Search

Rice (Oryza sativa L.) is the primary staple crop in Taiwan, and it can be grown twice a year. The prevalent subspecies grown in Taiwan is Japonica, and a transplanting system is used for rice production. Although the transplanting system is known for efficient weed control at the seedling stage, weedy red rice (WRR, O. sativa f. spontanea) infestation is progressively being reported. Fieldwork and previous studies have suggested that WRR infestation in Taiwan is probably related to growers’ operating practices and their perception of WRR. However, no data are available for a detailed investigation. The present study aimed to collect data on rice growers’ backgrounds, farming practices, and perceptions of WRR to quantify and characterize the patterns of farming operations for rice growers in Taiwan and to investigate factors contributing to WRR infestation. We collected 408 questionnaires completed by rice growers from 17 counties covering all rice production regions in Taiwan. The growers’ median age was 51 to 60 yr, and 75% of respondents had paddies from 0.25 to 2.75 ha in size, which corresponded with nationwide data for farmers’ backgrounds. In general, growers applied similar farming practices for both cropping seasons. Most respondents did not notice WRR infestation or consider it to be a problem: only 9.8% noticed a moderate to severe infestation of WRR in their fields. The major perceived causes of WRR infestation was seed impurity (55.1%) or cultivar degeneration (18.6%). Correlation analysis and farming patterns estimated with a nonnegative matrix factorization algorithm showed that WRR contamination rate was due to the use of dry or wet tillage. The present study provides the first quantitative and qualitative evidence of rice production practices and growers’ perceptions of WRR infestation in Taiwan.

// Kuender D. Yang 1, 2, 3, * , Chih-Chiang Wu 3, * , Ming-Tsung Lee 4, Chia-Yu Ou 5, Jen-Chieh Chang 6, Chih-Lu Wang 5, Hau Chuang 6, Ho-Chang Kuo 6, Chie-Pein Chen 7 and Te-Yao Hsu 8 1 Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan 2 Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan 3 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 4 Research Assistance Center, Show Chwan Memorial Hospital, Changhua, Taiwan 5 Department of Pediatrics, Po-Jen Hospital, Kaohsiung, Taiwan 6 Department of Pediatrics and Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 7 Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Mackay Medical College, Taiwan 8 Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Taiwan and Chang Gung University College of Medicine, Kaohsiung, Taiwan * These authors contributed equally to this work Correspondence to: Te-Yao Hsu, email: yangkd.yeh@gmail.com Ho-Chang Kuo, email: erickuo48@yahoo.com.tw Keywords: asthma; allergic rhinitis; atopic dermatitis; birth cohort; infant sneezing without colds Received: January 13, 2017 Accepted: October 11, 2017 Published: November 07, 2017 ABSTRACT Background: Allergy sensitization may begin during the perinatal period, but predicting allergic diseases in infancy remains difficult. This study attempted to identify early predictors of childhood allergy diseases in a prospective cohort study. Materials and Methods: In a prospective birth cohort study at southern Taiwan locating in a subtropical region, questionnaire surveys of sneezing or cough without colds at 6 and 18 months of age were recorded, and the correlation with allergy diseases was assessed at 3 and 6 years of age. Results: A total of 1812 pregnant women and 1848 newborn infants were prenatally enrolled, and 1543, 1344, 1236, and 756 children completed the follow-up at ages 6 months, 18 months, 3 years and 6 years, respectively. The prevalence of infant sneezing without colds at 6 and 18 months of age was 30.3% and 19.2%, respectively. The prevalence of infant cough without colds at 6 and 18 months of age was 10.6% and 5.7%, respectively. Infant sneezing without colds at 18 months of age was significantly correlated with atopic dermatitis, allergic rhinitis and asthma at 6 years of age. Infant cough without colds at 18 months of age significantly predicted asthma but not atopic dermatitis or allergic rhinitis at 6 years of age. Conclusions: Infant sneezing without colds predicted all allergy diseases at 6 years of age in a subtropical country. This highlights a potential non-invasive clue in a subtropical region for the early prediction, treatment and prevention of childhood allergy diseases in infancy.

Rice (Oryza sativa L.) is the primary staple crop in Taiwan, and it can be grown twice a year. The prevalent subspecies grown in Taiwan is Japonica, and a transplanting system is used for rice production. Although the transplanting system is known for efficient weed control at the seedling stage, weedy red rice (WRR, O. sativa f. spontanea) infestation is progressively being reported. Fieldwork and previous studies have suggested that WRR infestation in Taiwan is probably related to growers' operating practices and their perception of WRR. However, no data are available for a detailed investigation. The present study aimed to collect data on rice growers' backgrounds, farming practices, and perceptions of WRR to quantify and characterize the patterns of farming operations for rice growers in Taiwan and to investigate factors contributing to WRR infestation. We collected 408 questionnaires completed by rice growers from 17 counties covering all rice production regions in Taiwan. The growers' median age was 51 to 60 yr, and 75% of respondents had paddies from 0.25 to 2.75 ha in size, which corresponded with nationwide data for farmers' backgrounds. In general, growers applied similar farming practices for both cropping seasons. Most respondents did not notice WRR infestation or consider it to be a problem: only 9.8% noticed a moderate to severe infestation of WRR in their fields. The major perceived causes of WRR infestation was seed impurity (55.1%) or cultivar degeneration (18.6%). Correlation analysis and farming patterns estimated with a nonnegative matrix factorization algorithm showed that WRR contamination rate was due to the use of dry or wet tillage. The present study provides the first quantitative and qualitative evidence of rice production practices and growers' perceptions of WRR infestation in Taiwan.

// Ming-Tsung Lee 1 , Chih-Chiang Wu 2,3 , Chia-Yu Ou 3 , Jen-Chieh Chang 4 , Chieh-An Liu 3 , Chih-Lu Wang 3 , Hau Chuang 4,5 , Ho-Chang Kuo 4,5 , Te-Yao Hsu 6,7 , Chie-Pein Chen 8 and Kuender D. Yang 2,8,9,10 1 Research Assistant Center, Show Chwan Memorial Hospital, Changhua, Taiwan 2 Institute of Clinical Medicine, National Yang-Ming University, Taiwan 3 Department of Pediatrics, Po-Jen Hospital, Kaohsiung, Taiwan 4 Departments of Pediatrics and Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 5 Chang Gung University College of Medicine, Kaohsiung, Taiwan 6 Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Taiwan 7 Chang Gung University College of Medicine, Kaohsiung, Taiwan 8 Department of Medical Research, MacKay Memorial Hospital, Taipei 9 Department of Pediatrics, MacKay Memorial Hospital, Taipei 10 Institute of Biomedical Sciences, MacKay Medical College, New Taipei, Taiwan Correspondence to: Kuender D. Yang, email: // Te-Yao Hsu, email: // Keywords : birth cohort, atopic dermatitis, allergic rhinitis, asthma, perinatal environment Received : October 22, 2016 Accepted : December 26, 2016 Published : January 09, 2017 Abstract Background: Allergic diseases are thought to be inherited. Prevalence of allergic diseases has, however, increased dramatically in last decades, suggesting environmental causes for the development of allergic diseases. Objective: We studied risk factors associated with the development of atopic dermatitis (AD), allergic rhinitis (AR) and asthma (AS) in children of non-atopic parents in a subtropical country. Methods: In a birth cohort of 1,497 newborns, parents were prenatally enrolled and validated for allergic diseases by questionnaire, physician-verified and total or specific Immunoglobulin E (IgE) levels; 1,236 and 756 children, respectively, completed their 3-year and 6-year follow-up. Clinical examination, questionnaire, and blood samples for total and specific IgE of the children were collected at each follow-up visit. Results: Prevalence of AD, AR and AS was, respectively, 8.2%, 30.8% and 12.4% in children of non-atopic parents. Prevalence of AR ( p

Objective Kawasaki disease (KD) is characterized by systemic vasculitis, and it is the most common acquired heart disease in children. However, the etiology and immunopathogenesis of KD are still unclear. A genome-wide association study (GWAS) identified polymorphisms in CD40, BLK, and FCGR2A as the susceptibility genes for KD. No epigenetic array studies of KD have previously been published. This study was undertaken to investigate differences in DNA methylation in patients with KD as compared to controls. Methods The HumanMethylation27 BeadChip (Illumina) was used to survey the differences in DNA methylation between KD patients and controls. DNA methylation array validation was performed in a separate cohort by pyrosequencing assay and reporter gene assays. Messenger RNA (mRNA) expression was determined, and the association of methylation with response to intravenous immunoglobulin (IVIG) treatment was analyzed. Results HumanMethylation27 BeadChip assay showed a 15% difference in methylation of 10 genes between KD patients and controls. The FCGR2A cg24422489 group, which was recently reported to be associated with KD susceptibility in a GWAS, had significant hypomethylation of 15.54% less in the KD group than in the control group. Validation of FCGR2A methylation in another cohort also showed significant hypomethylation in the KD group (5 of 5 CpG sites [P < 0.01]; n = 43 in the KD group and n = 55 in the control group). KD patients with IVIG resistance showed hypomethylation of 5 CpG sites (P < 0.05). FCGR2A mRNA expression was significantly increased in patients in the acute stage of KD compared to controls. Reporter gene assays indicated that the CpG sites of the FCGR2A promoter region were sufficient to modulate gene expression. Conclusion This is the first study to examine the DNA methylation array in KD and identify a role of hypomethylation of FCGR2A in susceptibility to KD and IVIG resistance.

Aim To evaluate the early success of transarterial embolization (TAE) in patients with traumatic liver haemorrhage and to determine independent factors for its failure. Materials and methods From January 2009 to December 2012, TAE was performed in 48 patients for traumatic liver haemorrhage. Their medical charts were reviewed for demographic information, pre-TAE vital signs and laboratory data, injury grade, type of contrast medium extravasation (CME) at CT, angiography findings, and early failure. “Early failure” was defined as the need for repeated TAE or a laparotomy for hepatic haemorrhage within 4 days after TAE. Variables were compared between the early success and early failure groups. Variables with univariate significance were also analysed using multivariate logistic regression for predictors of early failure. Results Among 48 liver TAE cases, nine (18.8%) were early failures due to liver haemorrhage. Early failure was associated with injury grade (p = 0.039), major liver injury (grades 4 and 5; p = 0.007), multiple CMEs at angiography (p = 0.031), incomplete TAE (p = 0.002), and elevated heart rate (p = 0.026). Incomplete embolization (OR = 8; p = 0.042), and heart rate >110 beats/min (bpm; OR = 8; p = 0.05) were independent factors for early failure of TAE in the group with major liver injuries. Conclusion Major hepatic injury is an important factor in early failure. Patients with a heart rate >110 bpm and incomplete embolization in the major injury group have an increased rate of early failure. The success rate of proximal TAE was comparable to that of the more time-consuming, superselective, distal TAE.

It remains unclear whether the GSTM1 genotype interacts with tobacco smoke exposure (TSE) in asthma development. This study aimed to investigate the interactions among GSTM1 genotype, gender, and prenatal TSE with regard to childhood asthma development. In a longitudinal birth cohort in Taiwan, 756 newborns completed a 6-year follow-up, and 591 children with DNA samples available for GSTM1 genotyping were included in the study,and the interactive influences of gender-GSTM1 genotyping-prenatal TSE on childhood asthma development were analyzed. Among these 591 children, 138 (23.4%) hadphysician-diagnosed asthmaat 6 years of age, and 347 (58.7%) werenull-GSTM1. Prenatal TSE significantly increased the prevalence of childhood asthma innull-GSTM1children relative to those withpositiveGSTM1. Further analysis showed that prenatal TSE significantly increased the risk of childhood asthma in girls withnull-GSTM1. Furthermore, among the children without prenatal TSE, girls withnull-GSTM1had a significantly lower risk of developing childhood asthma and a lower total IgE level at 6 years of age than those withpositiveGSTM1. This study demonstrates that the GSTM1 null genotype presents a protective effect against asthma development in girls, but the risk of asthma development increases significantly under prenatal TSE.

This study investigated the molecular changes of DKK-1, MMP13, Wnt-5a and $$\upbeta $$ -catenin after extracorporeal shockwave therapy (ESWT) in anterior cruciate ligament transected (ACLT) osteoarthritic (OA) knee in rats. 27 male Spraque-Dawley rats were divided into three groups. Group I was the control one and received sham knee arthrotomy but no ACLT or ESWT. Group II underwent ACLT, but no ESWT. Group III underwent ACLT and received ESWT. The animals were killed at 12 weeks, and the harvested knee specimens were subjected to histopathological examination and immunohistochemical analysis. Radiographs of the knees were obtained at 0 and 12 weeks. At 12 weeks, radiographs of group II showed more arthritic changes with formation of osteochondral fragments, whereas very subtle arthritis was noted in groups I and III. In histopathological examination, group II showed a significant increase of Mankin score and a decrease of subchondral bone as compared to groups I and III. Group III showed a significant decrease of Mankin score and an increase of subchondral bone, with the data comparable to group I. In immunohistochemical analysis, group II showed significant increases of DKK-1 and MMP13 and decreases of Wnt-5a and $$\upbeta $$ -catenin in articular cartilage and subchondral bone as compared to groups I and III. Group III showed significant decreases of DKK-1 and MMP13 and increases of Wnt-5a and $$\upbeta $$ -catenin, with the data comparable to group I. In conclusion, the application of ESWT causes molecular changes that are consistent with the improvement in subchondral bone remodeling and chondroprotective effect in ACLT OA knees in rats.

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Thymus and activation-regulated chemokine/chemokine ligand 17 (TARC/CCL17) is one of the Th2 chemokines and has been suggested as a candidate gene for conferring susceptibility to Th2 associated with allergy diseases. This study examined the correlation between gene polymorphisms and plasma levels of TARC/CCL17 in patients with KD and the outcomes of KD. A total of 381 KD patients and 564 controls were subjected to determination of five tagging single-nucleotide polymorphisms of TARC/CCL17. In addition, plasma TARC/CCL17 levels were measured by enzyme-linked immunosorbent assay. Polymorphisms of TARC/CCL17 were significantly different between normal children and patients with KD. A allele of rs4784805 has better intravenous immunoglobulin (IVIG) treatment response to KD. Furthermore, plasma TARC/CCL17 levels were higher in KD patients than that in controls before IVIG treatment. After IVIG treatment, plasma TARC/CCL17 levels decreased significantly. This study provides the first evidence supporting the association between TARC/CCL17 polymorphisms, susceptibility of KD, and IVIG responses in KD patients.

Background. Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. Our previous studies showed expression ofCD40ligand on CD4+ T cells correlated to the coronary artery lesion (CAL) and disease progress in KD. Other studies from Japan suggested the role ofCD40Lin the pathogenesis of CAL, and this might help explain the excessive number of males affected with KD but cannot be reproduced by Taiwanese population. This study was conducted to investigate theCD40polymorphism in KD and CAL formation.Methods. A total of 950 subjects (381 KD patients and 569 controls) were investigated to identify 2 tagging single-nucleotide polymorphisms (tSNPs) ofCD40(rs4810485 and rs1535045) by using the TaqMan allelic discrimination assay.Results. A significant association was noted with regards toCD40tSNPs (rs1535045) between controls and KD patients (P=0.0405, dominant model). In KD patients, polymorphisms ofCD40(rs4810485) showed significant association with CAL formation (P=0.0436, recessive model). Haplotype analysis did not yield more significant results between polymorphisms ofCD40and susceptibility/disease activity of KD.Conclusions. This study showed for the first time that polymorphisms ofCD40are associated with susceptibility to KD and CAL formation, in the Taiwanese population.

Background: Exposure to cow’s milk protein in early infancy could lead to increased rates of allergic diseases later in life. We investigated whether feeding a protein-hydrolyzed formula (HF) in the first 6 months of life decreased allergic diseases up to 36 months later. Methods: Newborns who had at least 1 first-degree family member with a history of atopy and could not breast-feed were enrolled. They were fed with HF or cow’s milk infant formula (CM) for at least 6 months via an open-label protocol and were monitored prospectively at 6, 18 and 36 months of age to assess allergy sensitization and allergic diseases. Results: A total of 1,002 infants were enrolled and 679 infants were consistently fed the same formula for the first 6 months of life (345 HF and 334 CM). The percentage of food sensitization (especially to milk protein) was significantly lower in the HF group than in the CM group at 36 months (12.7 vs. 23.4%, p = 0.048). There was no significant difference in the prevalence of aeroallergen sensitization between the groups. Occurrence of allergic diseases during the first 3 years of life was significantly correlated with aeroallergen sensitization, but not to food allergen sensitization, parental atopy or feeding types. Conclusions: Infants fed with HF during the first 6 months of life had a significantly lower percentage of sensitization to milk protein allergens, but not allergic diseases during the first 3 years of life. Avoidance of cow’s milk protein alone in infancy is not enough to decrease rates of allergic diseases.

Objectives: Kawasaki disease (KD) is a systemic vasculitis primarily affecting children who are

Kawasaki disease (KD) is the leading cause of acquired heart disease during childhood in the developed countries. The mechanism and biomarkers of KD remain to be determined. In this study, we sought to elucidate potential plasma proteomic markers in KD patients in comparison to that in febrile controls. Plasma samples from KD patients and febrile controls were subjected to two-dimensional polyacrylamide gel electrophoresis analysis. Differential protein displays between KD patients and febrile controls were determined. Fibrinogen beta and gamma chains, alpha-1-antitrypsin (A1AT), CD5 antigen-like precursor (CD5L), and clusterin were increased in KD patients, whereas immunoglobulin free light chains were decreased, as compared with controls. The differential protein displays were validated with enzyme-linked immunosorbent assay tests. We found higher fibrinogen-related proteins (fibrinogen, A1AT, clusterin, and CD5L), along with a lower level of the immunoglobulin free light chains that involve fibrin degradation in KD. Results from this study showing a unique proteomic profiling with abnormal fibrinogen cascade may afford a good biomarker of KD and a better strategy to prevent cardiovascular complications of KD by correcting abnormal fibrin deposition or degradation.

Patients with systemic lupus erythematosus (SLE) frequently received corticosteroid therapy, resulting in osteonecrosis of the femoral head (ONFH). Prior studies demonstrated the effectiveness of extracorporeal shockwave treatment (ESWT) for ONFH.. This study evaluated the effectiveness of ESWT for ONFH in patients with SLE. We studied 39 patients, including 15 patients with SLE (26 hips) and 24 controls (29 hips). To each affected hip we applied ESWT (6000 impulses at 28 kV in a single session). Patients were ambulated with partial weight bearing for 4–6 weeks. The primary endpoint was the need for hip replacement. The secondary endpoints were improvement in hip pain and function and image changes on X-ray and MRI. Patients received total hip replacement in 12% of patients with SLE and in 14% of controls ( P = 0.802). There was no statistically significant difference in pain scores (0.86 vs. 0.89; P = 0.467) and function scores (89% vs. 91%; P = 0.194) between patients with SLE and controls. SLE response to ESWT for ONFH is comparable with ONFH in patients without SLE.

To investigate the role of eosinophils in Kawasaki disease (KD) and the relationship to initial intravenous immunoglobulin (IVIG) treatment failure. A retrospective analysis of all children who were admitted and met the criteria of KD between 1999 and 2005. The patients were divided into IVIG-responsive and IVIG-resistant groups. A total of 185 patients were enrolled during the study period. A series of blood eosinophils and biochemistry studies were correlated to the effectiveness of IVIG. The neutrophils percentage before IVIG treatment (pre-IVIG), leukocyte counts within 3 days after IVIG treatment (post-IVIG), liver enzyme, albumin levels, and post-IVIG eosinophils percentage were all significantly different between the two groups in univariate analysis. Under multivariate analysis with logistic regression, post-IVIG eosinophilia [peripheral blood (PB) eosinophils >or=4%] had an inverse correlation to KD patients with IVIG-resistance (p = 0.003). Also, pre-IVIG hypoalbuminemia (albumin

Kawasaki disease is an acute multisystem vasculitic syndrome of unknown etiology occurring mostly in infants and children younger than 5 years of age. In developed countries, Kawasaki disease is currently the leading cause of acquired heart diseases in children. However, it is still a mysterious disease. In this article, we reviewed and summarized from the aspects based on infection agents, host immune dysregulation and genetic background intended to establish a feasible infection-immunogenetic pathogenesis for this mysterious disease and also provided the rational strategy to explore optimal treatment of this disease.

Granulocytes play an important role in inflammatory diseases. Neonates tend to develop granulocytopenia under sepsis and stress. It remains unclear whether apoptosis of neonatal granulocytes is different from that of adult granulocytes. In this study, we analyzed the discrepancy of granulocyte apoptosis between cord blood (CB) and adult blood (AB). We found that spontaneous and tumor necrosis factor-alpha (TNFalpha)-induced granulocyte apoptosis as determined by phosphatidylserine expression and DNA fragmentation were more prominent in CB granulocytes than AB granulocytes. CD95 ligand and TNFalpha levels were significantly higher in CB than in AB (p = 0.001 and p0.001, respectively). TNF receptor-2 and CD95 expression on CB granulocytes were not different from those on AB granulocytes. However, the TNF receptor-1 (TNFR1) expression was lower on CB granulocytes than that on AB granulocytes (69.98 +/- 7.32 versus 89.04 +/- 3.73%, p = 0.029). This decrease of TNFR1 expression on neonatal granulocytes might be related to a higher plasma TNFalpha level associated with an intrinsic defect on the dynamic change of membrane TNFR1 expression in neonatal granulocytes. The expression of anti-apoptotic molecule Bcl-2 in neonatal granulocytes was also lower than that in adult granulocytes (4.64 +/- 0.51 versus 7.24 +/- 1.17 unit/mg protein, p = 0.032). Moreover, another anti-apoptotic signal, nuclear factor-kappaB nuclear translocation, was also lower in CB than AB granulocytes. Results from this study suggest that higher plasma death ligands associated with lower anti-apoptotic molecules in granulocytes may act an important role in triggering neonatal granulocyte apoptosis.

Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurological cognitive deficits. In rats at postnatal days 10–12 (P10–P12), global hypoxia induced spontaneous seizures and chronic brain injury, mimicking clinical aspects of neonatal hypoxia. Synaptic Ras-GTPase activating protein (SynGAP) has important roles in RAS/MAPK-dependent synaptic plasticity and mammalian learning. We investigated possible alterations of SynGAP expression occurring in memory-impaired animals previously exposed to perinatal hypoxia insults. We also evaluated the therapeutic efficacy of A68930, a selective agonist of dopamine D1/D5 receptors, on perinatal hypoxia insults. In the hippocampal CA1 region, perinatal hypoxia insults (P10) led to a reduction in SynGAP expression associated with impairment in long-term spatial learning and memory performance at P45. The use of A68930 (at a dose of 1, 2, 3 mg/kg, P17–P23) effectively attenuated the deleterious effects as described above. Our results may indicate the involvement of SynGAP in certain forms of brain injury, leading to long-term learning and memory deficits. A68930 may have clinical potential as a therapeutic agent for alleviation of long-term cognitive deficits in rats and other animal models.

Background: Many studies have shown that certain cytokines in amniotic fluids are correlated to premature labor and neonatal brain insults. Aims: We investigated whether different fetal phagocyte and vascular mediators including IL-8, myeloperoxidase (MPO), PGE 2 and soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were correlated to prematurity and cerebral palsy (CP) of premature infants. Subjects: Umbilical cord blood samples from 96 preterm babies from 2250 cord blood collections were studied. Method: The enzyme-linked immunoassay (ELISA) technique was used to determine concentrations of cord blood IL-8, MPO, PGE 2 and sVCAM-1. Results: Preterm babies with gestational age (GA) ≦32 weeks had significant higher cord blood IL-8, MPO and PGE 2 levels than full-term babies. These mediators, however, were not correlated to gestational age, suggesting that increases of these mediators are more related to preterm delivery but not fetal maturation. Further analysis showed that IL-8, a mediator mainly from monocytes, but not MPO, another mediator mostly from granulocytes, was correlated to cerebral palsy. Conclusions: Taken together, these results suggest that both premature monocytes and granulocytes activation are involved in preterm delivery, but maybe only monocytes activation is correlated to premature infants' cerebral palsy. Selective manipulation of monocytes activation may be useful to prevent premature-related cerebral palsy.

The atopic history of parents has long been used to predict infant atopy. However, bias from questionnaires of allergic history are also frequently suspected, because a large number of vasomotor rhinitis, intrinsic asthma, and seborrheic dermatitis cases are probably misinterpreted to be atopic diseases.We attempted to identify a risk factor other than parental atopic history to predict elevated infant IgE levels and infant atopy.A total of 655 core families were prenatally recruited, and finally 545 families completed the study for the prospective analysis of infant atopy at 6 months of age. Atopic history and blood samples of parents were collected in the third trimester during pregnancy. Cord blood (CB) was collected immediately after birth. Infant blood samples and history of infant eczema were collected in the 6-month physical checkup clinic. Blood total IgE and specific IgE levels were determined by use of the Pharmacia CAP system.In univariate analysis, maternal, but not paternal, atopic history correlated with elevated CB IgE levels and the occurrence of infant eczema. Elevated maternal, but not paternal, total IgE levels (150 KU/L) significantly correlated with increases of CB IgE levels (median, 0.54 vs 0.17 KU/L, P.001), infant IgE levels (log-transformed mean values, 1.32 +/- 0.51 vs 1.13 +/- 0.51 KU/L, P.001), and infant eczema (P =.008). Multivariate logistical regression analysis, however, showed that only maternal total IgE levels correlated with CB and infant IgE levels and the development of infant eczema.The maternal, but not paternal, total IgE level correlates with elevated infant IgE levels and infant atopy. This provides a high specificity (83%) and a sensitivity of 34% for prediction of infant atopy. This suggests that maternal factors, placental factors, or both have an impact on perinatal allergic sensitization.

Malnutrition and/or seizure in the developing brain cause hippocampal damages. However, underlying mechanisms remain unclear. The malnutrition group (MN) subjected with malnutrition alone was culled to 20-22 rats per dam on postnatal day 1 (P1). The rats subjected to lithium-pilocarpine (Li/PC)-induced status epilepticus at P21 were grouped as the SE group. The rats subjected to malnutrition and subsequent status epilepticus were grouped as the MS group. Visual-spatial memory test using the Morris water maze task was performed at P80. Following behavioral tests, the hippocampus was evaluated for histological lesions and phosphorylated cAMP-responsive, element-binding protein at serine-133 (pCREB(Ser-133)), an important transcription factor underlying learning and memory in the mammalian brain. Here, the MN group exhibited decreased body weight at P21. There was no significant difference in the seizure duration and mortality between the SE and MS groups. In adulthood (P80), both the SE and MS groups showed the spatial learning deficit, hippocampal cell loss and decreased pCREB(Ser133) level within hippocampal CA1 region. Although the MN group demonstrated a decreased level of pCREB(Ser133), no distinguishable changes in the cognitive deficit and hippocampal neuronal loss were detected. Collectively, the present results suggest that early-life malnutrition led to a reduced phosphorylation of CREB(Ser133) in hippocampal CA1 in the absence of the long-term spatial learning deficit. This decreased phosphorylation of CREB(Ser133) could suggest that cascades of signal transduction responsible for the phosphorylation of CREB(Ser133) might be disturbed by early-life malnutrition. In addition, malnutrition caused no discernible synergistic effects on Li/PC-induced status epilepticus.

Objective.Kawasaki disease (KD) is an acute febrile vasculitic syndrome in children. CD40 ligand (CD40L) has been implicated in certain types of vasculitis. We proposed that CD40L expression might be correlated with coronary artery lesions in KD.Methods.Blood samples were collected from 43 patients with KD before intravenous immunoglobulin (IVIG) treatment and 3 days afterward. Forty-three age-matched febrile children with various diseases were studied in parallel as controls. CD40L expression on T-cells and platelets were detected by flow cytometry, and soluble CD40L (sCD40L) levels were measured by enzyme-linked immunosorbent assay.Results.We found that CD40L expression on CD4+ T-cells was significantly higher in patients with KD than in the febrile control (FC) group (28.69 ± 1.17% vs 4.37 ± 0.36%). CD40L expression decreased significantly 3 days after IVIG administration (28.69 ± 1.17% vs 13.53 ± 0.55%). CD40L expression on platelets from patients with KD was also significantly higher than in the FC group (8.20 ± 0.41% vs 1.26 ± 0.12%) and decreased after IVIG therapy. sCD40L levels were also significantly higher in KD patients with those of FC (9.69 ± 0.45 ng/mL vs 2.25 ± 0.19 ng/mL) but were not affected by IVIG treatment 3 days afterward (9.69 ± 0.45 ng/mL vs 9.03 ± 0.32 ng/mL). More interesting, we found that in KD patients, CD40L expression on CD4+ T-cells and platelets but not on CD8+ T-cells or sCD40L was correlated with the occurrence of coronary artery lesions.Conclusions.CD40L might play a role in the immunopathogenesis of KD. IVIG therapy might downregulate CD40L expression, resulting in decrease of CD40L-mediated vascular damage in KD. This implicates that modulation of CD40L expression may benefit to treat KD vasculitis.

Objective: To assess nitric oxide (NO) production and different displays of NO synthase (NOS) isoforms in patients with Kawasaki disease (KD) before and after intravenous immunoglobulin (IVIG) treatment. Study design: Blood and urine samples were collected from patients with KD before IVIG treatment and 3 days afterward. Age-matched febrile patients with various diseases served as control patients. Plasma NOx (NO3- + NO2-) levels were measured as NO production. Real-time reverse transcriptase–polymerase chain reaction and immunohistochemical staining were used to detect differential NOS isoform expression in mononuclear leukocytes (MNCs). Results: Patients with KD (n = 40) had higher levels of NOx than the non-KD febrile control patients. The elevated NOx levels in patients with KD were significantly associated with the occurrence of coronary artery dilation (>3 mm). These elevated NOx levels significantly decreased after IVIG treatment (157.8 ± 15.9 μmol/L vs 57.0 ± 4.27 μmol/L, P

Adenosine is an endogenous modulator that has an inhibitory effect on neuronal activity. The aim of this work was to investigate the role of aminophylline, an adenosine receptor antagonist, on the long-term effects of status epilepticus (SE) in the developing brain. Four groups of rats at the postnatal age of 12 days were intraperitoneally administered with saline, aminophylline (50 mg/kg), lithium–pilocarpine (Li–PC) (3 mEq/kg–60 mg/kg), and Li–PC plus aminophylline, respectively. The four groups were tested for spatial memory using the Morris water maze task at P80 and motor performance by the Rotarod test at P100. The brains were then analyzed with cresyl violet stain for histological lesions and evaluated for mossy fiber sprouting with the Timm stain. At the acute stage, all rats subjected to Li–PC developed SE and no seizures were elicited in the saline-treated or aminophylline-treated rats. The seizure duration was longer in the Li–PC plus aminophylline group (346.9±32.7 min) as compared with that in the Li–PC group (265.2±9.8 min). The difference of mortality was not significant. Rats without seizures exhibited no motor imbalance, spatial deficits, or morphological changes. The rats with Li–PC-induced SE demonstrated spatial memory deficits without motor incoordination or morphological changes. However, the rats subjected to Li–PC plus aminophylline exhibited motor impairment and morphological changes, including neuronal cell loss in CA1 area and increased mossy fiber sprouting in CA3 area. In addition, the rats of Li–PC plus aminophylline had greater spatial memory deficits than that seen in rats with Li–PC. We concluded that an adenosine receptor antagonist, such as aminophylline, had synergistic effects on the SE-induced long-term deficit of cognition and motor performance in the developing brain. The present study may provide experimental evidence and lead to novel therapeutic interventions.

Hypokalemia is a common side effect in adult asthmatic patients on beta 2 adrenergic therapy. There is limited information in regard to hypokalemia and its relation to the clinical responses following administration of beta 2 agonist therapy in children with asthma. We observed that salbutamol inhalation significantly improved asthmatic symptoms as demonstrated by increases in peak expiratory flow (PEF: 122.37+/-75.38 vs. 152.59+/-80.29; P < 0.001) and venous oxygen tension (Pv,O2: 33.24+/-4.95 vs. 58.16+/-2.31; P < 0.001), and decreases in respiratory rate (RR: 36.39+/-3.78 vs. 28.62+/-3.12; P< 0.01), clinical scores (CS: 3.59+/-1.28 vs. 1.59+/-0.71), and venous PCO2 tensions (Pv,CO2: 40.84+/-2.67 vs. 34.75+/-2.31; P < 0.001). Salbutamol-induced hypokalemia was correlated with a decrease in RR, and an increase of Pv,O2 and PEF. These findings suggest that the same mechanism is involved in eliciting hypokalemia and bronchodilatation.

Kawasaki disease (KD) is characterized by systemic vasculitis, and it is the most common acquired heart disease in children. However, the etiology and immunopathogenesis of KD are still unclear. A genome-wide association study (GWAS) identified polymorphisms in CD40, BLK, and FCGR2A as the susceptibility genes for KD. No epigenetic array studies of KD have previously been published. This study was undertaken to investigate differences in DNA methylation in patients with KD as compared to controls.The HumanMethylation27 BeadChip (Illumina) was used to survey the differences in DNA methylation between KD patients and controls. DNA methylation array validation was performed in a separate cohort by pyrosequencing assay and reporter gene assays. Messenger RNA (mRNA) expression was determined, and the association of methylation with response to intravenous immunoglobulin (IVIG) treatment was analyzed.HumanMethylation27 BeadChip assay showed a 15% difference in methylation of 10 genes between KD patients and controls. The FCGR2A cg24422489 group, which was recently reported to be associated with KD susceptibility in a GWAS, had significant hypomethylation of 15.54% less in the KD group than in the control group. Validation of FCGR2A methylation in another cohort also showed significant hypomethylation in the KD group (5 of 5 CpG sites [P0.01]; n = 43 in the KD group and n = 55 in the control group). KD patients with IVIG resistance showed hypomethylation of 5 CpG sites (P0.05). FCGR2A mRNA expression was significantly increased in patients in the acute stage of KD compared to controls. Reporter gene assays indicated that the CpG sites of the FCGR2A promoter region were sufficient to modulate gene expression.This is the first study to examine the DNA methylation array in KD and identify a role of hypomethylation of FCGR2A in susceptibility to KD and IVIG resistance.

BackgroundThe risk of allergic diseases among Kawasaki disease (KD) patients relative to the general population is not known. The aim of this study was to perform a population-based cohort study to investigate the risk of allergic diseases among children after KD in Taiwan- a country with the third highest incidence of KD in the world.MethodsData were obtained from the Taiwan National Health Insurance Research Database. In total, 253 patients who were 5 years of age or younger and had a first-time hospitalization with a diagnosis of KD between 1997 and 2005 were included as the study cohort and 1,012 non-KD patients matched for age and sex were included as comparison cohort. Multivariate Cox proportional hazard regression model was used to adjust for confounding and to compare the 6-year allergic-free survival rate between these two cohorts.ResultsThe incidence rate of allergic diseases (184.66 per 1000 person-year) was significantly higher in the KD cohort than in the control cohort (124.99 per 1000 person-years). After adjusting for potential confounders, the adjusted hazard ratios of asthma and allergic rhinitis were 1.51 (95% confidence interval = 1.17-1.95) and 1.30 (95% confidence interval = 1.04-1.62), respectively.ConclusionWe conclude that KD patients were at an increased risk for allergic diseases compared with the comparison cohort.

BackgroundKawasaki disease (KD) of unknown immunopathogenesis is an acute febrile systemic vasculitis and the leading cause of acquired heart diseases in childhood. To search for a better strategy for the prevention and treatment of KD, this study compared and validated human KD immunopathogenesis in a mouse model of Lactobacillus casei cell wall extract (LCWE)-induced coronary arteritis.MethodsRecruited subjects fulfilled the criteria of KD and were admitted for intravenous gamma globulin (IVIG) treatment at the Kaohsiung Chang Gung Memorial Hospital from 2001 to 2009. Blood samples from KD patients were collected before and after IVIG treatment, and cardiovascular abnormalities were examined by transthoracic echocardiography. Wild-type male BALB/c mice (4-week-old) were intraperitoneally injected with LCWE (1 mg/mL) to induce coronary arteritis. The induced immune response in mice was examined on days 1, 3, 7, and 14 post injections, and histopathology studies were performed on days 7 and 14.ResultsBoth human KD patients and LCWE-treated mice developed coronary arteritis, myocarditis, valvulitis, and pericarditis, as well as elevated plasma levels of interleukin (IL)-2, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α in acute phase. Most of these proinflammatory cytokines declined to normal levels in mice, whereas normal levels were achieved in patients only after IVIG treatment, with a few exceptions. Toll-like receptor (TLR)-2, but not TLR4 surface enhancement on circulating CD14+ monocytes, was augmented in KD patients before IVIG treatment and in LCWE-treated mice, which declined in patients after IVIG treatment.ConclusionThis result suggests that that not only TLR2 augmentation on CD14+ monocytes might be an inflammatory marker for both human KD patients and LCWE-induced CAL mouse model but also this model is feasible for studying therapeutic strategies of coronary arteritis in human KD by modulating TLR2-mediated immune activation on CD14+ monocytes.

Trichomonas vaginalis virus is a double-stranded (ds) RNA virus found in the parasitic protozoan T. vaginalis. To examine the possible existence of related viruses in various T. vaginalis strains and isolates, we screened 20 such isolates and found the characteristic 5.5-kb viral ds RNA in 16 of them. An additional 0.5-kb ds RNA band was also identified in 10 of these virus-infected T. vaginalis isolates. In a local isolate T1, this 0.5-kb ds RNA cross-hybridized with the 5.5-kb ds RNA. Preliminary evidence from CsCl buoyant density gradient centrifugations suggests that the two ds RNA species are encapsidated in separate viral particles by the same capsid protein. The 5.5-kb ds RNA in isolate T1 exhibited moderate hybridization with the prototype 5.5-kb ds RNA in T. vaginalis stratin NIH-Cl. Little cross-hybridization was observed among the 5.5-kb ds RNAs from T. vaginalis isolates JH32A No. 4, T1 and T5, although the viral proteins in these isolates are of similar molecular weight and share common epitopes as viewed by Western blotting. Hybridization characteristics of the 5.5-kb ds RNAs in individual isolates were further analyzed, and the results suggest great ds RNA divergence among the T. vaginalis viruses. Interestingly, the 0.5-kb ds RNA in different isolates of T. vaginalis also exhibited divergence in patterns closely associated with that of the 5.5-kb ds RNA.

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology and primarily affects children less than 5 years of age. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) has been suggested as a candidate gene for conferring susceptibility to autoimmunity. This study examined the correlation of CTLA-4 gene polymorphisms in KD with and without coronary artery lesions (CAL). A total of 233 KD patients and 644 controls were subjected to determination of CTLA-4 polymorphisms at (−318) C/T and (+49) A/G positions by restriction fragment length polymorphism. Susceptibility, CAL, and intravenous immunoglobulin treatment response of KD were then analyzed with genetic variants. Polymorphisms of CTLA-4 (+49 A/G) and (−318 C/T) were not significantly different between normal children and patients with KD. The CTLA-4 (+49) A allele (AA+AG genotype), however, was significantly associated with CAL formation, especially in female patients. This study provides the first evidence supporting the association of CTLA-4 (+49) A/G polymorphism with the CAL formation of KD particularly in female patients.

Kawasaki disease (KD) is the leading cause of acquired heart disease during childhood in the developed countries. Coronary artery lesions (CAL) are the major complications of KD. A unique proteomic profiling with increased or decreased fibrinogen, alpha-1-antitrypsin, clusterin, and immunoglobulin free light chains were noted in KD in our previous study. The purpose of this study was to evaluate relations between these biomarkers and CAL in KD and to establish within the markers the appropriate cut-off value with which to predict the occurrence of CAL. A total of 47 KD patients were enrolled, including 14 with CAL and 33 without CAL. Plasma samples from patients with KD before intravenous immunoglobulin administration were indicated for measurement of these biomarkers. A potential relation among CAL, clinical characteristics, and these biomarkers was investigated, and a receiver operating characteristic curve was used to identify a cut-off value of the significant marker that best predicated the occurrence of CAL. Among these biomarkers, only plasma clusterin level was associated with the occurrence of CAL. Using a cut-off value of clusterin

Scrub typhus called tsutsugamushi disease, is a mite-born acute febrile disease caused by Rickettsia tsutsugamushi. To our knowledge, neonatal scrub typhus has not been reported in the literature. We report on a 26-day-old newborn with aseptic meningitis. The newborn showed an increased specific 1gM antibody to R.tsutsugamushi conjointly with his mother's 1gM titer to the organism. This is the first case in the literature documenting neonatal scrub typhus and may be related to infection in the mother. CASE REPORT A 26-day-old male newborn was well until 4 days prior to this admission. He suffered from intermittent high fever, abdominal distention, and skin pallor.

Kawasaki disease (KD) is a systemic febrile vasculitis particular coronary artery involvement. Eosinophilia has been found in our and other studies in KD. This study further investigates whether eosinophil-related T helper 2 (Th2) cytokines or the activation marker (eosinophil cationic protein - ECP) is involved in KD with coronary artery lesions (CAL). A total of 95 KD patients were enrolled for this study. Plasma samples were subjected to the measurement of interleukin (IL)-4, IL-5, and eotaxin by Luminex-Bedalyte multiplex beadmates system and to the measurement of ECP by fluoroimmunoassay. Patients with KD had higher eosinophils than controls. Eosinophil-related mediators: IL-4, IL-5, eotaxin, and ECP levels were also higher in KD patients than controls before intravenous immunoglobulin (IVIG) treatment. After IVIG treatment, ECP decreased but IL-4, IL-5, and eotaxin increased significantly. The higher the IL-5 and eosinophil levels after IVIG treatment, the lower rate of CAL was found. Changes of eosinophils after IVIG treatment were positively correlated to changes of IL-5 levels but not ECP levels. An increase of eosinophils and IL-5, but not ECP levels after IVIG treatment, was inversely correlated with CAL formation in KD.

The aim of this study was to investigate the rate, risks factors, and clinical impact of coronary artery fistula (CAF) in Kawasaki disease (KD).From February 1999 to December 2007, a total of 325 pediatric patients fulfilled the diagnostic criteria of KD and admitted for intravenous immunoglobulin treatment were enrolled in this study. Patients with and without CAF were designated as group 1 and group 2, respectively. Patients of group 1 were further subdivided as with and without coronary artery lesions (CALs). The clinical presentations, laboratory data, and outcomes were compared among the groups.The mean age of the 325 patients was 21.1 months. Group 1 had 17 patients, and group 2 had 308 patients. The rate of CAF in KD was 5.3%. There were significant differences between group 1 and group 2 patients regarding age (11.8 +/- 1.8 vs 21.5 +/- 1.2 months, P = .01), the presence of CAL (64.7% vs 25%, P.01), white blood cell counts (16.4 +/- 1.3 vs 13.5 +/- 0.3 x 10(3)/mm(3), P = .01), and platelet counts (432.1 +/- 39.1 vs 346.4 +/- 8.4 x 10(3)/mm(3), P = .02). Spontaneous closure of CAF was observed in 7 (41%) of the 17 patients during follow-up (mean 45 months). Group 1 patients without CAL had a more benign clinical course (total fever day 5.8 +/- 0.6 vs 8.6 +/- 0.8, P = .03) and higher spontaneous closure rate (5/6 vs 2/11, P = .035) than patients with CAL.Patients of young age, CAL, high white blood cell counts, and high platelet counts have higher rate of CAF formation. Approximately 5% KD patients may associate with CAF, but most of them have good clinical outcome during follow-up.

This study was conducted to investigate whether changes in the complete blood count (CBC)/differential count (DC) and C-reactive protein (CRP) were correlated to Kawasaki disease (KD) with coronary artery lesions (CALs).A retrospective analysis was performed of all children with KD at Chang Gung Memorial Hospital at Kaohsiung from 2001 to 2006. KD patients were divided into those with and without CALs for testing of correlations with changes in CBC/DC and CRP levels.A total of 147 patients were enrolled for this analysis. Serial CBC/DC and CRP measurements and echocardiographic data for determination of CAL formation were obtained before and after intravenous immunoglobulin (IVIG) treatment. There were 44 (29%) KD patients having CAL formation (3 mm in diameter of internal lumen). There was no significant difference in terms of age distribution and major diagnostic criteria between KD patients with and without CALs. Male KD patients, however, had a significantly higher rate of CAL formation (p=0.009). In multivariate logistical regression analysis, persistent monocytosis after IVIG treatment was the only factor significantly correlated to CAL formation (p=0.003).Of the febrile routine measurements of CBC/DC and CRP in KD, persistent monocytosis after IVIG treatment was correlated to CAL formation. Further studies to clarify the mechanism of monocytosis may help prevent the CALs of KD.

Childhood septic arthritis is not only an uncommon presentation with polyarticular involvement, but is also rarely complicated with thromboembolism. We report a case of a 10-year-old boy who suffered multiple staphylococcal arthritis, deep vein thrombosis, pulmonary embolism, pericardial effusion and occlusion of the anterior parietal branch of the right middle cerebral artery. Oxacillin-sensitive Staphylococcus aureus was isolated from blood, synovial fluid and pericardial effusion. Intravenous six-week oxacillin combined with two-week gentamicin for eradicating the pathogen, arthrotomy for debridment and subcutaneous low-molecular-weight heparin for preventing further thromboembolism were administered during admission. In addition, surveys for immunodeficiency, connective tissue disease and hemostatic dysfunction produced negative findings. The patient was discharged with neither painful disability of involved joints nor neurological sequelae.

Kawasaki disease (KD) is an acute febrile multi-system vasculitis of unknown etiology. The diagnosis is based on clinical features. We describe a case of intravenous immunoglobulins (IVIG)-resistant KD presenting with persistent fever and massive cervical lymphadenopathy associated with mild respiratory distress. The symptoms resolved after methylprednisolone pulse therapy. High-dose pulse steroid may be an alternative therapeutic option in KD which presents with possible life-threatening complications or failure to respond to high-dose IVIG infusion.

We describe the beneficial effects of treatment with cyclosporin A in a 10-year-old boy with hyperimmunoglobulin E and refractory nephrotic syndrome. The patient was initially resistant to steroid therapy with prednisolone alone. Additional therapy with cyclosporin A was then prescribed, effectively reducing levels of serum immunoglobulin E and preventing flare up of nephrotic syndrome.

Henoch-Schonlein purpura (HSP) is the most common form of acute vasculitis primarily affecting children. Clinical features include skin rashes, arthritis, abdominal pain and nephritis. Skin biopsy on immunofluorescence often reveals granular depositions of immunoglobulin A (IgA) and C3 within the walls of the dermal vessels as well as in the connective tissue of the upper dermis. The diversity of skin rashes produces confusion in diagnosis of HSP, especially in the presence of bullous lesions. Bullous lesions are very rare in children with HSP, whereas they often appear in adults with HSP. We report 2 cases of HSP in whom hemorrhagic bullae manifested predominantly. In our report, the skin biopsies of both patients revealed typical leukocytoclastic vasculitis without IgA and complement depositions on direct immunofluorescence studies. Dramatic improvement of clinical symptoms and signs was observed within a few days after corticosteroids were administered. There was neither recurrence nor nephritis in these 2 patients.

Although maternal amniotic and vaginocervical cytokines are known to play a role in triggering preterm delivery, the effects of activating fetal phagocytes and platelets are not clear. In an attempt to clarify this issue, we measured levels of myeloperoxidase (MPO), a phagocyte activation marker, and soluble p-selectin (sCD62p), a platelet activation marker, in umbilical cord blood samples from 2200 consecutive cord blood collections, 106 of which were from preterm infants. MPO and sCD62p levels were correlated to gestational age and preterm delivery. It was found that MPO levels were significantly higher in preterm infants and were not significantly correlated to gestational age. In contrast, sCD62p levels were lower in preterm infants and were negatively correlated to gestational age. In summary, we showed that fetal phagocyte activation as demonstrated by higher cord blood MPO levels is associated with preterm delivery, but platelet activation as shown by lower sCD62p levels is not. This suggests that fetal phagocyte activation may be implicated in preterm delivery, and subsequently in pre-maturity-related inflammatory insults.

The central nervous system (CNS) exhibits remarkable plasticity in early life and can be altered significantly by various prenatal influences. We previously showed that prenatal exposure to morphine altered kinetic properties of N-methyl-D-aspartate (NMDA) receptor-mediated synaptic currents in the hippocampus of young rat offspring at the age of 14 days (P14). The present study further investigates whether NMDA receptor-mediated synaptic plasticity and/or cyclic adenosine monophosphate-responsive element-binding protein (CREBSerine-133), an important transcription factor underlying learning and memory, can be altered by prenatal morphine exposure in these offspring. Subsequently, the Morris water maze task was performed at the older ages (P28-P31). The magnitude of long-term depression (LTD) generated by a low-frequency stimulation (LFS, 1 Hz for 15 min) in hippocampal slices from the vehicle-control offspring (P14) was significantly larger than that in slices from the morphine-treated offspring, although there was no such difference in the magnitude of long-term potentiation (LTP) elicited by a high-frequency stimulation (100 Hz for 1 s) between the two groups. Comparison of the expression range of glutamatergic synaptic plasticity in slices from the vehicle-control and morphine-treated offspring, calculated as the difference in the maximal magnitude between LTP and LTD, demonstrated a remarkably smaller range in the slices from the morphine-treated offspring. In addition, the decreased phosphorylation of CREBSerine-133 and the impaired ability of spatial learning were also seen in the morphine-treated offspring, as compared with the vehicle-control offspring. Collectively, the study suggests that maternal exposure to morphine reduces the range of synaptic plasticity by decreasing the expression of LTD, but not of LTP, in CA1 pyramidal neurons of the hippocampus from rat offspring. More importantly, decreased phosphorylation of CREBSerine-133 may play a role for the impaired spatial learning and memory in rat offspring exposure to prenatal morphine. Thus, the findings here may provide important insights into cellular/molecular mechanisms underlying pathophysiological changes in the CNS of young offspring from morphine-addicted mothers and serve as a basis for possible therapeutic intervention.

Nitric oxide (NO) induced by bacterial lipopolysaccharide (LPS) plays a critical role in various patho-physiological implications, such as atherosclerosis, vasculitis and septic shock. In addition, cAMP-responsive element binding protein (CREB), an important transcription factor for cell differentiation, has been shown to be involved in atherosclerogenesis in VSMCs. Here we investigated the possibility whether LPS-induced NO signaling led to phosphorylation of cAMP-responsive element binding protein on Serine-133 (CREBSer-133) in cultured vascular smooth muscle cells (VSMCs) from rats. Addition of LPS (1-10 microg/ml) for 48 hours increased not only the production NO, but also the phosphorylation of CREBSer-133. The use of NOS inhibitor (100-500 microM L-NAME) blocked the magnitudes of both LPS-induced NO production and CREBSer-133 phosphorylation. In addition, either a guanylyl cyclase (GC) inhibitor (30 microM ODQ) or a cGMP-dependent protein kinase (PKG) inhibitor (20 microM (Rp)-8-pCPT-cGMPs) significantly attenuated the magnitudes of LPS-induced CREBSer-133 phosphorylation, suggesting the involvement of NO-GC-PKG signaling. Thus, the present study suggests that NO-mediated signaling activated by bacterial LPS, at least in part, enhance CREBSer-133 phosphorylation in cultured VSMCs. The findings here may provide not only signaling pathway involved in VSMC differentiation during inflammatory response, but also new insight into possible therapeutic intervention.