Allergen-Vaccine Immunotherapy And Its Effect On Immunological Markers In Asthmatic Children

Abstract: Allergen immunotherapy is the administration of gradually increasing quantities of an allergen vaccine to an allergic subject, reaching a dose which is effective in ameliorating the symptoms associated with subsequent exposure to the causative allergen. So allergy vaccine immunotherapy is a treatment that can modify allergic disease. In the present study we evaluated a period of one and half year of house dust mite immunotherapy on the concentrations of two immunologic markers: Eosinophil cationic protein (ECR) and nitric oxide (NO). We also compared the effect on asthma symptoms, allergen specific bronchial challenge test and the skin prick test. The immunotherapy was performed on 36 mite allergic, asthmatic children (age range from 6-15 years) were included in our study. Twenty of the cases were treated with sublingual immunotherapy (55.5%) and 17 cases were controls as they refused to receive the medication. Efficacy was evaluated clinically on asthma symptoms and by measuring the serum NO and ECP, allergen specific bronchial challenge test and the skin prick test. Results: The sublingual immunotherapy (SLIT) group detected a significant improvement in asthma symptoms (P=0.001) and skin reactivity to dermatophagoides ptronyssinus (P=0.020) whereas the control group did not. The result of bronchial challenge to D pteronyssinus showed a similar pattern at baseline and after 2 years of treatment in both groups. The serum levels of NO and ECP were significantly reduced in the SLIT group (P=0.01 and P=0.018) compared to baseline, whereas the values remained the same in the control group. The result of bronchial challenge to D pteronyssinus showed similar results at baseline after 2 years of treatment in both groups. The tolerated allergen concentration increased in both groups (p<0.05). Lung function tests, total immunoglobulin (IgE) and specific IgE to D pteronyssinus and Dermatophagoides farinae did not change after 2 years of treatment in either group. Conclusion: The SLIT with D pteronyssinus improves the clinical parameters and the immunological parameters in mite allergic asthmatic children after one and half year of treatment. The skin prick test may be used as a marker of efficacy of therapy

Can montelukast correct immune dysregulation in preschool children with mild persistent asthma?

Background: Asthma is the most common inflammatory disorder among preschool and school-age children. Regulation of immune cells and their cytokines is essential to control asthma. Montelukast is a leukotriene receptor antagonist that suppresses inflammatory cell proliferation, and reduces cytokines and mediator secretion. Objective: The research team's goal was to study the immunological parameters among mild  asthmatic patients before and after the treatment with Montelukast. Methods: Forty preschool children with mild persistent asthma and twenty healthy, non-allergic children were included in the study. Blood eosinophil count, total IgE, serum IL-4, IL-10, and IL-13 levels were  assessed. T helper (CD3+CD4+) and T regulatory (CD4+CD25+) cell counts were measured using flow cytometry; for mild asthmatics before and after six weeks of treatment with Montelukast and for the control group. Results: Asthmatic children have shown a significant elevation of serum levels of IgE, IL4 and IL13, and also an increase of eosinophils, total lymphocyte T cells and T helper cell count. However; serum levels of IL10 and Treg cell count was lower in asthmatics compared to control. Following six weeks of Montelukast treatment, all immunological parameters improved. There was a significant elevation of serum levels of IL10 and Treg cell count, with a decrease in serum levels of IgE, IL4 and IL13; eosinophil counts, and helper T cells. Conclusion: Montelukast treatment improves the impaired immunological balance of mild asthmatic children through the increase of serum IL-10, T regulatory cell counts that have anti-inflammatory and immunoregulatory effects. It also decreases T helper cells and their proinflammatory cytokines

Comparison of Serum IgG Antibody Test with Gastric Biopsy for the Detection of Helicobacter Pylori Infection among Egyptian Children

BACKGROUND: In developing countries, Helicobacter pylori (H. pylori) infection is mainly acquired during childhood and may be a predisposing factor for peptic ulcer or gastric cancer later in life. Noninvasive diagnostic tools are particularly useful in children for screening tests and epidemiological studies. Data on serologic testing of children are lacking. Accurate noninvasive tests for diagnosing Helicobacter pylori infection in children are strongly required.AIM: The aim of this study was to evaluate the performance of a serological test (serum IgG antibody for H. pylori) in Egyptian children with recurrent abdominal pain necessitating endoscopy.SUBJECTS AND METHODS: One hundred children, referred to the endoscopy unit at Mansoura University. Upper endoscopy was done for each with rapid urease test (RUT) and histological examination as the gold standard test for detection of H. pylori infection. Serum samples were collected for detecting IgG for H. pylori infection.RESULTS: The mean age of the subjects included in the study was 7.23 ± 1.94 year. Serological test (IgG to H. pylori) was positive in 60% of all cases. A highly significant association between the standard test and the serological test at a cutoff > 10 U/ml at p = 0.001 were detected for the diagnosis of H. pylori infection. The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio for the IgG antibody a cutoff > 10 U/ml, were 96.5%, 93%, 13.83, 0.038 respectively.CONCLUSION: Serum IgG antibody to H. pylori infection has a high diagnostic value and can be considered as a suitable and reliable noninvasive test for detection of H. pylori infection

Relationship of Oxidant and Antioxidant Markers to Asthma Severity in Egyptian Asthmatic Children

BACKGROUND: Asthma is a chronic airway disease which is characterized by oxidant antioxidant imbalance with the generation of oxidative stress related mediators.AIM: The study aimed to evaluate the role of asymmetric dimethylarginine, and malondialdehyde as oxidant markers and serum paraoxonase activity as an antioxidant marker in asthma, and to determine their relationship to the asthma severity and lung function among asthmatic children in Egypt.PATIENTS AND METHODS: This case control study was conducted on sixty patients with asthma compared with sixty apparently healthy children of matched age and sex.RESULTS: Serum concentrations of oxidant markers as asymmetric dimethylarginine and malondialdehyde were significantly increased in asthmatic patients while anti-oxidant marker as paraoxonase activity was significantly decreased compared to healthy controls (P < 0.05). ANOVA test revealed highly significant elevation of the serum concentrations of oxidant markers while anti-oxidant marker was significantly decreased in severe asthmatic patients (P < 0.001) compared to the patients with moderate and mild asthma respectively. Serum malondialdehyde concentration was a strong predictor of asthma severity by multiple regression analysis (P < 0.05).CONCLUSION: The study revealed an imbalance between oxidative and antioxidant defence systems in asthmatic children. Serum concentration of malondialdehyde was the most predictive biomarker having a significant association with asthma severity

A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.ope

IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype

Background: Bidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies. Methods: We screened 1628 individuals with reno-ocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes. Results: Consequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling. Conclusions: This work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies

Rare single-gene disorders cause chronic disease. However, half of the 6,000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sib-ships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy we detect the causative gene. In six sib-ships we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sib-ships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus whole exome resequencing establishes an efficient, non-invasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms