• Biomolecules & Therapeutics
• /
• 제26권6호
• /
• pp.599-607
• /
• 2018

Fasiglifam (TAK-875) a G-protein coupled receptor 40 (GPR40) agonist, significantly improves hyperglycemia without hypoglycemia and weight gain, the major side effects of conventional anti-diabetics. Unfortunately, during multi-center Phase 3 clinical trials, unexpected liver toxicity resulted in premature termination of its development. Here, we investigated whether TAK-875 directly inflicts toxicity on hepatocytes and explored its underlying mechanism of toxicity. TAK-875 decreased viability of 2D and 3D cultures of HepG2, a human hepatocarcinoma cell line, in concentration-(>$50{\mu}M$) and time-dependent manners, both of which corresponded with ROS generation. An antioxidant, N-acetylcysteine, attenuated TAK-875-mediated hepatotoxicity, which confirmed the role of ROS generation. Of note, knockdown of GPR40 using siRNA abolished the hepatotoxicity of TAK-875 and attenuated ROS generation. In contrast, TAK-875 induced no cytotoxicity in fibroblasts up to $500{\mu}M$. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at$25{\mu}M$. Histopathological examination of zebrafish exposed to TAK-875 revealed severe hepatotoxicity as manifested by degenerated hypertrophic hepatocytes with cytoplasmic vacuolation and acentric nuclei, confirming that TAK-875 may induce direct hepatotoxicity and that ROS generation may be involved in a GPR40-dependent manner.

• Biomolecules & Therapeutics
• /
• 제13권1호
• /
• pp.20-25
• /
• 2005

The present study was performed to evaluate antiarrhythmic effects of KR-32570, a novel inhibitor of sodium hydrogen exchanger subtype-1 (NHE-1), in rat arrhythmia induced by focal ischemia and reperfusion. During ischemia, KR-32570 significantly decreased the number of premature ventricular contraction (PVC) from 152.0 times to 75.5, 52.4 and 20.0 times for 0.1, 0.3 and 1.0 mg/kg, respectively (p<0.05) and the duration of ventricular tachycardia (VT) from 88.1 s to 35.8, 7.7 and 1.3 s, respectively(p<0.05) in anesthetized rats subjected to 10-min coronary occlusion of coronary artery. Similarlt to ischemia-induced arrhythmia, KR-32570 significantly decreased reperfusion-induced arrhythmia including PVC (41.3, 21.5, 11.3 and 6.6 times at vehicle, 0.1, 0.3 and 1.0 mg/kg, respectively, p<0.05) and VT (100.5, 64.2, 25.8 and 25.2 s, respectively, p<0.05), and VF (86.9, 27.5, 6.9 and 0 s, respectively, p<0.05). Moreover, KR-32570 dose-dependently decreased the incidence of mortality occurring after reperfusion (41, 27, 18 and 0% at vehicle, 0.1, 0.3, 1.0 mg/kg, respectively). These results suggest that KR-32570 has a potent antiarrhythmic effect in rat arrhythmia induced by ischemia and reperfusion.

• Clinical and Experimental Pediatrics
• /
• 제58권8호
• /
• pp.288-293
• /
• 2015

Purpose: In this study, we aimed to review the clinical presentation of preterm infants with gastrointestinal perforations and compare the clinical features of gastric perforation with other intestinal perforations. Methods: The medical records of preterm neonates with pneumoperitoneum, admitted to the neonatal intensive care unit (NICU) between January 1994 and December 2013, were retrospectively reviewed. Results: Twenty-one preterm infants underwent exploratory laparotomy to investigate the cause of the pneumoperitoneum. The sample consisted of five patients (23.8%) with gastric perforation and 16 patients (76.2%) with intestinal perforation. No statistical differences were found in the birth history and other perinatal factors between the two groups. Underlying necrotizing enterocolitis, bilious vomiting, and paralytic ileus preceding the perforation were statistically more common in the intestinal perforation group. All preterm infants with gastric perforation survived to discharge; however, six preterm infants with intestinal perforation expired during treatment in the NICU. In the gastric perforation group, sudden pneumoperitoneum was the most common finding, and the mean age at diagnosis was $4.4{\pm}1.7days$ of life. The location and size of the perforations varied, and simple closure or partial gastrectomy was performed. Conclusion: Patients with gastric perforation did not have a common clinical finding preceding the perforation diagnosis. Although mortality in previous studies was high, all patients survived to discharge in the present study. When a preterm infant aged less than one week presents with sudden abdominal distension and pneumoperitoneum, gastric perforation should first be excluded. Prompt exploratory laparotomy will increase the survival rates of these infants.

• Journal of Korean Neurosurgical Society
• /
• 제42권4호
• /
• pp.281-285
• /
• 2007

Objective : Distal anterior cerebral artery (DACA) aneurysms are fragile and known to have high risks for intraoperative premature rupture and a relatively high associated morbidity. To improve surgical outcomes of DACA aneurysms, we reviewed our surgical strategy and its results postoperatively. Methods : A total of 845 patients with ruptured cerebral aneurysms were operated in our hospital from January 1991 to December 2005. Twenty-three of 845 patients had ruptured DACA aneurysms which were operated on according to our surgical strategy. Our surgical strategy was as follows; early surgery, appropriate releasing of CSF, appropriate surgical approach, using neuronavigating system, securing the bridging veins, using temporary clipping and/or tentative clipping, meticulous manipulation of aneurysm, and using micro-Doppler flow probe. Twenty of 23 patients who had complete medical records were studied retrospectively. We observed the postoperative radiographic findings and checked Glasgow Outcome Scale score sixth months after the operation. Results : Nineteen DACA aneurysms were clipped through a unilateral interhemispheric approach and one DACA aneurysm was clipped through a pterional approach. Postoperative radiographic findings revealed complete clipping of aneurysmal neck without stenosis or occlusion of parent arteries. In two patients, a residual neck of aneurysm was visualized. Seventeen patients showed good recovery, one patient resulted in moderate disability, while 2 patients died. Conclusion : With our surgical strategy it was possible to achieve acceptable surgical morbidity and mortality rates in patients with DACA aneurysms. Appropriate use of tentative clipping, temporary clipping and neuro-navigating systems can give great help for safe approach and clipping of DACA aneurysm.

• Parasites, Hosts and Diseases
• /
• 제52권6호
• /
• pp.639-644
• /
• 2014

Congenital malaria is assumed to be a risk factor for infant morbidity and mortality in endemic areas like Maumere, Indonesia. Infected infants are susceptible to its impact such as premature labor, low birth weight, anemia, and other unspecified symptoms. The aim of this study was to investigate the prevalence of congenital malaria and the influence of mother-infant paired parasite densities on the clinical outcome of the newborns at TC Hillers Hospital, Maumere. An analytical cross sectional study was carried out in newborns which showed criteria associated with congenital malaria. A thick and thin blood smear confirmed by nested PCR was performed in both mothers and infants. The association of congenital malaria with the newborn's health status was then assessed. From 112 mother-infant pairs included in this study, 92 were evaluated further. Thirty-nine infants (42.4%) were found to be infected and half of them were asymptomatic. Infected newborns had a 4.7 times higher risk in developing anemia compared to uninfected newborns (95% CI, 1.3-17.1). The hemoglobin level, erythrocyte amount, and hematocrit level were affected by the infants' parasite densities (P<0.05). Focusing on newborns at risk of congenital malaria, the prevalence is almost 3 times higher than in an unselected collective. Low birth weight, anemia, and pre-term birth were the most common features. Anemia seems to be significantly influenced by infant parasite densities but not by maternal parasitemia.

• Journal of Yeungnam Medical Science
• /
• 제15권1호
• /
• pp.67-74
• /
• 1998

Successful management of duodenal obstruction in newborn infant implies not only satisfactory nutrition but also achievement of normal growth. To aid early diagnosis and management, we evaluated the diagnostic methods, operative interventions and clinical characteristics of thirty-nine infants with congenital duodenal obstructions. In the 11-year period from July 1986 through June 1997, thirty-nine patients with congenital duodenal obstruction (23 males and 16 females) were treated and reviewed at the Department of Pediatric Surgery, Yeungnam University Hospital. The ratio of male to female was 1.4:1, and 29 cases(74.1%) among total 39 patients were newborn. There were 5 premature patients and 16 patients of small for gestational age. The most common causes of the congenital duodenal obstruction was malrotation (26 cases, 66.7%) and followed by annular pancreas (9 cases, 23.1 %), type 1 atresia (3 cases, 7.7%) and wind-sock anomaly (1 case, 2.6%). Common symptoms were vomiting, abdominal distention, jaundice. Plain abdominal X-ray study combined with upper gastrointestinal series was the most commonly used diagnostic method. The operative procedures were performed by same pediatric surgeon utilizing Ladd's procedure in 26, duodenoduodenostomy in 8, duodenojejunostomy in 4, excision of wind-sock membrane in 1. A total of 15 associated congenital anomalies were found in 9 patients. Postoperative complications occurred in 13(33.3%). Overall mortality was 2.6%(1/39). Bilious vomiting and plain abdominal radiologic study were most useful for the diagnosis of congenital duodenal obstruction. Early diagnosis and operative intervention were important to prevent complications such as sepsis and peritonitis.

• Asian Pacific Journal of Cancer Prevention
• /
• 제17권7호
• /
• pp.3533-3540
• /
• 2016

Background: Cigarette smoking is one of the leading global causes of premature and preventable death. In Brunei Darussalam, smoking-related diseases have been a primary cause of mortality for the past three decades. Despite the increasing efforts that have been made in recent years to reduce the consumption of tobacco products in Brunei, the prevalence of adolescent smoking cigarette, however has risen alarmingly, from 8.9% in 2013 to 11.4% in 2014, with a higher prevalence found in males (17.8%) than in females (4.8%). In response to the need for more effective smoking prevention programmes in Brunei, this study sought to explore factors that influence Bruneian male adolescents to start and continue smoking. Materials and Methods: A qualitative study using focus group discussions (FGDs) as the data collection method was conducted from October to November 2015. A total of 43 studentss, comprising 31 smokers and 12 non-smokers, aged 13-17 years, from two government secondary schools in Bandar Seri Begawan, participated in six FGDs. Discussions were recorded and translated. Transcripts were entered into NVivo10, before thematic analysis was conducted. Results: We identified three themes under the core construct of 'factors influencing smoking initiation' ('family as teachers', 'overt pressure from peers' and 'perceived smoking has many advantages') and three themes under the core construct of 'factors influencing smoking continuation' ('craving and addiction', 'smoking as a 'social activity' and 'easy accessibility of cigarettes'). Conclusions: Based on the findings, it is recommended that future prevention activities should be embedded in a comprehensive approach, involving all stakeholders within a community, and should be focused towards bringing a change in smoking and parenting behavior of parents, social norms within the culture towards all population levels, and at strengthening the existing non-smoking policies in schools and other public places where young people congregate.

• Clinical and Experimental Pediatrics
• /
• 제63권8호
• /
• pp.284-290
• /
• 2020

Korea currently has the world's lowest birth rate but a rapidly inreasing number of preterm infants. The Korean Neonatal Network (KNN), launched by the Korean Society of Neonatology under the support of Korea Centers for Disease Control, has collected population-based data for very low birth weight infants (VLBWIs) born in Korea since 2013. In terms of the short-term outcomes of VLBWIs born from 2013 to 2016 registered in the KNN, the survival rate of all VLBWIs was 86%. Respiratory distress syndrome and bronchopulmonary dysplasia were observed in 78% and 30% of all VLBWIs, respectively. Necrotizing enterocolitis occurred in 7%, while 8% of the VLBWIs needed therapy for retinopathy of prematurity in the neonatal intensive care unit (NICU). Sepsis occurred in 21% during their NICU stay. Intraventricular hemorrhage (grade ≥III) was diagnosed in 10%. In terms of the long-term outcomes for VLBWIs born from 2013 to 2014 registered in the KNN, the post-discharge mortality rate was approximately 1.2%-1.5%, mainly owing to their underlying illness. Nearly half of the VLBWIs were readmitted to the hospital at least once in their first 1-2 years of life, mostly as a result of respiratory diseases. The overall prevalence of cerebral palsy was 6.2%-6.6% in Korea. Bilateral blindness was reported in 0.2%-0.3% of VLBWIs, while bilateral hearing loss was found in 0.8%-1.9%. Since its establishment, the KNN has published annual reports and papers that facilitate the improvement of VLBWI outcome and the formulation of essential healthcare policies in Korea.

• Pediatric Gastroenterology, Hepatology & Nutrition
• /
• 제23권4호
• /
• pp.377-387
• /
• 2020

Purpose: To compare between sodium acetate (SA) and sodium chloride (SC) in parenteral nutrition (PN) with associated metabolic acidosis and neonatal morbidities in preterm infants. Methods: Preterm infants below 33 weeks gestational age, and with a birth weight under 1,301 g were enrolled and further stratified into two groups: i) <1,000 g, or ii) ≥1,000 g in birth weight. The subjects were randomized to receive PN containing SA or SC within the first day of life. The results of routine blood investigations for the first 6 days of PN were collated, and the neonatal outcomes were recorded upon discharge or demise. Results: Fifty-two infants entered the study, with 26 in each group: 29 infants had extremely low birth weight (ELBW). There were no significant differences in birth weight, gestation, sex, exposure to chorioamnionitis and antenatal steroids, surfactant doses and duration of mechanical ventilation between groups. The SA group had significantly higher mean pH and base excess (BE) from days 4 to 6 than the SC (mean pH, 7.36 vs. 7.34; mean BE -1.6 vs. -3.5 [p<0.01]), with a two-fold increase in the mean BE among ELBW infants. Significantly fewer on SA required additional bicarbonate (n=4 vs. 13, p=0.01). The rate of bronchopulmonary dysplasia (BPD) was approximately four-fold lower in SA than SC (n=3 vs. 11, p<0.01). No significant differences were observed in necrotizing enterocolitis, patent ductus arteriosus, retinopathy of prematurity, cholestatic jaundice, and mortality between groups. Conclusion: The use of SA in PN was associated with reduced metabolic acidosis and fewer BPD.

• Neonatal Medicine
• /
• 제15권1호
• /
• pp.105-110
• /
• 2008

신생아 간농양은 특별한 증상이 발현되지 않거나 비특이적인 증상 때문에 진단이 늦어지는 경우가 많다. 항생제의 사용에도 불구하고 염증 반응이 지속되며 복부증상이 함께 나타나는 경우, 주산기 산모의 심한 감염, 융모양막염 등의 선행인자가 있고, 제대혈관 도관과 관련된 패혈증이 있는 경우에는 간농양의 가능성을 고려해야 한다. 저자들은 생후 9일된 미숙아에서 제대정맥 도관과 함께 산모의 폐렴 및 심한 융모양막염이 선행요인이 되어, 단일성 간농양이 발생한 진단된 사례를 경험하였기에 문헌 고찰과 함께 보고하는 바이다.