Effect of feed on cholesterol concentration and oxidation products development of longissimus dorsi muscle from Iberian pigs

peer-reviewedThe effect of dietary free-range feeding or supplementation with copper and/or vitamin E in confinement on total cholesterol, neutral and polar lipids and cholesterol oxidation of the longissimus dorsi muscle from Iberian pigs was studied. Free-range fed pigs had higher (P=0.001) contents of γ-tocopherol and lower concentrations of α-tocopherol in the muscle than pigs fed diets supplemented with 100 mg/kg vitamin E. The total cholesterol content of the muscle was not significantly affected by the diets. However, the cholesterol:phospholipid ratio was higher (P<0.05), and consequently the membrane fluidity was lower, in the free-range fed pigs than in the pigs fed in confinement with either copper-supplemented (P<0.05) or vitamin E-supplemented (P<0.01) diets. The proportion of saturated fatty acids in phospholipids was greater (P<0.05) in the free-range fed group, which suggests metabolic regulation to maintain membrane structure. Free-range feeding produced higher levels of free fatty acids (P<0.01), lysophosphatidylcholine (P<0.05) and phosphatidylserine (P<0.01) and lower cholesterol esters (P<0.01) and sphingomyelin (P<0.05) in the muscle than the other groups. The ratios of phosphatidylethanolamine:phosphatidylcholine and sphingomyelin: phosphatidylcholine, which are indicators of membrane fluidity, were not significantly affected in any group. Dietary α-tocopheryl acetate supplementation produced lower β-epoxide (P<0.01), 7β-OH (P<0.05), and total cholesterol oxides (P<0.01) in cooked muscle after refrigerated display than in the other groups. These results indicate that supplementation with dietary α-tocopheryl acetate is more effective in reducing cholesterol oxidation than free-range feeding in cooked muscle from Iberian pigs. In evaluating oxidation, the composition of the muscle and meat treatment have to be considered as well as membrane fluidity.This research was funded by the European Project AIR-CT94-1577 (DIETOX

Newborn screening for severe primary immunodeficiencies

Primary immunodeficiencies (PID) are congenital disorders of immune competence, which are mainly characterized by a pathological susceptibility to infection. This is often accompanied by severe recurrent infections with drug-resistant, long progressions. In addition, there are associated immune regulation disorders, which may manifest themselves in granuloma formation, autoimmunity, recurrent fever, eczema, lymphoproliferation and chronic intestinal inflammation. More than 240 disease entities have been defined so far as PID, and just as extensive is the spectrum of clinical severity. While the most common congenital immunodeficiencies, such as selective IgA deficiency or C2 complement deficiency, have a mild phenotype which often remains undetected, severe PID are characterized by significant mortality in the first years of life, as well as a serious morbidity with irreversible organ damage. This applies in particular to PID that are defined by the absence or functional anergy of T-lymphocytes (severe combined immunodeficiency; SCID) or B-lymphocytes (e.g. X-linked agammaglobulinemia; XLA). Patients with such severe congenital immunodeficiencies appear to be in perfect health at birth, yet show initial manifestations of SCID between the 14th day and the 4th month following birth; in patients with XLA usually between the 8th and 16th month after birth. Albeit increasingly becoming appreciated as a relevant health problem, there is a lack of diagnostic procedures and screening profiles that would allow earliest possible diagnosis of patients with severe PID on a population scale. As a superior prognosis could be given upon prompt diagnosis and immediate adequate treatment, one strategy to improve the outcome of severe PID shall be to test newborns for the presence of T and B cells. With the aim to develop a simple and reliable test for newborn screening using the established dried blood sampling system (Guthrie cards), a multiplex real-time quantitative qPCR assay for the quantitation of T cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) as surrogate markers of T and B cell development was designed and evaluated (publication I). This assay was further extended to allow detection of newborns with an inversion of the UNC13D gene, causing a severe PID characterized as familial hemophagocytic lymphohistiocytosis (publication III). Furthermore, the feasibility to identify several other severe PID, characterized by a functional defect of T- and B-cell interation (combined immunodeficiency diseases), was assessed using IgA-protein detection in neonatal Guthrie cards. However, this assay provided evidence of a maternal transfer mechanism for IgA, thereby preventing the use of this assay as a screening tool for severe PID (publication II). Finally, the TREC-KREC newborn screening assay was further improved in terms of assay performance and evaluated in retrospective cohorts of patients with the DiGeorge syndrome, or Down syndrome (publications IV and V). In addition, novel second-tier assays for comfirmation of the 22q11 microdeletion or the chromosome 21 triplication have been designed and succesfully tested with neonatal samples. In summary, new assays and concepts for newborn screening of severe primary immunodeficeincies were designed and benchmarked in retrospective and prospective neonatal dried blood spot samples, thereby underlining the potential of this preventive health care strategy

The South China Sea International Disputes with the ASEAN Area (in International Maritime Law)

In history, the sea has been shown to have had various functions, including as a source of food for mankind, as a trade highway, as a means of conquest, as a place for battles, as a place for fun and recreation, and as a means of unifying or separating nations. nation. As one of the regions with a high degree of heterogeneity, the Asia Pacific region is often considered a region that is very vulnerable to conflict on the basis of a fragile regional balance. The purpose of this study is to find out that one of the territorial conflicts in the Asia Pacific is the South China Sea conflict which involves several countries including China, Taiwan, the Philippines, Vietnam, Malaysia and Brunei Darussalam. This research uses a normative approach in accordance with international maritime regulations, especially UNCLOS and the UN Arbitration Council. The results of this study indicate that she said the South China Sea entered a new chapter by submitting a dispute over the issue of territorial claims to the Arbitration Court in The Hague, Netherlands. The Philippines in January 2013 has officially brought the territorial dispute in the South China Sea to the international arbitration body. Political disputes have been stopped and entered a new phase, namely legal settlement. The issue that arises is whether legal settlement can be the key answer to this territorial dispute, then whether legal settlement can create justice for the disputing countries. Furthermore, whether a legal settlement can dampen and create stability and security in the region. It may be very far if a legal settlement can fulfill some of the questions above

Maternal stress, child behavior and the promotive role of older siblings

Abstract Background: In the first years of their lives, children develop the cognitive, social and emotional skills that will provide the foundations for their lifelong health and achievements. To increase their life prospects and reduce the long-term effects of early aversive conditions, it is therefore crucial to understand the risk factors that negatively affect child development and the factors that are instead beneficial. In this study, we tested (i) the effects of different social and environmental stressors on maternal stress levels, (ii) the dynamic relationship between maternal stress and child behavior problems during development, and (iii) the potential promotive (i.e. main) or protective (i.e. buffering) effect of siblings on child behavior problems during development.Methods: We used longitudinal data from 373 mother–child pairs (188 daughters, 185 sons) from pregnancy until 10 years of age. We assessed maternal stress and child behavior problems (internalizing and externalizing) with vali-dated questionnaires, and then used linear mixed models, generalized linear mixed models and longitudinal cross-lagged models to analyze the data.Results: Our results showed that higher maternal stress levels were predicted by socio-environmental stressors (i.e. the lack of sufficient social areas in the neighborhood). Moreover, prenatal maternal stress reliably predicted the occurrence of behavior problems during childhood. Finally, the presence of older siblings had a promotive function, by reducing the likelihood that children developed externalizing problems.Conclusions: Overall, our results confirm the negative effects that maternal stress during pregnancy may have on the offspring, and suggest an important main effect of older siblings in promoting a positive child development

BT595, a 10% Human Normal Immunoglobulin, for Replacement Therapy of Primary Immunodeficiency Disease: Results of a Subcohort Analysis in Children

Children; Pharmacokinetics; Serious bacterial infectionsNiños; Farmacocinética; Infecciones bacterianas gravesNens; Farmacocinètica; Infeccions bacterianes greusPurpose To assess the efficacy, pharmacokinetics, and safety of a new, highly purified 10% IVIg (BT595, Yimmugo®) administered in children with PID. Methods This was an open-label, prospective, uncontrolled, multicenter Phase III pivotal trial. Among the 67 subjects in the trial were 18 pediatric patients aged 2 to 17 years with diagnosis of PID included in this analysis. They received doses between 0.2 and 0.8 g/kg body weight for approximately 12 months at intervals of either 3 or 4 weeks. Dosage and dosing interval were based on each patient’s pre-trial infusion schedule. The rates of acute serious bacterial infections (SBI), secondary efficacy, safety, and pharmacokinetic outcomes were evaluated. Results No SBI occurred in the pediatric population. Two hundred sixty infusions were administered to the 18 pediatric patients. The mean (SD) IgG trough level was 8.55 (1.67) g/L at baseline and 8.84 (2.17) g/L at the follow-up visit after the last BT595 infusion. At the single infusions respectively, the average mean IgG trough levels ranged between 8.52 and 10.58 g/L. More than 85% of all infusions administered were not associated with any infusional AE (start during or within 72 h post-infusion). None of the severe or serious AEs were related to the investigational medicinal product (IMP). No premedication was used. Thirteen children reached a maximum infusion rate between > 2.0 and 8 mL/kg/h; no AE with an onset during the infusion occurred at these infusion rates. Conclusion BT595 is effective, convenient, well tolerated, and safe for the treatment of children with PID.This trial was funded by Biotest AG, Dreieich, Germany

Associations between BMI and the FTO Gene Are Age Dependent: Results from the GINI and LISA Birth Cohort Studies up to Age 6 Years

Objective: The association between polymorphisms in intron 1 of the fat mass and obesity associated gene (FTO) and obesity-related traits is one of the most robust associations reported for complex traits and is established both in adults and children. However, little is known about the longitudinal dynamics of these polymorphisms on body mass index (BMI), overweight, and obesity. Methods: This study is based on the 2,732 full-term neonates of the German GINI-plus and LISA-plus birth cohorts, for whom genotyping data on the FTO variants rs1558902 (T>A) or rs9935401 (G>A) were available. Children were followed from birth up to age 6 years. Up to 9 anthropometric measurements of BMI were obtained. Fractional-Polynomial-Generalized-Estimation-Equation modeling was used to assess developmental trends and their potential dependence on genotype status. Results: We observed no evidence for BMI differences between genotypes of both variants for the first 3 years of life. However, from age 3 years onwards, we noted a higher BMI for the homozygous minor alleles carriers in comparison to the other two genotype groups. However, evidence for statistical significance was reached from the age of 4 years onwards. Conclusions: This is one of the first studies investigating in detail the development of BMI depending on FTO genotype between birth and the age of 6 years in a birth cohort not selected for the phenotype studied. We observed that the association between BMI and FTO genotype evolves gradually and becomes descriptively detectable from the age of 3 years onwards

Real-World Use, Safety, and Patient Experience of 20% Subcutaneous Immunoglobulin for Primary Immunodeficiency Diseases.

INTRODUCTION The CORE study aimed to provide a detailed understanding of real-world immune globulin subcutaneous (human) 20% solution (Ig20Gly) utilization in patients with primary immunodeficiency diseases (PIDs) in Germany and Switzerland. METHODS Patients with PIDs receiving a stable dose of any subcutaneous immunoglobulin for ≥ 3 months before enrollment were eligible for this multicenter (n = 5), phase 4, non-interventional, prospective, longitudinal cohort study. Besides baseline demographics and clinical characteristics, Ig20Gly utilization and safety data, and patient-reported outcomes (Life Quality Index/Treatment Satisfaction Questionnaire for Medication) were collected at baseline, 6 and 12 months. Statistical analysis was descriptive. RESULTS Overall, 36 patients provided data at baseline [69.4% female; mean age: 41.6 years (7-78 years)]. Totals of 23 and 26 patients attended 6- and 12-month visits, respectively; 16 attended all three visits. One patient withdrew consent before 6-month follow-up. Median maximum infusion rates of Ig20Gly at baseline, 6 months, and 12 months were 26.7, 24.5, and 40.0 mL/h, respectively (10-60 mL/h). Infusion and dosing parameters remained consistent across time points: patients used a median of two infusion sites, primarily the abdomen, and all patients used an infusion pump; all but one infused at home and most self-administered Ig20Gly (80.8-83.3%) at once-weekly intervals (69.2-73.9%). During follow-up, 10 adverse events were reported: none were rated serious, while 2 were considered probably related to Ig20Gly. Total patient-reported outcome scores remained high throughout the study. CONCLUSION The CORE study provides real-world evidence of the flexibility, feasibility, safety, and tolerability of Ig20Gly infusions, at mostly weekly intervals, over 1 year in patients with PIDs. TRIAL REGISTRATION German Clinical Trials Register, DRKS00014562. Registered April 9, 2018, https://drks.de/search/en/trial/DRKS00014562

Elevated Gestational IL-13 During Fetal Development Is Associated With Hyperactivity and Inattention in Eight-Year-Old Children

Maternal immune activation (MIA) during fetal development leads to behavioral and psychological disorders in the offspring. Concomitantly, insufficient supply of polyunsaturated fatty acids (PUFAs) is suspected to contribute to early neuronal maldevelopment due to the immune modulatory capabilities of PUFAs. However, human data are missing considering both of these aspects and their impact on children's behavioral outcomes. In line, this study aimed to elucidate the influence of gestational cytokines and PUFA-containing lipids during late pregnancy on behavioral sequelae in childhood, particularly focusing on an immune activation shaped by a history of maternal atopic diseases instead of a pathogen-mediated immune response. Based on the prospective mother-child cohort LINA we assessed the unstimulated blood cytokine profiles and concentrations of PUFA-containing lipids of 293 mothers at the 34th week of pregnancy. Maternal history of atopic diseases was obtained from questionnaires and behavior in eight-year-old children was assessed by the standardized Strength and Difficulties Questionnaires (SDQ) generating scores for hyperactivity/inattention, emotional symptoms, conduct problems, and peer relationship problems. Elevated IL-13 increased the risk for the child to show behavioral difficulties, in particular, hyperactive/inattentive behavior [adj. OR (95% CI): 2.47 (1.51-4.02), n = 255 vs. 38] at the age of eight years. Although the presence of maternal atopic dermatitis (AD) was associated with increased gestational IL-13 concentrations [adj. MR (95% CI): 1.17 (1.04-1.32)], no effect on children's behavioral difficulties was observed. However, a decrease in the PUFA containing lipid species PC aa C38:6 was not only associated with an increased gestational IL-13 concentration but also mediated the indirect effect of low PC aa C38:6 concentrations on children's abnormal behavior independent of maternal AD. We additionally assessed whether maternal IL-13 and PC aa C38:6 concentrations translate their effect by altering children's cord blood PC aa C38:6 and IL-13. While also the children's cord blood IL-13 was related to children's behavior, no effect of children's PC aa C38:6 was observed. This is the first study demonstrating that elevated gestational IL-13 increases the risk for children to develop behavioral difficulties. Analyses suggest that a reduced supply of gestational PC aa C38:6 contributes to elevated gestational IL-13 leading to behavioral sequelae in the offspring

Long-term efficacy and safety of Hizentra® in patients with primary immunodeficiency in Japan, Europe, and the United States: a Review of 7 Phase 3 Trials

Many patients with primary immunodeficiency (PID) require immunoglobulin G (IgG) replacement therapy, delivered as intravenous IgG (IVIG) or subcutaneous IgG (SCIG). We aim to identify trends in efficacy and safety that would not be evident in individual studies of small patient numbers. Seven open-label, Phase 3, prospective, multicenter studies of the efficacy and safety of Hizentra® (a SCIG), conducted in Japan, Europe, and the US were summarized. Overall, 125 unique patients received 15,013 weekly infusions during a total observation period of 250.9 patient-years. Mean weekly doses of Hizentra® were 83.22–221.3 mg/kg body weight; infusion rates per patient (total body rate) were 25.2–49.3 mL/h across studies. The rates of infections and serious bacterial infections were 3.10 and 0.03 events per patient/year, respectively. Annualized rates of days hospitalized due to infection, out of work/school, and prophylactic antibiotic use were 0.95, 5.14, and 36.78 per patient, respectively. For the equivalent monthly dose, weekly Hizentra® SCIG administration resulted in expectedly-increased serum IgG trough levels in patients switching from IVIG, and maintained levels in patients switching from previous SCIG. Adverse events (AEs) totaled 5039 (events/infusion 0.094–0.773), almost all of which were mild/moderate. Three thousand one hundred ninety-seven were considered treatment-related, the most common of which were injection site reactions (2919 events; 0.001–0.592 AEs per infusion). Systemic AEs were very uncommon. The results from these seven studies indicate that Hizentra® therapy was both efficacious and well tolerated during long-term treatment. This is particularly important in patients with PID, who may require lifelong IgG replacement therapy