Background/Aims: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. Methods: The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. Results: The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. Conclusions The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.

YH4808 is a novel potassium-competitive acid blocker developed for gastric acid-related disorders. Previous studies indicate its potential to improve symptoms of gastric acid-related disorders. The current study was aimed to find the optimal regimen of YH4808 for night time pH control. This study was performed in two parts. Each was a randomized, open-label, active-controlled, multiple-doses, two-treatment, two-period crossover study conducted in 20 healthy Korean volunteers. Subjects were randomly assigned to one of the four groups.The three groups received different dosage regimens of YH4808 (100 mg twice a day, 200 mg once a day, or 200 mg twice a day), and the fourth group received esomeprazole 40 mg twice a day. The pharmacokinetic parameters demonstrated that the systemic exposure of YH4808 increased in a dose-proportional manner. The difference in the proportion of time above pH 4 over 24 h from the baseline was the greatest in the group receiving YH4808 200 mg twice a day. The values of the area under the effect curve at night time (12 A.M.–7 A.M.) were higher in all YH4808 groups than in the esomeprazole group. However, the differences among the YH4808 groups were not statistically significant (p > 0.05). YH4808 exhibited potential for better pH control during the night in comparison to esomeprazole. The optimal regimen for night time pH control among all the YH4808 regimens was 200 mg twice a day.

PURPOSE: Abdominoperineal solid tumors presenting in neonates often require surgical intervention during the neonatal period. Although we report our single-center experience, this study would be meaningful to understand the clinical implications of these neoplasms. METHODS: We retrospectively reviewed and analyzed the clinical data and characteristics of 22 patients (≤28 days old) diagnosed with histopathologically confirmed abdominoperineal solid neoplasms (benign or malignant) after surgical resection. RESULTS: The mean gestational age and postnatal age at the time of operation were 38.3±1.8 weeks and 13.5±8.3 days, respectively. Most patients (18/22, 81.8%) were diagnosed during antenatal care visits; however, 4 (18.2%) were identified after birth. The mean tumor size was 6.4×5.3 cm (3.5–17.0 cm), and tumors occurred most frequently within the sacrococcygeal region (8/22, 36.4%). Histopathologically, 14 patients (63.6%) demonstrated benign tumors and 8 (36.4%) demonstrated malignant tumors. Germ cell tumors and hepatoblastomas were the most commonly observed tumors. Fortunately, all patients showed a localized pattern of tumor involvement without distant metastasis. No recurrence or mortality was observed during the follow-up period (mean 66.4±44.2 months). CONCLUSION: Abdominoperineal solid tumors occurring in neonates show variable clinical patterns during the antenatal and postnatal monitoring/screening periods. We conclude that aggressive and multidisciplinary approaches could achieve good clinical results in these patients.
Follow-Up Studies ; Gestational Age ; Hepatoblastoma ; Humans ; Infant, Newborn ; Mortality ; Neoplasm Metastasis ; Neoplasms, Germ Cell and Embryonal ; Parturition ; Recurrence ; Retrospective Studies ; Sacrococcygeal Region

Esophageal atresia (EA) with proximal tracheoesophageal fistula (TEF; gross type B) is a rare defect. Although most patients have long-gap EA, there are still no established surgical guidelines. A premature male infant with symmetric intrauterine growth retardation (birth weight, 1,616 g) was born at 35 weeks and 5 days of gestation. The initial diagnosis was pure EA (gross type A) based on failure to pass an orogastric tube and the absence of stomach gas. A “feed and grow” approach was implemented, with gastrostomy performed on postnatal day 2. A fistula was detected during bronchoscopy for recurrent pneumonia; thus, we confirmed type B EA and performed TEF excision and cervical end esophagostomy. As the infant's stomach volume was insufficient for bolus feeding after reaching a body weight of 2.5 kg, continuous tube feeding was provided through a gastrojejunal tube. On the basis of these findings, esophageal reconstruction with gastric pull-up was performed on postnatal day 141 (infant weight, 4.7 kg), and he was discharged 21 days postoperatively. At 12 months after birth, there was no catch-up growth; however, he is currently receiving a baby food diet without any complications. In patients with EA, bronchoscopy is useful for confirming TEF, whereas for those with long-gap EA with a small stomach volume, esophageal reconstruction with gastric pull-up after continuous feeding through a gastrojejunal tube is worth considering.
Body Weight ; Bronchoscopy ; Diagnosis ; Diet ; Enteral Nutrition ; Esophageal Atresia* ; Esophagostomy ; Fetal Growth Retardation ; Fistula ; Gastrostomy ; Humans ; Infant ; Infant, Newborn ; Infant, Premature* ; Male ; Parturition ; Pneumonia ; Pregnancy ; Stomach ; Tracheoesophageal Fistula

Iliopsoas abscess (IPA) is rare in neonates. We present a case of neonatal IPA that was initially believed to bean inguinal hernia. A 20-day-old male infant was referred to our hospital for herniorrhaphy after a 2-day history of swelling and bluish discoloration of the left inguinal area and leg without limitation of motion. Abdominal and pelvic ultrasonography suggested a femoral hernia, but the anatomy was unclear. Abdominal computed tomography revealed a multi-septated cystic mass extending into the psoas muscle from the lower pole of the left kidney to the femur neck. Broad spectrum antibiotics were initiated, and prompt surgical exploration was planned. After opening the retroperitoneal cavity via an inguinal incision, an IPA was diagnosed and surgically drained. Culture of the abscess fluid detected Staphylococcus aureus, sensitive to methicillin. The patient was discharged without complication on the 17th postoperative day.
Diagnosis, Differential ; Drainage ; Hernia, Inguinal/*diagnosis ; Humans ; Infant, Newborn ; Male ; Psoas Abscess/*diagnosis/*therapy ; Radiography, Abdominal/methods ; Rare Diseases ; Republic of Korea ; Staphylococcal Infections/*diagnosis/*therapy ; Tomography, X-Ray Computed/methods ; Treatment Outcome

PURPOSE: One of the major causes of bowel obstruction in extremely premature infants is a meconium obstruction. However, there are many challenges not only in the recognition and diagnosis, but also in the management of meconium obstruction. This study aimed to find perioperative clinical features and determine the postoperative course of meconium-related ileus in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants. METHODS: We retrospectively reviewed the clinical data of premature infants (n = 11, VLBW infnats; n = 16, ELBW infants) with a meconium-related ileus who underwent operation for intractable ileus between January 2009 and May 2013. RESULTS: The average duration of conservative management was longer and postnatal age was older in ELBW infants than VLBW infants: 19.9 days vs. 11.5 days and 34.9 days vs. 19.2 days. The immediate postoperative course (day that beginning feeding and full feeding) was not significantly different based on birth weight, but the ELBW infants had slightly higher mortality. At 12 months of corrected age after operation, both average body weight and average height was below 10th percentile for growth in most infants (61.1%). CONCLUSION: There was a slightly high mortality in the ELBW infants, but two groups did not experience significant differences in the immediate postoperative course of meconium-related ileus. Nevertheless, considering their growth patterns, it is necessary to do a close follow-up and more aggressive nutritional management to achieve optimal growth and development in both patient groups.
Birth Weight ; Body Weight ; Diagnosis ; Growth and Development ; Humans ; Ileus* ; Infant* ; Infant, Extremely Low Birth Weight ; Infant, Extremely Premature ; Infant, Low Birth Weight* ; Infant, Newborn ; Infant, Premature ; Infant, Very Low Birth Weight* ; Meconium ; Mortality ; Retrospective Studies

PURPOSE: This study was performed to investigate the differences in gastric perforation in the neonatal period between preterm and term infants. METHODS: We retrospectively reviewed the medical records of neonates who underwent abdominal surgery between January 2005 and December 2014 at a single institution. Eleven neonates who were managed for gastric perforation were enrolled in this study. RESULTS: There were 8 preterm and 3 term neonates. In preterm neonates, the mean gestational age and birth weight were 29.7+/-3.7 weeks and 1,538.7+/-774.9 g, respectively. Two preterm neonates had very low birth weight and three had extremely low birth weight. In most of the preterm neonates, possible contributing factors were identified, such as maternal problems, mechanical ventilator support, and medication. In contrast, in term neonates, gastric perforation seemed to be associated with other gastrointestinal anomalies or occurred spontaneously. Two neonates died: one preterm (12.5%) and one term (33.3%) neonate; both had a linear, necrotic perforation. CONCLUSION: Gastric perforation rarely occurred in the neonatal period. Contributing factors for gastric perforation were identified in preterm neonates, but this occurred spontaneously or with other gastrointestinal anomalies in term neonates. A linear, necrotic perforation was associated with poor outcomes, regardless of gestational age.
Birth Weight ; Gestational Age ; Humans ; Infant* ; Infant, Low Birth Weight ; Infant, Newborn ; Infant, Very Low Birth Weight ; Medical Records ; Retrospective Studies ; Ventilators, Mechanical

The receptor activator of NF-kappaB ligand (RANKL) signal is an activator of tumor necrosis factor receptor-associated factor 6 (TRAF6), which leads to the activation of NF-kappaB and other signal transduction pathways essential for osteoclastogenesis, such as Ca2+ signaling. However, the intracellular levels of inositol 1,4,5-trisphosphate (IP3) and IP3-mediated cellular function of RANKL during osteoclastogenesis are not known. In the present study, we determined the levels of IP3 and evaluated IP3-mediated osteoclast differentiation and osteoclast activity by RANKL treatment of mouse leukemic macrophage cells (RAW 264.7) and mouse bone marrow-derived monocyte/macrophage precursor cells (BMMs). During osteoclastogenesis, the expression levels of Ca2+ signaling proteins such as IP3 receptors (IP3Rs), plasma membrane Ca2+ ATPase, and sarco/endoplasmic reticulum Ca2+ ATPase type2 did not change by RANKL treatment for up to 6 days in both cell types. At 24 h after RANKL treatment, a higher steady-state level of IP3 was observed in RAW264.7 cells transfected with green fluorescent protein (GFP)-tagged pleckstrin homology (PH) domains of phospholipase C (PLC) delta, a probe specifically detecting intracellular IP3 levels. In BMMs, the inhibition of PLC with U73122 [a specific inhibitor of phospholipase C (PLC)] and of IP3Rs with 2-aminoethoxydiphenyl borate (2APB; a non-specific inhibitor of IP3Rs) inhibited the generation of RANKL-induced multinucleated cells and decreased the bone-resorption rate in dentin slice, respectively. These results suggest that intracellular IP3 levels and the IP3-mediated signaling pathway play an important role in RANKL-induced osteoclastogenesis.
Animals ; Blood Proteins ; Boron Compounds ; Calcium-Transporting ATPases ; Cell Membrane ; Dentin ; Estrenes ; Inositol ; Inositol 1,4,5-Trisphosphate ; Inositol 1,4,5-Trisphosphate Receptors ; Macrophages ; Mice ; NF-kappa B ; Osteoclasts ; Phosphoproteins ; Proteins ; Pyrrolidinones ; Receptor Activator of Nuclear Factor-kappa B ; Reticulum ; Signal Transduction ; Tumor Necrosis Factor-alpha ; Type C Phospholipases

PURPOSE: To report our experience of gastrointestinal operations performed in neonates including low birth weight infants and to evaluate their clinical characteristics. METHODS: We retrospectively reviewed the medical records of patients who underwent neonatal gastrointestinal surgery or had necrotizing enterocolitis (NEC) or inguinal hernia from January 2008 to December 2010 at Pusan National University School of Medicine. RESULTS: The main disease was anorectal malformation and male patients were dominant. Twenty four patients (19.2%) had one or more associated anomalies including hydronephrosis and congenital heart disease. Eighteen patients (43.9%) of anorectal malformation had other anomalies. Seventy six percent of NEC cases were very low birth weight infants. Concerning mean days of full enteral feeding after operation, NEC patients needed 30.8 days, which was the longest period. Overall mortality of operation (except NEC and inguinal hernia operation) was 1.6%. The mortality of NEC with surgical treatment was 18.8%. The direct bilirubin in the operation group was significant higher than in the non-operation group in NEC patients. CONCLUSION: The morbidity and mortality after neonatal gastrointestinal surgery were excellent. The direct bilirubin in the operation group was significant higher than in the non-operation group in NEC.
Anus, Imperforate ; Bilirubin ; Enteral Nutrition ; Enterocolitis, Necrotizing ; Gastrointestinal Diseases ; Heart Diseases ; Hernia, Inguinal ; Humans ; Hydronephrosis ; Infant ; Infant, Low Birth Weight ; Infant, Newborn ; Infant, Very Low Birth Weight ; Intensive Care, Neonatal ; Male ; Medical Records ; Retrospective Studies

PURPOSE: The aim of present study was to assess the utility of serum biochemical markers for predicting the metabolic bone disease (MBD) in very low birth weight infants (VLBWI). METHODS: Medical records of 104 VLBWI from 2003 to 2008 were reviewed in this retrospective study. Study patients were divided in MBD and control group according to the finding of wrist radiography performed at 4 weeks of life. We compared the serum biochemical markers including alkaline phosphate (ALP), calcium (Ca), phosphate (P) between two groups at birth, 1 and 4 weeks of life. The value of serum vitamin D (Vit. D) was measured at 4-5 weeks of life. RESULTS: The mean gestational age and birth weight of study patients were 30(+6) +/- 2.0 weeks and 1,308.2 +/- 136.7 g. The incidence of MBD was 28.9% (31 / 104). At birth, higher values of serum ALP (438.1 +/- 129.1 mg/dL vs 360.5 +/- 122.8 mg/dL) were found in MBD group. At 1 week of life, higher values of serum Ca (11.0 +/- 1.7 mg/dL vs 10.3 +/- 1.7 mg/dL) and lower values of serum P (3.2 +/- 1.2 mg/dL vs 4.1 +/- 1.3 mg/dL) were found in MBD group. At 4 weeks of life, higher values of serum ALP activities (1,397.6 +/- 635.6 U/L vs 789.0 +/- 573.0 U/L), lower values of serum P (4.2 +/- 2.0 mg/dL vs 5.4 +/- 1.8 mg/dL) and Vit. D (17.7 +/- 7.2 ng/mL vs 30.0 +/- 15.5 ng/mL) were found in MBD group. Risk factors of MBD were male and Vit. D deficiency with high ALP at 4 weeks of life. CONCLUSION: These results suggest that high ALP concentrations at 4 weeks of life may predict MBD with Vit. D deficiency in VLBWI.
Biomarkers ; Birth Weight ; Bone Diseases ; Bone Diseases, Metabolic ; Calcium ; Gestational Age ; Humans ; Incidence ; Infant ; Infant, Very Low Birth Weight ; Male ; Medical Records ; Parturition ; Retrospective Studies ; Risk Factors ; Vitamin D ; Wrist