The boronic acid dipeptide bortezomib, able to induce tumor cell death by degradation of key proteins, is the first proteasome inhibitor drug to enter clinical practice. It is employed as first-line treatment in relapsed or resistant multiple myeloma (MM) patients. However, bortezomib often induces a dose-limiting toxicity in the form of painful sensory neuropathy, which can mainly be reduced by subcutaneous administration or dose modification. In this review we focus on the current understanding of the pathophysiological mechanisms of bortezomib-induced neuropathy to allow further studies in animal models and humans, including analysis of clinical and pharmacogenetic aspects, to optimize the treatment regimens. In partpatients . Howeverpatients ,13. On tet al. have reported that the incidence of BIPN in newly diagnosed MM patients by NCI-CTC v.3.0 was as high as 64% [2), and thereafter neurotoxicity remains stable [According to the most widely used National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grading scale, BTZ appears with grade 1–2 BIPN in the relapsed or refractory MM patients , with an overall incidence up to 22% of patients, while the treatment of grade 3–4 neurotoxicity may appear in 13% of BTZ-treated patients (NCI-CTC v.2.0) . Moreoveh as 64% . The mais stable ,17. Furts stable ,19. Hencs stable . In facts stable ,22,23. As stable ,25,26. Is stable .BIPN is a typically painful sensory neuropathy characterized by neuropathic pain in a stocking-and-glove distribution and by paresthesias in distal extremities of limbs, mainly due to unmyelinated and thin myelinated sensory fibers impairment  ,28. SincClinical practice evidenced that BTZ causes a mild hematological toxicity, but the most common dose-limiting side effect is BIPN. The mechanisms underlying the pathogenesis of BIPN still remains elusive due to the amount of sites involved in BTZ-induced peripheral nervous system damage, from the level of the sensory cell bodies in the dorsal root ganglion (DRG) to the distal terminal axon .C-fiber damage [et al. in which several changes were founded at nuclear levels, with disruption of the protein synthesis mechanism and DNA damage without induced DRG neuronal death [et al. proposed that BTZ mainly affected DRG neurons and induced neurite dysfunction altering the axonal transport, due to more marked susceptibility of sensory neurons to BTZ compared with Schwann cells [in vivo studies by Staff et al. and Meregalli et al. both reported that BTZ is a drug that increases the polymerized tubulin in microtubules, thus affecting microtubule function and stabilization, altering axonal transport in rat DRG neurons [Concerning the mechanism of BIPN, a multifactorial cause seems likely. The first study conducted by Cavaletti and colleagues in bortezomib-induced neurotoxicity performed in a rat model suggested that BTZ causes a dying-back degeneration of sensory nerves with pathological changes to both Schwann and Satellite cells, representative of a toxic axonopathy . In the r damage . Conversr damage . Furtherr damage . Moreoveal death . Moreovenn cells . Severalnn cells . Subsequ neurons ,44. More neurons .in vitro and in vivo models, ROS generation and dysfunction into mitochondrial-based apoptotic pathway are BTZ-mediated [C-fibers, and the use of a TRPA1 antagonist in mice is able to give a transient benefit in painful BIPN [In neurons, the calcium homeostasis disruption promoting bioenergetics deficits that induced depolarization and spontaneous discharge, probably responsible of the typical degeneration in primary sensory neurons and intraepidermal nerve fibers observed in BTZ-treated patients ,46. Moremediated ,50,51,52mediated . In addiful BIPN .i.e., TNFα or IL-6) are associated with the neuropathic pain onset [Finally, dysregulation of neurotrophins and blockage of nerve-growth-factor-mediated neuronal survival (through inhibition of NF-κB activation) are indicated as mechanisms potentially involved in BTZ neurotoxicity, as well as autoimmune factors and inflammation contributors through the expression of pro-inflammation genes  may be able to ameliorate BIPN through the increase of mucosal blood flow via capsaicin sensitive neurons [i.e., pregabalin and gabapentin), selective serotonin and norepinephrine reuptake inhibitors  and opioids [2 receptor imidazoline (CR4056), that provide successful evidences in reducing pain in a rat model of neuropathic pain induced by chronic administration of BTZ [C and N-acetyl-l-cysteine administration in Schwann cell treated with BTZ was able to reduce the ER stress and to improve the neuropathic condition in an in vitro study [There is no currently accepted proven therapy for BIPN, so knowledge of preventive measures and recognition of imminent serious neurotoxicity are needed. Fortunately, a dose reduction of BTZ leads to reversal of BTZ toxicity without affecting the anti-tumor effect and the correlated neuropathic symptoms in MM patients . Several taxanes . Unfortu taxanes ,59,60. C effects . Meantim effects . In addi neurons . Therefon of BTZ . Thereforo study . Finallyro study .in vitro and in vivo studies.The long-term toxicity of BTZ-treatment (BIPN) is critical due to its potential impact on the quality of life (QoL) of cancer patients. To date, apart from drug treatment modification, discontinuation or withdrawal, no efficient prevention or therapeutic strategy for BIPN prevention and management is employed. Since the pathogenesis of BIPN remains unclear and the anatomical structure of peripheral nervous system that is primarily or secondarily affected by BTZ is only partially defined, the pathogenesis of BTZ-related neurotoxicity needs to be further explored through additional


The aim of this study was to explore differences in the effects of modifiable factors on oral squamous cell carcinoma (OSCC) occurring in the lower oral fissure (LOF) and upper oral fissure (UOF). We conducted a case-control study with 697 OSCC patients (119 UOF and 578 LOF) and 1910 frequency-matched controls in Fujian province, China. Data on demographic characteristics and possible modifiable factors was collected using a structured questionnaire. Unconditional logistic regression was utilized to calculate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Alcohol drinking was more strongly associated with an increased risk of OSCC-LOF than OSCC-UOF. Tobacco smoking, the number of teeth lost ≥5, wearing denture, and recurrent oral ulceration showed similarly associations with OSCC-LOF and -UOF risk. Similarly, the beneficial effects of tea consumption, tooth-brushing ≥2times per day, high intake of fresh fish, seafood, green-leafy vegetables, other vegetables and fruits were not significantly different on OSCC-LOF and -UOF. Although most of the modifiable factors exert similar effects on both OSCC sites, this study suggests that the sites of oral cavity in LOF may be affected more by alcohol drinking than the sites in UOF. Further studies with larger samples are warranted to confirm our findings. Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral cavity, is a growing health problem in the world . As repoet al [The cause of OSCC is multifactorial. In terms of extrinsic factors, tobacco smoking and alcohol drinking have been established two major risk factors for OSCC . Moreoveet al  demonstrIt is conceivable that these modifiable factors may have different effects on different anatomical sites of oral cavity. According to a recent report , the proTherefore, we performed a hospital-based case-control study in southeast of China to assess modifiable factors and the risk of two groups of OSCC-LOF and -UOF, respectively. And then, we further compared the differences of such factors between the two groups which may provide an explanation for the different incidence in OSCC-LOF and -UOF.Table trend <0.001). Alcohol drinking was only significantly associated with the risk of OSCC-LOF , but not in OSCC-UOF . Furthermore, our case-case studies showed that alcohol drinking was found more strongly associated with an increased risk of OSCC-LOF than OSCC-UOF . Additionally, tea consumption showed a decreased risk of either OSCC group.As shown in Table Table The associations between dietary factors and OSCC risk are summarized in Table To our knowledge, the current study is the first to differentiate the effects of modifiable factors on OSCC-UOF and -LOF. One important novel finding was that alcohol drinking was more closely associated with OSCC-LOF risk than OSCC-UOF. Additionally, we also observed that tobacco smoking, the number of teeth lost≥5, wearing denture, and recurrent dental ulceration were risk factors for both OSCC-UOF and -LOF. Likewise, the protect effects of tea consumption, tooth-brushing ≥2times per day, high intake of fresh fish, seafood, vegetables, and fruits showed no differences between OSCC-UOF and -LOF.Interestingly, the present study demonstrated that alcohol consumers were more prone to develop OSCC-LOF, which is in line with a previous study , showingRecurrent oral ulceration is a common oral mucosal inflammatory lesion. A recent study reported that recurrent oral ulceration have increased the risk of oral cancer in Chinese women by nearly 5-fold . The prein vivo [in vitro [The anticancer effects of tea consumption on different anatomical sites of oral cancer were reported in vivo , in vitrin vitro  and epidin vitro , 23. Ourin vitro . Regardiin vitro . Vegetabin vitro .There are several limitations in this study. First, as a retrospective case-control study, recall bias should be concerned. In order to minimize recall bias, all patients were newly diagnosed, and the definitions of lifestyle variables were clearly given during the interview. Second, this study only compared the major modifiable lifestyle risk factors between OSCC-UOF and -LOF. Therefore, other factors such as HPV infection, betel chewing, oral flora and genetic factors should be also considered in future studies. Third, we only collected the frequency of each food item which may not reflect standard amounts per day/week. Hopefully, the effects of dietary factors were estimated according to the quantity of food intake in the future studies. Fourth, the sample size of the OSCC-UOF group is relatively small, which may limit the statistical power of this study. Further studies with larger samples are warranted to confirm our findings.In conclusion, although most of the modifiable factors show similar important for the etiology of OSCC-UOF and -LOF, the present study suggests that alcohol drinking may increase the risk of OSCC-LOF more strongly than the risk of OSCC-UOF. This finding may provide an additional understanding of the higher incidence of OSCC in LOF.From September 2010 to December 2016, a hospital-based case-control study was carried out in Fujian province, China. As described previously , eligiblDuring the same period as cases, 1910 controls were randomly selected from medical examination center in the same hospital. They were free of any malignant disease. Controls and cases were frequency matched by age and gender. The recruiting rates were 98.1% for cases and 91.7% for controls. All participants signed an informed consent after told about the purpose of this research. The present study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments and was approved by the Institutional Review Board of Fujian Medical University .Face to face interviews were conducted by well-trained interviewers to obtain participants’ information using a structured questionnaire. Information collected included demographic characteristics, family history of cancer, main lifestyle such as tobacco smoking, alcohol drinking and tea consumption and dietary habits, and oral hygiene related variables.Subjects were considered tobacco smokers if they had smoked at least 100 cigarettes during their lifetime. Alcohol drinkers were defined as those had consumed at least one drink per week for more than 6 months continuously. Those who had consumed at least 1 cup of tea per week continuously for at least 6 months were considered tea drinkers. Detailed information on oral hygiene was recorded as follows: tooth brushing/day, the number of missing teeth, wearing of dentures (no/yes), regular dental visits (years/time) and recurrent dental ulcer (no/yes).Regarding to dietary intake, participants were asked about the intake frequency of 10 broad categories food . The intake frequency options of each food item were: 3 times per day; 2 times per day; 1 time per day; 5-6 times per week, 3-4 times per week; or 1-2 times per week; less than 1 time per week or not at all. The questionnaire referred to food intake during the previous 12 months.P < 0.05 (two-sided).The distributions of demographic characteristics between two case groups and controls were compared by chi square test. The continuity variables and each dietary item were grouped according to the median of the controls. Unconditional logistic regression models were used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the relationship between modifiable lifestyle factors and OSCC risk in both case-control and case-case comparisons. Wald chi square test was used to test for trends by treating categorical variables as continuous factors in the regression model. All analyses were conducted using R software version 3.1.1. Statistical significance was considered at


The aim of this study was to compare the therapeutic efficacy of alginate-based reflux suppressant and magnesium-aluminium antacid gel for treatment of heartburn in pregnancy. A double-blinded, randomized, controlled trial was conducted. One hundred pregnant women at less than 36 weeks gestation with heartburn at least twice per week were randomized to either alginate-based reflux suppressant or to magnesium-aluminium antacid gel. Details of heartburn were recorded before beginning the treatment and the second week of study. Primary outcome measure was the improvement of heartburn frequency after treatment and secondary outcome were the improvement of heartburn intensity, quality of life, maternal satisfaction, maternal side effects, pregnancy and neonatal outcomes. There was no difference between treatment and control groups in improvement of heartburn frequency , 50% reduction of frequency of heartburn , improvement of heartburn intensity  and 50% reduction of heartburn intensity . There were also no significant differences in quality of life, maternal satisfaction, maternal side effects, pregnancy and neonatal outcomes. Alginate-based reflux suppressant was not different from magnesium-aluminium antacid gel in the treatment of heartburn in pregnancy. Heartburn or pyrosis is a burning or painful sensation in the upper part of the digestive tract including the throat124Many interventions have been used for the treatment of heartburn in pregnancy. These interventions include changes in diet, lifestyle modification and medications. Common drugs used for the treatment of heartburn in pregnancy include antacids, sucralfate, histamine 2-receptor antagonists, promotility drugs, proton pump inhibitors, and a raft-forming alginate reflux suppressant. However, there has been no evidence-based recommendation for the treatment of heartburn in pregnancy1Alginate-based reflux suppressants are licensed for use in pregnant women to combat the frequent symptoms of heartburn and regurgitation. It is equal to or significantly better than traditional antacids for relieving heartburn symptomsTo date, there has been no randomized controlled trial to compare the efficacy of alginate-based reflux suppressants to magnesium-aluminium antacid gel for treatment of heartburn in pregnancy. Thus, the primary aim of this study was to compare the reduction of heartburn frequency after treatment. Secondary aims were to compare the reduction of heartburn intensity, quality of life, maternal satisfaction, maternal side effects, pregnancy and neonatal outcomes.This study was a randomized, double blinded, controlled trial conducted at the Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, between June 1, 2015 and July 31, 2016. This study was approved by the Research Ethics Committee of the Faculty of Medicine, Chulalongkorn University. The methods were performed in accordance with approved guidelines. Written informed consent was obtained from all participants. This clinical trial was registered at ClinicalTrials.gov .Pregnant women aged 18 to 40 years who presented to antenatal care clinic in our hospital with the diagnosis of heartburn and less than 36 weeks of gestation were invited to join this study. Pregnant women with medical diseases, with study drug contraindications and allergies to alginate-based reflux suppressant and magnesium-aluminium antacid gel were excluded. Participants were advised to undergo lifestyle modification including reducing risk factors of heartburn symptoms such as tobacco and alcohol abstinence, avoiding postprandial recumbent and trigger foods ex. spicy foods, citrus products, fatty or fried foods, carbonated beverages, coffee or other caffeinated beverages. At 1-week follow-up, participants who had persisting or worsened symptoms (heartburn frequency at least two times per week) were included into the study.® Reckitt Benckiser Healthcare (UK) Ltd, Hull, UK) contains 500 mg sodium alginate, 267 mg sodium bicarbonate and 160 mg calcium carbonate and 5 ml of magnesium-aluminium antacid gel  Co., Ltd., Thailand) contains 120 mg magnesium hydroxide and 220 mg aluminium hydroxide. Each 840 ml of alginate-based reflux suppressant and 840 ml of magnesium-aluminium antacid gel was put into 2 opaque bottles. The bottles were put into an opaque bag. As soon as a study subject met the inclusion criteria, the primary investigator proceeded to select a sequentially numbered opaque bag.After the study was approved, eligible women who gave informed consent were enrolled. Pregnant women were randomized into two groups: treatment or control group. A randomization scheme was generated by random number table using a block-of-four technique. The co-investigator, who had no contact with patients, generated the allocation sequence prior to the study. The primary investigator enrolled and assigned participants to their respective groups. Alginate-based reflux suppressant and magnesium-aluminium antacid gel were prepared prior to the study by a pharmacist who had no involvement in the study. 10 ml of alginate-based reflux suppressant  were sequentially labeled and used for participants with 2-week follow-up. To ensure randomization, each bag was distributed in sequential numerical order. Both health care providers and study participants were masked to treatment assignment. Alginate-based reflux suppressant was assigned to the treatment group and magnesium-aluminium antacid gel to the control group. Drug dose was 15 ml oral three times after meal and before bedtime. Treatment was continued for 2 weeks. Treatment assignment was not revealed until data collection was completed. Participants recorded details of heartburn (frequency and intensity) and side effects in a diary chart. Participants were asked to return the bottles and diary chart at the end of study to evaluate compliance. Good compliance was defined as participants who completed the required medication doses. Pregnancy and neonatal outcomes were followed-up until delivery.® Health Survey (Thai version), maternal satisfaction, maternal side effects, pregnancy and neonatal outcomes. Satisfaction answer choices consisted of the following: very satisfactory, satisfactory, neutral, unsatisfactory, and very unsatisfactory. Neonatal outcomes included birth weight, Apgar scores, neonatal intensive care unit (NICU) admission and congenital abnormality.The primary outcome was to assess the reduction of heartburn frequency after treatment. Secondary outcomes were to assess the reduction of heartburn intensity measured by 100-mm visual analogue scale after treatment, health-related quality of life was self-evaluated using the Optum™ SF-12v2Sample size calculations were based upon the efficacy from previous studies8SPSS version 22  was used for statistical analysis. Chi-square test and Fisher-exact test for categorical variables, independent t-test for continuous variables, and Mann-Whitney U test for nonparametric variables were used when appropriate. A p < 0.05 was considered statistically significant. Analysis of the trial was conducted in intent-to-treat (ITT) analysis.One hundred and thirty-four women enrolled in the study . Thirty-Median numbers of heartburn before treatment were 13 and 12 times per week in the treatment and control groups, respectively (p = 0.649). Median pain score of heartburn before treatment, which was evaluated by 100-mm visual analogue scale, were 42.5 and 43.5 in the treatment and control groups, respectively (p = 0.942) .The satisfactory rate of treatment and side effects were not statistically different between groups  and , respectively. The two most common side effects in both study groups were constipation  and chalk-like taste . Pregnancy and neonatal outcome measures included birth weight, APGAR scores and NICU admission did not differ between groups . No congThis randomized, double blinded, controlled trial compared the therapeutic efficacy of alginate-based reflux suppressant and magnesium-aluminium antacid gel for treatment of heartburn in pregnancy. This study showed no difference in the improvement of heartburn frequency between alginate-based reflux suppressant and magnesium-aluminium antacid gel groups. Similar results were found in terms of the improvement of heartburn intensity, quality of life, maternal satisfaction, maternal side effects and neonatal outcomes.et al. performed a multicentre, prospective, open-label, and baseline-controlled study of Liquid Gaviscon in the treatment of heartburn in pregnant womenet al. performed an open-label, multicentre study to assess the safety and efficacy of a novel reflux suppressant (Gaviscon Advance) in the treatment of heartburn during pregnancyThe improvement of heartburn frequency in this study was 80% in alginate-based reflux suppressant group. This result was similar to previous studies11Quality of life after treatment was improved but not statistically different between both groups. This might be due to the treatment efficacy of both drugs. Overall, the satisfaction of treatment was high (80%) in both groups. This might be due to the minor side effects of drugs.No neonatal complications occurred in both alginate-based reflux suppressant and magnesium-aluminium antacid gel groups. This confirmed the safety of alginate-based reflux suppressant use in pregnancy as reported from previous studies111011The strength of this study was that it is the first randomized, double blinded, controlled trial conducted to evaluate the efficacy of alginate-based reflux suppressant and magnesium-aluminium antacid gel for treatment of heartburn in pregnancy. Another strength was that we were able to assess patient quality of life before and after treatment, which has yet to be assessed in any current or previous studies. The limitations of this study were that it was a short period of treatment (2-week) and it was underpowered to evaluate some secondary outcomes.In conclusion, there was no difference between the efficacy of alginate-based reflux suppressant and magnesium-aluminium antacid gel in the treatment of heartburn in pregnancy.How to cite this article: Meteerattanapipat, P. and Phupong, V. Efficacy of alginate-based reflux suppressant and magnesium-aluminium antacid gel for treatment of heartburn in pregnancy: a randomized double-blind controlled trial. Sci. Rep.7, 44830; doi: 10.1038/srep44830 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Split-networks are a generalization of phylogenetic trees that have proven to be a powerful tool in phylogenetics. Various ways have been developed for computing such networks, including split-decomposition, NeighborNet, QNet and FlatNJ. Some of these approaches are implemented in the user-friendly SplitsTree software package. However, to give the user the option to adjust and extend these approaches and to facilitate their integration into analysis pipelines, there is a need for robust, open-source implementations of associated data structures and algorithms. Here, we present SPECTRE, a readily available, open-source library of data structures written in Java, that comes complete with new implementations of several pre-published algorithms and a basic interactive graphical interface for visualizing planar split networks. SPECTRE also supports the use of longer running algorithms by providing command line interfaces, which can be executed on servers or in High Performance Computing environments.https://github.com/maplesond/SPECTRE. SPECTRE’s core library is available from Maven Central at: https://mvnrepository.com/artifact/uk.ac.uea.cmp.spectre/core. Documentation is available at: http://spectre-suite-of-phylogenetic-tools-for-reticulate-evolution.readthedocs.io/en/latest/Full source code is available under the GPLv3 license at: Bioinformatics online. Split-networks are a generalization of phylogenetic trees that are commonly used to analyze reticulate evolution in organisms such as plants, bacteria and viruses see , NeighboNeighborNet rapidly constructs a circular split network from a distance matrix or a sequence alignment . NetMakeSuperQ constructs a circular split network from a set of  input trees (FlatNJ constructs a flat split network from a multiple sequence alignment, weighted quartet data or location data (NetME produces a minimum evolution tree compatible with an existing circular split network (These tools are accessible to the user via graphical and command line interfaces. Apart from driving the tools, the interactive graphical interface can visualize planar split networks using the drawing algorithm in (Here, we present SPECTRE, a suite of tools for computing, modelling and visualizing reticulate evolution based on split-networks. SPECTRE builds in part on existing open-source implementations of some of these tools, in particular for QNet, SuperQ and FlatNJ, integrating them into a unified and extendible library. The main tools available through SPECTRE are summarized below (for more details see Section 1 of SPECTRE provides a collection of open-source tools and resources for modelling, understanding and visualizing reticulate evolution based on split networks. We believe that our software will both enable bioinformaticians to easily test and compare methods for inferring planar split networks and help computer scientists build their own methods for inferring phylogenetic networks by reusing our existing data structures and algorithms via the open-source library. Moreover, this also provides the option to easily add such new tools to the library making them readily available to other users.Supplementary DataClick here for additional data file.


Venous thromboembolic events (VTE) are common in cancer patients and associated with higher mortality. In vivo thrombosis and anticoagulation might be involved in tumor growth and progression. We studied the association of warfarin and other anticoagulant use as antithrombotic medication and prostate cancer (PCa) death in men with the disease.The study included 6,537 men diagnosed with PCa during 1995-2009. Information on anticoagulant use was obtained from a national reimbursement registry. Cox regression with adjustment for age, PCa risk group, primary therapy and use of other medication was performed to compare risk of PCa death between warfarin users with 1) men using other types of anticoagulants and 2) non-users of anticoagulants. Medication use was analyzed as a time-dependent variable to minimize immortal time bias.In total, 728 men died from PCa during a median follow-up of 9 years. Compared to anticoagulant non-users, post-diagnostic use of warfarin was associated with an increased risk of PCa death . However, this was limited to low-dose, low-intensity use. Otherwise, the risk was similar to anticoagulant non-users. Additionally, we found no risk difference between warfarin and other types of anticoagulants. Pre-diagnostic use of warfarin was not associated with the risk of PCa death.We found no reduction in risk of PCa death associated with warfarin use. Conversely, the risk was increased in short-term use, which is probably explained by a higher risk of thrombotic events prompting warfarin use in patients with terminal PCa.The online version of this article (10.1186/s12885-017-3579-8) contains supplementary material, which is available to authorized users. VTE in PCa patients has been associated with more than 6-fold mortality in both symptomatic and incidental venous thromboembolic diseases [, anticoagulant drugs could have an impact on PCa prognosis by reducing deaths from VTE. Furthermore, anticoagulants, including warfarin, have shown promising antitumor properties in vivo [Venous thromboembolism (VTE) has been proposed as prognostic factor in prostate cancer (PCa). VTE is common in cancer patients and associated with poor prognosis, risk of death is 8-fold higher in cancer patient with VTE –3. This diseases . Thus, a in vivo  mainly iPrevious fairly small studies on anticoagulant use and PCa survival have reported differing results –13. A poFinRSPC includes 80,458 men aged 55-67 years at baseline (i.e. at FinRSPC randomization). After exclusion of prevalent PCa cases, the men were randomized during 1996-1999 either to PSA screening at four-year intervals (the screening arm) or to no intervention (the control arm). All men were followed via Finnish Cancer Registry, which covers 99% of cancers diagnosed in Finland . This stPCa cases were stratified into low/intermediate-risk and high-risk groups according to the definition of the European Association of Urology (EAU) . All M1 Information on deaths was obtained from the Statistics Finland, which assigns official causes of death based on mandatory death certificates, covering all deaths in Finland . The accA sensitivity analysis with PCa as an intermediate cause of death was also performed.In order to obtain information on anticoagulant drug purchases during 1995-2009, the study cohort was linked to a national medication reimbursement database maintained by the Finnish Social Insurance Institution (SII) using the unique personal identification code as the key. As a part of the national health insurance that covers all Finnish citizens, SII provides reimbursements for purchases of physician-prescribed drugs [All 13 anticoagulant drugs used in outpatient setting during the study period were identified based on their ATC codes , venous thromboembolism , pulmonary embolism ICD-10: I26.0, I26.9) and thrombocytosis. The register covers all of Finland and registers all diagnoses made during in- and out-patient hospital visits during 1996-2014, but does not cover diagnoses from primary care .0, I26.9 calculatst, 2015, whichever was first. Time metric was years and months since the PCa diagnosis.Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) for PCa death. Follow-up started at PCa diagnosis and continued until death, emigration from Finland or January 1We used two different model adjustments. The first Cox regression model was adjusted for age only and the second for age, EAU tumor risk group and other medications. The analysis was performed separately for pre-diagnostic and post-diagnostic use of warfarin and additionally for other types of anticoagulants. Separate comparisons were performed between all anticoagulant users and non-users to estimate the overall effect of anticoagulant usage, and between warfarin users and men using non-warfarin anticoagulants to estimate specific effects of warfarin with simultaneous control of confounding by indication.For each man in the study cohort, the total annual amount of medication purchases was calculated for each calendar year, and then separately for pre- and post-diagnostic use. Standardization of doses between different anticoagulants was performed by dividing the annual total milligram amount with the standard Defined Daily Dose (DDD) as listed by the WHO . Each yePre-diagnostic medication use was analyzed as a time-independent variable, and cumulative pre-diagnostic anticoagulant usage beginning from 1995 was stratified by tertiles. Post-diagnostic use was analyzed as a time-dependent variable; the usage status and cumulative use were updated separately for each year of follow-up, beginning from the year of diagnosis.All men were categorized as non-users until the potential first anticoagulant purchase. After the first purchase, the status was changed into a user, which was maintained for each year with recorded purchases. Men who discontinued the purchases during the follow-up were kept as ever-users. In analysis of warfarin users compared to non-warfarin users, men were categorized as warfarin users each year with recorded warfarin purchases, even if they had used other types of anticoagulants. Only for years with recorded anticoagulant purchases without warfarin use, were they recorded as non-warfarin users.Long-term impact of timing of post-diagnostic anticoagulant use was evaluated in lag-time analysis, where anticoagulant exposure was lagged 1 to 3 years forward from the actual year of usage i.e. its effect was ignored for that duration from the first exposure.Competing risks analysis using Fine and Gray regression method with non-PCa death and major thromboembolic diseases as the competing cause of death was performed.All statistical analyses were carried out using IBM SPSS Statistics 22.0. All statistical tests are two-sided.During the median follow-up of 9 years after PCa diagnosis 2,296 men died, of whom 728 from PCa Table . The medIn general, when compared to anticoagulant non-users, there was no clear association between pre-diagnostic use of warfarin and PCa death in either age-adjusted or multivariable-adjusted analysis . No statistically significant risk trends by cumulative amount or duration of use were observed Table . HoweverWhen users of other anticoagulants were used as the reference group, warfarin use was not associated with PCa death. No risk trends by cumulative use were observer either Table .In the analysis of post-diagnostic use of warfarin, the overall risk of PCa death was significantly higher among warfarin users in comparison to anticoagulant non-users  . In the stratified analysis, short-term use of warfarin was associated with an increased risk of PCa death, but again the risk increase was smaller in high-intensity use Table .In order to evaluate long-term effects of warfarin use and minimize bias due to thrombotic events triggering the prescription, we performed an analysis lagging warfarin use by one, two and three years, i.e. relating it to events at least 1-3 years later than the exposure to allow for latency. The risk increase compared to anticoagulant non-users was decreased already in the analysis lagged by one year, but remained non-significantly elevated  , but no apparent risk trends by cumulative amount or duration were observed. In the lag-time analyses, no statistically significant risk increase was present . The findings were similar when deaths caused by pulmonary embolism or stroke were analyzed as the competing causes of death .Short-term and low-dose warfarin use after the diagnosis was associated with increased risk of PCa death compared to anticoagulant non-users. However, in analyses allowing for lag-time, the risk was attenuated after one year and disappeared in 2-year or 3-year lag-time analysis. This suggests that the risk increase occurs only for a short time period after starting drug use. We found no statistically significant risk difference between users of warfarin and other types of anticoagulants. Additionally, we found no association between pre-diagnostic use of warfarin and PCa survival. Although the indication for anticoagulant treatment did not modify the risk association, it is likely that the short-term increased risk is explained by thrombotic events as indications for anticoagulation. In epidemiological literature this phenomenon where pharmaceutical drug is prescribed for early manifestation of yet un-diagnosed disease is referred to as ‘protopathic bias’ .Previous studies on warfarin and PCa mortality are sparse. To date, three published studies have assessed the association between PCa survival and use of vitamin K antagonists –13. TagaIn a cohort study including 12,186 men with PCa, but no information on stage no evidence was found for an association between PCa death and pre-diagnostic use of warfarin during a mean follow-up of 3.7 years [A third study of Park et al.  was limiIn vitro studies have suggested that the coagulation cascade and thrombocytes might be involved in tumor growth and progression, and that anticoagulant drugs could in theory improve prognosis –10. HoweThe main strengths of this study are the large population-based cohort as well as comprehensive and our ability to use detailed, nationally comprehensive register-based information on anticoagulant use unaffected by recall bias. Being able to study large populations through national registries allows us to estimate even relatively uncommonly used drugs such as anticoagulants as cancer risk factor. Our study included substantially more warfarin users than in previous studies. We were able to analyze post-diagnostic use of warfarin more comprehensively than before. We also performed lag-time analyses to estimate the risk associations allowing for latency and removing effects limited to the immediate period following first subscription. Furthermore, we had longer follow-up than in previous studies.Our study also has some limitations. We were not able to adjust our analysis for smoking, life-style factors or BMI which may be associated with risk of PCa death –33. NeveIn a population-based setting, warfarin or other types of anticoagulants are not associated with improved PCa prognosis. Conversely, in short-term use risk of PCa death was increased, which is most likely due to thrombosis caused by an advanced cancer, as the risk increase was not observed in long term.Additional file 1: Table S1.ATC codes for anticoagulant drugs included in the study. (DOCX 207 kb)Additional file 2: Figure S1.Pre-diagnostic subgroup analysis between users of warfarin and other anticoagulant drugs. (DOCX 224 kb)Additional file 3: Figure S2.Post-diagnostic subgroup analysis between users of warfarin and users of other anticoagulant drugs. (DOCX 224 kb)Additional file 4: Table S2.Table S3. Post-diagnostic results for combined anticoagulant usage. Age-adjusted, multivariable-adjusted and lag-time hazard ratios (95% CI) related to all PCa deaths. (DOCX 405 kb)Pre-diagnostic analysis of combined anticoagulant drug usage stratified by number of Defined Daily Doses (DDD), duration and intensity of usage. Age-adjusted and multivariable-adjusted hazard ratios (95% CI) related to all PCa deaths. Additional file 5: Figure S3.Subgroup analysis of pre-diagnostic combined anticoagulant usage compared to non-users. (DOCX 224 kb)Additional file 6: Figure S4.Subgroup analysis of combined anticoagulant usage compared to non-users in post-diagnostic setting. (DOCX 224 kb)


Cognitive impairment is a common disabling symptom in PD. Unlike motor symptoms, the mechanism underlying cognitive dysfunction in Parkinson's disease (PD) remains unclear and may involve multiple pathophysiological processes. Resting state functional magnetic resonance imaging (rs-fMRI) is a fast-developing research field, and its application in cognitive impairments in PD is rapidly growing. In this review, we summarize rs-fMRI studies on cognitive function in PD and discuss the strong potential of rs-fMRI in this area. rs-fMRI can help reveal the pathophysiology of cognitive symptoms in PD, facilitate early identification of PD patients with cognitive impairment, distinguish PD dementia from dementia with Lewy bodies, and monitor and guide treatment for cognitive impairment in PD. In particular, ongoing and future longitudinal studies would enhance the ability of rs-fMRI in predicting PD dementia. In combination with other modalities such as positron emission tomography, rs-fMRI could give us more information on the underlying mechanism of cognitive deficits in PD. Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Traditionally, it has been regarded as a movement disorder characterized by the motor symptoms, such as bradykinesia, resting tremor, and rigidity. Up to now, it is well known that cognitive impairment is a common nonmotor symptom in patients with PD, even in the early stages or before motor symptom onset . Furtherα-synuclein, β-amyloid, and tau proteins might play a role [The underlying mechanism of motor symptoms of PD is depleted dopaminergic cells in the substantia nigra . In conty a role , 7. VariFunctional MRI (fMRI) measures the blood-oxygen-level dependent (BOLD) signal in the brain, which is determined by the amount of oxyhemoglobin and deoxyhemoglobin and reflects neuronal activity. Resting state fMRI (rs-fMRI) estimates the brain BOLD signal while the subjects are awake without performing any specific task . MRI is Cognitive activities rely on the coordination of various brain regions. Several networks have been established by rs-fMRI: the default mode network (DMN), the visual network, the sensorimotor network, the executive control network, and the frontoparietal network . rs-fMRIrs-fMRI is a sensitive imaging modality that can reveal dysfunction in cognition-related brain regions in PD patients with only subtle cognitive changes or even without cognitive symptoms. This property makes rs-fMRI a promising tool for the early identification of patients with a high risk for PDD. Lucas-Jimenez et al. used a seed-based FC analysis and showed reduced DMN FC in nondemented PD patients, and this FC change was correlated with lower verbal and visual memory and visual abilities in PD . Manza eα-synuclein, β-amyloid, and tau proteins in neurological disorders [α-synuclein and amyloid-β42 levels. In addition, increased correlation of the insula with the DMN was associated with worse attentional function. Therefore, both α-synuclein and amyloid-β42 might play a role in disrupting cognitive-related brain regions [123I-FP-CIT SPECT imaging. In their study, executive function was associated with dorsal frontoparietal cortical processing and sensory involvement, as well as the striatal dopamine transporter binding ratios. Memory performance was correlated with prefrontolimbic processing but not associated with nigrostriatal dopaminergic function. Their study confirmed that distinct from executive dysfunction, memory deficits in PD was not induced by dopaminergic insufficiency [α-synuclein, β-amyloid, and tau proteins) and laboratory examinations using other body fluids can promote our recognition of the underlying mechanism of cognitive impairment in PD.Until now, various methods have been applied in investigating neurological disorders, and each has its advantage and disadvantage. PET and SPECT using different radio ligands can display abnormalities of neurotransmitters in the brain and deposition of aggregated proteins such as isorders . EEG hasisorders . Combini regions . Lebedevficiency . In futuSo far, most of the rs-fMRI studies in PD enrolled small numbers of patients. However, we can obtain preliminary consistent conclusions on the networks disrupted in PD and their relationship with cognitive dysfunction. We still need more evidence to apply rs-fMRI as a diagnostic tool in clinical practice. Abos et al. used a support vector machine method to distinguish PD patients with and without MCI with an accuracy of 80%, and the connectivity of the selected edges was correlated with memory and executive function in the PD patients . Peraza α-synuclein, β-amyloid, and tau proteins are under active investigation and are hopeful to be available in clinical practice in the near future. Early identification of PD patients with a high risk for dementia is critical for potential disease-modifying therapies. As far as we know, most of the studies using rs-fMRI for cognitive function in PD are cross-sectional. Only two studies explored the progression of cognitive impairment and brain network changes in a longitudinal design. However, they only enrolled small numbers of patients and had a short time of follow-up  [Disease-modifying therapies targeting , resp.) , 27. Ongrs-fMRI has been applied in the assessment of the effects of levodopa and cognitive rehabilitation in PD cognition. Simioni et al. tested the effect of levodopa on brain networks and cognitive function using seed-based and ICA analyses. Levodopa increased resting state FC between caudate and right parietal cortex , and this effect was associated with improvement in working memory performance . Diez-CiIn summary, rs-fMRI might be a useful tool for the exploration of underlying mechanism of cognitive dysfunction in PD and can help diagnose cognitive dysfunction in PD and assist treatments. More longitudinal studies using rs-fMRI and the combination of rs-fMRI with other modalities are needed.


The mucosal immune system and the microbiota in the intestinal tract have recently been shown to play a key role in the pathogenesis of inflammatory bowel disease (IBD). Both of these can be influenced by food. Thus, we propose dietary intervention as a therapeutic option for IBD. In this review, we discuss the interaction of the intestinal mucosal immune system and the intestinal microbiota in the context of IBD. In addition, we discuss the impact of food components on immune responses in IBD. Finally, we address the current evidence of how this interaction  can be modulated by food components, pre/probiotics, and fecal microbiota transplantation (FMT) and how these approaches can support intestinal homeostasis. By gathering the vast amount of literature available on the impact of food on IBD, we aim to distinguish between scientifically sound data and theories, which have not been included in this review. IBD is a group of chronic disorders characterized by relapsing inflammation of the gastrointestinal (GI) tract. The most common entities are Crohn’s Disease (CD) and Ulcerative Colitis (UC). While CD is characterized by a segmental transmural inflammation and granulomatous lesions of the whole GI tract, inflammation in UC is mostly restricted to the colon and the rectum. Both incidence and prevalence of IBD are currently increasing worldwide .Although the etiology of IBD has not yet been fully elucidated, more than a hundred genetic risk loci have been identified so far. These genetic studies point toward an important role of the immune system and its interaction with the microbiota in the development of IBD. The majority of these loci are indeed linked to loss of barrier function , to host interaction with bacteria , or to immune pathways  implicated in the control of cytokines, such as interleukin (IL)-17 and IL-22 . This reIn this section, we will refresh the knowledge on the intestinal microbiota, how it interacts with the immune system, and furthermore the role of the key cytokines , which result from this interaction in the context of IBD.13 bacterial organisms, which colonize different sides of the body, such as the intestine and the skin [The human body coexists with around 10the skin . In the the skin , 9. The the skin .An altered microbiota has been associated with IBD, and a variety of extra-intestinal diseases, such as obesity, type 1 and type 2 diabetes, asthma, and liver disease highlighting the systemic impact of the intestinal flora , 14. SeqFaecalibacterium prausnitzii was shown to be protective in chemically induced colitis in mice. This observation has been further sustained by human twin studies [Various studies demonstrated a marked reduction of Firmicutes within the microbiota of patients with IBD –19. With studies , 21.Escherichia coli (E. coli) was shown to be more abundant in patients with active IBD [Bacterial species from the Proteobacteria phylum have mainly been reported as holding pathogenic potential in the development of IBD. For example, tive IBD . In parttive IBD , 24.Prevotella genus and the TM7 phylum [Moreover, sulfate-reducing bacteria (SRB), most of which belong to the Deltaproteobacteria class (Proteobacteria phylum), are increased in IBD and have been shown to promote a chemically induced colitis in mice underlining a possible role in IBD pathogenesis , 26. How7 phylum .The immune system has several sensors, which detect the microbiota and its changes and consequently can promote intestinal inflammation or maintain homeostasis. For the maintenance of a physiological interaction, a highly regulated network of microbial sensor systems has evolved.The mucosal immune system recognizes the conserved microbe-associated molecular patterns (MAMP) via pattern recognition receptors (PRR), such as Toll-like receptors (TLR) and nucleotide oligomerization domain (NOD)-like receptors (NLR). These specialized receptors respond to a variety of triggers, including unmethylated double-stranded DNA, single-stranded RNA, and bacterial products . Ligand-A variety of bacterial products have been reported as TLR ligands, such as lipopolysaccharide (LPS) from gram-negative bacteria, peptidoglycans from gram-positive bacteria, or flagellin derived from flagellated bacterial species . SensingBacterial products are also sensed by inflammasomes, which are multiprotein complexes assembling with the adapter protein apoptosis-associated speck-like protein (ASC) and procaspase-1. In response to PAMPs, activated caspase-1 cleaves the pro-forms of the pro-inflammatory cytokines IL-1β and IL-18 . ImpaireEscherichia coli. Interestingly, patients with CD show flagellin-specific circulating antibodies in contrast to healthy controls underlining the immunogenicity of flagellin in the context of intestinal inflammation [. One of the cellular sources of IL-23 are dendritic cells located in the lamina propria of the epithelial layer, which produce IL-23 upon sensing bacterial-derived flagellin via TLR-5 [Intestinal immune responses and intestinal tissue homeostasis are regulated by cytokines, which are produced when the abovementioned sensory systems are engaged. Within these cytokines IL-23 has a prominent role in the intestine, specifically in IBD as highlighted by genome-wide association studies (GWAS) . Interleammation . One of ia TLR-5 . Recentlia TLR-5 . IL-23 pH17 cells can produce IL-17. These cells are a subtype of effector T helper cells, which express high levels of IL-17A and IL-17F and which are highly enriched in the inflamed mucosal tissue of IBD patients [H17 cells [In particular, the role of IL-17 in IBD became the subject of controversial debate. Among the IL-17 family members, the biological role of IL-17A and IL-17F are best characterized. On the one hand, in line with the GWAS, IL-23-dependent secretion of IL-17 was shown to promote T cell-mediated colitis , 44. Recpatients , 51. Int17 cells .In conclusion, these findings suggest that IL-17A can have dual functions, which might depend on the cellular source, on the environment, such as the microbiota, and on the type of intestinal pathology. Of note, IL-17A blockade using an antibody was not effective in IBD in humans . HoweverE. coli infection [IL-22 acts also downstream of IL-23 and plays a central role in promoting barrier homeostasis by regulating genes encoding molecules associated with tissue repair or antimicrobial properties . Both adnfection . Innate nfection .However, as shown for the IL-17 family, IL-22 can also mediate pathogenic activity in intestinal inflammation. For example, T cell-derived IL-22 promotes colitis upon transfer of memory cells into Rag1-deficient recipients . FurtherIn conclusion, IL-22 has pathogenic and protective properties. Therefore, a tight control is essential. This control is exerted on at least two levels. First, as mentioned above, the production of IL-22 is regulated by IL-23. Second, there is an endogenous inhibitor of IL-22, namely IL-22 binding protein (IL-22BP). IL-22BP binds and blocks IL-22 activity. IL-22BP can be produced by DCs, granulocytes, and T cells –62. InteBacteroides fragilis show induction of IL-10-producing regulatory T (Treg) cells via lipopolysaccharide A (LPA) [Intestinal homeostasis is the result of a fine-tuned balance of factors promoting immune responses and signals mediating immune tolerance. A key player in limiting immune responses is the anti-inflammatory cytokine IL-10 . Polymor A (LPA) . In line A (LPA) , 69. Var A (LPA) , 71. Als A (LPA) , 73.Overall, IL-10 is a crucial player in controlling inflammatory responses in the intestine. In particular, understanding the microbiota-derived signals promoting Treg cell responses will help to optimize flora-based therapeutic approaches for IBD.Epidemiological studies support the role of environmental factors in pathogenesis of IBD. In particular, the association between dietary intake and incidence of IBD points to food components as a potential pathogenic agent. Indeed, certain food components, such as polyunsaturated fatty acids (PUFA), omega-6 fatty acids, and meat seem to predispose for IBD, whereas fibers and fruits or vegetables were associated with a decreased risk of CD or CU, respectively .et al. showed that different diets are associated with specific bacterial clusters of the microbiota. Diets based on protein and animal fat compared to carbohydrates were associated with two enterotypes according to the levels of Bacteroides and Prevotella, both of which are genera, which are involved in colitis development [H17 cells [While there is little evidence of food components having a direct impact on IBD, they do impact in an indirect fashion Fig. . Food coelopment . These oelopment . Of noteelopment . On the 17 cells . CollectFurther, important modulators of the microbiota are dietary fibers. A diet low in fibers (considered the Western diet), results in a loss of the microbial diversity as observed in IBD patients . FermentThe intestinal microbiota is also involved in the synthesis and the metabolism of various vitamins, such as B-group vitamins and vitamin K. On the other hand, vitamins have been shown to modulate the microbiota, and to act directly on the immune system; vitamin A and its down-stream metabolite retinoic acid (RA) are involved in multiple immune processes, such as Treg homeostasis and IgA antibody production , 82.Deciphering the role of food components in modulating the intestinal immune system might help to use this potential to expand treatment options for IBD. In this section, we summarize current evidence of how certain food components  modulate the intestinal immune system.Prevotella-enterotype [Several studies showed a positive, but still not consistent, association between high carbohydrate intake and an increased risk of IBD . Based oterotype . CurrentHowever, there are several studies pointing toward a role of fat intake in IBD, although this role is still controversial. A positive association has been reported between high intake of saturated fats, mono- and polyunsaturated fatty acids (PUFA), and an increased risk of CD, whereas high total fats correlated with an increased CU risk . LikewisH17 cells. A possible mechanism, by which PUFA control TH17 cell pathogenicity is the modulation of cholesterol-derived ligands for RORγt, the major transcription factor of TH17 cells and group 3 ILC [In contrast to the pathogenic properties, beneficial effects of fat have also been reported. In particular, omega-3 (3-n) PUFA might play a protective role in IBD . Indeed,up 3 ILC .Finally, dietary fiber has been linked to IBD. In a meta-analysis, high intake of dietary fiber was associated with a decreased risk of IBD . As ment+ T cells. Indeed, butyrate and propionate were shown to promote extra-thymic Treg generation [+ T cell generation. Compared to effector T cells, such as TH17 cells, which are reliant on glucose metabolism, the generation of regulatory CD4+ T cells has been shown to be selectively dependent on lipid oxygenation [Second, SCFA have indirect protective properties, which are mediated via regulatory CD4neration . Furtherneration . Besidesgenation . The incgenation . Of notegenation .In conclusion, several studies underline the central role of metabolites in controlling the balance of inflammatory and regulatory immune responses based on immune cell-specific metabolic programs.Vitamin deficiency is a common feature of IBD. Malnutrition due to decreased food intake, increased requirements, malabsorption, and maldigestion as possible causes are being discussed. A recent retrospective study in IBD patients showed high frequencies of Vitamins D and A deficiency . There iH2 cells, a T helper cell subset characterized by the production of the anti-inflammatory cytokines IL-4, IL-5, and IL-13. Furthermore, the suppression of TH17 cells and the induction of IL-10-producing Treg cells in response to vitamin D have been reported [Indeed, several studies demonstrated that vitamin D enhances the development of Treported , 98. Intreported .Bacteroides, which was associated with an increased susceptibility toward DSS-induced colitis [Furthermore, Vitamin D might influence IBD via interactions with the microbiota. Indeed, absence of the Vitamin D receptor can directly impact the intestinal microbiota with an increase in  colitis .In line with the mouse studies, there are also human data supporting the role of Vitamin D in IBD. First, VDR gene polymorphisms are linked to increased IBD susceptibility . Second,+ T cells into Treg cells and inhibits the differentiation of TH17 cells thereby promoting immune tolerance [Vitamin A is a group of nutritional organic compounds. The exact role of Vitamin A in IBD is currently unknown. However, there are some data linking vitamin A-derived metabolites to the immune response in the intestine. One example is retinol, which is one principal compound of the vitamin A group that is metabolized to retinoic acid (RA) by the sequential action of retinol dehydrogenase (RDH) and retinaldehyde dehydrogenase (RALDH) enzymes . Dendritolerance , 104. Fuolerance . Thus, RTo maintain homeostasis, a fine-tuned balance between immune tolerance and immune activation toward the intestinal microbiota is critical. Regarding IBD patients, observations have shown that this critical balance is deregulated favoring chronic immune activation. There are several possible ways to reset this balance with the aim of treating IBD patients. The first is to target the microbiota directly by microbiota transplantation; the second is to target the microbiota indirectly by diet Fig. . In addiThis section will provide a summary of the most recent evidence relating to the role of probiotics, prebiotics, diets, and fecal microbiota transplantation in the treatment of IBD.Escherichia coli Nissle 1917 and VSL#3 seem to be efficient in UC as outlined below. However, there is not sufficient evidence to support the use of probiotics in daily clinical practice in Crohn’s disease [An option to influence the composition of intestinal microbiota is the use of probiotics. Specific microorganisms are deemed probiotic based on their scientifically proven effect on the promotion of health or prevention and treatment of a specific disease. Probiotics, such as  disease .Escherichia coli Nissle 1917 compared to immunosuppressive therapy with 5-aminosalicylic acid showed a comparable clinical relapse rate [Lactobacillus was shown to induce a significantly higher rate of remission compared to placebo in mild-to-moderately active UC [Patients with CU in remission treated with pse rate . Likewispse rate . Furtherctive UC .Probiotics show signs of exerting their effects via at least two mechanisms. First, probiotics are able to enhance mucosal barrier function. They were shown to promote secretion of IgA and mucins  and tighLactobacilli, a bacterial genus contained in many probiotic products, to indole-3-aldehyde (IAld). IAld induced AhR-dependent IL-22 production by ILC and mediated both antifungal activity and amelioration of chemically induced colitis [Finally, probiotics impact the IL-22-mediated antimicrobial response. It has been shown that tryptophan is metabolized by a subset of commensal  colitis .Prebiotics are indigestible substances, mostly carbohydrates that can be metabolized by beneficial bacterial strains hence enhancing their activity. Prebiotics in clinical use include fructo-oligosaccharides (FOSs), inulin, galacto-oligosaccharides (GOSs), and soybean oligosaccharides that stimulate mainly bifidobacteria species . There iet al. observed a significantly reduced clinical disease activity after 4 weeks of treatment with a prebiotic combination of oligofructose and inulin [Patients with active CD were randomized and treated with fructo-oligosaccharides (FOSs) versus placebo with no significant difference in clinical response . In a mod inulin . In thisd inulin . Therefod inulin .Exclusive enteral nutrition (EEN) is a dietary therapy comprised of a period of 6–8 weeks of exclusive liquid feeding with either elemental or polymeric formulae. Elemental diets contain all essential nutrients and protein in the form of free amino acids whereas polymeric formulae comprise non-hydrolyzed proteins and long-chain triglycerides. These formulae were developed to improve nutrient absorption and to limit mucosal antigen exposure.Interestingly, several studies demonstrated effectiveness of EEN in the treatment of CD equivalent to the use of corticosteroids mainly in pediatric patients , 123. InOne possible reason for the discrepancy between the efficacy of ENT in pediatric and adult patients might be the higher chance of non-compliance by adult patients, which in turn might be related to an increased intolerance of the formula observed in adult patients.Faecalibacterium prausnitzii was reported, which might help to explain a therapy failure in some cases [The exact mechanism of EEN in IBD is unknown, but several possibilities are being explored. First, the effects might be linked to the intestinal microbiota. During the dietary treatment, profound modification of all predominant bacterial groups were observed with a decrease in microbiota diversity . Interesme cases . Second,me cases –130. Finme cases .Overall, conflicting results regarding the clinical effectiveness and the loss of protective microbiota species point out that a more defined formula or more stringent diet is needed to effectively use this therapy for adult IBD patients. For pediatric IBD patients, EEN is an established therapy . Even thClostridium difficile infection, a colitis triggered by antibiotic-induced dysbiosis [The idea of modulating dysbiosis to treat IBD gave rise to the proposal of direct microbiota transplantation with a donor microbiota as a potential therapeutic option Fig. . Fecal mysbiosis . Low freysbiosis . Fecal mysbiosis .Data evaluating FMT in IBD still present some limitations. Initial evidence of the role of microbiota transplant in IBD was shown in case reports as having lead to a relief of symptoms in disease refractory to sulfasalazine , 137. InThe regimen used by Paramsothy et al.  showed aThe role of FMT in the treatment of IBD remains to be fully defined, and more controlled clinical trials are necessary to critically assess its therapeutic effect. It is currently not clear whether antibiotic pretreatment is necessary and which method of administration is the most effective. In the abovementioned study of Pramsothy et al.,  specificTaken together, the abovementioned studies point to the fact that the local immune response to intestinal microbiota could be one key mechanism involved in IBD pathogenesis. Numerous risk loci and independent observations described above point to a model where deregulation of the interaction between the immune system and the microbiota favors chronic intestinal inflammation. However, further insights are needed to better decipher the molecular and cellular mechanisms and to develop future therapeutic approaches without the current limitations, such as lack of long-term remission. We hope to have highlighted the need for a unified, scientifically sound basis for future development in this growing field. The identification of food components with an anti-inflammatory function can help to further control IBD and serve as a proof of concept for an approach to induce and maintain remission that could potentially be extended to other immune-mediated diseases. Keeping in mind that each patient’s immune system and microbiota may respond to food components differently, individual dietary approaches will be essential.


It is reported recently Tropomyosin-related receptor Kinase B (TrkB) plays key roles in the anoikis resistance during the processes of tumorigenesis and metastasis. However, its prognostic significance for clinical patients remains inconclusive. In order to establish a correct and practicable link between increased TrkB and prognostication of human solid tumors, a meta-analysis was performed in this article. A systematic literature research in the electronic databases PubMed, Embase and Web of Science was performed to identify eligible studies. A fixed-effects meta-analytical model was employed to correlate TrkB expression with OS, DFS and clinicopathological features. A total of 11 studies covering 1516 patients with various solid tumors were recruited in this meta-analysis. TrkB over-expression was associated with poorer OS and poorer DFS in multivariate analysis. Additionally, the pooled odds ratios (ORs) indicated that TrkB over-expression was associated with large tumor size, lymph node metastasis, distant metastasis and a higher clinical stage. Overall, these results indicated that TrkB over-expression in patients with solid tumors might be related to poor prognosis and serve as a potential predictive marker of poor clinicopathological prognosis factor. Anoikis is a form of programmed cell death that occurs in anchorage-dependent cells when they detach from the surrounding extracellular matrix –3. AnoikTropomyosin-related receptor Kinase B (TrkB) is a tyrosine kinase receptor for brain-derived neutrophic factor (BDNF), which triggers several intracellular signals –10. TrkBIn this study, we conducted a meta-analysis to investigate the significance of over-expressed TrkB in the prediction of prognosis of corresponding patients. The results showed that increased TrkB expression in patients with solid tumors related to poor prognosis and served as a potential prediction of poor clinicopathological prognosis factor.The initial search identified 315 publications, of which, 18 studies were of acceptable relevance. However, four of these studies were excluded because the survival curve was based on NTRK2 expression, and three were excluded because of the absence of information about clinicopathological characteristics. Ultimately, 11 studies met the eligibility criteria and were included in the current meta-analysis  was observed when using a fixed-effects model to analyze the pooled HR of the OSs.The pooled hazard ratio (HR) revealed that over-expressed TrkB was significantly associated with poor overall survival (OS) for cancer victims in multivariate analysis .A significant correlation between over-expressed TrkB and disease-free survival (DFS) was also observed in the patients with solid tumors in multivariate analysis , which triggers several intracellular signals. TrkB is over-expressed in various human malignancies and growing evidence demonstrated its association with tumour cell proliferation, invasion and metastasis –31. TrkBIn this meta-analysis, we evaluated survival data from 1516 solid tumor patients from 11 eligible studies, which met the inclusion criteria, were organized according to OS and DFS. For all studies, TrkB expression was detected by IHC. By meta-analysis of the 11 studies, we identified the pool HRs which indicated that TrkB was a factor in poor prognosis in various cancers. Because there is no significant heterogeneity among our included studies, so we did not perform further subgroup analyses. Additionally, no publication bias was observed. These results indicated over-expressed TrkB was positive related to poor OS and DFS in solid tumor patients. In addition, pooled results of the correlations were identified between over-expressed TrkB and clinicopathological features of patients with solid tumors. The results showed the expression of TrkB was positively associated with large tumor size, lymph node metastasis, distant metastasis and a higher clinical stage. We can explain this result by TrkB’s ability to enhance anoikis resistance, promote tumour cell proliferation, invasion and metastasis. Because of its involvement in these processes, TrkB is likely to be causally involved in tumor progression and, consequently, increased levels of TrkB would be expected to indicate a poor prognosis.This meta-analysis was properly conducted, however, further analysis with several limitations would be considered in the future. first, need more trials to analysis; second, some of the survival data were extracted from Kaplan-Meier curves and might be less reliable than a direct analysis of variance; third, we need to search more non-English publications. In addition, the possible existence of unpublished studies could also result in potential publication bias. In general, concerning these limitations mentioned above, we must interpret these results with adequate caution.In conclusion, our meta-analysis indicated that over-expressed TrkB was positive related to poor OS and DFS in solid tumor patients. Over-expressed TrkB could be served as a potential marker for poor clinicopathological prognostic factors in patients with various solid tumors. However, additional studies related to specific tumor types are necessary to illuminate the clinical utility of increased TrkB in solid tumors.This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement. The literatures relevant to TrkB expression and survival in solid tumors were searched in the PubMed, Embase and Web of Science databases through March 31, 2017. The search terms included the following key words in various combinations: TrkB, NTRK2, prognosis, prognostic, survival, and overall survival. The hits were limited to human studies and those published in English. The references list of review and bibliographies were further sifted to identify additional potentially relevant studies to avoid omission due to the electronic search approach.The collected studies included in this meta-analysis had to meet the following criteria: (1) a pathological diagnosis of cancer was made; (2) TrkB expression in patients with any type of tumor was measured via immunohistochemistry; (3) associations of TrkB expression with OS, DFS or clinicopathological features were described; (4) HRs and 95% confidence intervals (CIs) were reported or could be calculated (based on the information in the paper); and (5) when the same author reported repeated results from the same population, the most complete report was included. The exclusion criteria for this meta-analysis were as follows: (1) unpublished papers; (2) laboratory articles, reviews and letters; (3) non-English language articles; (4) overlapping articles or ones with duplicate data; (5) articles with only animal experiments; (6) studies without information about survival curves; and (7) TrkB expression in patients with any type of tumor was analyzed only using RT-PCR method.All data were extracted independently by two investigators (Chunze Zhang and Dan Gao). For each eligible study, the following characteristics were extracted: first author’s name, publication year, region, type of cancer, number of patients, patients’ ages, follow-up times, detection methods, staining position, cut-off values, survival data (including OS and DFS) and clinicopathological parameters, such as tumor differentiation, tumor size, lymph node metastasis and TNM stage. For studies that presented only Kaplan-Meier curves was used to extract the survival data. The Newcastle-Ottawa-Scale (NOS) was adopted to assess the study quality of each individual study. The NOS score ranged from 0 to 9, and studies with NOS score ≥ 7 were defined as high-quality studies.Q test) and I-squared statistical test were used to analyze the heterogeneity between studies. When the result of a Q-test (I2 > 50% or P < 0.05) indicated heterogeneity, the random-effects model was used for the meta-analysis. Otherwise, a fixed-effects model was used. HR with its value over 1.0 indicated poor prognosis patients with increased TrkB expression. Funnel plots were used to graphically represent the publication bias. Begg’s (rank correlation) test was adopted to confirm the publication bias.This meta-analysis was performed using Stata 12.0  software. Pooled estimates of HRs and their 95% CIs were used to estimate the association between TrkB expression and patients’ survival. The chisquared test (Cochrane’ s


Relatives often take on great responsibility for helping the patient in his or her daily life, and many relatives experience lack of support from health care services. Cooperation with relatives is a central component in Resource groups Assertive Community Treatment (R-ACT). This person-centered model has been found to decrease symptoms, increase level of function, and strengthen well-being in patients with psychotic disorders. However, little is known about relatives’ experiences of the model.To examine relatives experiences of R-ACT. Further, to compare relatives’ experiences of treatment and feelings of being alienated from care services in relatives’ with and without experience of R-ACT. We hypothesize higher levels of family burden, and family stigma and lower quality of life in relatives without R-ACT.Cross-sectional study focusing on relatives of persons with psychotic disorders during the period of October 1, 2017 – May 31, 2018.Relatives of next of kin suffering from psychotic disorders, treated in health care clinics with and without R-ACT in Västra Götaland County in Sweden.The postal questionnaire includes four self-reported instruments: the Family Involvement and Alienation Questionnaire, the Burden Inventory for Relatives of Persons Psychotic Disturbances, the Inventory of Stigmatizing Experiences (family version), and RAND-36.Recruitment is ongoing. Preliminary results will be presented at the conference.Increased knowledge about relatives’ experiences of psychosis care can inform the development of R-ACT, a care model that focuses on participation of both patients and their relatives.


Huangjinya, a natural mutant, contains enhanced levels of free amino acids in its leaves, which improves the drinking quality of its brewed tea. Consequently, this chlorotic mutant has a higher economic value than the non-chlorotic varieties. However, the molecular mechanisms behind the increased levels of free amino acids in this mutant are mostly unknown, as are the possible effects of this mutation on the overall metabolome and biosynthetic pathways in tea leaves. To gain further insight into the effects of chlorosis on the global metabolome and biosynthetic pathways in this mutant, Huangjinya plants were grown under normal and reduced sunlight, resulting in chlorotic and non-chlorotic leaves, respectively; their leaves were analyzed using transcriptomics as well as targeted and untargeted metabolomics. Approximately 5,000 genes  and ca. 300 metabolites  were significantly differentially regulated, thus indicating the occurrence of marked effects of light on the biosynthetic pathways in this mutant plant. Considering primary metabolism, including that of sugars, amino acids, and organic acids, significant changes were observed in the expression of genes involved in both nitrogen (N) and carbon metabolism. The suite of changes not only generated an increase in amino acids, including glutamic acid, glutamine, and theanine, but it also elevated the levels of free ammonium, citrate, and α-ketoglutarate, and lowered the levels of mono- and di-saccharides and of caffeine as compared with the non-chlorotic leaves. Taken together, our results suggest that the increased levels of amino acids in the chlorotic vs. non-chlorotic leaves are likely due to increased protein catabolism and/or decreased glycolysis and diminished biosynthesis of nitrogen-containing compounds other than amino acids, including chlorophyll, purines, nucleotides, and alkaloids.The chlorotic tea variety  The flavor and quality of tea are attributed to the presence of polyphenols, alkaloids, and amino acids. In particular, each free amino acid (or amide) has its own taste–as one of or a combination of sweet, salty, sour, bitter, and umami–which is why amides are recognized as the principal contributor to the mellow taste of brewed green tea  O. Kuntze cv. Huangjinya, one of the albino tea plant species, produces yellow-colored young shoots/leaves–the harvested parts for tea production–but green-colored mature leaves  under normal conditions of sunlight  (cv. Huangjinya) was planted in pots at the Tea Research Institute, Chinese Academy of Agricultural Sciences . In March 2014, 60 pots (Four plants per pot) of tea plants that had uniform young shoots  were selected for this experiment: half of the pots were treated with “High-density Polyethylene Tape Two-Pin Net” (60% shading of sunlight) and the remaining 30 pots were exposed to full sunlight for 10 days  were fixed with a 2.5% glutaraldehyde solution overnight at 4°C. Ultrathin sections were cut and stained; these were viewed under a transmission electron microscope  at an accelerating voltage of 80 kV, as described by Li et al. (Transmission electron microscopy (TEM) was used to observe the ultrastructure of the chlorotic leaf. Chlorotic and non-chlorotic Leaf samples  following the manufacturer's protocol. The RNA integrity was confirmed by a 2100 Bioanalyzer (Agilent Technologies). The RNA samples for the transcriptome analysis were prepared using an Illumina kit, following the manufacturer's recommendations. The fragments were purified via agarose gel electrophoresis and enriched by PCR amplification to create a cDNA library. Sequencing and data processing  were all performed following the methods described by Wang et al. . The traAll 12 samples obtained–six biological replicates from each chlorotic and non-chlorotic plant group–were used for the metabolomics analysis. The tea leaves were extracted and derivatized as described by Lisec et al.  and Liu Total ion chromatograms (TIC) were processed using the automated data processing software, ChromaTOF . Metabolite identification from these selected variables was achieved via the NIST 05 Standard mass spectral databases . The resulting data containing sample information, peak retention times, and peak intensities, were normalized to the area of the IS (afterward the IS peaks were removed), and then mean-centered.t-test (P < 0.05).Univariate statistics were carried out using one-way ANOVA in SPSS software . The unit variance was scaled for further statistical analysis using SIMCA-P software . To obtain a general overview of the variance in metabolites, an unsupervised principal component analysis (PCA) was performed. To obtain information on the differences in the metabolite composition of the samples, a supervised orthogonal projection to latent structure discriminant analysis (OPLS-DA) was performed. The “variable importance in the projection” (VIP) values of all the data from the 7-fold cross-validated OPLS model were taken as the coefficients for the metabolite selection. For the purpose of group discrimination, only those variables that had a VIP > 1.0 and |p(corr)| > 0.65 were considered relevant. After the multivariate approaches were completed, the significance of each metabolite in the group discrimination was further evaluated by the Student's GAPDH was used as the reference gene. For each target gene, triplicate reactions were performed. Relative transcript levels were calculated against that of the internal control GAPDH using the formula 2−ΔΔCt.Total RNA was isolated using an RNAplant plus kit . Complementary DNA (cDNA) was synthesized using a PrimeScriptTM RT reagent Kit (TaKaRa). Quantitative real-time PCR (qRT-PCR) was performed on the Applied Biosystems 7,300 machine . The primer pairs used for the qRT-PCR are shown in Table 4Cl standard curve.Free amino acids, chlorophylls, and carotenoids in the young shoot/leaves samples were measured using an automatic amino-acid analyzer  and by high-performance liquid chromatography with diode array detector , as previously reported by Liu et al. . Ammoniu−2 s−1), while the leaves of plants shaded to 60% of the full sunlight intensity turned green . Approximately 300 metabolites were significantly differentially regulated and 41 compounds related to the amino acid and carbon skeleton metabolism, the amino acids and derivatives, carbohydrates and organic acids and derivatives, have been identified , nitrate reductase (NR), glutamine synthetase (GS), and theanine synthase (TS) but higher expression levels of those encoding glutamate synthase (GOGAT), glutamate dehydrogenase (GDH), and asparagine synthase (AS) in the chlorotic as compared with the non-chlorotic leaves Figure . The traed Table . The expN-acetylglutamate synthase (NAGS), glutamate-5-semialdehyde dehydrogenase (GSADH), glutamate decarboxylase (GAD), and argininosuccinate synthase (ASS), whereas the genes encoding pyrroline-5-carboxylate reductase (P5CR), histidinol dehydrogenase (HDH), and argininosuccinate lyase (ASL) showed a converse expression pattern  and pyruvate kinase (PK), which are involved in the pathway leading to the synthesis of alanine and valine from pyruvate, were also up-regulated in the chlorotic leaves. In the biosynthetic pathway to the aspartate-derived amino acids, the expression levels of the genes encoding asparagine synthase (AS), aspartate kinase (AK), and aspartate-semialdehyde dehydrogenase (ASADH) were increased, while those of homoserine dehydrogenase (HSDH) and branched-chain-amino-acid transaminase (BCAT) were decreased.In the aromatic amino acid biosynthetic pathway, we observed down-regulation in the chlorotic leaves of the genes encoding 3-deoxy-D-arabinoheptulosonate 7-phosphate synthase (DAHPS), 3-dehydroquinate synthase (DHQS), shikimate dehydrogenase (SDH), 5-enolpyruvylshikimate-3-phosphate (EPSPS), chorismate synthase (CS), prephenate dehydratase (PDH), and arogenate dehydrogenase  and chorismate mutase (CM).The abnormal development of the chloroplast and of the membrane structure in the chlorotic leaves inhibited photosynthesis, which impaired both glucose metabolism and carbon assimilation. Biological classification using GO suggested that in the “Cellular Component” classification, the expression of genes related to plastids and to membrane structure was strongly suppressed in the chlorotic leaves Table . These gMetabolite profiling based on the GC × GC-TOF/MS showed that, compared to the non-chlorotic leaves, the chlorotic leaves had lower levels of most carbohydrates and their conjugates, such as glucose, fructose, sucrose, sorbose, arabinose, D-galactose, D-mannose, fucose, and fructose 2, 6-bisphosphate Table . By contRegarding the TCA cycle, the chlorotic leaves showed an increase in their ketoglutarate and citric acid contents, but a decrease in their malic acid content, as compared with the non-chlorotic leaves Figure . The expHuangjinya showed two stark phenotypes of chlorotic vs. non-chlorotic when grown under normal and reducedlight conditions, respectively. Moreover, particular genes and metabolites were significantly differentially regulated in the chlorotic vs. non-chlorotic leaves. However, the effect of shading on Huangjinya differs completely from its effect on a normal tea species , which show reduced photosynthetic rates and carbon metabolism but enhanced nitrogen metabolism. Returning to the present study, the results suggest that the chlorotic leaves were in a carbon-deficient condition: there were insufficient carbon skeletons present for the biosynthesis of amino acids  leaves , and by the Chinese Academy of Agricultural Sciences through an Innovation Project for Agricultural Sciences and Technology (CAAS-ASTIP-2016-TRICAAS).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.


Familial Mediterranean fever (FMF) is a chronic, recurrent auto-inflammatory disease characterised by self-terminating attacks of fever and sterile polyserositis. The main cause of death in auto-inflammatory diseasesis cardiovascular events. Additionally, auto-inflammatory diseases have potential effects on the myocardial repolarisation parameters, including the T-wave peak-to-end (Tp-Te) interval, cTp-Te interval (corrected Tp-Te) and the cTp-Te/ QT ratio. The aim of this study was to analyse the efficacy of myocardial repolarisation alterations in anticipation of cardiovascular risks in patients with FMF.This study included 66 patients with FMF and 58 healthy control subjects. Tp-Te and cTp-Te intervals and the cTp-Te/QT ratio were measured from the 12-lead electrocardiogram.In electrocardiographic parameters, analysis of QT, QT dispersion, corrected QT (QTc) and QTc dispersion were similar between the groups. The Tp-Te and cTp-Te intervals and Tp-Te/QT and cTp-Te/QT ratios were significantly prolonged in FMF patients. Multivariate linear regression analyses indicated that erythrocyte sedimentation rate was an independent predictor of a prolonged cTp-Te interval.Our study revealed that when compared with control subjects, Tp-Te and cTp-Te intervals and cTp-Te/QT ratio were increased in FMF patients. Familial Mediterranean fever (FMF) is a chronic, recurrent autoinflammatory disorder with autosomal recessive inheritance characterised by self-limiting attacks of arthritis, peritonitis or pleuritis and fever.Mutations in the MEFV (MEditerranean FeVer) gene, which encodes for a protein called pyrin, is necessary for a diagnosis of FMF.3Chronic systemic inflammation accelerates the natural process of atherosclerosis. The main cause of death in auto-inflammatory disorders is related to atherosclerosis and cardiovascular events.peak–Tend interval (Tp-Te), which is the interval between the peak and the end-point of the T wave on a resting ECG, and Tp-Te/QT ratio are accepted as a novel index of myocardial repolarisation. These are associated with an increased risk of ventricular arrhythmias.11The T wave on electrocardiography (ECG) indicates myocardial repolarisation, which can be evaluated with several ECG parameters, such as QT interval (QT), QT dispersion (QTd), corrected QT interval (QTc) and transmural dispersion of repolarisation.In this study, we investigated the possible effects on myocardial repolarisation of ongoing subclinical inflammation in FMF patients by analysis of ECGs. We aimed to evaluate the efficacy of the prediction of cardiovascular risks of possible non-specific repolarisation changes in patients with FMF.This study had a cross-sectional and observational design. Between August 2014 and January 2015, 66 FMF patients without cardiovascular involvement , who were diagnosed with FMF according to the Tell– Hashomer diagnostic criteria,12 and 58 healthy controls matched for gender and age , were included in this study. All the patients with FMF were treated chronically with colchicine. Mean duration of time elapsed from diagnosis of FMF was 7.9 ± 4.9 years.Excluded from the study were patients with diabetes mellitus, hypertension, congestive heart failure, smoking, coronary artery disease, valvular heart disease, previous history of myocardial infarction, hyperthyroidism, hypothyroidism, atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease, bundle brunch block, atrioventricular block and malignancy. The patients were evaluated with echocardiography and 12-lead ECG at least 10 days after an attack. Levels of haemoglobin and C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) and white blood cell count (WBC) were obtained from laboratory records.The study protocol was approved by the institutional ethics committee. Informed written consent was obtained from each patient.Twelve-lead ECGs  were obtained with the subject at rest in the supine position. All ECGs were transferred to a computer via a scanner and then used at 400% magnification via Adobe Photoshop software. Measurements of Tp-Te and QT intervals were performed on the computer by two experienced cardiologists, who were blinded to the clinical data of each patient and control subject.QT and R-R intervals were measured in all derivations. The QT interval was defined as the time from the start of the QRS to the point at which the T wave returns to the isoelectric line. The R-R interval, which was measured as the average of three complexes, was used to calculate heart rate, and the QTc was calculated with Bazett’s formula.Although tail and tangent methods can be used in the measurement of Tp-Te interval, the tail method is a better predictor of mortality than the tangent method,Measurements were made by two independent cardiologists taking the average of three consecutive beats. Intra-observer variability for Tp-Te interval obtained from leads V2 and V5 were 3.4 and 3.8%, respectively. Furthermore, inter-observer variability for the Tp-Te interval obtained from leads V2 and V5 were 2.5 and 2.9%, respectively.All echocardiographic examinations  were performed in all subjects using a 2.5–3.5-MHz transducer in the left decubitus position. Two-dimensional and pulsed Doppler measurements were obtained using the criteria of the American Society of Echocardiography.Statistical analyses were performed using SPSS software . Categorical variables are expressed as n (%) and continuous variables are expressed as mean ± standard deviation. Mean values of continuous variables were compared between the groups using the Student’s t-test. The chi-squared test was used to assess differences between categorical variables. The relationship between parameters was determined using Pearson’s coefficient of correlation. Multivariate linear regression analysis was used to identify the independent predictors of prolonged cTp-Te interval and independent variables that differed significantly in the bivariate analyses (p < 0.1). A p-value < 0.05 was considered significant.Baseline demographic, clinical and echocardiographic characteristics of all subjects are shown in Correlations and regression analyses between the cTp-Te interval in the V5 lead and the study parameters were performed. There were significant correlations between the cTp-Te interval and ESR  and CRP levels  and neutrophil–lymphocyte ratio (NLR)  and mitral E/A ratio  .Multivariate linear regression analysis demonstrated that the ESR  was an independent predictor of a prolonged cTp-Te interval . In addiIn the current study, we found that cTp-Te interval and cTp-Te/ QT ratio were significantly increased in the FMF group compared to the control group. In addition we found that the increased cTp-Te interval and cTp-Te/QT ratio were positively correlated with CRP and ESR levels and NLR and mitral E/A ratios. We also found that ESR was an independent predictor of a prolonged cTp-Te interval in patients with FMF.FMF is a hereditary transmitted auto-inflammatory disease characterised by recurrent and paroxysmal fever, peritonitis, pericarditis, arthritis and skin rashes.23Previous studies investigated vascular and cardiac function in FMF. Calıskan et al.Fibrosis in the heart muscle plays an important role in the pathogenesis of ventricular arrhythmias. Parameters of autonomic cardiac tone, such as heart rate variability (HRV), heart rate turbulance (HRT) and QT dynamics, are useful for risk evaluation for ventricular arrhythmias, and abnormalities in these parameters may precede the development of fibrosis.26To date, subclinical cardiovascular involvement associated with cardiac autonomic dysfunction in FMF has been reported in many studies. Fidanci et al.Myocardial repolarisation is mostly evaluated using measurements of QT interval and T wave on ECG and it may be affected by some pathophysiological processes such as genetic diseases, acquired clinical conditions, and/or drugs.31Several investigators have evaluated QT and QTc intervals in inflammatary diseases. In a study by Acar et al.,QTd is the most frequently used parameter to detect the dispersion of ventricular repolarisation and is accepted as a marker for arrhythmia and sudden death.37A number of studies have investigated the effect on QTd of systemic inflammation in patients with FMF. Akcay et al.Tp-Te interval is a new index of dispersion of myocardial repolarisation, which is related to ventricular arrhythmogenesis and sudden cardiac death.Increased Tp-Te interval may also be a predicting index for elevated risk of cardiovascular mortality in inflammatory diseases. It was reported that the Tp-Te interval was prolonged in patients with rheumatoid arthritis and systemic lupus erythematosus.Tp-Te interval is affected by variations in heart rate and body weight.15 Recently, the cTp-Te interval and cTp-Te/QT ratio were suggested to be more accurate measurements of the dispersion of myocardial repolarisation, compared to the QT, QTd, and Tp-Te intervals. In our study, we found significant differences in the cTp-Te interval and cTp-Te/QT ratio between FMF patients and control subjects. In the light of these data, we evaluated the effect of inflammatory markers on the cTp-Te interval in FMF patients and found that prolonged Tp-Te was positively correlated with ESR and CRP levels and NLR. In addition, we found that ESR was an independent predictor of a prolonged cTp-Te interval in patients with FMF.Our study has several limitations. The major limitation is the small size of the study population and it may have negatively affected the statistical results. Second, the study had a crosssectional design and there was no follow up of arrhythmic episodes in patients.The findings of this study demonstrate that increased cTp-Te interval and cTp-Te/QT ratio may create a specific risk for ventricular arrhythmias in patients with FMF. However, the underlying mechanism and prognostic effects are as yet unknown. Therefore larger, long-term prospective and multicentre followup studies are needed.


Mature microRNA is a crucial component in the gene expression regulation network. At the same time, microRNA gene expression and procession is regulated in a precise and collaborated way. Pre-microRNAs mediate products during the microRNA transcription process, they can provide hints of microRNA gene expression regulation or can serve as alternative biomarkers. To date, little effort has been devoted to pre-microRNA expression profiling. In this study, three human and three mouse microRNA profile data sets, based on the Affymetrix miRNA 2.0 array, have been re-analyzed for both mature and pre-microRNA signals as a primary test of parallel mature/pre-microRNA expression profiling on a single platform. The results not only demonstrated a glimpse of pre-microRNA expression in human and mouse, but also the relationship of microRNA expressions between pre- and mature forms. The study also showed a possible application of currently available microRNA microarrays in profiling pre-microRNA expression in a time and cost effective manner. MicroRNAs (miRNA) are short conservative endogenous non-coding RNAs with a length of around 22 nucleotides, which have diverse functions . Since imiRNA genes are transcribed by RNA polymerase II (Pol II)  in the nDiverse techniques are available for the purpose of miRNA expression profiling, e.g., Northern blotting , dot bloMuch more attention has been dedicated to mature miRNA expression profiling, although pri-miRNA and pre-miRNA are important intermediates during miRNA biogenesis . Pre-miR® miRNA 2.0 arrays  contain probes that interrogate the mature miRNA and pre-miRNA of a wide spectrum of species. In this study, profiling data of human and mouse samples  for study, i, , the expression values of pre-miRNAs can be described as plot see . (ii) Thistogram . Statist® miRNA 2.0 has 4,592 probe sets for human and 1,412 probe sets for mouse. Seven hundred sixty seven pre-miRNAs and 919 mature miRNAs are annotated for human samples. For the mouse samples, 510 pre-miRNAs and 601 mature miRNAs are available on the platform. Eight hundred thirty six pre-miRNA/mature-miRNA pairs can be mapped in human miRNA annotation, while there are 579 according to the mouse annotation. GeneChipPre-miRNAs showed lower expression in these data sets than their matured products. Boxplots of expression values of pre- and mature miRNAs in three human and three mouse studies, respectively, are shown . In all The general higher expression level of mature miRNA was also reflected in the detection call of present miRNAs. Present calls were made for pre-miRNA and mature miRNAs compared to background signals. Mature miRNAs have almost doubled present calls with respect to pre-miRNAs in all data sets . vice versa . At the same time, we can obtain a genome-wide overview for pre-miRNA and miRNA expression. An additional advantage of this platform is that only one simple labeling procedure is sufficient for both pre-miRNA and mature miRNA profiling.