is quite unique among members of the γ c cytokine receptor family. However, the consequences of this altruistic signaling behavior at the molecular, single cell and population levels are less well understood and require further investigation. In this regard, mathematical modeling of how a limited resource can be shared, while maintaining the clonal diversity of the T cell pool, can help decipher the molecular or cellular mechanisms that regulate T cell homeostasis. Thus, the current review aims to provide a mathematical modeling perspective of IL7-dependent T cell homeostasis at the molecular, cellular and population levels, in the context of recent advances in our understanding of the IL7 biology. This article is categorized under: Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models Analytical and Computational Methods > Computational Methods.


SU-E-E-05: An Educational Physical Environment Concept with Close Research and Clinical Collaborations.
To create a physical environment where imaging medical physicists can be educated in a real-work, clinical and research setting in close collaboration with professionals such as physicians, biomédical engineers, and other medical personnel. A single building structure has been designed where medical physics students can be immersed in a collaborative clinical and research educational environment. A Clinical Translational Research Center has been constructed on the top four floors over a new Global Vascular Institute (GVI) which is connected to the main university hospital complex and adjacent to radiation therapy facilities. The research and educational component including offices, labs, and conference rooms for the Medical Physics Program is on the top floor and dedicated research imaging suites (fluoroscopic interventional systems, CT, PET/CT, and MRI) along with complete animal facilities and additional research labs for cardiac and vascular investigators are on the two top floors. An atrium and numerous meeting spaces are in place to encourage informal communication among students and science and clinical investigators. The clinical GVI, which occupies the lower four floors, has a full upper floor containing 15 vascular imaging suites for cardiac, neuro, and peripheral vascular imaging and interventions while the floors below have short-term hotel-like patient and family rooms favoring ambulatory patients having minimally invasive procedures. Medical physics didactic education is designed to take place in modern meeting rooms; however, because of the close proximity to research labs and clinical suites, students are expected to get a unique perspective on how research is done and how it is translated into clinical practice. A new physical structure has been built which enables medical physics education to be an integral part of a highly collaborative clinical translational research environment. Research funds provided by NIH grants and equipment grants from Toshiba Medical Systems Corp.


Multiple sclerosis: MHC associations and therapeutic implications.
Multiple sclerosis (MS) is an autoimmune disease with an important genetic component. The strongest genetic association is with the major histocompatibility complex (MHC) region. Several MHC alleles predispose to the disease, the most prominent of which are certain alleles in the HLA-DR2 haplotype. Functional and structural studies have helped to explain the molecular basis of these associations. Although there is currently no curative treatment for MS, an increased understanding of the disease has aided the design of immunotherapies that act on the immune system more specifically than the longstanding drugs. Many of these therapies work at the antigen-specific level, disrupting the interaction between T-cell receptors and MHC molecules that leads to disease.


The association of colonoscopy quality indicators with the detection of screen-relevant lesions, adverse events, and postcolonoscopy cancers in an asymptomatic Canadian colorectal cancer screening population.
Although several quality indicators of colonoscopy have been defined, quality assurance activities should be directed at the measurement of quality indicators that are predictive of key screening colonoscopy outcomes. The goal of this study was to examine the association among established quality indicators and the detection of screen-relevant lesions (SRLs), adverse events, and postcolonoscopy cancers. Historical cohort study. Canadian colorectal cancer screening center. A total of 18,456 asymptomatic men and women ages 40 to 74, at either average risk or increased risk for colorectal cancer because of a family history, who underwent a screening colonoscopy from 2008 to 2010. Using univariate and multivariate analyses, we explored the association among procedural quality indicators and 3 colonoscopy outcomes: detection of SRLs, adverse events, and postcolonoscopy cancers. The crude rates of SRLs, adverse events, and postcolonoscopy cancers were 240, 6.44, and .54 per 1000 colonoscopies, respectively. Several indicators, including endoscopist withdrawal time (OR, 1.3; 95% CI, 1.2-1.4) and cecal intubation rate (OR, 13.9; 95% CI, 1.9-96.9), were associated with the detection of SRLs. No quality indicator was associated with the risk of adverse events. Endoscopist average withdrawal time over 6 minutes (OR, .12; 95% CI, .002-.85) and SRL detection rate over 20% (OR, .17; 95% CI, .03-.74) were associated with a reduced risk of postcolonoscopy cancers. Single-center study. Quality assurance programs should prioritize the measurement of endoscopist average withdrawal time and adenoma (SRL) detection rate.


Non-pseudogene-derived complex acid beta-glucosidase mutations causing mild type 1 and severe type 2 gaucher disease.
Gaucher disease is an autosomal recessive inborn error of glycosphingolipid metabolism caused by the deficient activity of the lysosomal hydrolase, acid beta-glucosidase. Three phenotypically distinct subtypes result from different acid beta-glucosidase mutations encoding enzymes with absent or low activity. A severe neonatal type 2 variant who presented with collodion skin, ichthyosis, and a rapid neurodegenerative course had two novel acid beta-glucosidase alleles: a complex, maternally derived allele, E326K+L444P, and a paternally inherited nonsense mutation, E233X. Because the only other non-pseudogene-derived complex allele, D140H+E326K, also had the E326K lesion and was reported in a mild type 1 patient with a D140H+E326K/K157Q genotype, these complex alleles and their individual mutations were expressed and characterized. Because the E233X mutation expressed no activity and the K157Q allele had approximately 1% normal specific activity based on cross-reacting immunologic material (CRIM SA) in the baculovirus system, the residual activity in both patients was primarily from their complex alleles. In the type 1 patient, the D140H+E326K allele was neuroprotective, encoding an enzyme with a catalytic efficiency similar to that of the N370S enzyme. In contrast, the E326K+L444P allele did not have sufficient activity to protect against the neurologic manifestations and, in combination with the inactive E233X lesion, resulted in the severe neonatal type 2 variant. Thus, characterization of these novel genotypes with non-pseudogene-derived complex mutations provided the pathogenic basis for their diverse phenotypes.


Serum levels of beta2-microglobulin and free light chains of immunoglobulins are associated with systemic disease activity in primary Sjögren's syndrome. Data at enrollment in the prospective ASSESS cohort.
To analyze the clinical and immunological characteristics at enrollment in a large prospective cohort of patients with primary Sjögren's syndrome (pSS) and to investigate the association between serum BAFF, beta2-microglobulin and free light chains of immunoglobulins and systemic disease activity at enrollment. Three hundred and ninety five patients with pSS according to American-European Consensus Criteria were included from fifteen centers of Rheumatology and Internal Medicine in the "Assessment of Systemic Signs and Evolution of Sjögren's Syndrome" (ASSESS) 5-year prospective cohort. At enrollment, serum markers were assessed as well as activity of the disease measured with the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). Patient median age was 58 (25(th)-75(th): 51-67) and median disease duration was 5 (2-9) years. Median ESSDAI at enrollment was 2 (0-7) with 30.9% of patients having features of systemic involvement. Patients with elevated BAFF, beta2-microglobulin and kappa, lambda FLCS had higher ESSDAI scores at enrollment (4 [2]-[11] vs 2 [0-7], P = 0.03; 4 [1]-[11] vs 2 [0-7], P< 0.0001); 4 [2]-[10] vs 2 [0-6.6], P< 0.0001 and 4 [2-8.2] vs 2 [0-7.0], P = 0.02, respectively). In multivariate analysis, increased beta2-microglobulin, kappa and lambda FLCs were associated with a higher ESSDAI score. Median BAFF and beta2-microglobulin were higher in the 16 patients with history of lymphoma (1173.3(873.1-3665.5) vs 898.9 (715.9-1187.2) pg/ml, P = 0.01 and 2.6 (2.2-2.9) vs 2.1 (1.8-2.6) mg/l, P = 0.04, respectively). In pSS, higher levels of beta2-microglobulin and free light chains of immunoglobulins are associated with increased systemic disease activity.


Acquired alexithymia following damage to the anterior insula.
Alexithymia is a subclinical condition characterized by impaired awareness of one's emotional states, which has profound effects on mental health and social interaction. Despite the clinical significance of this condition, the neurocognitive impairment(s) that lead to alexithymia remain unclear. Recent theoretical models suggest that impaired anterior insula (AI) functioning might be involved in alexithymia, but conclusive evidence for this hypothesis is lacking. We measured alexithymia levels in a large sample of brain-injured patients (N=129) and non-brain-injured control participants (N=33), to determine whether alexithymia can be acquired after pronounced damage to the AI. Alexithymia levels were first analysed as a function of group, with patients separated into four groups based on AI damage: patients with >15% damage to AI, patients with <15% damage to AI, patients with no damage to AI, and healthy controls. An ANOVA revealed that alexithymia levels varied across groups (p=0.009), with >15% AI damage causing higher alexithymia relative to all other groups (all p<0.01). Next, a multiple linear regression model was fit with the degree of damage to AI, the degree of damage to a related region (the anterior cingulate cortex, ACC), and the degree of damage to the whole brain as predictor variables, and alexithymia as the dependent variable. Critically, increased AI damage predicted increased alexithymia after controlling for the other two regressors (ACC damage; total lesion volume). Collectively, our results suggest that pronounced AI damage causes increased levels of alexithymia, providing critical evidence that this region supports emotional awareness.


Feasibility and effect of integrating tuberculosis screening and detection in postnatal care services: an operations research study.
Tuberculosis still remains a major cause of maternal and newborn morbidity and mortality. Integrating tuberculosis screening and detection into postnatal care services ensures prompt and appropriate treatment for affected mothers and their babies. This study therefore examined the feasibility and effect of screening and referral for tuberculosis within postnatal care settings from the perspective of providers. This operations research study used a pre- and post-intervention design without a comparison group. The study was implemented between March 2009 and August 2010 in five health facilities located in low-income areas of Nairobi, Kenya, which were suspected to have relatively high prevalence of both tuberculosis and HIV. Descriptive statistics and significance tests were employed to determine changes in the indicators of interest between baseline and endline. Among the 12,604 postnatal care clients screened, 14 tuberculosis cases were diagnosed. The proportion of clients screened for at least one cardinal sign of tuberculosis rose from 4% to 66%, and 21% of clients were screened for all six tracer signs and symptoms. A comparison of 10 quality of postnatal care and tuberculosis screening components at baseline and endline showed a highly significant effect on all 10 components. The findings demonstrate that using postnatal care services as a platform for tuberculosis screening and detection is acceptable and feasible. In addition, linking clients identified through screening to further treatment significantly improved. However, the actual number of cases detected was low. A policy debate on whether to link tuberculosis screening with reproductive health services is recommended before full scale-up of this intervention.


Considerations for the design, analysis and presentation of in vivo studies.
To describe, explain and give practical suggestions regarding important principles and key methodological challenges in the study design, statistical analysis, and reporting of results from in vivo studies. Pre-specifying endpoints and analysis, recognizing the common underlying assumption of statistically independent observations, performing sample size calculations, and addressing multiplicity issues are important parts of an in vivo study. A clear reporting of results and informative graphical presentations of data are other important parts.


Activated RET and ROS: two new driver mutations in lung adenocarcinoma.
Rearrangements of ROS1 and RET have been recently described as new driver mutations in lung adenocarcinoma with a frequency of about 1% each. RET and ROS1 rearrangements both represent unique molecular subsets of lung adenocarcinoma with virtually no overlap with other known driver mutations described so far in lung adenocarcinoma. Specific clinicopathologic characteristics have been described and several multitargeted receptor kinase inhibitors have shown in vitro activity against NSCLC cells harbouring these genetic alterations. In addition, the MET/ALK/ROS inhibitor crizotinib has already shown impressive clinical activity in patients with advanced ROS1-positive lung cancer. Currently, several early proof of concept clinical trials are testing various kinase inhibitors in both molecular subsets of lung adenocarcinoma patients. Most probably, personalized treatment of these genetically defined new subsets of lung adenocarcinoma will be implemented in routine clinical care of lung cancer patients in the near future.


Long non-coding RNAs and their implications in cancer epigenetics.
LncRNAs (long non-coding RNAs) have emerged as key molecular players in the regulation of gene expression in different biological processes. Their involvement in epigenetic processes includes the recruitment of histone-modifying enzymes and DNA methyltransferases, leading to the establishment of chromatin conformation patterns that ultimately result in the fine control of genes. Some of these genes are related to tumorigenesis and it is well documented that the misregulation of epigenetic marks leads to cancer. In this review, we highlight how some of the lncRNAs implicated in cancer are involved in the epigenetic control of gene expression. While very few lncRNAs have already been identified as players in determining the cancer-survival outcome in a number of different cancer types, for most of the lncRNAs associated with epigenetic regulation only their altered pattern of expression in cancer is demonstrated. Thanks to their tissue-specificity features, lncRNAs have already been proposed as diagnostic markers in specific cancer types. We envision the discovery of a wealth of novel spliced and unspliced intronic lncRNAs involved in epigenetic networks or in highly location-specific epigenetic control, which might be predominantly altered in specific cancer subtypes. We expect that the characterization of new lncRNA (long non-coding RNA)-protein and lncRNA-DNA interactions will contribute to the discovery of potential lncRNA targets for use in therapies against cancer.


Olfactory conditioning facilitates diet transition in human infants.
We evaluated whether Pavlovian conditioning methods could be used to increase the ingestion of non-preferred solutions by formula-fed human infants. In baseline measures, 5-7 month old infants sucked less frequently and consumed less water than regular formula. During a 3-day olfactory conditioning period, parents placed a small scented disk, the conditioned stimulus, on the rim of their infants' formula bottle at every feeding. Following this training, infants' responses to water were tested when their water bottles had a disk scented with the training odor, a novel odor, or no odor. Infants tested with the training odor sucked more frequently and consumed significantly more water than they had at baseline. Infants tested with no odor or a novel odor consumed water at or below baseline levels. These data demonstrate that olfactory conditioning can be used to enhance ingestion in infants and suggest that such methods may be useful for infants experiencing difficulty when making transitions from one diet to another.


ADAMTS19-associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype.
Recently, ADAMTS19 was identified as a novel causative gene for autosomal recessive heart valve disease (HVD), affecting mainly the aortic and pulmonary valves. Exome sequencing and data repository (CentoMD) analyses were performed to identify patients with ADAMTS19 variants (two families). A third family was recognized based on cardiac phenotypic similarities and SNP array homozygosity. Three novel loss of function (LoF) variants were identified in six patients from three families. Clinically, all patients presented anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. Three patients had (recurrent) subaortic membrane, suggesting that ADAMTS19 is the first gene identified related to discrete subaortic stenosis. One case presented a bi-commissural pulmonary valve. All patients displayed some degree of atrioventricular valve insufficiency. Other cardiac anomalies included atrial/ventricular septal defects, persistent ductus arteriosus, and mild dilated ascending aorta. Our findings confirm that biallelic LoF variants in ADAMTS19 are causative of a specific and recognizable cardiac phenotype. We recommend considering ADAMTS19 genetic testing in all patients with multiple semilunar valve abnormalities, particularly in the presence of subaortic membrane. ADAMTS19 screening in patients with semilunar valve abnormalities is needed to estimate the frequency of the HVD related phenotype, which might be not so rare.


Endothelial dysfunction: methods of assessment and application to hypertension.
Interest in the endothelium has been growing in recent decades and the traditional belief that it provides an inert interface between blood and the vessel wall is no longer the case. It is now clear that the endothelium produces a large number of substances that influence blood flow, and it is in turn affected by changes in the blood and the pressure of blood flow. Nitric oxide and endothelins are the major regulators of the vascular tone, and thereby the blood pressure. Historically speaking, concepts such as endothelial cell damage and injury were described in the 1960s and 1970s. More recently, terms such as endothelial cell activation and dysfunction have also been introduced. Although similar in some respects or part of a continuum, these terms differ in the actual effects on the endothelium, and hence differentiation is important. In hypertension, the delicate balance between the vasodilators and the vasoconstrictors is upset, with disturbance in the nitric oxide pathways that lead to a predominance of the vasoconstrictors. This in turn leads to many other changes that take place in the endothelium, setting up a vicious cycle that maintains the high blood pressure. Therefore, accurate assessment of vascular function is important in linking pathophysiology with clinical disease, such as hypertension. Indeed, there are several methods currently employed experimentally to assess endothelial dysfunction. However, the most widely studied and accepted tests are the estimation of plasma markers such as von Willebrand factor, E-selectin and thrombomodulin, and studies of forearm circulation in response to hypoxia induced stress ('flow mediated dilatation', FMD) or intra arterially administered drugs such as acetyl choline. The present document examines these topics. Whilst acknowledging the debt owed to animal models in the study of hypertension, we shall focus on work where primary study is in homo sapiens. A greater appreciation of how endothelial assessments are made in hypertension will have relevance for drug development and future management strategies.


Reversible chromosome condensation induced in Drosophila embryos by anoxia: visualization of interphase nuclear organization.
We have studied the morphology of nuclei in Drosophila embryos during the syncytial blastoderm stages. Nuclei in living embryos were viewed with differential interference-contrast optics; in addition, both isolated nuclei and fixed preparations of whole embryos were examined after staining with a DNA-specific fluorescent dye. We find that: (a) The nuclear volumes increase dramatically during interphase and then decrease during prophase of each nuclear cycle, with the magnitude of the nuclear volume increase being greatest for those cycles with the shortest interphase. (b) Oxygen deprivation of embryos produces a rapid developmental arrest that is reversible upon reaeration. During this arrest, interphase chromosomes condense against the nuclear envelope and the nuclear volumes increase dramatically. In these nuclei, individual chromosomes are clearly visible, and each condensed chromosome can be seen to adhere along its entire length to the inner surface of the swollen nuclear envelope, leaving the lumen of the nucleus devoid of DNA. (c) In each interphase nucleus the chromosomes are oriented in the "telophase configuration," with all centromeres and all telomeres at opposite poles of the nucleus; all nuclei at the embryo periphery (with the exception of the pole cell nuclei) are oriented with their centromeric poles pointing to the embryo exterior.


T tubules and surface membranes provide equally effective pathways of carbonic anhydrase-facilitated lactic acid transport in skeletal muscle.
We have studied lactic acid transport in the fast mouse extensor digitorum longus muscles (EDL) by intracellular and cell surface pH microelectrodes. The role of membrane-bound carbonic anhydrases (CA) of EDL in lactic acid transport was investigated by measuring lactate flux in muscles from wildtype, CAIV-, CAIX- and CAXIV-single ko, CAIV-CAXIV double ko and CAIV-CAIX-CAXIV-triple ko mice. This was complemented by immunocytochemical studies of the subcellular localization of CAIV, CAIX and CAXIV in mouse EDL. We find that CAXIV and CAIX single ko EDL exhibit markedly but not maximally reduced lactate fluxes, whereas triple ko and double ko EDL show maximal or near-maximal inhibition of CA-dependent lactate flux. Interpretation of the flux measurements in the light of the immunocytochemical results leads to the following conclusions. CAXIV, which is homogeneously distributed across the surface membrane of EDL fibers, facilitates lactic acid transport across this membrane. CAIX, which is associated only with T tubular membranes, facilitates lactic acid transport across the T tubule membrane. The removal of lactic acid from the lumen of T tubuli towards the interstitial space involves a CO2-HCO3- diffusional shuttle that is maintained cooperatively by CAIX within the T tubule and, besides CAXIV, by the CAIV, which is strategically located at the opening of the T tubules. The data suggest that about half the CA-dependent muscular lactate flux occurs across the surface membrane, while the other half occurs across the membranes of the T tubuli.


Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex.
The role of dopamine in the addictive process (loss of control and compulsive drug intake) is poorly understood. A consistent finding in drug-addicted subjects is a lower level of dopamine D2 receptors. In cocaine abusers, low levels of D2 receptors are associated with a lower level of metabolism in the orbitofrontal cortex. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. This study explored whether a similar association occurs in methamphetamine abusers. Fifteen methamphetamine abusers and 20 non-drug-abusing comparison subjects were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors and with [18F]fluorodeoxyglucose to assess regional brain glucose metabolism, a marker of brain function. Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a difference of 16% in the caudate and 10% in the putamen). D2 receptor availability was associated with metabolic rate in the orbitofrontal cortex in abusers and in comparison subjects. Lower levels of dopamine D2 receptor availability have been previously reported in cocaine abusers, alcoholics, and heroine abusers. This study extends this finding to methamphetamine abusers. The association between level of dopamine D2 receptors and metabolism in the orbitofrontal cortex in methamphetamine abusers, which replicates previous findings in cocaine abusers, suggests that D2 receptor-mediated dysregulation of the orbitofrontal cortex could underlie a common mechanism for loss of control and compulsive drug intake in drug-addicted subjects.


Operational assessment of isoniazid prophylaxis in a community AIDS service organisation in Uganda.
Isoniazid therapy was shown to be 70% effective at preventing tuberculosis in HIV-infected, PPD-positive Ugandan adults, but the feasibility of implementation outside an efficacy trial has not been established. To study uptake, adherence and feasibility of a 6-month course of isoniazid preventive therapy in community-based HIV clinics in Uganda. Observational cohort study describing selection of patients and adherence to isoniazid 300 mg daily. Adherence was measured by clinic attendance, pill counts and urine isoniazid metabolite testing. Implementation was costed on a service delivery basis. Of 1597 cohort members, 22% were PPD-positive. Over 18 months, 193 PPD-positive individuals were assessed for prophylaxis and 98 (51%) were enrolled. Of those enrolled, 74 (76%) completed their course of isoniazid therapy, and 80% were fully adherent. Symptoms or previous treatment for tuberculosis and suspicion of tuberculous lymphadenopathy were the main reasons for exclusion. The additional cost of providing this service was US $14,549. Clinics specialising in the care of persons with HIV/AIDS can successfully implement isoniazid prophylaxis. Difficulties in excluding active tuberculosis and the costs of running the programme may limit its widespread implementation.


Regulation of connexin 43-mediated gap junctional intercellular communication by Ca2+ in mouse epidermal cells is controlled by E-cadherin.
Gap junctional intercellular communication (GJIC) of cultured mouse epidermal cells is mediated by a gap junction protein, connexin 43, and is dependent on the calcium concentration in the medium, with higher GJIC in a high-calcium (1.2 mM) medium. In several mouse epidermal cell lines, we found a good correlation between the level of GJIC and that of immunohistochemical staining of E-cadherin, a calcium-dependent cell adhesion molecule, at cell-cell contact areas. The variant cell line P3/22 showed both low GJIC and E-cadherin protein expression in low- and high-Ca2+ media. P3/22 cells showed very low E-cadherin mRNA expression. To test directly whether E-cadherin is involved in the Ca(2+)-dependent regulation of GJIC, we transfected the E-cadherin expression vector into P3/22 cells and obtained several stable clones which expressed high levels of E-cadherin mRNA. All transfectants expressed E-cadherin molecules at cell-cell contact areas in a calcium-dependent manner. GJIC was also observed in these transfectants and was calcium dependent. These results suggest that Ca(2+)-dependent regulation of GJIC in mouse epidermal cells is directly controlled by a calcium-dependent cell adhesion molecule, E-cadherin. Furthermore, several lines of evidence suggest that GJIC control by E-cadherin involves posttranslational regulation (assembly and/or function) of the gap junction protein connexin 43.


Do statins interfere with lifestyle intervention in the prevention of diabetes in primary healthcare? One-year follow-up of the FIN-D2D project.
To examine whether the use of statins is associated with the incidence of type 2 diabetes (T2D) and changes in glucose metabolism among individuals at high risk for T2D participating in 1-year lifestyle intervention in primary healthcare setting. Prospective follow-up study. In all, 400 primary healthcare centres and occupational healthcare clinics in Finland. We screened altogether 10 149 individuals at increased risk for T2D; of these, 2798 non-diabetic individuals verified by a 2 h glucose tolerance test participated in the 1-year follow-up. Lifestyle intervention (individual and/or group-based counselling). Incidence of T2D and fasting and 2 h glucose measured at baseline and follow-up. A total of 484 individuals (17.3%) used statins at the baseline. Of them 31 (7.5%) developed T2D during the follow-up, compared to 126 (6.5%) of statin non-users (OR 1.17, 95% CI 0.78 to 1.76, p=0.442). Interestingly, fasting glucose increased by 0.08 mmol/l in statin users, but remained unchanged in non-users, the difference being 0.074 mmol/l (95% CI 0.014 to 0.134) and remained significant even after adjustment for age, sex, baseline fasting glucose, the presence of cardiovascular disease (CVD), use of antihypertensive and/or coronary artery disease medication, weight and 1-year weight change (adjusted p=0.042). The incidence of T2D did not differ between the statin users and non-users. The finding that fasting glucose slightly increased in statin users in spite of lifestyle interventions suggests the view that the use of statins might have unfavourable effects on glucose metabolism and that statins might hamper beneficial effects of lifestyle intervention in people at high risk of T2D.


Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene.
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV(1)) before and after the administration of a short-acting β(2)-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β(2)-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV(1) after administration of a β(2)-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β(2)-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β(2)-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β(2)-agonists through GWAS.


Eye movements under various conditions of image fading.
Under normal viewing conditions, the image on the retina is always in motion. Images fade and may eventually disappear when the physiological motion of the retinal stimulus is reduced or eliminated. According to a widespread theory, microsaccades are responsible for maintaining visibility during fixation. However, while it is clear that the sudden changes in visual input caused by microsaccades are sufficient to restore visibility, it has long been questioned whether this effect might be an epiphenomenon, rather than an important function of microsaccades. In this study, we compared the eye movements measured under conditions that either simulated or induced loss of visibility to those recorded when fading did not occur. Both drifts and microsaccades were unaffected by changes in the stimulus contrast and bandwidth that recreated the percept experienced during image fading. Under retinal stabilization, a condition in which observers reported fading, microsaccade rates decreased, instead of increasing as predicted by the fading prevention hypothesis. While image fading had no influence on oculomotor activity, eye movements were instead strongly modulated by the onset of the stimulus and by the requested precision of fixation. Microsaccades occurred more frequently and were more corrective for preceding drifts during accurate fixation on a cue than during relaxed fixation on a region of the screen. These results do not support a causal relationship between image fading and microsaccade production and show that the precision of required fixation is a major contributor to microsaccades.


Balgacyclamides, antiplasmodial heterocyclic peptides from Microcystis aeruguinosa EAWAG 251.
The isolation and structural characterization of three new heterocyclic and macrocyclic peptides, balgacyclamides A-C, from Microcystis aeruginosa EAWAG 251 are reported. The constitutions were determined by 2D-NMR methods and mass spectrometry, and the configurations were assigned after ozonolysis and hydrolysis by HPLC-MS methods using Marfey's method as well as GC-MS using authentic standards. Balgacyclamides A and B were active against Plasmodium falciparum K1 in the low micromolar range, while displaying low toxicity to rat myoblasts.


The attitudes and beliefs of healthcare professionals on the causes and reporting of medication errors in a UK Intensive care unit.
Our aim was to explore the attitudes and beliefs of healthcare professionals relating to the causes and reporting of medication errors in a UK intensive care unit. Medication errors were identified by the unit pharmacist and semi-structured qualitative interviews conducted with 13 members of staff involved with 12 errors. Interviews were analysed using a model of human error theory. Staff identified many contributing factors, including poor communication and frequent interruptions. Organisational factors included lack of clarity on the responsibility of the second nurse's check for medication administration, lack of feedback on medication errors, and a common and accepted practice of administering medication without a complete medication order. Barriers to reporting included administrative paperwork and lack of encouragement by management. Greater feedback on medication errors seems essential to improve current practice and increase reporting.


A molecular cytogenetic map of sorghum chromosome 1. Fluorescence in situ hybridization analysis with mapped bacterial artificial chromosomes.
We used structural genomic resources for Sorghum bicolor (L.) Moench to target and develop multiple molecular cytogenetic probes that would provide extensive coverage for a specific chromosome of sorghum. Bacterial artificial chromosome (BAC) clones containing molecular markers mapped across sorghum linkage group A were labeled as probes for fluorescence in situ hybridization (FISH). Signals from single-, dual-, and multiprobe BAC-FISH to spreads of mitotic chromosomes and pachytene bivalents were associated with the largest sorghum chromosome, which bears the nucleolus organizing region (NOR). The order of individual BAC-FISH loci along the chromosome was fully concordant to that of marker loci along the linkage map. In addition, the order of several tightly linked molecular markers was clarified by FISH analysis. The FISH results indicate that markers from the linkage map positions 0.0-81.8 cM reside in the short arm of chromosome 1 whereas markers from 81.8-242.9 cM are located in the long arm of chromosome 1. The centromere and NOR were located in a large heterochromatic region that spans approximately 60% of chromosome 1. In contrast, this region represents only 0.7% of the total genetic map distance of this chromosome. Variation in recombination frequency among euchromatic chromosomal regions also was apparent. The integrated data underscore the value of cytological data, because minor errors and uncertainties in linkage maps can involve huge physical regions. The successful development of multiprobe FISH cocktails suggests that it is feasible to develop chromosome-specific "paints" from genomic resources rather than flow sorting or microdissection and that when applied to pachytene chromatin, such cocktails provide an especially powerful framework for mapping. Such a molecular cytogenetic infrastructure would be inherently cross-linked with other genomic tools and thereby establish a cytogenomics system with extensive utility in development and application of genomic resources, cloning, transgene localization, development of plant "chromonomics," germplasm introgression, and marker-assisted breeding. In combination with previously reported work, the results indicate that a sorghum cytogenomics system would be partially applicable to other gramineous genera.


Developing and validating a school-based screening tool of Fundamental Movement Skills (FUNMOVES) using Rasch analysis.
A large proportion of children are not able to perform age-appropriate fundamental movement skills (FMS). Thus, it is important to assess FMS so that children needing additional support can be identified in a timely fashion. There is great potential for universal screening of FMS in schools, but research has established that current assessment tools are not fit for purpose. To develop and validate the psychometric properties of a FMS assessment tool designed specifically to meet the demands of universal screening in schools. A working group consisting of academics from developmental psychology, public health and behavioural epidemiology developed an assessment tool (FUNMOVES) based on theory and prior evidence. Over three studies, 814 children aged 4 to 11 years were assessed in school using FUNMOVES. Rasch analysis was used to evaluate structural validity and modifications were then made to FUNMOVES activities after each study based on Rasch results and implementation fidelity. The initial Rasch analysis found numerous psychometric problems including multidimensionality, disordered thresholds, local dependency, and misfitting items. Study 2 showed a unidimensional measure, with acceptable internal consistency and no local dependency, but that did not fit the Rasch model. Performance on a jumping task was misfitting, and there were issues with disordered thresholds (for jumping, hopping and balance tasks). Study 3 revealed a unidimensional assessment tool with good fit to the Rasch model, and no further issues, once jumping and hopping scoring were modified. The finalised version of FUNMOVES (after three iterations) meets standards for accurate measurement, is free and able to assess a whole class in under an hour using resources available in schools. Thus FUNMOVES has the potential to allow schools to efficiently screen FMS to ensure that targeted support can be provided and disability barriers removed.


Laparoscopic surgery for the management of ovarian endometriomas.
Treatment for mild and moderate endometriosis is controversial, whereas ovarian endometriomas of diameter > 3 cm must be treated surgically. A minimally invasive and inexpensive surgical approach should be always preferred. The objective of this randomized, prospective, clinical trial was to assess operative time, hemostasis, accuracy, recurrence rates, and pregnancy outcomes of 2 different laparoscopic techniques for management of ovarian endometriomas. Ninety-two patients with ovarian endometriomas were randomized to undergo direct stripping of cystic wall from the initial adhesion site (group A), or circular excision of ovarian tissue around the initial adhesion site and then stripping (group B). Pregnancy outcome results were retrieved at 36 months after surgery. Recurrence rate corresponded to evaluation at 4 and 12 months after surgery performed by transvaginal ultrasound and Ca125 serum level. Direct stripping leads to bleeding more frequently than does circular excision. Hemostasis at the ovarian hilus does show differences between groups; an easy exposure of damage after circular excision reduces execution time. Cumulative pregnancy outcomes at 36 months, and recurrence rates during follow-up, did not significantly differ among techniques. Circular excision of endometrioma cystic wall reduces surgical time, and results in better hemostasis. In addition, excision techniques allow complete removal of the cystic wall in 93% of cases (compared to 74.5% for direct stripping technique), showing differences in recurrence rate, and bringing about a better pregnancy. Data are not statistically significant owing to the small number of collected cases.


Shared brain activity for aesthetic and moral judgments: implications for the Beauty-is-Good stereotype.
The Beauty-is-Good stereotype refers to the assumption that attractive people possess sociably desirable personalities and higher moral standards. The existence of this bias suggests that the neural mechanisms for judging facial attractiveness and moral goodness overlap. To investigate this idea, we scanned participants with functional magnetic resonance imaging while they made attractiveness judgments about faces and goodness judgments about hypothetical actions. Activity in the medial orbitofrontal cortex increased as a function of both attractiveness and goodness ratings, whereas activity in the insular cortex decreased with both attractiveness and goodness ratings. Within each of these regions, the activations elicited by attractiveness and goodness judgments were strongly correlated with each other, supporting the idea of similar contributions of each region to both judgments. Moreover, activations in orbitofrontal and insular cortices were negatively correlated with each other, suggesting an opposing relationship between these regions during attractiveness and goodness judgments. These findings have implications for understanding the neural mechanisms of the Beauty-is-Good stereotype.


Immunologic and molecular characterization of an estrogen-dependent glycoprotein in the rhesus (Macaca mulatta) oviduct.
The objective of this study was to detect and characterize a secreted oviduct-specific glycoprotein (OGP) in the rhesus macaque (Macaca mulatta) and to compare the characteristics of this OGP to those previously characterized in baboons and women. Oviducts were obtained from untreated ovariectomized rhesus and from ovariectomized rhesus either treated with estradiol (E2) for 14 days or treated sequentially with E2 for 14 days and then with E2 plus progesterone (P4) for an additional 14 days. Segments of oviducts were either fixed for morphological analysis, cultured for OGP synthesis and release, or frozen for RNA analysis. The proteins present in the culture media were separated by one-dimensional SDS-PAGE, and OGP was detected on Western blots using polyclonal antibodies generated against the reduced form of baboon OGP or a 17-amino acid segment of the baboon core protein. Cross-reacting antigens were present in the 120-kDa region, identical to what was observed for baboon and human OGP. Indirect immunogold localization of OGP on thin sections demonstrated specific clustering of gold particles over the apical secretory granules of the secretory cells of the oviductal epithelium. A cDNA was generated using RT-PCR and 5' and 3' rapid amplification of cDNA ends (RACE), and sequenced. The total transcript was 2237 nucleotides in length plus a poly(A) tail. The largest open reading frame was 624 amino acids, which would produce a protein of 69.3 kDa. The nucleotide sequence was more than 95% identical to the nucleotide sequences of baboon and human OGP. Northern blots revealed a single message at 2.4 kilobases (kb) in oviduct samples obtained from E2-treated rhesus. This message was absent in oviducts obtained from untreated ovariectomized and from sequential E2 plus P4-treated rhesus macaques. In summary, the rhesus oviduct synthesizes and secretes an OGP in the presence of E2 that is immunologically and structurally similar to the baboon and human OGP. The presence of a highly homologous glycoprotein in several primates suggests a similar function for OGP in the reproductive process.


Anaerobic digestion of ultrasonicated sludge at different solids concentrations - Computation of mass-energy balance and greenhouse gas emissions.
Two cases of anaerobic digestion (AD) of sludge, namely (i) with pre-treatment and (ii) without pre-treatment, were assessed using mass-energy balance and the corresponding greenhouse gas (GHG) emissions. For a digestion period of 30 days, volatile solids degradation of the control sludge and the ultrasonicated secondary sludge was 51.4% and 60.1%, respectively. Mass balance revealed that the quantity of digestate required for dewatering, transport and land application was the lowest (20.2 × 10(6) g dry sludge/day) for ultrasonicated secondary sludge at 31.4 g TS/L. Furthermore, for ultrasonicated secondary sludge at 31.4 g TS/L, the maximum net energy (energy output - energy input) of total dry solids (TDS) was 7.89 × 10(-6) kWh/g and the energy ratio (output/input) was 1.0. GHG emissions were also reduced with an increase in the sludge solids concentration (i.e., 40.0 g TS/L < 30.0 g TS/L < 20.0 g TS/L). Ultrasonication pre-treatment proved to be efficient and beneficial for enhancing anaerobic digestion efficiency of the secondary sludge when compared to the primary and mixed sludge.


Identification of Metabolic Changes in Ileum, Jejunum, Skeletal Muscle, Liver, and Lung in a Continuous I.V. Pseudomonas aeruginosa Model of Sepsis Using Nontargeted Metabolomics Analysis.
Sepsis is a multiorgan disease affecting the ileum and jejunum (small intestine), liver, skeletal muscle, and lung clinically. The specific metabolic changes in the ileum, jejunum, liver, skeletal muscle, and lung have not previously been investigated. Live Pseudomonas aeruginosa, isolated from a patient, was given via i.v. catheter to pigs to induce severe sepsis. Eighteen hours later, ileum, jejunum, medial gastrocnemius skeletal muscle, liver, and lung were analyzed by nontargeted metabolomics analysis using gas chromatography/mass spectrometry. The ileum and the liver demonstrated significant changes in metabolites involved in linoleic acid metabolism: the ileum and lung had significant changes in the metabolism of valine/leucine/isoleucine; the jejunum, skeletal muscle, and liver had significant changes in arginine/proline metabolism; and the skeletal muscle and lung had significant changes in aminoacyl-tRNA biosynthesis, as analyzed by pathway analysis. Pathway analysis also identified changes in metabolic pathways unique for different tissues, including changes in the citric acid cycle (jejunum), β-alanine metabolism (skeletal muscle), and purine metabolism (liver). These findings demonstrate both overlapping metabolic pathways affected in different tissues and those that are unique to others and provide insight into the metabolic changes in sepsis leading to organ dysfunction. This may allow therapeutic interventions that focus on multiple tissues or single tissues once the relationship of the altered metabolites/metabolism to the underlying pathogenesis of sepsis is determined.


Counteracting the Slowdown of Reaction Times in a Vigilance Experiment With 40-Hz Transcranial Alternating Current Stimulation.
Indicators for a decrement in vigilance are a slowdown in reaction times and an increase in alpha power in the electroencephalogram in posterior regions of the brain. Transcranial alternating current stimulation (tACS) is a neuropsychological technique that has been found to interact with intrinsic brain oscillations and is able to enhance cognitive and behavioral performance. Recent studies show that tACS in the gamma frequency range (30-80 Hz) is able to downregulate amplitudes in the alpha frequency range (8-12 Hz), in accordance to the effect referred to as cross-frequency coupling, where intrinsic alpha and gamma waves modulate each other. We applied 40 Hz gamma-tACS to the visual cortex during a vigilance experiment and investigated if stimulation improves reaction times and error rates with time-on-task. In our sham controlled experiment, participants completed two blocks of 30 minutes duration while performing the same visual two-choice task. The first block was used as BASELINE. A statistical analysis with a linear mixed model revealed a significantly lower increase of modeled reaction times over time in the INTERVENTION-block of the tACS-group as compared with their BASELINE-block whereas there was no significant change between the BASELINE- and INTERVENTION-block for the SHAM-group. Error rates did not differ between groups. This paper indicates that gamma-tACS can enhance performance in vigilance tasks as it significantly decreased the slowdown of reaction times in our study.


Antisense knockdown of GLAST, a glial glutamate transporter, compromises retinal function.
To elucidate the role of the glial glutamate transporter GLAST, in the regulation of retinal function. Antisense oligonucleotides to GLAST were injected intravitreally into the left eye of Wistar rats. Sense oligonucleotides (control) were injected into the right eye over a period of 3 days. Scotopic flash electroretinograms were recorded over a 20-day period. To assay whether the antisense oligonucleotides caused a reduction in the expression or the activity of GLAST, retinas were exposed to D-aspartate, a nonendogenous substrate of glutamate transporters. The retinas were immunolabeled with specific antibodies for D-aspartate. Retinal GLAST and glutamate distributions also were determined immunocytochemically. Antisense oligonucleotides markedly suppressed the electroretinogram b-wave, whereas sense oligonucleotides had no significant effect. Significant changes in the electroretinogram were apparent 5 days after injection of antisense oligonucleotide and were sustained for at least 20 days. A marked reduction of D-aspartate uptake into Muller cells of retinas that had been exposed to the antisense oligonucleotides 5 days previously suggests a reduction of GLAST activity. The retinas, however, displayed no evidence of excitotoxic neuronal degeneration, and the distribution of glutamate was unaffected by antisense treatment. The observed lack of neuronal degeneration suggests that reduced glutamate uptake into Muller cells does not cause excitotoxic tissue damage. A direct perturbation of glutamatergic signaling is more likely, because the rapid clearance of glutamate is necessary for light elicited signaling between photoreceptors and bipolar cells. This suggests that GLAST is essential for the maintenance of normal retinal transmission.


Efficacy of anti-microbial catheters in preventing catheter associated urinary tract infections in hospitalized patients: A review on recent updates.
Catheter-associated urinary tract infections (CAUTIs) are the common hospital-associated infections (HAIs), which can be prevented by practicing necessary precautions and by using antimicrobial urinary catheters (UCs). The efficacy of antimicrobial UCs against standard catheters for averting CAUTIs is poorly studied. The objective of the review is to analyze the efficacy of various types of antimicrobial UCs used in hospitalized patients in preventing CAUTIs. The major antimicrobial UCs are silver and antibiotic catheters, in contrast, few antimicrobial catheters include antimicrobial peptides, bactericidal enzymes, bacteriophages, and many are under clinical evaluation. The review concludes that even though many antimicrobial methods are available to prevent CAUTIs, the incidence rate is still high. Antibiotic resistance, leaching of catheter materials which may cause side effects and additional costs are the major challenges for the UCs. Further research is warranted and should focus on cost-effective and ideal antimicrobial UCs, in which the microorganisms cannot form biofilms or develop resistance.


Lumbar intervertebral disk degeneration in athletes.
Several studies have reported that physical loading related to competitive sports activities is associated with lumbar intervertebral disk degeneration. However, the association between types of sports activities and disk degeneration has not been clarified. The frequencies of disk degeneration may vary with the competitive sport because of the different postures and actions specific to each sport. Cross-sectional study (prevalence); Level of evidence, 3. Study participants were 308 well-trained university athletes (baseball players, basketball players, kendo competitors, runners, soccer players, swimmers) and 71 nonathlete university students (reference group). Disk degeneration was evaluated using T2-weighted magnetic resonance imaging. A self-reported questionnaire concerning low back pain was also conducted. The proportions of the participants who had disk degeneration among the baseball players (odds ratio, 3.23) and the swimmers (odds ratio, 2.95) were significantly higher than among the nonathletes using logistic regression analysis. When all patients were grouped together, the association between lifetime experience of low back pain and participants with disk degeneration was significant, and a linear association between the degree of severest low back pain experienced and participants with disk degeneration, analyzed by a Cochran-Mantel-Haenszel test, was also significant. Continuous competitive baseball and swimming activities during youth may be associated with disk degeneration. Furthermore, the study indicates that the experience of severe low back pain might be a predictor of disk degeneration in youth. The authors hope that preventive measures and management to protect against disk degeneration and low back pain in athletes will be established by further studies based on these results.


Prevalence and prognostic impact of hypocobalaminemia in dogs with lymphoma.
To determine the prevalence of hypocobalaminemia in dogs with multicentric lymphoma and to investigate any relationship between serum cobalamin concentration and disease outcome. Cohort study. 58 dogs with multicentric lymphoma. Serum cobalamin concentrations were measured in 58 dogs with multicentric lymphoma. Clinical signs, stage, and immunophenotype for dogs with hypocobalaminemia were compared with those for dogs with serum cobalamin concentrations above the lower end of the reference range. Survival times for dogs undergoing a cyclic multidrug chemotherapy protocol (n = 53) were similarly compared. Serum cobalamin concentrations for treated dogs that died or were euthanized before day 60 were compared with those of dogs still alive at day 60. Serum cobalamin concentrations ranged from < 150 to 1,813 ng/L, with a median concentration of 401 ng/L. Nine of the 58 (16%) dogs had hypocobalaminemia (serum cobalamin concentration < 252 ng/L). Three of 9 dogs with hypocobalaminemia survived to at least day 60, compared with 40 of 44 (91%) dogs without hypocobalaminemia (serum cobalamin concentration >or= 252 ng/L). Ten (10/53 [19%]) dogs undergoing a cyclic multidrug chemotherapy protocol died before day 60, and the median serum cobalamin concentration for these dogs (232 ng/L) was significantly lower than for those still alive at the end point of the study (556 ng/L). Hypocobalaminemia was relatively uncommon in this population of dogs with multicentric lymphoma, but was associated with a poor outcome. Serum cobalamin concentrations may provide prognostic information in dogs with multicentric lymphoma.


An Incident of a Massive Pulmonary Embolism Following Acute Aortic Dissection. a Case Report.
Acute aortic dissection and acute pulmonary embolism are two life-threatening emergencies. The presented case is of an 81-year-old man who has been diagnosed with an acute Stanford type A aortic dissection and referred to a tertiary hospital for surgical treatment. After a successful aortic repair and an overall favourable postoperative recovery, he was diagnosed with cervical and upper extremity deep vein thrombosis and was anticoagulated accordingly. He later presented with massive bilateral pulmonary embolism.


Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.
Systems for protein degradation are essential for tight control of the inflammatory immune response. Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long-lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation. However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease, regulates endotoxin-induced inflammasome activation in mice. Atg16L1-deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor 4 (refs 8, 9), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL-1beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1beta and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.


Alexander's law and the oculomotor neural integrator: three-dimensional eye velocity in patients with an acute vestibular asymmetry.
According to Alexander's law (AL), the slow phase velocity of nystagmus of vestibular origin is dependent on horizontal position, with lower velocity when gaze is directed in the slow compared with the fast phase direction. Adaptive changes in the velocity-to-position neural integrator are thought to cause AL. Although these changes have been described for the horizontal neural integrator, nystagmus often includes vertical and torsional components, but the adaptive abilities of the vertical and torsional integrators have not been investigated. We measured 11 patients with a peripheral vestibular asymmetry and used second-order equations to describe how velocity varied with position. Horizontal velocity changed with horizontal position in accordance with AL and the second-order term for horizontal position was also significant. Whereas velocity decreased in the slow phase direction, it was relatively unchanged >10 degrees into the fast phase direction. Vertical velocity was also highest in the vertical fast phase direction and the second-order term for vertical position was also significant, in that vertical velocity increased in the vertical fast phase direction, but was unchanging in the slow phase direction. Torsional velocity varied linearly with horizontal, but not vertical, position. These results show that the horizontal and vertical oculomotor neural integrators react to altered vestibular input by maintaining different integrating time constants depending on gaze direction.


Human liver methionine cycle: MAT1A and GNMT gene resequencing, functional genomics, and hepatic genotype-phenotype correlation.
The "methionine cycle" plays a critical role in the regulation of concentrations of (S)-adenosylmethionine (AdoMet), the major biological methyl donor. We set out to study sequence variation in genes encoding the enzyme that synthesizes AdoMet in liver, methionine adenosyltransferase 1A (MAT1A) and the major hepatic AdoMet using enzyme, glycine N-methyltransferase (GNMT), as well as functional implications of that variation. We resequenced MAT1A and GNMT using DNA from 288 subjects of three ethnicities, followed by functional genomic and genotype-phenotype correlation studies performed with 268 hepatic biopsy samples. We identified 44 and 42 polymorphisms in MAT1A and GNMT, respectively. Quantitative Western blot analyses for the human liver samples showed large individual variation in MAT1A and GNMT protein expression. Genotype-phenotype correlation identified two genotyped single-nucleotide polymorphisms (SNPs), reference SNP (rs) 9471976 (corrected p = 3.9 × 10(-10)) and rs11752813 (corrected p = 1.8 × 10(-5)), and 42 imputed SNPs surrounding GNMT that were significantly associated with hepatic GNMT protein levels (corrected p values < 0.01). Reporter gene studies showed that variant alleles for both genotyped SNPs resulted in decreased transcriptional activity. Correlation analyses among hepatic protein levels for methionine cycle enzymes showed significant correlations between GNMT and MAT1A (p = 1.5 × 10(-3)) and between GNMT and betaine homocysteine methyltransferase (p = 1.6 × 10(-7)). Our discovery of SNPs that are highly associated with hepatic GNMT protein expression as well as the "coordinate regulation" of methionine cycle enzyme protein levels provide novel insight into the regulation of this important human liver biochemical pathway.


Additive effects of gastric volumes and macronutrient composition on the sensation of postprandial fullness in humans.
Intake of food or fluid distends the stomach and triggers mechanoreceptors and vagal afferents. Wall stretch and tension produces a feeling of fullness. Duodenal infusion studies assessing gastric sensitivity by barostat have shown that the products of fat digestion have a greater effect on the sensation of fullness and also dyspeptic symptoms than carbohydrates. We tested here the hypothesis that fat and carbohydrate have different effects on gastric sensation under physiological conditions using non-invasive magnetic resonance imaging (MRI) to measure gastric volumes. Thirteen healthy subjects received a rice pudding test meal with added fat or added carbohydrate on two separate occasions and underwent serial postprandial MRI scans for 4.5 h. Fullness was assessed on a 100-mm visual analogue scale. Gastric half emptying time was significantly slower for the high-carbohydrate meal than for the high-fat meal, P=0.0327. Fullness significantly correlated with gastric volumes for both meals; however, the change from baseline in fullness scores was higher for the high-fat meal for any given change in stomach volume (P=0.0147), despite the lower energy content and faster gastric emptying of the high-fat meal. Total gastric volume correlates positively and linearly with postprandial fullness and ingestion of a high-fat meal increases this sensation compared with high-carbohydrate meal. These findings can be of clinical interest in patients presenting with postprandial dyspepsia whereby manipulating gastric sensitivity by dietary intervention may help to control digestive sensations.


Phase-contrast 3D tomography of HeLa cells grown in PLLA polymer electrospun scaffolds using synchrotron X-rays.
Advanced imaging is useful for understanding the three-dimensional (3D) growth of cells. X-ray tomography serves as a powerful noninvasive, nondestructive technique that can fulfill these purposes by providing information about cell growth within 3D platforms. There are a limited number of studies taking advantage of synchrotron X-rays, which provides a large field of view and suitable resolution to image cells within specific biomaterials. In this study, X-ray synchrotron radiation microtomography at Diamond Light Source and advanced image processing were used to investigate cellular infiltration of HeLa cells within poly L-lactide (PLLA) scaffolds. This study demonstrates that synchrotron X-rays using phase contrast is a useful method to understand the 3D growth of cells in PLLA electrospun scaffolds. Two different fiber diameter (2 and 4 µm) scaffolds with different pore sizes, grown over 2, 5 and 8 days in vitro, were examined for infiltration and cell connectivity. After performing visualization by segmentation of the cells from the fibers, the results clearly show deeper cell growth and higher cellular interconnectivity in the 4 µm fiber diameter scaffold. This indicates the potential for using such 3D technology to study cell-scaffold interactions for future medical use.


Wegener granulomatosis of the eustachian tube and skull base mimicking a malignant tumor.
Wegener granulomatosis is a well-studied yet sometimes difficult-to-diagnose systemic vasculitis. Early treatment with immunosuppressants is the therapy of choice and usually controls the disease. Two cases of Wegener granulomatosis are presented, both with symptoms and imaging findings suggestive of a malignant tumor of the nasopharynx or skull base. The focus of upper respiratory involvement in each case was the eustachian tube.


Neuroradiologic diagnosis of subdural empyema and CT limitations.
Five cases of subdural empyema are described. Two of the cases eluded a definitive computed tomography (CT) diagnosis despite classical clinical background. Extracerebral collection with definitive border enhancement was seen in the other three cases. Mass effect, present in all five cases, was related to the extracerebral collection in three cases and diffuse cerebral edema and/or infarction in two. Angiography in four cases initially demonstrated an extracerebral collection in three and inflammatory angiospasm in two. Repeat angiography demonstrated an extracerebral collection in the fourth case. In the proper clinical setting subdural empyema should be considered even in the absence of an extracerebral collection when mass effect or an infarction pattern is seen on CT. Angiography may be diagnostic in such cases. Hopefully, newer techniques will further the diagnostic efficacy of CT in this disease.


Are metabolic oscillations responsible for normal oscillatory insulin secretion?
Normal insulin secretion is oscillatory in vivo and in vitro, with a period of approximately 5-10 min. The mechanism of generating these oscillations is not yet established, but a metabolic basis seems most likely for glucose-stimulated secretion. The rationale is that 1) spontaneous oscillatory operation of glycolysis is a well-established phenomenon; 2) oscillatory behavior of glycolysis involves oscillations in the ATP/ADP ratio, which can cause alternating opening and closing of ATP-sensitive K+ channels, leading to the observed oscillations in membrane potential and Ca2+ influx in pancreatic beta-cells, and may also have downstream effects on exocytosis; 3) spontaneous Ca2+ oscillations are an unlikely basis in this case, since intracellular stores are not of primary importance in the stimulus-secretion coupling, and furthermore, insulin oscillations occur under conditions when intracellular Ca2+ levels are not changing; 4) a neural basis cannot account for insulin oscillations from perifused islets and clonal beta-cells or from transplanted islets or pancreas in vivo; 5) observed oscillations in metabolite levels and fluxes further support a metabolic basis, as does the presence in beta-cells of the oscillatory isoform of phosphofructokinase (PFK-M). The fact that normal oscillatory secretion is impaired in patients with NIDDM and in their near relatives suggests that such derangement may be involved in the development of the disease; furthermore, this probably reflects an early defect in the regulation and operation of the fuel metabolizing/sensing pathways of the pancreatic beta-cell.


Early dynamics of the emission of solvated electrons from nanodiamonds in water.
Solvated electrons are among the most reductive species in an aqueous environment. Diamond materials have been proposed as a promising source of solvated electrons, but the underlying emission process in water remains elusive so far. Here, we show spectroscopic evidence for the emission of solvated electrons from detonation nanodiamonds upon excitation with both deep ultraviolet (225 nm) and visible (400 nm) light using ultrafast transient absorption. The crucial role of surface termination in the emission process is evidenced by comparing hydrogenated, hydroxylated and carboxylated nanodiamonds. In particular, a transient response that we attribute to solvated electrons is observed on hydrogenated nanodiamonds upon visible light excitation, while it shows a sub-ps recombination due to trap states when excited with deep ultraviolet light. The essential role of surface reconstructions on the nanodiamonds in these processes is proposed based on density functional theory calculations. These results open new perspectives for solar-driven emission of solvated electrons in an aqueous phase using nanodiamonds.


Children's and adults' interpretation of covariation data: Does symmetry of variables matter?
In a series of 3 experiments, the authors investigated the influence of symmetry of variables on children's and adults' data interpretation. They hypothesized that symmetrical (i.e., present/present) variables would support correct interpretations more than asymmetrical (i.e., present/absent) variables. Participants were asked to judge covariation in a series of data sets presented in contingency tables and to justify their judgments. Participants in Experiments 1 and 2 were elementary school children (Experiment 1: n = 52 second graders, n = 44 fourth graders; Experiment 2: n = 50 second graders). Participants in Experiment 3 were adults (n = 62). In Experiment 1, children in the symmetrical variables condition performed better than those in the asymmetrical variables condition. Children in the symmetrical variables condition judged more data patterns correctly and they more frequently justified their choices by referring to the complete table. Experiment 2 ruled out the possibility that this effect was caused by differences in question format. Even when question format was held constant, second graders performed better with symmetrical variables. Experiment 3 showed that adults' data interpretation is also affected by symmetry of variables. Collectively, these results indicate that symmetry of variables affects interpretation of covariation data. The authors argue that symmetrical variables provide a context for meaningful comparison. With asymmetrical variables, the importance of the comparison is less salient. Thus, the symmetry of variables should be considered by researchers as well as educators. (PsycINFO Database Record


Current management of acute lymphoblastic leukemia in adults.
Intensive remission chemotherapy followed by post-remission consolidation and maintenance therapies has achieved complete remission rates of 75% to 90% and 3-year survival rates of 25% to 50% in adults with acute lymphoblastic leukemia (ALL). These results, although promising, are still less favorable than those achieved in childhood ALL. However, various novel experimental and clinical approaches show promise for improving cure rates. Also, specific therapies directed at high-risk subgroups with ALL are beginning to emerge. Detection of specific chromosomal abnormalities at diagnosis identifies patients who are at risk of failing to achieve remission, as well as those who are likely to have short, intermediate, or prolonged disease-free intervals after successful remission induction. Such prognostic information may, ultimately, be used to assign risk categories and to individualize post-remission therapy.


Intravaginal live attenuated Salmonella increase local antitumor vaccine-specific CD8+ T cells.
We have recently reported that the intravaginal instillation of synthetic Toll-like receptor 3 (TLR3) or TLR9 agonists after a subcutaneous vaccination against human papillomavirus E7 highly increases (~5-fold) the number of vaccine-specific CD8+ T cells in the genital mucosa of mice, without affecting E7-specific systemic responses. Here, we show that the instillation of live attenuated Salmonella enterica serovar Typhimurium similarly, though more efficiently (~15- fold), increases both E7-specific and total CD8+ T cells in the genital mucosa. Cancer immunotherapeutic strategies combining vaccination with local immunostimulation with live bacteria deserve further investigations.


Nonlinear optical beam propagation for optical limiting.
We implement numerical modeling of high-energy laser-pulse propagation through bulk nonlinear optical materials using focused beams. An executable program with a graphical user interface is made available to researchers for modeling the propagation of beams through materials much thicker than the diffraction length (up to 10(3) times longer). Ultrafast nonlinearities of the bound-electronic Kerr effect and two-photon absorption as well as time-dependent excited-state and thermal nonlinearities are taken into account. The hydrodynamic equations describing the rarefaction of the medium that is due to heating are solved to determine thermal index changes for nanosecond laser pulses. We also show how this effect can be simplified in some cases by an approximation that assumes instantaneous expansion (so-called thermal lensing approximation). Comparisons of numerical results with several Z-scan, optical limiting and beam distortion experiments are presented. Possible application to optimization of a passive optical limiter design is discussed.


The death receptor antagonist FLIP-L interacts with Trk and is necessary for neurite outgrowth induced by neurotrophins.
FLICE-inhibitory protein (FLIP) is an endogenous inhibitor of the signaling pathway triggered by the activation of death receptors. Here, we reveal a novel biological function for the long form of FLIP (FLIP-L) in neuronal differentiation, which can be dissociated from its antiapoptotic role. We show that FLIP-L is expressed in different regions of the mouse embryonic nervous system. Immunohistochemistry of mouse brain sections at different stages reveals that, in neurons, FLIP is expressed early during the embryonic neuronal development (embryonic day 16) and decreases at later stages (postnatal days 5-15), when its expression is essentially detected in glial cells. FLIP-L overexpression significantly enhances neurotrophin-induced neurite outgrowth in motoneurons, superior cervical ganglion neurons, and PC12 cells. Conversely, the downregulation of FLIP-L protein levels by specific RNA interference significantly reduces neurite outgrowth, even in the presence of the appropriate neurotrophin stimulus. Moreover, NGF-dependent activation of two main intracellular pathways involved in the regulation of neurite outgrowth, extracellular signal-regulated kinases (ERKs) and nuclear factor kappaB (NF-kappaB), is impaired when endogenous FLIP-L is downregulated, although TrkA remains activated. Finally, we demonstrate that FLIP-L interacts with TrkA, and not with p75(NTR), in an NGF-dependent manner, and endogenous FLIP-L interacts with TrkB in whole-brain lysates from embryonic day 15 mice embryos. Altogether, we uncover a new role for FLIP-L as an unexpected critical player in neurotrophin-induced mitogen-activated protein kinase/ERK- and NF-kappaB-mediated control of neurite growth in developing neurons.


ACR Appropriateness Criteria® Suspected Osteomyelitis, Septic Arthritis, or Soft Tissue Infection (Excluding Spine and Diabetic Foot).
Infection of the musculoskeletal system is a common clinical problem. Differentiating soft tissue from osseous infection often determines the appropriate clinical therapeutic course. Radiographs are the recommend initial imaging examination, and although often not diagnostic in acute osteomyelitis, can provide anatomic evaluation and alternative diagnoses influencing subsequent imaging selection and interpretation. MRI with contrast is the examination of choice for the evaluation of suspected osteomyelitis, and MRI, CT, and ultrasound can all be useful in the diagnosis of soft tissue infection. CT or a labeled leukocyte scan and sulfur colloid marrow scan combination are alternative options if MRI is contraindicated or extensive artifact from metal is present. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.


Excitatory and Inhibitory Neuronal Circuits in the Spinal Cord and Their Role in the Control of Motor Neuron Function and Degeneration.
The complex neuronal networks of the spinal cord coordinate a wide variety of motor functions, including walking, running, and voluntary and involuntary movements. This is accomplished by different groups of neurons, called center pattern generators, which control left-right alternation and flexor-extensor patterns. These spinal circuits, located in the ventral horns, are formed by several neuronal types, and the specific function of most of them has been identified by means of studies in vivo and in the isolated spinal cord of mice harboring genetically induced ablation of specific neuronal populations. These studies have shown that the coordinated activity of several interneuron types, mainly GABAergic and glycinergic inhibitory neurons, have a crucial role in the modulation of motor neurons activity that finally excites the corresponding muscles. A pharmacological experimental approach by administering in the spinal cord agonists and antagonists of glutamate, GABA, glycine, and acetylcholine receptors to alter their synaptic action has also produced important results, linking the deficits in the synaptic function with the resulting motor alterations. These results have also increased the knowledge of the mechanisms of motor neuron degeneration, which is characteristic of diseases such as amyotrophic lateral sclerosis, and therefore open the possibility of designing new strategies for the prevention and treatment of these diseases.


PChopper: high throughput peptide prediction for MRM/SRM transition design.
The use of selective reaction monitoring (SRM) based LC-MS/MS analysis for the quantification of phosphorylation stoichiometry has been rapidly increasing. At the same time, the number of sites that can be monitored in a single LC-MS/MS experiment is also increasing. The manual processes associated with running these experiments have highlighted the need for computational assistance to quickly design MRM/SRM candidates. PChopper has been developed to predict peptides that can be produced via enzymatic protein digest; this includes single enzyme digests, and combinations of enzymes. It also allows digests to be simulated in 'batch' mode and can combine information from these simulated digests to suggest the most appropriate enzyme(s) to use. PChopper also allows users to define the characteristic of their target peptides, and can automatically identify phosphorylation sites that may be of interest. Two application end points are available for interacting with the system; the first is a web based graphical tool, and the second is an API endpoint based on HTTP REST. Service oriented architecture was used to rapidly develop a system that can consume and expose several services. A graphical tool was built to provide an easy to follow workflow that allows scientists to quickly and easily identify the enzymes required to produce multiple peptides in parallel via enzymatic digests in a high throughput manner.


The relationship between premorbid neuroticism, cognitive dysfunction and persistence of depression: a 1-year follow-up.
In a previous report of patients with unipolar major depressive disorder, we found that deficits in autobiographical memory predicted depression levels over a 7-month interval. This follow-up examined predictors of recovery as defined by a period of 8 weeks with no or minimal symptoms of depression and examined the extra predictor variable, neuroticism. In a sample of 21 patients, episode duration was significantly correlated with high levels of premorbid neuroticism, dysfunctional attitudes and overgeneral autobiographical memories produced in response to emotionally negative cue words. When severity of depression was partialled out, high N score was significantly but independently correlated with each of these cognitive variables. The implication of these attitudinal and information processing biases were explored.


Clinical consequences of immune response to CT upper genital tract infection in women.
C. TRACHOMATIS (CT) infections of the upper genital tract in women are either acute, sub acute or chronic. CT infection has a tendency to be chronic, latent and persistent as a consequence of the host immune reaction to CT major outer membrane protein, 57 Kd heat shock protein and lipopolysaccharide. Chlamydial persistence can be induced as a result of inflammatory and/or immune regulated cytokines, Interferon gamma depletion of tryptophan causes a stress response involving development of abnormal forms with increased levels of stress response proteins which maintain host immune responses with continuous fibrin exudate.The main clinical consequences are acute and chronic pelvic inflammatory disease, with infertility, ectopic pregnancy and, less frequently, chronic pelvic pain as late sequelae.PID, WHEN ACUTE, IS MARKED BY BILATERAL PELVIC PAIN, PLUS OTHER INFECTIOUS SIGNS IN TYPICAL CASES: fever, leucorrhea, red and purulent cervix. In 50% cases, infectious signs are slight or absent or there is an atypical clinical situation. Laparoscopy is the key for diagnosis. It allows the surgeon to have a direct look at the pelvic organs and perform microbiologic and histologic sampling. In severe cases, laparoscopy allows the surgeon to aspirate the purulent discharge and successfully treat pelvic abscesses.Chronic PID usually is clinically silent. It is in most cases discovered some years after the onset of CT infection, in women operated on for tubal infertility or ectopic pregnancy. Further studies, to evaluate treatments efficiency in chronic cases and factors leading to ectopic pregnancy or to recurrence, are indicated.