A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α-mediated aerobic glycolysis.

Hepatocellular carcinoma (HCC) is characterized by rapid growth, early vascular invasion, and high metastasis. Currently available US Food and Drug Administration (FDA)-approved drugs show low therapeutic efficacy, limiting HCC treatment to chemotherapy. We designed and synthesized a novel small molecule, SCT-1015, that allosterically activated adenosine monophosphate-activated protein kinase (AMPK) to suppress the aerobic glycolysis in HCC. SCT-1015 was shown to bind the AMPK α and ß-subunit interface, thereby exposing the kinase α domain to the upstream kinases, resulting in the increased AMPK activity. SCT-1015 dramatically reduced HCC cell growth in vitro and tumor growth in vivo. We further found that AMPK formed protein complexes with hypoxia-inducible factor 1-alpha (HIF1α) and that SCT-1015-activated AMPK promoted hydroxylation of HIF1α (402P and 564P), resulting in HIF1α degradation by the ubiquitin-proteasome system. With declined HIF1α abundance, many glycolysis-related enzymes were downregulated, suppressing aerobic glycolysis, and promoting oxidative phosphorylation. These results indicated that SCT-1015 channeled HCC cells into an unfavorable metabolic status. Overall, we reported SCT-1015 as a direct activator of AMPK signaling that held therapeutic potential in HCC.

Plasma IP-10 as a predictor of serious bacterial infection in infants less than 4 months of age.

BACKGROUND: Early diagnosis of serious bacterial infection (SBI) in young infants is a difficult problem by clinical symptoms and signs. The goal of this study is to evaluate the predictive value of plasma IP-10 levels for early diagnosis of SBI in young infants <4 months of age. METHODS: We enrolled pediatric patients who were <4 months of age with a clinical suspicion to have SBI admitted in neonatal intensive care unit or complete nursing unit of Pediatric Department of Kaohsiung Medical University Hospital. Blood was drawn for measurement of complete blood counts, C-reactive protein (CRP) and plasma IP-10 levels and microbiological cultures were obtained at the time of admission. RESULTS: There were 60 patients enrolled in this study. The SBI group (n = 21) have higher plasma IP-10 levels than those infants without SBI (n = 39) [median 104.8 (range 0-1457.1) versus 0 (range 0-129.3) pg ml(-1), P = 0.0161 after adjusting age]. A plasma IP-10 level >48.2 pg ml(-1) had the best diagnostic accuracy for indicating SBI {sensitivity 81.0% [95% confidence interval (CI) 71.1-90.1%]; specificity 94.9% [95% CI 65.4-87.0%]; positive likelihood ratio 15.9, negative likelihood ratio 0.2}. CONCLUSION: In infants who were <4 months of age with suspicion of SBI, IP-10 assay might be a good predictor. Key words: chemokine, IP-10, serious bacterial infection, young infant, C-reactive protein.

B-type natriuretic peptide predicts responses to indomethacin in premature neonates with patent ductus arteriosus.

OBJECTIVES: To determine whether B-type natriuretic peptide (BNP) predicts indomethacin responsiveness in premature neonates with patent ductus arteriosus (PDA). STUDY DESIGN: Premature neonates receiving indomethacin for an echocardiograhically large (diameter>1.5 mm) and clinically significant PDA were prospectively studied. All neonates underwent paired echocardiography and BNP measurements at baseline and 24 hours after each dose of indomethacin. After treatment, neonates who responded (with closed or insignificant PDA) and neonates who did not respond (with persistent significant PDA requiring surgical ligation) were compared. RESULTS: Thirty-one premature neonates (mean gestational age, 30 weeks) underwent 119 paired echocardiography and BNP determinations. Mean BNP levels (1286+/-986 pg/mL) associated with significant PDA (n=96) were higher than those associated with closed or insignificant PDA (n=23; 118+/-124 pg/mL; P<.001). Twenty-three neonates responded and 8 neonates did not respond to indomethacin. Mean baseline BNP levels were higher in neonates who were non-responders (2234+/-991 pg/mL) than neonates who were responders (983+/-814 pg/mL; P=.001). A baseline BNP level>1805 pg/mL had a sensitivity rate of 88% and a specificity rate of 87% for predicting indomethacin non-responsiveness (P=.003). CONCLUSIONS: High baseline BNP levels predict poor responses to indomethacin and the need for surgery in premature neonates with PDA.

The effects of NOS1 gene on asthma and total IgE levels in Taiwanese children, and the interactions with environmental factors.

Asthma is a complex disorder, which is known to be affected by interactions between genetic and environmental factors. The aim of this study was to investigate the three microsatellite polymorphisms of GT repeats in intron 2, AAT repeats in intron 20, and CA repeats in exon 29 of the NOS1 gene in 155 asthmatic children and 301 control children, and the interaction with environmental factors in southern Taiwan. Total serum IgE, phadiatop test and genetic polymorphisms were measured. The genotype frequency of 14/14-AAT repeats of the NOS1 gene was significantly higher in the asthmatic group (p = 0.01). Total IgE concentrations were higher in asthmatic children (p = 0.015) carrying the NOS1 14/14-AAT genotype than in subjects with other polymorphisms. The gene and environmental interaction effects were 3.83-fold, 6.86-fold, and 8.04-fold (all corrected p-values <0.001) between subjects carrying at least one NOS1 14-AAT allele and exposure to cockroaches, high levels of total IgE, and positive response against the phadiatop test in asthmatic children. The findings of this study provide strong evidence that NOS1 gene with 14-AAT tandem repeats has a significant effect in asthmatic children. Environmental factors and atopic status will enhance the asthmatic risk for children who carry NOS1 susceptible allele.

Assisted exercise improves bone strength in very low birthweight infants by bone quantitative ultrasound.

AIM: To evaluate whether assisted exercise could prevent the development of osteopenia of prematurity, we performed assisted exercise in the study group of very low birthweight (VLBW) premature infants. METHODS: Sixteen premature infants with birthweight below 1500 g were enrolled in this study and randomly assigned into the exercise (n = 8) and control (n = 8) groups. Assisted exercise involved full extension and flexion range of motion of the upper and lower extremities by a trained nurse with a schedule of 5 days a week for a total of 4 weeks. Bone strength was determined by quantitative ultrasound measurement of tibial bone speed of sound every 2 weeks during the study period. RESULTS: No difference in gender, birthweight, and gestation age between the exercise and control groups was noted. There was statistically significant less tibial bone speed of sound decrease in the exercise group on the sixth and eighth week of life. During the study period, there were no statistically significant differences in blood biochemistry data, including calcium, phosphorus, magnesium, alkaline phosphatase, osteocalcin and osteoprotegerin, between the two groups. CONCLUSIONS: This study revealed that early assisted exercise could improve bone strength in very low birthweight infants. The biochemical markers of bone metabolism, osteocalcin and osteoprotegerin, could not be the indicators for early diagnosis of osteopenia of prematurity.

The effectiveness of structured discharge education on maternal confidence, caring knowledge and growth of premature newborns.

AIMS: The aim of this study is to evaluate the effectiveness of structured discharge education on maternal confidence and caring knowledge and the growth of premature newborns. BACKGROUND: Parents of premature newborns are usually confronted with great difficulties in caring for their babies after discharge. Building maternal confidence and caring knowledge can help mothers reduce such difficulties of caring for their babies after discharge from hospital. DESIGN: Randomised controlled trial. METHODS: Mothers with premature babies were randomly assigned into experimental (n=29) and control groups (n=30) at a medical centre in southern Taiwan. The mothers of both groups had received a questionnaire concerning maternal confidence and caring knowledge at pretest. After the pretest, a structured discharged education programme was provided to the mothers of the experimental group. The control group only received traditional discharge education. Mothers of experimental and control groups again received the questionnaire of maternal confidence and caring knowledge at the day before discharge and one month after discharge. At that time, the body height and body weight of newborns were measured and recorded. RESULTS: Maternal confidence and caring knowledge of mothers in the experimental group were significantly higher than those of the control group at the day before discharge; however, there were no significant differences between the two groups one month after discharge. Using repeated anova analysis, the time × group interaction was significant for maternal confidence and caring knowledge, indicating that the groups differed significantly in changes in maternal confidence and caring knowledge over the three time points. CONCLUSIONS: Structured discharge education on mothers could significantly increase maternal confidence and caring knowledge at the day before discharge. Furthermore, structured discharge education could significantly increase the percentage of growth on body height of premature newborns. RELEVANCE TO CLINICAL PRACTICE: The results could help clinical nurses design appropriate discharge education programmes for mothers of premature newborns.

Cytotoxicity of calotropin is through caspase activation and downregulation of anti-apoptotic proteins in K562 cells.

Calotropin is one of cardenolides isolated from milkweed used for medicinal purposes in many Asian countries. Whereas calotropin possesses cytotoxicity against several cancer cells, the mechanisms of action remain unclear. We set out to evaluate the cytotoxic mechanism of calotropin on human chronic myeloid leukemia K562 cells. Calotropin inhibited the growth of K562 cells in a time- and dose-dependent manner by G(2)/M phase arrest. It upregulated the expression of p27 leading to this arrest by downregulating the G2/M regulatory proteins, cyclins A and B, and by upregulating the cdk inhibitor, p27. Furthermore, it downregulated anti-apoptotic signaling (XIAP and survivin) and survival pathways (p-Akt and NFkappaB), leading to caspase-3 activation which resulted in the induction of apoptosis. In all, calotropin exerted its anticancer activity on K562 cells by modulating the pro-survival signaling that leads to induction of apoptosis.

Plasma IP-10 as a predictor of serious bacterial infection in infants less than 4 months of age.

BACKGROUND: Early diagnosis of serious bacterial infection (SBI) in young infants is a difficult problem by clinical symptoms and signs. The goal of this study is to evaluate the predictive value of plasma IP-10 levels for early diagnosis of SBI in young infants <4 months of age. METHODS: We enrolled pediatric patients who were <4 months of age with a clinical suspicion to have SBI admitted in neonatal intensive care unit or complete nursing unit of Pediatric Department of Kaohsiung Medical University Hospital. Blood was drawn for measurement of complete blood counts, C-reactive protein (CRP) and plasma IP-10 levels and microbiological cultures were obtained at the time of admission. RESULTS: There were 60 patients enrolled in this study. The SBI group (n = 21) have higher plasma IP-10 levels than those infants without SBI (n = 39) [median 104.8 (range 0-1457.1) versus 0 (range 0-129.3) ng ml(-1), P = 0.0161 after adjusting age]. A plasma IP-10 level >48.2 ng ml(-1) had the best diagnostic accuracy for indicating SBI [sensitivity 81.0% [95% confidence interval (CI) 71.1-90.1%]; specificity 94.9% [95% CI 65.4-87.0%]; positive likelihood ratio 15.9, negative likelihood ratio 0.2}. CONCLUSION: In infants who were <4 months of age with suspicion of SBI, IP-10 assay might be a good predictor.

Soluble form of triggering receptor expressed on myeloid cells-1 (sTREM-1) as a diagnostic marker of serious bacterial infection in febrile infants less than three months of age.

Traditional risk factors are not adequate for predicting serious bacterial infection (SBI) in febrile infants. The purpose of this study was to evaluate the diagnostic value of the plasma level of soluble form of triggering receptor expressed on myeloid cells-1 (sTREM-1) in predicting SBI in febrile infants less than 3 months old. Forty-four febrile infants less than 3 months old with clinical suspicion of SBI were enrolled. Blood was drawn for measurement of plasma sTREM-1 levels, and microbiological cultures were obtained at the time of admission. Twenty-three infants (52.3%) had SBI and 21 infants (47.7%) had no evidence of SBI based on the results of bacterial culture. sTREM-1 levels were significantly higher in infants with SBI than in infants without SBI (mean+/-SD, 324.6+/-546.3 versus 7.7+/-16.4, P<0.0001 after adjusting for age). The area under the receiver-operating characteristic curve was 0.88 for the sTREM-1 level. At a cutoff level of 24.4 ng/mL, the sTREM-1 level yielded a sensitivity of 87%, a specificity of 81%, a positive likelihood ratio of 4.6, and a negative likelihood ratio of 0.2 for differentiating between presence and absence of SBI. In conclusion, sTREM-1 may become a valuable diagnostic tool in the initial evaluation of febrile young infants.

Determination of indomethacin in plasma by micellar electrokinetic chromatography with UV detection for premature infants with patent ducts arteriosus.

A simple and selective micellar electrokinetic chromatography (MEKC) is described for determination of indomethacin in plasma. Plasma proteins are precipitated by acetonitrile. An aliquot of supernatant was evaporated and reconstituted with Tris buffer for MEKC analysis. The separation of indomethacin was performed at 25 degrees C using a background electrolyte consisting of Tris buffer (30 mM; pH 8.0) with 100 mM sodium octanesulfonate (SOS) as an anionic surfactant. Under this condition, a good separation with high efficiency and short analysis time is achieved. Several parameters affecting the separation of indomethacin were studied, including pH and concentrations of the Tris buffer and SOS. The linear range of the method for the determination of indomethacin was over 0.3-10.0 microg/mL; the detection limit (signal-to-noise ratio=3; injection 0.5 psi 5s) was 0.1 microg/mL. The proposed method for determination of indomethacin in premature infants with patent ducts arteriosus has been demonstrated.

Ectopic pancreatic tissue presenting as an umbilcal mass in a newborn: a case report.

The case of an ectopic pancreatic mass at the umbilicus in an 8-day-old male neonate is reported, the youngest patient with this condition ever reported in an English-language journal. The patient was healthy except for a protruding mass with intermittent mucous discharge at the base of the umbilical stump. Surgical intervention was performed under the impression of the umbilical mass. Pathology diagnosed an ectopic pancreas with acute hemorrhage. To the best of our knowledge, only one case of ectopic pancreas presenting as an umbilical mass with intermittent mucous discharge has previously been reported.

Neonatal readmission within 2 weeks after birth.

To examine the causes of neonatal readmission within two weeks of discharge and identify the factors associated with neonatal readmission, newborns readmitted to Kaohsiung Municipal Hsiao-Kang (KMHK) Hospital within two weeks of discharge from our nursery between October 2001 and November 2003 were studied retrospectively. Of the 1099 deliveries during the study period, there were 63 newborns readmitted to KMHK Hospital within 14 days of discharge, with a rate of 5.7%. The control group consisted of a systematic sampling of newborns delivered over the same period that were not readmitted (n=74). The diagnoses of readmission included jaundice (73.0%), fever and suspected sepsis (19.0%), enteritis (4.8%), and others (3.2%). Factors associated with readmission included length of stay in nursery less than 72 hours, exclusive breast feeding, more body weight loss, and higher bilirubin level at discharge from nursery. After multiple logistic regression analysis, length of stay in nursery less than 72 hours, exclusive breast feeding and higher bilirubin level at discharge from nursery were the significant risk factors for neonatal readmission.

Total intravenous anesthesia for repair of congenitral diaphragmatic hernia: a case report.

Congenital diaphragmatic hernia is a cardiopulmonary anomaly that causes severe respiratory disorder. Traditionally, inhalational anesthetics with mechanical hyperventilation, opioids, and muscle relaxants are used in anesthesia for repair surgery. In this case, we used total intravenous anesthesia combined with high-frequency oscillatory ventilation and inhaled nitric oxide for surgical repair of the diaphragm. After surgery, the patient recovered well and was discharged from hospital 1 month later.

Hypertriglyceridemia in a 5-day-old newborn--a case report.

Neonatal hypertriglyceridaemia is extremely rare in pediatrics. We narrowed down the possibilities to a case of lipoprotein lipase (LPL) deficiency through a designed process of elimination with this particular patient. The biochemical hallmark of the disease is the presence of hyperchylomicronemia in fasting plasma. The patient responded well to a special formula containing median chain triglyceride (MCT). This was one of the youngest cases of hyperlipidemia and hyperlipoproteinemia to be reported during the neonatal period. Therefore the approach is mainly through the process of elimination because of inadequate laboratory facilities.

Bone status and associated factors measured by quantitative ultrasound in preterm and full-term newborn infants.

BACKGROUND: A clear understanding of the factors associated with bone status in newborn infants is essential for devising strategies for preventing osteoporotic fracture in future generations. OBJECTIVE: The aims of this study were to perform bone speed of sound (SOS) to assess the status of the tibia in preterm and full-term newborns, and to evaluate factors associated with bone status at birth. STUDY DESIGNS: Bone SOS was measured by quantitative ultrasonography on the left tibia in full-term and preterm newborn infants immediately after birth. A birth chart and maternal history were recorded. Univariate and multivariate analyses were performed to identify factors affecting bone SOS at birth. SUBJECTS: The study analyzed 667 infants, including 370 males and 297 females, during study period. RESULTS: Univariate analysis revealed that gender, gestational age (GA) and birth anthropometrics significantly affected tibial bone SOS at birth whereas maternal factors did not. Multivariate multiple regression analysis revealed that gender (male-to-female coefficient of 45.71 and 32.52 in premature and full-term infants, respectively), GA (coefficient of 32.55 and 31.27 in premature and full-term infants, respectively, for every 1-week increase), and birth weight (coefficient of -0.11 and -0.103 in premature and full-term infants, respectively, for every 1-gram increase) were important factors affecting tibial bone SOS in both preterm and full-term newborn infants at birth. CONCLUSIONS: Male gender and advanced GA have a positive effect on increasing tibial bone SOS at birth, while birth weight had a negative effect on increasing tibial bone SOS. Tibial bone SOS is higher in small-for-gestational-age infants than in those of appropriate-for-gestational-age infants.

Neonatal intensive care unit-specific screening criteria for retinopathy of prematurity.

This study investigated the incidence of retinopathy of prematurity (ROP) and its risk factors in a tertiary referral hospital in Taiwan to evaluate the applicability of the ROP screening guidelines published by the American Academy of Pediatrics, American Academy of Ophthalmology, and American Association for Pediatric Ophthalmology and Strabismus in 2006 (2006 guidelines). A pediatric ophthalmologist applied the 2006 guidelines to screen for ROP and to treat with laser photocoagulation in each case. We retrieved all records of premature infants referred for ROP screening at the hospital during 2004 to 2008. Univariate logistic regression analysis was applied firstly to identify factors correlating with stage 3 ROP or with laser treatment, and then those significant (p < 0.05) risk factors were analyzed by multivariate logistic regression. In the 138 male and 118 female premature infants in this study, mean gestation age was 30.8 ± 2.8 weeks, and mean birth weight was 1464.7 ± 434.2 g. The percentage of infants with ROP in at least one eye was 38.7%. Thirty two (12.5%) had ROP stage 3 or higher in at least one eye. Multivariate logistic regression analysis showed that the best predictors of type 1 pre-threshold ROP (requiring laser treatment) were young gestational age, low birth weight and male gender. As medical care of extremely premature infants improves, timely identification and treatment of conditions such as ROP are essential. Although the incidence of ROP in this institute was comparable to that in developing countries and higher than that in developed countries, the 2006 guidelines originally developed for a United States population were still applicable. However, the 2006 guidelines should be modified for a Taiwan population by considering gender.

Inattention and development of toddlers born in preterm and with low birth weight.

The objective of this study was to examine the impact of low birth weight and preterm birth on a toddler's inattention and development, including cognitive, language, motor, social-emotional and adaptive behaviors. A total of 105 toddlers enrolled for the study; they were divided into four groups: 40 full-term and normal birth weight (NBW, birth weight greater than 2500 g) toddlers, 24 moderate birth weight (MLBW, birth weight between 2499 and 1500 g) toddlers, 20 very to extremely low birth weight (V-ELBW, 12 between 1000 and 1499 g and 8 lower than 1000 g) toddlers, and 21 term toddlers who were recruited from a clinic of developmental delay as the developmental delay at risk (DDR) group. The Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III) and Disruptive Behavior Rating Scale-Toddler were used. The findings were as follows: (1) DDR group performed worst in BSID-III; (2) although there were no statistical differences among the NBW, MLBW, and V-ELBW groups in BSID-III, the lower the birth weight, the lower the average performance, especially in language, adaptive social behavior, and adaptive practical behavior; and (3) comparing the inattention score, the DDR group was the poorest, normal and V-ELBW groups were the best, and MLBW group was in the middle. In conclusion, low birth weight and preterm delivery affected children's inattention and development of language, adaptive social behavior, and adaptive practical behavior.

A strategy for reduction of antibiotic use in new patients admitted to a neonatal intensive care unit.

BACKGROUND: In order to reduce the unnecessary use of and provide appropriate guidance for the administration of antibiotics, the neonatal bacterial infections screening score (NBISS) was developed to assess each new patient that is admitted to the neonatal intensive care unit (NICU). METHODS: NBISS was designed based on maternal risk factors, clinical presentations, and laboratory data. The total score of each new patient is calculated at the time of admission. The first period of this study was an observational survey. Receiver operating characteristic (ROC) curves were used to determine the best cut-off NBISS for the diagnosis of bacterial infection (BI) and guide the use of antibiotics during the second period of this study. RESULTS: Of 250 neonates who were admitted to the NICU, 237 (94.8%) received antibiotics during the first period of study. The initial total scores were not statistically different between the BI and non-BI groups (p = 0.155). We weighted C-reaction protein (CRP) (by 8×), the presence of a bulging fontanelle, pus from the ear canal, redness around the umbilicus, reduced movement, and being unable to feed (each by 5×) as significantly different between the BI and non-BI groups (p = 0.015). Weighted scores >8 points demonstrated the best diagnostic accuracy for indicating BI. After introducing NBISS for predicting BI in new patients admitted to NICU, the rate of antibiotic use significantly decreased from 94.8% to 60.3% between the two periods. CONCLUSION: Using this simple screening strategy, we were able to clinically reduce the use of unnecessary antibiotics.

Effects of antenatal corticosteroids on neonatal outcomes in very-low-birth-weight preterm newborns: a 10-year retrospective study in a medical center.

OBJECTIVE: To evaluate the effects on neonatal outcomes between very-low-birth-weight (VLBW) preterm newborns with and without maternal use of antenatal corticosteroids (ACS). METHODS: We retrospectively reviewed medical records of VLBW premature infants who were admitted to Kaohsiung Medical University Hospital between 1999 and 2008. A total of 256 infants were enrolled in this study. A total of 174 neonates did not receive any ACS, and 82 neonates received ACS. A total of 37 neonates received one dose of ACS, and 45 neonates received more than one dose of ACS, referred to as "multiple-dose ACS." In addition, these 82 infants were divided to betamethasone group (n=8) and dexamethasone group (n=50) with 24 infants excluded because of inadequate information. RESULTS: Neonates with multiple-dose ACS had lower incidence of surfactant use and lower rate of intubation than neonates without ACS. There were no differences in the occurrences of intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, sepsis, and chronic lung disease with one-dose vs. multiple-dose ACS and in the betamethasone group vs. the dexamethasone group. CONCLUSIONS: ACS reduces the need for exogenous surfactant, and the need for endotracheal tube insertion at birth in VLBW premature infants.