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Data exploring normal values of different ventricular–arterial coupling (VAC) parameters and their association with anthropometric and cardiovascular (CV) factors are scarce. We aim to report values of two different methods of VAC assessment according to age and sex and explore their association with CV factors within a large population-based cohort of middle-aged individuals. For 1333 (mean age 48 ± 14) individuals participating in the 4th visit of the STANISLAS cohort, VAC was assessed by two methods [1]: arterial elastance (E a)/end-systolic elastance (E es) and [2] Pulse wave velocity (PWV)/Global longitudinal strain (GLS). The mean values of E a /E es and PWV/GLS were 1.06 ± 0.20 and 0.42 ± 0.12, respectively. The two methods of VAC assessment were poorly correlated (Pearson's correlation coefficient r = 0.14 (0.08; 0.19)). Increased PWV/GLS was associated with older age and a higher degree of cardiovascular risk factors (i.e., BMI, blood pressure, LDL, diabetes, hypertension) in the whole population as well as in the parent generation. In contrast, higher E a /E es were associated with decreasing age, and lower prevalence of risk factors in the whole cohort but neutrally associated with risk factors in the parent generation. Higher PWV/GLS is significantly associated with CV factors regardless of age. In contrast, worse E a /E es is associated with a better CV risk profile when considering individuals aged 30 to 70 but neutrally associated with CV factors when considering only older patients. These results may suggest that PWV/GLS should preferably be used to explore VAC. In addition, age-individualized threshold of E a /E es should be used. [Display omitted] • This study provides reference values of ventricular-arterial coupling (VAC) according to age and gender. • Increased PWV/GLS is associated with older age and a higher degree of cardiovascular risk factors. • Higher E a /E es is associated with decreasing age, and lower prevalence of risk factors. • Age-individualized threshold of E a /E es should be used. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel. Though no pharmacological agents have been identified to prevent CIPN, cryotherapy with frozen gloves and socks may reduce the risk of developing CIPN and thereby increase the likelihood of patients completing the planned dose of paclitaxel.Patients and Methods: Among women with early-stage breast cancer who received at least one cycle of paclitaxel, 119 were included in the 2016 cohort who received cryotherapy when they developed symptoms of CIPN, and 96 patients in the 2017 cohort who received prophylactic cryotherapy. From electronic patient records, data were abstracted on dates and doses of adjuvant paclitaxel, dose reductions, cycle delays, symptoms of CIPN, and whether and when frozen gloves and socks were used. The outcome was the proportion of patients completing the planned 720 mg/m2 of paclitaxel cumulated over nine cycles. The hazard ratio (HR) of a dose-limiting event due to CIPN was estimated in a Cox proportional hazards model.Results: In the 2016 cohort, cryotherapy was needed due to symptoms of CIPN in 54 (45%) patients. Significantly, more patients, 77% in the 2017 cohort, completed the planned dose of 720 mg/m² compared with 64% in the 2016 cohort, p = 0.017. The HR of a dose reduction or cessation due to CIPN, adjusted for age and HER-2 status, was 0.50 (95% confidence interval 0.30-0.84), p = 0.009, for the 2017 cohort compared with the 2016 cohort.Conclusions: The results of this study suggest that prophylactic cryotherapy may reduce the risk of a dose-limiting event due to CIPN and increase the proportion of patients completing the planned dose of paclitaxel in adjuvant treatment of early-stage breast cancer. Despite this, CIPN remains to be an important dose-limiting toxicity of paclitaxel. [ABSTRACT FROM AUTHOR]

Midregional Pro-enkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) have been associated with vascular dementia. However, the longitudinal relationship between these biomarkers and incident dementia has not been fully investigated. In the population-based Malmö Preventive Project, circulating levels of MR-PENK A and NT-PTA were determined in a random sample of 5,323 study participants (mean age: 69 ± 6 years) who were followed-up over a period of 4.6 ± 1.6 years. The study sample included 369 patients (7%) who were diagnosed in the same period with dementia. We analyzed relationship of MR-PENK A and NT-PTA with the risk of developing dementia by using multivariable-adjusted Cox regression models adjusted for traditional risk factors. Increased plasma levels of MR-PENK A were associated with higher risk of incident vascular dementia whereas no associations were found with all-cause or Alzheimer dementia. The risk of vascular dementia was mainly conferred by the highest quartile of MR-PENK as compared with lower quartiles. Elevated levels of NT-PTA yielded significant association with all-cause dementia or dementia subtypes. Elevated plasma concentration of MR-PENK A independently predicts vascular dementia in the general population. MR-PENK A may be used as an additional tool for identifying vascular subtype in ambiguous dementia cases. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) defines a spectrum of complex disorders. Understanding how environmental risk factors, alterations of the intestinal microbiota, and polygenetic and epigenetic susceptibility impact on immune pathways is key for developing targeted therapies. Mechanistic understanding of polygenic IBD is complemented by Mendelian disorders that present with IBD, pharmacological interventions that cause colitis, autoimmunity, and multiple animal models. Collectively, this multifactorial pathogenesis supports a concept of immune checkpoints that control microbial-host interactions in the gut by modulating innate and adaptive immunity, as well as epithelial and mesenchymal cell responses. In addition to classical immunosuppressive strategies, we discuss how resetting the microbiota and restoring innate immune responses, in particular autophagy and epithelial barrier function, might be key for maintaining remission or preventing IBD. Targeting checkpoints in genetically stratified subgroups of patients with Mendelian disorder-associated IBD increasingly directs treatment strategies as part of personalized medicine. [ABSTRACT FROM AUTHOR]

Genomic technologies inform the complex genetic basis of polygenic inflammatory bowel disease (IBD) as well as Mendelian disease-associated IBD. Aiming to diagnose patients that present with extreme phenotypes due to monogenic forms of IBD, genomics has progressed from ‘orphan disease’ research towards an integrated standard of clinical care. Advances in diagnostic clinical genomics are increasingly complemented by pathway-specific therapies that aim to correct the consequences of genetic defects. This highlights the exceptional potential for personalized precision medicine. IBD is nevertheless a challenging example for genomic medicine because the overall fraction of patients with Mendelian defects is low, the number of potential candidate genes is high, and interventional evidence is still emerging. We discuss requirements and prospects of explanatory and predictive clinical genomics in IBD. [ABSTRACT FROM AUTHOR]

Background: Cerebral endothelial dysfunction occurs in a spectrum of neurodegenerative diseases. Whether biomarkers of microvascular endothelial dysfunction can predict dementia is largely unknown. We explored the longitudinal association of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal endothelin-1 (CT-proET-1) and midregional proadrenomedullin (MR-proADM) with dementia and subtypes amongst community-dwelling older adults.Methods: A population-based cohort of 5347 individuals (men, 70%; age, 69 ± 6 years) without prevalent dementia provided plasma for determination of MR-proANP, CT-proET-1 and MR-proADM. Three-hundred-and-seventy-three patients (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) over a period of 4.6 ± 1.3 years. Relations between baseline biomarker plasma concentrations and incident dementia were assessed using multivariable Cox regression analysis.Results: Higher levels of MR-proANP were significantly associated with increased risk of all-cause and vascular dementia (hazard ratio [HR] per 1 SD: 1.20, 95% confidence interval [CI], 1.07-1.36; P = 0.002, and 1.52; 1.21-1.89; P < 0.001, respectively). Risk of all-cause dementia increased across the quartiles of MR-proANP (p for linear trend = 0.004; Q4, 145-1681 pmol L-1 vs. Q1, 22-77 pmol L-1 : HR: 1.83; 95%CI: 1.23-2.71) and was most pronounced for vascular type (p for linear trend = 0.005: HR: 2.71; 95%CI: 1.14-6.46). Moreover, the two highest quartiles of CT-proET-1 predicted vascular dementia with a cut-off value at 68 pmol L-1 (Q3-Q4, 68-432 pmol L-1 vs. Q1-Q2,4-68 pmol L-1 ; HR: 1.94; 95%CI: 1.12-3.36). Elevated levels of MR-proADM indicated no increased risk of developing dementia after adjustment for traditional risk factors.Conclusions: Elevated plasma concentration of MR-proANP is an independent predictor of all-cause and vascular dementia. Pronounced increase in CT-proET-1 indicates higher risk of vascular dementia. [ABSTRACT FROM AUTHOR]

Atlantic salmon skin tissues with and without scales were taken from two preferred sites of salmon louse ( Lepeophtheirus salmonis ) attachment, behind the dorsal fin (scaled) and from the top of the head (scaleless), respectively. Tissues were profiled by qPCR of 32 genes to study responses to copepodids, 4 days post infection (dpi), and during the moult of copepodids to the chalimus stage, at 8 dpi. Basal/constitutive differences were found for many immune-related genes between the two skin sites; e.g., mannose binding protein C was over 100 fold higher expressed in the scaled skin from the back in comparison to the skin without scales from the head. With lice-infection, at 4 dpi most genes in both tissues showed lower values than in the non-infected control. By 8 dpi, the majority of responses increased towards the control levels, including cytokines of Th1, Th17 and Th2 pathways. Immunohistochemistry of three immune factors revealed an even distribution of MHC class II positive cells throughout epidermis, including the top layer of keratinocytes, marked compartmentalization of Mx + and CD8α + cells close to stratum basale , and an increase in numbers of CD8α + cells in response to infection. In conclusion, suppression of immune genes during the copepodid stage likely sets off a beneficial situation for the parasite. At the moult to chalimus stage 8 dpi, only few genes surpassed the non-infected control levels, including CD8α. The gene expression pattern was reflected in the increased number of CD8α expressing cells, thus revealing a relatively minor activation of skin T-cell defenses in Atlantic salmon in response to L. salmonis infection. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, has multifactorial aetiology with complex interactions between genetic and environmental factors. Over 150 genetic loci are associated with IBD. The genetic contribution of the majority of those loci towards explained heritability is low. Recent studies have reported an increasing spectrum of human monogenic diseases that can present with IBD-like intestinal inflammation. A substantial proportion of patients with those genetic defects present with very early onset of intestinal inflammation. The 40 monogenic defects with IBD-like pathology selected in this review can be grouped into defects in intestinal epithelial barrier and stress response, immunodeficiencies affecting granulocyte and phagocyte activity, hyper- and autoinflammatory disorders as well as defects with disturbed T and B lymphocyte selection and activation. In addition, there are defects in immune regulation affecting regulatory T cell activity and interleukin (IL)-10 signalling. Related to the variable penetrance of the IBD-like phenotype, there is a likely role for modifier genes and gene-environment interactions. Treatment options in this heterogeneous group of disorders range from anti-inflammatory and immunosuppressive therapy to blockade of tumour necrosis factor α and IL-1β, surgery, haematopoietic stem cell transplantation or gene therapy. Understanding of prototypic monogenic 'orphan' diseases cannot only provide treatment options for the affected patients but also inform on immunological mechanisms and complement the functional understanding of the pathogenesis of IBD. [ABSTRACT FROM AUTHOR]

Gut-associated lymphoid tissue (GALT) is a sensor region for luminal content and plays an important role in lymphoid maturation, activation and differentiation. It comprises isolated and aggregated lymphoid follicles, cryptopatches (CPs) and tertiary lymphoid tissue. Innate lymphoid cells (ILCs) play a central role within GALT. Prenatal GALT development is dependent on ILC lymphoid-inducer function. Postnatally, these cells rapidly respond to commensal and pathogenic intestinal bacteria, parasites and food components by polarized cytokine production [such as interleukin (IL)-22, IL-17 or IL-13] and further contribute to GALT formation and function. Here, we discuss how ILCs shape lymphoid intestinal microenvironments and act as amplifier cells for innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Abstract: Background: Indeterminate colitis (IC) remains an enigmatic inflammatory bowel disease (IBD) phenotype. It is currently not clear whether it constitutes merely a problem of terminology, classification, or possibly an early stage of IBD distinct from Crohn''s disease (CD) and ulcerative colitis (UC). Methods: We analysed epidemiological data of studies comparing IC, UC and CD. We selected 14 studies investigating paediatric patients (10 prospective and 4 retrospective) and 18 studies investigating adult IBD patients (11 prospective and 7 retrospective) for this analysis. Results: Compared to adults (n =15,776) the frequency of IC is higher in children (n =6262) (children 12.7% versus adults 6.0%, p <0.0001). This difference between children and adults has been detected irrespective whether prospective or retrospective studies were selected. In both, children and adults IC was more frequent in prospective studies compared to retrospective studies (children p =0.0004; adults p =0.0024). Conclusions: IC has been detected in a substantial proportion of paediatric patients with IBD. IC is more frequently found in children compared to adults. Further studies are required to clarify whether IC represents an IBD phenotype associated with childhood disease onset or whether the high IC frequency is due to difficulties in establishing a UC or CD diagnosis. [Copyright &y& Elsevier]

Summary: The CD40-CD154 pathway is important in the pathogenesis of inflammatory bowel disease. Here we show that injection of an agonistic CD40 mAb to T and B cell-deficient mice was sufficient to induce a pathogenic systemic and intestinal innate inflammatory response that was functionally dependent on tumor necrosis factor-α and interferon-γ as well as interleukin-12 p40 and interleukin-23 p40 secretion. CD40-induced colitis, but not wasting disease or serum proinflammatory cytokine production, depended on interleukin-23 p19 secretion, whereas interleukin-12 p35 secretion controlled wasting disease and serum cytokine production but not mucosal immunopathology. Intestinal inflammation was associated with IL-23 (p19) mRNA-producing intestinal dendritic cells and IL-17A mRNA within the intestine. Our experiments identified IL-23 as an effector cytokine within the innate intestinal immune system. The differential role of IL-23 in local but not systemic inflammation suggests that it may make a more specific target for the treatment of IBD. [Copyright &y& Elsevier]

Focuses on the role of dendritic cells and the intestinal bacterial flora in localized mucosal immune response. Illustration of how dendritic cells sense bacterial flora; Specialized commensal bacteria that occupy niches in different compartments of the gastrointestinal tracts; Localized mucosal responses as a result of differential colonization and pathogenicity.

This paper describes a provisional not fully developed architecture of a thermal feedback system for closed-loop control of robotic arc welding. The architecture is based on an off-line planning system for welding and an on-line welding control system, where the off-line planning system builds the reference to be followed by the on-line closed-loop system. The main aim of this architecture is to develop a method by which thermal feedback welding control systems can be designed. This control system is meant for control of welding of thick-walled sheet metal geometries and the system feeds back the temperatures on the surface of the geometry. The temperature is fed back by an infrared CCD-array camera. [Copyright &y& Elsevier]

Objective: The objective of the study was to investigate the prevalence of depressive symptoms and the self-reported psychiatric treatment after myocardial infarction. Method: Depressive symptoms and medication were studied in 85 consecutive acute myocardial infarction patients during 18 months follow-up. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Results: The proportion of patients with depressive symptoms (BDI ≥ 10) was 21.2% while in hospital, 30.0% at 6 months and 33.9% at 18 months. At 18 months, none of the patients were receiving adequate antidepressive medication. There were eight patients with BDI scores corresponding to moderate/severe depression (BDI ≥ 19). Six of these patients were receiving benzodiazepine medication and two of them had been treated in the mental health care system after the myocardial infarction. Conclusion: There seems to be considerable problems in the diagnosis and/or treatment of depression after myocardial infarction. [ABSTRACT FROM AUTHOR]

In a game of incomplete information we analyze the consequences of giving an employer access to imperfect genetic information about his employees. The employer chooses whether to invest in the employee and the employee chooses a life style. We derive the condition for markets of information services to exist and the conditions for when it is beneficial to the various parties. In one specification of the game, the mere introduction of the information service may change the employee's choice of health behavior, which means that the value of genetic information may be negative to the employer. [ABSTRACT FROM AUTHOR]

Discusses the reasons for changes in the North-South policies of Denmark, Canada, the Netherlands, Norway, and Sweden, which concern Third World demands for global equality and justice. Critically evaluates proposals for what needs to be done torevive Northern responsiveness; Description of the North-South policy; Humane internationalism.

It has been unclear whether an innate lymphoid cell (ILC) counterpart to the T helper 1 cell type exists. New studies, including Fuchs et al. (2013) in this issue of Immunity, identify T-bet+IFN-γ+ ILC1 that accumulate in the inflamed intestine of IBD patients. [ABSTRACT FROM AUTHOR]

There are a few studies that report cognitive impairment as a complication of treatment with beta- blockers. We aimed to evaluate the longitudinal association between use of beta-blockers, as a class, and incident risk of all-cause dementia, vascular dementia, Alzheimer's and mixed dementia in the prospective population-based Malmö Preventive Project. We included 18,063 individuals (mean age 68.2, males 63.4%) followed up for 84,506 person-years. Dementia cases were retrieved from the Swedish National Patient Register and validated by review of medical records and neuroimaging data. We performed propensity score matching analysis, resulting in 3720 matched pairs of beta-blocker users and non-users at baseline, and multivariable Cox proportional-hazards regression. Overall, 122 study participants (1.6%) were diagnosed with dementia during the follow-up. Beta-blocker therapy was independently associated with increased risk of developing vascular dementia, regardless of confounding factors (HR: 1.72, 95%CI 1.01–3.78; p =.048). Conversely, treatment with beta-blockers was not associated with increased risk of all-cause, Alzheimer's and mixed dementia (HR:1.15; 95%CI 0.80–1.66; p =.44; HR:0.85; 95%CI 0.48–1.54; P =.59 and HR:1.35; 95%CI 0.56–3.27; p =.50, respectively). We observed that use of beta-blockers, as a class, is associated with increased longitudinal risk of vascular dementia in the general elderly population, regardless of cardiovascular risk factors, prevalent or incident history of atrial fibrillation, stroke, coronary events and heart failure. Further studies are needed to confirm our findings in the general population and to explore the mechanisms underlying the relationship between use of beta- blockers and increased risk of vascular dementia. Unlabelled Image [ABSTRACT FROM AUTHOR]

Cell-cell communication is mediated by many soluble mediators, including over 40 cytokines. Cytokines, e.g. TNF, IL1β, IL5, IL6, IL12 and IL23, represent important therapeutic targets in immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease (IBD), psoriasis, asthma, rheumatoid and juvenile arthritis. The identification of cytokines that are causative drivers of, and not just associated with, inflammation is fundamental for selecting therapeutic targets that should be studied in clinical trials. As in vitro models of cytokine interactions provide a simplified framework to study complex in vivo interactions, and can easily be perturbed experimentally, they are key for identifying such targets. We present a method to extract a minimal, weighted cytokine interaction network, given in vitro data on the effects of the blockage of single cytokine receptors on the secretion rate of other cytokines. Existing biological network inference methods typically consider the correlation structure of the underlying dataset, but this can make them poorly suited for highly connected, non-linear cytokine interaction data. Our method uses ordinary differential equation systems to represent cytokine interactions, and efficiently computes the configuration with the lowest Akaike information criterion value for all possible network configurations. It enables us to study indirect cytokine interactions and quantify inhibition effects. The extracted network can also be used to predict the combined effects of inhibiting various cytokines simultaneously. The model equations can easily be adjusted to incorporate more complicated dynamics and accommodate temporal data. We validate our method using synthetic datasets and apply our method to an experimental dataset on the regulation of IL23, a cytokine with therapeutic relevance in psoriasis and IBD. We validate several model predictions against experimental data that were not used for model fitting. In summary, we present a novel method specifically designed to efficiently infer cytokine interaction networks from cytokine perturbation data in the context of IMIDs. Author summary: Cytokines are the messenger molecules of the immune system, allowing intercellular communication and mediating effective immune responses. They are an important therapeutic target in immune mediated inflammatory diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis. Cytokines interact in a tightly regulated network and depending on the context a particular cytokine can be involved in anti-inflammatory or inflammatory activities. In order to determine which cytokines to target in specific disease types and patient subsets, it is critical to study the effects of the inhibition of one or more cytokines on the larger cytokine interaction network. We present a novel method to extract a minimal, weighted network from cytokine interaction data. Existing biological network inference methods typically consider the correlation structure of the underlying dataset and/or make further assumptions of the dataset such as the existence of a small core of regulators. This can make them poorly suited for highly connected, non-linear cytokine interaction data. We validated our method using synthetic data and applied our method to a dataset on the regulation of IL23, a cytokine implicated in IBD pathogenesis. Predictions of the extracted IL23 network were validated using additional experimental data and were used to support the view of the cytokines IL1 and IL23 as promising targets for those patients that fail to respond to TNFα inhibition, the current golden standard in IBD treatment. [ABSTRACT FROM AUTHOR]

We discovered high-titer neutralizing autoantibodies against interleukin-10 in a child with infantile-onset inflammatory bowel disease (IBD), a phenocopy of inborn errors of interleukin-10 signaling. After B-cell-depletion therapy and an associated decrease in the anti-interleukin-10 titer, conventional IBD therapy could be withdrawn. A second child with neutralizing anti-interleukin-10 autoantibodies had a milder course of IBD and has been treated without B-cell depletion. We conclude that neutralizing anti-interleukin-10 autoantibodies may be a causative or modifying factor in IBD, with potential implications for therapy. [ABSTRACT FROM AUTHOR]

Obesity associates with reduced life expectancy, type 2 diabetes, hypertension and cardiovascular disease, and is characterized by chronic inflammation. Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein, dead cells and some microorganisms. Antibodies against PC (anti-PC) have anti-inflammatory properties. Here, we explored the role of anti-PC in hospitalized versus non-hospitalized obese. One-hundred-and-twenty-eight obese (BMI ≥ 30 kg/m2) individuals (59.8 (± 5.5) years, 53.9% women) from the Malmö Diet and Cancer Cardiovascular Cohort were examined and IgM, IgG1 and IgG2 anti-PC were analyzed by ELISA. Individuals with at least one recorded history of hospitalization prior to study baseline were considered hospitalized obese (HO). Associations between IgM, IgG1 and IgG2 anti-PC and HO (n = 32)/non-hospitalized obese (NHO) (n = 96), but also with metabolic syndrome and diabetes were analysed using logistic regressions. Both IgM and IgG1 anti-PC were inversely associated with HO, also after controlling for age and sex. When further adjusted for waist circumference, systolic blood pressure, glucose levels and smoking status, only IgG1 anti-PC remained significantly associated with HO. In multivariate models, each 1 standard deviation of increment in anti-PC IgG1 levels was inversely associated with prevalence of HO (odds ratio 0.57; CI 95% 0.33–0.98; p = 0.044). IgG2 anti-PC did not show any associations with HO. Low levels of IgM and IgG1 anti-PC are associated with higher risk of being a HO individual independent of sex and age, IgG1 anti-PC also independently of diabetes and metabolic syndrome. The anti-inflammatory properties of these antibodies may be related to inflammation in obesity and its complications. [ABSTRACT FROM AUTHOR]

In this issue of Blood, Bocchini et al report a novel mechanism by which STAT3 mutations result in an unstable protein and give rise to a reduction in STAT3 signaling, suggesting that pathogenic mutations do not always confer dominantnegative effects via forming of nonfunctional STAT3 dimers but some may limit availability of total protein causing STAT3 haploinsufficiency. [ABSTRACT FROM AUTHOR]

Genetic variants in IL6ST encoding the shared cytokine receptor for the IL-6 cytokine family GP130 have been associated with a diverse number of clinical phenotypes and disorders. We provide a molecular classification for 59 reported rare IL6ST pathogenic or likely pathogenic variants and additional polymorphisms. Based on loss- or gain-of-function, cytokine selectivity, mono- and biallelic associations, and variable cellular mosaicism, we grade six classes of IL6ST variants and explore the potential for additional variants. We classify variants according to the American College of Medical Genetics and Genomics criteria. Loss-of-function variants with (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic IL6ST variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome. In addition to Mendelian IL6ST coding variants, there are common non-coding cis-acting variants that modify gene expression, which are associated with an increased risk of complex immune-mediated disorders and trans-acting variants that affect GP130 protein function. Our taxonomy highlights IL6ST as a gene with particularly strong functional and phenotypic diversity due to the combinatorial biology of the IL-6 cytokine family and predicts additional genotype-phenotype associations. [ABSTRACT FROM AUTHOR]

The article reports the case of a girl with chronic hereditary pancreatitis and the R122H-mutation of the cationic trypsinogen gene, in whom pancreatic diabetes regressed in the course of the disease. The cholecystokinin-secretin stimulation test revealed global exocrine insufficiency. Oral pancreatic enzyme supplementation was initiated with porcine pancreatic extracts. Under the suspicion of pancreatic diabetes, conventional insulin therapy was initiated.

The reactive hyperaemia index (RHI) assesses endothelial function, with a proposed cut-off of <1.67 for prevalent endothelial dysfunction (ED). However, uncertainties remain about whether this cut-off is age-dependent and applicable in healthy individuals. We aimed to explore ED in relation to age within a large population-based cohort of young to middle-aged, healthy individuals. Within the Malmö Offspring Study, a total of 1812 subjects (50.9% women, mean age 48 ± 11 years) were included. Post-occlusion/pre-occlusion ratio of the pulsatile signal amplitudes in the non-dominant upper arm was used to calculate RHI by EndoPat®. ED was defined as RHI < 1.67. Multivariable regression models were used to explore associations between ED and age. Prevalent ED was found in 534 (29.5%) participants. In subjects aged ≤30 years, ED was present in 47.4% compared to 27.6% in subjects ≥30 years (p < 0.001). In multivariable logistic regression analyses, ED was associated with younger age (p < 0.001), higher BMI (p < 0.001) and current smoking (p < 0.001). No sex differences were observed. In a large healthy population, RHI < 1.67, an early marker of endothelial dysfunction, was more prevalent in younger individuals, implying that RHI might not be a suitable measure of endothelial function in individuals under 30 years of age. Our findings suggest that low RHI in young, healthy individuals may not necessarily indicate true ED but rather an artefact of the limited ability of young and healthy arteries to dilate post-occlusion. Therefore, the term "pseudo-ED" may be applicable to young individuals with low RHI values. What is the context? The endothelium is a thin layer of cells that lines the inside of blood vessels, and its proper function is crucial for the maintenance of vascular health. Endothelial dysfunction (ED) is an early marker of cardiovascular disease and is characterised by impaired dilation of blood vessels, which can lead to reduced blood flow and increased risk of heart attacks and strokes. The reactive hyperaemia index (RHI) is a widely used non-invasive test that measures endothelial function by evaluating the dilation of blood vessels in response to temporary occlusion. What is new? This study aimed to investigate the relationship between age and ED in a large population-based cohort of young to middle-aged healthy individuals. The results showed that prevalent ED was more common in younger individuals, with 47.4% of participants aged ≤30 years having ED, compared to 27.6% in those ≥30 years. The study also found that ED was associated with higher BMI and current smoking, but no sex differences were observed. What is the impact? The findings suggest that the proposed RHI cut-off of <1.67 for prevalent ED may not be applicable to individuals under the age of 30, as young and healthy arteries may have limited ability to dilate post-occlusion, resulting in low RHI values that do not necessarily indicate true ED. Therefore, the term "pseudo-ED" may be more appropriate for young individuals with low RHI values. [ABSTRACT FROM AUTHOR]

Introduction: Young women with personality disorders (PD) are common in psychiatric inpatient care. The clinical impression is that there is a considerably increased incidence the last decade. Objectives and aim: To show changes in frequency and extent of inpatient care for PD, and the relation to suicide. Method: All admissions for inpatient care given a primary diagnosis of PD in compulsory or voluntary care years 1990 to 2010 were extracted from the National Patient Register. Subsequently, data from the Cause of Death Register were extracted and linked for the same time period. Results: There were more than 60,000 admissions for PD in Sweden 1990–2010. During the last ten years there was a doubling of the number of yearly admissions for young women in the ages 18 to 24 years, and inpatient care hospitalization for PD are currently six times more common for women than for men in this age group. The same is true for compulsory care. Every fifth woman in this age group who had committed suicide had been treated for PD within the last five year period prior to the suicide. Conclusions: The incidence of inpatient care in young women with PD did show a sharp rise during the last decade. There was a corresponding increase in suicide with a diagnosis of PD. Guidelines for treatment and care exist but more knowledge and action plans directed both to health care and the society are urgently needed. [Copyright &y& Elsevier]

Phosphomannomutase 2 (PMM2) deficiency causes Congenital Disorder of Glycosylation (PMM2-CDG), but does not have a recognised association with Inflammatory Bowel Disease (IBD). A distinct clinical syndrome of hyperinsulinism and autosomal recessive polycystic kidney disease (HIPKD) arises in the context of a specific variant in the PMM2 promotor, either in homozygosity, or compound heterozygous with a deleterious PMM2 variant. Here, we describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6, and 10 years of age. In each case, intestinal inflammation coincided with the unusual finding of gastric antral foveolar hyperplasia. IBD disease was of variable severity at onset but well controlled with conventional and first-line biologic treatment approaches. The organ-level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A). Analysis of published transcriptomic data suggests that IBD most likely arises due to an impact on epithelial cellular function. We identify a specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology. [ABSTRACT FROM AUTHOR]

Over 100 genes are associated with monogenic forms of inflammatory bowel disease (IBD). These genes affect the epithelial barrier function, innate and adaptive immunity in the intestine, and immune tolerance. We provide an overview of newly discovered monogenic IBD genes and illustrate how a recently proposed taxonomy model can integrate phenotypes and shared pathways. We discuss how functional understanding of genetic disorders and clinical genomics supports personalised medicine for patients with monogenic IBD. [ABSTRACT FROM AUTHOR]

Balancing natural selection is a process by which genetic variants arise in populations that are beneficial to heterozygous carriers, but pathogenic when homozygous. We systematically investigated the prevalence, structural, and functional consequences of pathogenic IL10RA variants that are associated with monogenic inflammatory bowel disease. We identify 36 non-synonymous and non-sense variants in the IL10RA gene. Since the majority of these IL10RA variants have not been functionally characterized, we performed a systematic screening of their impact on STAT3 phosphorylation upon IL-10 stimulation. Based on the geographic accumulation of confirmed pathogenic IL10RA variants in East Asia and in Northeast China, the distribution of infectious disorders worldwide, and the functional evidence of IL-10 signaling in the pathogenesis, we identify Schistosoma japonicum infection as plausible selection pressure driving variation in IL10RA. Consistent with this is a partially augmented IL-10 response in peripheral blood mononuclear cells from heterozygous variant carriers. A parasite-driven heterozygote advantage through reduced IL-10 signaling has implications for health care utilization in regions with high allele frequencies and potentially indicates pathogen eradication strategies that target IL-10 signaling. [ABSTRACT FROM AUTHOR]

Abstract: This study followed the time-related changes in intestinal digestive physiology of post-smolt Atlantic salmon (Salmo salar L.; initial weight 500–600g) during the development of soybean meal induced enteritis. Intestinal tissue and content (chyme) were sampled after 1, 2, 3, 5, 7, 10, 14, 17, and 21days of dietary exposure to a 20% extracted soybean meal-containing (SBM) diet. Fish fed a fishmeal-based control diet sampled on day 0 (prior to SBM feeding) served as controls. From the different intestinal regions, histomorphological evaluation was conducted, activities of the pancreatic enzymes trypsin, chymotrypsin, elastase and lipase, as well as leucine aminopeptidase (LAP) were determined in chyme, and the brush border membrane (BBM) enzymes LAP and maltase were measured in homogenates of the intestinal wall. Epithelial cell functional differentiation was visually assessed using immunohistochemical expression of carbonic anhydrase 12 (CA-12). Histological signs of SBM-induced inflammation were observed in the distal intestine (DI) from day 5. At each given sampling time, pancreatic enzyme activities generally decreased aborally along the intestinal tract. Within each intestinal region, pancreatic protease activities tended to increase with exposure time to the SBM diet, with the greatest activity increases observed in the DI. The magnitude of the decrease in activity between the most proximal region and the most distal decreased with SBM exposure. DI tissue weight and BBM maltase and LAP activities were significantly reduced from day 1–2 and continued to decrease progressively with increasing SBM exposure time. Immunohistochemical staining of CA-12 also diminished over time starting at day 5. By day 7, very little CA-12 staining was observed. The data suggests an immediate and generalized physiological response to a change in diet and/or feed intake in all regions of the intestine, as well as a more localized functional loss in the DI that progressed with the development of SBM-induced inflammation from day 5. The diet change appeared to cause a rapid pancreatic response with increased secretion of all the enzymes investigated, while the longer term responses of the pancreatic proteases differed from that of lipase. [Copyright &y& Elsevier]

The key role of interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (TH17) cells. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-γ in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-γ exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-γt and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-γt, which controls IL-23R expression, has a functional role, because Rag-/-Rorc-/- mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Abstract: Protein degradation of caprine whey by human proteolytic enzymes was studied with regard to antibacterial effect on Listeria monocytogenes. The digestion was performed by a two-step degradation-assay, using human gastric juice (HGJ) at pH 2.5, and human duodenal juice (HDJ) at pH 8. Protein profiles were studied by SDS-PAGE after each step and compared with degradation performed by commercial enzymes. Both types of enzymes, both human and commercial, left most of β-LG intact. However, proteins like serum albumin, laktoferrin and immunoglobulins were rapidly degraded. Only minor parts of α-lactalbumin (α-LA) was degraded by human enzymes, while treatment with commercial enzymes gave full degradation of α-LA. The two types of enzymes resulted in different peptide profiles, where the commercial enzymes degraded whey into smaller peptides much more efficiently. The protein digests produced by HGJ and HDJ were screened for antibacterial effects against L. monocytogenes, a food born bacteria responsible for fatal and sometimes deadly infections. Cells of L. monocytogenes were strongly inhibited by caprine whey obtained after reaction with both HGJ and HDJ. Undigested caprine whey and the products from the first step of digestion with HGJ demonstrated no significant effect. This indicates that during digestion the antibacterial effect of caprine whey hydrolysates are most effective in the duodenum. This gives a promising opportunity to inhibit listeriosis in humans, and results are also useful for development of dietary supplement, nutraceuticals and functional foods. [Copyright &y& Elsevier]

NOD2 polymorphisms may affect sensing of the bacterial muramyl dipeptide (MDP) and trigger perturbed inflammatory responses. Genetic screening of a patient with immunodeficiency and enteropathy revealed a rare homozygous missense mutation in the first CARD domain of NOD2 (ENST00000300589; c.160G > A, p.E54K). Biochemical assays confirmed impaired NOD2-dependent signaling and proinflammatory cytokine production in patient's cells and heterologous cellular models with overexpression of the NOD2 mutant. Immunoprecipitation-coupled mass spectrometry unveiled the ATPase valosin-containing protein (VCP) as novel interaction partner of wildtype NOD2, while the binding to the NOD2 variant p.E54K was abrogated. Knockdown of VCP in coloncarcinoma cells led to impaired NF-κB activity and IL8 expression upon MDP stimulation. In contrast, tunicamycin-induced ER stress resulted in increased IL8, CXCL1, and CXCL2 production in cells with knockdown of VCP, while enhanced expression of these proinflammatory molecules was abolished upon knockout of NOD2. Taken together, these data suggest that VCP-mediated inflammatory responses upon ER stress are NOD2-dependent. [ABSTRACT FROM AUTHOR]

The IL-6 family of cytokines mediates functions in host protective immunity, development of multiple organs, tissue regeneration and metabolism. Inborn errors in cytokines or cytokine receptor units highlight specific roles for IL-6, IL-11, LIF, OSM, and CLC signaling whereas incomplete loss-of-function variants in the common receptor chain GP130 encoded by IL6ST or the transcription factor STAT3, as well as genes that affect either GP130 glycosylation (PGM3) or STAT3 transcriptional control (ZNF341) lead to complex phenotypes including features of hyper-IgE syndrome. Gain-of-function variants in the GP130-STAT3 signaling pathway cause immune dysregulation disorders. Insights into IL-6 family cytokine signaling inform on therapeutic application in immune-mediated disorders and potential side effects such as infection susceptibility. [ABSTRACT FROM AUTHOR]

A recent meta-analysis analyzed BCG vaccine-associated complications in patients with primary immunodeficiency, most frequently in those with severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and Mendelian susceptibility to mycobacterial disease [[1]]. BCG vaccine-associated complications have previously been reported in patients with activated PI3K delta syndrome (APDS), which like PHTS is associated with increased cellular PI3K signaling. For patients with APDS, it has been recommended that BCG vaccination should be avoided until the risks of adverse reactions are better understood; our data suggest a cautious approach should also be adopted for patients with PHTS. The report of two adverse reactions to BCG vaccination in PHTS is significant, especially in the context of overactive PI3K signaling in APDS being associated with persistent local BCG vaccine-associated complications. [Extracted from the article]

A training programme for educational supervisors for medical doctors in specialist training was introduced in Norway in October 1986. By March 1997 approximately 550 senior consultants from major Norwegian hospitals had participated in the programme. The programme has been continuously evaluated by a questionnaire returned by participants at the closing session of each course. The effects of the training programme on educational supervision in specialist training has been evaluated in two postal survey studies. The results show that the training programme has helped the consultants to become better supervisors and motivated them to supervise trainees. The programme has stimulated the consultants to improve the structure of the teaching programmes in the hospital ward. [ABSTRACT FROM AUTHOR]

Background: Traditionally, the transcriptomic and proteomic characterisation of CD4+ T cells at the single-cell level has been performed by two largely exclusive types of technologies: single-cell RNA sequencing (scRNA-seq) and antibody-based cytometry. Here, we present a multi-omics approach allowing the simultaneous targeted quantification of mRNA and protein expression in single cells and investigate its performance to dissect the heterogeneity of human immune cell populations. Methods: We have quantified the single-cell expression of 397 genes at the mRNA level and up to 68 proteins using oligo-conjugated antibodies (AbSeq) in 43,656 primary CD4+ T cells isolated from the blood and 31,907 CD45+ cells isolated from the blood and matched duodenal biopsies. We explored the sensitivity of this targeted scRNA-seq approach to dissect the heterogeneity of human immune cell populations and identify trajectories of functional T cell differentiation. Results: We provide a high-resolution map of human primary CD4+ T cells and identify precise trajectories of Th1, Th17 and regulatory T cell (Treg) differentiation in the blood and tissue. The sensitivity provided by this multi-omics approach identified the expression of the B7 molecules CD80 and CD86 on the surface of CD4+ Tregs, and we further demonstrated that B7 expression has the potential to identify recently activated T cells in circulation. Moreover, we identified a rare subset of CCR9+ T cells in the blood with tissue-homing properties and expression of several immune checkpoint molecules, suggestive of a regulatory function. Conclusions: The transcriptomic and proteomic hybrid technology described in this study provides a cost-effective solution to dissect the heterogeneity of immune cell populations at extremely high resolution. Unexpectedly, CD80 and CD86, normally expressed on antigen-presenting cells, were detected on a subset of activated Tregs, indicating a role for these co-stimulatory molecules in regulating the dynamics of CD4+ T cell responses. [ABSTRACT FROM AUTHOR]

Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar Typhimurium SL1344 infection. A combination of transcriptomics, bacterial invasion assays, and imaging suggests that IL-22-induced antimicrobial activity is driven by increased phagolysosomal fusion in IL-22- pretreated cells. The antimicrobial phenotype was absent in hIPSCs derived from a patient harboring a homozygous mutation in the IL10RB gene that inactivates the IL-22 receptor but was restored by genetically complementing the IL10RB deficiency. This study highlights a mechanism through which the IL-22 pathway facilitates the human intestinal epithelium to control microbial infection. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of inflammatory bowel disease (IBD) is complex and involves the contribution of genetic and environmental factors. Many patients with very early onset IBD are difficult to treat. The current antibiotic medication that targets gram-negative and anaerobic bacteria provides only moderate efficacy in subsets of patients with IBD. Methods: We report a case series of 5 children with a mean age of 1.6 years (range 6 months to 2.7 years) during IBD onset, who were previously refractory to standard treatments and who received oral vancomycin with or without gentamicin. Results: Four out of 5 children demonstrated substantial therapeutic effect, and the effect was sustained in 3 children over a follow-up period of 12–33 months. Conclusion: Our findings are consistent with model systems and suggest that randomized trials are required to establish whether a change in therapeutic paradigm, that is, targeting gram-positive bacteria with nonabsorbable antibiotics, may have therapeutic benefits. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response. [ABSTRACT FROM AUTHOR]

Summary RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers. [ABSTRACT FROM AUTHOR]

Diagnosis of coeliac disease (CD) relies on a combination of clinical, genetic, serological and duodenal morphological findings. The ESPGHAN suggested that biopsy may not be necessary in all cases. New guidelines include omission of biopsy if the concentration of CD-specific antibodies exceeds 10 times the upper limit of normal (10 ULN) and other criteria are met. We analysed the 10 ULN criterion and investigated multiple antibody-assays. Serum was collected from 1071 children with duodenal biopsy (376 CD patients, 695 disease-controls). IgA-antibodies to tissue transglutaminase (IgA-aTTG), IgG-antibodies to deamidated gliadin peptides (IgG-aDGL) and IgA-endomysium antibodies (IgA-EMA) were measured centrally. We considered 3 outcomes for antibody test procedures utilizing IgA-aTTG and/or IgG-aDGL: positive (≥10 ULN, recommend gluten-free diet), negative (<1 ULN, no gluten-free diet) or unclear (perform biopsy). Positive (PPV) and negative (NPV) predictive values were based on clear test results. We required that they and their lower confidence bounds (LCB) be simultaneously very high (LCB >90% and PPV/NPV >95%). These stringent conditions were met for appropriate antibody-procedures over a prevalence range of 9–57%. By combining IgG-aDGL with IgA-aTTG, one could do without assaying total IgA. The PPV of IgG-aDGL was estimated to be extremely high, although more studies are necessary to narrow down the LCB. The proportion of patients requiring a biopsy was <11%. The procedures were either equivalent or even better in children <2 years compared to older children. All 310 of the IgA-aTTG positive children were also IgA-EMA positive. Antibody-assays could render biopsies unnecessary in most children, if experienced paediatric gastroenterologists evaluate the case. This suggestion only applies to the kits used here and should be verified for other available assays. Confirming IgA-aTTG positivity (≥10 ULN) by EMA-testing is unnecessary if performed on the same blood sample. Prospective studies are needed. [ABSTRACT FROM AUTHOR]

Lactoferrin (LF) is a protein present in milk and other body fluids that plays important biological roles. As part of a diet, LF must survive gastrointestinal conditions or create bioactive fragments to exert its effects. The degradation of LF and formation of bioactive peptides is highly dependent on individual variation in intraluminal composition. The present study was designed to compare the degradation and peptide formation of bovine LF (bLF) following in vitro digestion under different simulated intraluminal conditions. Human gastrointestinal (GI) juices were used in a 2-step model digestion to mimic degradation in the stomach and duo-denum. To account for variation in the buffering capacity of different lactoferrin-containing foods, gastric pH was adjusted either slowly or rapidly to 2.5 or 4.0. The results were compared with in vivo digestion of bLF performed in 2 volunteers. High concentration of GI juices and fast pH reduction to 2.5 resulted in complete degradation in the gastric step. More LF resisted gastric digestion when pH was slowly reduced to 2.5 or 4.0. Several peptides were identified; however, few matched with previously reported peptides from studies using nonhuman enzymes. Surprisingly, no bovine lactoferricin, f(17-41), was identified during in vitro or in vivo digestion under the intraluminal conditions used. The diversity of enzymes in human GI juices seems to affect the hydrolysis of bLF, generating different peptide fragments compared with those obtained when using only one or a few proteases of animal origin. Multiple sequence analysis of the identified peptides indicated a motif consisting of proline and neighboring hydrophobic residues that could restrict proteolytic processing. Further structure analysis showed that almost all proteolytic cutting sites were located on the surface and mainly on the nonglycosylated half of lactoferrin. Digestion of bLF by human enzymes may generate different peptides from those found when lactoferrin is digested by nonhuman enzymes. The degradation of LF in the GI tract should be taken into consideration when health effects are proposed, because LF has now been approved by the European Food Safety Authority as a dietary supplement in food products. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have shown an association between gastro-oesophageal reflux disease (GORD) and asthma, and oesophageal acid perfusion may cause bronchial constriction. However, no causative relation has been proven. Aim: To assess whether acid suppression would lead to reduced asthma symptoms in children with concomitant asthma and GORD. Methods: Thirty eight children (mean age 10.8 years, range 7.2-16.8; 29 males) with asthma and a reflux index ⩾5.0 assessed by 24 hour oesophageal pH monitoring were randomised to 12 weeks of treatment with omeprazole 20 mg daily or placebo. The groups were similar in age, gender, mean reflux index, and asthma severity. Primary endpoints were asthma symptoms (daytime wheeze, symptoms at night, in the morning, and during exercise) and quality of life (PAQLQ). Secondary endpoints were changes in lung function and the use of short acting bronchodilators. At the end of the study a repeated pH study was performed to confirm the efficacy of acid suppression. Results: The change in total symptom score did not differ significantly between the omeprazole and the placebo group, and decreased by 1.28 (95% CI -0.1 to 2.65) and 1.28 (95% CI -0.72 to 3.27) respectively. The PAQLQ score increased by 0.62 (95% CI 0.29 to 0.95) in the omeprazole group compared to 0.50 (95% CI 0.29 to 0.70) in the placebo group. Change in lung function and use of short acting bronchodilators were similar in the groups. The acid suppression was adequate (reflux index <5.0) under omeprazole treatment. Conclusion: Omeprazole treatment did not improve asthma symptoms or lung function in children with asthma and GORD. [ABSTRACT FROM AUTHOR]

Murine models of inflammatory bowel disease (IBD) are useful tools for the study of the pathogenesis and regulation of intestinal inflammation. Colitis can be induced in immune-deficient mice following transfer of populations of T cells or following infection withHelicobacter hepaticusand other intestinal pathogens. In these situations, colitis occurs as a result of the absence of a specialized population of regulatory cells, as transfer of CD4+CD25+ T cells prevents disease. Importantly, from a clinical perspective, CD4+CD25+ T cells can also reverse an established colitis. CD4+CD25+ T cells proliferate both in the secondary lymphoid organs and at the site of inflammation, suggesting that regulation occurs both locally and systemically. CD4+CD25+ T cells are not only capable of regulating other T cells but are also capable of suppressing components of the innate immune system. Control of colitis is dependent on the presence of the immunosuppressive cytokines interleukin-10 and transforming growth factor-β, although their roles are divergent and complex. Regulatory T cells represent one of the host's mechanisms to prevent immune pathology during chronic immune stimulation. Enhancement of regulatory T-cell activity may be useful to control autoreactive T-cell responses and inhibit harmful inflammatory diseases such as asthma and IBD. [ABSTRACT FROM AUTHOR]

Gastrointestinal lipid absorption in Atlantic salmon was studied following force-feeding with a standard grower diet to which isotope-labelled free fatty acid (FFA) [1-14C]-decanoic acid (14C-10:0) and triacylglycerol (TAG) [9,10-3H(N)]-triolein (trioleic acid; 3H-18:1) were added. Following force-feeding, the 15 fish, with an average weight of 704 g, were kept in five circular tanks, three fish per tank, supplied with seawater (salinity, 32 g l−1). At 3, 6, 12, 18 and 48 h, the fish from one tank were killed, and the gastrointestinal (GI) tract was removed and divided into six segments: stomach (ST), anterior, mid, and distal pyloric ceca (PCA, PCM, and PCD, respectively), mid intestine (MI), and distal intestine (DI). The levels of radioactivity (dpm [disintegrations per minute] μg−1 tissue) from the 14C-10:0 and the 3H-18:1 substrates were measured in tissue samples from each segment, allowing an estimation of the amounts of fatty acid substrates absorbed from the lumen into the intestinal cells. The highest levels of radioactivity from both fatty acid substrates were measured in tissue from pyloric ceca (PC) 12 to 18 h after force-feeding. The level of radioactivity from the 14C-10:0 substrate was significantly higher in the PCA than in the PCM and PCD, while there was no clear difference in the level of radioactivity from the 3H-18:1 substrate measured among the different PC tissue segments and the level measured in MI. The level of radioactivity in tissue from DI was negligible to low for both fatty acid substrates. Total lipid accumulation in tissue from PCM, MI and DI was quantified morphometrically at each sampling point using light microscopy and image analysis. These results confirmed the findings from the isotope study, where the highest levels of fat were present at 12 and 18 h following force-feeding. In conclusion, PC was the most important site for fatty acid absorption in the GI tract of Atlantic salmon. [Copyright &y& Elsevier]

Abstract Fifteen experimental diets with five levels of medium chain triglycerides (MCT) (0, 39, 78, 117 and 156 g kg-1 ) and three levels of cysteine supplementations (0.0, 2.5 and 5.0 g kg-1 ) were fed ad libitum to Atlantic salmon (mean weight at start 846 g) in sea water for 71 days. Nutrient digestibilities and protein retention improved significantly with increasing dietary MCT level following simple linear regression models. Positive effects were also observed on proteolytic enzyme activities in chyme of the pyloric region with peak value around 117 g kg-1 MCT. However, strong inverse relationships were observed between MCT level and feed intake, growth, body lipid and energy retention, and these effects accelerated with increasing MCT level. Also chyme dry matter decreased with increasing MCT level which also seemed to stimulate pancreatic and bile secretion. MCT did not significantly affect condition factor, dress out percentage, relative liver size or pH in gastrointestinal contents. The only significant effects of dietary cysteine supplementation were increased enzyme activities in chyme of the pyloric region with peak values for the intermediate cysteine level. The results elucidate the importance of diet composition for digestive functions, production efficiency and composition quality. [ABSTRACT FROM AUTHOR]

Background: Mivacurium is hydrolyzed by plasma cholinesterase, and is therefore less dependent on liver metabolism and renal elimination than other neuromuscular blocking drugs. This might favor the use of mivacurium in elderly patients. The purpose of this study was to compare the pharmacodynamics and the pharmacokinetics of the three isomers of mivacurium and their metabolites in young adult and elderly patients.Methods: Sixty-four patients were included in a dose-response study, in which 32 young adults and 32 elderly patients received one of four doses of mivacurium. An additional bolus dose of mivacurium to a total of 0.1 mg/kg was given followed by a continuous infusion adjusted to maintain a 91-99% neuromuscular block. The times to maximum block and different levels of recovery were measured using mechanomyography and train-of-four (TOF) nerve stimulation. Thirty-two patients were randomly selected for the pharmacokinetic study. Venous samples were taken for determination of the three mivacurium isomers and the metabolites.Results: The estimated ED95 were 0.053 and 0.061 mg/kg in young adults and elderly patients, respectively (NS). The median infusion rate did not differ, but duration to a TOF ratio of 0.7 was significantly longer in elderly patients than in young adult patients (21.0 vs. 16.5 min). No statistically significant difference between the age groups in clearance and elimination half-life of the isomers was seen. The half-lives of the metabolites were significantly prolonged in the elderly patients.Conclusion: There were no significant differences in the potency or infusion requirements between the adult and elderly patients, but the rate of recovery was significantly, though only moderately prolonged, in the elderly patients. No significant difference in clearance was seen but the elimination half-lives of the metabolites was longer in the elderly patients. [ABSTRACT FROM AUTHOR]