Direct Excitation of Aldehyde to Activate the C(sp2 )-H Bond by Cobaloxime Catalysis toward Fluorenones Synthesis with Hydrogen Evolution.

A new way to form fluorenones via the direct excitation of substrates instead of photocatalyst to activate the C(sp2 )-H bond under redox-neutral condition is reported. Our design relies on the photoexcited aromatic aldehyde intermediates that can be intercepted by cobaloxime catalyst through single electron transfer for following ß-H elimination. The generation of acyl radical and successful interception by a metal catalyst cobaloxime avoid the use of a photocatalyst and stoichiometric external oxidants, affording a series of highly substituted fluorenones, including six-membered ketones, such as xanthone and thioxanthone derivatives in good to excellent yields, and with hydrogen as the only byproduct. This catalytic system features a readily available metal catalyst, mild reaction conditions and broad substrate scope, in which sunlight reaction and scale-up experiments by continuous-flow approach make the new methodology sustainable and amenable for potentially operational procedures.

Value of bedside echocardiography in predicting persistent patency of the ductus arteriosus during the early postnatal period in very low birth weight infants. / ç”ŸåŽæ—©æœŸåºŠæ—å¿ƒè„è¶ å£°é¢„æµ‹æžä½Žå‡ºç”Ÿä½“é‡å„¿åŠ¨è„‰å¯¼ç®¡æŒç»­å¼€æ”¾çš„ç ”ç©¶.

OBJECTIVES: To study the value of bedside echocardiography in predicting persistent patency of the ductus arteriosus during the early postnatal period in very low birth weight (VLBW) infants. METHODS: A retrospective analysis was performed for 51 VLBW infants who were admitted from March 2020 to June 2021, with an age of ≤3 days and a length of hospital stay of ≥14 days. According to the diameter of patent ductus arteriosus (PDA) on days 14 and 28 after birth, the infants were divided into three groups: large PDA group (PDA diameter ≥2 mm), small PDA group (PDA diameter <2 mm), and PDA closure group (PDA diameter =0 mm). The echocardiographic parameters measured at 72 hours after birth were compared among the three groups. The receiver operating characteristic (ROC) curve was used to evaluate the value of the echocardiographic parameters in predicting persistent patency of the ductus arteriosus (PDA≥2 mm) at the ages of 14 and 28 days. RESULTS: On day 14 after birth, there were 17 infants in the large PDA group, 11 in the small PDA group, and 23 in the PDA closure group. On day 28 after birth, there were 14 infants in the large PDA group, 9 in the small PDA group, and 26 in the PDA closure group. There were significant differences in gestational age, birth weight, rate of pulmonary surfactant use, and incidence rate of hypotension among the three groups (P<0.05). PDA diameter, end-diastolic velocity of the left pulmonary artery, left ventricular output, and left ventricular output/superior vena cava flow ratio measured at 72 hours after birth were associated with persistent patency of the ductus arteriosus at the ages of 14 and 28 days (P<0.05), and the ratio of the left atrium to aorta diameter was associated with persistent patency of the ductus arteriosus at the age of 28 days (P<0.05). The ROC curve analysis showed that the area under the curve that the PDA diameter measured at 72 hours after birth predicting the persistent patency of the ductus arteriosus at the ages of 14 and 28 days was the largest (0.841 and 0.927 respectively), followed by end-diastolic velocity of the left pulmonary artery, with the area under the curve of 0.793 and 0.833 respectively. CONCLUSIONS: The indicators obtained by beside echocardiography at 72 hours after birth, especially PDA diameter and end-diastolic velocity of the left pulmonary artery, can predict persistent patency of the ductus arteriosus at the ages of 14 and 28 days in VLBW infants, which provides a basis for the implementation of early targeted treatment strategy for PDA.

Developmental population pharmacokinetics of caffeine in Chinese premature infants with apnoea of prematurity: A post-marketing study to support paediatric labelling in China.

AIMS: The aim of the study was to evaluate the suitability of the current caffeine dosing regimen for the Chinese population using modelling and simulation approach. METHODS: Pharmacokinetic samples were collected from 99 Chinese newborns with premature apnoea. The median (range) of gestational age and postmenstrual age were 28.3 (25.0-33.4) weeks and 31.1 (26.4-38.0) weeks, respectively. Newborns were receiving caffeine citrate at a loading dose of 20 mg/kg/d and a maintenance dose of 5-10 mg/kg/d. Caffeine concentrations and CYP1A2 polymorphisms were investigated. Population pharmacokinetic modelling of caffeine in Chinese preterm newborn on a population-wide scale was conducted using NONMEM. RESULTS: A 1-compartment model with first-order elimination was used to describe population pharmacokinetic. With current weight implemented using 0.75 allometric scaling, clearance (CL) was positively related to current weight and postmenstrual age, but a negative relationship was observed with serum creatinine concentration. Eight genotypes of CYP1A2 were tested and none of them had a significant impact on caffeine pharmacokinetic parameters. Interindividual variability of CL and volume of distribution was 7.70 and 65.9%. The median (range) of 95% confidence intervals of CL were 0.0128 (0.0128-0.0131) L/h/kg. Monte Carlo simulation demonstrated that 80% (loading dose) and 98% (maintenance dose) of premature infants treated with a labelled dosing regimen attained the concentration target range of 5-20 mg/L. CONCLUSION: A population PK model of caffeine was developed in Chinese newborns. Body weight-implemented allometric scaling, postmenstrual age and serum creatinine concentration markedly affected caffeine clearance. The labelled dosing regimen is suitable for Chinese premature infants.

[Clinical features and prognosis of bronchopulmonary dysplasia complicated by pulmonary hypertension in preterm infants].

OBJECTIVE: To study the clinical features and prognosis of bronchopulmonary dysplasia (BPD) complicated by pulmonary hypertension (PH) in preterm infants. METHODS: A retrospective analysis was performed on the clinical data of 191 preterm infants with BPD. RESULTS: In the 191 preterm infants with BPD, 37 (19.4%), all with moderate or severe BPD, developed PH beyond 36 weeks' corrected age. The incidence rates of PH in infants with moderate and severe BPD were 5.7% (5/87) and 47.8% (32/67) respectively. Gestational age and birth weight were lower in infants with PH than in those without PH (P<0.01). Infants with PH had higher incidence rates of small for gestational age (SGA), severe BPD, surgical ligation of patent ductus arteriosus (PDA), neonatal respiratory distress syndrome, hemodynamically significant PDA, and pneumonia than those without PH (P<0.01). Durations of oxygen therapy, intubation, and positive pressure ventilation were longer in infants with PH than in those without PH (P<0.01). Infants with PH had higher incidence rates of retinopathy of prematurity and extrauterine growth retardation, a higher mortality, and a longer length of hospital stay compared with those without PH (P<0.01). In the 37 infants with PH (6 with mild PH, 14 with moderate PH, and 17 with severe PH), those with mild or moderate PH all survived; 15(88%) out of 17 infants with severe PH died. CONCLUSIONS: The incidence of PH is high in preterm infants with moderate or severe BPD. Regular screening of pulmonary artery pressure is recommended for infants with BPD. Infants with low gestational age and birth weight, SGA, and severe BPD are more likely to develop PH. Infants with BPD complicated by PH have relatively high incidence rates of complications, high mortality, and poor prognosis.

[Factors influencing the prognosis of patent ductus arteriosus in very low birth weight infants].

OBJECTIVE: To investigate the factors influencing the prognosis of patent ductus arteriosus (PDA) in very low birth weight (VLBW) infants. METHODS: A total of 194 VLBW infants who were admitted from January 2012 to December 2014 were enrolled as study subjects. According to cardiac ultrasound findings and treatment outcome, these infants were divided into non-PDA group, spontaneous closure group, pharmaceutical closure group, and surgical closure group. Their clinical and echocardiographic characteristics were analyzed. RESULTS: The spontaneous closure rate of PDA was 58.7%. The spontaneous closure group showed significantly higher gestational age, birth weight, and proportion of small-for-gestational-age infants than the pharmaceutical and surgical closure groups (P<0.05). The pharmaceutical and surgical closure groups had a significantly higher incidence rate of neonatal respiratory distress syndrome and a significantly higher proportion of infants who were given pulmonary surfactant (PS) than the spontaneous closure group (P<0.05). During different periods of time, the spontaneous closure group had a significantly smaller ductus arteriosus diameter than the pharmaceutical and surgical closure groups (P<0.05). The multivariate logistic regression analysis showed that gestational age, application of PS, and ductus arteriosus diameter at 48 hours were significantly associated with the prognosis of PDA. The major transductal flow pattern in the spontaneous closure group was closing pattern, while in the pharmaceutical and surgical closure groups, the main flow patterns were pulmonary hypertension and growing patterns within 48 hours and growing pattern on days 4 and 7. CONCLUSIONS: The VLBW infants have a high spontaneous closure rate of PDA. A decreased closure rate of PDA is associated with the lower gestational age and the application of PS. PDA with a large ductus arteriosus diameter and a growing or pulsatile flow pattern cannot easily achieve spontaneous closure.

[Infant Neurological International Battery predicts neurological outcomes of preterm infants discharged from the neonatal intensive care unit].

OBJECTIVE: To explore the Infant Neurological International Battery (Infanib) as a screening tool for early detection of gross motor developmental delay in preterm infants discharged from NICU, and to predict their later neuromotor dysfunction (cerebral palsy or motor retardation). METHODS: A cohort of preterm infants who were admitted to the neonatal intensive care unit between June 2008 and March 2010 were enrolled in the study. Infanib assessment was performed at corrected age 3-4 months and 6-7 months. Peabody Developmental Motor scale-2 (PDMS-2) and neuro-examinations were used to confirm the last motor retardation. The sensitivity, specificity, positive predictive value and negative predictive value of the Infanib were calculated. RESULTS: A total of 147 preterm infants were participated in this study, and 129 infants were followed up at correct age 12 months or more than 12 months. Eleven (8.5%) had celebral palsy, 28 (21.7%) had motor retardation, and 90 (69.8%) normal mortor development. The predictive validity of the Infanib at correct age 3-4 months (n=14) was: sensitivity 84.6%, specificity 75.6%, positive predictive value 60.0% and negative predictive value 91.9%. The predictive validity of the Infanib at correct age 6-7 months (n=117) was: sensitivity 100%, specificity 91.7%, positive predictive value 82.5% and negative predictive value 100%. CONCLUSIONS: The Infanib can be used as an appropriate screening tool and validity measurement for early detection of gross motor developmental delay in preterm infants.

Guanylate binding protein 5 accelerates gastric cancer progression via the JAK1-STAT1/GBP5/CXCL8 positive feedback loop.

Guanylate binding protein 5 (GBP5) is a member of the interferon (IFN)-inducible large guanosine triphosphate hydrolases (GTPase) family that regulates cell-autonomous immunity and malignant tumor transformation. However, its specific roles and underlying mechanisms GBP5 in gastric cancer (GC) remain unknown. In this study, we aimed to determine the role GBP5 and underlying mechanism of GBP5 in GC cell progression. Potential oncogenic roles of GBP5 in GC as well as its relationship with the tumor immune microenvironment (TIME) were comprehensively evaluated using bioinformatics analysis. Protein expression levels of GBP5 and their correlation with clinicopathological features of patients were assessed using immunohistochemistry. In addition, diverse in vitro functional experiments were performed to identify the functions of GBP5 in GC. Downstream targets of GBP5 were identified using RNA-sequencing analysis and verified using western blotting or quantitative polymerase chain reaction analysis in different cell lines. GBP5 expression is commonly upregulated and promotes the proliferation and migration of GC cells. Mechanistically, GBP5 was regulated by the IFNγ-Janus kinase (JAK1)-signal transducer and activator of transcription 1 (STAT1) axis and induced CXCL8 expression. Interestingly, GBP5-induced CXCL8 regulated the JAK1-STAT1 signaling pathway to form a positive feedback loop. Moreover, GBP5 is closely related to the TIME and may be used as a biomarker for predicting the efficacy of immunotherapy. Our findings revealed a new JAK1-STAT1/GBP5/CXCL8 pathway and highlighted the value of GBP5 as a predictive biomarker and novel target for GC intervention.

Acute lung inflammatory response and injury after hemorrhagic shock are more severe in postpartum rabbits.

OBJECTIVE: The acute respiratory distress syndrome may complicate postpartum hemorrhagic shock and resuscitation, but its mechanisms are not yet well defined. We studied the lung inflammatory response to postpartum hemorrhagic shock and resuscitation in a rabbit model and the role of the nuclear factor-κB pathway. DESIGN: Randomized, controlled, prospective study. SETTING: University hospital laboratory. SUBJECTS: Nonobstetric (not pregnant nor postpartum) and obstetrical (within 2 hrs postpartum) rabbits. INTERVENTIONS: Nonobstetric and obstetric female New Zealand white rabbits underwent fixed-pressure or fixed-volume hemorrhagic shock for 30 mins and then were rapidly resuscitated with the shed blood and Ringer's solution. Finally, they were either monitored for survival time or euthanized by exsanguination for lung tissue examination 24 hrs after hemorrhage. MEASUREMENTS AND MAIN RESULTS: After hemorrhagic shock and resuscitation, median survival time in obstetric rabbits (3 days) was significantly shorter (p<.05) than that in nonobstetric rabbits (5 days). Compared with nonobstetric rabbits, obstetric rabbits had more severe lung injury as indicated by alveolar and interstitial fluid accumulation and marked neutrophil sequestration and greater lung injury score, myeloperoxidase activity, expression of intercellular adhesion molecule-1, serum tumor necrosis factor-α levels, and nuclear factor-κB activation, and lower serum interleukin-10 levels (p<.05 for all). CONCLUSIONS: After hemorrhage and resuscitation, obstetric rabbits had significantly shorter survival time and more severe lung injury than nonobstetric rabbits. The mechanism may be through upregulation of the signal transductions of the nuclear factor-κB pathways.

[Clinical study of 12 cases with obstetric mirror syndrome].

OBJECTIVE: To discuss the clinical features, management, pregnancy outcome and prognosis of obstetric mirror syndrome. METHODS: The clinical data of 12 cases with obstetric mirror syndrome at Shenzhen Maternity and Child Healthcare Hospital from April 2008 to December 2010 were collected to retrospectively analyze the clinical features, management, pregnancy outcome and prognosis. RESULTS: (1) ETIOLOGY: 12 cases with obstetric mirror syndrome included 9 cases of Bart's hydrops fetalis, 2 cases with fetal complicated congenital cardiac anomalies, and 1 case of unknown etiology. (2) Gestational age at diagnosis and at delivery: gestational age at diagnosis ranged from 28 to 36 weeks [mean (31.5 ± 4.7) weeks], and gestational age at delivery ranged from 28(+3) to 38 weeks [mean (32.9 ± 2.9) weeks]. There were no significant differences between the gestational age at diagnosis and at delivery in consistence with severe preeclampsia group and mild preeclampsia group [(31.8 ± 2.3) weeks vs. (30.9 ± 7.2) weeks, (32.5 ± 2.3) weeks vs. (33.5 ± 3.9) weeks, P > 0.05]. (3) The patients with obstetric mirror syndrome can present a preeclampsia-like syndrome: maternal extremity edema in 12 cases, headache and visual disturbance in 1 case, proteinuria in 11 cases, elevated blood pressure in 5 cases, elevated uric acid in 9 cases, hypoproteinemia in 12 cases, elevated creatinine in 3 case, elevated liver enzyme in 1 case, thrombocytopenia in 2 cases. The major complications included 1 case of HELLP syndrome, acute pulmonary edema, placental abruption, amnionic fluid embolism, DIC respectively, 3 cases of acute kidney failure and 6 cases of postpartum hemorrhage. (4) Sonographic findings: 1) Hydrops fetalis: fetal ultrasound revealed pleural fluid, fetal ascites, skin edema, scalp edema, encephalocolele enlargement, hydropericardium and increased cardio-chest ratio. 2) Placenta megaly: the placental pathological examination revealed edematous and large in 12 cases. Placental thickness was beyond 4 cm in all cases [(6.3 ± 1.9) cm]. 3) Hydramnios: hydramnios could be found in 11 cases [amniotic fluid index (19.7 ± 3.1) cm]. (5) Postnatal conditions:all blood pressure and laboratory findings including urine protein normalized within 5 to 7 days after delivery. (6) Pregnancy outcome:all 12 patients survived, however the perinatal mortality rate was 100%. Two of 12 cases with mirror syndrome underwent cesarean section, and 10 were vaginal delivery, of which 1 need uterine artery embolisom due to postpartum hemorrhage. CONCLUSIONS: Obstetric mirror syndrome seems to simulate preeclampsia although there are distinguishing features, such as hemodilution, placental edema, and polyhydramnios. When the specific cause of obstetric mirror syndrome can not be identified and corrected, the decision for delivery should be made as soon as possibly.

Design and Synthesis of Dipeptidomimetic Isocyanonaphthalene as Enhanced-Fluorescent Chemodosimeter for Sensing Mercury Ion and Living Cells.

A novel valine-based isocyanonaphthalene (NpI) was designed and synthesized by using an easy method and enabled the selective fluorescence detection of Hg2+. The chemodosimeter can display an immediate turn-on fluorescence response (500-fold) towards target metal ions upon the Hg2+-mediated conversion of isocyano to amino within NpI. Based on this specific reaction, the fluorescence-enhancement probe revealed a high sensitivity toward Hg2+ over other common metal ions and exhibited excellent aqueous solubility, good antijamming capability, high sensitivity (detection limit: 14.2 nM), and real-time detection. The response mechanism of NpI was supported by NMR spectroscopy, MS analysis and DFT theoretical calculation using various techniques. Moreover, a dipeptidomimetic NpI probe was successfully applied to visualize intracellular Hg2+ in living cells and monitor Hg2+ in real water samples with good recoveries and small relative standard deviations.

Hypotensive resuscitation combined with polydatin improve microcirculation and survival in a rabbit model of uncontrolled hemorrhagic shock in pregnancy.

BACKGROUND: Obstetric hemorrhage remains a leading cause of maternal death internationally. Polydatin is an effective drug in ameliorating microcirculatory insufficiency and increasing survival rate in non-pregnant animal model of controlled hemorrhagic shock. In the present study, we investigated the effects of hypotensive resuscitation combined with Polydatin administration on microcirculation and survival rate in a clinically relevant model of uncontrolled hemorrhagic shock in pregnancy. MATERIALS AND METHODS: Twenty anesthetized New Zealand white rabbits at mid and late gestation were anesthetized, and an ear chamber was prepared to examine microvessels by intravital microscopy. Shock was induced by transecting a small artery in mesometrium, followed by blood withdrawal via the femoral artery to a mean arterial pressure (MAP) of 40-45 mm Hg. Animals were randomly divided into two groups (n=10 per group): 30 min after hemorrhage induction, hypotensive resuscitation with Ringer's solution to MAP of 60 mm Hg, followed by a single volume infusion of 4 mL/Kg of normal saline or Polydatin at 60 min after hemorrhage induction (group NS, PD). Finally all the animals received hemorrhage control and resuscitated with half of the heparinized shed blood and Ringer's solution to MAP of 80 mm Hg. RESULTS: At the end of resuscitation, compared with group NS, group PD showed significantly improved capillary perfusion as indicated by increased arteriole diameter [0.95±0.02 of baseline (PD), 0.71±0.05 of baseline (NS); P=0.000] and higher functional capillary density[95.3% ± 2.6% (PD), 57.2% ± 4.1% (NS); P=0.000]. Median survival time was significantly longer in group PD than that in group NS [4 d (PD), 2 d (NS); P=0.000]. CONCLUSIONS: On the basis of hypotensive resuscitation, Polydatin administration improved microcirculation and prolonged survival time in pregnant rabbit model of uncontrolled hemorrhagic shock.

[Clinical study on 156 cases with hydrops fetalis].

OBJECTIVE: To investigate the ultrasound characteristics, etiology and prognosis in hydrops fetalis. METHODS: From September 2002 to May 2010, 156 hydrops fetalis presented in Shenzhen Maternity and Child Healthcare Hospital were studied retrospectively, including ultrasound characteristics, etiology, and prognosis. RESULTS: All of the 112 typical hydrops fetalis, 20 cases with isolated ascites, 8 cases with isolated pleural effusion, 7 cases with isolated pericardial effusion, 5 cases with isolated subcutaneous edema, 4 cases with isolated placental thickening were observed by ultrasonography. The major etiology and associated diagnosis consisted of 35.9% (56/156) of non-immune anemia, 9.6% (15/156) of cardiac abnormalities, 7.1% (11/156) of intrauterine infection, 6.4% (10/156) of twin problems, 5.8% (9/156) of meconium peritonitis, 5.1% (8/156) of thoracic-lung disease, 4.5% (7/156) of chromosomal abnormalities, 1.9% (3/156) of immune anemia. Alpha thalassemia was the most common non-immune anemia (96%, 54/56). An etiology and associated diagnosis could be determined in 81.4% (127/156) of cases. Follow-up data showed that 7 cases were fetal death, 110 women elected to terminate their pregnancies, 3 cases lost follow-up, the other 36 cases preserve continuing pregnancy, including 28 liveborn infants and 8 fetal deaths. Etiology of twin-twin transfusion syndrome, meconium peritonitis, congenital chylothorax, intrauterine infection, cardiac abnormalities and so on had survived fetus cases. The survival rate of typical hydrops fetalis in the present series was 3.6% (4/112). CONCLUSIONS: Ascites is the most common characteristics of sonogram in hydrops fetalis. The etiology of hydrops fetalis is extremely complex. The prognosis is associated with the etiology and hydrops subtype.

[The lung injury in postpartum and non-pregnant rabbits after resuscitation from hemorrhagic shock].

OBJECTIVE: To investigate the difference in the development of acute lung injury after hemorrhagic shock in postpartum and non-pregnant rabbits. METHODS: Hemorrhagic shock/resuscitation was produced on 9 pregnant New-Zealand rabbits postpartum (within 24 hours after giving birth) and 9 non-pregnant controls via carotid artery bleeding and perfusion (i.v.) of lactate Ringer solution for 3 hours. The serum level of cytokine tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in the animals were measured at different time points. Lung tissue were taken 3 hours after resuscitation for the determination of malondialdehyde (MDA),the activity of superoxide dismutase (SOD), myeloperoxidase (MPO), dry/wet weight (D/W), nuclear factor-ΚB (NF-ΚB), and mRNA content of intercellular adhesion molecule-1 (ICAM-1). RESULTS: Serum TNF-α (ng/L) and IL-10 (ng/L) in antepartum pregnant rabbits were not significantly different from non-pregnant rabbits (TNF-α: 87.6 ± 6.8 vs. 83.2 ± 5.3; IL-10: 44.9 ± 3.9 vs. 42.7 ± 3.4, both P > 0.05). However, the serum TNF-α increased significantly after delivery (102.5 ± 8.1 vs. 87.6 ± 6.8, P < 0.05). TNF-α and IL-10 increased 1 hour after shock in both postpartum and non-pregnant rabbits. The serum TNF-α in postpartum rabbits was significant higher than non-pregnant rabbits in each resuscitation period (1 hour: 230.0 ± 14.9 vs. 202.0 ± 10.1, 2.5 hours: 290.0 ± 18.6 vs. 236.0 ± 14.4, 4 hours: 265.0 ± 15.9 vs. 217.0 ± 12.8, all P < 0.05), meanwhile the serum IL-10 in postpartum animals was significantly lower than the non-pregnant controls(1 hour: 104.3 ± 6.9 vs. 135.0 ± 7.8, 2.5 hours: 146.8 ± 9.4 vs. 178.3 ± 11.7, 4 hours: 126.0 ± 7.9 vs. 165.8 ± 9.6, all P < 0.05). The value of MDA, MPO, D/W, NF-ΚB activity and ICAM-1 mRNA content in lung tissue of postpartum rabbits were all significant higher than non-pregnant rabbits after resuscitation [MDA (nmol/mg): 52.6 ± 5.9 vs. 39.4 ± 4.7, MPO (U/mg): 4.62 ± 0.85 vs. 3.26 ± 0.62, D/W: 0.186 ± 0.025 vs. 0.143 ± 0.016, NF-ΚB activity (A value): 0.89 ± 0.27 vs. 0.46 ± 0.15, ICAM-1 mRNA: 4.6 ± 1.2 vs. 2.5 ± 0.7, all P < 0.05], but the activity of SOD (U/mg) was lower (47.8 ± 6.7 vs. 63.5 ± 8.2, P < 0.05) in the controls after resuscitation. CONCLUSIONS: Delivery causes significant increase in serum TNF-α in pregnant rabbits. Inflammatory lung injury is more severe in postpartum rabbits after resuscitation from hemorrhagic shock, and the increased serum level of inflammatory mediators may be part of the mechanism for such difference.

[Effect of hypotensive fluid resuscitation on microcirculation in an uncontrolled hemorrhagic shock of pregnant rabbits].

OBJECTIVE: to study the effects of hypotensive resuscitation on microvascular perfusion in a clinically relevant model of uncontrolled hemorrhagic shock in pregnancy. METHODS: thirty New Zealand white rabbits at 15 - 25 days, pregnanal age were randomly divided into three groups; Group normal saline traditional aggressive resuscitation (NS), traditional aggressive resuscitation in the prehospital phase with a large quantity of normal saline and Ringer's solution to maintain mean arterial pressure (MAP) at the approximately 80 mm Hg (1 mm Hg = 0.133 kPa) level: Group normal saline hypotensive resuscitation (NH) and group hypertonic hyperosmotic hypotension resuscitation (HHH), hypotensive resuscitation in the prehospital phase with a bolus dose of 4 ml/kg normal saline or hypertonic hydroxyl ethyl starch (10% hydroxyl ethyl starch +7.5% NaCl), followed by Ringer's solution to maintain MAP at 60 mm Hg. Production pregnant rabbit model with hemorrhagic shock. The experiment consisted of four phases:basic phase (0 miniutes), shock phase (0 - 30 miniutes), prehospital phase (30 - 90 miniutes) and hospital phase (90 - 180 miniutes). MEASUREMENTS: (1) arteriole and venule diameter were continuously monitored by microcirculatory detecting instrument; (2) functional capillary density (FCD) of each phase was expressed by the percentage of opening capillaries segments relative to basic phase; (3) blood pH, BE PCO(2), PO(2) in pregnant rabbits were determined with a Medica Easy Blood Gas Analyzer. RESULTS: (1) there were no significant differences among three groups in arteriole and venule diameter at baseline (P > 0.05). After hemorrhagic shock arteriole diameter were NS (50.8 ± 5.6) µm, NH (47.6 ± 3.7) µm, HHH (51.3 ± 2.4) µm, respectively, with no significant differences between groups (P > 0.05). At the end of prehospital resuscitation phase and hospital resuscitation phase, significant differences were found in arteriole diameter in group NS (52.8 ± 4.9, 56.0 ± 3.8) µm, NH (61.3 ± 2.9, 65.4 ± 3.2)µm and HHH group (67.0 ± 4.1, 74.1 ± 4.8) µm (P < 0.05); after hemorrhagic shock venule diameter were NS (79.6 ± 7.0) µm, NH (75.3 ± 5.3) µm and HHH (76.2 ± 5.8) µm, respectively, with no significant differences between groups (P > 0.05). At the end of prehospital resuscitation phase and hospital resuscitation phase, venule diameter were NS (81.1 ± 6.7, 84.4 ± 6.0) µm, NH (82.8 ± 3.3, 85.4 ± 4.3) µm and HHH (86.9 ± 5.8, 89.4 ± 6.8) µm, respectively, with no significant differences between groups (P > 0.05). (2) The values of FCD in every groups were all 100%. After hemorrhagic shock FCD were NS (39.8 ± 6.8)%, NH (43.9 ± 4.0)%, HHH (44.0 ± 4.8)%, respectively, with no significant differences between groups (P > 0.05); at the end of prehospital resuscitation phase and hospital resuscitation phase, FCD were NS (54.5 ± 7.3, 59.7 ± 4.8)%, NH (63.1 ± 5.8, 70.3 ± 5.6)% and HHH (80.5 ± 6.9, 91.7 ± 4.7)%, respectively, with significant differences between groups (P < 0.05). (3) Blood gas parameter: the values of blood pH, BE, PO(2), PCO(2) in pregnant rabbits in all groups were within normal bounds at basic phase. Shock phase induced typical hyperventilation in all groups, with increase of arterial PO(2) and decrease of PCO(2); at the end of hospital resuscitation phase, there were no significant difference among the three groups in the values of blood PCO(2) (P > 0.05); the values of blood PO(2) at the hospital resuscitation phase were significantly lower in NS groups than corresponding values in the other groups (P < 0.05). After hemorrhagic shock there was significant metabolic acidosis as shown by decrease of pH, BE; at prehospital resucitation phase, pH, BE values tended to increase in all the groups but not reach to base period. At the end of hospital resucitation phase. The pH, BE value was significantly higher in NS group than those in the other two groups (P < 0.05). (4) Median survival time in NS (2.1 ± 0.2) days group was significantly shorter than NH (3.0 ± 0.3) days and HHH (3.6 ± 0.3) days group (P < 0.05). FCD at the end of the hospital resuscitation were significantly related with survival time (r = 0.655, P = 0.000). CONCLUSION: compared with traditional aggressive fluid resuscitation, hypotensive resuscitation reduce constriction of arterial and venule diameter, increase FCD, alleviate metabolic acidosis and improve long-term survival. Hypertonic hydroxyl ethyl starch resuscitation ameliorate microcirculation without improving survival rate.

MiR-126a-5p is involved in the hypoxia-induced endothelial-to-mesenchymal transition of neonatal pulmonary hypertension.

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterized by increased medial and adventitial thickness of the lung vasculature. The underlying mechanisms that regulate the cell phenotype alteration during PPHN remodeling are largely unknown. We randomly selected newborn rats that were exposed to hypoxia (10-12%) or room air for 2 weeks and used a microarray to identify the lung tissue microRNAs (miRNAs) involved in PPHN progression. The role of a key miRNA that affects the endothelial-to-mesenchymal transition (EndMT) in primary cultured rat pulmonary microvascular endothelial cells (RPMECs) was investigated. The expression of miR-126a-5p was elevated in the PPHN model according to microarray analysis. The relative expression of miR-126a-5p in RPMECs increased when they were exposed to hypoxia (P<0.05), consistent with the microarray results. Pecam1 expression decreased, whereas alpha-smooth muscle actin (α-SMA) increased in the hypoxic RPMECs. Knockdown of miR-126a-5p in RPMECs followed by treatment with hypoxia for 48 h resulted in a significant increase in the expression of Pecam1 and a reduction in α-SMA expression, with a simultaneous increase in PI3K (p85ß) and phosphorylation of AKT at serine 473 compared with the negative control. Finally, the circulating miR-126a-5p concentration was upregulated in the PPHN model compared with healthy neonates. We concluded that hypoxia changed the cell homeostasis and that miR-126a-5p was upregulated in PPHN, which is partly responsible for hypoxia-induced EndMT. The mechanism underlying the upregulation of miR-126a-5p by hypoxia probably acts through the p85-ß/p-AKT pathway.

The Vascular Notch Ligands Delta-Like Ligand 4 (DLL4) and Jagged1 (JAG1) Have Opposing Correlations with Microvascularization but a Uniform Prognostic Effect in Primary Glioblastoma: A Preliminary Study.

PURPOSE: Delta-like ligand 4 (DLL4) and Jagged1 (JAG1), 2 vascular Notch ligands, are involved in the process of tumor angiogenesis. The present study investigates their relationship with microvascularization and the prognostic effect in primary glioblastoma. METHODS: Tumor tissues from 61 glioblastomas were analyzed using immunohistochemistry for DLL4/JAG1 expression and microvascular formations. The correlations between DLL4/JAG1 and microvascularization were analyzed. The survival probabilities were computed using the Kaplan-Meier method. The Cox proportional hazards regression model was used for multivariate analysis of time to progression (TTP) and overall survival (OS). RESULTS: The results showed increased DLL4 and JAG1 expression in glioblastoma tissues. Five types of basic microvascular formations, including microvascular sprouting, vascular cluster, vascular garland, glomeruloid vascular proliferation, and vasculogenic mimicry, were detected. Glioblastomas with the type I microvascular pattern (MVP) that displayed prominent microvascular sprouting and vascular clusters tended to have higher DLL4 expression, whereas those with the type II MVP that had numerous vascular garlands, glomeruloid vascular proliferations, and vasculogenic mimicries showed upregulated JAG1 expression. Univariate analysis documented that high DLL4 expression, high JAG1 expression, and type II (MVP) were statistically associated with reduced TTP and OS. Multivariate analysis confirmed high DLL4 expression, high JAG1 expression, and type II MVP as significant prognostic factors for both shorter TTP and OS, independent of age, Karnofsky performance scale, and other molecular markers (vascular endothelial growth factor, Ki67, and P53). CONCLUSIONS: DLL4 and JAG1 may have opposing effects on tumor angiogenesis in glioblastoma. The Notch pathway may be a new target for antiangiogenic therapy in glioblastoma.

Analysis of In-hospital Neonatal Death in the Tertiary Neonatal Intensive Care Unit in China: A Multicenter Retrospective Study.

BACKGROUND: Globally, the proportion of child deaths that occur in the neonatal period remains a high level of 37-41%. Differences of cause in neonate death exist in different regions as well as in different economic development countries. The specific aim of this study was to investigate the causes, characteristics, and differences of death in neonates during hospitalization in the tertiary Neonatal Intensive Care Unit (NICU) of China. METHODS: All the dead neonates admitted to 26 NICUs were included between January l, 2011, and December 31, 2011. All the data were collected retrospectively from clinical records by a designed questionnaire. Data collected from each NICU were delivered to the leading institution where the results were analyzed. RESULTS: A total of 744 newborns died during the 1-year survey, accounting for 1.2% of all the neonates admitted to 26 NICUs and 37.6% of all the deaths in children under 5 years of age in these hospitals. Preterm neonate death accounted for 59.3% of all the death. The leading causes of death in preterm and term infants were pulmonary disease and infection, respectively. In early neonate period, pulmonary diseases (56.5%) occupied the largest proportion of preterm deaths while infection (27%) and neurologic diseases (22%) were the two main causes of term deaths. In late neonate period, infection was the leading cause of both preterm and term neonate deaths. About two-thirds of neonate death occurred after medical care withdrawal. Of the cases who might survive if receiving continuing treatment, parents' concern about the long-term outcomes was the main reason of medical care withdrawal. CONCLUSIONS: Neonate death still accounts for a high proportion of all the deaths in children under 5 years of age. Our study showed the majority of neonate death occurred in preterm infants. Cause of death varied with the age of death and gestational age. Accurate and prompt evaluation of the long-term outcomes should be carried out to guide the critical decision.

High Jagged1 expression is associated with poor outcome in primary glioblastoma.

Glioblastoma is a highly aggressive brain tumor. Aberrant Notch pathway has been implicated in the formation and progression of glioblastoma. The present study attempted to investigate the expression of Notch ligand Jagged1 and its association with patient outcome in primary glioblastoma. Tumor tissues from 82 patients with primary glioblastoma were analyzed using immunohistochemistry for Jagged1 expression. Relationships between Jagged1 expression and clinical features (age, gender, KPS, symptom duration, extent of resection and Ki67 index) were evaluated. The prognostic value of Jagged1 was assessed using the Kaplan-Meier survival estimates and the Cox proportional hazard models. Immunohistochemistry results showed markedly increased Jagged1 expression in glioblastoma tissues compared to adjacent non-neoplastic brain tissues. Univariate analysis documented that high Jagged1 expression in tumor cells (TC) and endothelial cells (EC) were both statistically associated with reduced time to progression (TTP) (P < 0.001 for TC, P = 0.001 for EC) and overall survival (OS) (P < 0.001 for TC, P = 0.003 for EC) in primary glioblastoma. The median TTP (P < 0.001) and OS (P = 0.001) were higher in patients with dual-low Jagged1 expression in TC and EC compared to those in patients with non-dual Jagged1 expression and dual high expression. By multivariate survival analysis, we found that high Jagged1 expression in both tumor cells and endothelial cells was independent unfavorable prognostic factors TTP (P < 0.001 for TC, P < 0.001 for TC) and OS (P < 0.001 for TC, P < 0.001 for TC) in primary glioblastoma patients. Jagged1-Notch signaling plays an important role in the progress of glioblastoma. Jagged1 expression may be used as an independent prognosis factor in patients with glioblastoma.

Correlation of high delta-like ligand 4 expression with peritumoral brain edema and its prediction of poor prognosis in patients with primary high-grade gliomas.

OBJECT: Peritumoral brain edema (PTBE) is a common phenomenon associated with high-grade gliomas (HGGs). In this study, the authors investigated the expression of Notch delta-like ligand 4 (DLL4) and its correlation with PTBE and prognosis in patients with an HGG. METHODS: Tumors from 99 patients with HGG were analyzed for DLL4 expression using immunohistochemistry. PTBE on preoperative MR images and the relationship between PTBE and DLL4 expression were evaluated. The effect of DLL4 on patient prognosis was assessed by using Kaplan-Meier survival and Cox proportional hazard models. RESULTS: Immunohistochemistry results revealed that the expression of DLL4 was distributed primarily within the cytoplasm of tumor vascular endothelial cells and seldom detected in tumor cells. DLL4 expression was correlated positively with the degree of edema (r = 0.845 and p < 0.001, Spearman's test). In addition, DLL4 was an independent predictor of prognosis in patients with HGGs (p = 0.001). CONCLUSIONS: DLL4 expression was correlated positively with the degree of PTBE and was an independent unfavorable prognostic indicator in patients with HGG.

High delta-like ligand 4 (DLL4) is correlated with peritumoral brain edema and predicts poor prognosis in primary glioblastoma.

Delta-like ligand 4 (DLL4), 1 of the 5 known Notch ligands, is involved in a variety of tumor initiation and progression, particularly in the process of tumor angiogenesis. However, the clinical and prognostic significance of DLL4 in glioblastoma have not been fully elucidated.Tumor tissues from 69 glioblastoma patients were analyzed using immunohistochemistry for DLL4 expression. Peritumoral brain edema (PTBE) on preoperative magnetic resonance imaging of these patients and the relationship with DLL4 expression were evaluated. The effect on prognosis was assessed by using the Kaplan-Meier survival and the Cox proportional hazard model.The results showed that elevated DLL4 expression was primarily distributed in the cytoplasm of tumor vascular endothelial cells and rarely detected in tumor cells. Univariate analysis indicated significant correlation of high DLL4 expression with shorter time to progression (TTP) (P < 0.001) and overall survival (OS) (P < 0.001) in glioblastoma. Multivariate analysis confirmed high DLL4 expression as an unfavorable prognostic indicator for TTP (P < 0.001) and OS (P < 0.001), independent of age, gender, symptom duration, resection degree, and PTBE. Importantly, the study also found that DLL4 expression was positively related with PTBE (Spearman's test: r = 0.845, P < 0.001). A multiple linear regression model was constructed to confirm that the positive index of DLL4 was associated with an increase in maximum extent of PTBE (P < 0.001).It is thus concluded that DLL4 is correlated with PTBE and may be useful for predicting prognosis in glioblastoma.