As of yet, no collective agreement has been reached regarding the precise factor structure of posttraumatic stress disorder (PTSD). Several alternative factor-models have been proposed in the last decades.Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV), a correlated four-factor emotional numbing, and a correlated four-factor dysphoria model.The current study examined the fit of a hierarchical adaptation of the Simms et al.  dysphoriN=276).Data were collected using the Clinician-Administered PTSD Scale in a mixed-trauma sample of treatment-seeking PTSD patients (DSM-IV. The hierarchical four-factor solution provided a better fit than competing models.All examined models provided superior fit to the three-factor model of The present study provides empirical support for a conceptualization of PTSD that includes a higher-order PTSD factor that encompasses re-experiencing, arousal, and effortful avoidance sub-factors and a dysphoria factor. DSM-IV-TR; American Psychiatric Association, Individuals who are exposed to extreme or prolonged stress are at risk of developing mental disorders such as posttraumatic stress disorder (PTSD). In the latest revision of the Diagnostic and Statistical manual for Mental disorders  components and to determine which of these are specific to PTSD, versus those that would explain existing comorbidity with other (mood and anxiety) disorders   avoidance, emotional numbing, and arousal. In this model symptoms from the avoidance cluster (C) in lleagues  proposedlleagues , as welllleagues .As noted before, both the emotional numbing and dysphoria models differentiate between active or effortful avoidance and emotional numbing  and civilian (n=161) treatment facilities. Sites included the department of Military Mental Healthcare in Utrecht, the Netherlands, the Overwaal Centre for Anxiety Disorders in Lent, the Netherlands, and the Hendriks & Rooseboom Psychiatric and Psychotherapeutic Centre in Arnhem, the Netherlands. Data were collected from 2002 till 2011. Data were included from all patients who consented to have their data used for research. The CAPS was administered during the initial intake prior to the start of treatment. Participants were included in the study if they met DSM-IV criteria for PTSD, with a CAPS total score of ≥45 on the CAPS  were included in the analysis. Trauma exposure was assessed with the Life Event Checklist . Total PTSD severity is calculated as the sum of 17 symptom frequency and intensity scores. The CAPS has been shown to have excellent psychometric properties in a variety of populations ; therefore, CFA was conducted using maximum likelihood estimation with robust standard errors (MLR) in M-Plus v. 6.11 , Standardized Root-Mean-Square Residual (SRMR), Comparative Fit Index (CFI), Tucker-Lewis Index (TLI), Akaike's Information Criterion (AIC), and the Bayesian Information Criterion (BIC). Cut-off scores of >0.95 for CFI and TLI, <0.07 for RMSEA, and < 0.08 for SRMR suggest good model fit ; the King et al. correlated four-factor emotional numbing model . Variations of the dysphoria model slightly outperformed the numbing model. Additionally, although differences in fit-indices across models were small, the 10 point difference in BIC value between Simms et al. correlated (3a) and hierarchical dysphoria model (3b) should be considered as positive evidence that the latter is a better-fitting model =0.64, p=0.73], suggesting that the more parsimonious nested hierarchical model (3b) should be retained over the inter-correlated four-factor dysphoria model (3a). As can be seen in Raftery, . MoreoveThe present study examined the latent structure of PTSD symptoms in a mixed-trauma sample. Although the differences between fit-indices were small, the hierarchical dysphoria model fitted the data best. The proposed model that included clusters of arousal, intrusion, and effortful avoidance symptoms subsumed under a higher-order PTSD factor, and a separate dysphoria factor fitted the data  better than the original dysphoria model. Superior fit was also confirmed by a Chi-square difference test. The focus on a mixed-trauma sample in the present study suggests that the reported factor structure is fairly robust to inter-subject variation in type of trauma. Additionally, the results converge with previous studies  performed poorly across models. Therefore, these findings lend empirical support to McNally's  proposalThe present study underscores the validity of a demarcation between specific and non-specific  PTSD symptoms. This view is further supported by the proposed reformulation of PTSD by Brewin and colleagues  as caused by the remaining PTSD items. An alternative explanation is that the items in the dysphoria cluster actually tap on aspects of (trait) neuroticism/negative affectivity (N/NA). N/NA incorporates negative emotional states such as fear, anger, sadness, guilt, and disgust  N/NA, can be expected to further increase the overlap of PTSD with other distress disorders. If so, this would inadvertently and somewhat paradoxically strengthen claims for a need to change the nosologic system of DSM , the TLI and CFI values indicated poor model fit. The CFI values were lower in the present study than in other studies that used the CAPS  in all models , as was the case in most previous studies, may have biased the results. Indeed, a factorial invariance study in US veterans suggests that although model fit may be equal across groups (PTSD vs. criterion A), there may exists (subtle) differences between (treatment-seeking) PTSD patients and trauma-controls in the way they perceive and respond to PTSD questionnaires  correlates of the factors described in this and previous studies, as well as studies into dimensions that may underlie the general distress/dysphoria factor, would help to further our understanding of the pathogenesis of PTSD and other distress disorders.Uncovering the latent structure of PTSD is important in identifying distinct aspects of PTSD symptomatology and sources of comorbidity with order disorders. The present study demonstrates once more that the three-factor solution in


Lipid-reduction pharmacotherapy is often employed to reduce morbidity and mortality risk for patients with dyslipidemia or established cardiovascular disease. Associations between socioeconomic factors and the prescribing and use of lipid-lowering agents have been reported in several developed countries.We evaluated the association of census tract-level neighborhood household income (nINC) and lipid-lowering medications received during hospitalization or at discharge among 3,546  myocardial infarction (MI) events in the United States (US) Atherosclerosis Risk In Communities (ARIC) surveillance study (1999–2002). Models included neighborhood household income, race, gender, age, study community, year of MI, hospital type (teaching vs. nonteaching), current or past history of hypertension, diabetes or heart failure, and presence of cardiac pain.About fifty-nine percent of patients received lipid-lowering pharmacotherapy during hospitalization or at discharge. Low nINC was associated with a lower likelihood  of receiving lipid-lowering pharmacotherapy compared to high neighborhood household income, and no significant change in this association resulted when adjusted for the above-mentioned covariates.Patient’s socioeconomic status appeared to influence whether they were prescribed a lipid-lowering pharmacotherapy after hospitalization for myocardial infarction in the US ARIC surveillance study (1999–2002). Lipid reduction can significantly improve cardiovascular risk and lower morbidity and mortality following myocardial infarction (MI). Pharmacotherapy, along with lifestyle changes, plays an essential role in improving lipid profiles. Statins, arguably the most efficacious of the lipid-lowering drug classes, are often first-line therapy for the dyslipidemias and for decreasing cardiovascular risk. However, investigators worldwide have reported that socioeconomic factors often influence the prescribing and use of statins and other lipid-lowering agents. In 2007 Ward et. al. published data from four primary-care trusts in Northwest England that indicated ethnic inequities in statin prescribing rates. A DanisWe evaluated the association between tertiles  of census tract-level neighborhood household income (nINC) and lipid-lowering medications received during hospitalization or at discharge among 3,546  MI events in the US Atherosclerosis Risk In Communities (ARIC) surveillance study (1999–2002). The ARIC study’s community-based surveillance of coronary heart disease has been ongoing since 1987 and is designed to capture MI and fatal coronary heart disease events in four US communities ). While it comprises the same communities from which ARIC cohort members were recruited, ARIC community surveillance does not include in-person physical exams, annual follow-up, or any contact with ARIC cohort participants (unless they happen to be sampled as a surveillance case). ARIC community-surveillance staff ascertained coronary heart disease-related hospital discharges and deaths and abstracted data related to the event of interest. Institutional Review Board (IRB) approvals were obtained by each participating ARIC study center  and the coordinating center (University of NC), and the research was conducted in accordance with the principles described in the Declaration of Helsinki. Data for this study were abstracted from medical records and strict data confidentiality was maintained. Further details regarding ARIC’s methods for data collection are provided elsewhere[We estimated prevalence ratios and 95% confidence intervals for receipt of lipid-lowering medication post-MI using weighted Poisson regression, and we used generalized estimation equations  to account for the clustering of MI events within census tracts and within patients, as incident and recurrent MI events were considered together based upon our previous analyses,8. ModelThe MI cases were distributed across the four ARIC study communities as follows: 25.7% in MS, 36.7% in NC, 15.9% in MD, and 21.7% in MN. The MI patients were 34.5% female, 25.3% black, and had an average age of 60.2 years. The mean nINC was approximately $42,700. Overall, 58.5% of patients received lipid-lowering pharmacotherapy during hospitalization or at discharge. In models adjusted for race, gender, age, study community and year of MI, there was no significant effect modification of the nINC- lipid-lowering therapy relationship by race, gender, age, study community or year of MI as indicated in these data. Results of models utilizing overall cut-points are reported in Table Our results demonstrate that a patient’s SES may influence whether they were prescribed a lipid-lowering pharmacotherapy after hospitalization for MI in the US ARIC surveillance study (1999–2002). This observation should be noted by clinicians, patients, and policy makers. Efforts to decrease or eliminate the influence of socioeconomic factors on the prescribing of pharmacotherapy should be implemented.US: United States; ARIC: Atherosclerosis risk in communities; MI: Myocardial infarction; SES: Socioeconomic status; nINC: neighborhood household income; MS: Mississippi; NC: North Carolina; MD: Maryland; MN: MinneapolisThe authors declare that they have no competing interests.JPK drafted the manuscript and contributed to the analysis and interpretation of data. REF participated in the design of the study, acquired the data, performed the data analysis and interpretation, and assisted in drafting and revising the manuscript. KMR participated in the design of the study, assisted in the data analysis and interpretation, and also assisted in revising the manuscript. All three authors certify that they have participated sufficiently in the work and believe in its overall validity and take public responsibility for its content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/488/prepub


Classical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage. However, it is still uncertain whether delayed preconditioning can effectively salvage myocardium in patients with co-morbidities, such as diabetes and the metabolic syndrome. We investigated delayed preconditioning in mice models of type II diabetes and the metabolic syndrome and investigated interventions to optimize the preconditioning potential.t-test or one-way ANOVA followed by a Fisher’s LSD post hoc test. Factorial ANOVA was used to determine the interaction term between preconditioning and treatments, followed by a Fisher’s LSD post hoc test. Two-way ANOVA was used to determine the relationship between infarct size and contractility (PRSW). A value of p<0.05 was considered significant.Hypoxic preconditioning was induced in C57Bl6-mice (WT), leptin deficient ob/ob (model for type II diabetes) and double knock-out (DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome). Twenty-four hours later, 30 min of regional ischemia was followed by 60 min reperfusion. Left ventricular contractility and infarct size were studied. The effect of 12 weeks food restriction or angiotensin-converting enzyme inhibition (ACE-I) on this was investigated. Differences between groups were analyzed for statistical significance by student’s Left ventricular contractility is reduced in ob/ob compared with WT and even further reduced in DKO. ACE-I improved contractility in ob/ob and DKO mice. After ischemia/reperfusion without preconditioning, infarct size was larger in DKO and ob/ob versus WT. Hypoxic preconditioning induced a strong protection in WT and a partial protection in ob/ob mice. The preconditioning potential was lost in DKO. Twelve weeks of food restriction or ACE-I restored the preconditioning potential in DKO and improved it in ob/ob.Delayed preconditioning is restored by food restriction and ACE-I in case of type II diabetes and the metabolic syndrome. Tissues and organs can be protected from ensuing longer ischemia-reperfusion (IR) periods by short preceding episodes of ‘preconditioning’ ischemia . HoweverThe number of patients with diabetes and the metabolic syndrome increases in Western societies and reaches epidemic proportions -9. The iDelayed preconditioning might be an interesting technique for this, since it is capable to induce cardioprotection in a controlled way for longer periods. Most of our knowledge concerning preconditioning however has been gathered from experiments in normal healthy animal models . These mMost patients with T2D or the MS are treated . These tAngiotensin-converting enzyme inhibition (ACE-I) is also a standard therapy in the treatment of hypertension in diabetic patients . It was Therefore, the aim of this study is to investigate the effects of food restriction and ACE-I on delayed cardiac preconditioning in diabetic or metabolic syndrome models. We tested the hypotheses that 1° mice with T2D or the MS are resistant to hypoxic delayed preconditioning; and 2° the interventions food restriction or ACE-I restore the preconditioning potential in these mouse models.Experiments were conducted in 49 C57BL/6J WT-mice, 71 leptin deficient ob/ob, and 68 double knock-out (DKO)-mice with combined leptin and LDL-receptor deficiency. The ob/ob mouse is a model for T2D, featuring abdominal obesity and insulin resistance. DKO feature many characteristics of the metabolic syndrome, i.e. obesity, dyslipidemia, hypertension, insulin resistance and impaired glucose tolerance and/or diabetes . These mThe experimental technique was previously described . BrieflyFood intake  of diet-restricted ob/ob  and DKO  mice was restricted to 2.5 g/day, which is the normal daily intake of lean WT-mice, between 12 and 24 weeks of age ,21. ACE-Experiments in untreated WT , ob/ob  and DKO  mice served as controls.The experimental technique was previously described ,20. BrieThe technique was previously described ,20. At tes), reflects left ventricular chamber end-systolic stiffness and is used as an index of contractility. Tau is the time constant of left ventricular relaxation during isovolumetric diastole. The end-diastolic PV-relationship (EDPVR) represents the compliance of the ventricular myocardium at the end of the diastole. Augmented stiffness of the ventricular wall increases the slope of the EDPVR. Arterial elastance (Ea), a measure for afterload, is defined as the end-systolic pressure to stroke volume ratio [Preload recruitable stroke work (PRSW) is the slope of the relationship between end-diastolic volume and SW performed by the ventricle. PRSW is the most reliable and useful parameter for general contractility since it is chamber size independent and robust . The slome ratio .Before excision of the heart, Evans blue  was injected intravenously after re-occlusion of the LAD, to determine the left ventricular perfusion area at risk. The heart was cut in 1 mm-slices and the slices were stained with triphenyl-tetrazolium-chloride solution  and fixed in paraformaldehyde . All slices were weighed and photographed with a digital camera under magnification.Analysis of the pressure-conductance data was performed using PVAN 3.2 software  as previously described ,20,21,23Infarct size and area at risk were determined by the number of pixels in each zone with Adobe Photoshop 8.0 (Adobe System Inc.) multiplied by the weight of the respective slices.t-test or one-way ANOVA followed by a Fisher’s LSD post hoc test. Factorial ANOVA was used to determine the interaction term between preconditioning and treatments, followed by a Fisher’s LSD post hoc test. Two-way ANOVA was used to determine the relationship between infarct size and contractility (PRSW). A value of p<0.05 was considered significant.All statistical analyses were performed using statistical software . Data are expressed as mean ± standard deviation. Differences between groups were analyzed for statistical significance by student’s Preconditioning without subsequent ischemia, was investigated in WT  and DKO  mice. As expected, this had no effect on the contractility parameters. These results can be found in Additional file Left ventricular contractility, expressed as PRSW Figure , is redues, Ea and PRSW were significantly better preserved after preconditioning , generated in response to a preconditioning stimulus ,2. IncreFourth, the role of NO in IR injury and preconditioning is complex and depends on its concentration and cellular origin ,26. eNOSFifth, delayed preconditioning is regulated through an up regulation of several other cardioprotective proteins . PreviouFinally, although a plethora of mechanisms are involved in preconditioning, it is widely accepted that all these mechanisms converge at the inhibition of the mitochondrial permeability transition pore (mPTP) opening at early reperfusion . InhibitIn an attempt to restore delayed preconditioning in ob/ob and DKO mice, therapeutic strategies were investigated. After food restriction or ACE-I, hypoxic preconditioning reduced infarct size and preserved PRSW up to the level without ischemia in both ob/ob and DKO. Furthermore, ACE-I restored the proportional effect of preconditioning on infarct limitation and contractility improvement to the WT-level. Comparable with our previous study , we founIt is already shown that food restriction reduces insulin levels and ACE-I improves insulin sensitivity ,19. FurtFood restriction partially restores classical preconditioning in senescent animals, but in combination with exercise, this restoration becomes complete. A restored norepinephrine release was suggested as the underlying mechanism . FurtherFood restriction prevents ROS production  and alsoAnother possible explanation why the treatments induced cardioprotection after preconditioning but did not have a direct effect during IR injury, is the different role and levels of iNOS in both pathways. As described earlier, basal iNOS-levels are higher and the increase of iNOS-levels after IR injury is larger than in non-diabetic myocardium  with a dHypoxic preconditioning induces a strong protection in WT and a partial protection in ob/ob mice. The preconditioning potential is lost in DKO. Twelve weeks of food restriction or ACE-I restores the preconditioning potential in DKO and improves it in ob/ob. After preconditioning, PRSW is preserved to the level without ischemia, after 12 weeks food restriction or ACE-I. As previously shown, food restriction and ACE-I did not protect the diabetic myocardium against IR injury. The regained preconditioning potential appears to be independent from the direct effects of food restriction ACE-I on IR injury.ACE: Angiotensin-converting enzyme;ACE-I: Angiotensin-converting enzyme inhibition;DKO: Double knock-out;Ea: Arterial elastance;EDPVR: End-diastolic pressure volume relationship;Ees: End-systolic elastance;eNOS: Endothelial nitric oxide synthase;iNOS: Inducible nitric oxide synthase;IR: Ischemia-reperfusion;LAD: Left anterior descending artery;LDL: Low density lipoprotein;LDLR: Low density lipoprotein receptor;mPTP: Mitochondrial permeability transition pore;NO: Nitric oxide;NP: Non-Preconditioned and ischemia/reperfusion;Ob/ob: Leptin deficient mouse model for type II diabetes;P: Preconditioned and ischemia/reperfusion;Ped: End-diastolic pressure;PRSW: Preload recruitable stroke work;Psys: Systolic pressure;PV: Pressure-volume;ROS: Reactive oxygen species;STAT-3: Signal transducer and activator of transcription-3;SW: Stroke work;TTC: Triphenyl-tetrazolium chloride;WT: Wild typeThe authors declare that they have no competing interest.GVDM carried out the mice breeding, treatments, preconditioning, PV-loop experiments and infarct size determination, data and statistical analysis, and drafted the manuscript. IN, AV and WO contributed to the mice breeding, treatments and preconditioning. WF participated in the design of the study and general supervision. PH designed the study, obtained funding, did supervision of the analysis and interpretation of data, and revised the manuscript for important intellectual content. All authors have read and approved the final manuscript.Hemodynamic parameters and infarct size of the non-preconditioned and preconditioned wild type and DKO, without subsequent ischemia (shams).Click here for fileHemodynamic parameters.Click here for fileRelationship between infarct limitation and improved contractility.Click here for file


The objective of this study was to evaluate the anti-tumor effects of Ad/gTRAIL  on malignant meningiomas and gliomas.Gliomas and meningiomas are the two most common types of human brain tumors. Currently there is no effective cure for recurrent malignant meningiomas or for gliomas. Ad/gTRAIL has been shown to be effective in killing selected lung, colon and breast cancer cells, but there have been no studies reporting its antitumor effects on malignant meningiomas. Therefore, we tested the antitumor effect of Ad/gTRAIL for the first time in human malignant meningioma and glioma cell lines, and in intracranial M6 and U87 xenografts.Materials and Methods: Human malignant meningioma and glioma cells were infected with adenoviruses, Ad/gTRAIL and Ad/CMV-GFP. Cell viability was determined by proliferation assay. FACS analysis and quantification of TRAIL were used to measure apoptosis in these cells. We injected Ad/gTRAIL viruses in intracranial M6 and U87 xenografts, and measured the brain tumor volume, quantified apoptosis by TUNEL assay in the brain tumor tissue.Our studies demonstrate that in vitro/in vivo treatment with Ad/gTRAIL virus resulted in significant increase of TRAIL activity, and elicited a greater tumor cell apoptosis in malignant brain tumor cells as compared to treatment with the control, Ad/CMV-GFP virus without TRAIL activity.We showed for the first time that adenovirus Ad/gTRAIL had significant antitumor effects against high grade malignant meningiomas as well as gliomas. Although more work needs to be done, our data suggests that Ad/gTRAIL has the potential to be useful as a tool against malignant brain tumors. Gliomas and meningiomas are the two most common types of human brain tumors. Malignant gliomas are the most aggressive and deadliest type of brain tumor. MeningiTelomerase is the cellular enzyme responsible for the replication of chromosomal ends or telomeres. It is a multiunit ribonucleoprotein complex that contains an essential RNA component, human telomerase RNA (hTR) and essential protein components including the rate-limiting catalytic subunit human telomerase reverse transcriptase (hTERT). The strong link between telomerase activity and cancer was initially reported by Kim et al . Using ain vivo. More recently, we constructed a bicistronic adenoviral vector expressing the GFP-TRAIL fusion protein from the hTERT promoter via GAL4 gene regulatory system (Ad/gTRAIL) and demonstrated that Ad/gTRAIL treatment effectively elicited apoptosis in various tumor cells in vitro and suppressed xenograft tumor growth in vivo, with no detectable toxicity in human primary hepatocytes -2H-tetrazolium-5-carboxanilide inner salt; NG-1: neural glioma MOI-: Multiplicity Of Infection; SDS-PAGE:Sodium dodecyl sulfate polyacrylamide gel electrophoresis; PBS: phosphate-buffered saline; UNG: Uracil N-glycosyladse RT Q-PCR: Real-time quantitative polymerase chain reaction; AOV: Analysis of varianceThe authors declare that they have no competing interests.JL, IM and BF designed the study. JL draft of the manuscript, JL, AZ, performed experiments, WA, BF, participated in manuscript correction and Performed data analysis, KB RN, DK, FM, IM revised the manuscript. All authors read and approved the final manuscript.


Introduction: Event-related brain potentials (ERPs) provide important information about the sensitivity of the brain to process varying risks. The aim of the present study was to determine how different risk levels are reflected in decision-related ERPs, namely the feedback-related negativity (FRN) and the P300. Materials and Methods: Twenty participants conducted a probabilistic two-choice gambling task while an electroencephalogram (EEG) was recorded. Choices were provided between a low-risk option yielding low rewards and low losses and a high-risk option yielding high rewards and high losses. While options differed in expected risks, they were equal in expected values and in feedback probabilities. Results: At the behavioral level, participants were generally risk-averse but modulated their risk-taking behavior according to reward history. An early positivity (P200) was enhanced on negative feedbacks in high-risk compared to low-risk choices. With regard to the FRN, there were significant amplitude differences between positive and negative feedbacks on high-risk choices, but not on low-risk choices. While the FRN on negative feedbacks did not vary with decision riskiness, reduced amplitudes were found for positive feedbacks in high-risk relative to low-risk choices. P300 amplitudes were larger in high-risk decisions, and in an additive way, after negative compared to positive feedback. Discussion: The present study revealed significant influences of risk and valence processing on ERPs. FRN findings suggest that the reward prediction error signal is increased after high-risk decisions. The increased P200 on negative feedback in risky decisions suggests that large negative prediction errors are already processed in the P200 time range. The later P300 amplitude is sensitive to feedback valence as well as to the risk associated with a decision. Thus, the P300 carries additional information for reward processing, mainly the enhanced motivational significance of risky decisions. A significant function of the human brain is to assess the riskiness of decisions in order to prevent negative outcomes. Brain imaging studies indicate that frontolimbic brain circuits involving the ventromedial prefrontal cortex, amygdala, insula, ventral striatum, and anterior cingulate cortex (ACC), are implicated in risk processing. In particular, the ACC is important for detecting and evaluating unfavorable outcomes  have revealed that the human brain is able to evaluate the outcome of actions within a few 100 ms. Specific brain potentials are elicited by self-generated responses and performance feedback . The associated electrocortical indicators of risk-taking behavior were examined in the main experiment. Considering that expected values of high-risk and low-risk options were equal, we predicted that participants are predominantly risk-averse, namely that they are less willing to choose risky options  took part in the pilot experiment. Their mean age was 30.5 years . Three of the participants were left-handed. Participants had no history of neurological or psychiatric diseases. All participants received verbal and written explanations of the purpose and procedures of the study, and gave written informed consent in accordance with the Declaration of Helsinki.A computerized probabilistic two-choice gambling task was administered, which involved low-risk and high-risk options. On each trial participants were asked to choose between two options that were presented on a computer screen , performing two-tailed t-tests. Moreover, we analyzed whether the probability of high-risk choices on a given trial varied as a function of prior feedback valence and prior risk-taking behavior. This was done with an ANOVA with the within-subject factors previous feedback valence  and previous risk-taking . Statistical analysis was carried out with the Predictive Analytic Software (PASW) 19.0 for Windows.To assess risk-taking behavior, percentages  of low-risk (options A and C) and high-risk choices (options B and D) were determined and analyzed using two-tailed t(49)= 2.84, p = 0.007]. The analysis of risk-taking as a function of actual account balance revealed that participants avoided high-risk options when their current balance was positive, . By contrast, high-risk options were preferred when the current balance was negative, . Further, it was shown that risk preference varied as a function of prior feedback valence, , and prior risk-taking, . The interaction of feedback valence and prior risk-taking was not significant, . These effects reflect that participants preferred higher risks following losses than following gains, as well as following a high-risk decision as compared to a low-risk decision.Table With this pilot experiment we aimed to explore risk-taking behavior using a probabilistic two-choice gambling task. During each trial, participants were required to choose between options associated with two different risk levels. As expected, participants preferred the low-risk options over the high-risk options, although options did not differ with respect to expected values. Results are consistent with previous findings of Polezzi et al. . In that20 participants (five men) attended in the ERP study. Their mean age was 29.5 years . All participants were right-handed and had no history of neurological or psychiatric disorders. All participants received verbal and written explanations of the purpose and procedures of the study, and gave written informed consent in accordance with the Declaration of Helsinki. Participants gave written informed consent in accordance with the Declaration of Helsinki.Task and procedure for Experiment 2 were identical to the pilot experiment except that it comprised of 640 trials that were divided into three blocks with short breaks between blocks. Again, positions of high and low-risk options (left or right on the screen) varied across trials in pseudo-random order. In each trial, participants had to chose between options A and B , or options C and D . The increase in trial number was necessary to obtain a sufficient number of trials for ERP analyses in all conditions. The experiment lasted about 40 min. All participants were paid 15€ for their participation. To ensure ecological validity of the task and to enhance motivation, participants were informed that they would additionally receive the highest amount they earned in one of the three blocks. The average earning was 6.70€ in this experiment.The electroencephalogram (EEG) was recorded from 64 electrodes sites including Cz as a recording reference, using an equidistant electrode system . The montage also included additional electrodes that were placed on external locations: below the left and right eye (IO1 and IO2) and in the neck. The ground electrode was located below T1. Electrode impedances were kept below 5 kΩ. Electrical activity was sampled digitally at a rate of 500 Hz, using a time constant of 10 s and a low-pass filter of 250 Hz. Individual electrode positions were digitized based on the run-time measurement of ultrasonic pulses using ELPOS . Offline, the EEG data were re-referenced to average reference and corrected for eye-movement artifacts using the multiple source eye correction method as implemented in BESA 5.1 . For the FRN and P300 analyses, raw data were filtered offline with a low-pass filter of 40 Hz and an additional notch filter at 50 Hz. Feedback-locked epochs were obtained for each trial, starting 200 ms prior to feedback onset and continuing for 1000 ms post-feedback. Individual averages were baseline-corrected to an average activity between –200 and 0 ms before feedback onset. Feedback-locked epochs were excluded from further analyses if they still contained artifacts. For each participant, ERPs were averaged separately for feedback valance (positive vs. negative) and risk levels (low-risk options vs. high-risk options).r) were used to examine associations between FRN and P300 magnitude and percentage of low-risk choices (relative to the percentage of the high-risk choices). All statistical tests were two-tailed.Three components were analyzed. The P200 is a positive component peaking at around 200 ms after feedback onset and measured over frontal areas = 2.09, p = 0.050] (cf. Table t(19)= 3.15, p = 0.005]. Unlike the pilot data, participants only tended to increase risk-taking behavior when their current balance was negative compared to when it was positive, . Furthermore, it was found that the proportion of chosen high-risk options varied as a function of previous outcome valence and previous risk-taking. Consistent with the pilot experiment, we found main effects for feedback valence, , and for risk-taking, . Following losses, participants made more risky decisions than after gains. Following risky choices, participants were more likely to choose a high-risk option than after having made a low-risk choice. Finally, a significant interaction was found between previous feedback valence and previous risk-taking, indicating that most high-risk choices were made after high-risk choices followed by negative feedback, .As in the pilot experiment, we found a preference for low-risk options over high-risk options, , indicating larger amplitudes for losses compared to gains. There was also a significant main effect of risk, , revealing enhanced amplitudes in high-risk options compared to low-risk options. Furthermore, a significant interaction of risk and valence was found, . In high-risk decisions, larger amplitude differences between positive and negative feedbacks were found which was due to enhanced P200 amplitudes on negative feedbacks in high-risk options. The main effect of electrode was also significant, , with larger P200 at FCz compared to Fz.Figure F= 11.08, p = 0.004]. Furthermore, the FRN was modulated by risk as evidenced by a significant interaction between valence and risk option, . After choosing the high risk option, large amplitude differences between losses and gains were found, . By contrast, there was no significant amplitude difference between losses and gains in the low-risk condition, . While the FRN on losses did not differ with respect to the riskiness of options, , amplitudes on gains were reduced in the high-risk compared to the low-risk option, . The main effect of electrode also approached significance, , due to larger FRN amplitudes at Fz relative to FCz.Consistent with previous findings, a main effect of valence was found for FRN amplitudes, indicating enhanced FRN amplitudes on losses compared to gains, , indicating that the P300 was larger on losses compared to gains. There was a significant main effect of risk option, , showing enhanced amplitudes in high-risk compared to low-risk choices. No significant interaction between feedback valence and risk option was observed (F < 1). The P300 tended to be larger at CPz compared to Pz, .The P300 is also depicted in Figures Bivariate correlations were computed relating ERPs following losses and following gains  to the percentage of low-risk choices. Negative correlations for FRN amplitudes indicate an increase in FRN  with risk aversion.r = −0.47, p = 0.039), the FRN on losses at a trend level , and P300 amplitudes on losses . No significant correlations were found between risk-avoidance and P300 amplitudes after gains. Note that FRN and P300 amplitudes were not correlated .We found significant correlations between risk avoidance and FRN amplitudes on gains (The current study focused on decision-making and its neural correlates using a monetarily motivated probabilistic two-choice gambling task. In accordance with previous findings, participants were generally risk-averse but modulated their risk-taking behavior according to reward history (Tversky and Kahneman, Differential processing of risky decisions was reflected in the FRN amplitudes. The FRN was modulated by the well-known distinction between gains and losses (Gehring and Willoughby, Decision riskiness also affected the P200, a component that has previously been associated with the attention processing of emotional stimuli, such as faces. The more negative the valence, the larger the P200 amplitude (Carretié et al., In agreement with previous studies (Frank et al., Interestingly, FRN and P300 appear to reflect risk-taking behavior, but they might reflect different aspects of risky decision-making. Whereas FRN amplitudes are reduced by large positive prediction errors, P300 amplitudes are enhanced due to larger negative outcomes. Importantly, risk-avoidance behavior was associated with enhanced FRN and P300 amplitudes. Possibly, increased FRN amplitudes reflect enhanced cognitive control that is essential for the avoidance of risky decisions. The association between FRN and risk-avoidance is in line with previous findings, revealing an inverse relation between ERN/FRN amplitudes and risk-taking behavior in healthy individuals (e.g., Hewig et al., To our knowledge, this is the first study that independently controlled for different risk parameters. Nevertheless, there are possible confounds that should be discussed. First, the comparison between positive and negative feedbacks is confounded with feedback probability, i.e., positive feedbacks were more frequent than negative feedbacks. Therefore, reward probability may have influenced the difference between positive and negative feedbacks (Holroyd et al., To conclude, the present findings indicate that the processes underlying human decision-making are significantly affected by decision riskiness when controlling for reward probility and expected value. The increased P200 on negative feedback in high-risk decisions suggests that large reward prediction errors are processed as early as in the P200 time range. The FRN is affected by feedback valence depending on decision riskiness. Considered in the framework of the RL theory of the FRN, it has been suggested that the reward prediction error signal is increased after high-risk decisions compared to low-risk decisions. The later P300 amplitude is sensitive to feedback valence as well as to the risk associated with a decision. Thus, the P300 carries additional information for reward processing, mainly the enhanced motivational significance of risky decisions. Due to the potential negative consequences of high-risk choices, rapidly processing the relevant and informative features of a context when decisions have to be made seemed highly important for optimizing future decision-making. Risk-taking is a central cognitive-motivational construct accounting for many everyday decisions. In addition, understanding the neurocognitive basis of risk-taking behavior might also be central to explaining certain symptoms of psychopathological conditions, e.g., borderline personality disorder, patients with bipolar disorders or patients with substance dependency.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Gastrointestinal relapse in patients with multiple myeloma is very rare and, when reported, always associated with a poor prognosis.We describe the case of a 71-year-old Caucasian man who presented with life-threatening hematemesis and melena due to a digestive relapse of his multiple myeloma. Despite the active hemorrhage, we initiated a third-line treatment with lenalidomide. The response was spectacular and long-lasting.Clinicians must consider digestive tract involvement in myeloma patients presenting with a gastrointestinal hemorrhage. Furthermore, myeloma patients do benefit from novel oral drugs, even when they are critically ill. The involvement of the gastrointestinal tract years after an initial diagnosis of multiple myeloma (MM) is exceptional and, when reported, always associated with a poor prognosis -4. We reWe report the case of a 71-year-old Caucasian diabetic man with severe diabetic neuropathy who was diagnosed with stage IIIA IgG λ MM in 2004. He was initially treated with three cycles of vincristine, doxorubicin and dexamethasone, followed by high-dose melphalan and autologous stem-cell transplantation, which resulted in a partial response. His monoclonal IgG had dropped from 65 g/L before treatment to 11 g/L after transplantation. In 2007, a second-line chemotherapy treatment  for a relapse characterized by diffuse spinal involvement and an increase in monoclonal IgG (22 g/L) stabilized the disease. His neuropathy had precluded treatment with thalidomide or bortezomib. Eight months after the second-line chemotherapy, an irradiation to the T10-L1 vertebrae (30 Gy) was undertaken for symptomatic, localized bone involvement. Ten months later, an increase in his level of IgG (34 g/L), combined with widespread bone pain and a worsening of his general condition, led to the introduction of high-dose steroids.Legionella pneumophila antigen was positive and a computed tomography (CT) scan showed trilobar consolidation and a bilateral pleural effusion. A heterogeneous solid mass extending from the retroperitoneal to the peritoneal spaces  and his inflammatory parameters were increased (C-reactive protein 91 mg/L). A urinary test for the s Figure  providedShortly after the antibiotic therapy was discontinued, he presented with sudden hematemesis and melena, requiring fifteen 500 ml units of packed red cells, in total, over a period of twenty days. His platelet count and coagulation parameters were normal. A bleeding, ulcerated jejunal mass was revealed by an upper gastrointestinal endoscopy Figure  and biopet al. reported the case of a 60-year-old patient with MM with hematemesis, melena and gastroduodenal mucosal lesions [Gastrointestinal involvement in MM is very rare. It most often occurs in the context of an isolated, primary, extramedullary plasmacytoma . Patient lesions . The patOur case report is well documented and highly informative. It reminds us that, in addition to much more common causes , clinicians must consider digestive tract involvement in patients with MM presenting with a gastrointestinal hemorrhage. It also shows that patients with MM who have been heavily pre-treated can benefit from novel drugs, even when they are critically ill. We suggest that the major clinical improvement has to be linked to lenalidomide, since high-dose steroids had been ineffective in this case. Our patient's recovery and the drop in his monoclonal IgG were very rapid. This effect of lenalidomide has already been observed in other life-threatening situations associated with MM, such as severe renal impairment or high-output heart failure secondary to intramedullary arteriovenous fistulas ,10. FinaWritten informed consent was obtained from the patient's next-of-kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.PRB, JMD, LF, ACG and PYD were directly involved in the management of the patient. PRB wrote the manuscript with support from TAM and PYD. TAM and XM reviewed and interpreted the pathology slides and CT scan images, respectively. All authors read and approved the final manuscript.


Endothelial progenitor cells (EPC) are a type of stem cell used in the treatment of atherosclerosis, vascular injury and regeneration. At present, most of the EPCs studied are from human and mouse, whereas the study of poultry-derived EPCs has rarely been reported. In the present study, chicken bone marrow-derived EPCs were isolated and studied at the cellular level using immunofluorescence and RT-PCR.in vitro were EPCs. Observation of endothelial-specific Weibel-Palade bodies using transmission electron microscopy further confirmed that the cells were of endothelial lineage. In addition, chicken EPCs differentiated into endothelial cells and smooth muscle cells upon induction with VEGF and PDGF-BB, respectively, suggesting that the chicken EPCs retained multipotency in vitro.We found that the majority of chicken EPCs were spindle shaped. The growth-curves of chicken EPCs at passages (P) 1, -5 and -9 were typically “S”-shaped. The viability of chicken EPCs, before and after cryopreservation was 92.2% and 81.1%, respectively. Thus, cryopreservation had no obvious effects on the viability of chicken EPCs. Dil-ac-LDL and FITC-UAE-1 uptake assays and immunofluorescent detection of the cell surface markers CD34, CD133, VEGFR-2 confirmed that the cells obtained These results suggest that chicken EPCs not only have strong self-renewal capacity, but also the potential to differentiate into endothelial and smooth muscle cells. This research provides theoretical basis and experimental evidence for potential therapeutic application of endothelial progenitor cells in the treatment of atherosclerosis, vascular injury and diabetic complications. Endothelial progenitor cells (EPCs) are precursors of vascular endothelial cells. Progenitor cells . EPCs orin vitro, early and late EPCs. While early EPCs display a linear growth structure termed spindle-shaped, late EPCs form cobblestone-like, oval shaped strutures   were first isolated from peripheral blood by Asahara et al in 1997 . How. Howin v+CD133+VEGFR-2+ cells are considered putative EPCs by most researchers . CD1. CD1+CD1earchers 23]. Mor. Mor+CD1P < 0.05) before and after VEGF-induced differentiation of EPCs into mature endothelial cells. Thus, cultured chicken EPCs can develop into mature endothelial cells in response to VEGF as identified by morphological and phenotypic characteristics.EPCs are responsible for the construction of the blood vessel lumen, and are able to differentiate into mature endothelial cells and smooth muscle cells. There are many factors influencing the differentiation of EPCs into mature endothelial cells, among which the central factor is VEGF. Apart from inducing the differentiation of EPCs, VEGF also induces the differentiation of other stem/progenitor cells into mature endothelial cells . The undin vitro.EPCs are also known to develop into smooth muscle cells. Smooth muscle cells are the main functional cells of the vascular mesosphere and are involved in the synthesis of the vascular matrix and vasomotor function. Platelet-derived growth factor-BB (PDGF-BB) was used to induce EPC differentiation into smooth muscle cells. Seven days post-induction, cells with myoid morphology were observed. In accordance with the morphology, immunolabelling for the stem cell marker CD133 was negative in the inducted cells, while expression of the smooth muscle cell specific marker α-MSA was positive as determined using immunofluorescence and RT-PCR. Together, these data indicate that chicken EPCs can be differentiated into both mature endothelial cells and smooth muscle cells by stimulation with VEGF and PDGF-BB, respectively, In conclusion, this study establishes an optimized method for the isolation and culture of chicken EPCs as suggested by characterization of cell morphology, surface markers and biological features. We also demonstrate that chicken EPCs can be induced to differentiate into endothelial and smooth muscle cells, which supports the notion that the chicken EPCs retained multipotency. This study not only provides a technological platform for the establishment of a chicken EPC bank, but also proposes a new method to preserve the valuable genetic resources of chicken and other poultry.CB carried out the cell culture, participated in the cell assay and drafted the manuscript. LH carried out the detection of Weibel-Palade bodies. YP participated in drafted the manuscript. MZ participated in performed the statistical analysis. WG and YM conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.


Gemcitabine, a third-generation anticancer agent, has been shown to be active in several solid tumors. High-grade hemorrhage (grade≥3) has been reported with this drug, although the overall risk remains unclear. We conducted a meta-analysis of randomized controlled trials evaluating the incidence and risk of high-grade hemorrhage associated with gemcitabine.Pubmed was searched for articles published from January 1, 1990 to December 31, 2012. Eligible studies included prospective randomized controlled phase II and III trials evaluating gemcitabine-based vs non-gemcitabine-based therapy in patients with solid tumors. Data on high-grade hemorrhage were extracted. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of included trials.p<0.001), phase II trials , trials reported during 2006–2012  and gemcitabine used as single agent .A total of 6433 patients from 20 trials were included. Among patients treated with gemcitabine-based chemotherapy, the overall incidence of high-grade hemorrhage was 1.7% (95%CI: 0.9–3.1%), and the RR of high-grade hemorrhage was 2.727 . Exploratory subgroup analysis revealed the highest RR of hemorrhage in non-small-cell lung cancer (NSCLC) patients (RR: 3.234; 95%CI, 1.678–6.233; Gemcitabine is associated with a significant increase risk of high-grade hemorrhage in patients with solid tumors when compared with non-gemcitabine-based therapy. High-grade hemorrhage is a significant cause of morbidity and mortality in patients with cancer The selection and systematic review of trials was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement see  [26]. TrOur primary objective was to evaluate the association between treatment with gemcitabine-based therapy and high-grade hemorrhage in patients with cancer. Clinical trials meeting the following criteria were included in the meta-analysis: 1) prospective randomized controlled phase II or III trial of cancer patients, 2) random assignment of participants to treatment with gemcitabine or non-gemcitabine-containing therapy, and 3) available data on high-grade hemorrhage. The quality of reports of clinical trials was assessed and calculated using the 5-item Jadad scale including randomization, double-blinding, and withdrawals as previously described 2). The following adverse outcomes were considered as hemorrhagic events and included in the main analysis: ecchymosis or petechiae; epistaxis; eye hemorrhage; gastrointestinal hemorrhage; gum hemorrhage; injection-site hemorrhage; hematemesis; hematuria; hemoptysis; non-specific hemorrhage; hemothorax; melaena; menorrhagia; metrorrhagia; purpura; rectal hemorrhage; retroperitoneal hemorrhage; CNS hemorrhage; and vaginal hemorrhage (includes menorrhagia and metrorrhagia). We also included (when available) the incidences of high-grade (grade 3 or above) hemorrhagic events. We assessed and recorded adverse events according to the National Cancer Institute’s common toxicity criteria (version 2 or 3), which have been adopted widely in cancer clinical trials Data extraction was conducted independently by two investigators (Y.H. and W.J.), and any discrepancy between the reviewers was resolved by consensus. For each study, the following information was extracted: author, publication year, trial phase, treatment arms, number of patients enrolled, number evaluable for toxicity, underlying malignancy, median age, median treatment duration, median progression-free survival, adverse outcomes of interest (high-grade hemorrhagic events), gemcitabine dosage (mg/mhttp://tuftscaes.org/open_meta/). For the calculation of incidence, the number of patients with high-grade hemorrhagic events and the number of patients receiving gemcitabine were extracted from the selected clinical trials; the proportion of patients with high-grade hemorrhagic events and 95% confidence interval (CI) were derived for each study. For the calculation of relative risk (RR), patients assigned to gemcitabine-based therapy were compared only with those assigned to control treatment in the same trial. Between-study heterogeneity was estimated using the χ2-based Q statistic Pheterogeneity <0.1. If heterogeneity existed, data was analyzed using a random effects model (DerSimonian Larid method). In the absence of heterogeneity, a fixed effects model was used (Mantel-Haenszel method). Continuity corrections with 0.5 were adopted for trials with zero events in either or both arms. A two-sided p-value less than 0.05 was considered significant. Prespecified subgroup analyses were performed according to tumor type, phase of trials, publication year or treatment regimens. To assess the stability of results, sensitivity analysis was performed by sequential omission of individual studies. The presence of publication bias was evaluated by using the Begg and Egger tests All analyses were performed using Stata version 12.0 software  and Open Meta-Analyst software version 4.16.12 .No evidence of publication bias was detected for the RR of high-grade hemorrhagic events in this study by either Begg or Egger’s test , the summary incidence of high-grade hemorrhagic events in patients receiving gemcitabine-based therapy was 1.7%  as observed in a phase II NSCLC trial To investigate the specific contribution of gemcitabine to the development of hemorrhagic events and exclude the influence of confounding factors such as underlying malignancy, and other therapeutic interventions, we therefore determined the relative risk (RR) of gemcitabine associated hemorrhagic events. The combined results demonstrated that the use of gemcitabine was associated with a significantly increased risk of developing high-grade hemorrhage with a RR of 2.727 , but the differences among tumor types were not statistically significant.To better determine possible relationships between gemcitabine and high-grade hemorrhage, we performed several prespecified subgroup analyses, stratifying patients by malignancy, phase of trial and year of publication . The incGiven the potentially differing risks of hemorrhage between phase II and III trials, an exploratory analysis stratifying patients by phase of trial was performed . InteresWe hypothesized that the incidence of severe hemorrhage reported in cancer clinical trials may have increased over the past decade. Therefore, we explored the impact of publication year on incidence and RR of severe hemorrhage with gemcitabine-based therapy. Notably, the incidence of hemorrhage in the 9 trials published from 1999 to 2005 was 2.1% (95%CI: 0.8–5.4%), compared with an incidence of 1.6% (95%CI: 0.9–2.6%) in the 11 trials published from 2006 to 2012. In the 11 trials published from 2005 to 2012, gemcitabine-based therapy was associated with an RR of hemorrhage of 3.75 . In trials published from 1999 to 2005, gemcitabine-based therapy was associated with an RR of hemorrhage of 1.808 . This difference did not reach statistical significance.Concomitant agents with gemcitabine, including bevacizumab and sorafenib, might increase the risk of gemcitabine-related hemorrhage events. We therefore performed sub-group analysis according to gemcitabine-based regimens. An increased risk of hemorrhage events was observed in gemcitabine used as single agent , doublet combination  and triplet combination  when compared to controls, though the risk did not significantly increase in gemcitabine therapy used as single agent (p = 0.081) and triplet combination (p = 0.67) . One posTo our best knowledge, this is the first meta-analysis to investigate the risk of high-grade hemorrhage associated with gemcitabine. Our analysis of data from randomized controlled trials shows a nearly three-times increased risk of high-grade hemorrhage in cancer patients treated with gemcitabine-based therapy. Additionally, the overall incidence of gemcitabine associated high-grade hemorrhagic events is 1.7% . Based on these results, we could conclude that while the incidence of high-grade hemorrhage in patients treated with gemcitabine is low, the use of gemcitabine is associated with significantly increased risk of high-grade hemorrhage when compared with non-gemcitabine-based therapy. These results would provide important information for clinicians who use gemcitabine to treat patients with solid cancer.p<0.001). However, the interpretation of these findings is hampered by the low number of patients and events in certain subgroups. As a result, more high-quality trials are still needed to investigate the risk of gemcitabine associated hemorrhage in these tumors. We hypothesize that the incidence of serious hemorrhage reported in clinical trials over the last decade may have increased because of an increased awareness that serious hemorrhage may be treatment rather than disease related. Indeed, the incidence of serious hemorrhage is higher in trials published between 2006 and 2012 compared with trials published between 1999 and 2005. Then, we also investigate the differing risks of hemorrhage between phase II and III trials. Interestingly, the effect size is greater in the phase II trials versus phase III trials. However, there is no significant difference between these subgroups. Finally, we perform sub-group analysis to detect the influence of concomitant agents on risk of hemorrhage, and find that there is an increased risk of hemorrhage events in gemcitabine used as single agent, doublet combination and triplet combination when compared to controls, though the risk did not significantly increase in gemcitabine therapy used as single agent and triplet combination.Many factors such as age, race, sex, mobility, underlying cancer, and concurrent use of anticoagulants or chemotherapy are known to contribute to the development of hemorrhage in cancer patients The pathogenesis of gemcitabine-induced hemorrhage remains unclear, gemcitabine-induced thrombocytopenia may be directly related to its increased risk of hemorrhage, but the risk of hemorrhage depends not only the platelet count, but also on the underlying disease, platelet function and complications such as fever and infection or the presence of coagulation defects Our meta-analysis had several limitations. First, this meta-analysis was not based on individual patient data, and meta-analyses based on published data tended to overestimate treatment effects compared with individual patient data analyses. In addition, it precluded a more comprehensive analysis such as adjusting for baseline factors and other differences that existed between the trials from which the data were pooled. Therefore, the results must be interpreted cautiously, as an individual patient data-based meta-analysis would give more reliable estimation than one based on published data. Secondly, trials reported zero high-grade hemorrhage in one or both arms were also included for analysis. In this setting, using fixed effects models and continuity corrections would bias the results towards null. But we felt that including trials reporting zero high-grade hemorrhage would provide the most conservative estimate. Thirdly, different treatment strategy, duration, and regimens contributed to increase the clinical heterogeneity of the meta-analysis, which made the interpretation of the meta-analysis more problematic, although we performed sub-group analysis and sensitive analysis. Additionally, targeted drugs including bevacizumab In conclusion, although the incidence of high-grade hemorrhage in patients treated with gemcitabine is low, a significantly increased risk of high-grade hemorrhage is detected when compared with non-gemcitabine therapy. Clinicians should be cautious when using gemcitabine-based therapy for treating cancer patients, especially those at high risk.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.


Links between the demanding nature of studies in the health sciences, students’ personality traits and psychological distress have been well-established. While considerable amount of work has been done in medicine, evidence from the dental education arena is sparse and data from Latin America are lacking. The authors conducted a large-scale investigation of psychological distress among dental students in Colombia and sought to determine its curriculum and student-level correlates.The Spanish version of the Derogatis’ Symptoms Checklist Revised (SCL-90-R) was administered to all students officially registered and attending classes or clinics in 17 dental schools in 4 geographic districts of Colombia between January and April 2012. Additional information was collected on participants’ socio-demographic information and first career choice, as well as school’s characteristics such as class size. The Global Severity Index (GSI) score, a measure of overall psychological distress, served as the primary analytical endpoint. Analyses relied on multilevel mixed-effects linear and log-binomial regression, accounting for study design and sample characteristics.A total of 5700 dental students completed the survey, a response rate of 67%. Pronounced gradients were noted in the association between socio-economic status and psychological distress, with students in higher strata reporting fewer problems. After adjustment for all important covariates, there was an evident pattern of increasing psychological distress corresponding to the transition from the didactic, to the preclinical and clinical phases of training, with few differences between male and female students. Independent of other factors, reliance on own funds for education and having dentistry as the first career choice were associated with lower psychological distress.Levels of psychological distress correlated with students’ socio-economic and study-level characteristics. Above and beyond the influence of person-level factors, variations in levels of distress paralleled specific transitional stages of the 5-year dental curriculum, providing opportunities for targeted interventions. A considerable body of literature has established the links between the demanding nature of studies in the health sciences, students’ personality characteristics and manifestations of psychological distress -6. Severet al. ; sex; study year (1–5); sources of funding for studies ; working while studying (yes/no) and socio-economic level . We also obtained information about the students’ first career choice (dentistry vs. other). With regard to school-level variables, we recorded its private or public character and the average class size .SD), medians and ranges], overall and stratified by sex. We used X2 tests and a p < 0.05 criterion to assess the distribution of covariates between male and female participants, and a t test for the ‘age’ variable. The use of a t test for non-normally distributed data was supported by the central limit theorem applied to a large sample [For initial data presentation and exploration we used descriptive statistics [simple proportions, means, standard deviations , mean scores, SD and 95% confidence intervals (CI) for all other SCL-90-R derived indices to offer an opportunity for comparisons with other samples and studies that employ these other metrics.We explored the factor structure of SCL-90-R in the context of our study using iterated principal factor analysis with varimax rotation . We empia priori terms for age, sex, socio-economic status and study year. Inclusion of additional covariates was based on forward selection and LR tests with a p-value criterion of <0.2. To allow for non-homogeneous effects of age, socio-economic status and first career choice between males and females and across study years, we included a five-way interaction term between these variables. We based our inference on crude and adjusted beta coefficients and corresponding p-values using a p <0.05 criterion, as well as inspection of predictive marginal effects [The sample’s clustered nature of observations  dictated the use of analytical methods based on multilevel modeling . To dete effects .To quantify the impact of student and school-level factors on the prevalence of high psychological morbidity we used a second series of multivariate models based on log-binomial regression. First, we generated normalized GSI (T) scores centered at 50 separately for males and females and, as in previous studies ,43-45, uThe study was approved by the Health Sciences Ethics Committee of Universidad Cooperativa de Colombia- Pasto (No. CECS02-12).st and 2nd years to 686 5th year students.The mean age of the 5700 dental students was 21 years, with approximately two-thirds being female and having dentistry as their first career choice  GSI scores were: overall—1.03 (0.69); females—1.08 (0.69); males—0.91 (0.68). Among female and male participants who had normalized T-scores of ≥63 and were classified as “high scorers” , these estimates were 2.62 and 2.48, respectively. Although the GSI was used as our primary analytical endpoint, to enable comparisons with previous and future studies we present PST, PSDI and the 9 SCL-90-R dimensions scores in the supplemental material , to the preclinical (3rd) and clinical (4th and 5th years) stage of the curriculum. Particularly among females, the transition into the clinical training phase was associated with a pronounced increase in GSI scores  and 5th year among males—PR = 1.54 .In Table In this study of student- and curriculum-level correlates of psychological distress among Colombian dental students we found that both demographic and socio-economic  and study-related (career choice and study-year) characteristics influenced the levels of students’ psychological disturbance. This report builds upon a robust sample of almost 6 thousand students to add to the knowledge base of health science students’ psychological distress, and provides insights into this important issue among an under-studied group of dental students, in Latin America. Although direct comparisons with other samples and populations should be made with caution, the levels of psychological distress in this group of dental students were considerably higher compared to previously reported estimates among young non-clinical samples. The findings of possible associations between dental curriculum stage and psychological morbidity provide insights into educational events and transitions that may be sources of distress for dental undergraduates.As mentioned previously, cross-cultural comparisons of SCL-90-R norms and scores is not well-supported . NeverthAs in previous investigations employing the same instrument (SCL-90-R), female dental students reported higher levels of psychological distress compared to their male counterparts. Given the ‘universality’ of this by-sex difference among normative and population-based samples, this finding should not be attributed to characteristics of the dental education environment. However, it is consistent with previous reports of females being more expressive of their emotions . FindingThe variation of psychological distress across study years above and beyond all other demographic, socio-economic, and institution-level parameters is noteworthy. Distress levels increased overall, but pronounced spikes were evident in the transition to from the didactic/basic science, preclinical and clinical phases of the training. This is consistent with evidence of perceived stress escalating over time  or varyist to the 5th study year. We cannot support that study non-participation was independent of psychological distress levels thus both these factors are potential threats to the external validity of our findings. Moreover, and although self-reported instruments are routinely used for screening purposes in psychiatry and social/behavioral epidemiology, students’ reports are also prone to biases of unknown magnitude and direction. Finally, our inferences with regard to differences in the levels of psychological distress by study-level were based on cross-sectional observations rather than longitudinal data, and therefore, should be interpreted with caution. A prospective survey design capturing student-level longitudinal data throughout the dental curriculum would enable investigators to make stronger inferences regarding the trends in psychological morbidity across the stages of dental training.Our findings must be regarded in view of the study’s limitations. The participants did not represent a probability sample of all Colombian dental students, and response rates varied considerably between the 17 participating dental schools. Moreover, due to student attrition, the sample size decreased progressively from the 1The issue of alarmingly high levels of psychological distress during medical training is well-established, and evidence now accumulates in dentistry. Acknowledging the limitations of our cross-sectional survey, we support that both personal  and curriculum or institution-level factors (career choice and study-year) are associated with dental undergraduates’ psychological distress. Under the conditions of our study, variations in levels of distress paralleled specific transitional stages of the 5-year dental curriculum, providing opportunities for targeted interventions in the curriculum. Based on these findings we further suggest that schools and states give special consideration to the students’ social and economic conditions, with the aim of allocating appropriate support to those most in need. Nonetheless, evidence of systematic application and evaluation of means to improve dental and health science students’ educational well-being is lacking and should be prioritized. It is imperative that such interventions, beyond evidence-based and effective, are participatory, socially and culturally-appropriate, and sustainable.Written informed consent was obtained from all participating dental students for the publication of this report, in compliance with the Health Sciences Ethics Committee of the Universidad Cooperative de Colombia - Pasto (ACT No. ECHS02-12).CI: Confidence interval; GSI: Global severity index; PR: Prevalence ratio; PSDI: Positive symptom distress index; PST: Positive symptoms total; SCL-90-R: Symptoms checklist revised; SD: Standard deviation.The authors declare that they have no competing interests.KD conducted the analysis and wrote the first draft of the manuscript; ACM conceived and coordinated study, participated in data collection and cleaning, and wrote the first outline of the manuscript; LVT participated in the study design, instrument piloting, and critically revised the manuscript; MSM, CLGG, LFVJ, JATC, DPC, MLVM, MASP participated in the planning of the study, data collection and entry, and critically revised the manuscript; AP oversaw the data design and analysis, and critically revised the manuscript. All authors approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6920/13/91/prepub Psychological distress estimates derived from the Symptom Check List 90-Revised (SCL-90-R).Click here for file


Patients with irritable bowel syndrome (IBS) often relate symptoms to theintake of certain foods. This study assesses differences in diet in subjectswith and without IBS.The cross-sectional, population-based study was conducted in Norway in 2001.Out of 11078 invited subjects, 4621 completed a survey about abdominalcomplaints and intake of common food items. IBS and IBS subgroups wereclassified according to Rome II criteria.= 0.001) and high intake of water (100 ml/day), tea  and carbonated beverages  were associated with IBS. A lowerintake of dairy products and a higher intake of alcohol and carbonatedbeverages were associated with D-IBS and a higher intake of water and teawas associated with A-IBS. In subjects with IBS the severity of symptoms wasassociated with a higher intake of vegetables and potatoes in subjects withC-IBS, with a higher intake of vegetables in subjects with A-IBS, and with ahigher intake of fruits and berries, carbonated beverages and alcohol insubjects with D-IBS.IBS was diagnosed in 388 subjects (8.4%) and, of these, 26.5% hadconstipation-predominant IBS (C-IBS), 44.8% alternating IBS (A-IBS), and28.6% diarrhoea-predominant IBS (D-IBS). Low intake of dairy products(portions/day) (Odds Ratio 0.85 [CI 0.78 to 0.93],p In this study, the diet differed in subjects with and without IBS and betweenIBS subgroups and was associated with the severity of symptoms. Functional gastrointestinal disorders are common in developed countries, andirritable bowel syndrome (IBS) is the most frequent disorder with a prevalence of5–10% . The treApproximately two-thirds of subjects with IBS relate their symptoms to their intakeof food ,4. Most The OPPHED (Oppland and Hedmark counties) Health Study was conducted in 2000 - 2001as a cross-sectional study by the National Health Screening Service . In this part of the study, all men and womenliving in Oppland County who were born in 1925, 1940, 1955, 1960 and 1970 wereinvited to participate.Subjects were asked to complete questionnaires in paper form on their own. Thefood and drink questions in our study were equal to the food and drink questionsin The Oslo Health Study (an English translation is available ). The foData were analysed with PASW Statistics 18.0 .U test, Chi-square test, and logistic regression analyses.Differences between the three subgroups of IBS were assessed with theKruskal-Wallis Test and Chi-square test, followed by pairwise comparisons whenthe overall test was significant. Logistic regression analyses were used toassess differences between each of the three IBS subgroups  versus subjects without IBS. Associations between the severity ofsymptoms and IBS subgroups were assessed with ordinal logistic regressionanalyses. In situations with fewer than 10 observations per covariate, we usedbackward stepwise elimination terminating in models that included age, gender,HSCL10, and musculoskeletal complaints, and as many other covariates as possiblewith at least 10 cases per covariate.Differences between subjects with and without IBS were assessed with Mann-WhitneyFor the regression analyses, missing values were handled by multiple imputations.All variables to be included in the regression analyses were included in theimputation model. Right-skewed variables were log-transformed before being usedin the imputation model and 20 datasets were created.Two-sided p < 0.05 was considered statistically significant, and95% confidence intervals (CI) are reported where relevant. All results are givenas the mean with the SD in parentheses unless otherwise indicated.All participants gave written informed consent to participation before enrolmentin the study. The project was approved by the Regional Committees for MedicalResearch Ethics, and the Data Inspectorate, Oslo, Norway.Questionnaires about abdominal complaints and diet were completed by 4621 subjects.The blood values of omega-3 fatty acids of fish origin (104.7 (37.8)) weresignificantly correlated with a diet containing omega-3 fatty acids from fatty fishand fish oil supplements (RThis study is the first one to show that the association between IBS and dietaryhabits refers to the whole population with IBS and not only those seeking medicaladvice. There were dietary differences between subjects with and subjects withoutIBS, between IBS subgroups and there were associations between diet and the severityof symptoms. As this was a cross-sectional study the possibilities for both causeand effect relationships are discussed.The lower intake of dairy products in IBS and particularly D-IBS compared to subjectswithout IBS is consistent with some studies that have shown avoidance of milkproducts and lower intakes of calcium in subjects with IBS compared to controls,11. IncA higher intake of vegetables was significantly associated with an increased severityof symptoms in C-IBS and A-IBS, and a higher intake of fruits and berries wassignificantly associated with the severity of symptoms in D-IBS. Other studiessupport these results ,27. VegeThe intake of water and tea was significantly higher in A-IBS compared to subjectswithout IBS and the intake of water and carbonated beverages was particularly highin subjects with D-IBS. Plain water is recommended as a beverage for subjects withIBS , while tSubjects with D-IBS showed the highest intakes of alcohol compared with othersubgroups and subjects without IBS, and in this subgroup, there was a significant,positive association between the intake of alcohol and the severity of symptoms. In,contrast, Williams et al. found no alcohol intake differences between IBS subgroups. SupportThere seems to be issues related to symptoms concerning diary products, fruits andvegetables, carbonated beverages and alcohol in subjects with IBS, but there may bedifferences between subgroups regards what kind of item causes symptoms. Thementioned food items may be discussed in dietary consultations, and the importanceof treating every patient with IBS individually is herby emphasised.The higher score for psychological distress measured by HSCL10 and the higher scoreof musculoskeletal complaints in subjects with IBS compared to subjects without IBSare consistent with the results of other studies . The higThe strengths of this study were the design based on the general population,which reduces the risk for a selection bias, and that the sample size was high,which increases the internal validity of the study and reduces the risk of typeII error. However, the response rate was low, which might again induce aselection bias and reduce the external validity. Still, a Norwegian study onnon-responders that shares many similarities with our study, such as timeperiod, design, and response rate, found no evidence of major systematic errors. As our The FFQ was unfortunately not validated, however the food questions have beenused and published by Lupton  andthe Our population-based study shows differences in diet in subjects with and withoutIBS. Some of the differences are more pronounced in subgroups and the diet isassociated with the severity of symptoms. The results may have importance fordietary advice. Future research should include all food groups, try to findplausible mechanisms underlying the dietary differences, and differentiate betweendifferent subgroups of IBS.IBS: irritable bowel syndrome; C-IBS: constipation-predominant IBS; A-IBS:alternating IBS; D-IBS: diarrhoea-predominant IBS; OR: odds ratio; CI: 95%confidence interval; HSCL10: hopkins symptom checklist 10; FFQ: food frequencyquestionnaire.The authors declare that they have no competing interests.PGF wrote the protocol. SCL, SL, and PGF performed statistical analyses. SCL wrotethe paper under the supervision of PGF. All authors have read and approved the finalmanuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/12/61/prepub


Hepatocellular carcinoma (HCC) is a fatal disease. Chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection is the major cause of HCC. High viral replication rate and related hepatic/systematic inflammation are the major risk factors in HCC recurrence after hepatectomy or liver transplantation.Some of the carcinogenesis-related HBV mutations are also associated with poor prognosis for HCC patients. Antiviral therapy is an option for improving HCC prognosis after surgery. In case of HBV-associated HCC, treatment with interferon and nucleos(t)ide analogues (NAs), especially interferon, is effective in improving the prognosis. However, long-term use of NAs increases the possibility of developing drug-resistant viral mutations such as the HBV rtA181T/sW172 mutation, which increases the risk of HCC recurrence.In cases of HCV-associated HCC, standard interferon with or without ribavirin therapy is effective in improving the prognosis of HCV-associated HCC; however, some HCV mutations, such as the amino acid substitution M91L, are associated with treatment failure and a poor prognosis. Therapeutic efficacy needs to be confirmed using largescale, randomized, placebo-controlled clinical trials.Surveillance of viral mutations during antiviral treatment and a better understanding of the associations of HCC recurrence with viral load, inflammation-associated signaling, and environmental factors can aid the development of more effective strategies for the prevention of HCC recurrence after surgery. Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer death worldwide . Chronic4 copies/mL) is significantly associated with improved long-term recurrence-free survival and OS  seropositivity indicate a high viral replication rate. The presence of HBeAg either before or after curative treatment for HCC is significantly associated with early recurrence and poor survival -12. Serul and OS . In addil and OS , 18. Thel and OS . High vil and OS -22. All k of HCC -25. C165k of HCC . PreS dek of HCC . The prek of HCC . All thek of HCC , 30. A17k of HCC . HCV is k of HCC . Moreovek of HCC . Currentk of HCC , HCC patvs. IFN/RBV for HCV-related HCC) after curative surgery, we summarized the results of HBV-related HCC RCTs and NRCTs in A meta-analysis conducted by Breitenstein et al.  pooled dHBV-positive patients require both sufficient antiviral therapy with NAs and hepatitis B immune globulins (HBIG) after successful liver transplantation to effectively prevent recurrence . The intLong-term use of NAs may generate drug-resistant viral mutations. The most frequently used antiviral therapy for post-transplantation recurrence of HBV infection is LAM, but this drug is associated with a high resistance rate due to tyrosine-methionine-aspartate-aspartate (YMDD) mutants . The YMDSo far, there is no consensus on the standard regimen, such as drug combination, dosage, and optimal time of initiation of therapy, to achieve the best prognosis for HCC after curative treatment. The current practice is largely experience-based, and most results, especially for NAs, are from NRCTs. For IFN, previous studies have indicated that there was no difference between intermittent and continuous treatment strategies. The usual dosage is 3-6 million international units (MIU), with some with a larger dosage of 10 MIU, subcutaneously or intramuscularly. It is usually administrated 2-3 times per week, and needs to last for more than 6 months. It is also a common practice to add RBV to the IFN treatment regimen for HCV-related HCC. IFN has a short half-life in the circulation and needs frequent administration, thus can produce severe side effects. As a result, PEG-IFN has recently been prescribed more often, with a dosage ranging from 90 to 180 μg per week. As for NAs, LAM is an often-used agent, with a common dosage of 100 mg/day, sometimes in combination with another NA, such as ADV, to reduce the possibility of developing drug-resistance. Results from NRCTs show that NAs are effective in improving survival. However, it is difficult to make any recommendation based on these data to guide clinical practice. No definite conclusions could be drawn without creditable evidence from RCTs. International collaborations are needed to conduct large multi-centered RCTs in different populations in order to evaluate the most effective combination and administration of these therapeutic agents.HBV and HCV related HCC cause a huge public health burden, especially in HBV endemic areas. Only a small proportion of HCC patients are eligible for curative treatment, namely surgical resection or OLT. Further, survival after the curative treatment is not optimal. High viral replication rates, viral mutations, and infection-associated inflammation are major factors associated with poor outcomes after surgery. Antiviral treatment is therefore an optimal option to prevent HCC recurrence and improve survival. IFN and NAs are currently the major antiviral agents in use. Use of antiviral agents not only inhibits virus replication and re-activation, but also decreases hepatic inflammation and can facilitate further treatment. IFN and NAs, especially IFN, have been proven to be effective in improving HCC prognosis. However, large multicenter RCTs are necessary to determine the most effective regimen of these antivirals in improving the HCC prognosis after surgery. The complex interactions among viral factors, host immunity, and environmental determinants may influence HCC recurrence and survival. However, the underlying mechanisms of this multi-way network have not yet been fully elucidated. A better understanding of the relationships among these factors can aid in developing advanced treatment strategies and improving the life quality of HCC patients. Future research should focus on the roles of viral factors, inflammation-related signaling molecules, and possible environmental factors on HCC occurrence and the effect of antiviral treatments on HCC - or HCC prognosis-associated viral mutants. A systematic scientific approach should be adopted to direct further studies.


This randomized controlled clinical study evaluated the efficacy of adapted yoga  to reduce psychosocial risks, which have been clinically shown to impact morbidity and mortality in implantable cardioverter defibrillator (ICD) recipients. The ICD collects and records real-time cardiac data, which were used in the study.Forty-six patients participated from a hospital in Connecticut. All participants were administered validated measures on psychosocial risk factors at weeks one and eight of the eight-week intervention. Patients in the intervention group participated in a weekly adapted yoga class for eighty minutes for eight weeks with assigned home practices. Clinical measures, including patients’ current and past medical health status and device usage, were collected three months prior to the study, during the study, and at a six-month follow-up.2=.98) of the observed anti-tachycardia pacing (ATP) events revealed that the expected number of ATP events in the intervention group was significantly lower than the control group. Additionally, the expected number of ATP events increased more rapidly as a function of the initial ATP events for the control group than for the intervention group.Data revealed that the yoga group’s overall shock anxiety decreased while the control group’s increased, t, p<0.0001 . The yoga group had less shock anxiety, t p=0.007 (mean consequence), greater overall self-compassion, t, p=0.007 , and greater mindfulness (equanimity) regarding emotions, t p=0.04 (mindfulness), than the control group. Exploratory analyses utilizing a linear model (ROur study demonstrated psychological benefits from a program of adapted yoga compared to usual care for ICD recipients. Marked improvements were reported in total shock anxiety, self-compassion, sense of equanimity, and decreased likelihood of ATPs. The data supports the continuation of research in mind-body interventions to better understand the role of complementary medicine to address ICD-specific psychosocial stress and its potential contributory role in cardiac outcomes.