Association of serum lipid parameters with the SCORAD index and onset of atopic dermatitis in children.

BACKGROUND: The association between dyslipidemia and atopic dermatitis in children is unclear. This study investigated the association between dyslipidemia and atopic dermatitis in children by analysis of disease onset, risk factors, and disease severity. METHODS: Subset I examined 7-year-old children in elementary school (n = 248), and Subset II was a retrospective long-term follow-up hospital-based study (n = 52 725) conducted from 1986 to 2016 that used propensity score matching. In the Subset I study, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were determined, and the SCORing Atopic Dermatitis (SCORAD) index was determined. In the Subset II study, the time of atopic dermatitis onset was determined for asymptomatic subjects whose TC levels were below or above 170 mg/dL. RESULTS: Our Subset I study indicated that children with atopic dermatitis (n = 69, 27.8%) had significantly higher levels of TC and TG, and that the SCORAD index had significant associations with high levels of TC and TG, and a low level of HDL-C. Our Subset II study (1722 with high TC and 6735 with normal TC after propensity score matching) indicated the high TC group had a greater hazard ratio (HR) for the onset of atopic dermatitis (consensus-based HR: 2.47; 95% CI: 1.23, 5.06, P = .012) during 5 years. CONCLUSION: An abnormal blood lipid profile in children is associated with the presence of atopic dermatitis and the SCORAD index. The risk of atopic dermatitis onset was significantly greater with high levels of TC.

Comparison of the reaction of methylglyoxal (MGO) with murine and human amyloid beta (Aß): Insights into a mechanism of Alzheimer's disease (AD).

Reacted with methylglyoxal (MGO), murine Aß(1-40) (mAß) produced significantly less superoxide anion (O2•-) compared to human Aß(1-40) (hAß). The reactions of MGO with mAß(R13H), hAß(H13F), Nα-acetyl-l-lysine, and Nα-acetyl-l-arginine implied that the lack of His13 in mAß prohibits its Lys16 residue from reacting to produce cross-linked reaction products and O2•-. Our results suggest that murine brains are under less oxidative stress than human brains, which may be one of the reasons why rodents do not develop AD-like symptoms, and which provides further insight into a chemical mechanism for the development of AD in humans.

A genomic region harboring the Pl1 allele from the Peruvian cultivar JC072A confers purple cob on Japanese flint corn (Zea mays L.).

Purple corn is a maize variety (Zea mays L.) with high anthocyanin content. When purple corn is used as forage, its anthocyanins may mitigate oxidative stresses causing lower milk production in dairy cows. In this study, we analyzed quantitative trait loci (QTLs) for anthocyanin pigmentation of maize organs in an F2 population derived from a cross between the Peruvian cultivar 'JC072A' (purple) and the inbred line 'Ki68' (yellowish) belonged to Japanese flint. We detected 17 significant QTLs on chromosomes 1-3, 6, and 10. Because the cob accounts for most of the fresh weight of the plant ear, we focused on a significant QTL for purple cob on chromosome 6. This QTL also conferred pigmentation of anther, spikelet, leaf sheath, culm, and bract leaf, and was confirmed by using two F3 populations. The gene Pl1 (purple plant 1) is the most likely candidate gene in this QTL region because the amino acid sequence encoded by Pl1-JC072A is similar to that of an Andean allele, Pl-bol3, which is responsible for anthocyanin production. The markers designed for the Pl1 alleles will be useful for the breeding of F1 lines with anthocyanin pigmentation in cobs.

Glycation of Lys-16 and Arg-5 in amyloid-ß and the presence of Cu2+ play a major role in the oxidative stress mechanism of Alzheimer's disease.

Extensive research has linked the amyloid-beta (Aß) peptide to neurological dysfunction in Alzheimer's disease (AD). Insoluble Aß plaques in the AD patient brain contain high concentrations of advanced glycation end-products (AGEs) as well as transition metal ions. This research elucidated the roles of Aß, sugars, and Cu2+ in the oxidative stress mechanism of AD at the molecular level. Mass spectral (MS) analysis of the reactions of Aß with two representative sugars, ribose-5-phosphate (R5P) and methylglyoxal (MG), revealed Lys-16 and Arg-5 as the primary glycation sites. Quantitative analysis of superoxide [Formula: see text] production by a cyt c assay showed that Lys-16 generated four times as much [Formula: see text] as Arg-5. Lys-16 and Arg-5 in Aß1-40 are both adjacent to histidine residues, which are suggested to catalyze glycation. Additionally, Lys-16 is close to the central hydrophobic core (Leu-17-Ala-21) and to His-13, both of which are known to lower the pKa of the residue, leading to increased deprotonation of the amine and an enhanced glycation reactivity compared to Arg-5. Gel electrophoresis results indicated that all three components of AD plaques-Aß1-40, sugars, and Cu2+-are necessary for DNA damage. It is concluded that the glycation of Aß1-40 with sugars generates significant amounts of [Formula: see text], owing to the rapid glycation of Lys-16 and Arg-5. In the presence of Cu2+, [Formula: see text] converts to hydroxyl radical (HO·), the source of oxidative stress in AD.

Phosphorylation and inactivation of glycogen synthase kinase 3ß (GSK3ß) by dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A).

Glycogen synthase kinase 3ß (GSK3ß) participates in many cellular processes, and its dysregulation has been implicated in a wide range of diseases such as obesity, type 2 diabetes, cancer, and Alzheimer disease. Inactivation of GSK3ß by phosphorylation at specific residues is a primary mechanism by which this constitutively active kinase is controlled. However, the regulatory mechanism of GSK3ß is not fully understood. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) has multiple biological functions that occur as the result of phosphorylation of diverse proteins that are involved in metabolism, synaptic function, and neurodegeneration. Here we show that GSK3ß directly interacts with and is phosphorylated by Dyrk1A. Dyrk1A-mediated phosphorylation at the Thr(356) residue inhibits GSK3ß activity. Dyrk1A transgenic (TG) mice are lean and resistant to diet-induced obesity because of reduced fat mass, which shows an inverse correlation with the effect of GSK3ß on obesity. This result suggests a potential in vivo association between GSK3ß and Dyrk1A regarding the mechanism underlying obesity. The level of Thr(P)(356)-GSK3ß was higher in the white adipose tissue of Dyrk1A TG mice compared with control mice. GSK3ß activity was differentially regulated by phosphorylation at different sites in adipose tissue depending on the type of diet the mice were fed. Furthermore, overexpression of Dyrk1A suppressed the expression of adipogenic proteins, including peroxisome proliferator-activated receptor γ, in 3T3-L1 cells and in young Dyrk1A TG mice fed a chow diet. Taken together, these results reveal a novel regulatory mechanism for GSK3ß activity and indicate that overexpression of Dyrk1A may contribute to the obesity-resistant phenotype through phosphorylation and inactivation of GSK3ß.

Socioeconomic and sociodemographic factors related to allergic diseases in Korean adolescents based on the Seventh Korea Youth Risk Behavior Web-based Survey: a cross-sectional study.

BACKGROUND: Various international reports have shown that socioeconomic and sociodemographic variables are correlated with allergic diseases; however, little is known about how these variables affect Korean adolescents. This study was conducted to identify socioeconomic and sociodemographic risk factors for allergic diseases in Korean adolescents to provide information for preventing and managing such conditions. METHODS: Data from the 2011 Korea Youth Risk Behavior Web-based Survey (KYRBWS-VII) of 75,643 adolescents were used. An anonymously administered online survey was conducted to collect dependent variable information on perceived sexes, residence, family affluence (Family Affluence Scale; FAS), parental education levels, subjective academic achievement, obesity, drinking and smoking. The independent variables were asthma, allergic rhinitis and atopic dermatitis. Multivariate logistic regression was used to analyze the correlations between the dependent and independent variables. RESULTS: Low subjective academic achievement, obesity, drinking and smoking were risk factors for asthma. High FAS, parental bachelor's degree and high subjective academic achievement were risk factors for allergic rhinitis. Finally, high FAS, maternal bachelor's degree and high subjective academic achievement were risk factors for atopic dermatitis. CONCLUSION: We found that high socioeconomic status (SES) was a risk factor for allergic diseases in Korean adolescents. We propose that the greater access to medical services and immunization (e.g., hygiene hypothesis) afforded by high SES influenced the prevalence of allergic diseases. Thus, as the Korean economy develops further, the prevalence of allergic diseases is likely to increase. Controlling harmful behavioral risk factors, such as drinking and smoking, may help to prevent adolescent allergic diseases.

Chronic Intussusception Caused by Diffuse Large B-Cell Lymphoma in a 6-Year-Old Girl Presenting with Abdominal Pain and Constipation for 2 Months.

The classical triad of abdominal pain, vomiting, and bloody stool is absent in chronic intussusception for more than 2 weeks. Here, we report a 6-year-old female with recurrent abdominal pain for 2 months. Ultrasonography of the abdomen revealed an ileocolic-type intussusception. The lesion accompanying the tight fibrous adhesion was treated by resection and ileocolic anastomosis. It was diagnosed as intussusception with diffuse large B-cell lymphoma. A high index of suspicion for abdominal pain in children should result in the correct diagnosis and appropriate management.

Oxidation of 5'-dGMP, 5'-dGDP, and 5'-dGTP by a platinum(IV) complex.

We previously reported that a Pt(IV) complex, [Pt(IV)(dach)Cl4] [trans-d,l-1,2-diaminocyclohexanetetrachloroplatinum(IV)] binds to the N7 of 5'-dGMP (deoxyguanosine-5'-monophosphate) at a relatively fast rate and oxidizes it to 8-oxo-5'-dGMP. Here, we further studied the kinetics of the oxidation of 5'-dGMP by the Pt(IV) complex. The electron transfer rate constants between 5'-dGMP and Pt(IV) in [H8-5'-dGMP-Pt(IV)] and [D8-5'-dGMP-Pt(IV)] were similar, giving a small value of the kinetic isotope effect (KIE: 1.2 ± 0.2). This small KIE indicates that the deprotonation of H8 in [H8-5'-dGMP-Pt(IV)] is not involved in the rate-determining step in the electron transfer between guanine (G) and Pt(IV). We also studied the reaction of 5'-dGDP (deoxyguanosine-5'-diphosphate) and 5'-dGTP (deoxyguanosine-5'-triphosphate) with the Pt(IV) complex. Our results showed that [Pt(IV)(dach)Cl4] oxidized 5'-dGDP and 5'-dGTP to 8-oxo-5'-dGDP and 8-oxo-5'-dGTP, respectively, by the same mechanism and kinetics as for 5'-dGMP. The Pt(IV) complex binds to N7 followed by a two-electron inner sphere electron transfer from G to Pt(IV). The reaction was catalyzed by Pt(II) and occurred faster at higher pH. The electron transfer was initiated by either an intramolecular nucleophilic attack by any of the phosphate groups or an intermolecular nucleophilic attack by free OH(-) in the solution. The rates of reactions for the three nucleotides followed the order: 5'-dGMP > 5'-dGDP > 5'-dGTP, indicating that the bulkier the phosphate groups are, the slower the reaction is, due to the larger steric hindrance and rotational barrier of the phosphate groups.

Recent change in congenital syphilis in Korea: Retrospective 10 year study.

BACKGROUND: This study was conducted to evaluate recent clinical and anthropologic features of neonates with reactive serology for syphilis and their mothers from three institutions in Korea over an 11-year-period. METHOD: The medical records of 20 neonates with reactive serology for syphilis and their mothers at three centers (Kyung Hee University Hospital, Kyung Hee University Hospital at Gangdong, and Korea Electric Power Corporation Hospital) seen between January 2000 and December 2010 were reviewed retrospectively. RESULTS: Among 20 mothers, 16 (80%) were native Korean and four (20%) were foreign-born immigrants. Two mothers (10%) were unmarried. The annual distribution of cases was three (15%) in 2000, one each (5%) in 2005 and 2006, respectively, two each (10%) in 2007 and 2008, respectively, six (30%) in 2009, and five (25%) in 2010. Just over half (55%) occurred across 2009 and 2010. All neonates, by definition, were diagnosed with presumptive congenital syphilis (CS). Among the neonates, four had positive cerebrospinal fluid venereal disease research laboratory test, and three exhibited symptoms and signs. CONCLUSIONS: In three centers in Seoul, Korea, the observed number of CS cases was higher in 2009 and 2010 than in previous years. This finding is consistent with a trend toward increasing prevalence of international marriage and suggests that more meticulous screening of CS is needed.

Reference levels of blood mercury and association with metabolic syndrome in Korean adults.

PURPOSE: Mercury (Hg) is a nonessential and toxic metal that is widely distributed in the environment. This study was performed to estimate the representative blood Hg level, to determine the contributing factors to Hg exposure, and to analyze the association of blood Hg with metabolic syndrome in Korean adults. METHODS: Mercury exposure is assessed by total Hg concentration in blood. A total of 2,114 healthy adults who have not been exposed to Hg occupationally were sampled by the multistaged, sex-, and age-stratified probability method. Information was collected regarding the subjects' demographic characteristics, lifestyles, and past medical history. The participants then underwent physical examination and blood sampling. RESULTS: The geometric mean concentration of Hg in whole blood was 3.90 µg/L, which was significantly influenced by sex, age, smoking, alcoholic consumption, residence area, and seafood intake after adjustment for confounders. Significant increases in body mass index, waist circumference, diastolic blood pressure, total cholesterol, and triglyceride were observed according to the blood Hg levels after adjustment for covariates. Also, Hg exposure was significantly associated with metabolic syndrome and their components such as obesity and increased fasting glucose. CONCLUSION: The blood Hg level in Korean adults is higher than that in USA and other Western countries, while it is similar to or lower than that in other Asian countries. The blood Hg level is influenced by sociodemographic factors and individual lifestyles including dietary habits. Furthermore, blood Hg is associated with metabolic syndrome, in which Hg exposure may play a role as a possible risk factor for cardiovascular diseases.

Experiences of Pediatric Palliative Care Among Bereaved Parents Who Lost a Child With Leukemia in South Korea.

Pediatric palliative care was introduced in South Korea in 2018, with an increased need for care of children with life-limiting conditions, such as leukemia. However, the perspective of parents, who are the primary caregivers, regarding pediatric palliative care has not been explored. This study aimed to describe the pediatric palliative care-related experiences of parents who had lost a child to leukemia to better understand their needs and care outcomes. Ten mothers of children who received pediatric palliative care were recruited. Individual in-depth interviews were conducted. Phenomenology was applied to elucidate parents' experiences during their children's illness and after bereavement. From 179 main statements and 46 meaningful units, 22 themes were derived and grouped into 11 theme clusters and 4 categories. The participants described that the pediatric palliative care team had an indispensable role in providing emotional support to them and their children; this support continued even after the child's death. In addition, the participants were satisfied with their choice to receive pediatric palliative care and hoped that more regions could benefit from the services. The study findings could contribute to advances and the popularization of pediatric palliative care in South Korea.

Rocuronium anaphylaxis in a 3-year-old girl with no previous exposure to neuromuscular blocking agents.

During the perioperative period, anaphylactic reactions rarely occur. Neuromuscular blocking agents (NMBAs) are responsible for 60-70% of perioperative anaphylactic reactions. This case, we report a case of rocuronium-induced anaphylaxis in a 3-year-old girl with no previous exposure to NMBAs. This case cautions and informs practitioners that an IgE-mediated anaphylactic reaction with rocuronium is possible even in young children with no previous exposure to NMBAs.

Infant Feeding Pattern Clusters Are Associated with Childhood Health Outcomes.

(1) Background: Feeding behavior habits have a pattern with a certain tendency during infancy. We aimed to identify the associations between feeding patterns in infancy and the subsequent 10-year childhood disease burden. (2) Methods: Data from 236,372 infants were obtained from the national health insurance and screening program records in South Korea. Parent-administered questionnaires during infancy provided details on the feeding type and types/frequency of complementary food for analyzing feeding patterns. The outcomes were all-cause hospitalization and the development of 15 representative childhood diseases until the age of 10 years. Anthropometric measurements obtained at 6 years of age were analyzed. To estimate outcome risks while considering multiple risk factors, we employed a Cox proportional hazard and modified Poisson regression. (3) Results: Three clusters were identified: high prevalence of breastfeeding with regular exposure to a variety of solid foods (n = 116,372, cluster 1), similar prevalence of breastfeeding and formula feeding with less exposure to solid foods (n = 108,189, cluster 2), and similar prevalence of breastfeeding and formula feeding with the least exposure to solid foods in infancy (n = 11,811, cluster 3). Compared with cluster 1, children in clusters 2 and 3 had increased risks of all-cause hospitalization (hazard ratio (HR), (95% confidence interval (CI)), 1.04 (1.03-1.06) and 1.08 (1.05-1.11), respectively). Children in clusters 2 and 3 had an increased risk of upper respiratory infection, pneumonia, and gastroenteritis, as well as neurobehavioral diseases. Overweight/obesity at the age of 6 years was associated with clusters 2 and 3. (4) Conclusions: Feeding patterns in infancy were associated with an increased risk of childhood disease burden.

Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation.

Two genes on chromosome 21, namely dual specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) and regulator of calcineurin 1 (RCAN1), have been implicated in some of the phenotypic characteristics of Down syndrome, including the early onset of Alzheimer disease. Although a link between Dyrk1A and RCAN1 and the nuclear factor of activated T cells (NFAT) pathway has been reported, it remains unclear whether Dyrk1A directly interacts with RCAN1. In the present study, Dyrk1A is shown to directly interact with and phosphorylate RCAN1 at Ser(112) and Thr(192) residues. Dyrk1A-mediated phosphorylation of RCAN1 at Ser(112) primes the protein for the GSK3ß-mediated phosphorylation of Ser(108). Phosphorylation of RCAN1 at Thr(192) by Dyrk1A enhances the ability of RCAN1 to inhibit the phosphatase activity of calcineurin (Caln), leading to reduced NFAT transcriptional activity and enhanced Tau phosphorylation. These effects are mediated by the enhanced binding of RCAN1 to Caln and its extended half-life caused by Dyrk1A-mediated phosphorylation. Furthermore, an increased expression of phospho-Thr(192)-RCAN1 was observed in the brains of transgenic mice overexpressing the Dyrk1A protein. These results suggest a direct link between Dyrk1A and RCAN1 in the Caln-NFAT signaling and Tau hyperphosphorylation pathways, supporting the notion that the synergistic interaction between the chromosome 21 genes RCAN1 and Dyrk1A is associated with a variety of pathological features associated with DS.

Disproportionation of pentaammineruthenium(III)-nucleoside complexes leads to two-electron oxidation of nucleosides without involving oxygen molecules.

Pentaammineruthenium(III) complexes of deoxyinosine (dIno) and xanthosine (Xao) ([Ru(III)(NH(3))(5)(L)], L is dIno, Xao) in basic solution were studied by UV-vis spectroscopy, liquid chromatography/electrospray ionization mass spectrometry, and high-performance liquid chromatography. Both Ru(III) complexes disproportionate to Ru(II) and Ru(IV). Disproportionation followed the rate law d[Ru(II)]/dt = (k (o) + k (1)[OH(-)])[Ru(III)]. k (o) and k (1) of disproportionation at 25 °C were 2.1 (±0.1) × 10(-3) s(-1) and 21.4 ± 3.2 M(-1) s(-1), respectively, for [Ru(III)(NH(3))(5)(dIno)], and 3.5 (±0.7) × 10(-4) s(-1) and 59.7 ± 3.6 M(-1) s(-1), respectively, for [Ru(III)(NH(3))(5)(Xao)]. The [Ru(III)(NH(3))(5)(Xao)] complex disproportionates at a faster rate than [Ru(III)(NH(3))(5)(dIno)] owing to the stronger electron-withdrawing effect of exocyclic oxygen in Xao. The activation parameters ΔH (‡) and ΔS (‡) for k (1) of [Ru(III)(NH(3))(5)(dIno)] were 80.2 ± 15.2 kJ mol(-1) and 47.6 ± 9.8 J K(-1) mol(-1), respectively, indicating that the disproportionation of Ru(III) to Ru(II) and Ru(IV) is favored owing to the positive entropy of activation. The final products of both complexes in basic solution under Ar were compared with those under O(2). Under both conditions [Ru(NH(3))(5)(8-oxo-L)] was produced, but via different mechanisms. In both aerobic and anaerobic conditions, the deprotonation of highly positively polarized C8-H of Ru-L by OH(-) initiates a two-electron redox reaction. For the next step, we propose a one-step two-electron redox reaction between L and Ru(IV) under anaerobic conditions, which differentiates from Clarke's mechanism of two consecutive one-electron redox reactions between L, Ru(III), and O(2).

Two-electron oxidation of deoxyguanosine by a Ru(III) complex without involving oxygen molecules through disproportionation.

Among the many mechanisms for the oxidation of guanine derivatives (G) assisted by transition metals, Ru(III) and Pt(IV) metal ions share basically the same principle. Both Ru(III)- and Pt(IV)-bound G have highly positively polarized C8-H's that are susceptible to deprotonation by OH(-), and both undergo two-electron redox reactions. The main difference is that, unlike Pt(IV), Ru(III) is thought to require O(2) to undergo such a reaction. In this study, however, we report that [Ru(III)(NH(3))(5)(dGuo)] (dGuo = deoxyguanosine) yields cyclic-5'-O-C8-dGuo (a two-electron G oxidized product, cyclic-dGuo) without O(2). In the presence of O(2), 8-oxo-dGuo and cyclic-dGuo were observed. Both [Ru(II)(NH(3))(5)(dGuo)] and cyclic-dGuo were produced from [Ru(III)(NH(3))(5)(dGuo)] accelerated by [OH(-)]. We propose that [Ru(III)(NH(3))(5)(dGuo)] disproportionates to [Ru(II)(NH(3))(5)(dGuo)] and [Ru(IV)(NH(3))(4)(NH(2)(-))(dGuo)], followed by a 5'-OH attack on C8 in [Ru(IV)(NH(3))(4)(NH(2)(-))(dGuo)] to initiate an intramolecular two-electron transfer from dGuo to Ru(IV), generating cyclic-dGuo and Ru(II) without involving O(2).

Distinct impact of glycation towards the aggregation and toxicity of murine and human amyloid-ß.

Glycation of human Aß (hAß) is implicated to induce the deposition of amyloid aggregates found in the Alzheimer's disease (AD)-affected brain. Murine Aß (mAß) differs from hAß in three different amino acid residues (Gly5, Phe10, and Arg13) and is less likely to form amyloid aggregates. Herein, we report that the advanced glycated end products of mAß40 over hAß40 are distinctly generated. The different glycation between the two peptides can govern their aggregation kinetics, structural transition, and cytotoxicity.

Involvement of the P1 cistron in overcoming eIF4E-mediated recessive resistance against Clover yellow vein virus in pea.

Two recessive genes (cyv1 and cyv2) are known to confer resistance against Clover yellow vein virus (ClYVV) in pea. cyv2 has recently been revealed to encode eukaryotic translation initiation factor 4E (eIF4E) and is the same allele as sbm1 and wlm against other potyviruses. Although mechanical inoculation with crude sap is rarely able to cause infection of a cyv2 pea, biolistic inoculation of the infectious ClYVV cDNA clone does. At the infection foci, the breaking virus frequently emerges, resulting in systemic infection. Here, a derived cleaved-amplified polymorphic sequence analysis showed that the breakings were associated with a single nonsynonymous mutation on the ClYVV genome, corresponding to an amino-acid substitution at position 24 (isoleucine to valine) on the P1 cistron. ClYVV with the point mutation was able to break the resistance. This is a first report demonstrating that P1 is involved in eIF4E-mediated recessive resistance.

Dyrk1A-mediated phosphorylation of Presenilin 1: a functional link between Down syndrome and Alzheimer's disease.

The dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) gene is located on human chromosome 21 and encodes a proline-directed protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease (AD) in Down syndrome (DS) patients. Presenilin 1 (PS1) is a key component of the γ-secretase complex in the generation of ß-amyloid (Aß), an important trigger protein in the pathogenesis of AD. Increased Dyrk1A expression has been reported in human AD and DS brains. We previously showed that Dyrk1A increased Aß production in mammalian cells and transgenic mice that over-express Dyrk1A. In this study, we describe a potential mechanism by which Aß is increased in Dyrk1A-over-expressing DS and AD brains. First, we show that PS1 is phosphorylated by the Dyrk1A at Thr(354) and that this phosphorylation increases γ-secretase activity. Then, using transgenic mice that over-express human Dyrk1A, we demonstrate that phospho-Thr354-PS1 (pT354-PS1) expression is enhanced when Dyrk1A level is increased. We also show that pT354-PS1 is more stable than the unphosphorylated form of PS1. These results reveal a potential regulatory link between Dyrk1A and PS1 in the Aß pathway of DS and AD brains, suggesting that up-regulated Dyrk1A may accelerate AD pathogenesis through PS1 phosphorylation.

Airway mechanics after withdrawal of a leukotriene receptor antagonist in children with mild persistent asthma: Double-blind, randomized, cross-over study.

BACKGROUND: To determine the response of airway mechanics and the changes in asthma symptoms to stepping down of leukotriene receptor antagonist (LTRA) therapy. METHODS: Thirty children (mean age: 7.1 years) with mild, well-controlled, and persistent asthma who took LTRA as maintenance treatment were randomized into a double-blind, placebo-controlled, cross-over study. Each group received an LTRA (montelukast) or placebo daily for 2 weeks, followed by a 1-week washout period, and then the alternate treatment for 2 weeks. Spirometry and impulse oscillation system (IOS) measurements before and after four puffs of salbutamol inhalation, fractional exhaled nitric oxide (FeNO), and the childhood asthma control test (C-ACT) were evaluated at baseline, the end of placebo treatment, and the end of LTRA treatment. RESULTS: Changes of FEV1 /FVC (p = .113) and FEV1 (p = .109) from baseline to posttreatment did not differ significantly between the placebo and montelukast groups. In the placebo group, prebronchodilator (pre-) FEV1 /FVC was decreased (83% vs. 86%) and bronchodilator response (BDR) in FEV1 was diminished (10.7% vs. 6.4%) at posttreatment compared with baseline. However, the montelukast group had no significant changes in pre-FEV1 /FVC (p = .865) and BDR in FEV1 (p = .461). In addition, compared with the montelukast group, the placebo group showed no significant changes in Rrs5 (total airway resistance), Rrs5-20 (peripheral airway resistance), FeNO, and symptoms by the C-ACT. CONCLUSION: In children with well-controlled mild persistent asthma, changes in spirometry, IOS, FeNO, and C-ACT results did not differ between the placebo and montelukast groups within 2 weeks.