42 research outputs found

    Quality of life and behavioral functioning in Dutch pediatric patients with hereditary spherocytosis

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    The objective of this study was to evaluate health-related quality of life (HRQoL) and behavioral functioning in pediatric patients with hereditary spherocytosis (HS). A cross-sectional study was conducted in 132 Dutch children and adolescents with HS and aged 8-18 years of whom 48 underwent splenectomy prior to the study. HRQoL was assessed using the KIDSCREEN-27, and behavioral functioning was evaluated using the strength and difficulties questionnaire (SDQ). Scores of pediatric patients with HS were compared to a Dutch norm population. Additionally, the effects of three factors were assessed: fatigue, self-image, and parents' perceived vulnerability (measured with the checklist individual strength, the self-perception profile for children and adolescents, and the child vulnerability scale). Both unsplenectomised and splenectomised pediatric patients reported lower HRQoL on the domain physical well-being (KIDSCREEN-27) compared to Dutch peers. For behavioral functioning, parents of both groups reported more emotional problems (SDQ) compared to the norm population. Pediatric patients with lower scores on physical well-being experienced more fatigue. The patients' perceived social acceptance and parents' perceived vulnerability appeared as determinants of emotional problems. Conclusion: Pediatric patients in the current study generally report few complaints, and the results suggest that these patients overall have a strong ability to cope with HS. Despite these few complaints, fatigue and parents' perceived vulnerability seem to be important determinants for lower HRQoL and more emotional problems. Therefore, screening on these factors could serve as an addition to the treatment of HS, to help pediatric patients who are at risk for lower HRQoL or more emotional problems

    Effect of painful Ledderhose disease on dynamic plantar foot pressure distribution during walking:a case-control study

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    Background: Plantar pressure distribution during walking in patients with painful Ledderhose disease is unknown.Research question: Do patients with painful Ledderhose disease have an altered plantar pressure distribution during walking compared to individuals without foot pathologies? It was hypothesized that plantar pressure is shifted away from the painful nodules.Methods: Pedobarography data of 41 patients with painful Ledderhose disease (cases, mean age: 54.2 ± 10.4 years) was collected and compared to pedobarography data from 41 individuals without foot pathologies (controls, mean age: 21.7 ± 2.0 years). Peak Pressure (PP), Maximum Mean Pressure (MMP) and Force-Time Integral (FTI) were calculated for eight regions (heel, medial midfoot, lateral midfoot, medial forefoot, central forefoot, lateral forefoot, hallux and other toes) under the soles of the feet. Differences between cases and controls were calculated and analysed by means of linear (mixed models) regression.Results: Proportional differences in PP, MMP and FTI showed increased values for the cases compared to the controls, especially in the heel, hallux and other toes regions, and decreased values in the medial- and lateral midfoot regions. In naïve regression analysis, being a patient was a predictor for increased- and decreased values for PP, MMP and FTI for several regions. When dependencies in the data were taken into account with linear mixed-model regression analysis, the increased- and decreased values for the patients were most prevalent for FTI at the heel, medial midfoot, hallux and other toes regions.Significance: In patients with painful Ledderhose disease, during walking, a shift of pressure was found towards the proximal and distal foot regions, while offloading the midfoot regions.</p

    Activation of proteinase 3 contributes to Non-alcoholic Fatty Liver Disease (NAFLD) and insulin resistance

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    Contains fulltext : 169891.pdf (publisher's version ) (Open Access)Activation of inflammatory pathways is known to accompany development of obesity-induced non-alcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive pro-inflammatory mediators IL-1beta and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In the present study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human alpha-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3 deficient mice showed strongly reduced levels of lipids in the liver after fed a high fat diet. Moreover, these mice were resistant to high fat diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1(-/-) mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with alpha-1 antitrypsin during the last 10 days of a 16 week high fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential

    Deletion of hematopoietic Dectin-2 or CARD9 does not protect against atherosclerotic plaque formation in hyperlipidemic mice

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    Inflammatory reactions activated by pattern recognition receptors (PRRs) on the membrane of innate immune cells play an important role in atherosclerosis. Whether the PRRs of the C-type lectin receptor (CLR) family including Dectin-2 may be involved in the pathogenesis of atherosclerosis remains largely unknown. Recently, the CLR-adaptor molecule caspase recruitment domain family member 9 (CARD9) has been suggested to play a role in cardiovascular pathologies as it provides the link between CLR activation and transcription of inflammatory cytokines as well as immune cell recruitment. We therefore evaluated whether hematopoietic deletion of Dectin-2 or CARD9 reduces inflammation and atherosclerosis development. Low-density lipoprotein receptor (Ldlr)- knockout mice were transplanted with bone marrow from wild-type, Dectin-2- or Card9-knockout mice and fed a Western-type diet containing 0.1% (w/w) cholesterol. After 10 weeks, lipid and inflammatory parameters were measured and atherosclerosis development was determined. Deletion of hematopoietic Dectin-2 or CARD9 did not influence plasma triglyceride and cholesterol levels. Deletion of hematopoietic Dectin-2 did not affect atherosclerotic lesion area, immune cell composition, ex vivo cytokine secretion by peritoneal cells or bone marrow derived macrophages. Unexpectedly, deletion of hematopoietic CARD9 increased atherosclerotic lesion formation and lesion severity. Deletion of hematopoietic CARD9 did also not influence circulating immune cell composition and peripheral cytokine secretion. Besides a tendency to a reduced macrophage content within these lesions, plasma MCP-1 levels decreased upon WTD feeding. Deletion of hematopoietic Dectin-2 did not influence atherosclerosis development in hyperlipidemic mice. The absence of CARD9 unexpectedly increased atherosclerotic lesion size and severity, suggesting that the presence of CARD9 may protect against initiation of atherosclerosis development

    Terrestrial behavior in titi monkeys (Callicebus, Cheracebus, and Plecturocebus) : potential correlates, patterns, and differences between genera

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    For arboreal primates, ground use may increase dispersal opportunities, tolerance to habitat change, access to ground-based resources, and resilience to human disturbances, and so has conservation implications. We collated published and unpublished data from 86 studies across 65 localities to assess titi monkey (Callicebinae) terrestriality. We examined whether the frequency of terrestrial activity correlated with study duration (a proxy for sampling effort), rainfall level (a proxy for food availability seasonality), and forest height (a proxy for vertical niche dimension). Terrestrial activity was recorded frequently for Callicebus and Plecturocebus spp., but rarely for Cheracebus spp. Terrestrial resting, anti-predator behavior, geophagy, and playing frequencies in Callicebus and Plecturocebus spp., but feeding and moving differed. Callicebus spp. often ate or searched for new leaves terrestrially. Plecturocebus spp. descended primarily to ingest terrestrial invertebrates and soil. Study duration correlated positively and rainfall level negatively with terrestrial activity. Though differences in sampling effort and methods limited comparisons and interpretation, overall, titi monkeys commonly engaged in a variety of terrestrial activities. Terrestrial behavior in Callicebus and Plecturocebus capacities may bolster resistance to habitat fragmentation. However, it is uncertain if the low frequency of terrestriality recorded for Cheracebus spp. is a genus-specific trait associated with a more basal phylogenetic position, or because studies of this genus occurred in pristine habitats. Observations of terrestrial behavior increased with increasing sampling effort and decreasing food availability. Overall, we found a high frequency of terrestrial behavior in titi monkeys, unlike that observed in other pitheciids

    Quality of life and behavioral functioning in Dutch pediatric patients with hereditary spherocytosis

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    The objective of this study was to evaluate health-related quality of life (HRQoL) and behavioral functioning in pediatric patients with hereditary spherocytosis (HS). A cross-sectional study was conducted in 132 Dutch children and adolescents with HS and aged 8-18 years of whom 48 underwent splenectomy prior to the study. HRQoL was assessed using the KIDSCREEN-27, and behavioral functioning was evaluated using the strength and difficulties questionnaire (SDQ). Scores of pediatric patients with HS were compared to a Dutch norm population. Additionally, the effects of three factors were assessed: fatigue, self-image, and parents' perceived vulnerability (measured with the checklist individual strength, the self-perception profile for children and adolescents, and the child vulnerability scale). Both unsplenectomised and splenectomised pediatric patients reported lower HRQoL on the domain physical well-being (KIDSCREEN-27) compared to Dutch peers. For behavioral functioning, parents of both groups reported more emotional problems (SDQ) compared to the norm population. Pediatric patients with lower scores on physical well-being experienced more fatigue. The patients' perceived social acceptance and parents' perceived vulnerability appeared as determinants of emotional problems. Conclusion: Pediatric patients in the current study generally report few complaints, and the results suggest that these patients overall have a strong ability to cope with HS. Despite these few complaints, fatigue and parents' perceived vulnerability seem to be important determinants for lower HRQoL and more emotional problems. Therefore, screening on these factors could serve as an addition to the treatment of HS, to help pediatric patients who are at risk for lower HRQoL or more emotional problems

    Different pathogenic stimuli induce specific metabolic rewiring in human monocytes

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    Recent studies have demonstrated that upon encountering a pathogenic stimulus, robust metabolic rewiring of immune cells occurs. A switch away from oxidative phosphorylation to glycolysis, even in the presence of sufficient amounts of oxygen (akin the Warburg effect), is typically observed in activated innate and adaptive immune cells and is thought to accommodate adequate inflammatory responses. However, whether the Warburg effect is a general phenomenon applicable in human monocytes exposed to different pathogenic stimuli is unknown. Our results using human monocytes from healthy donors demonstrate that the Warburg effect only holds true for TLR4 activated cells. Although activation of other TLRs leads to an increase in glycolysis, no reduction or even an enhancement in oxidative phosphorylation is observed. Moreover, specific metabolic rewiring occurs in TLR4 vs. TLR2 stimulated cells characterized by altered gene expression profiles of pathways related to metabolism, changes in spare respiratory capacity of the cells and differential regulation of mitochondrial enzyme activity. Similarly, results from ex vivo and in vivo studies demonstrate metabolic rewiring of immune cells that is highly dependent on the type of pathogenic stimulus. Although the Warburg effect is observed in human monocytes after TLR4 activation, we propose that this typical metabolic response is not applicable to other inflammatory signalling routes including TLR2 in human monocytes. Instead, each pathogenic stimulus and subsequently activated inflammatory signalling cascade induces specific metabolic rewiring of the immune cell to accommodate an appropriate response

    Proinflammatory effects of hypoglycemia in humans with or without diabetes

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    Severe hypoglycemic events have been associated with increased cardiovascular mortality in patients with diabetes, which may be explained by hypoglycemiainduced inflammation. We used ex vivo stimulations of peripheral blood mononuclear cells (PBMCs) and monocytes obtained during hyperinsulinemic-euglycemic (5.0 mmol/L)-hypoglycemic (2.6 mmol/L) clamps in 11 healthy participants, 10 patients with type 1 diabetes and normal awareness of hypoglycemia (NAH), and 10 patients with type 1 diabetes and impaired awareness (IAH) to test whether the composition and inflammatory function of immune cells adapt to a more proinflammatory state after hypoglycemia. Hypoglycemia increased leukocyte numbers in healthy control participants and patients with NAH but not in patients with IAH. Leukocytosis strongly correlated with the adrenaline response to hypoglycemia. Ex vivo, PBMCs and monocytes displayed a more robust cytokine response to microbial stimulation after hypoglycemia compared with euglycemia, although it was less pronounced in patients with IAH. Of note, hypoglycemia increased the expression of markers of demargination and inflammation in PBMCs. We conclude that hypoglycemia promotes mobilization of specific leukocyte subsets from themarginal pool and induces proinflammatory functional changes in immune cells. Inflammatory responses were less pronounced in IAH, indicating that counterregulatory hormone responses are key modulators of hypoglycemia-induced proinflammatory effects. Hypoglycemia-induced proinflammatory changes may promote a sustained inflammatory state.</p

    Genetic and pharmacological inhibition of vanin-1 activity in animal models of type 2 diabetes

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    Vanins are enzymes that convert pantetheine to pantothenic acid (vitamin B5). Insights into the function of vanins have evolved lately, indicating vanin-1 to play a role in inflammation, oxidative stress and cell migration. Moreover, vanin-1 has recently gained attention as a novel modulator of hepatic glucose and lipid metabolism. In the present study, we investigated the role of vanin-1 in the development of hepatic steatosis and insulin resistance in animal models of obesity and diabetes. In addition, we evaluated the potency of RR6, a novel pharmacological vanin-1 inhibitor, as an anti-diabetic drug. Increased vanin activity was observed in plasma and liver of high fat diet (HFD)-induced obese mice, as well as ZDF-diabetic rats. Ablation of vanin-1 (Vnn1-/- mice) mildly improved glucose tolerance and insulin sensitivity in HFD-fed mice, but had no effects on body weight, hepatic steatosis or circulating lipid levels. Oral administration of RR6 for 8 days completely inhibited plasma vanin activity, but did not affect hepatic glucose production, insulin sensitivity or hepatic steatosis in ZDF-diabetes rats. In conclusion, absence of vanin-1 activity improves insulin sensitivity in HFD-fed animals, yet short-term inhibition of vanin activity may have limited value as an anti-diabetic strategy
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