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Bacterial infections are prevalent and the major cause of morbidity and mortality in cirrhosis. Activation of human Kupffer cells (HKCs) from livers is essential for human innate immunity. Cytosolic phospholipase A2 (cPLA2) plays a crucial role in the control and balance of innate immune and inflammatory reactions. Uncharacterized is the role of cPLA2 in HKC activation by bacterial infection. This work aimed to determine the function and mechanism of cPLA2 in gram-negative bacteria (GNB)-induced HKC activation. In this study, we found that Escherichia coli (E. coli)-induced activation of HKCs led to a rise in cPLA2 mRNA and protein expression, where the ERK and NF-κB pathways were concurrently triggered. Luciferase activity of cPLA2' promoters, PLA2G4A promoters, was enhanced with the stimulation of E. coli or co-transfection with STAT3 or RelB in HKCs. E. coli massively boosted the binding activity of STAT3 and RelB to the specific regions of the PLA2G4A promoter as measured by ChIP-qPCR. The E. coli-ERK-STAT3 and E. coli-non-canonical NF-κB-RelB signaling axes were then identified using pathway inhibitors and transcription factors in the rescue experiments during E. coli-induced HKC activation. In conclusion, we discovered that cPLA2 is necessary for E. coli-induced HKC activation, and the underlying mechanism could be the transcriptional regulation of STAT3 and RelB on the PLA2G4A promoter following the ERK and non-canonical NF-κB signaling activation, implying that the regulation of cPLA2 expression via the E. coli-ERK/non-canonical NF-κB-STAT3/RelB signaling axis could be effective for controlling GNB-induced HKC activation in cirrhotic patients. [ABSTRACT FROM AUTHOR]

Mongolian nomadic herders traditionally pass on ecological knowledge intergenerationally, mainly within families. However, little is known about how current societal transformation processes may impact the application and transfer of traditional ecological knowledge (TEK) amongst herders. Combining quantitative household survey data with qualitative interviews, we show that TEK is still widely applied amongst herders. Our data show that households living under conditions of greater societal transformation apply TEK more often in order to adapt to the situation than households under lower transformation pressure. High transformation pressure goes along with high human population and livestock density and thus competition for good pastureland. In addition, our results show that intragenerational knowledge transfer between families is gaining more importance nowadays. For Mongolia, we recommend facilitating access to and strengthening the exchange of TEK to prepare herders for the future due to the high level of uncertainty accompanying societal transformations. [ABSTRACT FROM AUTHOR]

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Ensuring an adequate supply of physicians is paramount in securing the future of healthcare. To do so, accurate physician workforce predictions are needed to inform policymakers. However, the United States lacks such predictions from reliable sources. Several non-governmental organizations have actively been involved in attempting to quantify workforce needs, but they often employ opaque methodologies and are deeply conflicted, leading to potentially unreliable or biased results. Moreover, while federal and state entities invest approximately $15 billion annually in graduate medical education (GME) payments, they have very little control over how the funding is used to shape the future physician workforce. In this article, we review physician workforce predictions from both an international and a domestic perspective and finally discuss how the creation of an apolitical, data-driven, expert-led panel at the federal level with sufficient authority to influence broader workforce policy is the optimal solution for ensuring an adequate supply of physicians for generations to come. [ABSTRACT FROM AUTHOR]

This article summarises the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organised by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: (1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g. genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomisation in humans; (2) the highly individualised nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; (3) because single time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and (4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal. [ABSTRACT FROM AUTHOR]

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Acetylcarnitine is an essential metabolite for maintaining metabolic flexibility and glucose homeostasis. The in vivo behavior of muscle acetylcarnitine content during exercise has not been shown with magnetic resonance spectroscopy. Therefore, this study aimed to explore the behavior of skeletal muscle acetylcarnitine during rest, plantar flexion exercise, and recovery in the human gastrocnemius muscle under aerobic conditions. Ten lean volunteers and nine overweight volunteers participated in the study. A 7 T whole-body MR system with a double-tuned surface coil was used to acquire spectra from the gastrocnemius medialis. An MR-compatible ergometer was used for the plantar flexion exercise. Semi-LASER-localized 1H MR spectra and slab-localized 31P MR spectra were acquired simultaneously in one interleaved exercise/recovery session. The time-resolved interleaved 1H/31P MRS acquisition yielded excellent data quality. A between-group difference in acetylcarnitine metabolism over time was detected. Significantly slower τPCr recovery, τPCr on-kinetics, and lower Qmax in the overweight group, compared to the lean group was found. Linear relations between τPCr on-kinetics, τPCr recovery, VO2max and acetylcarnitine content were identified. In conclusion, we are the first to show in vivo changes of skeletal muscle acetylcarnitine during acute exercise and immediate exercise recovery with a submaximal aerobic workload using interleaved 1H/31P MRS at 7 T. [ABSTRACT FROM AUTHOR]

Remote health monitoring (RHM) provides various benefits to older adults, but its use is still limited. Remote monitoring may help in avoiding emergencies and prolong users' independence. To understand how to design systems which support older adults, we studied a large-scale remote health monitoring system. The system used fitness-grade smartwatches to monitor the vital signs of more than 2000 users constantly. To probe the lived experience of using RHM, we conducted an explorative interview study (N = 41) with operators, carers, and users of the RHM system. Our thematic analysis reveals that personalisation of care ecology is crucial for developing users' confidence and trust in the system. We found that participation in RHM may catalyse positive changes in older adults' lifestyles. Based on our findings, we formulate five recommendations for designing future health monitoring systems. Our work contributes to insights into the lived experience and stakeholder ecology of health monitoring systems. [ABSTRACT FROM AUTHOR]

Purpose: Immunotherapies have largely failed as treatment options for pancreatic ductal adenocarcinoma (PDAC). In this field, clinical translational studies into personalized treatment are of fundamental importance. In our study, we model tumor-cell immune-cell interactions in a co-culture of primary human PDAC organoids and matched peripheral blood mononuclear cells (PBMCs). Methods: Using flow cytometry, we evaluated changes in T cell subtypes upon co-culture of patient-derived PDAC organoids and matched PBMCs. Results: After co-culturing PDAC organoids with PBMCs, we observed changes in CD4+, CD8+ and Treg cell populations. We observed favorable clinical outcome in patients whose PBMCs reacted to the co-culture with organoids. Conclusion: This experimental model allows to investigate interactions between patient derived PDAC organoids and their PBMCs. This co-culture system could serve as a preclinical platform to guide personalized therapeutic strategies in the future. [ABSTRACT FROM AUTHOR]

Pancreatic injuries resulting from blunt abdominal trauma are uncommon but carry a high risk of morbidity and mortality for patients. Prompt diagnosis and management are critical to optimize patient outcomes. This review article provides an overview of the different types of pancreatic injuries and the various management strategies available, based on the severity of the injury. In unstable patients with a positive focused assessment with sonography for trauma (FAST), immediate trauma laparotomy is required. Stable patients should be assessed with contrast-enhanced computed tomography (CT) imaging. Low-grade injuries can be managed with irrigation and drainage. In cases of left-sided ductal injury below the level of the portal vein, left-sided pancreatic resection is often necessary. Higher grade injuries to the pancreatic head need to be evaluated in the context of other accompanying injuries, where damage control may be required. Pancreaticoduodenectomy is a rare intervention and is usually only required in the later course in these cases. [ABSTRACT FROM AUTHOR]

Key summary points: Aim: Can phase angle represents an additional parameter for quantifying sarcopenia among German nursing home residents? Findings: There is a limitation of the phase angle in differentiating between "confirmed/ severe sarcopenia" with "no sarcopenia" and "probable sarcopenia" groups among multimorbid nursing home residents in Germany. Message: Bioelectrical impedance analysis and determination of phase angle represent chances in the diagnostic of sarcopenia, but there is a limitation for differentiation in preliminary stage of sarcopenia among multimorbid NH residents. Purpose: Sarcopenia is characterized by the loss of muscle mass, strength, and physical functioning. The bioelectrical impedance analysis (BIA) is a simplify method for the measurement of muscle quantity and quality. But there is a lack of evidence in the interpretation of the muscle quality parameter phase angle (PhA), which was recommended by the European Working Group on Sarcopenia in Older People 2 (EWGSOP2). We hypothesize that the PhA shows differences between sarcopenia categorized groups and can be used as an additional parameter for sarcopenia quantification among residents of nursing homes (NH). Methods: Based on EWGSOP2 specifications, 78 residents from five German NH was categorized into sarcopenia groups. Group comparisons with Kruskal–Wallis tests, Dunn–Bonferroni post-hoc-Tests, and correlations with Spearman coefficients were conducted with the muscle quality parameter PhA. Results: Significant group differences by Kruskal–Wallis test for PhA was detected (H = 8.150, p = 0.017). The Dunn–Bonferroni post-hoc-Test showed significant results by group comparison for "confirmed/ severe sarcopenia" (4.1° [3.1–5.0]) with "no sarcopenia" (4.6° [3.7–11.2]; p =0.049) and "probable sarcopenia" (4.7° [3.4–13.5]; p = 0.016), respectively. Conclusions: There is a limitation for differentiation in preliminary stage of sarcopenia among multimorbid NH residents by PhA. Moreover, further research for specific cut-off-values and the individual sarcopenia progression monitoring by PhA are needed. Trial registration: No. AZ A2.5.4-096_aa (Date of approval: July 2019). [ABSTRACT FROM AUTHOR]

Purpose: Surgery and radiotherapy as part of breast cancer treatment can lead to lymphoedema of the upper extremities (breast cancer-related lymphoedema = BCRL) and reduce the quality of life (health-related quality of life = HRQoL). The aim of the present study was to investigate the influence of paddling in a dragon boat (PP) on HRQoL and BCRL in breast cancer survivors (BCS). Methods: Between April and October 2017, a prospective case–control study evaluated the effects of PP compared to a control group. In the paddle group (n = 28), weekly arm circumference measurements were taken at four defined anatomic areas of the arm before and after training; in the control group (n = 70), the measurements were taken once a month. At the beginning and end of the study, questionnaires from both groups (SF 36, EORTC QLQ C30) were evaluated to understand the differences in HRQoL. Results: The paddle group started with a higher HRQoL compared to the control group. Most interesting, whether the affected or unaffected arm, whether before or after training—the arm circumference decreased over time in the paddling group. A pre-existing lymphoedema was not negatively influenced by paddling. In the paddle group, the physical health was constant over the season, while the physical health of the control group decreased significantly over time. Conclusion: PP in a dragon boat does not lead to the development or worsening of pre-existing lymphoedema due to breast cancer therapy, and seems to have a positive effect on the quality of life. [ABSTRACT FROM AUTHOR]

Background: The formation of neutrophil extracellular traps (NETs) was initially discovered as a novel immune response against pathogens. Recent studies have also suggested that NETs play an important role in tumor progression. This review summarizes the cellular mechanisms by which NETs promote distant metastasis and discusses the possible clinical applications targeting NETs. Method: The relevant literature from PubMed and Google Scholar (2001–2021) have been reviewed for this article. Results: The presence of NETs has been detected in various primary tumors and metastatic sites. NET-associated interactions have been observed throughout the different stages of metastasis, including initial tumor cell detachment, intravasation and extravasation, the survival of circulating tumor cells, the settlement and the growth of metastatic tumor cells. Several in vitro and in vivo studies proved that inhibiting NET formation resulted in anti-cancer effects. The biosafety and efficacy of some NET inhibitors have also been demonstrated in early phase clinical trials. Conclusions: Considering the role of NETs in tumor progression, NETs could be a promising diagnostic and therapeutic target for cancer management. However, current evidence is mostly derived from experimental models and as such more clinical studies are still needed to verify the clinical significance of NETs in oncological settings. [ABSTRACT FROM AUTHOR]

Technological Pedagogical Content Knowledge (TPACK) describes a significant qualification for teachers and pre-service teachers to address the integration of contemporary technological advancements into lessons that adequately reflect the subject matter for a diverse set of students. Various methods and models have been identified to develop and evaluate the TPACK of teachers and pre-service teachers. This case study aimed to enrich and deepen the descriptors of the Niess (2013) model to better assist pre-service mathematics teacher educators as they redesign their teacher education programs for developing the TPACK needed in this digital age. Data were collected from semi-structured interview forms, lesson plans, micro teaching experiences, and interviews. The study group comprised seven volunteer mathematics pre-service teachers in the final term of their undergraduate education program. Analysis of the data generated a revised model to guide the TPACK development of pre-service mathematics teachers. [ABSTRACT FROM AUTHOR]

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Purpose: Posthepatectomy liver failure (PHLF) remains a leading cause of death after extensive liver resection. Apart from the size and function of the remaining liver remnant, the development of postresection portal hypertension (pHT) plays a crucial role in the development of PHLF. We hypothesize that the umbilical vein in the preserved round ligament (RL) may recanalize in response to new-onset pHT after extended hepatectomy, thus providing a natural portosystemic shunt. Methods: In this exploratory study, RL was preserved in 10 consecutive patients undergoing major liver resection. Postoperative imaging was pursued to obtain evidence of reopened umbilical vein in the RL. The postoperative course, including the occurrence of PHLF, as well as the rate of procedure-specific complications were recorded. Results: None of the 10 cases presented with an adverse event due to preservation of the RL. In 6 cases, postoperative imaging demonstrated reopening of the umbilical vein with hepatofugal flow in the RL. The rates of procedure-related surgical complications were lower than would be expected in this population; in particular, the rate of occurrence of PHLF as defined by the International Study Group of Liver Surgery (ISGLS) was low. Conclusion: Our results support the theoretical concept of portosystemic pressure relief via a preserved umbilical vein after major liver surgery. As preservation of the RL is easily done, we suggest keeping it intact in extended hepatectomy cases and in patients with preexistent pHT. [ABSTRACT FROM AUTHOR]

Sudden cardiac death (SCD) in adolescents and young adults may be the first manifestation of an inherited arrhythmic syndrome. Thus identification of a genetic origin in sudden death cases deemed inconclusive after a comprehensive autopsy and may help to reduce the risk of lethal episodes in the remaining family. Using next-generation sequencing (NGS), a large number of variants of unknown significance (VUS) are detected. In the majority of cases, there is insufficient evidence of pathogenicity, representing a huge dilemma in current genetic investigations. Misinterpretation of such variants may lead to inaccurate genetic diagnoses and/or the adoption of unnecessary and/or inappropriate therapeutic approaches. In our study, we applied current (ACMG) recommendations for variant classification in post-mortem genetic screening of a cohort of 56 SCD victims. We identified a total 53 rare protein-altering variants (MAF < 0.2%) classified as VUS or worse. Twelve percent of the cases exhibited a clinically actionable variant (pathogenic, likely pathogenic or VUS – potentially pathogenic) that would warrant cascade genetic screening in relatives. Most of the variants detected by means of the post-mortem genetic investigations were VUS. Thus, genetic testing by itself might be fairly meaningless without supporting background data. This data reinforces the need for an experienced multidisciplinary team for obtaining reliable and accountable interpretations of variant significance for elucidating potential causes for SCDs in the young. This enables the early identification of relatives at risk or excludes family members as genetic carriers. Also, development of adequate forensic guidelines to enable appropriate interpretation of rare genetic variants is fundamental. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate computed tomography fractional flow reserve (FFRCT) values in distal parts of the coronaries in an asymptomatic cohort of marathon runners without any coronary stenosis for potentially false-positive values. Methods: Ninety-eight asymptomatic male marathon runners (age 53 ± 7 years) were enrolled in a prospective monocentric study and underwent coronary computed tomography angiography (CCTA). CCTA data were analyzed for visual coronary artery stenosis. FFRCT was evaluated in 59 participants without coronary artery stenosis in proximal, mid, and distal coronary sections using an on-site software prototype. Results: In participants without coronary artery stenosis, abnormal FFRCT values ≤ 0.8 in distal segments were found in 22 participants (37%); in 19 participants in the LAD; in 5 participants in the LCX; and in 4 participants in the RCA. Vessel diameters in participants with FFRCT values > 0.80 compared to ≤ 0.80 were 1.6 ± 0.3 mm versus 1.5 ± 0.3 mm for distal LAD (p = 0.025), 1.8 ± 0.3 mm versus 1.6 ± 0.5 mm for distal LCX (p = 0.183), and 2.0 ± 0.4 mm versus 1.5 ± 0.2 mm for distal RCA (p < 0.001). Conclusions: Abnormal FFRCT values of ≤ 0.8 frequently occurred in distal coronary segments in subjects without any anatomical coronary artery stenosis. This effect is only to some degree explainable by small distal vessel diameters. Therefore, the validity of hemodynamic relevance evaluation using FFRCT in distal coronary artery segment stenosis is reduced. Key Points: • Abnormal FFRCT values (≤ 0.8) occurred in over a third of the subjects in the distal LAD despite the absence of coronary artery stenosis.. • Therefore, the validity of hemodynamic relevance evaluation in distal coronary artery segment stenosis is reduced. • Decision-making based on abnormal FFRCT values in distal vessel sections should be performed with caution and only in combination with visual assessment of the grade of stenosis.. [ABSTRACT FROM AUTHOR]

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Purpose: We investigated the cardiovascular individual response to 6 weeks (3×/week) of work-matched within the severe-intensity domain (high-intensity interval training, HIIT) or moderate-intensity domain (moderate-intensity continuous training, MICT). In addition, we analyzed the cardiovascular factors at baseline underlying the response variability.Methods: 42 healthy sedentary participants were randomly assigned to HIIT or MICT. We applied the region of practical equivalence-method for identifying the levels of responders to the maximal oxygen uptake (V̇O2max) response. For investigating the influence of cardiovascular markers, we trained a Bayesian machine learning model on cardiovascular markers.Results: Despite that HIIT and MICT induced significant increases in V̇O2max, HIIT had greater improvements than MICT (p < 0.001). Greater variability was observed in MICT, with approximately 50% classified as "non-responder" and "undecided". 20 "responders", one "undecided" and no "non-responders" were observed in HIIT. The variability in the ∆V̇O2max was associated with initial cardiorespiratory fitness, arterial stiffness, and left-ventricular (LV) mass and LV end-diastolic diameter in HIIT; whereas, microvascular responsiveness and right-ventricular (RV) excursion velocity showed a significant association in MICT.Conclusion: Our findings highlight the critical influence of exercise-intensity domains and biological variability on the individual V̇O2max response. The incidence of "non-responders" in MICT was one third of the group; whereas, no "non-responders" were observed in HIIT. The incidence of "responders" was 11 out of 21 participants in MICT, and 20 out of 21 participants in HIIT. The response in HIIT showed associations with baseline fitness, arterial stiffness, and LV-morphology; whereas, it was associated with RV systolic function in MICT. [ABSTRACT FROM AUTHOR]

Humans with the metabolic syndrome and type 2 diabetes have an altered gut microbiome. Emerging evidence indicates that it is not only the microorganisms and their structural components, but also their metabolites that influences the host and contributes to the development of the metabolic syndrome and type 2 diabetes. Here, we discuss some of the mechanisms underlying how microbial metabolites are recognised by the host or are further processed endogenously in the context of type 2 diabetes. We discuss the possibility that gut-derived microbial metabolites fuel the development of the metabolic syndrome and type 2 diabetes. [ABSTRACT FROM AUTHOR]

In murine models, the expression of inducible nitric oxide synthase (iNOS) in myocardial infarction (MI) has been reported to be the result of tissue injury and inflammation. In the present study, mRNA expression of iNOS, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was investigated in postmortem human infarction hearts. Since HIF-1α is the inducible subunit of the transcription factor HIF-1, which regulates transcription of iNOS and VEGF, the interrelation between the three genes was observed, to examine the molecular processes during the emergence of MI. iNOS and VEGF mRNAs were found to be significantly upregulated in the affected regions of MI hearts in comparison to healthy controls. Upregulation of HIF-1α was also present but not significant. Correlation analysis of the three genes indicated a stronger and significant correlation between HIF-1α and iNOS mRNAs than between HIF-1α and VEGF. The results of the study revealed differences in the expression patterns of HIF-1 downstream targets. The stronger transcription of iNOS by HIF-1 in the affected regions of MI hearts may represent a pathological process, since no correlation of iNOS and HIF-1α mRNA was found in non-affected areas of MI hearts. Oxidative stress is considered to cause molecular changes in MI, leading to increased iNOS expression. Therefore, it may also represent a forensic marker for detection of early changes in heart tissue. [ABSTRACT FROM AUTHOR]

Mongolian spots (MS) are congenital dermal conditions resulting from neural crest-derived melanocytes migration to the skin during embryogenesis. MS incidences are highly variable in different populations. Morphologically, MS present as hyperpigmented maculae of varying size and form, ranging from round spots of 1 cm in diameter to extensive discolorations covering predominantly the lower back and buttocks. Due to their coloring, which is also dependent on the skin type, MS may mimic hematoma thus posing a challenge on the physician conducting examinations of children in cases of suspected child abuse. In the present study, MS incidences and distribution, as well as skin types, were documented in a collective of 253 children examined on the basis of suspected child abuse. From these data, a classification scheme was derived to document MS and to help identify cases with a need for recurrent examination for unambiguous interpretation of initial findings alongside the main decisive factors for re-examination such as general circumstances of the initial examination (e. g., experience of the examiner, lighting conditions) and given dermatological conditions of the patient (e. g., diaper rash). [ABSTRACT FROM AUTHOR]

Increased inducible nitric oxide synthase (iNOS) expression has been reported in heart failure, cardiomyopathies, and arteriosclerosis. iNOS is expressed in the heart upon inflammatory stimuli and produces excessive amounts of nitric oxide (NO). The overproduction of NO is cytotoxic and involved in cardiovascular diseases. Furthermore, iNOS produces superoxide anion which proceeds with NO to the harmful oxidant peroxynitrite, causing oxidative stress in the heart. The aim of the study was to gain new insights into the role of iNOS in human myocardial infarction (MI) and its contribution to oxidative stress in the heart. Furthermore, we investigated the unaffected myocardium of the infarction hearts, to study if iNOS expression is increased, probably as an indicator for oxidative stress. Our results show a significant increase (p = 0.013) of the iNOS expression in the affected regions of MI hearts (n = 9) in comparison with healthy control hearts (n = 4). In the unaffected regions of MI hearts, an increase in the iNOS expression in some samples was found as well. Our study demonstrated the direct detection of iNOS mRNA in human myocardial tissue. The balance between beneficial and deleterious effects of iNOS may be particularly influenced by the presence or absence of concurrent oxidative stress. [ABSTRACT FROM AUTHOR]

Physical activity and sports play major roles in the overall health status of humans. It is well known that regular exercise helps to lower the risk for a broad variety of health problems, such as cardiovascular disease, type 2 diabetes, and cancer. Being physically active induces a wide variety of molecular adaptations, for example fiber type switches or other metabolic alterations, in skeletal muscle tissue. These adaptations are based on exercise-induced changes to the skeletal muscle transcriptome. Understanding their nature is crucial to improve the development of exercise-based therapeutic strategies. Recent research indicates that specifically epigenetic mechanisms, i.e., pathways that induce changes in gene expression patterns without altering the DNA base sequence, might play a major role in controlling skeletal muscle transcriptional patterns. Epigenetic mechanisms include DNA and histone modifications, as well as expression of specific microRNAs. They can be modulated by environmental factors or external stimuli, such as exercise, and eventually induce specific and fine-tuned changes to the transcriptional response. In this review, we highlight current knowledge on epigenetic changes induced in exercising skeletal muscle, their target genes, and resulting phenotypic changes. In addition, we raise the question of whether epigenetic modifications might serve as markers for the design and management of optimized and individualized training protocols, as prognostic tools to predict training adaptation, or even as targets for the design of "exercise mimics". [ABSTRACT FROM AUTHOR]

Dietary administration of orotic acid (OA), an intermediate in the pyrimidine biosynthetic pathway, is considered to provide a wide range of beneficial effects, including cardioprotection and exercise adaptation. Its mechanisms of action, when applied extracellularly, however, are barely understood. In this study, we evaluated potential effects of OA on skeletal muscle using an in vitro contraction model of electrically pulse-stimulated (EPS) C2C12 myotubes. By analyzing a subset of genes representing inflammatory, metabolic, and structural adaptation pathways, we could show that OA supplementation diminishes the EPS-provoked expression of inflammatory transcripts (interleukin 6, Il6; chemokine (C-X-C Motif) ligand 5, Cxcl5), and attenuated transcript levels of nuclear receptor subfamily 4 group A member 3 (Nr4A3), early growth response 1 (Egr1), activating transcription factor 3 (Atf3), and fast-oxidative MyHC-IIA isoform (Myh2). By contrast, OA had no suppressive effect on the pathogen-provoked inflammatory gene response in skeletal muscle cells, as demonstrated by stimulation of C2C12 myotubes with bacterial LPS. In addition, we observed a suppressive effect of OA on EPS-induced phosphorylation of AMP-activated protein kinase (AMPK), whereas EPS-triggered phosphorylation/activation of the mammalian target of rapamycin (mTOR) was not affected. Finally, we demonstrate that OA positively influences glycogen levels in EP-stimulated myotubes. Taken together, our results suggest that in skeletal muscle cells, OA modulates both the inflammatory and the metabolic reaction provoked by acute contraction. These results might have important clinical implications, specifically in cardiovascular and exercise medicine. [ABSTRACT FROM AUTHOR]

Our preliminary studies identified a small population side population (SP) cells in pancreatic cancer cells with stem cell-like properties, which were able to induce fast and aggressive tumor formation in nude mice. Gene expression analysis showed a significant difference in the expression of more than 1,300 genes in SP cells, among which a highly significant difference in microRNA expression of miR-21 and miR-221 between SP and NSP cells was identified. SP cells were identified and characterized by flow cytometry using Hoechst 33342 dye staining from a highly metastatic human pancreatic cancer cell line (L3.6pl). Antagomir transfection was performed using miRNA-21 and miRNA-221 antisense oligonucleotides (ASOs) and followed by detection of cell apoptosis, cell cycle progression, chemosensitivity, and invasion. Sorted SP cells from gemcitabine-resistant L3.6pl cells (L3.6pl(Gres)-SP) cells were orthotopically implanted in nude mice with or without miRNA-21 and miRNA-221 ASOs mono- and combination therapy. The administration of antagomir-21 and antagomir-221 significantly reduced the SP cell fraction, decreased SP cell differentiation, and downstream gene regulation, and thereby induced reduction of L3.6pl cell proliferation, invasion, and chemoresistance against gemcitabine and 5-Fluorouracil. Combination of ASOs therapy against miRNA-21 and miRNA-221 significantly inhibited primary tumor growth and metastasis compared to single antagomir treatment, especially, in L3.6plGres-SP-induced pancreatic tumor growth in vivo. These findings further indicate that the inhibition of miR-21 and miR-221 appear particularly suitable to target stem-like subpopulations and address their specific biological function to promote tumor progression in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Interleukin IL26 supports killing of microbes and the innate sensing of bacterial-derived DNA (bactDNA). We evaluated the relationship between IL26 serum levels and bactDNA translocation in Crohn's disease (CD). We ran a prospective study on CD patients in remission. IL26 common polymorphisms, serum cytokines and complement protein, amplified-bactDNA, and anti-TNF-α were evaluated. In vitro PBMC analysis was performed. Three hundred and thirteen patients were included (mean CDAI: 83.6 ± 32.8; mean fecal calprotectin: 55.4 ± 35.3 μg/g). A total of 106 patients (33.8%) showed bactDNA and 223 patients (71%) had a var IL26 genotype. BactDNA significantly correlated with increased IL26 levels compared with bactDNA-negative patients. PBMCs from var IL26 patients significantly reduced E. coli killing capacity compared with wt IL26-genotyped patients. The stimulation with a recombinant IL26 protein reduced pro-inflammatory cytokines in response to E. coli in the var IL26 cell supernatants. Serum anti-TNF-α levels in var IL26 vs wtIL26-genotyped patients on biologics were significantly lower in the presence of bactDNA. Cells from var IL26 vs wt IL26-genotyped patients cultured with E. coli DNA and infliximab showed a significant decrease in free anti-TNF-α concentration. A var IL26 genotype was associated with the initiation of anti-TNF-α in CD patients during the 6-month follow-up. IL26 polymorphisms may prevent bactDNA clearance and identify CD patients with a worse inflammatory evolution and response to therapy. Key messages: [ABSTRACT FROM AUTHOR]

Purpose: Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) gene from IFITs family is one gene among hundreds of IFN-stimulated genes. The potential role of IFIT3 in cancer is scarcely understood. In addition, the clinical relevance of IFIT3 is not yet known in pancreatic ductal adenocarcinoma (PDAC). We evaluated the prognostic significance of this gene in PDAC patients. Methods: The expression of IFIT3 was analyzed in pancreatic cancer cell lines with different metastatic potential (FG and L3.6pl) and one established gemcitabine resistant cell variant-L3.6plGres. Second, we analyzed the protein expression in tissue microarrays (TMA) from specimens of 254 radically resected patients with pancreatic adenocarcinoma. The prognostic relevance of IFIT3 was evaluated by the Kaplan-Meier and Cox regression analysis. Results: L3.6pl cells with an aggressive capacity showed a significant higher expression of IFIT3 as compared to FG cells. IFIT3 was accumulated in gemcitabine resistant cells. Overexpression of IFIT3 increased the resistance of apoptosis against gemcitabine treatment. Patients who had high expression of IFIT3 (32%) and received chemotherapy had a statistically significant reduced survival in multivariate analysis. Conclusions: High expression of IFIT3 enhances anti-apoptotic activity and chemotherapy resistance of PDAC cells. High expression of IFIT3 was independently correlated to shorter patients' survival and may serve as a prognostic marker. [ABSTRACT FROM AUTHOR]

The determination of the fundamental parameters of the Standard Model (and its extensions) is often limited by the presence of statistical and theoretical uncertainties. We present several models for the latter uncertainties (random, nuisance, external) in the frequentist framework, and we derive the corresponding p values. In the case of the nuisance approach where theoretical uncertainties are modeled as biases, we highlight the important, but arbitrary, issue of the range of variation chosen for the bias parameters. We introduce the concept of adaptive p value, which is obtained by adjusting the range of variation for the bias according to the significance considered, and which allows us to tackle metrology and exclusion tests with a single and well-defined unified tool, which exhibits interesting frequentist properties. We discuss how the determination of fundamental parameters is impacted by the model chosen for theoretical uncertainties, illustrating several issues with examples from quark flavor physics. [ABSTRACT FROM AUTHOR]

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Background: Interactive products for self-improvement (e.g., online trainings to reduce stress, fitness gadgets) have become increasingly popular among consumers and healthcare providers. In line with the idea of positive computing, these tools aim to support their users on their way to improved well-being and human flourishing. As an interdisciplinary domain, the design of self-improvement technologies requires psychological, technological, and design expertise. One needs to know how to support people in behavior change, and one needs to find ways to do this through technology design. However, as recent reviews show, the interlocking relationship between these disciplines is still improvable. Many existing technologies for self-improvement neglect psychological theory on behavior change, especially motivational factors are not sufficiently considered. To counteract this, we suggest a focus on the dialog and emerging communication between product and user, considering the self-improvement tool as an interactive coach and advisor. Methods: The present qualitative interview study (N = 18) explored the user experience of self-improvement technologies. A special focus was on the perceived dialog between tool and user, which we analyzed in terms of models from communication psychology. Results: Our findings show that users are sensible to the way the product 'speaks to them' and consider this as essential for their experience and successful change. Analysis revealed different communication styles of self-improvement tools (e.g., helpful-cooperative, rational-distanced, critical-aggressive), each linked to specific emotional consequences. Conclusions: These findings form one starting point for a more psychologically founded design of self-improvement technology. On a more general level, our approach aims to contribute to a better integration of psychological and technological knowledge, and in consequence, supporting users on their way to enhanced well-being. [ABSTRACT FROM AUTHOR]

Objectives: This study demonstrates the applicability of semi-LASER localized dynamic P MRS to deeper lying areas of the exercising human soleus muscle (SOL). The effect of accurate localization and high temporal resolution on data specificity is investigated. Materials and methods: To achieve high signal-to-noise ratio (SNR) at a temporal resolution of 6 s, a custom-built human calf coil array was used at 7T. The kinetics of phosphocreatine (PCr) and intracellular pH were quantified separately in SOL and gastrocnemius medialis (GM) muscle of nine volunteers, during rest, plantar flexion exercise, and recovery. Results: The average SNR of PCr at rest was $$64\pm 15$$ in SOL ( $$83\pm 12$$ in GM). End exercise PCr depletion in SOL ( $$19\pm 9$$ %) was far lower than in GM ( $$74\pm 14$$ %). The pH in SOL increased rapidly and, in contrast to GM, remained elevated until the end of exercise. Conclusion: P MRS in single-shots every 6 s localized in the deeper-lying SOL enabled quantification of PCr recovery times at low depletions and of fast pH changes, like the initial rise. Both high temporal resolution and accurate spatial localization improve specificity of Pi and, thus, pH quantification by avoiding multiple, and potentially indistinguishable sources for changing the Pi peak shape. [ABSTRACT FROM AUTHOR]

BACKGROUND: It is not known whether medical students support the Affordable Care Act (ACA) or possess the knowledge or will to engage in its implementation as part of their professional obligations. OBJECTIVE: To characterize medical students' views and knowledge of the ACA and to assess correlates of these views. DESIGN: Cross-sectional email survey. PARTICIPANTS: All 5,340 medical students enrolled at eight geographically diverse U.S. medical schools (overall response rate 52 % [2,761/5,340]). MAIN MEASURES: Level of agreement with four questions regarding views of the ACA and responses to nine knowledge-based questions. KEY RESULTS: The majority of respondents indicated an understanding of (75.3 %) and support for (62.8 %) the ACA and a professional obligation to assist with its implementation (56.1 %). The mean knowledge score from nine knowledge-based questions was 6.9 ± 1.3. Students anticipating a surgical specialty or procedural specialty compared to those anticipating a medical specialty were less likely to support the legislation (OR = 0.6 [0.4-0.7], OR = 0.4 [0.3-0.6], respectively), less likely to indicate a professional obligation to implement the ACA (OR = 0.7 [0.6-0.9], OR = 0.7 [0.5-0.96], respectively), and more likely to have negative expectations (OR = 1.9 [1.5-2.6], OR = 2.3 [1.6-3.5], respectively). Moderates, liberals, and those with an above-average knowledge score were more likely to indicate support for the ACA (OR = 5.7 [4.1-7.9], OR = 35.1 [25.4-48.5], OR = 1.7 [1.4-2.1], respectively) and a professional obligation toward its implementation (OR = 1.9 [1.4-2.5], OR = 4.7 [3.6-6.0], OR = 1.2 [1.02-1.5], respectively). CONCLUSIONS: The majority of students in our sample support the ACA. Support was highest among students who anticipate a medical specialty, self-identify as political moderates or liberals, and have an above-average knowledge score. Support of the ACA by future physicians suggests that they are willing to engage with health care reform measures that increase access to care. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) have been proposed to underlie the initiation and maintenance of tumor growth and the development of chemoresistance in solid tumors. The identification and role of these important cells in pancreatic cancer remains controversial. Here, we isolate side population (SP) cells from the highly aggressive and metastatic human pancreatic cancer cell line L3.6pl and evaluate their potential role as models for CSCs. SP cells were isolated following Hoechst 33342 staining of L3.6pl cells. SP, non-SP, and unsorted L3.6pl cells were orthotopically xenografted into the pancreas of nude mice and tumor growth observed. RNA was analyzed by whole genome array and pathway mapping was performed. Drug resistant variants of L3.6pl were developed and examined for SP proportions and evaluated for surface expression of known CSC markers. A distinct SP with the ability to self-renew and differentiate into non-SP cells was isolated from L3.6pl (0.9 % ± 0.22). SP cells showed highly tumorigenic and metastatic characteristics after orthotopic injection. Transcriptomic analysis identified modulation of gene networks linked to tumorigenesis, differentiation, and metastasization in SP cells relative to non-SP cells. Wnt, NOTCH, and EGFR signaling pathways associated with tumor stem cells were altered in SP cells. When cultured with increasing concentrations of gemcitabine, the proportion of SP cells, ABCG2, and CD24 cells were significantly enriched, whereas 5-fluorouracil (5-FU) treatment lowered the percentage of SP cells. SP cells were distinct from cells positive for previously postulated pancreatic CSC markers. The Hoechst-induced side population in L3.6pl cells comprises a subset of tumor cells displaying aggressive growth and metastasization, increased gemcitabine-, but not 5-FU resistance. The cells may act as a partial model for CSC biology. [ABSTRACT FROM AUTHOR]