Simulation-Oriented Methodology for Distortion Minimisation during Laser Beam Welding

Distortion is one of the drawbacks of any welding process, most of the time needed to be suppressed. One doubtful factor that could affect welding deformation is the shape of the liquid melt pool, which can be modified via variation of process parameters. The aim of this work was to numerically study the dynamics of the weld pool and its geometrical influence on welding distortion during laser beam welding. To achieve such a goal, a promising novel process simulation model, employed in investigating the keyhole and weld pool dynamics, has successfully been invented. The model incorporated all distinctive behaviours of the laser beam welding process. Moreover, identification of the correlation between the weld pool geometry and welding distortion as well as, eventually, weld pool shapes that favour distortion minimisation has also been simulatively demonstrated

Maintenance therapy with proton pump inhibitors and risk of gastric cancer : a nationwide population-based cohort study in Sweden

Objective: Proton pump inhibitors (PPIs) are among the most commonly prescribed drugs. Concerns have been raised about a potentially increased risk of gastric cancer following long-term use. Our aim is to assess the risk of gastric cancer associated with PPI use, taking into account underlying indications. Design: This is a population-based cohort study. Standardised incidence ratios (SIRs) and 95% CIs were calculated to compare the risk of gastric cancer among long-term PPI users with the corresponding background population, while taking confounding by indication into account. Setting: Population-based study in Sweden (2005-2012). Participants: This study included virtually all adults residing in Sweden exposed to maintenance therapy with PPIs. Exposure/Intervention: Maintenance use of PPIs, defined as at least 180 days during the study period. Maintenance use of histamine 2 receptor antagonist was evaluated for comparison reasons. Outcome measures: Gastric cancer (cardia and non-cardia), and subgroup analysis for gastric adenocarcinoma, as defined by the Swedish Cancer Registry. Results: Among 797 067 individuals on maintenance PPI therapy, the SIR of gastric cancer was over threefold increased (SIR=3.38, 95% CI 3.23 to 3.53). Increased SIRs were found in both sexes and all age groups, but were especially increased among PPI users younger than 40 years (SIR=22.76, 95% CI 15.94 to 31.52). Increased SIRs were found for each indication studied, including those without an association with gastric cancer, for example, gastro-oesophageal reflux (SIR=3.04, 95% CI 2.80 to 3.31), and those with a supposedly decreased risk, for example, aspirin users (SIR=1.93, 95% CI 1.70 to 2.18). The association was similar for cardia and non-cardia gastric cancer. Analyses restricted to adenocarcinoma showed similar results to those for all gastric cancers. Long-term users of histamine 2 receptor antagonists, which have the same indications as PPIs, were not at any increased risk. Conclusions: Long-term PPI use might be an independent risk factor for gastric cancer. This challenges broad maintenance PPI therapy, particularly if the indication is weak

Cornea organoids from human induced pluripotent stem cells.

The cornea is the transparent outermost surface of the eye, consisting of a stratified epithelium, a collagenous stroma and an innermost single-cell layered endothelium and providing 2/3 of the refractive power of the eye. Multiple diseases of the cornea arise from genetic defects where the ultimate phenotype can be influenced by cross talk between the cell types and the extracellular matrix. Cell culture modeling of diseases can benefit from cornea organoids that include multiple corneal cell types and extracellular matrices. Here we present human iPS cell-derived organoids through sequential rounds of differentiation programs. These organoids share features of the developing cornea, harboring three distinct cell types with expression of key epithelial, stromal and endothelial cell markers. Cornea organoid cultures provide a powerful 3D model system for investigating corneal developmental processes and their disruptions in diseased conditions

Epigenetics and cell death: DNA hypermethylation in programmed retinal cell death.

BackgroundVertebrate genomes undergo epigenetic reprogramming during development and disease. Emerging evidence suggests that DNA methylation plays a key role in cell fate determination in the retina. Despite extensive studies of the programmed cell death that occurs during retinal development and degeneration, little is known about how DNA methylation might regulate neuronal cell death in the retina.MethodsThe developing chicken retina and the rd1 and rhodopsin-GFP mouse models of retinal degeneration were used to investigate programmed cell death during retinal development and degeneration. Changes in DNA methylation were determined by immunohistochemistry using antibodies against 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC).ResultsPunctate patterns of hypermethylation paralleled patterns of caspase3-dependent apoptotic cell death previously reported to occur during development in the chicken retina. Degenerating rd1 mouse retinas, at time points corresponding to the peak of rod cell death, showed elevated signals for 5mC and 5hmC in photoreceptors throughout the retina, with the most intense staining observed in the peripheral retina. Hypermethylation of photoreceptors in rd1 mice was associated with TUNEL and PAR staining and appeared to be cCaspase3-independent. After peak rod degeneration, during the period of cone death, occasional hypermethylation was observed in the outer nuclear layer.ConclusionThe finding that cell-specific increases of 5mC and 5hmC immunostaining are associated with the death of retinal neurons during both development and degeneration suggests that changes in DNA methylation may play a role in modulating gene expression during the process of retinal degeneration. During retinal development, hypermethylation of retinal neurons associates with classical caspase-dependent apoptosis as well as caspase-3 independent cell death, while hypermethylation in the rd1 mouse photoreceptors is primarily associated with caspase-3 independent programmed cell death. These findings suggest a previously unrecognized role for epigenetic mechanisms in the onset and/or progression of programed cell death in the retina

Endogenous expression of ASLV viral proteins in specific pathogen free chicken embryos: relevance for the developmental biology research field

<p>Abstract</p> <p>Background</p> <p>The use of Specific Pathogen Free (SPF) eggs in combination with RCAS retrovirus, a member of the Avian Sarcoma-Leukosis Virus (ASLV) family, is of standard practice to study gene function and development. SPF eggs are certified free of infection by specific pathogen viruses of either exogenous or endogenous origin, including those belonging to the ASLV family. Based on this, SPF embryos are considered to be free of ASLV viral protein expression, and consequently in developmental research studies RCAS infected cells are routinely identified by immunohistochemistry against the ASLV viral proteins p19 and p27. Contrary to this generally accepted notion, observations in our laboratory suggested that certified SPF chicken embryos may endogenously express ASLV viral proteins p19 and p27. Since these observations may have significant implications for the developmental research field we further investigated this possibility.</p> <p>Results</p> <p>We demonstrate that certified SPF chicken embryos have transcriptionally active endogenous ASLV loci (<it>ev loci</it>) capable of expressing ASLV viral proteins, such as p19 and p27, even when those <it>loci </it>are not capable of producing viral particles. We also show that the extent of viral protein expression in embryonic tissues varies not only among flocks but also between embryos of the same flock. In addition, our genetic screening revealed significant heterogeneity in <it>ev loci </it>composition even among embryos of the same flock.</p> <p>Conclusions</p> <p>These observations have critical implications for the developmental biology research field, since they strongly suggest that the current standard methodology used in experimental studies using the chick embryo and RCAS vectors may lead to inaccurate interpretation of results. Retrospectively, our observations suggest that studies in which infected cells have been identified simply by pan-ASLV viral protein expression may need to be considered with caution. For future studies, they point to a need for careful selection and screening of the chick SPF lines to be used in combination with RCAS constructs, as well as the methodology utilized for qualitative analysis of experimental results. A series of practical guidelines to ensure research quality animals and accuracy of the interpretation of results is recommended and discussed.</p

Global time trends in the incidence of esophageal squamous cell carcinoma

Background & Aims: Esophageal squamous cell carcinoma (ESCC) is the dominant histological type of esophageal cancer worldwide (90%). We aimed to provide an update of the global temporal trends in the incidence of ESCC. Methods: Incidence data for ESCC were collected from 30 well-established cancer registries from 20 countries in Europe, Northern America, Australia, or Asia in 1970-2015. Time trends in annual age-standardized incidence rates of ESCC were assessed using joinpoint analysis and log-linear regression. Age-period-cohort analysis was used to estimate the influence of age, calendar-period, and birth-cohort on the observed time trends in incidence. Results: The age-standardized incidence rates of ESCC varied more than 8-fold in men and 7-fold in women across populations. In 2012, the highest rate in men was observed in Japan, Nagasaki (9.7/100 000 person-years) and women in Scotland (2.7/100 000 person-years). In men, the incidence decreased globally during the study period, as well as during the last few years. In women, the incidence increased in Japan (3 regions), the Netherlands, New Zealand, Norway, and Switzerland, while it was stable or decreased in other populations. Among ethnical groups in the United States, black men and women had more pronounced decreases in incidence than other groups. Generally, birth-cohort effects were stronger determinants of incidence trends than calendar-period effects. Conclusions: In men, the global ESCC incidence has decreased over time. In women, the incidence trends vary across populations, and the rates have increased in some countries. Changes in the prevalence of tobacco smoking and alcohol consumption may have contributed to these time trends.The Swedish Research Council (521-2014-2536)The Swedish Cancer Society (CAN 2015/460)Publishe

Photoreceptor Outer Segment-like Structures in Long-Term 3D Retinas from Human Pluripotent Stem Cells.

The retinal degenerative diseases, which together constitute a leading cause of hereditary blindness worldwide, are largely untreatable. Development of reliable methods to culture complex retinal tissues from human pluripotent stem cells (hPSCs) could offer a means to study human retinal development, provide a platform to investigate the mechanisms of retinal degeneration and screen for neuroprotective compounds, and provide the basis for cell-based therapeutic strategies. In this study, we describe an in vitro method by which hPSCs can be differentiated into 3D retinas with at least some important features reminiscent of a mature retina, including exuberant outgrowth of outer segment-like structures and synaptic ribbons, photoreceptor neurotransmitter expression, and membrane conductances and synaptic vesicle release properties consistent with possible photoreceptor synaptic function. The advanced outer segment-like structures reported here support the notion that 3D retina cups could serve as a model for studying mature photoreceptor development and allow for more robust modeling of retinal degenerative disease in vitro

Nordic registry-based cohort studies : possibilities and pitfalls when combining Nordic registry data

Aims: All five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) have nationwide registries with similar data structure and validity, as well as personal identity numbers enabling linkage between registries. These resources provide opportunities for medical research that is based on large registry-based cohort studies with long and complete follow-up. This review describes practical aspects, opportunities, and challenges encountered when setting up all-Nordic registrybased cohort studies. Methods: Relevant articles describing registries often used for medical research in the Nordic countries were retrieved. Further, our experiences of conducting this type of study, including planning, acquiring permissions, data retrieval, and data cleaning and handling, and the possibilities and challenges we have encountered, are described. Results: Combining data from the Nordic countries makes it possible to create large and powerful cohorts. The main challenges include obtaining all permissions within each country, usually in the local language, and to retrieve the data. These challenges emphasise the importance of having experienced collaborators within each country. Following the acquisition of data, data management requires the understanding of differences between the variables to be used in the various countries. A concern is the long time required between initiation and completion. Conclusions: Nationwide Nordic registries can be combined into cohorts with high validity and statistical power, but the considerable expertise, workload, and time required to complete such cohorts should not be underestimated.VetenskapsrådetAccepte

All-cause and cancer-specific mortality in GORD in a population-based cohort study (the HUNT study)

OBJECTIVE: Gastro-oesophageal reflux is a public health concern which could have associated oesophageal complications, including adenocarcinoma, and possibly also head-and-neck and lung cancers. The aim of this study was to test the hypothesis that reflux increases all-cause and cancer-specific mortalities in an unselected cohort. DESIGN: The Nord-Trondelag health study (HUNT), a Norwegian population-based cohort study, was used to identify individuals with and without reflux in 1995-1997 and 2006-2008, with follow-up until 2014. All-cause mortality and cancer-specific mortality were assessed from the Norwegian Cause of Death Registry and Cancer Registry. Multivariable Cox regression was used to calculate HRs with 95% CIs for mortality with adjustments for potential confounders. RESULTS: We included 4758 participants with severe reflux symptoms and 51 381 participants without reflux symptoms, contributing 60 323 and 747 239 person-years at risk, respectively. Severe reflux was not associated with all-cause mortality, overall cancer-specific mortality or mortality in cancer of the head-and-neck or lung. However, for men with severe reflux a sixfold increase in oesophageal adenocarcinoma-specific mortality was found (HR 6.09, 95% CI 2.33 to 15.93) and the mortality rate was 0.27 per 1000 person-years. For women, the corresponding mortality was not significantly increased (HR 3.68, 95% CI 0.88 to 15.27) and the mortality rate was 0.05 per 1000 person-years. CONCLUSIONS: Individuals with severe reflux symptoms do not seem to have increased all-cause mortality or overall cancer-specific mortality. Although the absolute risk is small, individuals with severe reflux symptoms have a clearly increased oesophageal adenocarcinoma-specific mortality.Swedish Research CouncilAccepte