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BackgroundCardiac rotational parameters in primary symptomatic left ventricular noncompaction (LVNC) with preserved left ventricular ejection fraction (LVEF) are not well understood. We aimed to analyze cardiac rotation measured with cardiac magnetic resonance feature-tracking (CMR-FT) and speckle-tracking echocardiography (Echo-ST) in LVNC morphology subjects with preserved LVEF and different genotypes and healthy controls.MethodsOur retrospective study included 54 LVNC subjects with preserved LVEF and 54 control individuals. We evaluated functional and rotational parameters with CMR in the total study population and with echocardiography in 39 LVNC and 40 C individuals. All LVNC subjects were genotyped with a 174-gene next-generation sequencing panel and grouped into the subgroups: benign (B), variant of uncertain significance (VUS), and pathogenic (P).ResultsIn comparison with controls, LVNC subjects had reduced apical rotational degree (p = 0.004) and one-third had negative apical rotation. While the degree of apical rotation was comparable between the three genetic subgroups, they differed significantly in the direction of apical rotation (pConclusionWhile measuring cardiac rotation using both CMR-FT and Echo-ST methods, subclinical mechanical differences were identified in subjects with LVNC phenotype and preserved LVEF, especially in cases with genetic involvement.

Using bibliometric analysis of large-scale publication data is a simple approach to exploring gender-related trends, especially gender equality in academic publishing. The aim of this study is to investigate gender trends in the fields of bio-economy and rural development sciences in two under develop regions as Latin America and Africa. This study examines gender differences in these fields in order to: (1) recognize the contribution of female researchers in bioeconomy and rural development, (2) explore the relational structure of gender aspects in academic publications, (3) identify trends in female authorship in these scientific research fields over time, and finally (4) identify gender potentials for women to become more visible in these fields of study. To achieve these objectives, we used bibliometric tools to analyses 1891 publication records in bioeconomy and rural development. After cleaning the database of full names of authors of academic publications relevant to the field studies, we performed a series of statistical analyses in R and SPSS software, such as Lotkas distribution, network analysis, co-authorship analysis and spatial distribution of authors in the study. The results show that the number of male authors is almost three times higher than the number of female authors, suggesting that women are under-represented in the fields studied. Men occupy the most important position of authorship in scientific articles; publications with corresponding male authors were found in 1389 out of 1891 publications related to the bio-economy and rural development. In terms of geographical regions, publications with female authors were more prevalent in European and North American areas, with a small exception in some developing countries such as Argentina and South Africa. In terms of research networks, from the total number of authors evaluated, only 23% are female authors on the map of research influence. This indicates that there is a significant gap to be filled in the promotion of scholarly impact through the sharing of knowledge and expertise among authors.

BackgroundFirearm dealer density is correlated with firearm interpersonal violence, but no quasi-experimental studies have assessed whether changes in dealer density lead to changes in firearm self-harm injuries and deaths. We assessed whether openings of firearm dealers are associated with short-term changes in local firearm self-harm injury rates.MethodsWe identified 718 openings of firearm dealers in California using licensing data, 2014-2016. We defined exposure regions based on aggregations of zip codes defined by proximity to firearm dealer openings and matched each opening to four control regions on time and determinants of firearm injury. We applied a differences-in-differences approach to compare rates of firearm self-harm, in the month before and after each opening, in places with and without openings.ResultsFirearm dealer openings were not associated with acute, local changes in firearm self-harm relative to places without openings (ratio of rate ratio: 0.90 [95% CI:0.68-1.19]). Results were robust to numerous sensitivity and secondary analyses.ConclusionWe found no associations of firearm dealer openings with acute, localized firearm self-harm deaths and injuries. Our focus on acute, local effects; broad availability of dealers and firearms; durability of firearms; or strong confounding-control may explain these null findings.

Interpersonal distance regulation is an essential element of social communication. Its impairment in autism spectrum disorder (ASD) is widely acknowledged among practitioners, but only a handful of studies reported empirical research in real-life settings, focusing mainly on children. Interpersonal distance in adults with ASD and related autonomic functions received less attention. Here, we measured interpersonal distance along with heart rate variability (HRV) in adults with ASD, and tested the modulatory effects of eye-contact and attribution. Twenty-two adults diagnosed with ASD and 21 matched neurotypical controls participated in our study from October 2019 to February 2020. Our experimental design combined the modified version of the stop distance paradigm with HRV measurement controlling for eye contact between the experimenter and the participant to measure interpersonal distance. Still, we did not detect significant modulatory effect of eye contact and attribution. Our results showed a greater preferred distance in ASD. Moreover, we found lower baseline HRV and reduced HRV reactivity in ASD; however, these autonomic measurements could not predict preferred interpersonal distance. Our study highlights the importance of interpersonal space regulation in ASD: it might be considered that people with ASD need individually variable, presumably greater interpersonal distance. In addition, regardless of the distance they may have reduced autonomic regulatory capacity in social situations. Our results could help shape future experiments with sophisticated designs to grasp the complexity and underlying factors of distance regulation in typical and atypical populations.

As pollinators and producers of numerous human-consumed products, honey bees have great ecological, economic and health importance. The composition of their bacteriota, for which the available knowledge is limited, is essential for their body's functioning. Based on our survey, we performed a metagenomic analysis of samples collected by repeated sampling. We used geolocations that represent the climatic types of the study area over two nutritionally extreme periods (March and May) of the collection season. Regarding bacteriome composition, a significant difference was found between the samples from March and May. The samples' bacteriome from March showed a significant composition difference between cooler and warmer regions. However, there were no significant bacteriome composition differences among the climatic classes of samples taken in May. Based on our results, one may conclude that the composition of healthy core bacteriomes in honey bees varies depending on the climatic and seasonal conditions. This is likely due to climatic factors and vegetation states determining the availability and nutrient content of flowering plants. The results of our study prove that in order to gain a thorough understanding of a microbiome's natural diversity, we need to obtain the necessary information from extreme ranges within the host's healthy state.

BackgroundLeft ventricular diastolic dysfunction is common in patients with aortic valve stenosis (AS) and reportedly affects prognosis after surgical aortic valve replacement (SAVR). Here we investigated whether and how diastolic function (assessed following the most recent guidelines) was affected by SAVR, and whether preoperative diastolic function affected postoperative outcome. We also examined whether long-term mortality was associated with preoperative NT-proBNP and postoperative heart failure (PHF).MethodsWe performed a prospective observational study of 273 patients with AS who underwent AVR with or without concomitant coronary artery bypass surgery. Of these patients, 247 were eligible for assessment of left ventricular (LV) filling pressure. Preoperatively and at the 6-month postoperative follow-up, we measured N-terminal pro-B type natriuretic peptide (NT-proBNP) in serum and assessed diastolic function with Doppler echocardiography. PHF was diagnosed using prespecified criteria. Multivariable logistic regression was performed to explore variables associated with high LV filling pressure. Cox regression was performed to explore variables associated with mortality, accounting for timeto-event.ResultsAt the time of surgery, 22% (n = 54) of patients had diastolic dysfunction expressed as high LV filling pressure. Of these 54 patients, 27 (50%) showed postoperative diastolic function improvement. Among the 193 patients with preoperative low LV filling pressure, 24 (12%) showed postoperative diastolic function deterioration. Increased long-term mortality was associated with PHF and high preoperative NT-proBNP, but not with preoperative or postoperative diastolic dysfunction. Cox regression revealed the following independent risk factors for long-term mortality: diabetes, renal dysfunction, preoperative NT-proBNP>960 ng/L, age, and male gender.ConclusionsSurgery for aortic stenosis improved diastolic function in patients with high LV filling pressure in 50% of the patients. Our results could not confirm the previously suggested role of diastolic dysfunction as a marker for poor long-term survival after SAVR. Our findings showed that both PHF and high preoperative NT-proBNP were associated with long-term mortality.

BackgroundFirearm dealer density is correlated with firearm interpersonal violence, but no quasi-experimental studies have assessed whether changes in dealer density lead to changes in firearm self-harm injuries and deaths. We assessed whether openings of firearm dealers are associated with short-term changes in local firearm self-harm injury rates.MethodsWe identified 718 openings of firearm dealers in California using licensing data, 2014-2016. We defined exposure regions based on aggregations of zip codes defined by proximity to firearm dealer openings and matched each opening to four control regions on time and determinants of firearm injury. We applied a differences-in-differences approach to compare rates of firearm self-harm, in the month before and after each opening, in places with and without openings.ResultsFirearm dealer openings were not associated with acute, local changes in firearm self-harm relative to places without openings (ratio of rate ratio: 0.90 [95% CI:0.68-1.19]). Results were robust to numerous sensitivity and secondary analyses.ConclusionWe found no associations of firearm dealer openings with acute, localized firearm self-harm deaths and injuries. Our focus on acute, local effects; broad availability of dealers and firearms; durability of firearms; or strong confounding-control may explain these null findings.

Background Historically, surgical bilioenteric bypass was the only treatment option for extrahepatic bile duct obstruction, but with technological advancements, percutaneous transhepatic drainage (PTD) and endoscopic solutions were introduced as a less invasive alternative. Endoscopic methods may lead to a decreasing indication of PTD in the future, but today it is still the standard treatment method, especially in hilar obstructions. Methods In our retrospective data analysis, we assessed technical success rate, reintervention rate, morbidity, mortality, and the learning curve of patients treated with PTD over 12 years in a tertiary referral center. Results 599 patients were treated with 615 percutaneous interventions. 94.5% (566/599) technical success rate; 2.7% (16/599) reintervention rate were achieved. 111 minor and 22 major complications occurred including 1 case of death. In perihilar obstruction, cholangitis were significantly more frequent in cases where endoscopic retrograde cholangiopancreatography had also been performed prior to PTD compared to PTD alone, with 39 (18.2%) and 15 (10.5%) occurrences, respectively. Discussion The results and especially the excellent success rates demonstrate that PTD is safe and effective, and it is appropriate for first choice in the treatment algorithm of perihilar stenosis. Ultimately, we concluded that PTD should be performed in experienced centers to achieve low mortality, morbidity, and high success rates.

Uncontrolled proliferation of endothelial cells is essential to the pathogenesis of pulmonary arterial hypertension (PAH). Both proliferation and cytoskeleton reorganization are associated with upregulation of the intermediate filament protein Nestin. Recently, accumulation of Nestin-expressing cells was found in pulmonary vascular lesions of PAH patients. The goal of this study is to determine if Nestin expression contributes to endothelial proliferation in pulmonary arterial hypertension, using both lung tissues and endothelial cells. Here we found that endothelial cells from complex and plexiform lesions of PAH patients expressed Nestin. These Nestin+ cells further stained positive for the angiogenic factors CXC chemokine ligand 12 and Wnt1. Likewise, in the chronic hypoxia/SU5416 animal model of pulmonary hypertension, Nestin+ endothelial cells were found in occlusive pulmonary vascular lesions. In vitro, both growing rat and human lung endothelial cells expressed Nestin protein. When Nestin was overexpressed in endothelial cells (both rat and human), Nestin overexpression promoted proliferation and expression of CXC chemokine ligand 12. Nestin overexpression further increased angiogenic tube formation in vitro. Conclusions: We found increased Nestin expression from endothelial cells of occlusive lung vascular lesions in severe pulmonary hypertension. Elevated Nestin expression likely contributes to unchecked pulmonary vascular proliferation and angiogenesis, possibly via induction of CXC chemokine ligand 12. Additional studies are required to determine whether targeting Nestin would be beneficial to treat PAH.

This study presents a new multimodal imaging approach that includes high-frequency ultrasound, fluorescence intensity, confocal, and spectral imaging to improve the preclinical evaluation of new therapeutics in vivo. Here we use this approach to assess in vivo the therapeutic efficacy of the novel chemotherapy construct, HerDox during and after treatment. HerDox is comprised of doxorubicin non-covalently assembled in a viral-like particle targeted to HER2+ tumor cells, causing tumor cell death at over 10-fold lower dose compared to the untargeted drug, while sparing the heart. Whereas our initial proof-of-principle studies on HerDox used tumor growth/shrinkage rates as a measure of therapeutic efficacy, here we show that multimodal imaging deployed during and after treatment can supplement traditional modes of tumor monitoring to further characterize the particle in tissues of treated mice. Specifically, we show here that tumor cell apoptosis elicited by HerDox can be monitored in vivo during treatment using high frequency ultrasound imaging, while in situ confocal imaging of excised tumors shows that HerDox indeed penetrated tumor tissue and can be detected at the subcellular level, including in the nucleus, via Dox fluorescence. In addition, ratiometric spectral imaging of the same tumor tissue enables quantitative discrimination of HerDox fluorescence from autofluorescence in situ. In contrast to standard approaches of preclinical assessment, this new method provides multiple/complementary information that may shorten the time required for initial evaluation of in vivo efficacy, thus potentially reducing the time and cost for translating new drug molecules into the clinic.

BACKGROUND:The incidence and prevalence of ulcerative colitis (UC) varies geographically. The risk of colorectal cancer (CRC) and possibly some other malignancies is increased among patients with UC. It is still debated if patients with UC are at a greater risk of dying compared with the general population. Our aim was to describe the epidemiology and mortality of the Hungarian UC population from 2010 to 2016 and to analyze the associated malignancies with a special focus on CRC. METHODS:This is an observational, descriptive, epidemiological study based on the National Health Insurance Fund social security databases from 2010 to 2016. All adult patients who had at least two events in outpatient care or at least two medication prescriptions, or at least one inpatient event with UC diagnosis were analyzed. Malignancies and CRC were defined using ICD-10 codes. We also evaluated the survival of patients suffering from UC compared with the general population using a 3 to 1 matched random sample (age, gender, geography) from the full population of Hungary. RESULTS:We found the annual prevalence of UC 0.24-0.34%. The incidence in 2015 was 21.7/100 000 inhabitants. Annual mortality rate was 0.019-0.023%. In this subpopulation, CRC was the most common cancer, followed by non-melanotic skin and prostate cancer. 8.5% of the UC incident subpopulation was diagnosed with CRC. 470 (33%) of the CRC patients died during the course of the study (25% of all deaths were due to CRC), the median survival was 9.6 years. UC patients had significantly worse survival than their matched controls (HR = 1.65, 95% CI: 1.56-1.75). SUMMARY:This is the first population-based study from Eastern Europe to estimate the different malignancies and mortality data amongst Hungarian ulcerative colitis patients. Our results revealed a significantly worse survival of patients suffering from UC compared to the general population.

The natural product nobiletin is a small molecule, widely studied with regard to its therapeutic effects, including in cancer cell lines and tumors. Recently, nobiletin has also been shown to affect circadian rhythms via their enhancement, resulting in protection against metabolic syndrome. We hypothesized that nobiletin's anti-oncogenic effects, such as prevention of cell migration and formation of anchorage independent colonies, are correspondingly accompanied by modulation of circadian rhythms. Concurrently, we wished to determine whether the circadian and anti-oncogenic effects of nobiletin differed across cancer cell lines. In this study, we assessed nobiletin's circadian and therapeutic characteristics to ascertain whether these effects depend on cell line, which here also varied in terms of baseline circadian rhythmicity. Three cell culture models where nobiletin's effects on cell proliferation and migration have been studied previously were evaluated: U2OS (bone osteosarcoma), which possesses robust circadian rhythms; MCF7 (breast adenocarcinoma), which has weak circadian rhythms; and MDA-MB-231 (breast adenocarcinoma), which is arrhythmic. We found that circadian, migration, and proliferative effects following nobiletin treatment were subtle in the U2OS and MCF7 cells. On the other hand, changes were clear in MDA-MB-231s, where nobiletin rescued rhythmicity and substantially reduced oncogenic features, specifically two-dimensional cell motility and anchorage-independent growth. Based on these results and those previously described, we posit that the effects of nobiletin are indeed cell-type dependent, and that a positive correlation may exist between nobiletin's circadian and therapeutic effects.

Magnesium isotope ratios (26Mg/24Mg) can provide insights into the origin of Mg pools and fluxes in catchments where Mg sources have distinct isotope compositions, and the direction and magnitude of Mg isotope fractionations are known. Variability in Mg isotope compositions was investigated in three small, spruce-forested catchments in the Czech Republic (Central Europe) situated along an industrial pollution gradient. The following combinations of catchment characteristics were selected for the study: low-Mg bedrock + low Mg deposition (site LYS, underlain by leucogranite); high-Mg bedrock + low Mg deposition (site PLB, underlain by serpentinite), and low-Mg bedrock + high Mg deposition (site UDL, underlain by orthogneiss). UDL, affected by spruce die-back due to acid rain, was the only investigated site where dolomite was applied to mitigate forest decline. The δ26Mg values of 10 catchment compartments were determined on pooled subsamples. At LYS, a wide range of δ26Mg values was observed across the compartments, from -3.38 ‰ (bedrock) to -2.88 ‰ (soil), -1.48% (open-area precipitation), -1.34 ‰ (throughfall), -1.19 ‰ (soil water), -0.99 ‰ (xylem), -0.95 ‰ (needles), -0.82 ‰ (bark), -0.76 ‰ (fine roots), and -0.76 ‰ (runoff). The δ26Mg values at UDL spanned 1.32 ‰ and were thus less variable, compared to LYS. Magnesium at PLB was isotopically relatively homogeneous. The δ26Mg systematics was consistent with geogenic control of runoff Mg at PLB. Mainly atmospheric/biological control of runoff Mg was indicated at UDL, and possibly also at LYS. Our sites did not exhibit the combination of low-δ26Mg runoff and high-δ26Mg weathering products (secondary clay minerals) reported from several previously studied sites. Six years after the end of liming at UDL, Mg derived from dolomite was isotopically undetectable in runoff.

IntroductionThe introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML). Although the efficacy of TKIs is beyond dispute, conception-related safety issues are still waiting to be explored, particularly in males. This systematic review aimed to summarize all available evidence on pregnancy outcomes of female spouses of male CML patients who fathered children after TKI treatment for CML.MethodsWe performed a systematic search in seven electronic databases for studies that reported on male CML patients who did or did not discontinue TKI treatment before conceiving, and the pregnancy outcomes of their female spouse are available. The search centered on the TKI era (from 2001 onward) without any other language or study design restrictions.ResultsOut of a total of 38 potentially eligible papers, 27 non-overlapping study cohorts were analyzed. All were descriptive studies (case or case series studies). Altogether, 428 pregnancies from 374 fathers conceived without treatment discontinuation, 400 of which (93.5%) ended up in a live birth. A total of ten offspring with a malformation (2.5%) were reported: six with imatinib (of 313 live births, 1.9%), two with nilotinib (of 26 live births, 7.7%), one with dasatinib (of 43 live births, 2.3%), and none with bosutinib (of 12 live births). Data on CML status were scarcely reported. Only nine pregnancies (from nine males) and no malformation were reported in males who discontinued TKI treatment before conception.ConclusionMalformations affected, on average 2.5% of live births from fathers who did not discontinue TKI treatment before conception, which is comparable with the rate of malformations in the general population. Large-scale studies with representative samples are awaited to confirm our results.

Human listeners can focus on one speech stream out of several concurrent ones. The present study aimed to assess the whole-brain functional networks underlying a) the process of focusing attention on a single speech stream vs. dividing attention between two streams and 2) speech processing on different time-scales and depth. Two spoken narratives were presented simultaneously while listeners were instructed to a) track and memorize the contents of a speech stream and b) detect the presence of numerals or syntactic violations in the same ("focused attended condition") or in the parallel stream ("divided attended condition"). Speech content tracking was found to be associated with stronger connectivity in lower frequency bands (delta band- 0,5-4 Hz), whereas the detection tasks were linked with networks operating in the faster alpha (8-10 Hz) and beta (13-30 Hz) bands. These results suggest that the oscillation frequencies of the dominant brain networks during speech processing may be related to the duration of the time window within which information is integrated. We also found that focusing attention on a single speaker compared to dividing attention between two concurrent speakers was predominantly associated with connections involving the frontal cortices in the delta (0.5-4 Hz), alpha (8-10 Hz), and beta bands (13-30 Hz), whereas dividing attention between two parallel speech streams was linked with stronger connectivity involving the parietal cortices in the delta and beta frequency bands. Overall, connections strengthened by focused attention may reflect control over information selection, whereas connections strengthened by divided attention may reflect the need for maintaining two streams in parallel and the related control processes necessary for performing the tasks.

The novel type, fungus specific protein phosphatase Z1 of the opportunistic pathogen, Candida albicans (CaPpz1) has several important physiological roles. It consists of a conserved C-terminal catalytic domain and a variable, intrinsically disordered, N-terminal regulatory domain. To test the function of these domains we modified the structure of CaPpz1 by in vitro mutagenesis. The two main domains were separated, four potential protein binding regions were deleted, and the myristoylation site as well as the active site of the enzyme was crippled by point mutations G2A and R262L, respectively. The in vitro phosphatase activity assay of the bacterially expressed recombinant proteins indicated that the N-terminal domain was inactive, while the C-terminal domain became highly active against myosin light chain substrate. The deletion of the N-terminal 1-16 amino acids and the G2A mutation significantly decreased the specific activity of the enzyme. Complementation of the ppz1 Saccharomyces cerevisiae deletion mutant strain with the different CaPpz1 forms demonstrated that the scission of the main domains, the two point mutations and the N-terminal 1-16 deletion rendered the phosphatase incompetent in the in vivo assays of LiCl tolerance and caffeine sensitivity. Thus our results confirmed the functional role of the N-terminal domain and highlighted the significance of the very N-terminal part of the protein in the regulation of CaPpz1.

Background and aimsExperimental data suggest that the HLA-DQ2 gene dose has a strong quantitative effect on clinical outcomes and severity of celiac disease (CD). We aimed to conduct a meta-analysis with systematic review to investigate the association between HLA-DQB1*02 gene doses and the characteristics of CD.MethodsWe searched seven medical databases for studies discussing HLA-DQB1 gene dose in CD and various disease characteristics, such as clinical presentation, histology, age at diagnosis, and comorbidities. Odds ratios (OR, for categorical variables) and weighted mean differences (for age) were calculated to compare patients with a double dose of HLA-DQB1*02 versus those with single and zero doses. Heterogeneity was tested with I2-statistics and explored by study subgroups (children and adults).ResultsTwenty-four publications were eligible for meta-analysis. Classical CD was more frequent with a double versus single dose of the HLA-DQB1*02 allele (OR = 1.758, 95%CI: 1.148-2.692, I2 = 0.0%). In pediatric studies, gene dose effect was more prominent (OR = 2.082, 95%CI: 1.189-3.646, I2 = 0.0% and OR = 3.139, 95%CI: 1.142-8.630, I2 = 0.0% for the comparisons of double versus single and double versus zero dose, respectively). Atrophic histology was more prevalent with a double versus zero dose (OR = 2.626, CI: 1.060-6.505, I2 = 21.3%). We observed no gene dose effect regarding diarrhea, age at diagnosis, the severity of villous atrophy, and the association with type 1 diabetes mellitus.ConclusionA double dose of HLA-DQB1*02 gene seems to predispose patients to developing classical CD and villous atrophy. Risk stratification by HLA-DQB1*02 gene dose requires further clarification due to the limited available evidence.

BackgroundNarratives of recovery from mental health distress have played a central role in the establishment of the recovery paradigm within mental health policy and practice. As use of recovery narratives increases within services, it is critical to understand how they have been characterised, and what may be missing from their characterisation thus far. The aim of this review was to synthesise published typologies in order to develop a conceptual framework characterising mental health recovery narratives.MethodA systematic review was conducted of published literature on the characteristics of mental health recovery narratives. Narrative synthesis involved identifying characteristics and organising them into dimensions and types; and subgroup analysis based on study quality, narrator involvement in analysis, diagnosis of psychosis and experience of trauma. The synthesis was informed by consultation with a Lived Experience Advisory Panel and an academic panel. The review protocol was pre-registered (Prospero CRD42018090188).Results8951 titles, 366 abstracts and 121 full-text articles published January 2000-July 2018 were screened, of which 45 studies analysing 629 recovery narratives were included. A conceptual framework of mental health recovery narratives was developed, comprising nine dimensions (Genre; Positioning; Emotional Tone; Relationship with Recovery; Trajectory; Use of Turning Points; Narrative Sequence; Protagonists; and Use of Metaphors), each containing between two and six types. Subgroup analysis indicated all dimensions were present across most subgroups, with Turning Points particularly evident in trauma-related studies.ConclusionsRecovery narratives are diverse and multidimensional. They may be non-linear and reject coherence. To a greater extent than illness narratives, they incorporate social, political and rights aspects. Approaches to supporting development of recovery narratives should expand rather than reduce available choices. Research into the narratives of more diverse populations is needed. The review supports trauma-informed approaches, and highlights the need to understand and support post-traumatic growth for people experiencing mental health issues.

INTRODUCTION:Chronic pancreatitis is an inflammatory disease associated with structural and functional damage to the pancreas, causing pain, maldigestion and weight loss and thus worsening the quality of life. AIMS AND METHODS:Our aim was to find correlations from a multicentre database representing the epidemiological traits, diagnosis and treatment of the disease in Hungary. The Hungarian Pancreatic Study Group collected data prospectively from 2012 to 2014 on patients suffering from chronic pancreatitis. Statistical analysis was performed on different questions. RESULTS:Data on 229 patients (74% male and 26% female) were uploaded from 14 centres. Daily alcohol consumption was present in the aetiology of 56% of the patients. 66% of the patients were previously treated for acute exacerbation. One third of the patients had had previous endoscopic or surgical interventions. Pain was present in 69% of the cases, endocrine insufficiency in 33%, diarrhoea in 13% and weight loss in 39%. Diagnosis was confirmed with US (80%), CT scan (52%), MRI-MRCP (6%), ERCP (39%), and EUS (7,4%). A functional test was carried out in 5% of the patients. In 31% of the cases, an endoscopic intervention was performed with the need for re-intervention in 5%. Further elective surgical intervention was necessitated in 44% of endoscopies. 20% of the registered patients were primarily treated with surgery. The biliary complication rate for surgery was significantly smaller (2%) than endoscopy (27%); however, pancreatic complications were higher in the patients treated with surgery. Patients who smoked regularly needed significantly more surgical intervention following endoscopy (66.7% vs. 26.9%, p = 0.002) than non-smokers, and the ratio of surgical intervention alone was also significantly higher (27.3% vs. 10.8%, p = 0.004). The ratio of surgery in patients who smoked and drank was significantly higher (30.09% vs. 12.5%, p = 0.012) than in abstinent and non-smoking patients, similarly to the need for further surgical intervention after endoscopic treatment (71.43% vs. 27.78%, p = 0.004). CONCLUSIONS:According to the data analysed, the epidemiological data and the aetiological factors in our cohort differ little from European trends. The study highlighted the overuse of ERCP as a diagnostic modality and the low ratio of use of endoscopic ultrasonography. The results proved that alcohol consumption and smoking represent risk factors for the increased need for surgical intervention. Chronic pancreatitis should be treated by multidisciplinary consensus grounded in evidence-based medicine.

Thinopyrum elongatum (Host) D.R. Dewey has served as an important gene source for wheat breeding improvement for many years. The exact characterization of its chromosomes is important for the detailed analysis of prebreeding materials produced with this species. The major aim of this study was to identify and characterize new molecular markers to be used for the rapid analysis of E genome chromatin in wheat background. Sixty of the 169 conserved orthologous set (COS) markers tested on diverse wheat-Th. elongatum disomic/ditelosomic addition lines were assigned to various Th. elongatum chromosomes and will be used for marker-assisted selection. The macrosyntenic relationship between the wheat and Th. elongatum genomes was investigated using EST sequences. Several rearrangements were revealed in homoeologous chromosome groups 2, 5, 6 and 7, while chromosomes 1 and 4 were conserved. Molecular cytogenetic and marker analysis showed the presence of rearranged chromosome involved in 6ES and 2EL arms in the 6E disomic addition line. The selected chromosome arm-specific COS markers will make it possible to identify gene introgressions in breeding programmes and will also be useful in the development of new chromosome-specific markers, evolutionary analysis and gene mapping.

Fish, birds, insects and robots frequently swim or fly in groups. During their three dimensional collective motion, these agents do not stop, they avoid collisions by strong short-range repulsion, and achieve group cohesion by weak long-range attraction. In a minimal model that is isotropic, and continuous in both space and time, we demonstrate that (i) adjusting speed to a preferred value, combined with (ii) radial repulsion and an (iii) effective long-range attraction are sufficient for the stable ordering of autonomously moving agents in space. Our results imply that beyond these three rules ordering in space requires no further rules, for example, explicit velocity alignment, anisotropy of the interactions or the frequent reversal of the direction of motion, friction, elastic interactions, sticky surfaces, a viscous medium, or vertical separation that prefers interactions within horizontal layers. Noise and delays are inherent to the communication and decisions of all moving agents. Thus, next we investigate their effects on ordering in the model. First, we find that the amount of noise necessary for preventing the ordering of agents is not sufficient for destroying order. In other words, for realistic noise amplitudes the transition between order and disorder is rapid. Second, we demonstrate that ordering is more sensitive to displacements caused by delayed interactions than to uncorrelated noise (random errors). Third, we find that with changing interaction delays the ordered state disappears at roughly the same rate, whereas it emerges with different rates. In summary, we find that the model discussed here is simple enough to allow a fair understanding of the modeled phenomena, yet sufficiently detailed for the description and management of large flocks with noisy and delayed interactions. Our code is available at http://github.com/fij/floc.

The primary aim was to investigate the role of underlying heart disease on preoperative NT-proBNP levels in patients admitted for adult cardiac surgery, after adjusting for the known confounders age, gender, obesity and renal function. The second aim was to investigate the predictive value of preoperative NT-proBNP with regard to severe postoperative heart failure (SPHF) and postoperative mortality.A retrospective cohort study based on preoperative NT-proBNP measurements in an unselected cohort including all patients undergoing first time surgery for coronary artery disease (CAD; n = 2226), aortic stenosis (AS; n = 406) or mitral regurgitation (MR; n = 346) from April 2010 to August 2016 in the southeast region of Sweden (n = 2978). Concomitant procedures were not included, with the exception of Maze or tricuspid valve procedures.Preoperative NT-proBNP was 1.67 times (p

Sexuality is a physiological component of adolescent development, though early initiation is associated with reproductive health risk. This study aimed at identifying correlates and predictors of sexual initiation in a large multinational cohort of European adolescents.A questionnaire addressing socio-demographics, behaviours, mental health and sexual activity, was delivered to 11,110 adolescents recruited from 168 randomly selected schools in 10 European countries between 2009 and 2011. A follow-up questionnaire was delivered after 12 months. The longitudinal association of baseline risk behaviors, psychological attributes and contextual vulnerabilities, with sexual initiation during follow-up was evaluated through simple and multivariable age/sex stratified logistic regression. Multinomial logistic regression measured the association between predictors and sexual initiation with or without coexisting reproductive risk factors, such as multiple partners or infrequent condom use.Baseline sexual experience was reported by 19.2% of 10,757 respondents (median age 15; IQR 14-15; females 59.6%). This was significantly more frequent among pupils older than 15 (41%) and males (20.8%). Of 7,111 pupils without previous experience who were available at follow-up (response rate 81.8%), 17% reported sexual initiation, without differences between females and males. Baseline smoking (age/sex adjusted odds ratio [aOR] 3.63), alcohol use (aOR 2.95), illegal drugs use (aOR 2.72), and poor sleep (aOR 1.71) predicted sexual initiation. Stratified analyses showed a particularly strong association in case of younger and female pupils, and, among girls, when initiation was reported together with multiple partners and/or infrequent condom use. Externalizing (i.e. conduct and hyperactivity) symptoms independently predicted sexual initiation. Internalizing difficulties (i.e. emotional and peer problems) were negatively associated with early and risky sexual initiation among boys. Significant predictors included also being bullied, fighting, truancy, and low parental involvement.Adolescent sexual behaviours are related to non-sexual risk behaviours, psychological difficulties and contextual vulnerabilities. While gateway effects explain some associations, a comprehensive model is needed to understand adolescent sexual behaviours, their physical, mental, and social health outcomes, and their potential positive effects on wellbeing. Tailored interventions may need to consider younger girls as a particularly vulnerable group in view of a strong association between non-sexual and sexual behaviors.

Inflammatory bowel diseases (IBD) [Crohn's disease (CD) and ulcerative colitis (UC)], are chronic relapsing disorders of unknown etiology. The aim of this study was to determine demographic features, disease phenotypes, medical and surgical therapies in our IBD patients and to identify which parameters are in association with the need of surgery and/or biologic therapy. Data on demographic and clinical characteristics of the patients were analyzed from the IBD registry of the 1st Department of Medicine, University of Szeged. The study period was between January 2007 and March 2015. Data of 911 IBD patients (428 CD, 483 UC) were analyzed. The median lag time between onset of symptoms and diagnosis proved to be significantly longer in UC than in CD (4.6 years vs. 2.1 years, p = 0.01). 40% of the patients received biological therapy, 301 patients underwent surgery required more frequently for CD than UC. Surgery was more common in CD patients with ileal location and penetrating behaviour. In UC, more severe disease onset predicted to unfavourable disease course. Higher proportion of surgery was shown in patient aged above 40 years in both CD and UC. Diagnostic delay of more than 1 year and appendectomy predicted to unfavourable disease outcome of both CD and UC. This analysis revealed that more than 1 year of diagnostic delay, disease activity at diagnosis in UC, CD, ileal location and penetrating behaviour are factors that may influence disease outcome. Use of thiopurines seemed to be protective in UC.

Barley chromosome 5H, carrying important QTLs for plant adaptation and tolerance to abiotic stresses, is extremely instable in the wheat genetic background and is eliminated in the early generations of wheat-barley crosses. A spontaneous wheat-barley 5HS-7DS.7DL translocation was previously obtained among the progenies of the Mv9kr1 x Igri hybrid. The present work reports on the transfer of the 5HS-7DS.7DL translocation into a modern wheat cultivar, Mv Bodri, in order to use it in the wheat breeding program. The comparison of the hybridization bands of DNA repeats HvT01, pTa71, (GAA)n and the barley centromere-specific (AGGGAG)n in Igri barley and the 5HS-7DS.7DL translocation, together with the visualization of the barley chromatin made it possible to determine the size of the introgressed barley segment, which was approximately 74% of the whole 5HS. Of the 29 newly developed PCR markers, whose source ESTs were selected from the Genome Zipper of barley chromosome 5H, 23 were mapped in the introgressed 1-0.26 FL 5HS bin, three were located in the missing C-0.26 FL region, while three markers were specific for 5HL. The translocation breakpoint was flanked by markers Hv7502 and Hv3949. A comparison of the parental wheat cultivars and the wheat-barley introgression lines indicated that the presence of the translocation improved tillering ability in the Mv9kr1 and Mv Bodri genetic background. The similar or better yield components under high- or low-input cultivation environments, respectively, indicated that the 5HS-7DS.7DL translocation had little or no negative effect on yield components, making it a promising genotype to improve wheat genetic diversity. These results promise to accelerate functional genomic studies on barley chromosome 5H and to support pre-breeding and breeding research on wheat.

Long intervening non-coding RNAs (lincRNAs) are increasingly being implicated as important factors in many aspects of cellular development, function, and disease, but remain poorly understood. In this study, we examine the human retinal pigment epithelium (RPE) lincRNA transcriptome using RNA-Seq data generated from human fetal RPE (fRPE), RPE derived from human induced pluripotent stem cells (iPS-RPE), and undifferentiated iPS (iPS). In addition, we determine the suitability of iPS-RPE, from a transcriptome standpoint, as a model for use in future studies of lincRNA structure and function. A comparison of gene and isoform expression across the whole transcriptome shows only minimal differences between all sample types, though fRPE and iPS-RPE show higher concordance than either shows with iPS. Notably, RPE signature genes show the highest degree of fRPE to iPS-RPE concordance, indicating that iPS-RPE cells provide a suitable model for use in future studies. An analysis of lincRNAs demonstrates high concordance between fRPE and iPS-RPE, but low concordance between either RPE and iPS. While most lincRNAs are expressed at low levels (RPKM < 10), there is a high degree of concordance among replicates within each sample type, suggesting the expression is consistent, even at levels subject to high variability. Finally, we identified and annotated 180 putative novel genes in the fRPE samples, a majority of which are also expressed in the iPS-RPE. Overall, this study represents the first characterization of lincRNA expression in the human RPE, and provides a model for studying the role lincRNAs play in RPE development, function, and disease.

Droplet digital PCR (ddPCR) is being advocated as a reference method to measure rare genomic targets. It has consistently been proven to be more sensitive and direct at discerning copy numbers of DNA than other quantitative methods. However, one of the largest obstacles to measuring microRNA (miRNA) using ddPCR is that reverse transcription efficiency depends upon the target, meaning small RNA nucleotide composition directly effects primer specificity in a manner that prevents traditional quantitation optimization strategies. Additionally, the use of reagents that are optimized for miRNA measurements using quantitative real-time PCR (qRT-PCR) appear to either cause false positive or false negative detection of certain targets when used with traditional ddPCR quantification methods. False readings are often related to using inadequate enzymes, primers and probes. Given that two-step miRNA quantification using ddPCR relies solely on reverse transcription and uses proprietary reagents previously optimized only for qRT-PCR, these barriers are substantial. Therefore, here we outline essential controls, optimization techniques, and an efficacy model to improve the quality of ddPCR miRNA measurements. We have applied two-step principles used for miRNA qRT-PCR measurements and leveraged the use of synthetic miRNA targets to evaluate ddPCR following cDNA synthesis with four different commercial kits. We have identified inefficiencies and limitations as well as proposed ways to circumvent identified obstacles. Lastly, we show that we can apply these criteria to a model system to confidently quantify miRNA copy number. Our measurement technique is a novel way to quantify specific miRNA copy number in a single sample, without using standard curves for individual experiments. Our methodology can be used for validation and control measurements, as well as a diagnostic technique that allows scientists, technicians, clinicians, and regulators to base miRNA measures on a single unit of measurement rather than a ratio of values.

Irritable bowel syndrome (IBS) and functional digestive tract disorders, e.g. functional bloating, carbohydrate maldigestion and intolerances, are very common disorders frequently causing significant symptoms that challenge health care systems. A low Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols (FODMAP) diet is one of the possible therapeutic approaches for decreasing abdominal symptoms and improving quality of life.We aimed to meta-analyze data on the therapeutic effect of a low-FODMAP diet on symptoms of IBS and quality of life and compare its effectiveness to a regular, standard IBS diet with high FODMAP content, using a common scoring system, the IBS Symptom Severity Score (IBS-SSS).A systematic literature search was conducted in PubMed, EMBASE and the Cochrane Library as well as in the references in a recent meta-analysis. Adult patients diagnosed with IBS according to the Rome II, Rome III, Rome IV or NICE criteria were included in the analysis.Mean differences with 95% confidence intervals were calculated from studies that contained means, standard deviation (SD) or mean differences and SD of differences and p-values. A random effect model was used because of the heterogeneity (Q test (χ2) and I2 indicator). A p-value of less than 0.05 was chosen to indicate a significant difference.The literature search yielded 902 publications, but only 10 were eligible for our meta-analysis. Both regular and low-FODMAP diets proved to be effective in IBS, but post-diet IBS-SSS values were significantly lower (p = 0.002) in the low-FODMAP group. The low-FODMAP diet showed a correlation with the improvement of general symptoms (by IBS-SSS) in patients with IBS.This meta-analysis provides high-grade evidence of an improved general symptom score among patients with irritable bowel syndrome who have maintained a low-FODMAP diet compared to those on a traditional IBS diet, therefore showing its superiority to regular IBS dietary therapy. These data suggest that a low-FODMAP diet with dietitian control can be a candidate for first-line therapeutic modality in IBS. Because of a lack of data, well-planned randomized controlled studies are needed to ascertain the correlation between improvement of separate key IBS symptoms and the effect of a low-FODMAP diet.

The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex.

Cone photoreceptors are required for color vision and high acuity vision, and they die in a variety of retinal degenerations, leading to irreversible vision loss and reduced quality of life. To date, there are no approved therapies that promote the health and survival of cones. The development of novel treatments targeting cones has been challenging and impeded, in part, by the limitations inherent in using common rodent model organisms, which are nocturnal and rod-dominant, to study cone biology. The African Nile grass rat (Arvicanthis ansorgei), a diurnal animal whose photoreceptor population is more than 30% cones, offers significant potential as a model organism for the study of cone development, biology, and degeneration. However, a significant limitation in using the A. ansorgei retina for molecular studies is that A. ansorgei does not have a sequenced genome or transcriptome. Here we present the first de novo assembled and functionally annotated transcriptome for A. ansorgei. We performed RNA sequencing for A. ansorgei whole retina to a depth of 321 million pairs of reads and assembled 400,584 Trinity transcripts. Transcriptome-wide analyses and annotations suggest that our data set confers nearly full length coverage for the majority of retinal transcripts. Our high quality annotated transcriptome is publicly available, and we hope it will facilitate wider usage of A. ansorgei as a model organism for molecular studies of cone biology and retinal degeneration.

BACKGROUND:Serum infliximab (IFX) and antibody-to-infliximab (ATI) levels are objective parameters, that may have a great role in the therapeutic decisions during maintenance biological therapy. RESEARCH DESIGN AND METHODS:48 inflammatory bowel disease patients receiving maintenance IFX therapy were prospectively enrolled and divided into adequate (complete remission N = 20) and inadequate responder (partial response, loss of response, dose escalation; N = 28) groups. Blood samples were collected just before (trough level, TL) and two (W2aTL) and six weeks (W6aTL) after the administration of IFX. RESULTS:Single measurement of ATI titer was insufficient for predicting therapeutic response due to transient expression of ATI, however, using the three points' measurements, significant difference has been detected between the adequate and inadequate responder group (5.0% vs 35.7%; p = 0.016). The mean value of TL was significantly higher in the adequate responder group (3.11±1.64 vs.1.19±1.11; p

Bladder cancer (BC) is a common malignancy of the urinary tract that has a higher frequency in men than in women. Cytostatic resistance and metastasis formation are significant risk factors in BC therapy; therefore, there is great interest in overcoming drug resistance and in initiating research for novel chemotherapeutic approaches. Here, we suggest that desethylamiodarone (DEA)-a metabolite of amiodarone-may have cytostatic potential. DEA activates the collapse of mitochondrial membrane potential (detected by JC-1 fluorescence), and induces cell death in T24 human transitional-cell bladder carcinoma cell line at physiologically achievable concentrations. DEA induces cell cycle arrest in the G0/G1 phase, which may contribute to the inhibition of cell proliferation, and shifts the Bax/Bcl-2 ratio to initiate apoptosis, induce AIF nuclear translocation, and activate PARP-1 cleavage and caspase-3 activation. The major cytoprotective kinases-ERK and Akt-are inhibited by DEA, which may contribute to its cell death-inducing effects. DEA also inhibits the expression of B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) and reduces colony formation of T24 bladder carcinoma cells, indicating its possible inhibitory effect on metastatic potential. These data show that DEA is a novel anti-cancer candidate of multiple cell death-inducing effects and metastatic potential. Our findings recommend further evaluation of its effects in clinical studies.

Successful curative treatment of severe pulmonary arterial hypertension with luminal obliteration will require a thorough understanding of the mechanism underlying the development and progression of pulmonary vascular lesions. But the cells that obliterate the pulmonary arterial lumen in severe pulmonary arterial hypertension are incompletely characterized. The goal of our study was to evaluate whether inhibition of CXC chemokine receptor 4 will prevent the accumulation of c-kit⁺ cells and severe pulmonary arterial hypertension. We detected c-kit⁺⁻ cells expressing endothelial (von Willebrand Factor) or smooth muscle cell/myofibroblast (α-smooth muscle actin) markers in pulmonary arterial lesions of SU5416/chronic hypoxia rats. We found increased expression of CXC chemokine ligand 12 in the lung tissue of SU5416/chronic hypoxia rats. In our prevention study, AMD3100, an inhibitor of the CXC chemokine ligand 12 receptor, CXC chemokine receptor 4, only moderately decreased pulmonary arterial obliteration and pulmonary hypertension in SU5416/chronic hypoxia animals. AMD3100 treatment reduced the number of proliferating c-kit⁺ α-smooth muscle actin⁺ cells and pulmonary arterial muscularization and did not affect c-kit⁺ von Willebrand Factor⁺ cell numbers. Both c-kit⁺ cell types expressed CXC chemokine receptor 4. In conclusion, our data demonstrate that in the SU5416/chronic hypoxia model of severe pulmonary hypertension, the CXC chemokine receptor 4-expressing c-kit⁺ α-smooth muscle actin⁺ cells contribute to pulmonary arterial muscularization. In contrast, vascular lumen obliteration by c-kit⁺ von Willebrand Factor⁺ cells is largely independent of CXC chemokine receptor 4.

Cell therapy with recipient Tregs achieves engraftment of allogeneic bone marrow (BM) without the need for cytoreductive conditioning (i.e., without irradiation or cytotoxic drugs). Thereby mixed chimerism and transplantation tolerance are established in recipients conditioned solely with costimulation blockade and rapamycin. However, clinical translation would be substantially facilitated if Treg-stimulating pharmaceutical agents could be used instead of individualized cell therapy. Recently, it was shown that interleukin-2 (IL-2) complexed with a monoclonal antibody (mAb) (clone JES6-1A12) against IL-2 (IL-2 complexes) potently expands and activates Tregs in vivo. Therefore, we investigated whether IL-2 complexes can replace Treg therapy in a costimulation blockade-based and irradiation-free BM transplantation (BMT) model. Unexpectedly, the administration of IL-2 complexes at the time of BMT (instead of Tregs) failed to induce BM engraftment in non-irradiated recipients (0/6 with IL-2 complexes vs. 3/4 with Tregs, p0.05). CD8 T cells and NK cells of IL-2 complex-treated naïve mice showed an enhanced proliferative response towards donor antigens in vitro despite the marked expansion of Tregs. However, IL-2 complexes also expanded conventional CD4 T cells, CD8 T cells, NK cells, NKT cells and notably even B cells, albeit to a lesser extent. Notably, IL-2 complex expanded Tregs featured less potent suppressive functions than in vitro activated Tregs in terms of T cell suppression in vitro and BM engraftment in vivo. In conclusion, these data suggest that IL-2 complexes are less effective than recipient Tregs in promoting BM engraftment and in contrast actually trigger BM rejection, as their effect is not sufficiently restricted to Tregs but rather extends to several other lymphocyte populations.

This study was carried out to investigate protective effect of chlorogenic acid against lipopolysaccharide-induced inflammation and oxidative stress in intestinal epithelial cells. As a marker of inflammatory response, IL-6, IL-8, TNF-α mRNA and protein levels, furthermore, COX-2 mRNA level were followed up. Intracellular redox status and extracellular H2O2 level were also monitored by two fluorescent assays (DCFH-DA, Amplex Red). Moreover, the effect of gut microbiota metabolites in the above mentioned processes was taken into account in our model using Lactobacillus plantarum 2142 bacterial strain. Our data revealed that chlorogenic acid had significant lowering effect on the inflammatory response. Treatment with chlorogenic acid (25-50 μM) significantly decreased gene expression and concentration of proinflammatory cytokines IL-6 and IL-8 compared to LPS-treated cells. COX-2 and TNF-α mRNA levels were also reduced. Furthermore, chlorogenic acid reduced the level of reactive oxygen species in IPEC-J2 cells. Simultaneous application of chlorogenic acid and Lactobacillus plantarum 2142 supernatant resulted protective effect against LPS-induced inflammation and oxidative stress as well.

Multi-stability refers to the phenomenon of perception stochastically switching between possible interpretations of an unchanging stimulus. Despite considerable variability, individuals show stable idiosyncratic patterns of switching between alternative perceptions in the auditory streaming paradigm. We explored correlates of the individual switching patterns with executive functions, personality traits, and creativity. The main dimensions on which individual switching patterns differed from each other were identified using multidimensional scaling. Individuals with high scores on the dimension explaining the largest portion of the inter-individual variance switched more often between the alternative perceptions than those with low scores. They also perceived the most unusual interpretation more often, and experienced all perceptual alternatives with a shorter delay from stimulus onset. The ego-resiliency personality trait, which reflects a tendency for adaptive flexibility and experience seeking, was significantly positively related to this dimension. Taking these results together we suggest that this dimension may reflect the individual's tendency for exploring the auditory environment. Executive functions were significantly related to some of the variables describing global properties of the switching patterns, such as the average number of switches. Thus individual patterns of perceptual switching in the auditory streaming paradigm are related to some personality traits and executive functions.

Duchenne muscular dystrophy (DMD) is a fatal disease where over 90% of patients succumb to respiratory or cardiac failure. Sleep apnea and sleep disordered breathing (SDB) are noted in a plurality of DMD patients, and the resulting nocturnal episodic hypoxia (EH) cannot be ruled out as a contributing factor to cardiac and respiratory dysfunction. In this study, we investigated the impact of long-term episodic hypoxia, which mimics the cyclic hypoxia seen in sleep apnea, on cardiac and respiratory function in a murine model of DMD (mdx mice). Since the severity and prevalence of sleep apnea in DMD increases with age, we studied the impact of EH on young (6-month) and on older (18-month) mdx mice. Mice were either exposed for 12 weeks to EH (8 hours/day, 5 days/week) or to room air. We noted a significant increase in left ventricular (LV) dilatation (transthoracic echocardiography) on EH exposure in both age groups, but reduced LV contractility was seen only in 6-month old mice. With EH exposure, an increased fibrosis (hydroxyproline) was noted in both cardiac and diaphragm muscle in 18-month but not 6-month old mice. No significant change in relative diaphragm strength (in-vitro) was noted on EH exposure in 18-month old mice. In contrast, EH exposed 6-month old mice showed a significant increase in relative diaphragm strength. EH exposure did not result in any significant change in ventilatory parameters (barometric plethysmography) in awake 6-month old mdx mice. In contrast, 18-month old mdx mice showed considerable ventilatory dysfunction, consistent with reduced ventilatory reserve. Our findings highlight that sleep apnea impacts respiratory and cardiac function in muscular dystrophy, and that EH can have divergent effects on both systems. To our knowledge, this is the first comprehensive study to investigate the impact of EH on cardiac and respiratory function in mdx mice.

Biomedical investment trends in 2015 show a huge decrease of investment in gastroenterology. Since academic research usually provides the basis for industrial research and development (R&D), our aim was to understand research trends in the field of gastroenterology over the last 50 years and identify the most endangered areas.We searched for PubMed hits for gastrointestinal (GI) diseases for the 1965-2015 period. Overall, 1,554,325 articles were analyzed. Since pancreatology was identified as the most endangered field of research within gastroenterology, we carried out a detailed evaluation of research activity in pancreatology.In 1965, among the major benign GI disorders, 51.9% of the research was performed on hepatitis, 25.7% on pancreatitis, 21.7% on upper GI diseases and only 0.7% on the lower GI disorders. Half a century later, in 2015, research on hepatitis and upper GI diseases had not changed significantly; however, studies on pancreatitis had dropped to 10.7%, while work on the lower GI disorders had risen to 23.4%. With regard to the malignant disorders (including liver, gastric, colon, pancreatic and oesophageal cancer), no such large-scale changes were observed in the last 50 years. Detailed analyses revealed that besides the drop in research activity in pancreatitis, there are serious problems with the quality of the studies as well. Only 6.8% of clinical trials on pancreatitis were registered and only 5.5% of these registered trials were multicentre and multinational (more than five centres and nations), i.e., the kind that provides the highest level of impact and evidence level.There has been a clear drop in research activity in pancreatitis. New international networks and far more academic R&D activities should be established in order to find the first therapy specifically for acute pancreatitis.

In this study the effects of a new, highly selective sodium-calcium exchanger (NCX) inhibitor, ORM-10962 were investigated on cardiac NCX current, Ca2+ transients, cell shortening and in experimental arrhythmias. The level of selectivity of the novel inhibitor on several major transmembrane ion currents (L-type Ca2+ current, major repolarizing K+ currents, late Na+ current, Na+/K+ pump current) was also determined.Ion currents in single dog ventricular cells (cardiac myocytes; CM), and action potentials in dog cardiac multicellular preparations were recorded utilizing the whole-cell patch clamp and standard microelectrode techniques, respectively. Ca2+ transients and cell shortening were measured in fluorescent dye loaded isolated dog myocytes. Antiarrhythmic effects of ORM-10962 were studied in anesthetized ouabain (10 μg/kg/min i.v.) pretreated guinea pigs and in ischemia-reperfusion models (I/R) of anesthetized coronary artery occluded rats and Langendorff perfused guinea pigs hearts.ORM-10962 significantly reduced the inward/outward NCX currents with estimated EC50 values of 55/67 nM, respectively. The compound, even at a high concentration of 1 μM, did not modify significantly the magnitude of ICaL in CMs, neither had any apparent influence on the inward rectifier, transient outward, the rapid and slow components of the delayed rectifier potassium currents, the late and peak sodium and Na+/K+ pump currents. NCX inhibition exerted moderate positive inotropic effect under normal condition, negative inotropy when reverse, and further positive inotropic effect when forward mode was facilitated. In dog Purkinje fibres 1 μM ORM-10962 decreased the amplitude of digoxin induced delayed afterdepolarizations (DADs). Pre-treatment with 0.3 mg/kg ORM-10962 (i.v.) 10 min before starting ouabain infusion significantly delayed the development and recurrence of ventricular extrasystoles (by about 50%) or ventricular tachycardia (by about 30%) in anesthetized guinea pigs. On the contrary, ORM-10962 pre-treatment had no apparent influence on the time of onset or the severity of I/R induced arrhythmias in anesthetized rats and in Langendorff perfused guinea-pig hearts.The present study provides strong evidence for a high efficacy and selectivity of the NCX-inhibitory effect of ORM-10962. Selective NCX inhibition can exert positive as well as negative inotropic effect depending on the actual operation mode of NCX. Selective NCX blockade may contribute to the prevention of DAD based arrhythmogenesis, in vivo, however, its effect on I/R induced arrhythmias is still uncertain.

Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.

Ego-resiliency (ER) is a capacity that enables individuals to adapt to constantly changing environmental demands. The goal of our research was to identify components of Ego-resiliency, and to test the reliability and the structural and convergent validity of the refined version of the ER11 Ego-resiliency scale. In Study 1 we used a factor analytical approach to assess structural validity and to identify factors of Ego-resiliency. Comparing alternative factor-structures, a hierarchical model was chosen including three factors: Active Engagement with the World (AEW), Repertoire of Problem Solving Strategies (RPSS), and Integrated Performance under Stress (IPS). In Study 2, the convergent and divergent validity of the ER11 scale and its factors and their relationship with resilience were tested. The results suggested that resiliency is a double-faced construct, with one function to keep the personality system stable and intact, and the other function to adjust the personality system in an adaptive way to the dynamically changing environment. The stability function is represented by the RPSS and IPS components of ER. Their relationship pattern is similar to other constructs of resilience, e.g. the Revised Connor-Davidson Resilience Scale (R-CD-RISC). The flexibility function is represented by the unit of RPSS and AEW components. In Study 3 we tested ER11 on a Hungarian online representative sample and integrated the results in a model of general resiliency. This framework allows us to grasp both the stability-focused and the plasticity-focused nature of resiliency.

Ecological photopollution created by artificial night lighting can alter animal behavior and lead to population declines and biodiversity loss. Polarized light pollution is a second type of photopollution that triggers water-seeking insects to ovisposit on smooth and dark man-made objects, because they simulate the polarization signatures of natural water bodies. We document a case study of the interaction of these two forms of photopollution by conducting observations and experiments near a lamp-lit bridge over the river Danube that attracts mass swarms of the mayfly Ephoron virgo away from the river to oviposit on the asphalt road of the bridge. Millions of mayflies swarmed near bridge-lights for two weeks. We found these swarms to be composed of 99% adult females performing their upstream compensatory flight and were attracted upward toward unpolarized bridge-lamp light, and away from the horizontally polarized light trail of the river. Imaging polarimetry confirmed that the asphalt surface of the bridge was strongly and horizontally polarized, providing a supernormal ovipositional cue to Ephoron virgo, while other parts of the bridge were poor polarizers of lamplight. Collectively, we confirm that Ephoron virgo is independently attracted to both unpolarized and polarized light sources, that both types of photopollution are being produced at the bridge, and that spatial patterns of swarming and oviposition are consistent with evolved behaviors being triggered maladaptively by these two types of light pollution. We suggest solutions to bridge and lighting design that should prevent or mitigate the impacts of such scenarios in the future. The detrimental impacts of such scenarios may extend beyond Ephoron virgo.

Inflammation and altered immunity are recognized components of severe pulmonary arterial hypertension in human patients and in animal models of PAH. While eicosanoid metabolites of cyclooxygenase and lipoxygenase pathways have been identified in the lungs from pulmonary hypertensive animals their role in the pathogenesis of severe angioobliterative PAH has not been examined. Here we investigated whether a cyclooxygenase-2 (COX-2) inhibitor or diethylcarbamazine (DEC), that is known for its 5-lipoxygenase inhibiting and antioxidant actions, modify the development of PAH in the Sugen 5416/hypoxia (SuHx) rat model. The COX-2 inhibitor SC-58125 had little effect on the right ventricular pressure and did not prevent the development of pulmonary angioobliteration. In contrast, DEC blunted the muscularization of pulmonary arterioles and reduced the number of fully obliterated lung vessels. DEC treatment of SuHx rats, after the lung vascular disease had been established, reduced the degree of PAH, the number of obliterated arterioles and the degree of perivascular inflammation. We conclude that the non-specific anti-inflammatory drug DEC affects developing PAH and is partially effective once angioobliterative PAH has been established.

To evaluate the relevance of the individual components of the Valve Academic Research Consortium (VARC)-2 criteria for periprocedural myocardial infarction (MI) in transcatheter aortic valve implantation (TAVI). The association between biomarkers and adverse procedural outcome has been established. However, the additive prognostic importance of signs and symptoms are more uncertain.A total of 125 consecutive TAVI patients were prospectively included in this study. Biomarkers for MI were analyzed and signs and symptoms according to VARC-2 criteria were collected from clinical records.The criteria of elevated biomarkers and of signs or symptoms were found in 27 (22%) and 32 (26%) of the patients, respectively. According to VARC-2 definition, 12 (10%) had MI. VARC-2 definition of MI, Troponin T (TnT) > 600 ng/L, and presence of signs or symptoms correlated with 6 months mortality, prolonged ICU stay, elevation of N-terminal prohormone brain natriuretic peptide, and renal impairment. No signs or symptoms were found in 7 (44%) of the patients who fulfilled the criterion of elevated TnT > 600 ng/L. In the group with positive TnT criterion, there were no significant differences between those with and without signs or symptoms in respect to levels of TnT (1014 [585-1720] ng/L versus 704 [515-905] ng/L, p = 0.17) or creatine kinase-MB (36 [25-52] μg/L versus 29 [25-39] μg/L, p = 0.32). In the multivariate Cox regression analysis, TnT > 600 ng/L was the only significant independent variable associated with 6-months postprocedural mortality.Myocardial injury in TAVI, measured with biomarkers, correlates well with adverse procedural outcome. In this study it is also the strongest predictor for early postprocedural mortality. The additional requirement of signs or symptoms for the diagnosis of MI results in omission of a considerable number of clinically significant MI.

To evaluate the diagnostic accuracy of IO-SE in comparison to IO-CEUS for the differentiation between malignant and benign liver lesions.In a retrospective diagnostic study IO-CEUS and SE examinations of 49 liver lesions were evaluated and compared to histopathological examinations. Ultrasound was performed using a multifrequency linear probe (6-9 MHz). The loops of CEUS were evaluated up to 5 min. The qualitative characterization of IO-SE was based on a color coding system (blue = hard, red = soft). Stiffness of all lesions was quantified by a specific scaling of 0-6 (0 = low, 6 = high) using 7 ROIs (2 central, 5 peripheral).All malignant lesions displayed a characteristic portal venous washout and could be diagnosed correctly by IO-CEUS. 3/5 benign lesions could not be characterized properly either by IO-CEUS or IO-SE prior to resection. Thus for IO-CEUS sensitivity, specificity, positive and negative predictive value and accuracy were 100%, 40%, 94%, 100% and 94%. Lesion sizes were between 8 and 59 mm in diameter. Regarding the IO-SE, malignant lesions showed a marked variability. In qualitative analysis, 31 of the malignant lesions were blue colored denoting overall induration. Thirteen malignant lesions showed an inhomogenous color pattern with partial indurations. Two of the benign lesions also displayed overall induration. The other benign lesions showed an inhomogenous color mapping. Calculated sensitivity of the SE was 70.5%, specificity 60%, PPV 94%, NPV 18.75%, and accuracy 69%.IO-CEUS is useful for localization and characterization of liver lesions prior to surgical resection whereas IO-SE provided correct characterization only for a limited number of lesions.

Copper is an important regulator of hypoxia inducible factor 1 alpha (HIF-1α) dependent vascular endothelial growth factor (VEGF) expression, and is also required for the activity of lysyl oxidase (LOX) to effect matrix protein cross-linking. Cell detachment from the extracellular matrix can induce apoptosis (anoikis) via inactivation of focal adhesion kinase (FAK).To examine the molecular mechanisms whereby copper depletion causes the destruction of the normal alveolar architecture via anoikis, Male Sprague-Dawley rats were fed a copper deficient diet for 6 weeks while being treated with the copper chelator, tetrathiomolybdate. Other groups of rats were treated with the inhibitor of auto-phosphorylation of FAK, 1,2,4,5-benzenetetraamine tetrahydrochloride (1,2,4,5-BT) or FAK small interfering RNA (siRNA).Copper depletion caused emphysematous changes, decreased HIF-1α activity, and downregulated VEGF expression in the rat lungs. Cleaved caspase-3, caspase-8 and Bcl-2 interacting mediator of cell death (Bim) expression was increased, and the phosphorylation of FAK was decreased in copper depleted rat lungs. Administration of 1,2,4,5-BT and FAK siRNA caused emphysematous lung destruction associated with increased expression of cleaved capase-3, caspase-8 and Bim.These data indicate that copper-dependent mechanisms contribute to the pathogenesis of emphysema, which may be associated with decreased HIF-1α and FAK activity in the lung.

Abnormal regulation of cell migration and altered rearrangement of cytoskeleton are characteristic of metastatic cells. The first described suppressor of metastatic processes is NM23-H1, which displays NDPK (nucleoside-diphosphate kinase) activity. To better understand the role of nm23 genes in cell migration, we investigated the function of NDK-1, the sole Caenorhabditis elegans homolog of group I NDPKs in distal tip cell (DTC) migration. Dorsal phase of DTC migration is regulated by integrin mediated signaling. We find that ndk-1 loss of function mutants show defects in this phase. Epistasis analysis using mutants of the α-integrin ina-1 and the downstream functioning motility-promoting signaling module (referred to as CED-10 pathway) placed NDK-1 downstream of CED-10/Rac. As DTC migration and engulfment of apoptotic corpses are analogous processes, both partially regulated by the CED-10 pathway, we investigated defects of apoptosis in ndk-1 mutants. Embryos and germ cells defective for NDK-1 showed an accumulation of apoptotic cell corpses. Furthermore, NDK-1::GFP is expressed in gonadal sheath cells, specialized cells for engulfment and clearence of apoptotic corpses in germ line, which indicates a role for NDK-1 in apoptotic corpse removal. In addition to the CED-10 pathway, engulfment in the worm is also mediated by the CED-1 pathway. abl-1/Abl and abi-1/Abi, which function in parallel to both CED-10/CED-1 pathways, also regulate engulfment and DTC migration. ndk-1(-);abi-1(-) double mutant embryos display an additive phenotype (e. g. enhanced number of apoptotic corpses) which suggests that ndk-1 acts in parallel to abi-1. Corpse number in ndk-1(-);ced-10(-) double mutants, however, is similar to ced-10(-) single mutants, suggesting that ndk-1 acts downstream of ced-10 during engulfment. In addition, NDK-1 shows a genetic interaction with DYN-1/dynamin, a downstream component of the CED-1 pathway. In summary, we propose that NDK-1/NDPK might represent a converging point of CED-10 and CED-1 pathways in the process of cytoskeleton rearrangement.

The T-cell immunoglobulin and mucin domain (TIM) family is a relatively newly described group of molecules with a conserved structure and important immunological functions. Identification of Galectin-9 as a ligand for TIM-3 has established the Galectin-9/TIM-3 pathway as an important negative regulator of Th1 immunity and tolerance induction. Data about the TIM-3/Gal-9 pathway in the pathogenesis of human diseases is emerging, but their possible role during human pregnancy is not precisely known. The aim of our study was to investigate the number, phenotype and functional activity of TIM-3+ peripheral blood mononuclear cells during healthy human pregnancy.57 healthy pregnant women [first trimester (n = 16); second trimester (n = 19); third trimester (n = 22)] and 30 non-pregnant controls were enrolled in the study. We measured the surface expression of TIM-3 by cytotoxic T cells, NK cells and NK cell subsets as well as Galectin-9 expression by regulatory T cells by flow cytometry. We analyzed the cytokine production and cytotoxicity of TIM3+ and TIM3- CD8 T and NK cells obtained from non-pregnant and healthy pregnant women at different stages of pregnancy by flow cytometry. Serum Galectin-9 levels were measured by ELISA.Our results show that the numbers of peripheral NK and cytotoxic T cells and their TIM-3 expression do not change between the first, second and third trimesters of pregnancy. Compared to non-pregnant individuals, regulatory T cells show higher level of Galectin-9 expression as pregnancy proceeds, which is in line with the level of Galectin-9 in the patients sera. Cytotoxic T cells, NK cells and NK cell subsets expressing TIM-3 molecule show altered cytokine production and cytotoxicity during pregnancy compared to non-pregnant individuals.Our results indicate that Galectin-9 expressing regulatory T cells, TIM-3+ cytotoxic T cells and NK cells could play an important role in the maintenance of healthy pregnancy.

Multispecies bacterial communities such as the microbiota of the gastrointestinal tract can be remarkably stable and resilient even though they consist of cells and species that compete for resources and also produce a large number of antimicrobial agents. Computational modeling suggests that horizontal transfer of resistance genes may greatly contribute to the formation of stable and diverse communities capable of protecting themselves with a battery of antimicrobial agents while preserving a varied metabolic repertoire of the constituent species. In other words horizontal transfer of resistance genes makes a community compatible in terms of exoproducts and capable to maintain a varied and mature metagenome. The same property may allow microbiota to protect a host organism, or if used as a microbial therapy, to purge pathogens and restore a protective environment.