Synthesis of Quillaic Acid through Sustainable C-H Bond Activations.

To meet the demand for quillaic acid, a multigram synthesis of quillaic acid was accomplished in 14 steps, starting from oleanolic acid, leading to an overall yield of 3.4%. Key features include C-H activation at C-16 and C-23. Through Pd-catalyzed C-H acetoxylation, the oxidation at C-23 was observed as the major product, as opposed to at C-24. A copper-mediated C-H hydroxylation using O2 successfully afforded the single isomer, 16ß-ol triterpenoid, followed by configuration inversion to the desired 16α-ol compound. In summary, with steps optimized and conducted on a multigram scale, quillaic acid could be feasibly acquired through C-H activation with inexpensive copper catalysts, promoting a more sustainable approach.

Sodium Glycerophosphate Use in Parenteral Nutrition Improves Mineral Metabolism in Extremely Low Birth Weight Infants.

OBJECTIVE: To evaluate the clinical effect of sodium glycerophosphate (NaGP) in parenteral nutrition solutions on mineral metabolism in extremely low birth weight (ELBW) infants. STUDY DESIGN: NaGP was introduced for use in place of potassium phosphate (K3PO4) in January 2018; this retrospective cohort study included 95 ELBW infants treated with K3PO4 between January 2015 and December 2017 and 77 infants treated with NaGP between August 2018 and January 2021. Mineral intake over the first 14 days; changes in serum calcium, phosphorus, sodium, and alkaline phosphatase (ALP) levels over the first 1-3 months; and the rates of electrolyte imbalance and clinical morbidity were compared. High-risk infants who had nil per os (NPO) status for >14 days and prolonged parenteral nutrition exposure were further analyzed as a subgroup. RESULTS: The use of NaGP instead of K3PO4 significantly increased Ca and P intake, but intakes remained below the recommended range (Ca, 64-140 mg/kg/day; P, 50-108 mg/kg/day). Compared with levels in the K3PO4 group, the NaGP group had significantly higher serum Ca and P levels after day 14 and lower ALP levels after day 56. In the subgroup analysis, the NaGP group had significantly lower incidences of hypophosphatemia, hyponatremia, bronchopulmonary dysplasia, and ALP >500 IU/L. CONCLUSIONS: Although the administration of NaGP instead of K3PO4 in parenteral nutrition regimens still did not provide adequate Ca and P intake for ELBW infants, higher intake significantly improved serum Ca and P levels, especially in ELBW infants with prolonged parenteral nutrition exposure.

Microrna-486-5P Regulates Human Pulmonary Artery Smooth Muscle Cell Migration via Endothelin-1.

Pulmonary arterial hypertension (PAH) is a fatal or life-threatening disorder characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance. Abnormal vascular remodeling, including the proliferation and phenotypic modulation of pulmonary artery smooth muscle cells (PASMCs), represents the most critical pathological change during PAH development. Previous studies showed that miR-486 could reduce apoptosis in different cells; however, the role of miR-486 in PAH development or HPASMC proliferation and migration remains unclear. After 6 h of hypoxia treatment, miR-486-5p was significantly upregulated in HPASMCs. We found that miR-486-5p could upregulate the expression and secretion of ET-1. Furthermore, transfection with a miR-486-5p mimic could induce HPASMC proliferation and migration. We also found that miRNA-486-5p could downregulate the expression of SMAD2 and the phosphorylation of SMAD3. According to previous studies, the loss of SMAD3 may play an important role in miRNA-486-5p-induced HPASMC proliferation. Although the role of miRNA-486-5p in PAH in in vivo models still requires further investigation and confirmation, our findings show the potential roles and effects of miR-486-5p during PAH development.

Risk factors for digestive morbidities after esophageal atresia repair.

Esophageal atresia with/without tracheoesophageal fistula (EA/TEF) is a congenital digestive tract anomaly that represents a major therapeutic challenge. Postoperative digestive morbidities such as gastroesophageal reflux disease (GERD) and esophageal stricture are common. The aim of this study was to identify the incidence of and potential risk factors for digestive morbidities after EA/TEF repair. We retrospectively reviewed all EA/TEF patients who underwent repair at a single institution between January 1999 and December 2018, excluding patients who died prior to discharge. Patient demographics, perioperative management, and postoperative GERD and esophageal stricture rates were collected. We performed univariate and multivariate analyses to examine risk factors associated with postoperative GERD and esophageal stricture. The study enrolled 58 infants (58.6% male, 17.2% with type A EA/TEF, 62.1% with associated anomalies). Postoperative GERD occurred in 67.2% of patients and was the most common digestive morbidity. Esophageal stricture occurred in 37.9% of patients after EA/TEF repair. Multivariate analysis showed that long-gap EA/TEF and postoperative GERD were independent risk factors for esophageal stricture after repair surgery.Conclusion: The incidence of postoperative GERD and esophageal stricture was 67.2% and 37.9%, respectively. The risk factors for postoperative esophageal stricture were long-gap EA/TEF and postoperative GERD. What is Known: • EA/TEF is a congenital digestive tract anomaly with a high postoperative survival rate but can be complicated by many long-term morbidities. What is New: • Long-gap EA/TEF and postoperative GERD are risk factors of anastomotic stricture after repair. • Surgeons and pediatricians should be highly experienced in managing anastomotic tension and the GERD.

Propolis alleviates 4-aminobiphenyl-induced oxidative DNA damage by inhibition of CYP2E1 expression in human liver cells.

4-Aminobiphenyl (4-ABP) may cause DNA damage in human liver cells (HepG2 and L-02). Propolis exhibits antioxidant properties through reactive oxygen species (ROS) scavenging. We determined the effects of propolis in alleviating 4-ABP -induced DNA damage using the comet assay. Results revealed that propolis could significantly alleviated oxidative damaged DNA by 4-ABP. Furthermore, we proved that inhibition of cytochrome P450 2E1 (CYP2E1) expression by propolis could contribute to the decreased oxidative DNA damage in the treated cells, as the conversion of 4-ABP into its metabolite, N-hydroxy-ABP (HOABP), was blocked; after all, HOABP showed more genotoxic than its parent chemical, 4-ABP. With the homologous recombination assay, propolis failed to induce DNA repair enzymes. Furthermore, the expression of RAD51, Ku70/Ku80, and OGG1 in treated cells were determined with the western blot, revealing that the expression of these protein were unchanged in comparison with those in nontreated cells. However, propolis could protect the treated cells from DNA damage. In conclusion, propolis could antagonize 4-ABP-induced oxidative DNA damage though the removal of ROS and inhibition of CYP2E1 expression in the treated cells.

Linear growth of corpus callosum and cerebellar vermis in very-low-birth-weight preterm infants.

BACKGROUND/PURPOSE: Impaired growth of the corpus callosum (CC) and cerebellar vermis (CV) is associated with poorer neurodevelopmental outcomes in preterm infants. However, references on the postnatal growth rate of the CC and CV by sonography are limited. The aim of this study is to assess the normal linear growth of CC and CV using a serial cranial ultrasound. METHODS: We prospectively enrolled preterm infants with very low birth weight from September 2008 to December 2009 after excluding those with congenital anomalies or diseases affecting the brain parenchyma. Serial sonographic measurements of the CC and CV were performed according to the standard protocol. Scheduled comprehensive neurodevelopmental evaluations were performed till the corrected age of 2 years. We excluded those with significant brain damages or poor neurodevelopmental outcomes in the final analysis. The growth rate was estimated using the loess smoothing curve and linear regression analysis. RESULTS: Among the 86 enrolled neonates, 14 with significant brain damage and 8 with poor neurodevelopmental outcomes were excluded from the final analysis. The growth rate of the CC length was 1.72 (95% confidence interval [CI]: 1.24-2.20) and 0.57 (95% CI: 0.33-0.80) mm per week before and after the postmenstrual age of 30.5 weeks, respectively. The growth rate of the CV length was 0.78 (95% CI: 0.68-0.89) mm per week. CONCLUSION: We proposed reference values of the normal linear growth rate of the CC and CV lengths in very-low-birth-weight preterm infants using the serial cranial ultrasound.

The gestational effect of antenatal corticosteroids on respiratory distress syndrome in very low birth weight infants: A population-based study.

BACKGROUND/PURPOSE: The aim of this study was to evaluate the efficacy of antenatal corticosteroids for preventing very low birth weight (VLBW) infants with respiratory distress syndrome (RDS) from surfactant use at different gestational ages (GA). METHODS: We retrospectively analyzed the VLBW preterm infants registered in the Premature Baby Foundation of Taiwan from 1997 through 2014. Infants at 20-37 weeks' gestation were included, and infants with lethal congenital anomaly, chromosomal anomaly, and congenital infection were excluded. Antenatal corticosteroid courses were classified into two groups (<2 doses or ≧2 doses). The beneficial effect of antenatal corticosteroids on preventing VLBW infants with RDS from surfactant use was evaluated according to gestational ages. RESULTS: Total 12,685 VLBW infants were included. For VLBW infants with gestational age 26-33 weeks, antenatal corticosteroid therapy has significantly protective effect (odds ratio 0.43 [95% CI 0.26 to 0.72] - 0.60 [95% CI 0.48 to 0.75], P < 0.05). The effect was not obvious for VLBW infants with gestational age 34 weeks and more (odds ratio 0.32 [95% CI 0.08 to 1.38], P = 0.127). CONCLUSION: For VLBW infants with RDS at 34 weeks' gestation and more, the beneficial effect of antenatal corticosteroids on preventing surfactant use was not evident. In conclusion, completion of two doses or more of antenatal corticosteroids is of great importance for VLBW infants with RDS at gestational age between 26 and 33 weeks on preventing surfactant use.

Extracorporeal membrane oxygenation for neonatal congenital diaphragmatic hernia: The initial single-center experience in Taiwan.

BACKGROUND/PURPOSE: Extracorporeal membrane oxygenation (ECMO) is a treatment option for stabilizing neonates with congenital diaphragmatic hernia (CDH) in a critical condition when standard therapy fails. However, the use of this approach in Taiwan has not been previously reported. METHODS: The charts of all neonates with CDH treated in our institute during the period 2007-2014 were reviewed. After 2010, patients who could not be stabilized with conventional treatment were candidates for ECMO. We compared the demographic data of patients with and without ECMO support. The clinical course and complications of ECMO were also reviewed. RESULTS: We identified 39 neonates with CDH with a median birth weight of 2696 g (range, 1526-3280 g). Seven (18%) of these patients required ECMO support. The APGAR score at 5 minutes differed significantly between the ECMO and non-ECMO groups. The survival rate was 84.6% (33/39) for all CDH patients and 57.1% (4/7) for the ECMO group. The total ECMO bypass times in the survivors was in the range of 5-36 days, whereas all nonsurvivors received ECMO for at least 36 days (mean duration, 68 days). Surgical bleeding occurred in four of seven patients in the ECMO group. CONCLUSION: The introduction of ECMO rescued some CDH patients who could not have survived by conventional management. Prolonged (i.e., > 36 days) ECMO support had no benefit for survival.

Morbidity and mortality of very low birth weight infants in Taiwan-Changes in 15 years: A population based study.

BACKGROUND/PURPOSE: Very low birth weight (VLBW) infants account for over 50% of perinatal deaths in Taiwan. This study aimed to identify changes in parental characteristics, perinatal conditions, mortality, and major neonatal morbidities for VLBW infants in Taiwan, and to highlight the challenges faced by patients, families, and caregivers. METHODS: We conducted a retrospective cohort study to investigate the mortality and morbidity of VLBW infants registered in the Taiwan Premature Infant Follow-up Network from 1997 through 2011. The exclusion criteria included congenital anomalies and chromosome anomalies. Continuous data was represented as mean ± SD, and changes over time in the variables were tested using one-way analysis of variance, with p < 0.05 considered statistically significant. RESULTS: A total of 13,159 VLBW infants were enrolled. We found significant increases over time in the parental age and educational level, in vitro fertilization, first livebirth, multiple births, maternal transfer, cesarean section, and complete antenatal steroid use. Apgar scores at 1 minute and 5 minutes after birth increased, and the intubation rate decreased gradually. Decreasing mortality over time for each successive period was demonstrated. Incidence of some morbidities increased, such as respiratory distress syndrome and patent ductus arteriosus; in contrast, incidence of others decreased, such as sepsis, necrotizing enterocolitis, intraventricular hemorrhage, and chronic lung disease. However, retinopathy of prematurity (ROP) incidence remained constant. CONCLUSION: Although the mortality and most of the morbidity of VLBW infants improved over time, the incidence of ROP remained constant. This requires us to further evaluate our strategy for preventing ROP in the future.

Taguchi's analysis to optimize descending aortography for patent ductus arteriosus, with clinical verification.

OBJECTIVE: Taguchi's analysis was adopted to optimize the various factors referring to cardiac angiographic examination used to delineating ductus arteriosus in pediatric patients. SUBJECTS AND METHODS: Thirty-six pediatric patients, 9 male and 27 female, mean age of 6.5±4.7yrs, range 0.6 to 16.6 years were included in the study from January 2004 to April 2005. All patients had patent ductus arteriosus (PDA). Taguchi's L9 orthogonal array was used to generate nine different designs of angiographic levels. Four control factors were selected: a) body surface area (BSA), b) projection angle, c) catheter location, and d) the volume of contrast medium. Each factor was set to three different levels. Statistical analysis, signal-to-noise (S/N) ratio, and analysis of variance (ANOVA) were used to estimate the optimum level of each control factor and to analyze the effect of each factor. RESULTS AND CONCLUSION: The optimal combinations that obtained the highest image quality for PDA were: a) at <0.65m(2) of BSA, b) right anterior oblique (RAO) position at 30(o) plus cranial position (Cr) at 15(o) and lateral view, c) catheter location at T2-3 and d) contrast medium volume: 1.0cc/kg. The projection angle was found to be the most significant factor to delineate ductus arteriosus using the ANOVA test and was not influenced by other factors. The setting of RAO at 30(o) plus Cr at 15(o) and the LAT view obtained the optimal image quality for PDA during descending aortography.

Hypoxic Preconditioning Suppresses Glial Activation and Neuroinflammation in Neonatal Brain Insults.

Perinatal insults and subsequent neuroinflammation are the major mechanisms of neonatal brain injury, but there have been only scarce reports on the associations between hypoxic preconditioning and glial activation. Here we use neonatal hypoxia-ischemia brain injury model in 7-day-old rats and in vitro hypoxia model with primary mixed glial culture and the BV-2 microglial cell line to assess the effects of hypoxia and hypoxic preconditioning on glial activation. Hypoxia-ischemia brain insult induced significant brain weight reduction, profound cell loss, and reactive gliosis in the damaged hemisphere. Hypoxic preconditioning significantly attenuated glial activation and resulted in robust neuroprotection. As early as 2 h after the hypoxia-ischemia insult, proinflammatory gene upregulation was suppressed in the hypoxic preconditioning group. In vitro experiments showed that exposure to 0.5% oxygen for 4 h induced a glial inflammatory response. Exposure to brief hypoxia (0.5 h) 24 h before the hypoxic insult significantly ameliorated this response. In conclusion, hypoxic preconditioning confers strong neuroprotection, possibly through suppression of glial activation and subsequent inflammatory responses after hypoxia-ischemia insults in neonatal rats. This might therefore be a promising therapeutic approach for rescuing neonatal brain injury.

Traumatic injury to the immature frontal lobe: a new murine model of long-term motor impairment in the absence of psychosocial or cognitive deficits.

Traumatic brain injury in children commonly involves the frontal lobes and is associated with distinct structural and behavioral changes. Despite the clinical significance of injuries localized to this region during brain development, the mechanisms underlying secondary damage and long-term recovery are poorly understood. Here, we have characterized the first model of unilateral focal traumatic injury to the developing frontal lobe. Male C57Bl/6J mice at postnatal day (p)21, an age approximating a toddler-aged child, received a controlled cortical impact or sham surgery to the left frontal lobe and were euthanized 1 or 7 days later. A necrotic cavity and local inflammatory response were largely confined to the unilateral frontal lobe, dorsal corpus callosum and striatum anterior to the bregma. While cell death and accumulated ß-amyloid precursor protein were characteristic features of the pericontusional motor cortex, corpus callosum, cingulum and dorsal striatum, underlying structures including the hippocampus showed no overt pathology. To determine the long-term functional consequences of injury at p21, two additional cohorts were subjected to a battery of behavioral tests in adolescence (p35-45) or adulthood (p70-80). In both cohorts, brain-injured mice showed normal levels of anxiety, sociability, spatial learning and memory. The signature phenotypic features were deficits in motor function and motor learning, coincident with a reduction in ipsilateral cortical brain volumes. Together, these findings demonstrate classic morphological features of a focal traumatic injury, including early cell death and axonal injury, and long-term volumetric loss of cortical volumes. The presence of deficits in sensorimotor function and coordination in the absence of abnormal findings related to anxiety, sociability and memory likely reflects several variables, including the unique location of the injury and the emergence of favorable compensatory mechanisms during subsequent brain development.

Large parietal midline defect with unusual ridge-like structure at the rim and persistent falcine sinus.

BACKGROUND: Midline cranial defects can be divided into lesions with intracranial tissue herniation (cranium bifidum cysticum) and lesions mainly with ossification failure (cranium bifidum occultum). Herniated cephaloceles mostly require surgical resection, while persisted parietal foramina might become smaller with age. CLINICAL CASE: Here, we report a neonate with large symmetric midline skull defect at high parietal area. A mild bulging mass was noticed. Interestingly, unlike sac herniation, it was surrounded by bony ridges extended from the rim of the calvarial defect, which suggests aberrant ossification. Persistent falcine sinus was also detected. At the corrected age of 11 months, the size of the skull defect had decreased spontaneously, favoring the diagnosis of parietal bone ossification defect. Potential mechanisms resulting in the special appearance of skull bone were discussed. CONCLUSION: Incomplete closing of the parietal foramina might be expected due to the aberrant ridge formation. We suggest protective measures for the calvarial defect.

Novel heterozygous tissue-nonspecific alkaline phosphatase (TNAP) gene mutations causing lethal perinatal hypophosphatasia.

Hypophosphatasia is a rare inherited disorder characterized by poor bone mineralization and deficiency of alkaline phosphatase activity. It is caused by mutations in the liver/bone/kidney alkaline phosphatase gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNAP), which displays many allelic heterogeneities, leading to different clinical phenotypes. This study reports the case of a patient diagnosed with lethal perinatal hypophosphatasia. His gene analysis showed compound heterozygocity of two novel mutations: c.650delTinsCTAA and c.984_986delCTT, which led to p.217delVinsAK and p.328delF, respectively. The two mutations originated separately from his parents, consistent with autosomal recessive perinatal hypophosphatasia. For these two novel mutations, we analyzed their functions through three-dimensional structural analysis. This revealed that V217 is located in the ß-sheet area, V217 is deleted, and insertion of alanine and lysine alter the secondary structure, causing instability in the hydrophobic region, which may influence the metal-binding vicinity. This mutant structure loses its catalytic activity. Deletion of 328F also results in protein structural alteration and affects TNAP functions. These results may provide an explanation of the two novel mutated alleles correlating with the lethal phenotype of our patient. In conclusion, we demonstrated the case of a patient with lethal perinatal hypophosphatasia caused by two novel heterozygous mutations.

Evaluating photoneutron dose equivalents for lung cancer using PMMA phantoms undergoing 15 MV IMRT.

BACKGROUND: According to statistics of the Ministry of Health and Welfare in 2017, the second leading cause of death in Taiwan was lung cancer. OBJECTIVE: Routine treatment planning does not consider photoneutron dose equivalent (PNDE) of patient induced secondary radiation resulting from primary exposure of lung cancer. However, such treatment is potentially important for improving estimates of health risks. METHODS: This study used 10, 30, 50, 70, and 90 kg of polymethylmethacrylate (PMMA) phantoms as patient to measure PNDE varying anatomical area during lung cancer of intensity modulated radiotherapy (IMRT) treatment. Paired thermoluminescent dosimeters (TLD-600 and 700) were calibrated using university reactor neutrons. TLDs were inserted into phantom which was closely corresponded of the represented tissues or organs. RESULTS: Neutron doses (ND) of organ or tissue (N⁢DT) were determined in these phantoms using paired TLDs approach. The risks of incurring fatal secondary malignancies, maximum statistical and total errors were estimated. Evaluated PNDE ranged from 0.80 ± 0.12 to 0.56 ± 0.08 mSv/Gy for these phantoms. CONCLUSION: The estimated N⁢DT decreased with increasing distance that is from the central axis. Evaluated PNDE and N⁢D𝑠𝑘𝑖𝑛 for these phantoms were discussed. This investigation also identified secondary risks associated with PNDE relating to radiation protection.

Evaluating dose distributions of normal organs for patients undergoing VMAT therapy of nasopharyngeal carcinoma using Rando phantom and TLD-100H.

BACKGROUND: The routine radiation therapy treatment planning does not include secondary radiation and peripheral doses resulting from radiotherapy exposure in patients with nasopharyngeal carcinoma (NPC) undergoing Volumetric Modulated Arc Therapy (VMAT) using an linear accelerator (linac) of Axesse (Elekta 2538). OBJECTIVE: VMAT has a better dose conformity of the tumor and is also operated by adjusting the shapes of mulileaf collimator. However, such treatment is potentially important to improve the accuracy of estimated health risks. METHODS: This study aimed to evaluate the equivalent dose of organ or tissue (DT) and effective dose (E) for normal organs using the Alderson Rando phantom as an equivalent of the human body. Thermoluminescent dosimeters (TLD-100H) were calibrated by 6 MV X-ray originated by the linac. A total of 252 TLDs were used. These TLDs were inserted into phantom organ or tissue which closely approximated to these places. RESULTS: The thyroid dose (D𝑡ℎ𝑦) had the highest dose, 1840 ± 202 mSv/treatment. The E of the Rando was 7.11 ± 0.61 mSv/treatment, as estimated using ICRP 103. The skin doses (D𝑠𝑘𝑖𝑛) varied significantly outside the treatment field and decreased as the distance from the treatment field increased. CONCLUSIONS: This study can be referred to practical guidance regarding radiation protections of the public.

Evaluating environmental radiations of the tomotherapy facility by optimizing full factorial design of the TLD technique.

BACKGROUND: In the last 40 years, the number of deaths due to cancer has been the highest in TaiwanOBJECTIVE: To optimize the readout system of the thermoluminescent dosimeter (TLD)-100H, the radiation rates among the Tomotherapy (TOMO) facility of the Department of Radiology Oncology of Chung Shan Medical University Hospital (CSMUH) were calculated with a 32 full factorial design (FFD). METHODS: A ten-month survey of the facility was employed using the sensitive and accurate TLD method. The TLD system was optimized for maximum temperature, heat rate, and preheat temperature of Harshaw 3500 reader. Eight analyzed groups with different factors were tested. RESULTS: The TOMO facility had significantly different radiation rates. The farther away from the gantry head, environmental radiation rates. The half value layer (HVL) was also determined. These results were compared with published. No significant contributions of environmental gamma radiations were detected except in the treatment room. CONCLUSIONS: Those were far below the occupational doses recommended by ICRP 60.

Specific Premature Groups Have Better Benefits When Treating Apnea With Caffeine Than Aminophylline/Theophylline.

Background: Methylxanthines (caffeine; aminophylline/theophylline) are commonly used for apnea of prematurity (AOP) treatment. We aimed to compare the efficacy and adverse effects of caffeine and aminophylline/theophylline. Methods: A retrospective case-control gestational age-matched study investigates patients born between January 2017 and December 2018, 23-35 weeks gestation with birth weights >500 g treating AOP with caffeine or aminophylline/theophylline. Results: There were 144 cases (48 in caffeine group and 96 in aminophylline/theophylline group). The median treatment durations were 11 and 17 days in caffeine and aminophylline/theophyllinegroup (p = 0.002). When tachycardia is defined as heart rate ≥160 bpm, the rates were 8.3 and 34.4% in caffeine and control group (p = 0.001). When tachycardia is defined as 10 bpm over baseline heart rate, the rates were 41.7 and 63.5% in caffeine and aminophylline/theophylline group (p = 0.01). Stratified by gestational age and sex, significant reductions in tachycardia rates with caffeine than with theophylline were limited to male infants and infants born at <30 weeks gestation. Conclusions: For apnea treatment, caffeine has greater efficacy and fewer tachycardia than aminophylline/theophylline, especially in male infants and infants born at <30 weeks gestation.