Asthma Exacerbation in Children: A Practical Review

Asthma is the most common chronic lower respiratory tract disease in childhood throughout the world. Despite advances in asthma management, acute exacerbations continue to be a major problem in patients and they result in a considerable burden on direct/indirect health care providers. A severe exacerbation occurring within 1 year is an independent risk factor. Respiratory tract viruses have emerged as the most frequent triggers of exacerbations in children. It is becoming increasingly clear that interactions may exist between viruses and other triggers, increasing the likelihood of an exacerbation. In this study, we provide an overview of current knowledge about asthma exacerbations, including its definition, impact on health care providers, and associated factors. Prevention management in intermittent asthma as well as intermittent wheeze in pre-school children and those with persistent asthma are discussed. Our review findings support the importance of controlling persistent asthma, as indicated in current guidelines. In addition, we found that early episodic intervention appeared to be crucial in preventing severe attacks and future exacerbations. Besides the use of medication, timely education after an exacerbation along with a comprehensive plan in follow up is also vitally important

Use of electroporation and reverse iontophoresis for extraction of transdermal multibiomarkers

Congo Tak-Shing Ching1,2, Lin-Shien Fu3-5, Tai-Ping Sun1, Tzu-Hsiang Hsu1, Kang-Ming Chang21Department of Electrical Engineering, National Chi Nan University, Puli, Nantou County, 2Department of Photonics and Communication Engineering, Asia University, Wufeng, Taichung, 3Department of Pediatrics, National Yang Ming University, Taipei, 4Institute of Technology, National Chi Nan University, Puli, 5Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, TaiwanBackground: Monitoring of biomarkers, like urea, prostate-specific antigen (PSA), and osteopontin, is very important because they are related to kidney disease, prostate cancer, and ovarian cancer, respectively. It is well known that reverse iontophoresis can enhance transdermal extraction of small molecules, and even large molecules if reverse iontophoresis is used together with electroporation. Electroporation is the use of a high-voltage electrical pulse to create nanochannels within the stratum corneum, temporarily and reversibly. Reverse iontophoresis is the use of a small current to facilitate both charged and uncharged molecule transportation across the skin. The objectives of this in vitro study were to determine whether PSA and osteopontin are extractable transdermally and noninvasively and whether urea, PSA, and osteopontin can be extracted simultaneously by electroporation and reverse iontophoresis.Methods: All in vitro experiments were conducted using a diffusion cell assembled with the stratum corneum of porcine skin. Three different symmetrical biphasic direct currents (SBdc), five various electroporations, and a combination of the two techniques were applied to the diffusion cell via Ag/AgCl electrodes. The three different SBdc had the same current density of 0.3 mA/cm2, but different phase durations of 0 (ie, no current, control group), 30, and 180 seconds. The five different electroporations had the same pulse width of 1 msec and number of pulses per second of 10, but different electric field strengths of 0 (ie, no voltage, control group), 74, 148, 296, and 592 V/cm. Before and after each extraction experiment, skin impedance was measured at 20 Hz.Results: It was found that urea could be extracted transdermally using reverse iontophoresis alone, and further enhancement of extraction could be achieved by combined use of electroporation and reverse iontophoresis. Conversely, PSA and osteopontin were found to be extracted transdermally only by use of reverse iontophoresis and electroporation with a high electrical field strength (>296 V/cm). After application of reverse iontophoresis, electroporation, or a combination of the two techniques, a reduction in skin impedance was observed.Conclusion: Simultaneous transdermal extraction of urea, PSA, and osteopontin is possible only for the condition of applying reverse iontophoresis in conjunction with high electroporation.Keywords: electroporation, reverse iontophoresis, nanochannels, noninvasive, urea, prostate-specific antigen, osteoponti

COMPARISON OF TORSO TWIST BETWEEN SLAP HIT AND ORDINARY HIT IN SOFTBALL BATTING

Softball batters take advantage of slap hit, by positioning the batters much closer to the first base. The purpose of this study was to compare the difference of torso twist between a slap hit and an ordinary hit in softball batting. Ten female college softball batters performed slap hits and ordinary hits. Reflective markers were placed on specific landmarks for each subject and VICON motion analysis system was used to record the hits. Slap hits showed less backward rotation during the torso wind-up phase while ordinary hit showed more forward rotation during the torso follow-through phase. No difference on trunk rotation was found at impact. The findings of this study suggested that the restricted backward torso twist during the wind-up phase and the limited forward torso twist during the follow-through phase should be taken into consideration in slap hits

Acute Kidney Injury Biomarkers for Patients in a Coronary Care Unit: A Prospective Cohort Study

Background: Renal dysfunction is an established predictor of all-cause mortality in intensive care units. This study analyzed the outcomes of coronary care unit (CCU) patients and evaluated several biomarkers of acute kidney injury (AKI), including neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and cystatin C (CysC) on the first day of CCU admission. Methodology/Principal Findings: Serum and urinary samples collected from 150 patients in the coronary care unit of a tertiary care university hospital between September 2009 and August 2010 were tested for NGAL, IL-18 and CysC. Prospective demographic, clinical and laboratory data were evaluated as predictors of survival in this patient group. The most common cause of CCU admission was acute myocardial infarction (80%). According to Acute Kidney Injury Network criteria, 28.7 % (43/150) of CCU patients had AKI of varying severity. Cumulative survival rates at 6-month follow-up following hospital discharge differed significantly (p,0.05) between patients with AKI versus those without AKI. For predicting AKI, serum CysC displayed an excellent areas under the receiver operating characteristic curve (AUROC) (0.89560.031, p,0.001). The overall 180-day survival rate was 88.7 % (133/150). Multiple Cox logistic regression hazard analysis revealed that urinary NGAL, serum IL-18, Acute Physiology, Age and Chronic Health Evaluation II (APACHE II) and sodium on CCU admission day one were independent risk factors for 6-month mortality. In terms of 6-month mortality, urinary NGAL had the best discriminatory power, the best Youden index, and the highest overall correctness of prediction

Slow conduction and gap junction remodeling in murine ventricle after chronic alcohol ingestion

<p>Abstract</p> <p>Background</p> <p>Long-term heavy alcohol drinkers are prone to the development of cardiac arrhythmia. To understand the mechanisms, we evaluated the cardiac structural and electrophysiological changes in mice chronically drinking excessive alcohol.</p> <p>Results</p> <p>Male C57BL/6J mice were given 36% alcohol in the drinking water. Those given blank water were used as control. Twelve weeks later, the phenotypic characteristics of the heart, including gap junctions and electrical properties were examined. In the alcohol group the ventricles contained a smaller size of cardiomyocytes and a higher density of capillary networks, compared to the control. Western blots showed that, after drinking alcohol, the content of connexin43 (Cx43) protein in the left ventricle was increased by 18% (p < 0.05). Consistently, immunoconfocal microscopy demonstrated that Cx43 gap junctions were up-regulated in the alcohol group with a disorganized distribution, compared to the control. Optical mapping showed that the alcohol group had a reduced conduction velocity (40 ± 18 vs 60 ± 7 cm/sec, p < 0.05) and a higher incidence of ventricular tachyarrhythmia (62% vs 30%, p < 0.05).</p> <p>Conclusion</p> <p>Long-term excessive alcohol intake resulted in extensive cardiac remodeling, including changes in expression and distribution of gap junctions, growth of capillary network, reduction of cardiomyocyte size, and decrease of myocardial conduction.</p

Paraoxonase-1 Is Not a Major Determinant of Stent Thrombosis in a Taiwanese Population

BACKGROUND: Clopidogrel is a prodrug that undergoes in vivo bioactivation to show its antiplatelet effects. Recent studies have shown that cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogrel bioactivation. Here, we aim to determine the effects of genetic polymorphisms of CYP (CYP 2C19*2, CYP 2C19*3, and CYP 2C19*17), ABCB1 (ABCB1 3435C>T, ABCB1 129T>C, and ABCB1 2677G>T/A), and PON1 (PON1 Q192R, PON1 L55M, and PON1 108C>T) on the development of stent thrombosis (ST) in patients receiving clopidogrel after percutaneous coronary intervention (PCI). METHODS AND RESULTS: We evaluated the incidence of ST (0.64%) in 4964 patients who were recruited in the CAPTAIN registry (Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions). The presence of genetic polymorphisms was assessed in 20 subjects who developed ST after aspirin and clopidogrel therapy and in 40 age- and sex-matched control subjects who did not develop ST, which was documented after 9 months of angiographic follow-up. ST was acute in 5 subjects, subacute in 7, late in 7, and very late in 1. The presence of CYP 2C19*2 allele was significantly associated with ST (adjusted odds ratio [ORadj]: 4.20, 95% confidence interval [CI], 1.263-9.544; P = 0.031). However, genetic variations in PON1 and ABCB1 showed no significant association with ST. CONCLUSION: We conclude that in a Taiwanese population, PON1 Q192R genotype is not associated with ST development after PCI. However, the presence of CYP 2C19*2 allele is a risk factor for ST development after PCI

Serine Protease PRSS23 Is Upregulated by Estrogen Receptor α and Associated with Proliferation of Breast Cancer Cells

Serine protease PRSS23 is a newly discovered protein that has been associated with tumor progression in various types of cancers. Interestingly, PRSS23 is coexpressed with estrogen receptor α (ERα), which is a prominent biomarker and therapeutic target for human breast cancer. Estrogen signaling through ERα is also known to affect cell proliferation, apoptosis, and survival, which promotes tumorigenesis by regulating the production of numerous downstream effector proteins

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Functional regulation of Brk through its substrate p190RhoGAP

乳癌激酶 (Breast tumor kinase, Brk) 是屬於Src-like酪氨酸激酶家族中的一員。其具有SH3，SH2及酪氨酸激酶催化區塊。一開始是在人類具有高度轉移性乳癌細胞中被發現，且其高度表現在乳癌以及許多其他的癌症細胞中。然而乳癌激酶參與在癌症形成的分子機制仍需要釐清。至今，乳癌激酶過量表現被發現會造成乳腺上皮細胞對表皮生長激素 (EGF) 敏感度上升。在本篇論文中，我們產製了同時可以辨識外生及內生乳癌激酶的抗體。而這支抗體也可以免疫沉澱下外生或內生的乳癌激酶。此外，在本篇論文中，我們發現了p190RhoGAP為乳癌激酶的新受質並更進一步確認其主要受到磷酸化作用的位置為酪氨酸1105。此外，我們也發現了乳癌激酶參與在由表皮生長激素引起的p190RhoGAP的酪氨酸1105磷酸化中。這樣的磷酸化會促進p190RhoGAP在表皮生長激素刺激之下被帶到細胞膜。而減少內生乳癌激酶會抑制細胞的延展也暗示了乳癌激酶在細胞移動性上的影響。最後，我們證實了乳癌激酶能夠經由p190RhoGAP的作用下增進細胞增生。綜觀以上，我們發現了乳酸激酶參與的嶄新訊息傳遞路徑以及其在生物學上可能扮演的角色，並提供了乳癌激酶與細胞移動性及細胞增生上可能的連結，這樣的連結也說明了乳癌激酶在癌症形成過程的重要性。Breast tumor kinase (Brk) is a nonreceptor tyrosine kinase that belongs to Src-like kinase family that containing SH3, SH2, and tyrosine kinase catalytic domains. Brk was originally identified from a human metastatic breast tumor, and its overexpression is frequently observed in breast cancer and several other caner types. However, the molecular mechanism of that Brk participates in tumorigenesis remains to be characterized. Brk overexpression has been shown to sensitize mammary epithelial cells to epidermal growth factor (EGF). In this study, we have generated antibody against Brk which specifically recognizes both exogenous and endogenous Brk. Moreover, this Brk specific antibody can be utilized for immunoprecipitation to pull down both exogenous and endogenous Brk. In addition, we have characterized p190RhoGAP as a novel substrate of Brk and further identified the major phosphorylation site Y1105. Furthermore, we have discovered the involvement of Brk in EGF-induced p190RhoGAP phosphorylation on Y1105. This phosphorylation promotes the membrane recruitment of p190RhoGAP in response to EGF stimulation. In addition, the result that knockdown of Brk can inhibit the cell spreading implies the biological effect of Brk in cell motility. Finally, we have demonstrated that Brk is capable of promoting cell proliferation through a p190RhoGAP-dependent manner. Together, our findings identify new signaling and biological roles of Brk and indicate the potential link between Brk and both cell motility and proliferation which may contribute to its involvement in tumorigenesis.Table of Content 2 中文摘要 4 Abstract 5 Introduction 6 Signal transduction in tumorigenesis 6 Src family tyrosine kinases (SFKs) 8 Breast tumor kinase (Brk) 10 p190RhoGAP 13 Materials & Methods 17 Cell culture and transfection 17 GST fusion proteins 17 Immunization procedure 18 Antibodies 18 Immunoprecipitations 19 Western blot analysis 19 Cell spreading assay 20 Subcellular fractionation 20 Immunofluorescence and microscope 21 Cell proliferation assay 21 Results 22 Generation and characterization of the polyclonal antibody against Brk 22 Brk phosphorylates p190RhoGAP on the Tyr1105 residue 22 Brk mediates EGF-induced tyrosine phosphorylation of p190RhoGAP 23 Knockdown of Brk inhibits cell spreading 24 Brk mediates EGF-induced membrane recruitment of p190RhoGAP 25 p190RhoGAP is required for the cell proliferative effect of Brk 26 Discussion 28 Reference 34 Figures 39 Figure 1. Characterization of the anti-Brk antiserum. 39 Figure 2. Brk phosphorylates p190RhoGAP at Y1105 in vivo. 39 Figure 3. Brk mediates EGF-induced p190RhoGAP phosphorylation. 42 Figure 4. Knockdown of Brk inhibits cell spreading. 43 Figure 5. Brk enhances EGF-induced translocation to membrane fraction of p190RhoGAP. 45 Figure 6. Brk promotes membrane localization of p190RhoGAP upon EGF stimulation. 46 Figure 7. Membrane localization of p190RhoGAP induced by EGF treatment is dramatically elevated by Brk while BrkKM can dominantly inhibit the enhancement. 47 Figure 8. Brk promotes cell proliferation in a p190RhoGAP-dependent manner. 4

Allergic children with extremely high total IgE but no allergen identified in the initial screening panel

Background: High serum IgE level in atopic children usually implies a highly sensitized condition. However, there is a subgroup of atopic children for whom a specific allergen cannot be identified. In this study, we analyzed follow-up data from these children. Methods: From March 2014 to July 2017, we recruited 14 atopic children with serum total IgE level higher than 500 Ku/L, but with no specific allergen identified by repeated MAST tests initially. Follow-up studies of specific IgE were conducted by the OPTIGEN MAST Allergy test and ImmunoCAP assays (Thermo Fisher Scientific/Phadia), while total IgE and specific IgG were measured by ImmunoCAP. Results: The patients were aged from 2 to 17 y/o. The follow-up MAST tests showed significantly positive results in 10 patients. There were no significant differences in any of the clinical characteristics between the MAST-positive and MAST-negative groups. In the MAST-negative group, five allergen-specific IgE antibodies, including those for cockroach, Euroglyphus maynei, Blomia tropicalis, shrimp, and crab, were strongly predictive of negative ImmunoCAP results, according to ROC (Receiver operating characteristic curve) analysis of the AUC (Area under the Curve of ROC) (0.70–0.95), with significance set at p < 0.05. Conclusion: In two thirds of atopic children with a high serum IgE whose specific allergen had yet to be identified, it was possible to identify the specific MAST allergen(s) after an average follow-up of 33.2 months. For patients who still had negative results in follow-up MAST, mite DP, DF, and DM may be suitable choices for further allergen identification by ImmunoCAP