Hyperbilirubinemia screening and treatment in neonates born prior to 35 weeks of gestation.

BACKGROUND: Guidelines on when to screen for neonatal hyperbilirubinemia apply to infants born at 35 weeks or later of gestation. It is unknown whether infants born earlier would benefit from similar guidelines. Our objective was to examine hyperbilirubinemia screening and phototherapy prescription among early preterm infants during the first 6 days of life. METHODS: We reviewed the charts of 193 infants born prior to 35 weeks of gestation who were admitted to a tertiary care NICU in Southeastern Ontario in 2018-2019. Information on total serum bilirubin (TSB) measurements over each 12-hour interval during the first six days of life and the treatment decision (no treatment, initiate, continue, or stop phototherapy) was extracted. We also examined what proportion of infants were prescribed phototherapy during each 12-hour interval. RESULTS: Of 1006 TSB measurements performed over the first 6 days of life, 605 were done to determine whether phototherapy should be initiated. Treatment was prescribed in 275 instances (45%). A higher proportion of infants born prior to 28 weeks of gestation required phototherapy in the first 12 hours of life (37%) compared to those born at 28-32 weeks (20%) and 33-34 weeks (5.7%). CONCLUSIONS: Our results suggest that TSB measurements are often poorly timed to detect treatment need in infants born prior to 35 weeks of gestation. This unnecessarily increases the risk of complications from phlebotomy and is an ineffective use of health care resources. There is a need to develop guidelines to optimize hyperbilirubinemia screening among early preterm infants.

Gene Therapy in Patients with the Crigler-Najjar Syndrome.

BACKGROUND: Patients with the Crigler-Najjar syndrome lack the enzyme uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1), the absence of which leads to severe unconjugated hyperbilirubinemia that can cause irreversible neurologic injury and death. Prolonged, daily phototherapy partially controls the jaundice, but the only definitive cure is liver transplantation. METHODS: We report the results of the dose-escalation portion of a phase 1-2 study evaluating the safety and efficacy of a single intravenous infusion of an adeno-associated virus serotype 8 vector encoding UGT1A1 in patients with the Crigler-Najjar syndrome that was being treated with phototherapy. Five patients received a single infusion of the gene construct (GNT0003): two received 2×1012 vector genomes (vg) per kilogram of body weight, and three received 5×1012 vg per kilogram. The primary end points were measures of safety and efficacy; efficacy was defined as a serum bilirubin level of 300 µmol per liter or lower measured at 17 weeks, 1 week after discontinuation of phototherapy. RESULTS: No serious adverse events were reported. The most common adverse events were headache and alterations in liver-enzyme levels. Alanine aminotransferase increased to levels above the upper limit of the normal range in four patients, a finding potentially related to an immune response against the infused vector; these patients were treated with a course of glucocorticoids. By week 16, serum bilirubin levels in patients who received the lower dose of GNT0003 exceeded 300 µmol per liter. The patients who received the higher dose had bilirubin levels below 300 µmol per liter in the absence of phototherapy at the end of follow-up (mean [±SD] baseline bilirubin level, 351±56 µmol per liter; mean level at the final follow-up visit [week 78 in two patients and week 80 in the other], 149±33 µmol per liter). CONCLUSIONS: No serious adverse events were reported in patients treated with the gene-therapy vector GNT0003 in this small study. Patients who received the higher dose had a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration. (Funded by Genethon and others; ClinicalTrials.gov number, NCT03466463.).

Pre-phototherapy total serum bilirubin levels in extremely preterm infants.

BACKGROUND: Extremely preterm infants are prone to hyperbilirubinemia and its sequelae. Currently recommended thresholds for initiating phototherapy in these newborns are consensus-based (CB). METHODS: A multi-site retrospective cohort study of 642 infants born at 240/7 to 286/7 weeks' gestation, between January 2013 and June 2017, was conducted at three NICUs in Canada. Pre-phototherapy TSB percentile levels at 24 h of age were generated and contrasted with published CB thresholds. RESULTS: Among infants born 240/7 to 256/7 weeks' gestation, the differences between our TSB percentiles vs. the CB threshold of 85.0 µmol/L were 10.0 µmol/L (95% CI, 6.0-16.0) at the 75th percentile and 35.3 µmol/L (95% CI, 26.1-42.8) at the 95th percentile. Respectively, among infants born at 260/7 to 276/7 weeks, differences were 19.4 µmol/L (95% CI, 16.8-23.4) and 43.3 µmol/L (95% CI, 34.7-46.9). Born at 280/7 to 286/7 weeks' gestation, differences between our 75th and 95th TSB percentiles and the CB threshold of 103 µmol/L were 6.9 µmol/L (95% CI, 3.2-12.0) and 36.0 µmol/L (95% CI, 31.0-44.3), respectively. CONCLUSIONS: We provide statistically derived pre-phototherapy TSB levels that may clarify patterns of pre-phototherapy TSB levels in extremely preterm infants. IMPACT: We present statistically derived pre-phototherapy total serum bilirubin levels in a cohort of extremely preterm infants. Most of these preterm infants received phototherapy-some at below currently published thresholds. There are notable differences between our statistically derived pre-phototherapy TSB levels and currently published lower limit TSB thresholds for phototherapy. Our study results assist in the understanding of pre-phototherapy TSB levels in extremely preterm infants.

[Components and lipid-lowering effect of total saponins from underground part of Gynostemma pentaphyllum].

The saponins in different parts of Gynostemma pentaphyllum were analyzed via UPLC-Q-TOF-MS~E. A total of 46 saponins were identified, and the underground part had 26 saponins more than the aboveground part, most of which were trisaccharide saponins. The rat model of hyperlipidemia was established with high-fat diet. This study explored the lipid-lowering activity of total saponins in the underground part of G. pentaphyllum, so as to provide a theoretical basis for the comprehensive utilization of the underground part of G. pentaphyllum. A total of 99 healthy SD rats were randomly assigned into a blank group, a model group, a positive drug group, an aboveground total saponins group, and low-, medium-, and high-dose underground total saponins groups. Except the blank group, the other groups were fed with high-fat diet for 6 weeks. Then, the blood was collected from the orbital cavity to determine whether the modeling was successful according to the serum levels of total cholesterol(TC) and triglyceride(TG). After intragastric administration of the corresponding agents for 30 continuous days, the physical state of the rats were observed, and the body weight and liver specific gravity were measured. Furthermore, the levels of TC, TG, low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), alanine transaminase(ALT), aspartate transaminase(AST), bilirubin, and total bile acids in serum, as well as the levels of superoxide dismutase(SOD), malondialdehyde(MDA), peroxidase proliferator-activated receptor(PPAR-γ) in the liver tissue, were determined. The pathological changes of liver was observed via HE staining. The results showed that the aboveground total saponins and medium-and high-dose underground total saponins can treat hepatocyte steatosis, lower TC, TG, LDL-C, ALT, AST, total bilirubin, MDA, and PPAR-γ levels, and increase HDL-C and SOD levels in the model rats. The effect tended to be more obvious with the increase in dosage. Therefore, the total saponins in the underground part of G. pentaphyllum have good pharmacological effect of reducing blood lipid, which provides a theoretical basis for the comprehensive utilization of the underground part of G. pentaphyllum.

Effects of curcumin supplementation on vitamin D levels in women with premenstrual syndrome and dysmenorrhea: a randomized controlled study.

BACKGROUND: Vitamin D has an established role in female reproduction. There is also evidence for an association between vitamin D levels and menstrual problems such as premenstrual syndrome (PMS) and dysmenorrhea. Curcumin, is a bioactive polyphenol constituent of turmeric, that can potentially interact with vitamin D receptors and its molecular targets. This study evaluated the effects of curcumin on vitamin D levels in young women with PMS and dysmenorrhea. METHODS: In this randomized, triple-blind, placebo-controlled trial, women with PMS and dysmenorrhea were divided randomly into experimental and control groups to receive one capsule (500 mg of curcuminoid+ 5 mg piperine, or placebo) daily, from approximately 7 days before until 3 days after menstruation for three consecutive menstrual cycles. Serum vitamin D levels, renal function, and liver enzymes were also measured before and after intervention. RESULTS: A total of 76 subjects (38 in each group) were recruited into the trial. Curcumin significantly increased the median (IQR) serum levels of vitamin D [from 12.8 ng/ml (7.0-24.6) to 16.2 ng/ml (6.4-28.8); P = 0.045], compared with placebo [from 18.6 ng/ml (2.2-26.8) to 21.3 ng/ml (5.2-27.1); P = 0.17]. Serum levels of aspartate aminotransferase and direct bilirubin were reduced by the end of trial in the curcumin group (p < 0.05), but did not change significantly in the control group (p > 0.05). Finally, no significant differences in levels of fasting blood glucose were detected between curcumin and placebo groups. CONCLUSION: Curcumin supplementation in women with PMS and dysmenorrhea led to a significant improvement of vitamin D, liver function enzyme test, but did not affect blood glucose. TRIAL REGISTRATION: The trial was registered on Iranian Registry of Clinical Trials registry (Trial ID: IRCT20191112045424N1 on 23 January 2020; available at https://www.irct.ir ).

Effect of incremental proportions of Desmanthus spp. in isonitrogenous forage diets on growth performance, rumen fermentation and plasma metabolites of pen-fed growing Brahman, Charbray and Droughtmaster crossbred beef steers.

Desmanthus (Desmanthus spp.), a tropically adapted pasture legume, is highly productive and has the potential to reduce methane emissions in beef cattle. However, liveweight gain response to desmanthus supplementation has been inconclusive in ruminants. This study aimed to evaluate weight gain, rumen fermentation and plasma metabolites of Australian tropical beef cattle in response to supplementation with incremental levels of desmanthus forage legume in isonitrogenous diets. Forty-eight Brahman, Charbray and Droughtmaster crossbred beef steers were pen-housed and fed a basal diet of Rhodes grass (Chloris gayana) hay supplemented with 0, 15, 30 or 45% freshly chopped desmanthus forage on dry matter basis, for 140 days. Varying levels of lucerne (Medicago sativa) hay were added in the 0, 15 and 30% diets to ensure that all diets were isonitrogenous with the 45% desmanthus diet. Data were analyzed using the Mixed Model procedures of SAS software. Results showed that the proportion of desmanthus in the diet had no significant effect on steer liveweight, rumen volatile fatty acids molar proportions and plasma metabolites (P ≥ 0.067). Total bilirubin ranged between 3.0 and 3.6 µmol/L for all the diet treatments (P = 0.67). All plasma metabolites measured were within the expected normal range reported for beef cattle. Rumen ammonia nitrogen content was above the 10 mg/dl threshold required to maintain effective rumen microbial activity and maximize voluntary feed intake in cattle fed low-quality tropical forages. The average daily weight gains averaged 0.5 to 0.6 kg/day (P = 0.13) and were within the range required to meet the target slaughter weight for prime beef markets within 2.5 years of age. These results indicate that desmanthus alone or mixed with other high-quality legume forages can be used to supplement grass-based diets to improve tropical beef cattle production in northern Australia with no adverse effect on cattle health.

Effects of Umbilical Cord Milking on Anemia in Preterm Infants: A Multicenter Randomized Controlled Trial.

OBJECTIVE: This study aimed to investigate whether umbilical cord milking (UCM) prevents and controls anemia in preterm infants, as compared with immediate cord clamping (ICC). STUDY DESIGN: Pregnant women delivering at <34 weeks' gestation in four hospitals were randomly assigned to undergo UCM or ICC from July 2017 to June 2019. Hematological parameters and iron status were collected and analyzed as primary outcomes at 24 hours, 1 week, 2 weeks, and 6 months after delivery. RESULTS: Neonates receiving UCM had significant higher levels of hemoglobin (Hb), hematocrit, and serum iron (p < 0.05). Lower prevalence of anemia and lower need for transfusions were noted in UCM group. Although UCM was associated with prolonged duration of phototherapy, the maximum levels of bilirubin were similar between two groups (p > 0.05). CONCLUSION: UCM is an effective intervention to help preterm infants experience less anemia with the potential to increase blood volume, as seen by higher Hb levels and more enhanced iron stores.

Prognostic value of baseline imaging and clinical features in patients with advanced hepatocellular carcinoma.

AIMS: To investigate the prognostic value of baseline imaging features for overall survival (OS) and liver decompensation (LD) in patients with hepatocellular carcinoma (HCC). DESIGN: Patients with advanced HCC from the SORAMIC trial were evaluated in this post hoc analysis. Several radiological imaging features were collected from baseline computed tomography (CT) and magnetic resonance imaging (MRI) imaging, besides clinical values. The prognostic value of these features for OS and LD (grade 2 bilirubin increase) was quantified with univariate Cox proportional hazard models and multivariate Least Absolute Shrinkage and Selection Operator (LASSO) regression. RESULTS: Three hundred and seventy-six patients were included in this study. The treatment arm was not correlated with OS. LASSO showed satellite lesions, atypical HCC, peritumoral arterial enhancement, larger tumour size, higher albumin-bilirubin (ALBI) score, liver-spleen ratio <1.5, ascites, pleural effusion and higher bilirubin values were predictors of worse OS, and higher relative liver enhancement, smooth margin and capsule were associated with better OS. LASSO analysis for LD showed satellite lesions, peritumoral hypointensity in hepatobiliary phase, high ALBI score, higher bilirubin values and ascites were predictors of LD, while randomisation to sorafenib arm was associated with lower LD. CONCLUSIONS: Imaging features showing aggressive tumour biology and poor liver function, in addition to clinical parameters, can serve as imaging biomarkers for OS and LD in patients receiving sorafenib and selective internal radiation therapy for HCC.

Maternal Exposure to Air Pollution Is Associated with Neonatal Jaundice: A Retrospective Cohort Study.

OBJECTIVE: To evaluate the association between maternal ambient pollutant exposure and neonatal jaundice in multiple pollutant species and examine sex differences. STUDY DESIGN: Epidemiologic study: Records of 13 297 newborns (6153 male, 7144 female) born in Taichung, Taiwan were obtained from a national database. Average concentrations of prenatal air pollutants 3 months prior to birth were divided into low, middle, and high levels. Neonatal jaundice phototherapy rates between mothers who suffered varying air pollutant levels were compared. Clinical study: Three hundred seventy-six newborns (189 male, 187 female) born and received jaundice treatment with phototherapy in a hospital in Taichung, Taiwan were recruited. The correlation between prenatal exposure to air pollutants 3 months prior to birth, newborn's serum bilirubin, and serum hemoglobin were calculated. RESULTS: Epidemiologic study: Male newborns born to mothers exposed to high carbon monoxide (CO), nitric oxide (NO), nitrogen dioxide (NO2), and methane (CH4) levels had higher phototherapy rates. In female newborns, the same was noted for CO and CH4. Clinical study: Male newborns had a positive correlation between CO, ≤2.5 µm diameter particles, ≤10 µm diameter particles, NO, NO2, nonmethane hydrocarbon, and CH4 exposure 3 months prior to birth and serum bilirubin levels. Female newborns had a positive correlation for CH4. A positive correlation between CO, ≤2.5 µm diameter particles, ≤10 µm diameter particles, NO2, nonmethane hydrocarbon, CH4 exposure, and serum hemoglobin levels was noted in male newborns. CONCLUSION: Maternal exposure to air pollutants may increase neonatal jaundice treatment rates for phototherapy and higher neonatal serum total bilirubin level. Higher hemoglobin levels because of higher pollutant exposures may explain our findings. The association was more obvious in male newborns.

Erythrocyte fatty acid membrane composition in children on long-term parenteral nutrition enriched with ω-3 fatty acids.

BACKGROUND: Composite lipid emulsions containing soybean oil (30%), medium-chain triglycerides (30%), olive oil (25%), and fish oil (15%) (SMOF) are now widely used. OBJECTIVES: We aimed to evaluate the tolerance, the efficiency, and the erythrocyte fatty acid (FA) profile for children on long-term home parenteral nutrition (HPN) receiving a composite fish oil-based emulsion (FOLE). METHODS: At baseline, children (n = 46) with severe intestinal failure highly dependent on parenteral nutrition (PN) for ≥1 y were included in the study when they had received the composite FOLE for >6 mo. Out of this baseline group, only 25 children remained highly PN-dependent (SMOF1, n = 25) and could be assessed a second time, 2.4 y later (SMOF2, n = 25). An independent control group ("weaned off PN" group; n = 24) included children who had been weaned off PN for >2 y (median: 4 y). RBC-FA composition was established by GC-MS. Growth parameters, plasma citrulline, conjugated bilirubin, FA profiles, and the Holman ratio (20:3ω-9/20:4ω-6) were compared between groups. RESULTS: No difference for growth parameters, citrulline, and bilirubin was observed between the SMOF groups after 2.4 y (0.2 < P < 0.8). The weaned-off group did not differ from the SMOF groups for growth parameters (0.2 < P < 0.4) but citrulline was higher (P < 0.0001) and conjugated bilirubin lower (P < 0.01). The composite FOLE induced higher proportions of EPA (20:5n-3) (8.4% ± 2.9%) and DHA (22:6n-3) (11.7% ± 2.2%) than what was observed in weaned-off children (0.8% ± 0.4% and 6.6% ± 2.3%, respectively) but lower proportions of arachidonic acid (20:4n-6). However, the Holman ratio did not vary between groups (P = 0.9), whereas the PUFA concentrations varied widely. CONCLUSIONS: Long-term use of the composite FOLE was well tolerated in HPN-dependent children. The RBC-FA profile alterations were consistent with the ω-3 PUFA-enriched composition of this emulsion without evidence of essential FA deficiency.

Update on Phototherapy and Childhood Cancer in a Northern California Cohort.

OBJECTIVES: We aimed to reassess the relationship between phototherapy and cancer in an extended version of a previous cohort and to replicate a report from Quebec of increased cancer risk after phototherapy beginning at age 4 years. METHODS: This cohort study included 139 100 children born at ≥35 weeks' gestation from 1995 to 2017, followed through March 16, 2019, in Kaiser Permanente Northern California hospitals who had a qualifying bilirubin level from -3 mg/dL to +4.9 mg/dL from the American Academy of Pediatrics phototherapy threshold; an additional 40 780 children and 5 years of follow-up from our previous report. The exposure was inpatient phototherapy (yes or no), and the outcomes were various types of childhood cancer. We used Cox proportional hazard models, controlling for propensity-score quintiles, and allowed for time-dependent exposure effects to assess for the risk of cancer after a latent period. RESULTS: Over a mean (SD) follow-up of 8.2 (5.7) years, the crude incidence of cancer per 100 000 person-years was 25.1 among those exposed to phototherapy and 19.2 among those not exposed (233 cases of cancer). After propensity adjustment, phototherapy was not associated with any cancer (hazard ratio [HR]: 1.13, 95% confidence interval [CI]: 0.83-1.54), hematopoietic cancer (HR: 1.17, 95% CI: 0.74-1.83), or solid tumors (HR: 1.01, 95% CI: 0.65-1.58). We also found no association with cancer diagnoses at age ≥4 years. CONCLUSIONS: We did not confirm previous, concerning associations between phototherapy and adjusted risk of any cancer, nonlymphocytic leukemia, or brain and/or central nervous systems tumors in later childhood.

High levels of unbound bilirubin are associated with acute bilirubin encephalopathy in post-exchange transfusion neonates.

BACKGROUND: Although it is known that unbound bilirubin can enter the brain, there is little evidence of its association with the development of acute bilirubin encephalopathy. Here, we investigated this potential relationship in neonates who had undergone exchange transfusion. METHODS: Data from 46 newborns who underwent exchange transfusion between 2016 and 1-1 to 2018-12-31 at the First People's Hospital of Changde City in China were analyzed. The unbound bilirubin level was taken as the independent variable and the development of the acute bilirubin encephalopathy as the dependent variable. The covariates were age, birth weight, sex, red blood cell count, blood glucose, hemolytic disease, and whether the infant had received phototherapy. RESULTS: The mean age and gestational age of the neonates were 146.5 ± 86.9 h and 38.6 ± 1.3 weeks [38.7(34.6-41.1) weeks] old, respectively; 52.17% were male. Binary logistic regression analysis after adjustment for covariates showed a positive association between the levels of unbound bilirubin and the development of acute bilirubin encephalopathy (odds ratio = 1.41, 95% confidence intervals 1.05-1.91, P = < 0.05). CONCLUSION: There is a significant association between unbound bilirubin levels and the development of acute bilirubin encephalopathy in neonates. Further investigations are required to explore the mechanisms.

Health properties of the Italian San Martino® mineral-rich water: A self-controlled pilot study.

The effect of hyper-mineral waters on human health has long been debated. This pilot study evaluated the influence of San Martino® water (Sardinia, Italy), on clinical and biological parameters, following the treatment of 10 hospitalized patients. Crenotherapy consisted of 1-2 L of the water daily for 10 days. A complete blood count, serum electrolytes, liver and kidney function tests, fasting lipid profile and plasma glucose, and abdominal ultrasound imaging were assessed before and at the end of treatment. In addition, body weight, dyspeptic symptoms, bowel movements, diuresis, uricuria and blood pressure were evaluated daily. According to its physico-chemical properties, the water is hyper-mineral (TDS 2808 mg/L) with a high content of bicarbonate and iron. At the end of the study, diuresis increased by 60% (850 vs 1295 ml/24 h, P = 0.009) and uricuria by 41% (362 vs 490 mg/24 h, P = 0.022) respectively, whereas plasma uric acid level decreased by 7% (4.7 vs 4.3 mg/dL, P = 0.043). Compared to the basal values, serum gamma-glutamyl transferase, alkaline phosphatase and total bilirubin levels, showed a reduction of 65% (31 vs 18 U/L, P = 0.022), 15% (96 vs 90 U/L, P = 0.041), and 11% (0.53 vs 0.45 g/dL, P = 0.041), respectively. Bowel movements improved in 62.5% of patients with constipation, and 80% of dyspeptic patients experienced symptoms relief. Compliance to the treatment reached 100%. Mild differences were observed in body weight and blood pressure, although not in ultrasound imaging during crenotherapy. These findings suggest that the San Martino® hyper-mineral water may have some benefits to human health. Additional studies with a larger-sized cohort and for a longer period are needed to confirm these preliminary results.

Effect of Silymarin Treatment on Circulating Bilirubin and Cardiovascular Disease Risk Factors in Healthy Men: A Single-Blind, Randomized Crossover Trial.

This clinical trial (ACTRN12619001296123) investigated the impact of silymarin (Legalon®) on circulating bilirubin concentration, lipid status, systemic inflammation, and antioxidant status. The study design was a randomized, placebo-controlled, single-blind crossover trial of healthy men (18-65 years), conducted at Griffith University, Gold Coast, Australia. Participants were recruited from Griffith University and were randomized to silymarin (140 mg silymarin capsules thrice daily) or placebo (3 capsules containing mannitol taken daily) for 14 days followed by a ≥4-week washout and crossover to the other arm. The main outcomes were whether silymarin treatment would increase serum bilirubin concentration by >0.29 mg/dL, change serum lipid status (cholesterol and triglycerides), inflammation (c-reactive protein), and antioxidant capacity (ferric reducing ability of plasma) compared with baseline. Silymarin consumption (n = 17) did not affect serum concentrations of unconjugated bilirubin (0.73 versus 0.67 mg/dL, P = .79), cholesterol (185 versus 189 mg/dL, P = .19), triglycerides (94.2 versus 92.3 mg/dL, P = .79), c-reactive protein (0.17 versus 0.09 mg/dL, P = .23), or antioxidant status (6.61 versus 6.67 mg Fe2+ /dL, P = .40). These findings challenge previous reports and manufacturer claims of hyperbilirubinemia following silymarin treatment and are critical to guiding researchers toward an effective means to mildly elevate bilirubin, which evidence suggests could protect from cardiovascular disease.

Effects of nerol on paracetamol-induced liver damage in Wistar albino rats.

Nerol, a monoterpene is evident to possess diverse biological activities, including antioxidant, anti-microbial, anti-spasmodic, anthelmintic, and anti-arrhythmias. This study aims to evaluate its hepatoprotective effect against paracetamol-induced liver toxicity in a rat model. Five groups of rats (n = 7) were orally treated (once daily) with 0.05% tween 80 dissolved in 0.9% NaCl solution (vehicle), paracetamol 640 mg/kg (negative control), 50 mg/kg silymarin (positive control), or nerol (50 and 100 mg/kg) for 14 days, followed by the hepatotoxicity induction using paracetamol (PCM). The blood samples and livers of the animals were collected and subjected to biochemical and microscopical analysis. The histological findings suggest that paracetamol caused lymphocyte infiltration and marked necrosis, whereas maintenance of the normal hepatic structural was observed in group pre-treated with silymarin and nerol. The rats pre-treated with nerol significantly and dose-dependently reduced the hepatotoxic markers in animals. Nerol at 100 mg/kg significantly reversed the paracetamol-induced altered situations, including the liver enzymes, plasma proteins, antioxidant enzymes and serum bilirubin, lipid peroxidation (LPO) and cholesterol [e.g., total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c)] levels in animals. Taken together, nerol exerted significant hepatoprotective activity in rats in a dose-dependent manner. PCM-induced toxicity and nerol induced hepatoprotective effects based on expression of inflammatory and apoptosis factors will be future line of work for establishing the precise mechanism of action of nerol in Wistar albino rats.

Yinzhihuang Oral Liquid Ameliorates Hyperbilirubinemia Induced by δ-Aminolevulinic Acid and Novobiocin in Neonatal Rats.

Yinzhihuang oral liquid (YZH) is a traditional Chinese medicine that has been widely used in Asia to prevent and treat neonatal hyperbilirubinemia, but the published preclinical studies on its anti-hyperbilirubinemia effect are conducted in adult animals, partly due to the lack of preclinical neonatal hyperbilirubinemia animal models. In the present study, we tested six reagents to induce hyperbilirubinemia in neonatal rats, and established two appropriate neonatal hyperbilirubinemia rat models by subcutaneous injection of δ-Aminolevulinic acid (ALA, 200 mg/kg) or novobiocin (NOVO, 200 mg/kg). Oral treatment of YZH (80, 160 and 320 mg/kg) significantly decreased serum conjugated bilirubin levels in ALA-treated neonatal rats and serum unconjugated bilirubin levels in NOVO-treated neonatal rats, respectively. Additionally, pre-treatment of YZH also prevented the increase of serum bilirubin levels in both ALA- and NOVO-treated rats. Mechanistically, YZH significantly up-regulated the mRNA expression of genes involved in hepatic bilirubin disposition (organic anion-transporting polypeptide 1b2, Oatp1b2; multidrug resistance-associated protein 2, Mrp2) and bilirubin conjugation (UDP-glucuronosyltransferase 1a1, Ugt1a1). Additionally, YZH up-regulated the mRNA expression of cytochrome P450 1A1 (Cyp1a1), the target gene of aryl hydrocarbon receptor (AhR), and increased the nuclear protein levels of AhR in livers of neonatal rats. YZH and its two active ingredients, namely baicalin (BCL) and 4'-hydroxyacetophenone (4-HT), up-regulated the mRNA expression of AhR target genes (CYP1A1 and UGT1A1) and increased nuclear protein levels of AhR in HepG2 cells. In conclusion, the present study provides two neonatal hyperbilirubinemia animal models and evaluates the anti-hyperbilirubinemia effect and mechanisms of YZH in neonatal animals.

Easy clinical predictor for low BCAA to tyrosine ratio in chronic liver disease patients with hepatocellular carcinoma: Usefulness of ALBI score as nutritional prognostic marker.

BACKGROUND/AIM: Low branched-chain amino acid (BCAA) to tyrosine ratio (BTR) is known as an indicator of amino acid imbalance. We elucidated usefulness of newly developed albumin-bilirubin (ALBI) score as alternative methods of BTR in patients with naïve hepatocellular carcinoma (HCC) retrospectively. MATERIALS/METHODS: In 842 patients with HCC and without BCAA supplementation (71 years, male 614, Child-Pugh A:B:C = 689:116:37), relationships among BTR and clinical features were evaluated. Of those, 438 patients, with Milan criteria HCC, treated curatively were divided into the high-BTR (>4.4) (n = 293) and low-BTR (≤4.4) (n = 145) groups. The prognostic value of BTR was evaluated using inverse probability weighting (IPW) with propensity score. RESULTS: The low-BTR group showed worse prognosis than the other (3-, 5-, 10-year overall survival rates: 88.9% vs. 86.3%/70.5% vs. 78.1%/38.1% vs. 52.3%, respectively; p < 0.001). Multivariate Cox-hazard analysis adjusted for IPW showed elderly (≥65 years) HR 2.314, p = 0.001), female gender (HR 0.422, p < 0.001), ECOG PS ≥2 (HR 3.032, p = 0.002), low platelet count (HR 1.757, p = 0.010), and low BTR (≤4.4) (HR 1.852, p = 0.005) to be significant prognostic factors. Both serum albumin level (r = 0.370, p < 0.001) and ALBI score (r = -0.389, p < 0.001) showed a significant relationship with BTR. Child-Pugh class B, modified ALBI grade (mALBI) 2a, and mALBI 2b predictive values for BTR were 3.589, 4.509, and 4.155 (AUC range: 0.735-0.770), respectively, while the predictive value of ALBI score for low-BTR (≤4.4) was -2.588 (AUC 0.790). CONCLUSION: ALBI score -2.588 was a predictor for low-BTR (≤4.4), which was prognostic factors for early HCC patients, and at least patients with mALBI 2b might have an amino acid imbalance.

Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia.

Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10-14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.

A New Hour-Specific Serum Bilirubin Nomogram for Neonates ≥35 Weeks of Gestation.

OBJECTIVE: To develop a statistically rigorous, hour-specific bilirubin nomogram for newborns based on a very large data set; and use it prospectively as a replacement for the 1999 Bhutani nomogram. STUDY DESIGN: This was a retrospective analysis of first total serum bilirubin (TSB) measurements from 15 years of universal bilirubin screening during birth hospitalizations at 20 Intermountain Healthcare hospitals. Hour-specific TSB values were assembled into a nomogram by percentile, and subgroups were compared. RESULTS: The information obtained included robust data in the first 12 hours after birth (which was not included in the 1999 nomogram), general agreement with the 1999 nomogram for values in the first 60 hours, but higher 75th and 95th percentile TSB values thereafter in the new version, no difference in TSB between male and female infants, higher TSB values among earlier gestation neonates (350/7-366/7 weeks vs ≥37 weeks, P < .0001), and lower TSB values in neonates of Black race (P < .0001) and higher values in neonates of Asian race (P < .001). CONCLUSIONS: An updated and more informative Bhutani neonatal bilirubin nomogram, based on 140 times the number of subjects included the 1999 version, is now in place in our health care system.

Acute and Subacute Toxicity and Cytotoxicity of Opuntia Dillenii (Ker-Gawl) Haw. Seed Oil and Its Impact on the Isolated Rat Diaphragm Glucose Absorption.

This study aims to assess the safety of the Opuntia dillenii (Ker-Gawl) haw. seed oil (ODSO) and its effect on the glucose absorption activity of the isolated rat hemidiaphragm. This oil's safety was studied by exploring its acute (doses 1, 3, 5, and 7 mL/kg) and subacute (doses 1 and 2 mL/kg) toxicities in albino mice and Wistar rats, respectively. The safety of the ODSO was also assessed by studying its effect on the HepG2 cell viability in vitro. The effect of ODSO, or combined with the insulin, on the glucose absorption activity of isolated rat hemidiaphragm was evaluated at the dose 1 g/L in vitro. The results demonstrated the safety of ODSO. Indeed, this study showed that this oil does not produce any mortality or signs of toxicity after the single-dose administration in mice. Additionally, the daily intake of the ODSO during four weeks does not induce a significant variation in the biochemical parameters and body weight of rats compared with the control group. Besides, the cell viability of HepG2 did not change in the presence of ODSO. On the other hand, the ODSO increased the glucose absorption activity of the isolated rat hemidiaphragm, and this activity was significantly enhanced when combined with insulin. This study confirms, on one side, the safety of this oil and its efficacy and, on the other side, encourages its potential use as a complement to treat diabetes.