Hsuan-Chang Kuo

Correlation of pandemic (H1N1) 2009 viral load with disease severity and prolonged viral shedding in children.

Younger children may require a longer isolation period and more aggressive treatment.

Maternal citrulline supplementation prevents prenatal dexamethasone-induced programmed hypertension.

Abstract Glucocorticoids are administered to premature infants to accelerate pulmonary maturation. In experimental model, prenatal dexamethasone (DEX) results in reduced nephron number and adulthood hypertension. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), can cause oxidative stress and is involved in the development of hypertension. l-citrulline can be converted to l-arginine (the substrate for NOS) in the body. Thus we intended to determine if maternal l-citrulline therapy can prevent prenatal DEX-induced programmed hypertension by restoration ADMA/nitric oxide (NO) balance, alterations of renin–angiotensin system (RAS) and sodium transporters, and epigenetic regulation by histone deacetylases (HDACs). Male offspring were assigned to four groups: control, pregnancy rats received intraperitoneal DEX (0.2mg/kg body weight) daily on gestational days 15 and 16 (DEX), pregnancy rats received 0.25% l-citrulline in drinking water during the entire pregnancy and lactation period (CIT), and DEX + CIT. We found DEX group developed hypertension at 16 weeks of age, which was prevented by maternal l-citrulline therapy. Prenatal DEX exposure increased plasma ADMA concentrations and reduced renal NO production. However, l-citrulline reduced plasma ADMA level and increased renal level of NO in DEX + CIT group. Next, prenatal DEX-induced programmed hypertension is related to increased mRNA expression of angiotensin and angiotensin II type 1 receptor, and class I HDACs in the kidney. Prenatal DEX exposure increased renal protein abundance of Na+/Cl− cotransporter (NCC), which was prevented by l-citrulline therapy. The beneficial effects of l-citrulline therapy include restoration of ADMA/NO balance and alteration of NCC, to prevent the prenatal DEX-induced programmed hypertension.

Melatonin prevents neonatal dexamethasone induced programmed hypertension: Histone deacetylase inhibition

Adulthood hypertension can be programmed by corticosteroid exposure in early life. Oxidative stress, epigenetic regulation by histone deacetylases (HDACs), and alterations of renin-angiotensin system (RAS) are involved in the developmental programming of hypertension. We examined whether melatonin prevented neonatal dexamethasone (DEX)-induced programmed hypertension and how melatonin prevented these processes. We also examined whether HDAC inhibition by trichostatin A (TSA, a HDAC inhibitor) had similar effects. Male offspring were assigned to 5 groups (n=6/group): control, DEX, melatonin, DEX+melatonin, and DEX+TSA. Male rat pups were injected i.p. with DEX on day 1 (0.5mg/kg BW), day 2 (0.3mg/kg BW), and day 3 (0.1mg/kg BW) after birth. Melatonin was administered in drinking water at the dose of 0.01% during the lactation period. The DEX+TSA group received DEX and 0.5mg/kg TSA subcutaneous injection once daily for 1 week. All rats were killed at 16 weeks of age. Neonatal DEX exposure induced hypertension in male offspring at 16 weeks of age, which melatonin prevented. Neonatal DEX exposure decreased gene expression related to apoptosis, nephrogenesis, RAS, and sodium transporters. Yet DEX treatment increased protein levels of HDAC-1, -2, and -3 in the kidney. Melatonin therapy preserved the decreases of gene expression and decreased HDACs. Similarly, HDAC inhibition prevented DEX-induced programmed hypertension. In conclusion, melatonin therapy exerts a long-term protection against neonatal DEX-induced programmed hypertension. Its beneficial effects include alterations of RAS components and inhibition of class I HDACs. Given that the similar protective effects of melatonin and TSA, melatonin might inhibit HDACs to epigenetic regulation of hypertension-related genes to prevent programmed hypertension.

Metformin reduces asymmetric dimethylarginine and prevents hypertension in spontaneously hypertensive rats

Elevated asymmetric dimethylarginine (ADMA) levels and nitric oxide (NO) deficiency are associated with the development of hypertension. Metformin, an antidiabetic agent, is a structural analog of ADMA. We examined whether metformin can prevent the development of hypertension in spontaneously hypertensive rats (SHRs) by restoration of ADMA-NO balance. SHRs and control normotensive Wistar-Kyoto (WKY) rats were assigned to 4 groups (N = 8 for each group): untreated SHRs and WKY rats, metformin-treated SHRs and WKY rats. Metformin-treated rats received metformin 500 mg/kg per day via oral gavage for 8 weeks. All rats were sacrificed at the age of 12 weeks. We found an increase in the blood pressure of SHRs was prevented by metformin. ADMA levels in the plasma and lung were elevated in SHRs, which metformin prevented. Lung dimethylarginine dimethylaminohydrolase (DDAH, ADMA-metabolizing enzyme) activity was lower in SHRs than WKY rats. Next, metformin had no effect on protein arginine methyltransferase 1 (ADMA-synthesizing enzyme), DDAH-1, DDAH-2, NO synthase enzymes, and DDAH activity in the kidney. Moreover, metformin increased the levels of NO in kidney. Conclusively, the observed antihypertensive effect of metformin in SHRs is because of the restoration of the ADMA-NO pathway. Our findings support the consideration of metformin as an antihypertensive agent for diabetic patients with prehypertension.

Urinary arginine methylation index associated with ambulatory blood pressure abnormalities in children with chronic kidney disease.

Arginine (ARG) metabolites are interrelated and are involved in chronic kidney disease (CKD) and cardiovascular disease. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) appears to correlate with cardiovascular outcomes. We investigated the relationship between ARG metabolites, and their combined ratios in urine, and the ABPM profiles of children and adolescents with CKD. This cross-sectional study included 45 children and adolescents (age, 5-18 years) with stage 1 to 4 CKD. Each child underwent office blood pressure (BP) measurements, 24-hour ABPM, and urinary ARG metabolite determinations. Seventy percent of children with CKD had abnormal 24-hour ABPM profiles, including nocturnal hypertension, increased BP load, and nondipping nocturnal BP. The urinary ARG-to-asymmetric dimethylarginine (ADMA) ratio was lower, and the ADMA-to-symmetric dimethylarginine (SDMA) ratio was higher in children with advanced CKD (stages 2-4) than those with stage 1 CKD. CKD patients with BP abnormalities also had reduced urinary ARG and dimethylamine (DMA) levels. The higher urinary (ADMA+SDMA)-to-ARG ratios were correlated to ABPM abnormalities, including increased systolic BP load and non-dipping nocturnal BP. ABPM abnormalities were significantly associated with a high urinary (ADMA+SDMA)-to-ARG ratio, suggesting the possible involvement of methylated ARG in the development of hypertension among children with CKD.

Drug reaction with eosinophilia and systemic symptoms syndrome associated myocarditis: a survival experience after extracorporeal membrane oxygenation support

Myocarditis that develops because of the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a life‐threatening disease. We report a case of DRESS‐associated myocarditis with cardiac failure that required extracorporeal membrane oxygenation (ECMO) for cardiovascular support.

Impact of extracorporeal membrane oxygenation support on clinical outcome of pediatric patients with acute cardiopulmonary failure: a single-center experience.

Background: Conventional therapy against acute pediatric cardiopulmonary failure (APCPF) caused by a variety of disease entities remains unsatisfactory with extremely high morbidity and mortality. For refractory APCPF, extracorporeal membrane oxygenation (ECMO) is one of the last resorts. Methods: In this study, the in-hospital outcomes of pediatric patients with refractory APCPF receiving ECMO support were reviewed. Results: Between August 2006 and May 2011, a single-center cohort study was performed in pediatric patients who required ECMO support due to cardiogenic shock or severe hypoxemia. A total of 22 patients with mean age of 7.0 ± 6.3 years received ECMO (male = 11; female = 11). The indications included acute fulminant myocarditis (AFM) (n = 6), congenital diaphragmatic hernia (CDH) (n = 3), acute respiratory distress syndrome (ARDS) (n = 6), enterovirus 71 (n = 3), viral sepsis (n = 2), refractory ventricular fibrillation due to long QT syndrome (n = 1), and pulmonary edema with brain herniation (n = 1). Eighteen patients received veno-arterial (VA) mode ECMO, while another four patients undertook the veno-venous (VV) mode. The duration of ECMO use and hospitalization were 6.1 ± 3.1 and 24.4 ± 19.4 days, respectively. The survival rate in patients with AFM was 100% (n = 6). Successful ECMO weaning with uneventful discharge from hospital was noted in 14 (63.6%) patients, whereas in-hospital mortality despite successful ECMO weaning occurred in 5 patients (22.7%). Failure in ECMO weaning and in-hospital death was noted in 3 patients (13.6%). Conclusions: ECMO resuscitation is an effective strategy in the clinical setting of APCPF.

ISQUA17-1218PRECISION MEDICINE PLAN TO IMPROVE THE DIAGNOSIS AND CARE OF KAWASAKI DISEASE

Objectives: Kawasaki Disease (KD) is a acute febrile systemic vasculitis and mainly affected children less than 5 years old. It has been the major cause of acquired heart disease in children from developing countries. The most important complication of KD is coronary artery involved that will cause activity limitation in the whole life. It will also bring anxiety and stress to family who had KD patient. In this stud, we used precision medicine plan to diminish medical cost, to shorten diagnosis duration, and to improved clinical care satisfaction. Methods: The average diagnosis days in year 2015 was 7.4 days after disease onset and with 78.6 % response to initial intravenous immunoglobulin (IVIG) treatment in the Kawasaki Disease Center of Kaohsiung Chang Gung Memorial Hospital in Taiwan. Anxiety scale (ranged from 0-100mm, Wewers & Lowe,1990) showed status of extremity anxiety with average scale of 79.1mm in family. The satisfactory scale including physician care, nursing, team care and education tool survey showed only 68.7%. We found the major problems were from searching admission ward for KD patient, waiting for physician check and for making diagnosis of KD. Process cycle efficiency (PCE) was 5.8%. Our precision medicine care were included KD specific admission ward with specific nursing and physician care, team care to diminish the diagnosis duration, interesting and useful education tools and set up the clinical treatment protocol. The clinical characteristics of KD include fever lasting for more than 5 days, as well as at least 4 of the following 5 symptoms: diffuse mucosal inflammation with strawberry tongue and fissure lips (1 mouth), bilateral non-purulent conjunctivitis (2 eyes), unilateral cervical lymphadenopathy (3 fingers check lymph node), indurative angioedema over the hands and feet (4 limbs), dysmorphic skin rashes (5 much skin rashes). The 5 KD character symptoms may be not easy to remember or keep in mind for parents or first line clinician. Easier way to remember the 5 characters of KD is important for parents and clinician to identify KD earlier. In order to help remember the 5 KD character symptoms, we created the “Kuo mnemonic” for rapid memory of KD diagnosis criteria that is modified from our previous review. Results: After the precision medicin care, in year 2016, we found the diagnosis days was shorten from 7.4 to 5.8 days after disease onset. IVIG treatment response showed significant increase from 78.6% to 90%. The anxiety scale of family were significant improved from 78.3mm at diagnosis to 30.1mm after treatment (p<0.0001, paired t test). The satisfaction scale improved from 68.7% to 95.1%. PCE also showed markedly improved from 5.8% to 6.9% (19% improvement). We have set up the KD clinic for outpatient check and specific ward for KD patients. The figure showed our KD team. Conclusion: In this study, we reported that precision medicine care with education tool, team care and treatment standard protocol setup can improved treatment outcome and anxiety condition of family. It will also improve medical cost through diminish IVIG treatment failure rate and coronary artery involved. References Kuo HC, Yang KD, Chang WC et al. Kawasaki disease: an update on diagnosis and treatment. Pediatr Neonatol 2012;53:4–11. Kuo HC, Hsu YW, Wu MS et al. Intravenous immunoglobulin, pharmacogenomics, and Kawasaki disease. J Microbiol Immunol Infect 2016;49:1–7.