Profile of women not attending in the Swiss Mammography Screening Pilot Programme.
The Swiss Mammography Screening Pilot Programme was conducted between 1993 and 1998 in three areas of the French-speaking canton of Vaud. Socio-demographic characteristics were available for the whole of the target population and were used to identify determinants of initial (in the first round) and repeated (in both first and second rounds) non-attendance by means of logistic regression analyses. Initial non-attendance was higher among non-Swiss, single or divorced/separated women, and increased with distance between the residence and the screening centre. Being single and aged 65-70, not living in the vicinity of the screening centre and replying to decline the invitation to the initial screening session significantly increased the odds of persisting in non-attendance for screening within the programme. Factors such as age, nationality, marital status and screening centre differed in their influence on initial and repeated non-attendance, and the type of reply to the invitation was strongly predictive of non-attendance in the next round.


Impact of an equality constraint on the class-specific residual variances in regression mixtures: A Monte Carlo simulation study.
Regression mixture models are a novel approach to modeling the heterogeneous effects of predictors on an outcome. In the model-building process, often residual variances are disregarded and simplifying assumptions are made without thorough examination of the consequences. In this simulation study, we investigated the impact of an equality constraint on the residual variances across latent classes. We examined the consequences of constraining the residual variances on class enumeration (finding the true number of latent classes) and on the parameter estimates, under a number of different simulation conditions meant to reflect the types of heterogeneity likely to exist in applied analyses. The results showed that bias in class enumeration increased as the difference in residual variances between the classes increased. Also, an inappropriate equality constraint on the residual variances greatly impacted on the estimated class sizes and showed the potential to greatly affect the parameter estimates in each class. These results suggest that it is important to make assumptions about residual variances with care and to carefully report what assumptions are made.


Phase noise tolerant inter-carrier-interference cancellation for WDM superchannels with sub-Nyquist channel spacing.
We propose and demonstrate a novel multi-input multi-output (MIMO) equalization based inter-carrier-interference (ICI) cancellation approach employing constant modulus algorithm (CMA) for supperchanels with sub-Nyquist channel spacing, where optical combs are used as optical sources. Compared with the least mean square (LMS) algorithm based ICI canceller, the proposed approach has comparable capability to accomplish the ICI mitigation for 56 Gbaud dual-polarization quadrature phase shift keying (DP-QPSK) signals with tight channel spacing till 50 GHz. In particular, compared with the LMS-MIMO based ICI canceller, the optical linewidth tolerance of 6 MHz is relaxed to 20 MHz given a 1dB required optical signal-to-noise ratio (OSNR) penalty for the CMA-MIMO based ICI canceller. Meanwhile, the CMA-MIMO based ICI canceller is ideal for real-time processing, since the number of parallel processing pipelines can be greater than 240 even in the presence of large linewidth.


MR Imaging-Based Radiomic Signatures of Distinct Molecular Subgroups of Medulloblastoma.
Distinct molecular subgroups of pediatric medulloblastoma confer important differences in prognosis and therapy. Currently, tissue sampling is the only method to obtain information for classification. Our goal was to develop and validate radiomic and machine learning approaches for predicting molecular subgroups of pediatric medulloblastoma. In this multi-institutional retrospective study, we evaluated MR imaging datasets of 109 pediatric patients with medulloblastoma from 3 children's hospitals from January 2001 to January 2014. A computational framework was developed to extract MR imaging-based radiomic features from tumor segmentations, and we tested 2 predictive models: a double 10-fold cross-validation using a combined dataset consisting of all 3 patient cohorts and a 3-dataset cross-validation, in which training was performed on 2 cohorts and testing was performed on the third independent cohort. We used the Wilcoxon rank sum test for feature selection with assessment of area under the receiver operating characteristic curve to evaluate model performance. Of 590 MR imaging-derived radiomic features, including intensity-based histograms, tumor edge-sharpness, Gabor features, and local area integral invariant features, extracted from imaging-derived tumor segmentations, tumor edge-sharpness was most useful for predicting sonic hedgehog and group 4 tumors. Receiver operating characteristic analysis revealed superior performance of the double 10-fold cross-validation model for predicting sonic hedgehog, group 3, and group 4 tumors when using combined T1- and T2-weighted images (area under the curve = 0.79, 0.70, and 0.83, respectively). With the independent 3-dataset cross-validation strategy, select radiomic features were predictive of sonic hedgehog (area under the curve = 0.70-0.73) and group 4 (area under the curve = 0.76-0.80) medulloblastoma. This study provides proof-of-concept results for the application of radiomic and machine learning approaches to a multi-institutional dataset for the prediction of medulloblastoma subgroups.


Estimating brain functional connectivity with sparse multivariate autoregression.
There is much current interest in identifying the anatomical and functional circuits that are the basis of the brain's computations, with hope that functional neuroimaging techniques will allow the in vivo study of these neural processes through the statistical analysis of the time-series they produce. Ideally, the use of techniques such as multivariate autoregressive (MAR) modelling should allow the identification of effective connectivity by combining graphical modelling methods with the concept of Granger causality. Unfortunately, current time-series methods perform well only for the case that the length of the time-series Nt is much larger than p, the number of brain sites studied, which is exactly the reverse of the situation in neuroimaging for which relatively short time-series are measured over thousands of voxels. Methods are introduced for dealing with this situation by using sparse MAR models. These can be estimated in a two-stage process involving (i) penalized regression and (ii) pruning of unlikely connections by means of the local false discovery rate developed by Efron. Extensive simulations were performed with idealized cortical networks having small world topologies and stable dynamics. These show that the detection efficiency of connections of the proposed procedure is quite high. Application of the method to real data was illustrated by the identification of neural circuitry related to emotional processing as measured by BOLD.


Oral Candidiasis: A Disease of Opportunity.
Oral candidiasis, commonly referred to as "thrush," is an opportunistic fungal infection that commonly affects the oral mucosa. The main causative agent, Candida albicans, is a highly versatile commensal organism that is well adapted to its human host; however, changes in the host microenvironment can promote the transition from one of commensalism to pathogen. This transition is heavily reliant on an impressive repertoire of virulence factors, most notably cell surface adhesins, proteolytic enzymes, morphologic switching, and the development of drug resistance. In the oral cavity, the co-adhesion of C. albicans with bacteria is crucial for its persistence, and a wide range of synergistic interactions with various oral species were described to enhance colonization in the host. As a frequent colonizer of the oral mucosa, the host immune response in the oral cavity is oriented toward a more tolerogenic state and, therefore, local innate immune defenses play a central role in maintaining Candida in its commensal state. Specifically, in addition to preventing Candida adherence to epithelial cells, saliva is enriched with anti-candidal peptides, considered to be part of the host innate immunity. The T helper 17 (Th17)-type adaptive immune response is mainly involved in mucosal host defenses, controlling initial growth of Candida and inhibiting subsequent tissue invasion. Animal models, most notably the mouse model of oropharyngeal candidiasis and the rat model of denture stomatitis, are instrumental in our understanding of Candida virulence factors and the factors leading to host susceptibility to infections. Given the continuing rise in development of resistance to the limited number of traditional antifungal agents, novel therapeutic strategies are directed toward identifying bioactive compounds that target pathogenic mechanisms to prevent C. albicans transition from harmless commensal to pathogen.


Role of tobacco use in the etiology of acoustic neuroma.
Two previous studies suggest that cigarette smoking reduces acoustic neuroma risk; however, an association between use of snuff tobacco and acoustic neuroma has not been investigated previously. The authors conducted a case-control study in Sweden from 2002 to 2007, in which 451 cases and 710 population-based controls completed questionnaires. Cases and controls were matched on gender, region, and age within 5 years. The authors estimated odds ratios using conditional logistic regression analyses, adjusted for education and tobacco use (snuff use in the smoking analysis and smoking in the snuff analysis). The risk of acoustic neuroma was greatly reduced in male current smokers (odds ratio (OR) = 0.41, 95% confidence interval (CI): 0.23, 0.74) and moderately reduced in female current smokers (OR = 0.70, 95% CI: 0.40, 1.23). In contrast, current snuff use among males was not associated with risk of acoustic neuroma (OR = 0.94, 95% CI: 0.57, 1.55). The authors' findings are consistent with previous reports of lower acoustic neuroma risk among current cigarette smokers than among never smokers. The absence of an association between snuff use and acoustic neuroma suggests that some constituent of tobacco smoke other than nicotine may confer protection against acoustic neuroma.


Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.
The cytochrome P450 CYP2C9 is responsible for the metabolism of S-warfarin. Two known allelic variants CYP2C9*2 and CYP2C9*3 differ from the wild type CYP2C9*1 by a single aminoacid substitution in each case. The allelic variants are associated with impaired hydroxylation of S-warfarin in in-vitro expression systems. We have studied the effect of CYP2C9 polymorphism on the in-vivo warfarin dose requirement. Patients with a daily warfarin dose requirement of 1.5 mg or less (low-dose group, n=36), randomly selected patients with a wide range of dose requirements from an anticoagulant clinic in north-east England (clinic control group, n=52), and 100 healthy controls from the community in the same region were studied. Genotyping for the CYP2C9*2 and CYP2C9*3 alleles was done by PCR analysis. Case notes were reviewed to assess the difficulties encountered during the induction of warfarin therapy and bleeding complications in the low-dose and clinic control groups. The odds ratio for individuals with a low warfarin dose requirement having one or more CYP2C9 variant alleles compared with the normal population was 6.21 (95% CI 2.48-15.6). Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy (5.97 [2.26-15.82]) and have increased risk of major bleeding complications (rate ratio 3.68 [1.43-9.50]) when compared with randomly selected clinic controls. We have shown that there is a strong association between CYP2C9 variant alleles and low warfarin dose requirement. CYP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.


Comparison of Steroid Modulation of Spontaneous Inhibitory Postsynaptic Currents in Cultured Hippocampal Neurons and Steady-State Single-Channel Currents from Heterologously Expressed α1β2γ2L GABA(A) Receptors.
Neuroactive steroids are efficacious modulators of γ-aminobutyric acid type A receptor (GABA(A)) receptor function. The effects of steroids on the GABA(A) receptor are typically determined by comparing steady-state single-channel open probability or macroscopic peak responses elicited by GABA in the absence and presence of a steroid. Due to differences in activation conditions (exposure duration, concentration of agonist), it is not obvious whether modulation measured using typical experimental protocols can be used to accurately predict the effect of a modulator on native receptors under physiologic conditions. In the present study, we examined the effects of 14 neuroactive steroids and analogs on the properties of spontaneous inhibitory postsynaptic currents (sIPSCs) in cultured rat hippocampal neurons. The goal was to determine whether the magnitude of modulation of the decay time course of sIPSCs correlates with the extent of modulation and kinetic properties of potentiation as determined in previous single-channel studies. The steroids were selected to cover a wide range of efficacy on heterologously expressed rat α1β2γ2L GABA(A) receptors, ranging from essentially inert to highly efficacious (strong potentiators of single-channel and macroscopic peak responses). The data indicate a strong correlation between prolongation of the decay time course of sIPSCs and potentiation of single-channel open probability. Furthermore, changes in intracluster closed time distributions were the single best predictor of prolongation of sIPSCs. We infer that the information obtained in steady-state single-channel recordings can be used to forecast modulation of synaptic currents.


Identification and localization of TRPC channels in the rat kidney.
It is well established that transient receptor potential (TRP) channels are activated following stimulation of G protein-coupled membrane receptors linked to PLC, but their differential expression in various cells of the renal nephron has not been described. In the present study, immunoprecipitations from rat kidney lysates followed by Western blot analysis using TRPC-specific, affinity-purified antibodies revealed the presence of TRPC1, -C3, and -C6. TRPC4, -C5, and -C7 were nondetectable. TRPC1 immunofluorescence was detected in glomeruli and specific tubular cells of the cortex and outer medulla. TRPC1 colocalized with aquaporin-1, a marker for proximal tubule and thin descending limb, but not with aquaporin-2, a marker for connecting tubule and collecting duct cells. TRPC3 and -C6 immunolabeling was predominantly confined to glomeruli and specific tubular cells of the cortex and both the outer and inner medulla. TRPC3 and -C6 colocalized with aquaporin-2, but not with the Na(+)/Ca(2+) exchanger or peanut lectin. Thus TRPC3 and -C6 proteins are expressed in principle cells of the collecting duct. In polarized cultures of M1 and IMCD-3 collecting duct cells, TRPC3 was localized exclusively to the apical domain, whereas TRPC6 was found in both the basolateral and apical membranes. TRPC3 and TRPC6 were also detected in primary podocyte cultures, whereas TRPC1 was exclusively expressed in mesangial cell cultures. Specific immunopositive labeling for TRPC4, -C5, or -C7 was not observed in kidney sections or cell lines. These results suggest that TRPC1, -C3, and -C6 may play a functional role in PLC-dependent signaling in specific regions of the nephron.


The Stillbirth Collaborative Research Network neuropathologic examination protocol.
We describe the neuropathologic procedure utilized in the Stillbirth Collaborative Research Network (SCRN), focusing on the examination of central nervous system (CNS) in stillbirth (SB). The SCRN was organized to perform a case-control study to determine the scope and causes of SB. Pathologists at all the participating centers agreed on and used the same standardized neuropathologic techniques. Standardized sections were taken and detailed data were collected. Fresh brain tissue was saved for investigative purposes. A total of 663 women with SB were enrolled into the case-control study: 620 delivered a single stillborn, 42 delivered twins, and 1 delivered triplets. Of the 560 (84.5%) who consented to postmortem examination, 465 (70.1%) also gave consent to the examination of the CNS. In the 440 stillborn infants in whom CNS examination was possible, 248 (56.4%) of the brains were intact, 72 were fragmented (16.4%), and 120 (27.3%) were liquefied. In summary, this is the largest prospective study dedicated to investigate the causes of SB and collect essential information and biological samples in the United States. A protocol for neuropathologic examination was instituted, and a brain tissue repository was created to provide samples and related data for future investigations.


Hyperoxia-induced preconditioning against renal ischemic injury is mediated by reactive oxygen species but not related to heat shock proteins 70 and 32.
Pre-exposure of rats to normobaric hyperoxia (O2 ≥ 95%) may induce late preconditioning against renal ischemia-reperfusion (IR) injury. In this study we investigated probable mechanisms of IR injury such as the role of reactive oxygen species (ROS), renal antioxidant agents, and heat shock proteins (HSP) 32 and 70 during delayed hyperoxia-preconditioning (HO). Fifty-two rats were divided into 7 groups: (A) IR, (B) HO + IR, (C) mercaptopropionyl glycine (MPG) + HO + IR, (D) MPG + IR, (E) HO + sham, (F) MPG + sham, and (G) sham. Rats in the following study groups (group B, C and E) were kept in a normobaric hyperoxic environment for 4 h/day for 6 consecutive days, after which they were subjected to 40 minutes of ischemia; animals in the control group (group A, D, F, and G) were kept in a normoxic cage. At the end of the preconditioning period, 24 hours of reperfusion was performed. Renal function was assessed by measuring serum creatinine (Cr), blood urea nitrogen (BUN), and creatinine clearance (CLCr). Induction of the antioxidant system was evaluated by measuring renal catalase (CAT) and superoxide dismutase (SOD) activities and glutathione (GSH) and malondialdehyde (MDA) content. The role of ROS was investigated by use of MPG (a ROS scavenger). HSP32 & 70 mRNA and protein also were determined. The hyperoxia-preconditioned IR group (B) had a lower plasma Cr and BUN and greater CLCr compared with the IR group (A) (P ≤ .016). Administration of MPG led to an increase in plasma Cr and BUN and a decrease in CLCr in group C compared with the hyperoxia-preconditioned group B (P ≤ .004). The hyperoxia-preconditioned IR group had a greater CAT activity and GSH level compared with the IR group A (P ≤ .007), whereas the administration of MPG did not change the GSH level but led to a decrease in CAT activity in group D compared with group B (P < .001). SOD activity did not change in hyperoxia-preconditioned ischemic rats compared with ischemic rats. Hyperoxia preconditioning and MPG administration in ischemic animals did not result in any considerable change in MDA level compared with the IR group A. Also, there were no clinically relevant differences in HSP32 & 70 mRNA and protein between all groups. The present study demonstrates that repeated pre-exposure to hyperoxia can decrease subsequent renal IR damage in this rat model of renal ischemia. Free radical production after hyperoxia appears to play a pivotal role in the hyperoxia-induced renal protection independent of HSP level. Antioxidant enzyme activities and especially catalase seem to be implicated in this renal protective mechanism.


Unchain My Heart: Integrins at the Basis of iPSC Cardiomyocyte Differentiation.
The cellular response to the extracellular matrix (ECM) microenvironment mediated by integrin adhesion is of fundamental importance, in both developmental and pathological processes. In particular, mechanotransduction is of growing importance in groundbreaking cellular models such as induced pluripotent stem cells (iPSC), since this process may strongly influence cell fate and, thus, augment the precision of differentiation into specific cell types, e.g., cardiomyocytes. The decryption of the cellular machinery starting from ECM sensing to iPSC differentiation calls for new in vitro methods. Conveniently, engineered biomaterials activating controlled integrin-mediated responses through chemical, physical, and geometrical designs are key to resolving this issue and could foster clinical translation of optimized iPSC-based technology. This review introduces the main integrin-dependent mechanisms and signalling pathways involved in mechanotransduction. Special consideration is given to the integrin-iPSC linkage signalling chain in the cardiovascular field, focusing on biomaterial-based in vitro models to evaluate the relevance of this process in iPSC differentiation into cardiomyocytes.


From patient centered risk factors to comprehensive prognostic models: a suggested framework for outcome prediction in umbilical cord blood transplantation.
Prospectively identifying patients who will gain maximal benefit from umbilical cord blood transplantation (UCBT) with minimal risk is a desirable unmet need. A complex network of parameters related to patient, disease, donor, and procedure all come into play. We review the prognostic role of patient-related risk factors in adults undergoing UCBT. Furthermore, since comprehensive prognostic models are lacking in UCBT, we suggest a framework for integrating patients' features in the development of prediction models for UCBT outcomes. Such models could contribute to patient selection, optimization of the various modifiable features in the process of UCBT, analysis of retrospective data, and design of interventions.


ROC curves for clinical prediction models part 1. ROC plots showed no added value above the AUC when evaluating the performance of clinical prediction models.
Receiver operating characteristic (ROC) curves show how well a risk prediction model discriminates between patients with and without a condition. We aim to investigate how ROC curves are presented in the literature and discuss and illustrate their potential limitations. We conducted a pragmatic literature review of contemporary publications that externally validated clinical prediction models. We illustrated limitations of ROC curves using a testicular cancer case study and simulated data. Of 86 identified prediction modeling studies, 52 (60%) presented ROC curves without thresholds and one (1%) presented an ROC curve with only a few thresholds. We illustrate that ROC curves in their standard form withhold threshold information have an unstable shape even for the same area under the curve (AUC) and are problematic for comparing model performance conditional on threshold. We compare ROC curves with classification plots, which show sensitivity and specificity conditional on risk thresholds. ROC curves do not offer more information than the AUC to indicate discriminative ability. To assess the model's performance for decision-making, results should be provided conditional on risk thresholds. Therefore, if discriminatory ability must be visualized, classification plots are attractive.


Cancer Clinicians' Views Regarding an App That Helps Patients With Cancer Meet Their Information Needs: Qualitative Interview Study.
Many patients with cancer have unmet information needs during the course of the illness. Smart devices, such as smartphones and tablet computers, provide an opportunity to deliver information to patients remotely. We aim to develop an app intervention to help patients with cancer meet their illness-related information needs in noninpatient settings. In addition to the in-depth exploration of the issues faced by the target users of a potential intervention, it is important to gain an understanding of the context in which the intervention will be used and the potential influences on its adoption. As such, understanding the views of clinicians is key to the successful implementation of this type of app in practice. Additionally, clinicians have an awareness of their patients' needs and can provide further insight into the type of app and features that might be most beneficial. This study aims to explore cancer clinicians' views on this type of intervention and whether they would support the use of an app in cancer care. Specifically, the perceived acceptability of an app used in consultations, useful app features, the potential benefits and disadvantages of an app, and barriers to app use were explored. A total of 20 qualitative, semistructured interviews were conducted with 22 clinicians from urological, colorectal, breast, or gynecological cancer clinics across 2 hospitals in South Wales. The interviews were audio recorded, transcribed, and analyzed using thematic analysis. Clinicians felt that it would be acceptable for patients to use such an app in noninpatient settings, including during consultations. The benefits of this type of app were anticipated to be a more informed patient, an increased sense of control for patients, better doctor-patient communication, and a more efficient and effective consultation. In contrast, an increase in clinicians' workload and poorer communication in consultations, which depended on the included app features, were identified as potential disadvantages. The anticipated barriers to app use included patients' age and prior experience with smart technology, their access to smart devices, the confidentiality of information, and an avoidant coping approach to their condition. This study suggests that clinicians should support their patients in using an app to help them meet their information needs both at home and during consultations. This study highlights some of the potential barriers for this type of intervention in practice, which could be minimized during the intervention design process.


Time to Treatment and Mortality during Mandated Emergency Care for Sepsis.
In 2013, New York began requiring hospitals to follow protocols for the early identification and treatment of sepsis. However, there is controversy about whether more rapid treatment of sepsis improves outcomes in patients. We studied data from patients with sepsis and septic shock that were reported to the New York State Department of Health from April 1, 2014, to June 30, 2016. Patients had a sepsis protocol initiated within 6 hours after arrival in the emergency department and had all items in a 3-hour bundle of care for patients with sepsis (i.e., blood cultures, broad-spectrum antibiotic agents, and lactate measurement) completed within 12 hours. Multilevel models were used to assess the associations between the time until completion of the 3-hour bundle and risk-adjusted mortality. We also examined the times to the administration of antibiotics and to the completion of an initial bolus of intravenous fluid. Among 49,331 patients at 149 hospitals, 40,696 (82.5%) had the 3-hour bundle completed within 3 hours. The median time to completion of the 3-hour bundle was 1.30 hours (interquartile range, 0.65 to 2.35), the median time to the administration of antibiotics was 0.95 hours (interquartile range, 0.35 to 1.95), and the median time to completion of the fluid bolus was 2.56 hours (interquartile range, 1.33 to 4.20). Among patients who had the 3-hour bundle completed within 12 hours, a longer time to the completion of the bundle was associated with higher risk-adjusted in-hospital mortality (odds ratio, 1.04 per hour; 95% confidence interval [CI], 1.02 to 1.05; P<0.001), as was a longer time to the administration of antibiotics (odds ratio, 1.04 per hour; 95% CI, 1.03 to 1.06; P<0.001) but not a longer time to the completion of a bolus of intravenous fluids (odds ratio, 1.01 per hour; 95% CI, 0.99 to 1.02; P=0.21). More rapid completion of a 3-hour bundle of sepsis care and rapid administration of antibiotics, but not rapid completion of an initial bolus of intravenous fluids, were associated with lower risk-adjusted in-hospital mortality. (Funded by the National Institutes of Health and others.).


Activity-dependent presynaptic regulation of quantal size at the mammalian neuromuscular junction in vivo.
Changes in synaptic activity alter quantal size, but the relative roles of presynaptic and postsynaptic cells in these changes are only beginning to be understood. We examined the mechanism underlying increased quantal size after block of synaptic activity at the mammalian neuromuscular junction in vivo. We found that changes in neither acetylcholinesterase activity nor acetylcholine receptor density could account for the increase. By elimination, it appears likely that the site of increased quantal size after chronic block of activity is presynaptic and involves increased release of acetylcholine. We used mice with muscle hyperexcitability caused by mutation of the ClC-1 muscle chloride channel to examine the role of postsynaptic activity in controlling quantal size. Surprisingly, quantal size was increased in ClC mice before block of synaptic activity. We examined the mechanism underlying increased quantal size in ClC mice and found that it also appeared to be located presynaptically. When presynaptic activity was completely blocked in both control and ClC mice, quantal size was large in both groups despite the higher level of postsynaptic activity in ClC mice. This suggests that postsynaptic activity does not regulate quantal size at the neuromuscular junction. We propose that presynaptic activity modulates quantal size at the neuromuscular junction by modulating the amount of acetylcholine released from vesicles.


ACR Appropriateness Criteria® Radiologic Management of Uterine Leiomyomas.
Uterine fibroids, also known as leiomyomas, are the most common benign tumor in women of reproductive age. When symptomatic, these patients can present with bleeding and/or bulk-related symptoms. Treatment options for symptomatic uterine leiomyomas include medical management, minimally invasive treatment such as uterine artery embolization, and surgical options, such as myomectomy. It is important to understand the role of these treatment options in various clinical scenarios so that appropriate consultation is performed. Furthermore, patients should be presented with the outcomes and complications of each of these treatment options. A summary of the data and clinical trials of the treatment options for symptomatic uterine leiomyomas is outlined in this article. 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.


Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation-Structure-Based Hit Evaluation and Chemistry Exploration.
Soluble epoxide hydrolase (sEH) is involved in the regulation of many biological processes by metabolizing the key bioactive lipid mediator, epoxyeicosatrienoic acids. For the development of sEH inhibitors with improved physicochemical properties, we performed both a fragment screening and a high-throughput screening aiming at an integrated hit evaluation and lead generation. Followed by a joint dose-response analysis to confirm the hits, the identified actives were then effectively triaged by a structure-based hit-classification approach to three prioritized series. Two distinct scaffolds were identified as tractable starting points for potential lead chemistry work. The oxoindoline series bind at the right-hand side of the active-site pocket with hydrogen bonds to the protein. The 2-phenylbenzimidazole-4-sulfonamide series bind at the central channel with significant induced fit, which has not been previously reported. On the basis of the encouraging initial results, we envision that a new lead series with improved properties could be generated if a vector is found that could merge the cyclohexyl functionality of the oxoindoline series with the trifluoromethyl moiety of the 2-phenylbenzimidazole-4-sulfonamide series.


Persistence of HCV in Acutely-Infected Patients Depletes C24-Ceramide and Upregulates Sphingosine and Sphinganine Serum Levels.
Hepatitis C virus (HCV) substantially affects lipid metabolism, and remodeling of sphingolipids appears to be essential for HCV persistence in vitro. The aim of the current study is the evaluation of serum sphingolipid variations during acute HCV infection. We enrolled prospectively 60 consecutive patients with acute HCV infection, most of them already infected with human immunodeficiency virus (HIV), and serum was collected at the time of diagnosis and longitudinally over a six-month period until initiation of antiviral therapy or confirmed spontaneous clearance. Quantification of serum sphingolipids was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spontaneous clearance was observed in 11 out of 60 patients (18.3%), a sustained viral response (SVR) in 43 out of 45 patients (95.5%) receiving an antiviral treatment after follow-up, whereas persistence of HCV occurred in six out of 60 patients (10%). C24-ceramide (C24-Cer)-levels increased at follow-up in patients with spontaneous HCV eradication (p < 0.01), as compared to baseline. Sphingosine and sphinganine values were significantly upregulated in patients unable to clear HCV over time compared to patients with spontaneous clearance of HCV infection on follow-up (p = 0.013 and 0.006, respectively). In summary, the persistence of HCV after acute infection induces a downregulation of C24Cer and a simultaneous elevation of serum sphingosine and sphinganine concentrations.


Dichotic listening impairments in early onset schizophrenia are associated with reduced left temporal lobe volume.
Dichotic listening (DL) impairments, in particular the loss or reduction of right ear advantage (REA) in people with schizophrenia have been variously interpreted as both a state and trait marker for schizophrenia. To date, there has been no comprehensive investigation of dichotic language impairments in relation to the structural integrity of the temporal cortex--the likely neural substrate for such impairments. In this study of 39 early onset patients and matched controls we used a dichotic listening procedure and examined the findings in relation to MRI measurements of gross and regional cerebral volumes. No overall group difference in ear advantage was found between patients and controls but patients who showed absence of REA also demonstrated an accompanying reduction of left temporal lobe volume compared with patients who showed normal ear advantage and controls. The findings suggest that impaired DL performance is a correlate of structural change in the temporal lobe and that this is apparent in early onset cases.


Management of paroxysmal atrioventricular nodal reentrant tachycardia in the critically ill surgical patient.
Paroxysmal atrioventricular nodal reentrant tachycardia is an infrequently encountered supraventricular arrhythmia that continues to present difficult management problems in the critically ill surgical patient. The purpose of this study was to evaluate the efficacy of a new treatment algorithm involving the sequential administration of different classes of antiarrhythmic agents until conversion to sinus rhythm was achieved. Nonrandomized, consecutive, protocol-driven descriptive cohort. University hospital surgical and trauma intensive care unit (ICU). During an 11-month period, we prospectively evaluated all hemodynamically stable patients who sustained new-onset atrioventricular nodal reentrant tachycardia. Vagal maneuver, followed by the rapid, sequential infusion of antiarrhythmic agents (i.e., adenosine, verapamil, and esmolol, respectively) until the arrhythmia was terminated. Twenty-seven patients (4% of all admissions) were evaluated, including 16 trauma patients (injury Severity Score of 20 +/- 8) and 11 general surgical patients (Acute Physiology and Chronic Health Evaluation II score of 17 +/- 7). Time from ICU admission to onset of atrioventricular nodal reentrant tachycardia was 4.5 +/- 5 days (median 2.5). Arrhythmia termination was achieved in all patients within minutes (mean 13 +/- 10 [SD]). Incremental sequential adenosine administration alone, however, was successful in affecting conversion to sinus rhythm in only 44% of initial episodes of atrioventricular nodal reentrant tachycardia (95% confidence interval 21% to 67%). A total of 14 (52%) patients developed 38 relapses of paroxysmal supraventricular tachycardia in the ICU after initial conversion to sinus rhythm. These relapses required additional antiarrhythmic therapy. Adenosine was only effective in 34% of the relapses (95% confidence interval 17% to 53%). Seven (50%) of these 14 patients developed multiple relapses. However, only two patients were receiving suppressive calcium-channel or beta-adrenergic receptor blockade at the time of relapse. The use of a multiagent algorithm was effective for the initial conversion of new-onset atrioventricular nodal reentrant tachycardia to sinus rhythm in critically ill surgical and trauma patients. This preliminary report suggests that adenosine has marginal efficacy in the critically ill surgical or trauma patient. Given the high frequency of relapses, regardless of the agents used to achieve initial control, suppression therapy for the arrhythmia during the period of maximal cardiovascular stress is essential.


Natural history of nicotine withdrawal.
To examine the natural history of nicotine withdrawal and individual differences associated with withdrawal duration and severity. Prospective study of withdrawal symptoms among smokers who quit for at least 24 hours. Participants used Ecological Momentary Assessment to monitor symptoms in their natural environment using an Electronic Diary (ED). A total of 214 cigarette smokers (59% female, 92% Caucasian). All participants received a clinic-based, behavioral, group cessation intervention. Severity and duration of withdrawal was not addressed explicitly in treatment. Participants were 'beeped' by the ED approximately five times/day to complete affect assessments (negative affect, arousal, attention disturbance, restlessness), and daily assessments of sleep disturbance (at waking) and of cognitive performance (each evening) for a week prior to quitting and for up to 21 days after quitting. Withdrawal was considered resolved when withdrawal scores returned to baseline levels for at least 2 consecutive days. All symptoms returned to baseline levels within 10 days of quitting. All variables except arousal and sleep disturbance showed change over time. No robust predictors of individual differences in withdrawal responses emerged. The time-course of withdrawal may be shorter than previously reported. The natural history of nicotine withdrawal may have implications for theories of withdrawal and smoking relapse and for smoking cessation treatment.


Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death.
The molecular events causing memory loss and neuronal cell death in Alzheimer's disease (AD) over time are still unknown. Here we found that picomolar concentrations of soluble oligomers of synthetic beta amyloid (Aβ42) aggregates incubated with BV2 cells or rat astrocytes caused a sensitised response of Toll-like receptor 4 (TLR4) with time, leading to increased production of TNF-α. Aβ aggregates caused long term potentiation (LTP) deficit in hippocampal slices and predominantly neuronal cell death in co-cultures of astrocytes and neurons, which was blocked by TLR4 antagonists. Soluble Aβ aggregates cause LTP deficit and neuronal death via an autocrine/paracrine mechanism due to TLR4 signalling. These findings suggest that the TLR4-mediated inflammatory response may be a key pathophysiological process in AD.


Wellness in older adults: a concept analysis.
The purpose of this analysis is to examine the concept of wellness within the context of older adulthood. Identifying characteristics of wellness will clarify and develop conceptual strengths and limitations, providing a step toward evaluating its relevance in older adults and increasing utility in geriatric nursing. Rodger's evolutionary perspective. Computer and manual searches were conducted of articles in the English language from 1950 to 2010, addressing wellness across the life span or among older adult populations. An inductive analysis of articles produced descriptive themes. A historical time line traced the evolution of the wellness concept and its operationalization. Wellness has evolved from a little used concept to one commonly applied across many industries. Antecedents, attributes, and consequences of wellness are described. Concepts related to wellness are also identified. This concept analysis adds clarity to wellness in older adults. The state of wellness development as a concept in geriatric nursing is moving from conceptualization to use and testing in nursing theory and interventions. Increased knowledge of wellness will enable geriatric nurses to discover the strengths of older adults thereby promoting their ongoing growth and development while simultaneously guiding care for their changing and diverse health.


Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours.
Although compulsive sexual behaviour (CSB) has been conceptualized as a "behavioural" addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions.


Multiple particle tracking study of thermally-gelling nanoemulsions.
We perform multiple particle tracking (MPT) on a thermally-gelling oil-in-water nanoemulsion system. Carboxylated and plain polystyrene probes are used to investigate the role of colloidal probe size and surface chemistry on MPT in the nanoemulsion system. As temperature increases, hydrophobic groups of PEG-based gelators (PEGDA) partition into the oil/water interface and bridge droplets. This intercolloidal attraction generates a wide variety of microstructures consisting of droplet-rich and droplet-poor phases. By tailoring the MPT colloidal probe surface chemistry, we can control the residence of probes in each domain, thus allowing us to independently probe each phase. Our results show stark differences in probe dynamics in each domain. For certain conditions, the mean squared displacement (MSD) can differ by over four orders of magnitude for the same probe size but different surface chemistry. Carboxylated probe surface chemistries result in "slippery" probes while plain polystyrene probes appear to tether to the nanoemulsion gel network. We also observe probe hopping between pores in the gel for carboxylated probes. Our approach demonstrates that probes with different surface chemistries are useful in probing the local regions of a colloidal gel and allows the measurement of local properties within structurally heterogeneous hydrogels.


Characterization of glutamatergic neurons in the rat atrial intrinsic cardiac ganglia that project to the cardiac ventricular wall.
The intrinsic cardiac nervous system modulates cardiac function by acting as an integration site for regulating autonomic efferent cardiac output. This intrinsic system is proposed to be composed of a short cardio-cardiac feedback control loop within the cardiac innervation hierarchy. For example, electrophysiological studies have postulated the presence of sensory neurons in intrinsic cardiac ganglia (ICG) for regional cardiac control. There is still a knowledge gap, however, about the anatomical location and neurochemical phenotype of sensory neurons inside ICG. In the present study, rat ICG neurons were characterized neurochemically with immunohistochemistry using glutamatergic markers: vesicular glutamate transporters 1 and 2 (VGLUT1; VGLUT2), and glutaminase (GLS), the enzyme essential for glutamate production. Glutamatergic neurons (VGLUT1/VGLUT2/GLS) in the ICG that have axons to the ventricles were identified by retrograde tracing of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) injected in the ventricular wall. Co-labeling of VGLUT1, VGLUT2, and GLS with the vesicular acetylcholine transporter (VAChT) was used to evaluate the relationship between post-ganglionic autonomic neurons and glutamatergic neurons. Sequential labeling of VGLUT1 and VGLUT2 in adjacent tissue sections was used to evaluate the co-localization of VGLUT1 and VGLUT2 in ICG neurons. Our studies yielded the following results: (1) ICG contain glutamatergic neurons with GLS for glutamate production and VGLUT1 and 2 for transport of glutamate into synaptic vesicles; (2) atrial ICG contain neurons that project to ventricle walls and these neurons are glutamatergic; (3) many glutamatergic ICG neurons also were cholinergic, expressing VAChT; (4) VGLUT1 and VGLUT2 co-localization occurred in ICG neurons with variation of their protein expression level. Investigation of both glutamatergic and cholinergic ICG neurons could help in better understanding the function of the intrinsic cardiac nervous system.


Large-scale arrays of single- and few-layer MoS2 nanomechanical resonators.
We report the fabrication of large-scale arrays of suspended molybdenum disulfide (MoS2) atomic layers, as two-dimensional (2D) MoS2 nanomechanical resonators. We employ a water-assisted lift-off process to release chemical vapor deposited (CVD) MoS2 atomic layers from a donor substrate, followed by an all-dry transfer onto microtrench arrays. The resultant large arrays of suspended single- and few-layer MoS2 drumhead resonators (0.5-2 μm in diameter) offer fundamental resonances (f0) in the very high frequency (VHF) band (up to ∼120 MHz) and excellent figures-of-merit up to f0 × Q ≈ 3 × 10(10) Hz. A stretched circular diaphragm model allows us to estimate low pre-tension levels of typically ∼15 mN m(-1) in these devices. Compared to previous approaches, our transfer process features high yield and uniformity with minimal liquid and chemical exposure (only involving DI water), resulting in high-quality MoS2 crystals and exceptional device performance and homogeneity; and our process is readily applicable to other 2D materials.


Assessment of the body burden of chelatable lead: a model and its application to lead workers.
A hypothetical model was introduced to estimate the body burden of chelatable lead from the mobilisation yield of lead by calcium disodium ethylenediamine tetra-acetate (CaEDTA). It was estimated that, on average, 14 and 19% of the body burden was mobilised into the urine during the 24 hours after an injection of 53.4 mumol (20 mg) and 107 mumol (40 mg) CaEDTA per kg bodyweight, respectively. The body burden of chelatable lead ranged from 4 mumol (0.8 mg) to 120 mumol (24.9 mg) (mean 37 mumol (7.7 mg) in lead workers with blood lead concentrations of 0.3-2.9 mumol/kg (6-60 microgram/100 g) (mean 1.4 mumol/kg (29 microgram/100 g)). There were linear relationships between blood lead concentrations and body burden of chelatable lead on a log scale.


SU-E-T-175: A Study on Design and Fabrication of 25 * 25 cm2 Beam Monitor for Scanning Carbon Beam.
The KHIMA is developing a superconducting cyclotron of 430 MeV/u for carbon therapy. In order to verify the irradiated beam dose and position, detectors have been developed. The detector has a considered in the active area of 25*25cm2 to cover the entire beam scanning area. To minimize the loss of data during beam irradiation, a fast data acquisition system was required. A PPIC type was adopted. To measure the beam position and profile, the electrode of PPIC was designed to have a strip pattern. The PCB technique was applied to large area with thin FR-4 plate of electrodes. The chamber has a strip interval of 1.7mm. He was used as the filling gas in order to reduce the ion collection time. Output signal from the detector connected to the two charge integrators was transferred every 10us. The signal can be stored temporarily in memory of FPGA through one of 2 integrators. The fabricated large electrode plates did not show any deformation on their shape. Depending on the beam position, the amount of dose from the ion chamber will be measured. For fast data acquisition, the DAQ board was fabricated by using 2 charge integrators and the FPGA. The obtained data from the ion chamber was displaced on the PC screen every 10us. The fluence map of a single layer will be shown on the PC screen at the end of beam irradiation on the layer. The output data from the profile monitor will be compared with Gafchromic Film results. PCB method for active area of thin electrodes was used in the strip pattern. To reduce the loss of data during irradiation, 2 charge integrators are used alternately. The response of the readout data was set 1 0us. The beam tests will be performed with the MC-50 Cyclotron.


Scribble1/AP2 complex coordinates NMDA receptor endocytic recycling.
The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs) internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling.


The transformation of the nuclear nanoarchitecture in human field carcinogenesis.
Morphological alterations of the nuclear texture are a hallmark of carcinogenesis. At later stages of disease, these changes are well characterized and detectable by light microscopy. Evidence suggests that similar albeit nanoscopic alterations develop at the predysplastic stages of carcinogenesis. Using the novel optical technique partial wave spectroscopic microscopy, we identified profound changes in the nanoscale chromatin topology in microscopically normal tissue as a common event in the field carcinogenesis of many cancers. In particular, higher-order chromatin structure at supranucleosomal length scales (20-200 nm) becomes exceedingly heterogeneous, a measure we quantify using the disorder strength (Ld ) of the spatial arrangement of chromatin density. Here, we review partial wave spectroscopic nanocytology clinical studies and the technology's promise as an early cancer screening technology.


Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.
Methadone maintenance was the first widely used form of opioid replacement therapy developed to treat heroin dependence, and it remains the best-researched treatment for this problem. Despite the widespread use of methadone in maintenance treatment for opioid dependence in many countries, it is a controversial treatment whose effectiveness has been disputed. To evaluate the effects of methadone maintenance treatment (MMT) compared with treatments that did not involve opioid replacement therapy (i.e., detoxification, offer of drug-free rehabilitation, placebo medication, wait-list controls) for opioid dependence. We searched all the following databases up to 2001: Cochrane Drugs and Alcohol Review Group Register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE, Current Contents, Psychlit, CORK [www. state.vt.su/adap/cork], Alcohol and Drug Council of Australia (ADCA) [www.adca.org.au], Australian Drug Foundation (ADF-VIC) [www.adf.org.au], Centre for Education and Information on Drugs and Alcohol (CEIDA) [www.ceida.net.au], Australian Bibliographic Network (ABN), and Library of Congress databases, available NIDA monographs and the College on Problems of Drug Dependence Inc. proceedings, the reference lists of all identified studies and published reviews; authors of identified RCTs were asked about other published or unpublished relevant RCTs. All randomised controlled clinical trials of methadone maintenance therapy compared with either placebo maintenance or other non-pharmacological therapy for the treatment of opioid dependence. Reviewers evaluated the papers separately and independently, rating methodological quality of concealment of allocation, data were extracted independently for meta-analysis and double-entered. Six studies met the criteria for inclusion in this review, all were randomised clinical trials, two were double-blind. There were a total number of 954 participants. The method of concealment of allocation was inadequate in one study, not clearly described in four studies, but adequate in a sixth study. Based on the meta-analysis, methadone appeared statistically significantly more effective than non-pharmacological approaches in retaining patient in treatment (3 RCTs, RR=3.05; 95%CI: 1.75-5.35) and in the suppression of heroin use (3 RCTs, RR=0.32; 95%CI: 0.23-0.44), but not statistically in criminal activity (3 RCTs, RR=0.39; 95%CI: 0.12-1.25). Methadone is an effective maintenance therapy intervention for the treatment of heroin dependence as it retains patients in treatment and decreases heroin use better than treatments that do not utilise opioid replacement therapy. It does not show a statistically significant superior effect on criminal activity.


Early Palaeozoic ocean anoxia and global warming driven by the evolution of shallow burrowing.
The evolution of burrowing animals forms a defining event in the history of the Earth. It has been hypothesised that the expansion of seafloor burrowing during the Palaeozoic altered the biogeochemistry of the oceans and atmosphere. However, whilst potential impacts of bioturbation on the individual phosphorus, oxygen and sulphur cycles have been considered, combined effects have not been investigated, leading to major uncertainty over the timing and magnitude of the Earth system response to the evolution of bioturbation. Here we integrate the evolution of bioturbation into the COPSE model of global biogeochemical cycling, and compare quantitative model predictions to multiple geochemical proxies. Our results suggest that the advent of shallow burrowing in the early Cambrian contributed to a global low-oxygen state, which prevailed for ~100 million years. This impact of bioturbation on global biogeochemistry likely affected animal evolution through expanded ocean anoxia, high atmospheric CO2 levels and global warming.


The addition of heat shock protein HSPA8 to cryoprotective media improves the survival of brown bear (Ursus arctos) spermatozoa during chilling and after cryopreservation.
The Cantabrian brown bear survives as a small remnant population in northern Spain and semen cryopreservation for future artificial insemination is one of the measures being implemented for conservation of this species. As part of this program we investigated the value of adding heat shock protein A8 (HSPA8) to media (N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid-TRIS-fructose with 20% egg yolk) used for chilling and cryopreserving the spermatozoa. Semen samples from eight brown bears were obtained by electroejaculation during the breeding season. In experiment 1, we tested three concentrations of HSPA8 (0.5, 1, and 5 μg/mL) to determine whether sperm motility (computer assisted sperm analysis system) and sperm survival could be improved during refrigeration (5 °C) up to 48 hours. Results showed that sperm viability (test with propidium iodide) was improved by the addition of 0.5 and 5 μg/mL HSPA8. In experiment 2, HSPA8 was added to the cryopreservation media (6% final glycerol concentration) before the freezing process. Though there were no differences in sperm viability immediately after thawing (analyses to 0 hours), plasma membrane permeability (test with YO-PRO-1) was significantly lower by the presence of HSPA8 (1 μg/mL) and acrosomal damage (test with peanut agglutinin-fluorescein isothiocyanate conjugate) was reduced by higher concentrations of HSPA8 (1 and 5 μg/mL) (analyses after thermal stress test incubating over 2 hours to 37 °C). In experiment 3, results of a simple progression test carried out through artificial mucus (hyaluronic acid 4 mg/mL) showed a significant decrease in the total number of sperm able to swim a distance of 0.5 to 2 cm through a capillary tube for all HSPA8-based extenders. Nevertheless, the distance traveled by the vanguard spermatozoa, which represent a highly motile subpopulation, was restored by the inclusion of 1 and 5 μg/mL HSPA8 in the cryopreservation media. Thus, the HSPA8 addition to extender improves the quality of brown bear (Ursus arctos) sperm during chilling (viability) and after cryopreservation (number of sperm with damaged acrosomes and "apoptotic-like" changes).


Requirement of JIP1-mediated c-Jun N-terminal kinase activation for obesity-induced insulin resistance.
The c-Jun NH(2)-terminal kinase (JNK) interacting protein 1 (JIP1) has been proposed to act as a scaffold protein that mediates JNK activation. However, recent studies have implicated JIP1 in multiple biochemical processes. Physiological roles of JIP1 that are related to the JNK scaffold function of JIP1 are therefore unclear. To test the role of JIP1 in JNK activation, we created mice with a germ line point mutation in the Jip1 gene (Thr(103) replaced with Ala) that selectively blocks JIP1-mediated JNK activation. These mutant mice exhibit a severe defect in JNK activation caused by feeding of a high-fat diet. The loss of JIP1-mediated JNK activation protected the mutant mice against obesity-induced insulin resistance. We conclude that JIP1-mediated JNK activation plays a critical role in metabolic stress regulation of the JNK signaling pathway.


Nucleosome remodeler SNF2L suppresses cell proliferation and migration and attenuates Wnt signaling.
ISWI is an evolutionarily conserved ATPase that catalyzes nucleosome remodeling in different macromolecular complexes. Two mammalian ISWI orthologs, SNF2H and SNF2L, are thought to have specialized functions despite their high sequence similarity. To date, the function of SNF2L in human cells has not been a focus of research. Newly established specific monoclonal antibodies and selective RNA interference protocols have now enabled a comprehensive characterization of loss-of-function phenotypes in human cells. In contrast to earlier results, we found SNF2L to be broadly expressed in primary human tissues. Depletion of SNF2L in HeLa cells led to enhanced proliferation and increased migration. These phenomena were explained by transcriptome profiling, which identified SNF2L as a modulator of the Wnt signaling network. The cumulative effects of SNF2L depletion on gene expression portray the cell in a state of activated Wnt signaling characterized by increased proliferation and chemotactic locomotion. Accordingly, high levels of SNF2L expression in normal melanocytes contrast with undetectable expression in malignant melanoma. In summary, our data document an inverse relationship between SNF2L expression and features characteristic of malignant cells.


Structural basis for dodecameric assembly states and conformational plasticity of the full-length AAA+ ATPases Rvb1 · Rvb2.
As building blocks of diverse macromolecular complexes, the AAA+ ATPases Rvb1 and Rvb2 are crucial for many cellular activities including cancer-related processes. Their oligomeric structure and function remain unclear. We report the crystal structures of full-length heteromeric Rvb1·Rvb2 complexes in distinct nucleotide binding states. Chaetomium thermophilum Rvb1·Rvb2 assemble into hexameric rings of alternating molecules and into stable dodecamers. Intriguingly, the characteristic oligonucleotide-binding (OB) fold domains (DIIs) of Rvb1 and Rvb2 occupy unequal places relative to the compact AAA+ core ring. While Rvb1's DII forms contacts between hexamers, Rvb2's DII is rotated 100° outward, occupying lateral positions. ATP was retained bound to Rvb1 but not Rvb2 throughout purification, suggesting nonconcerted ATPase activities and nucleotide binding. Significant conformational differences between nucleotide-free and ATP-/ADP-bound states in the crystal structures and in solution suggest that the functional role of Rvb1·Rvb2 is mediated by highly interconnected structural switches. Our structures provide an atomic framework for dodecameric states and Rvb1·Rvb2's conformational plasticity.


Positive selection of AS3MT to arsenic water in Andean populations.
Arsenic is a carcinogen associated with skin lesions and cardiovascular diseases. The Colla population from the Puna region in Northwest Argentinean is exposed to levels of arsenic in drinking water exceeding the recommended maximum by a factor of 20. Yet, they thrive in this challenging environment since thousands of years and therefore we hypothesize strong selection signatures in genes involved in arsenic metabolism. We analyzed genome-wide genotype data for 730,000 loci in 25 Collas, considering 24 individuals of the neighbouring Calchaquíes and 24 Wichí from the Gran Chaco region in the Argentine province of Salta as control groups. We identified a strong signal of positive selection in the main arsenic methyltransferase AS3MT gene, which has been previously associated with lower concentrations of the most toxic product of arsenic metabolism monomethylarsonic acid. This study confirms recent studies reporting selection signals in the AS3MT gene albeit using different samples, tests and control populations.


Healthcare access and mammography screening in Michigan: a multilevel cross-sectional study.
Breast cancer screening rates have increased over time in the United States. However actual screening rates appear to be lower among black women compared with white women. To assess determinants of breast cancer screening among women in Michigan USA, focusing on individual and neighborhood socio-economic status and healthcare access. Data from 1163 women ages 50-74 years who participated in the 2008 Michigan Special Cancer Behavioral Risk Factor Survey were analyzed. County-level SES and healthcare access were obtained from the Area Resource File. Multilevel logistic regression models were fit using SAS Proc Glimmix to account for clustering of individual observations by county. Separate models were fit for each of the two outcomes of interest; mammography screening and clinical breast examination. For each outcome, two sequential models were fit; a model including individual level covariates and a model including county level covariates. After adjusting for misclassification bias, overall cancer screening rates were lower than reported by survey respondents; black women had lower mammography screening rates but higher clinical breast examination rates than white women. However, after adjusting for other individual level variables, race was not a significant predictor of screening. Having health insurance or a usual healthcare provider were the most important predictors of cancer screening. Access to healthcare is important to ensuring appropriate cancer screening among women in Michigan.


[Rectal barostat in irritable bowel syndrome].
Many patients with irritable bowel syndrome (IBS) have lowered sensory thresholds to rectal distention when compared to control subjects, a phenomenon called visceral hypersensitivity. To investigate the usefulness of a rectal barostat as a diagnostic tool in IBS and if there are differences in visceral hypersensitivity in different groups of IBS patients. Ten healthy subjects and 19 IBS patients, defined using Rome II criteria (12 with constipation, three with diarrhea and four alternating between diarrhea and constipation), were studied. Sequential isobaric rectal distentions, from 2 mmHg up to a maximal pressure of 52 mmHg or when the patients reported pain, were carried out. Visceral hypersensitivity was defined as a pain threshold under 38 mmHg. Only 26% of IBS patients had visceral hypersensitivity (16% and 43% of patients with IBS and constipation and IBS and diarrhea or alternating symptoms, respectively, p =NS). Pain threshold in controls, patients with IBS and constipation and patients with IBS and diarrhea or alternating symptoms was 43.8+/-6.6, 45.3+/-9.2 and 40.8+/-9.2 mmHg, respectively (p =NS). Our results do not support the usefulness of the electronic rectal barostat as a diagnostic method to diagnose IBS.


Improved Placement of Multi-mapping Small RNAs.
High-throughput sequencing of small RNAs (sRNA-seq) is a popular method used to discover and annotate microRNAs (miRNAs), endogenous short interfering RNAs (siRNAs), and Piwi-associated RNAs (piRNAs). One of the key steps in sRNA-seq data analysis is alignment to a reference genome. sRNA-seq libraries often have a high proportion of reads that align to multiple genomic locations, which makes determining their true origins difficult. Commonly used sRNA-seq alignment methods result in either very low precision (choosing an alignment at random), or sensitivity (ignoring multi-mapping reads). Here, we describe and test an sRNA-seq alignment strategy that uses local genomic context to guide decisions on proper placements of multi-mapped sRNA-seq reads. Tests using simulated sRNA-seq data demonstrated that this local-weighting method outperforms other alignment strategies using three different plant genomes. Experimental analyses with real sRNA-seq data also indicate superior performance of local-weighting methods for both plant miRNAs and heterochromatic siRNAs. The local-weighting methods we have developed are implemented as part of the sRNA-seq analysis program ShortStack, which is freely available under a general public license. Improved genome alignments of sRNA-seq data should increase the quality of downstream analyses and genome annotation efforts.


Short-term increases in stocking density affect the lying and social behavior, but not the productivity, of lactating Holstein dairy cows.
Reduced access to resources because of increased stocking density may have a detrimental effect on the behavior of the lactating dairy cow. The objective of this study was to determine the short-term responses in behavior, productivity, fecal cortisol metabolites, and udder and leg hygiene of lactating Holstein dairy cows housed at stocking densities of 100 (1 cow per freestall and headlock), 113, 131, and 142%. Multiparous cows (n=92) and primiparous cows (n=44) were assigned to 1 of 4 pens (34 cows per pen) in a 4-row freestall barn. Pens were balanced for parity, milk production, and days in milk. Stocking densities were imposed for 14 d using a 4 × 4 Latin square design. Time spent feeding and time spent ruminating were quantified by 24 h of direct observation of focal cows (n=12 per pen) beginning at 0800 h on d 11 of each period. Data loggers recorded lying behavior (time and bouts) from the same focal cows per pen at 1-min intervals during the final 5 d of each period. Fecal cortisol metabolites were quantified from samples collected on d 13 and 14 of each period from the same focal cows. Displacements from the feed barrier were recorded on a pen basis after 9 milkings over the last 4 d of each period. Productivity was assessed on a pen basis from milk yield (recorded from d 10 to 14 of each period) and milk components (quantified from composite samples collected on d 12 of each period). Milk composition was further analyzed for milk fatty acid profiles, which were determined from a subset (n=6 per pen) of the focal cows. Data were analyzed using the MIXED procedure of SAS, with the pen (n=4 per treatment, except displacements where n=3 per treatment) as the experimental unit. Feeding and ruminating (h/d) did not differ among treatments. Lying time was reduced at stocking densities of 131 and 142%, relative to 100 or 113%. Lying bouts were not affected by treatment. Stocking densities of 131 and 142% reduced the percentage of time cows spent ruminating within a freestall relative to 100%. Displacements from the feed bunk increased linearly across treatments. Fecal cortisol metabolites, udder hygiene score, milk yields, milk composition, and milk fatty acids did not differ among treatments. Decreased lying time and increased aggression at the feed bunk suggest that an alteration of the time budgets of lactating dairy cows may occur at higher stocking densities, but it is unclear at what point these changes might have further biological consequences.


Characterization of long non-coding RNA transcriptome in clear-cell renal cell carcinoma by next-generation deep sequencing.
Long non-coding RNA (lncRNA) have proven to play key roles in cell physiology from nuclear organization and epigenetic remodeling to post-transcriptional regulation. Last decade, gene expression based-classifications have been developed in clear-cell renal cell carcinoma (ccRCC) to identify distinct subtypes of disease and predict patient's outcome. However, there are no current lncRNA comprehensive characterizations in ccRCC. RNA-sequencing profiles of 475 primary ccRCC samples from the Cancer Genome Atlas (TCGA) were used to assess expressed lncRNA and identify lncRNA-based classification. In addition, integrative analysis was performed to correlate tumor subtypes with copy-number alterations and somatic mutations. Using stringent criteria, we identified 1934 expressed lncRNA and assessed their chromatin marks. Unsupervised clustering unravels four lncRNA subclasses in ccRCC associated with distinct clinicopathological and genomic features of this disease. Cluster C2 (23.4%) defines the most aggressive tumours, with the highest Fuhrman grade and stage and the worst overall survival time. Furthermore, cluster C2 is enriched for 9p deletion and chromatin remodeler BAP1 somatic mutations. Interestingly, cluster C4 (7.8%) is related to a tumor subtype arising from the distal tubules of the nephron. Consistent with its distinct ontogeny, cluster C4 is devoid of classical alterations seen in ccRCC, bears frequent 1p deletion and 17q gain, and is enriched for MiTF/TFE translocations. In addition, reexaminations of copy-number data from one side and tumor histology by pathologists from the other side reveal misclassified tumors within C4 cluster including chromophobe RCC and clear cell papillary RCC. This study establishes a foundation for categorizing lncRNA subclasses, which may contribute to understand tumor ontogeny and help predicting patients' outcome in ccRCC.


Protection and reactivation of oxidative phosphorylation in mitochondria by a stable free-radical prostaglandin polymer (PGBx).
A stable free-radical polymeric derivative of prostaglandin B1 (PGBx) has been synthesized that exhibits regenerative effects on oxidative phosphorylation in aged mitochondria. The molecular weights of the most active preparations fall between 2000 and 2600. PGBx is characterized by a single-line electron spin resonance spectrum that is stable at room temperature. PGBx restores phosphorylating ability and net ATP synthesis in isolated mitochondria aged for 4 days at 0 degrees C and protects against further degradation of phosphorylating activity when such aged mitochondria are preincubated at 28 degrees C in the absence of adenine nucleotide phosphate acceptors. This compound has been reported to exert beneficial effects in vivo in experimental pathological conditions, such as regional ischemia, in which the mitochondria of the ischemic region may have been damaged.


Atomic-Scale in Situ Observations of Crystallization and Restructuring Processes in Two-Dimensional MoS2 Films.
We employ atomically resolved and element-specific scanning transmission electron microscopy (STEM) to visualize in situ and at the atomic scale the crystallization and restructuring processes of two-dimensional (2D) molybdenum disulfide (MoS2) films. To this end, we deposit a model heterostructure of thin amorphous MoS2 films onto freestanding graphene membranes used as high-resolution STEM supports. Notably, during STEM imaging the energy input from the scanning electron beam leads to beam-induced crystallization and restructuring of the amorphous MoS2 into crystalline MoS2 domains, thereby emulating widely used elevated temperature MoS2 synthesis and processing conditions. We thereby directly observe nucleation, growth, crystallization, and restructuring events in the evolving MoS2 films in situ and at the atomic scale. Our observations suggest that during MoS2 processing, various MoS2 polymorphs co-evolve in parallel and that these can dynamically transform into each other. We further highlight transitions from in-plane to out-of-plane crystallization of MoS2 layers, give indication of Mo and S diffusion species, and suggest that, in our system and depending on conditions, MoS2 crystallization can be influenced by a weak MoS2/graphene support epitaxy. Our atomic-scale in situ approach thereby visualizes multiple fundamental processes that underlie the varied MoS2 morphologies observed in previous ex situ growth and processing work. Our work introduces a general approach to in situ visualize at the atomic scale the growth and restructuring mechanisms of 2D transition-metal dichalcogenides and other 2D materials.


Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model.
Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies.


Identification of a novel modulator of thyroid hormone receptor-mediated action.
Diabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. Here we identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle. We have identified a gene, named DOR, abundantly expressed in insulin-sensitive tissues such as skeletal muscle and heart, whose expression is highly repressed in muscle from obese diabetic rats. DOR expression is up-regulated during muscle differentiation and its loss-of-function has a negative impact on gene expression programmes linked to myogenesis or driven by thyroid hormones. In agreement with this, DOR enhances the transcriptional activity of the thyroid hormone receptor TR(alpha1). This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR( alpha1) and to T(3)-responsive promoters, as shown by ChIP assays. T(3) stimulation also promotes the mobilization of DOR from its localization in nuclear PML bodies, thereby indicating that its nuclear localization and cellular function may be related. Our data indicate that DOR modulates thyroid hormone function and controls myogenesis. DOR expression is down-regulated in skeletal muscle in diabetes. This finding may be of relevance for the alterations in muscle function associated with this disease.


Daphnia galeata responds to the exposure to an ichthyosporean gut parasite by down-regulation of immunity and lipid metabolism.
Regulatory circuits of infection in the emerging experimental model system, water flea Daphnia and their microparasites, remain largely unknown. Here we provide the first molecular insights into the response of Daphnia galeata to its highly virulent and common parasite Caullerya mesnili, an ichthyosporean that infects the gut epithelium. We generated a transcriptomic dataset using RNAseq from parasite-exposed (vs. control) Daphnia, at two time points (4 and 48 h) after parasite exposure. We found a down-regulation of metabolism and immunity-related genes, at 48 h (but not 4 h) after parasite exposure. These genes are involved in lipid metabolism and fatty acid biosynthesis, as well as microbe recognition (e.g. c-type lectins) and pathogen attack (e.g. gut chitin). General metabolic suppression implies host energy shift from reproduction to survival, which is in agreement with the known drastic reduction in Daphnia fecundity after Caullerya infection. The down-regulation of gut chitin indicates a possible interaction between the peritrophic matrix and the evading host immune system. Our study provides the first description of host transcriptional responses in this very promising host-parasite experimental system.


Genetic testing in colorectal cancer: who, when, how and why.
Colorectal cancer (CRC) is among the most prevalent and preventable forms of cancer worldwide, accounting for over 600,000 deaths in 2005. Both genetic and environmental factors contribute to cancer etiology and estimates suggest that at least one third of CRC has a familial component. There is increased awareness of a strong genetic component to CRC risk, with the identification of several high penetrance alleles that predict increased CRC susceptibility. These include familial adenomatous polyposis (FAP), linked to mutations or deletions of the APC tumor suppressor gene, as well as Lynch syndrome (formerly known as hereditary non-polyposis colorectal cancer or HNPCC), which is linked to mutations or deletions of one or more mismatch repair genes including MLH1, MSH2 and MSH6. In addition, mutations in genes encoding key signaling molecules have been linked to autosomal dominant hamartomatous syndromes that are associated with increased susceptibility to CRC. These include Peutz-Jeghers syndrome, which is linked to mutations in STK11/LKB and Juvenile polyposis, which is linked to mutations in the genes encoding SMAD4 and BMPR1A. In addition to these high penetrance autosomal dominant alleles, recessive mutations in the MYH mismatch repair gene are associated with a phenotype similar to FAP. With the widespread availability of genetic testing for these alleles, physicians will be faced with a complex array of choices in terms of advocating who should be tested, when should such testing take place, how it should be conducted and interpreted and why it changes the management and outcomes for the patient and his or her family.


Caring for a frail older person: the association between informal caregiver burden and being unsatisfied with support from family and friends.
although informal caregivers (ICG) find caring for a relative mainly satisfying, it can be difficult at times and it can lead to a state of subjective burden characterised by -among others- fatigue and stress. The objective of this study is to analyse the relationship between perceived social support and subjective burden in providing informal care to frail older people. a descriptive cross-sectional study was conducted using data from a large nationwide longitudinal effectiveness study. Pearson correlations were calculated between the variables for support and burden. Logistic regression models were applied to determine the association between being unsatisfied with support and burden, taking into account multiple confounding variables. of the 13,229 frail older people included in this study, 85.9% (N = 11,363) had at least one informal caregiver. Almost 60% of the primary informal caregivers manifested subjective burden, measured with the 12-item Zarit-Burden-Interview (ZBI-12). The percentage of informal caregivers that were unsatisfied with support from family and friends was on average 11.5%. Logistic regression analysis showed that being unsatisfied with support is associated with burden (OR1.85; 95%CI1.53-2.23). These results were consistent for the three groups of impairment level of the frail older persons analysed. the association between perceived social support and subjective caregiver burden was explored in the context of caring for frail older people. ICGs who were unsatisfied with support were more likely to experience burden. Our findings underline the importance of perceived social support in relation to caregiver burden reduction. Therefore efforts to improve perceived social support are worth evaluating.


Differential Post-Exercise Blood Pressure Responses between Blacks and Caucasians.
Post-exercise hypotension (PEH) is widely observed in Caucasians (CA) and is associated with histamine receptors 1- and 2- (H1R and H2R) mediated post-exercise vasodilation. However, it appears that blacks (BL) may not exhibit PEH following aerobic exercise. Hence, this study sought to determine the extent to which BL develop PEH, and the contribution of histamine receptors to PEH (or lack thereof) in this population. Forty-nine (22 BL, 27 CA) young and healthy subjects completed the study. Subjects were randomly assigned to take either a combined H1R and H2R antagonist (fexofenadine and ranitidine) or a control placebo. Supine blood pressure (BP), cardiac output and peripheral vascular resistance measurements were obtained at baseline, as well as at 30 min, 60 min and 90 min after 45 min of treadmill exercise at 70% heart rate reserve. Exercise increased diastolic BP in young BL but not in CA. Post-exercise diastolic BP was also elevated in BL after exercise with histamine receptor blockade. Moreover, H1R and H2R blockade elicited differential responses in stroke volume between BL and CA at rest, and the difference remained following exercise. Our findings show differential BP responses following exercise in BL and CA, and a potential role of histamine receptors in mediating basal and post-exercise stroke volume in BL. The heightened BP and vascular responses to exercise stimulus is consistent with the greater CVD risk in BL.


Cigarette smoking prevalence in US counties: 1996-2012.
Cigarette smoking is a leading risk factor for morbidity and premature mortality in the United States, yet information about smoking prevalence and trends is not routinely available below the state level, impeding local-level action. We used data on 4.7 million adults age 18 and older from the Behavioral Risk Factor Surveillance System (BRFSS) from 1996 to 2012. We derived cigarette smoking status from self-reported data in the BRFSS and applied validated small area estimation methods to generate estimates of current total cigarette smoking prevalence and current daily cigarette smoking prevalence for 3,127 counties and county equivalents annually from 1996 to 2012. We applied a novel method to correct for bias resulting from the exclusion of the wireless-only population in the BRFSS prior to 2011. Total cigarette smoking prevalence varies dramatically between counties, even within states, ranging from 9.9% to 41.5% for males and from 5.8% to 40.8% for females in 2012. Counties in the South, particularly in Kentucky, Tennessee, and West Virginia, as well as those with large Native American populations, have the highest rates of total cigarette smoking, while counties in Utah and other Western states have the lowest. Overall, total cigarette smoking prevalence declined between 1996 and 2012 with a median decline across counties of 0.9% per year for males and 0.6% per year for females, and rates of decline for males and females in some counties exceeded 3% per year. Statistically significant declines were concentrated in a relatively small number of counties, however, and more counties saw statistically significant declines in male cigarette smoking prevalence (39.8% of counties) than in female cigarette smoking prevalence (16.2%). Rates of decline varied by income level: counties in the top quintile in terms of income experienced noticeably faster declines than those in the bottom quintile. County-level estimates of cigarette smoking prevalence provide a unique opportunity to assess where prevalence remains high and where progress has been slow. These estimates provide the data needed to better develop and implement strategies at a local and at a state level to further reduce the burden imposed by cigarette smoking.


Dark Dune Spots: possible biomarkers on Mars?
Dark Dune Spots (DDSs) are transitional geomorphologic formations in the frost-covered polar regions of Mars. Our analysis of the transformations and arrangements of subsequent stages of DDSs into time sequence revealed their: (i) hole-like characteristics, (ii) development and formation from the bottom of the frosted layer till the disapperance of the latter, (iii) repeated (seasonal and annual) appearance in a pattern of multiple DDSs on the surface, and (iv) probable origin. We focused our studies on a model in which DDSs were interpreted as objects triggered by biological activity involved in the frosting and melting processes. We discuss two competing interpretations of DDSs: development by defrosting alone, and by defrosting and melting enhanced by the activity of Martian Surface Organisms (MSOs). MSOs are hypothetical Martian photosynthetic surface organisms thought to absorb sunlight. As a result they warm up by late winter and melt the ice around them, whereby their growth and reproduction become possible. The ice cover above the liquid water lens harbouring the MSOs provides excellent heat and UV insulation, prevents fast evaporation, and sustains basic living conditions until the ice cover exists. When the frost cover disappears MSOs go to a dormant, desiccated state. We propose further studies to be carried out by orbiters and landers travelling to Mars and by analysis of partial analogues on earth.


Identification of chemical mixtures to which Canadian pregnant women are exposed: The MIREC Study.
Depending on the chemical and the outcome, prenatal exposures to environmental chemicals can lead to adverse effects on the pregnancy and child development, especially if exposure occurs during early gestation. Instead of focusing on prenatal exposure to individual chemicals, more studies have taken into account that humans are exposed to multiple environmental chemicals on a daily basis. The objectives of this analysis were to identify the pattern of chemical mixtures to which women are exposed and to characterize women with elevated exposures to various mixtures. Statistical techniques were applied to 28 chemicals measured simultaneously in the first trimester and socio-demographic factors of 1744 participants from the Maternal-Infant Research on Environment Chemicals (MIREC) Study. Cluster analysis was implemented to categorize participants based on their socio-demographic characteristics, while principal component analysis (PCA) was used to extract the chemicals with similar patterns and to reduce the dimension of the dataset. Next, hypothesis testing determined if the mean converted concentrations of chemical substances differed significantly among women with different socio-demographic backgrounds as well as among clusters. Cluster analysis identified six main socio-demographic clusters. Eleven components, which explained approximately 70% of the variance in the data, were retained in the PCA. Persistent organic pollutants (PCB118, PCB138, PCB153, PCB180, OXYCHLOR and TRANSNONA) and phthalates (MEOHP, MEHHP and MEHP) dominated the first and second components, respectively, and the first two components explained 25.8% of the source variation. Prenatal exposure to persistent organic pollutants (first component) were positively associated with women who have lower education or higher income, were born in Canada, have BMI ≥25, or were expecting their first child in our study population. MEOHP, MEHHP and MEHP, dominating the second component, were detected in at least 98% of 1744 participants in our cohort study; however, no particular group of pregnant women was identified to be highly exposed to phthalates. While widely recognized as important to studying potential health effects, identifying the mixture of chemicals to which various segments of the population are exposed has been problematic. We present an approach using factor analysis through principal component method and cluster analysis as an attempt to determine the pregnancy exposome. Future studies should focus on how to include these matrices in examining the health effects of prenatal exposure to chemical mixtures in pregnant women and their children.


The influence of the angle of gaze upon the excitability of the light-sensitive neurons of the posterior parietal cortex.
The responses of parietal visual neurons are markedly increased during attentive fixation, as compared to those evoked in relaxed wakefulness, an effect specific for directed attention and unrelated to putative differences in the general level of arousal. Those responses are also strongly influenced by the angle of gaze, an effect observed only during directed visual attention. The change in response is smoothly graded along a meridian for about one-half the neuron population; the average spatial gradient from maximum to minimum is 78% response for a 20 degrees shift in eye position. No lateral preference was observed. For the remaining half, responses were either maximal or minimal for fixations dead ahead, and changes occurred with deviations in any direction. Angle of gaze effects were observed for neurons with foveal as well as eccentrically located receptive fields, all of which were organized in retinotopic not spatial coordinates. Control experiments showed that the effect was not produced by changes in visual background with changes in the angle of gaze, nor to changes in fixation distance, nor to variations in the intensity of stimuli viewed from different angles. The effect depends upon the position of the eye in the orbit, but is unlikely due to a direct central action of changes in nonretinal orbital afferent activity at different angles of gaze, for the effect was rarely observed with changes in the angle of gaze during relaxed wakefulness without directed visual attention. The evidence supports the interpretation that the effect is produced by a central influence of the systems controlling directed visual attention and the angle of gaze upon those linking the retinae to the parietal lobe.


First Report of Fire Blight Caused by Erwinia amylovora on Rosehip (Rosa canina) in Turkey.
During the summers of 2008 and 2010, leaf and shoot blight, wilting of the tips of young infected shoots, and cankers with brown discoloration on twigs were observed on six dog rosehip (Rosa canina) plants from four different private orchards in Eregli district of Konya Province, Turkey. Disease incidence was estimated to be approximately 0.5% on rosehips over 2 years within all survey areas, and surveys showed that ~4 ha was infested. Bacteria isolated from diseased leaf and shoot tissues was macerated and streaked on nutrient sucrose agar (NSA) and King's medium B (KB). Typical light cream, levan-positive colonies developed on NSA medium after a 2-day incubation at 25°C. Colonies on KB were white and non-fluorescent (1). Bacterial strains were identified on the basis of biochemical, physiological (2), and molecular tests (3). Eleven representative bacterial strains isolated were gram-negative, rod-shaped, mucoid, fermentative, yellow-orange on Miller & Scroth medium, positive for levan formation and acetoin production, no growth at 36°C, positive for gelatin hydrolysis, and negative for esculin hydrolysis, indole, urease, catalase, oxidase, arginine dehydrolase, reduction of nitrate, and acid production from lactose and inositol. Two reference strains of Erwinia amylovora (Burr.) Winslow et al. (Ea43b and NCPPB 2791) obtained from culture collection of Selcuk University, Department of Plant Protection, Turkey, were used as positive controls. All strains induced a hypersensitive response in tobacco (Nicotiana tabaccum cv. White Burley) plants within 24 h after inoculation with a 108 CFU/ml bacterial suspension in sterilized distilled water (SDW) (~50 μl), and the strains produced ooze on inoculated immature pear fruit slices cv. Ankara. All strains were identified as E. amylovora using the species-specific primers set A/B (A: 5' CGGTTTTTAACGCTGGG 3' and B: 5' GGGCAAATACTCGGATT 3') (3) by PCR assay to generate a 1-kb DNA fragment, and fatty acid methyl ester (FAME) profiles determined by Sherlock Microbial Identification System software with similarity indices ranging from 84 to 97%. Pathogenicity was tested by inserting a suspension (108 CFU/ml SDW) of each of the 11 bacterial strains and two references strains into actively growing shoot tips and petioles of 4-year-old plants of Rosa canina using a 0.46-mm-diameter hypodermic needle. Leaf and shoot blight symptoms resembling the natural infection were developed on the inoculated plants 7 to 10 days after inoculation. SDW was injected similarly as a negative control treatment, and no symptoms were observed on the control plants. All tests were repeated three times. Re-isolations were done from shoots and leaves of inoculated plants with the two reference strains and the 11 bacteria, and control plants. Obtaining bacteria were identified as E. amylovora using the biochemical, physiological, and molecular tests described above, but this bacterium was not isolated from the control plants. To our knowledge, this is the first report of E. amylovora on rosehip in Turkey. References: (1) R. A. Lelliott and D. E. Stead. Methods for Diagnosis of Bacterial Diseases of Plants (Methods in Plant Pathology). Oxford, UK, 1987. (2) A. L. Jones and K. Geider. Laboratory Guide for Identification of Plant Pathogenic Bacteria, Pp. 40-55, American Phytopathological Society, St. Paul, MN, 2001. (3) S. Bereswill et al. Appl. Environ. Microbiol. 58:3522, 1992.


Differential sensitivity of zinc finger transcription factors MTF-1, Sp1 and Krox-20 to CpG methylation of their binding sites.
Cytosine methylation at CpG sites is often negatively correlated with mammalian gene activity. Many transcription factors whose DNA binding site contains one or more CpG dinucleotides are no longer able to efficiently bind DNA when the site is methylated. A notable exception is the zinc finger factor Sp1 which binds DNA and activates transcription even when its binding site is methylated. Here we show that two other zinc finger factors, MTF-1 and Krox-20, can also bind to CpG methylated sites. MTF-1 regulates metallothionein gene transcription by binding to a number of metal responsive elements (MREs), and Krox-20 regulates Hox genes during hindbrain segmentation. However, a refined analysis of MTF-1/MRE binding shows that methylation is not tolerated at every binding site: the highest affinity site in the mouse metallothionein I gene, MREd, is unaffected by methylation, while two other MRE sites with CpGs at different positions are rendered partially or completely nonfunctional by methylation. Both methylation sensitive and insensitive factors/binding sites are likely to determine the developmental expression pattern of a gene.