Background IgE sensitization against grass pollen is a cause of seasonal allergic rhinitis. Objective We sought to investigate the evolution at the molecular level and the preclinical predictive ...value of IgE responses against grass pollen. Methods The German Multicentre Allergy Study examined a birth cohort born in 1990. A questionnaire was administered yearly, and blood samples were collected at 1, 2, 3, 5, 6, 7, 10, and 13 years of age. Grass pollen–related seasonal allergic rhinitis (SARg) was diagnosed according to nasal symptoms in June/July. Serum IgE antibodies to Phleum pratense extract and 8 P pratense molecules were tested with immune-enzymatic singleplex and multiplex assays, respectively. Results One hundred seventy-seven of the 820 examined children had SARg. A weak monomolecular/oligomolecular IgE response to P pratense was observed very frequently before SARg onset. These initial IgE responses increased in concentration and molecular complexity during the preclinical and clinical process. A typical progression of IgE sensitization was observed: Phl p 1 (initiator in >75% of cases); then Phl p 4 and Phl p 5; then Phl p 2, Phl p 6, and Phl p 11; and then Phl p 12 and Phl p 7. At age 3 years, IgE sensitization predicted SARg by age 12 years (positive predictive value, 68% 95% CI, 50% to 82%; negative predictive value, 84% 95% CI, 80% to 87%). At this preclinical prediction time, the number of recognized molecules and the serum levels of IgE to P pratense were significantly lower than at 3 or more years after SARg onset. Conclusions The IgE response against grass pollen molecules can start years before disease onset as a weak monosensitization or oligosensitization phenomenon. It can increase in serum concentration and complexity through a “molecular spreading” process during preclinical and early clinical disease stages. Testing IgE sensitization at a preclinical stage facilitates prediction of seasonal allergic rhinitis at its molecular monosensitization or oligosensitization stage.
Background
Remote ischemic preconditioning (RIPC) of the myocardium by limb ischemia/reperfusion may mitigate cardiac damage, but its interaction with the anesthetic regimen is unknown. We tested ...whether RIPC is associated with differential effects depending on background anesthesia. Specifically, we hypothesized that RIPC during isoflurane anesthesia attenuates myocardial injury in patients undergoing coronary artery bypass graft (CABG) surgery, and that effects may be different during propofol anesthesia.
Methods
In a randomized, single‐blinded, placebo‐controlled prospective study, serum troponin I concentration (cTnI) (baseline, and 1, 6, 12, 24, 48, and 72 h postoperatively) were measured during isoflurane/sufentanil or propofol/sufentanil anesthesia with or without RIPC (three 5‐min periods of intermittent left upper arm ischemia with 5 min reperfusion each) in non‐diabetic patients (n = 72) with three‐vessel coronary artery disease (ClinicalTrials.gov NCT01406678).
Results
RIPC during isoflurane anesthesia (n = 20) decreased the area under the cTnI time curve (cTnI AUC) (−50%, 190 ± 105 ng/ml × 72 h vs. 383 ± 262 ng/ml × 72 h, P = 0.004), and the peak (7.3 ± 3.6 ng/ml vs. 11.8 ± 5.5, P = 0.004) and serial (P < 0.041) postoperative cTnI when compared to isoflurane alone (n = 19). In contrast, RIPC during propofol anesthesia (n = 14) did not alter the cTnI AUC 263 ± 157 ng/ml × 72 h vs. 372 ± 376 ng/ml × 72 h (n = 19), P = 0.318 or peak postoperative cTnI (10.1 ± 4.5 ng/ml vs. 12 ± 8.2, P = 0.444). None of the patients experienced harm or side effects from the intermittent left arm ischemia.
Conclusion
Thus, RIPC during isoflurane but not during propofol anesthesia decreased myocardial damage in patients undergoing CABG surgery. Accordingly, effects of RIPC evoked by upper limb ischemia/reperfusion depend on background anesthesia, with combined RIPC/isoflurane exerting greater beneficial effects under conditions studied.
BACKGROUND: The prevalence of adiposity in childhood is increasing. Is breast-feeding protective as suggested by cross-sectional studies? OBJECTIVE: In a longitudinal birth cohort study, we tested ...whether breast-feeding for more than 2 months has preventive effects against overweight and adiposity at 6 y. DESIGN: Of 1314 children representing the catchment areas of six delivery units, 918 could be followed up to the age of 6 y. Height, weight, and skin-fold thickness were measured at regular visits. As the criteria of overweight, obesity, and adiposity in the children, the 90th and the 97th percentiles of BMI and skin-fold values were used. Parents with a BMI at or above the 90th percentile, which was 27 kg/m2 or more, were considered overweight. Infants bottle-fed from birth or breast-fed for less than 3 months were classified as 'bottle-fed' (BO), and those breast-fed for 3 months and more as 'breast-fed' (BR). Univariate comparisons and logistic regression analysis were performed applying SAS 6.12. The final logistic model consisted of the 480 cases for whom complete data for all variables were available. The potential effect of loss to follow-up was analysed by the Cochran-Mantel-Haenzel test: the outcomes were not significantly influenced by loss to follow-up. RESULTS: At birth BMIs were nearly identical in both groups. By 3 months, BO had significantly higher BMIs and thicker skin folds than BR. From 6 months on, compared to BR, a consistently higher proportion of BO children exceeded the 90th and the 97th percentile of BMI and skin-fold thickness reference values. From the age of 4 y to 5 and 6 y, in BO the prevalence of obesity nearly doubled and tripled, respectively. With only minor changes of obesity prevalence in BR, the difference of BMI and skin-fold thickness between groups became statistically significant. Logistic regression analysis revealed that overweight of the mother, maternal smoking during pregnancy, bottle feeding, and low social status remained important risk factors for overweight and adiposity at 6 y of age. CONCLUSION: A maternal BMI of greater than or equal to 27, bottle-feeding, maternal smoking during pregnancy, and low social status are risk factors for overweight and adiposity at 6 y of age. Early bottle-feeding brings forward the obesity rebound, predictive of obesity in later life.
Background
The occurrence of allergic multimorbidity (coexistence of asthma, allergic rhinitis and eczema) has not been evaluated longitudinally from early childhood up to adulthood in a ...population‐based study sample. We aimed to determine the prevalence of allergic multimorbidity up to age 20 stratified by parental allergies and sex/gender using extensive prospective follow‐up data from two decades of a birth cohort study.
Methods
In 1990, we recruited 1314 healthy newborns from 6 maternity wards across Germany for the population‐based MAS birth cohort study. The sample was purposely risk‐enriched by increasing the proportion of children at high allergy risk (i.e. at least 2 allergic family members among parents and siblings) from 19% in the source population to 38% in the final sample. The remaining 62% of all MAS children had a low or no allergy risk. Symptoms, medication and doctor's diagnoses of allergic diseases have been assessed using standardized questionnaires including validated ISAAC questions in 19 follow‐up assessments up to age 20. Allergic multimorbidity at each time point was defined as the coexistence of at least 2 of the following diseases in one participant: asthma, allergic rhinitis and eczema.
Results
Response at age 20 was 72% (n = 942) of all recruited participants. At age 20, 18.5% (95% CI, 15.0–22.5%) of all participants with allergic parents had 2 or 3 concurrent allergies as compared to only 6.3% (95% CI, 4.3–9.0%) of those with non‐allergic parents. At this age, allergic multimorbidity was similar in women and men (12.7% (95% CI, 9.7–16.2%) vs. 11.6% (95% CI, 8.9–14.8%)), whereas single allergic diseases were slightly more common in women than men (24.2% (95% CI, 20.2–28.5%) vs. 20.1% (95% CI, 16.6–24.0%)). Asthma occurred more frequently with coexisting allergic rhinitis and/or eczema than as a single entity from pre‐puberty to adulthood.
Conclusion
Having parents with allergies is not only a strong predictor to develop any allergy, but it strongly increases the risk of developing allergic multimorbidity. In males and females alike, coexisting allergies were increasingly common throughout adolescence up to adulthood. Particularly asthma occurred in both sexes more frequently with coexisting allergies than as a single entity.
Background The results of numerous studies on the influence of breastfeeding in the prevention of atopic disorders are often contradictory. One of the most important problems is confounding by other ...lifestyle factors.
Objective The aim of the present study was to analyse the effect of any breastfeeding duration on the prevalence of atopic eczema in the first seven years of life taking into account other risk factors.
Methods In an observational birth cohort study 1314 infants born in 1990 were followed‐up for seven years. At 3, 6, 12, 18, 24 months and every year thereafter, parents were interviewed and filled in questionnaires, children were examined and blood was taken for in vitro allergy tests. Generalized Estimation Equations (GEE)‐models were used to model risk factors for the prevalence of atopic eczema and for confounder adjustment
Results Breastfeeding was carried out for longer if at least one parent had eczema, the mother was older, did not smoke in pregnancy, and the family had a high social status. The prevalence of atopic eczema in the first seven years increased with each year of age (OR 1.05; 95% CI 1.01–1.09 for each year), with each additional month of breastfeeding (1.03; 1.00–1.06 for each additional month), with a history of parental atopic eczema (2.06; 1.38–3.08), and if other atopic signs and symptoms appeared, especially specific sensitization (1.53; 1.25–1.88), and asthma (1.41; 1.07–1.85). Although breastfeeding should be recommended for all infants, it does not prevent eczema in children with a genetic risk.
Conclusion Parental eczema is the major risk factor for eczema. But in this study, each month of breastfeeding also increased the risk
•A novel approach ion-pairing liquid chromatography – tandem mass spectrometry method.•Disadvantages of traditional ion-pairing chromatography are overcome.•The method has good analytical performance ...characteristics.•The principle has potential for being used with other polar analytes.
The catecholamines, epinephrine (E) and norepinephrine (NE) are small polar, hydrophilic molecules, posing significant challenges to liquid chromatography − tandem mass spectrometry (LC–MS/MS) method development. Specifically, these compounds show little retention on conventional reversed-phase liquid chromatography columns. This work presents development and validation of an LC–MS/MS method for determining catecholamines in urine, based on a new approach to ion-pairing chromatography (IPC), in which the ion-pairing reagent (IPR), 1-Heptane Sulfonic Acid (HSA), is added to the extracted samples instead of the mobile phases. A Hamilton STARlet workstation carried out the solid phase extraction of urine samples. The extracted samples were diluted with 60mmol/L HSA and injected on a Kinetex core-shell biphenyl column with conventional LC–MS/MS suitable mobile phases. Chromatographic separation of E and NE was achieved successfully with very stable retention times (RT). In 484 injections, the RTs were steady with a CV of less than ±4%. Furthermore, HSA was separated from E and NE, allowing HSA to be diverted to waste instead of entering the mass spectrometer ion chamber. The method was validated with good analytical performance, and even though the analysis for urinary catecholamines is increasingly being replaced by plasma free metanephrines in diagnosing pheochromocytomas, this work represents the application of a new analytical technique that can be transferred to other small polar molecules, that are difficult to chromatograph on traditional reversed phase columns.
Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and ...cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog LeuT. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed mutagenesis and by trapping the radiolabeled cocaine analog 3HCFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn2+-binding site that was situated extracellularly to the predicted common binding pocket. Our data demonstrate the molecular basis for the competitive inhibition of dopamine transport by cocaine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Orbital friction stir welding (FSW) has been applied to clad pipes, which is certainly of interest to the oil and gas industry. In this context, an FSW system capable of performing sound joints in ...one pass with full tool penetration was developed. Orbital FSW was executed in 6 mm thick API X65 PSL2 steel clad pipes with 3 mm thick Inconel 625 using a polycrystalline cubic boron nitride (pcBN) tool. The metallurgical and mechanical properties of the joints were investigated. Sound joints with axial forces of 45-50 kN, tool rotational speeds of 400-500 rpm, and a welding speed of 2 mm/s were obtained, illustrating that the developed system can perform FSW joints without volumetric defects.
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