The Inflammatory Prequel of Pediatric Appendicitis

AbstractBackground: Appendicitis is the most common disease requiring acute abdominal surgery in children, yet the pathogenesis of appendicitis is not fully understood. It can be challenging to diagnose appendicitis clinically, especially in young children, leading to high rates of initial misdiagnosis. It is not clear why some children are affected by a complicated disease course while others recover spontaneously. It has been proposed that different immune responses in different individuals propel the inflammation towards an uncomplicated or a complicated disease course. To date, there is no reliable measure to distinguish between patients with uncomplicated appendicitis and those with complicated appendicitis.Aims: To increase the knowledge of how the inflammatory processes anteceding pediatric appendicitis can be categorized, modulated, and detected.Methods: Papers I, IV and V were prospective clinical institution-based studies. Paper II was a retrospective institutionbased cohort study and Paper III a nationwide cohort study. In Paper I the diagnostic performances of four different clinical prediction scores for pediatric appendicitis were evaluated. In Papers II and III the associations of immunoglobulin E (IgE)-mediated allergy and complicated appendicitis in children were evaluated. In Paper IV we assessed the associations of biological stress, measured as hair cortisol concentrations (HCC) and pediatric appendicitis. In Paper V the associations of serum concentrations of IgE and T helper cell 2 (Th2)-associated cytokines with complicated appendicitis were evaluated.Results: The clinical prediction scores appendicitis inflammatory response (AIR) score and pediatric appendicitis risk calculator (pARC) displayed significantly higher specificity and positive predictive value and lower rates of negative appendectomies compared to the pediatric appendicitis score (PAS) and Alvarado score (I). Children with IgE-mediated allergy had a significantly reduced odds of complicated appendicitis (aOR 0.33 [95% CI 0.18-0.59], p<0.001 (II), and aOR 0.80 [95% CI 0.67-0.96], p=0.021 (III)). The risk of complicated appendicitis among allergic children was reduced by one-third compared to that in non-allergic children (IR 0.13 vs 0.20 per 1000 person-years, HR 0.68 [95% CI 0.58-0.81], p<0.001), while the risk of uncomplicated appendicitis did not vary with allergy status (IR 0.91 vs 0.91, HR 1.00 [95% CI 0.94-1.07], p=0.932). Seasonal antigen exposure was a protective factor for complicated appendicitis (aOR 0.82 [95% CI 0.71-0.94], p=0.004), and ongoing antihistamine medication was a risk factor (aOR 2.28 [95% CI 1.21-4.28], p=0.012) (III). An increase in HCC was associated with an increased risk of appendicitis (aOR 10.76 [95% CI 2.50-46.28], p=0.001) and complicated appendicitis (aOR 7.86 [95% CI 1.20-51.63], p=0.03) (IV). High concentrations of IL-13 were associated with an increased risk of complicated appendicitis (aOR 1.02 [95% CI 1.01-1.04], p=0.011). Serum concentrations of IgE, IL-4, and IL-9 were not significantly associated with the risk of complicated appendicitis (V).Conclusions: AIR score and pARC are superior to the PAS and Alvarado score for diagnosing appendicitis in children. Children with allergy have a lower risk of complicated appendicitis, but the same risk of uncomplicated appendicitis, compared to non-allergic children. Increased stress, measured as an increase in HCC, is associated with an increased risk of appendicitis and complicated appendicitis in children. High levels of IL-13 seem to be associated with an increased risk of complicated appendicitis in children

Автоматизированное рабочее место мастера участка тяговых подстанций КУП «Горэлектротранспорт»

Background: The elevated body swing test (EBST) is a behavioral test used to evaluate experimental stroke in rodents. The basic idea is that when the animal is suspended vertically by the tail, it will swing its head laterally to the left or right depending on lesion side. In a previous study from our lab using the EBST after middle cerebral artery occlusion (MCAo), rats swung contralateral to the infarct day 1 post-MCAo, but ipsilateral day 3 post-MCAo. This shift was unexpected and prompted us to perform the present study. First, the literature was systematically reviewed to elucidate whether a similar shift had been noticed before, and if consensus existed regarding swing direction. Secondly, an experiment was conducted to systematically investigate the suggested behavior. Eighty-three adult male and female Sprague-Dawley rats were subjected to MCAo or sham surgery and the EBST was performed up to 7 days after the lesion. Results: Both experimentally and through systematic literature review, the present study shows that the direction of biased swing activity in the EBST for rodents after cerebral ischemia can differ and even shift over time in some situations. The EBST curve for females was significantly different from that of males after the same occlusion time (p = 0.023). Conclusions: This study highlights the importance of adequate reporting of behavioral tests for lateralization and it is concluded that the EBST cannot be recommended as a test for motor asymmetry after MCAo in rats.Funding Agencies|Region Ostergotland/Linkoping University, Sweden</p

Elevated body swing test after focal cerebral ischemia in rodents: methodological considerations

Background: The elevated body swing test (EBST) is a behavioral test used to evaluate experimental stroke in rodents. The basic idea is that when the animal is suspended vertically by the tail, it will swing its head laterally to the left or right depending on lesion side. In a previous study from our lab using the EBST after middle cerebral artery occlusion (MCAo), rats swung contralateral to the infarct day 1 post-MCAo, but ipsilateral day 3 post-MCAo. This shift was unexpected and prompted us to perform the present study. First, the literature was systematically reviewed to elucidate whether a similar shift had been noticed before, and if consensus existed regarding swing direction. Secondly, an experiment was conducted to systematically investigate the suggested behavior. Eighty-three adult male and female Sprague-Dawley rats were subjected to MCAo or sham surgery and the EBST was performed up to 7 days after the lesion. Results: Both experimentally and through systematic literature review, the present study shows that the direction of biased swing activity in the EBST for rodents after cerebral ischemia can differ and even shift over time in some situations. The EBST curve for females was significantly different from that of males after the same occlusion time (p = 0.023). Conclusions: This study highlights the importance of adequate reporting of behavioral tests for lateralization and it is concluded that the EBST cannot be recommended as a test for motor asymmetry after MCAo in rats.Funding Agencies|Region Ostergotland/Linkoping University, Sweden</p

Association of IgE-Mediated Allergy with Risk of Complicated Appendicitis in a Pediatric Population

Importance: Childhood appendicitis is commonly complicated by gangrene and perforation, yet the causes of complicated appendicitis and how to avoid it remain unknown. Objective: To investigate whether children with IgE-mediated allergy have a lower risk of complicated appendicitis. Design, Setting, and Participants: This retrospective cohort study included all consecutive patients younger than 15 years (hereinafter referred to as children) who underwent appendectomy for acute appendicitis at a tertiary pediatric surgery center in Sweden between January 1, 2007, through July 31, 2017. Children were stratified between those with and without IgE-mediated allergies. Main Outcome and Measures: Risk of complicated appendicitis with gangrene or perforation, with occurrence of IgE-mediated allergy as an independent variable and adjusted for age, sex, primary health care contacts, seasonal antigenic exposure, allergy medications, appendicolith, and duration of symptoms. Results: Of 605 included children (63.0% boys; median age, 10 years; interquartile range, 7-12 years), 102 (16.9%) had IgE-mediated allergy and 503 (83.1%) had no allergy. Complicated appendicitis occurred in 20 children with IgE-mediated allergy (19.6%) compared with 236 with no allergy (46.9%; adjusted odds ratio, 0.33; 95% CI, 0.18-0.59). No significant allergy effect modification by sex, seasonal antigenic exposure, or allergy medication was found. Children with IgE-mediated allergy had a shorter hospital stay (median, 2 days for both groups; interquartile range, 1-2 days vs 1-5 days; P =.004). Conclusions and Relevance: In this study, children with IgE-mediated allergy had a lower risk of complicated appendicitis. The findings suggest that immunologic disposition modifies the clinical pattern of appendiceal disease. This theory introduces novel opportunities for understanding of the pathogenesis and clinical decision making for one of childhood's most common surgical emergencies

Associations of hair cortisol concentrations with paediatric appendicitis

The pathogenesis of paediatric appendicitis is still an enigma. In recent years, it has become more evident that our inherent immunological responses affect the trajectory of the disease course. Long-term stress has an impact on our immune system; however, it is practically and ethically challenging to prospectively track blood measurements of cortisol-levels in asymptomatic children should an acute appendicitis episode develop. The aim of this case-control study was therefore to evaluate the effect of increased stress measured as historical imprints in hair (hair cortisol concentrations [HCC]), on the risk of developing appendicitis and complicated appendicitis. 51 children (aged&amp;lt;15 years) with appendicitis (34 with complicated appendicitis), were compared to 86 healthy controls. HCC reflecting the activity of the HPA-axis 0-3 and 4-6 months prior to sampling was evaluated and compared between groups as well as between the two measurements of each study subject. In the univariate analysis with both cases and controls, an increase in HCC between the measurement timepoints was associated with a substantial increase in risk of appendicitis (OR 7.52 [95% CI 2.49-22.67], p=0.001). This increased risk remained in the multivariate analysis after adjustment for age, sex and season (aOR OR 10.76 [95%CI 2.50-46.28], p =0.001). When comparing the cases of uncomplicated and complicated appendicitis through a multivariate analysis, adjusted for age and sex, the children with an increased HCC prior to appendicitis had a substantial and statistically significant increase in risk of complicated appendicitis (aOR 7.86 [95% CI 1.20-51.63], p=0.03). Biological stress, measured as an increase in HCC, seems to be associated with an increased risk of paediatric appendicitis and a more complicated disease course.Funding Agencies|Bengt Ihre Research Fellowship; Lund University</p

An Evaluation of Serum IgE and Th2-Associated Interleukins in Children With Uncomplicated and Complicated Appendicitis

Background: The pathogenesis of appendicitis is not understood completely and establishing a correct diagnosis can be clinically challenging. Previous investigations have shown an association between a T helper cell (Th)2-mediated inflammatory response, for example immunoglobulin E (IgE)-mediated allergy, and a decreased risk of complicated appendicitis. The present study aimed to evaluate differences in serum concentrations of IgE and Th2-associated interleukins (IL) in children with uncomplicated and complicated appendicitis.Method: A prospective study including children <15 years with appendicitis. Blood samples were collected preoperatively at the time of clinical assessment at the Pediatric Emergency Department and analyzed for concentrations of serum total IgE and IL-4, IL-9, and IL-13. Associations with complicated appendicitis were evaluated through logistic regression adjusting for age, appendicolith, and symptom duration.Results: 138 children with confirmed appendicitis were included. The median age was 10 (IQR 8–12) years, 87 (63%) were boys and 58 (42%) had complicated appendicitis. Children with complicated appendicitis had significantly higher concentrations of IL-9 and IL-13 compared to children with uncomplicated appendicitis. In the univariate logistic regression, high concentrations of IL-13 were associated with an increased risk of complicated appendicitis [OR 1.02 (95% CI 1.01–1.04) p = 0.005], which remained in the multivariate analysis [aOR 1.02 (95% CI 1.01–1.04), p = 0.01]. Serum concentrations of IgE, IL-4, and IL-9 did not significantly affect the risk of complicated appendicitis.Conclusion: High levels of IL-13 seem to be associated with an increased risk of complicated appendicitis. This is incongruent with the hypothesis of an Th1/Th17-driven inflammation in this type of appendicitis

Shared Genetic Factors Involved in Celiac Disease, Type 2 Diabetes and Anorexia Nervosa Suggest Common Molecular Pathways for Chronic Diseases

Background and Objectives Genome-wide association studies (GWAS) have identified several genetic regions involved in immune-regulatory mechanisms to be associated with celiac disease. Previous GWAS also revealed an over-representation of genes involved in type 2 diabetes and anorexia nervosa associated with celiac disease, suggesting involvement of common metabolic pathways for development of these chronic diseases. The aim of this study was to extend these previous analyses to study the gene expression in the gut from children with active celiac disease. Thirty six target genes involved in type 2 diabetes and four genes associated with anorexia nervosa were investigated for gene expression in small intestinal biopsies from 144 children with celiac disease at median (range) age of 7.4 years (1.6-17.8) and from 154 disease controls at a median (range) age 11.4. years (1.4-18.3). A total of eleven of genes were differently expressed in celiac patients compared with disease controls of which CD36, CD38, FOXP1, SELL, PPARA, PPARG, AGT previously associated with type 2 diabetes and AKAP6, NTNG1 with anorexia nervosa remained significant after correction for multiple testing. Shared genetic factors involved in celiac disease, type 2 diabetes and anorexia nervosa suggest common underlying molecular pathways for these diseases