Effects of cold stress on growth performance, serum biochemistry, intestinal barrier molecules, and adenosine monophosphate-activated protein kinase in broilers.

The homeostasis dysfunctions caused by cold stress remain a threat to intestinal health, particularly for young broiler chickens. We hypothesized that adenosine monophosphate-activated protein kinase (AMPK) was involved in the regulation of cold stress on intestinal health. This study aimed to examine the effect of cold stress for 72 h on growth performance, serum biochemistry, intestinal barrier molecules, and AMPK in broilers. A total of 144 10-day-old male Arbor Acres broilers were subjected to temperature treatments (control 28  ±â€¯1 °C vs cold stress 16 ±â€¯1 °C) for 72 h. Growth performance was monitored, serum was collected for the analysis of physiological parameters, and jejunal mucosa was sampled for the determination of tight junction (TJ) proteins, heat shock proteins, and AMPK signaling molecules. Results showed that 72 h cold treatment reduced average BW gain and increased the feed conversion ratio of the broilers (P < 0.05). Cold stress for 72 h increased blood endotoxin, aspartate aminotransferase, glucose, and low-density lipoprotein cholesterol levels (P < 0.05). Moreover, 72 h cold treatment up-regulated jejunal Occludin, zonula occludin 1, inducible nitric oxide synthase, heat shock factor 1, and AMPKα1 gene expression (P < 0.05) but had no obvious effect on total AMPK protein expression (P > 0.05). In conclusion, cold stress significantly reduced the growth performance of broiler chickens. The intestinal barrier function might be impaired, and enhanced bacterial translocation might occur. The unregulated gene expression of TJ proteins implied the remodeling of intestinal barrier. The change of AMPK suggested the possible relationship between intestinal energy metabolism and barrier function under cold stress.

Correlation between AT1R gene polymorphism and epilepsy secondary to cerebral infarction.

OBJECTIVE: To explore the correlation between angiotensin II type 1 receptor (AT1R) gene polymorphism and epilepsy secondary to cerebral infarction and its significance for the diagnosis of this disease. PATIENTS AND METHODS: A total of 200 patients with epilepsy secondary to cerebral infarction were enrolled from our hospital as observation group, and 200 patients without epilepsy after cerebral infarction as control group. Genomic deoxyribonucleic acids (DNAs) were extracted from the peripheral blood of the subjects, and the polymorphic regions at AT1R gene loci rs380400, rs1799870, rs12721273, and rs55707609 were amplified via polymerase chain reaction (PCR) and sent to the company for sequencing. The concentration of farnesyl diphosphate synthase (FDPS) was determined using enzyme-linked immunosorbent assay (ELISA) kit, and activated partial thromboplastin time (APTT) and prothrombin time (PT) were measured in the Laboratory Department. RESULTS: There were no differences in the allele distributions at AT1R gene loci rs380400 (p=0.070), rs179987 (p=0.0.280), and rs55707609 (p=0.046), but in the allele distribution at rs12721273 (p=0.001) between control group and observation group, and observation group exhibited a significantly lower frequency of allele G in cerebral infarction patients than control group [153 (0.383) vs. 198 (0.495)]. The frequency of genotype GT at rs12721273 was lower [71 (0.355)] and that of genotype TT was evidently higher [88 (0.440)] in observation group (p=0.000). Control group showed a notably lower frequency of genotype AA [47 (0.235)] and a markedly higher frequency of genotype AT [110 (0.550)] at rs55707609 (p=0.000). Observation group exhibited a substantially lower frequency of recessive model AG+GG [128 (0.640)] (p=0.037), and a notably higher frequency of homozygous model AA [72 (0.360)] (p=0.048) at AT1R gene locus rs380400, a remarkably lower frequency of dominant model GG+GT [112 (0.560)] (p=0.002) at rs12721273, and a significantly lower frequency of recessive model AT+TT [126 (0.630)] (p=0.000) and a considerably lower frequency of heterozygous model AT [84 (0.420)] (p=0.026) at rs55707609. The frequencies of AT1R gene haplotypes ACGA (p=0.001), ACGT (p=0.045), ACTT (p=0.000), ATTT (p=0.048), GCTA (p=0.000), and GTGA (p=0.005) in observation group were distinctly higher than those in control group, and the frequencies of the haplotypes ACTA (p=0.000) and ATTA (p=0.029) were evidently lower than those in control group. The loci rs12721273 and rs1799870 showed a significant association (D'=0.783), and APTT was considerably correlated with genotype AG at rs380400 (p=0.042), PT with genotype CC at rs1799870 (p=0.002) and FDPS with genotype AA at rs55707609 (p=0.015). CONCLUSIONS: The polymorphisms of AT1R gene loci rs380400, rs1799870, rs12721273, and rs55707609 are correlated with the susceptibility to epilepsy secondary to cerebral infarction.

Regulatory mechanism of lncRNA NORAD on proliferation and invasion of ovarian cancer cells through miR-199a-3p.

OBJECTIVE: To explore the regulatory mechanism of lncRNA NORAD on proliferation and invasion of ovarian cancer cells through miR-199a-3p. PATIENTS AND METHODS: Eighty-six ovarian cancer tissues and 86 tissues adjacent to cancer, human ovarian cancer cell lines SKOV3, HO-8910, A2780, OVCAR-3, and human normal ovarian epithelial cell line IOSE80 were collected. MiR-199a-3p-mimics, miR-199a-3p-inhibitor, miR-NC, si-NORAD, Sh-NORAD, and NC were transfected into HO-8910 and A2780 cells, the expression levels of lncRNA NORAD and miR-199a-3p in ovarian cancer tissues and cells were detected by qRT-PCR, and the expression levels of N-cadherin, E-cadherin, and vimentin in cells were detected by WB. Cell Counting Kit-8 (CCK-8), transwell, and cell scratch tests were used to detect proliferation, invasion, and migration of cells, and the relationship between lncRNA NORAD and miR-199a-3p was confirmed by the Dual-Luciferase reporter assay. RESULTS: LncRNA NORAD was highly expressed and miR-199a-3p was lowly expressed in ovarian cancer, and the expression levels of LNCRNARAD and miR-199a-3p were negatively correlated. Cell experiments showed that inhibiting the expression of lncRNA NORAD or up-regulating the expression of miR-199a-3p could inhibit the proliferation, invasion, migration, and EMT of ovarian cancer cells, while up-regulating the expression of lncRNA NORAD or inhibiting the expression of miR-199a-3p could promote their proliferation, invasion, migration, and EMT. Dual-Luciferase reporter assay confirmed that there was a regulatory relationship between lncRNA NORAD and miR-199a-3p. CONCLUSIONS: LncRNA NORAD was highly expressed in ovarian cancer tissues, while silencing lncRNA NORAD expression could inhibit the proliferation, invasion, migration, and EMT of ovarian cancer cells by regulating miR-199a-3p, which might be a new target for the diagnosis and treatment of ovarian cancer.

[CD7 expression and its prognostic significance in acute myeloid leukemia patients with wild-type or mutant CEBPA].

Objective: To analyze the prognostic value of CD7 expression in newly diagnosed acute myeloid leukemia (AML) patients, and to further explore the correlation between CD7 expression and CEBPA mutation, and to clarify the prognostic value of CD7(+) in AML patients with wild-type (WT) or mutant-type (MT) CEBPA. Methods: The clinical data of 298 newly diagnosed non-M(3) AML patients between January 2010 and December 2016 were analyzed retrospectively. The clinical characteristics and prognosis of CD7(+) and CD7(-) patients were respectively compared in all patients, and in patients with WT and MT CEBPA. The relationship between CD7 expression and CEBPA mutation was determined by chi-square, and the effects of CEBPA mutation on survival and prognosis in CD7(+) group by Kaplan-Meier method. Results: In CD7(+) group, the frequencies of CEBPA mutation were 10.1% (single site) and 33.9% (double site) , significantly higher than those of the CD7(-) group (5.3% and 4.2%) (P=0.000) . Subgroup prognostic analysis showed a lower CR rate (P=0.001) and a higher RR (P=0.023) in CD7(+) group comparing to those of CD7(-) group in AML patients with wild type CEBPA. There were no statistical difference between CD7(+) group and CD7(-) group in overall survival (OS) and disease free survival (P>0.05) , while in the CEBPA mutant group the CD7(+) group has higher OS (P=0.019) and DFS (P=0.010) . Based on the CD7 expression and CEBPA mutation, 298 cases were divided into 3 subgroups, named as CD7(+)-CEBPA MT group, CD7(-) and CD7(+)-CEBPA WT group. The 3-year OS of the 3 groups were 80.2%, 48.0% and 30.6%, respectively (P<0.001) , and the 3-year DFS were 74.1%, 37.4% and 22.2%, respectively (P<0.001) . Conclusion: The CEBPA mutation rate was higher in CD7(+) AML patients then that of CD7(-) patients. CD7 expression has opposite prognostic significance in AML patients carrying the wild-type or mutant-type CEBPA. Based on CD7 expression and CEBPA mutation, a new risk stratification model can be established, which is helpful to guide the clinical individualized treatment for AML patients.

Micro-CT study on the removal of accumulated hard-tissue debris from the root canal system of mandibular molars when using a novel laser-activated irrigation approach.

AIM: To compare the efficacy of ultrasonically activated irrigation (UAI), photon-induced photoacoustic streaming (PIPS) and shock wave enhanced emission photoacoustic streaming (SWEEPS) activation for the removal of accumulated hard-tissue debris (AHTD) from the root canal system of mandibular molars when assessed using microcomputed tomography (micro-CT). METHODOLOGY: A total of 30 mandibular first and second molars with joining mesial root canals containing an isthmus and a single distal canal were subjected to three micro-CT scans (before and after canal instrumentation and after final irrigation) at a resolution of 15 µm. Mesial canals were prepared up to a ProTaper F3 rotary file, and distal canals were prepared up to a ProTaper F4 rotary file. Teeth were randomly assigned to three groups according to the irrigant activation method (n = 10): the UAI group, the PIPS group and the SWEEPS group. The final irrigation procedures were performed using a total of 15.5 mL of 1% NaOCl for each tooth with an activation time of 3 × 30 s. After three-dimensional model reconstruction and volumetric measurement of root canals, the percentage reduction (%Rd) of AHTD was calculated. The %Rd of AHTD was analysed statistically using one-way analysis of variance and nonparametric tests at a significance level of 5%. RESULTS: There were no significant differences between the three groups in terms of canal volume before or after instrumentation, or the volume of debris after canal preparation (P > 0.05). In the mesial canals, irrigation with SWEEPS reduced the overall debris by 84.31%, which was significantly more than the reduction associated with PIPS and UAI (58.79% and 50.27%, respectively). In the distal canals, the %Rd of AHTD was significantly different between PIPS and SWEEPS and between UAI and SWEEPS (P < 0.05), but was not significantly different between PIPS and UAI groups (P > 0.05). The SWEEPS was associated with a greater %Rd of AHTD than the PIPS and UAI groups. CONCLUSIONS: SWEEPS was associated with significantly less debris compared than PIPS and UAI, especially in isthmus-containing mesial roots. None of the activation techniques completely removed debris from root canal systems.

[Evaluation of peer support education mode for type 2 diabetes control in rural residents].

Objective: To evaluate the intervention effects of peer support education mode for type 2 diabetes control in rural residents. Methods: A random cluster sampling method has been used, including 300 rural residents aged above 18 years old from three villages (184 in control group, 116 in intervention group), in order to proceed the physical check-up and health education programs. Unchanged rate, transfer rate of patients, rate of impaired glucose tolerance, turn normal rate and other biochemical indicators of patients and people with impaired glucose tolerance from control group and intervention group were analyzed, to evaluate the intervention effects of peer support education mode. Results: The glycemic control rate of intervention group for patients and people with impaired glucose tolerance (72.2% and 71.4%) were higher than control group (43.6% and 26.7%), but the unchanged rate of intervention group (13.9% and 0.0%) were lower than control group (42.3% and 73.3%). Patients with diabetes or glucose intolerance in the education group improved significantly in waist-to-hip ratio, uric acid, total cholesterol and HDL-C. Glycemic hemoglobin level also improved significantly in diabetes patients of the education group. Conclusion: Peer support for education intervention seemed beneficial for diabetic control. The combination of education and effect evaluation was important in the evaluation of diabetes prevention and control. Peer support education also benefited the blood glucose control in general population.

[Neutrophil to lymphocyte ratio in peripheral blood: a novel independent prognostic factor in patients with head and neck squamous cell carcinoma].

Objective: To investigate whether neutrophil to lymphocyte ratio (NLR) in peripheral blood can be an independent prognostic factor in patients with head and neck squamous cell carcinoma (HNSCC). Methods: Clinical data of 97 HNSCC patients who received surgical treatment in our department between January 2008 and January 2012 were analyzed retrospectively. The 97 patients were divided into low NLR group (NLR≤5, n=69) and high NLR group (NLR>5, n=28) according to the NLR in preoperative peripheral blood. The relationships of NLR and clinicopathological features were analyzed. Kaplan-Meier method was used for univariate survival analysis and Cox proportional hazard model for multivariate survival analysis. Results: The clinical stages were significantly different between high NLR group and low NLR group (P<0.05), however, the age, gender, location, lymph node metastasis, smoking and alcohol of the two groups showed no significant differences (P> 0.05 of all). Univariate survival analysis showed that smoking, lymph node metastasis, clinical stage and NLR value were risk factors for 3-year overall survival (OS) rate and relapse-free survival (RFS) rate of HNSCC patients (P<0.05). The OS rate of high NLR and low NLR groups was 42.9% and 91.3%, and the RFS rate was 44.2% and 80.1%, respectively, with a statistically significant difference (P<0.05 for both). Cox multivariate survival analysis showed that clinical stage and NLR were independent factors for prognostic evaluation of HNSCC patients (P<0.05 for both). Conclusions: NLR level is significantly associated with clinical stage of HNSCC. High NLR is an independent prognostic rick factor and plays an important role in prognostic evaluation of HNSCC patients.

Effect of acute heat stress and slaughter processing on poultry meat quality and postmortem carbohydrate metabolism.

This study investigated the effects of acute heat stress and slaughter processing on poultry meat quality and carbohydrate metabolism. Broilers (200) were randomly divided into 2 groups receiving heat stress (HS; 36°C for one h), compared to a non-stressed control (C). At slaughter, each group was further divided into 2 groups for slaughter processing (L = laboratory; F = commercial factory). L group breasts were removed immediately after bleeding without carcass scalding or defeathering, and stored at 4°C. F group broilers were scalded (60°C, 45 s) after bleeding and defeathering. Then the breasts were removed and cooled in ice water until the core temperature was ≤4°C. Rates of Pectoralis core temperature and pH decline were changed by slaughter processing, but only HS affected ultimate pH in group L. HS muscles had higher L* values (P < 0.05) than controls at 24 h postmortem. Laboratory processing "hot-deboning" increased drip loss, which resulted in a lower cooked loss (P < 0.05). Postmortem glycolysis was affected only by HS. The speed of lactic acid accumulation and glycogen degradation was faster in the HS group than controls at 5 min postmortem. During storage the glycolysis rates were not different (P > 0.05). Sarcoplasmic protein solubility was higher in F processed birds (P < 0.05). HS decreased the solubility of myofibrillar and total protein in the L-slaughtered birds. Thus, HS caused a higher frequency of accelerated muscle glycolysis than controls. Factory processing (chilling) could not completely eliminate the effects of accelerated glycolysis caused by pre-slaughter HS.

Tenderness and sensory attributes of the longissimus lumborum muscles with different quality grades from Chinese fattened yellow crossbred steers.

The objectives were to investigate intramuscular fat (IMF) content,Warner­Bratzler shear force(WBSF) and sensory attributes of Chinese fattened yellow crossbred steer beef with different quality grades, and to determine the relationship between WBSF and Chinese consumers' sensory tender. WBSF of grades A1 to A5 decreased from 50.6 N to 33.1 N with IMF % increased from4.26 to 24.55 (P b 0.05). Consumer panelists showed more likeability grades A4 and A5 with no difference between them. Grades A2 and A3 were slightly preferred (P b 0.05). Grade A1 was undesirable. A regression relationship between WBSF and sensory tender was found, which indicated that consumers disliked beef when WBSF N55.43 N and preferred those with WBSF b41.4 N. The range of 41.4 N to 55.43 N was intermediate. Hence, WBSF N55.43 & b41.4 N allow classification of tough and tender for beef tenderness for Chinese consumers, and grade A4 was recommended as suitable top grade.

Use of Monoclonal Antibodies in an ELISA for Detecting an Invasive Pest Insect, Liriomyza trifolii (Diptera: Agromyzidae).

A monoclonal antibody was prepared by the hybridoma technology. It reacted only with the protein of Liriomyza trifolii (Burgess) and not with that of Chromatomyia horticola Goureau or Liriomyza sativae Blanchard in indirect enzyme-linked immunosorbent assay. It was effective even after being diluted more than 8.192×10(6)-fold. The detection sensitivity of the antibody was 31.3 µg/ml under controlled conditions. Positive reaction was achieved with all laboratory-reared L. trifolii samples, including larvae, pupae, and adults. An indirect enzyme-linked immunosorbent assay system was successfully established to detect L. trifolii in the field. This antibody was successfully used to determine the L. trifolii collected in different locations, from different host plants, and in different seasons. More than 50% of leafminers collected on Brassica chinensis var chinensis, Apium graveolens (Miller) Persoon, Vigna unguiculata (L.) Walpers, Phaseolus vulgaris L., Lactuca sativa L., and Chrysanthemum coronarium (L.) Cassini ex Spach were L. trifolii, indicating that those six plant species might be the preference host plants of L. trifolii. Population of L. trifolii peaked in September, October, or November in Hangzhou, Zhejiang. These results suggest a great potential of using this McAb for precisely identifying L. trifolii and monitoring the population dynamics of L. trifolii in the field.

3'-UTR polymorphism (rs10434) in the VEGF gene is associated with B-CLL in a Chinese population.

We investigated the relationship between a VEGF genetic polymorphism and B cell chronic lymphocytic leukemia (B-CLL). A total of 102 patients with B-CLL and 124 healthy subjects were included in this study. All individuals were typed for the rs10434 in the vascular endothelial growth factor (VEGF) gene using the TaqMan technique. We found that the A allele and the AA genotype of rs10434 were more frequent in B-CLL patients than in control subjects (0.54 vs 0.34; 27 vs 13%; respectively). VEGF alleles and genotypes segregated similarly in patients at different disease stages according to Rai classification. These results suggest a possible association between the VEGF polymorphism and high-risk B-CLL.

Promotion of Dental Pulp Cell Migration and Pulp Repair by a Bioceramic Putty Involving FGFR-mediated Signaling Pathways.

Mineral trioxide aggregate is the currently recommended material of choice for clinical pulp repair despite several disadvantages, including handling inconvenience. Little is known about the signaling mechanisms involved in bioceramic-mediated dental pulp repair-particularly, dental pulp cell (DPC) migration. This study evaluated the effects of iRoot BP Plus, a novel ready-to-use nanoparticulate bioceramic putty, on DPC migration in vitro and pulp repair in vivo, focusing on possible involvement of fibroblast growth factor receptor (FGFR)-related signaling, including mitogen-activated protein kinase and Akt pathways. Treatment with iRoot BP Plus extracts enhanced horizontal and vertical migration of DPCs, which was comparable with the effects induced by mineral trioxide aggregate extracts. The DPCs exposed to iRoot BP Plus extracts demonstrated no evident apoptosis. Importantly, treatment with iRoot BP Plus extracts resulted in rapid activation of FGFR, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK) 1/2, c-Jun-N-terminal kinase (JNK), and Akt signaling in DPCs. Confocal immunofluorescence staining revealed that iRoot BP Plus stimulated focal adhesion formation and stress fiber assembly in DPCs, in addition to upregulating the expression of focal adhesion molecules, including p-focal adhesion kinase, p-paxillin, and vinculin. Moreover, activation of FGFR, ERK, JNK, and Akt were found to mediate the upregulated expression of focal adhesion molecules, stress fiber assembly, and enhanced DPC migration induced by iRoot BP Plus. Consistent with the in vitro results, we observed induction of homogeneous dentin bridge formation and expression of p-focal adhesion kinase, p-FGFR, p-ERK 1/2, p-JNK, and p-Akt near injury sites by iRoot BP Plus in an in vivo pulp repair model. These data demonstrate that iRoot BP Plus can promote DPC migration and pulp repair involving the FGFR-mediated ERK 1/2, JNK, and Akt pathways. These findings provide valuable insights into the signaling mechanisms underlying nanoparticulate bioceramic-mediated pulp repair.

Dosage assessment of valnemulin in pigs based on population pharmacokinetic and Monte Carlo simulation.

To estimate the valnemulin pharmacokinetic profile in a swine population and to assess a dosage regimen for increasing the likelihood of optimization. This study was, respectively, performed in 22 sows culled by p.o. administration and in 80 growing-finishing pigs by i.v. administration at a single dose of 10 mg/kg to develop a population pharmacokinetic model and Monte Carlo simulation. The relationships among the plasma concentration, dose, and time of valnemulin in pigs were illustrated as C(i,v) = X(0 )(8.4191 × 10(-4) × e(-0.2371t) + 1.2788 × 10(-5) × e(-0.0069t)) after i.v. and C(p.o) = X(0) (-8.4964 × 10(-4) × e(-0.5840t) + 8.4195 × e(-0.2371t) + 7.6869 × 10(-6) × e(-0.0069t)) after p.o. Monte Carlo simulation showed that T(>MIC) was more than 24 h when a single daily dosage at 13.5 mg/kg BW in pigs was administrated by p.o., and MIC was 0.031 mg/L. It was concluded that the current dosage regimen at 10-12 mg/kg BW led to valnemulin underexposure if the MIC was more than 0.031 mg/L and could increase the risk of treatment failure and/or drug resistance.

Genetic analysis of grain shape and weight after cutting rice husk.

Grain shape and weight are the most important components of rice yield and are controlled by quantitative trait loci (QTLs). In this study, a double-haploid population, derived from the cross of japonica CJ06 and indica TN1, was used to analyze QTLs for grain shape and weight under two conditions: normal growth with unbroken husk and removing partial husk after flowering. Correlation analysis revealed that these traits, except grain weight, had a connection between the two conditions. Twenty-nine QTLs for grain shape and weight were detected on chromosomes 1 to 3; 6; 8 to 10; and 12, with the likelihood of odds value ranging from 2.38 to 5.36, including 10 different intervals. Some intervals were specifically detected after removing partial husk. The results contribute to the understanding of the genetic basis of grain filling and growth regulation, and provide us some assistance for improving grain plumpness in rice breeding.

Pharmacokinetics and bioavailability of valnemulin in broiler chickens.

The objective of this study was to investigate the pharmacokinetics and bioavailability of valnemulin in broiler chickens after intravenous (i.v.), intramuscular (i.m.) and oral administrations of 10 mg/kg body weight (bw). Plasma samples were analyzed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Pharmacokinetic characterization was performed by non-compartmental analysis using WinNonlin program. After intravenous administration, distribution was wide with the volume of distribution based on terminal phase(V(z)) of 4.27 ± 0.99 L /kg. Mean valnemulin t(1/2ß)(h), Cl(ß)(L /h /kg), V(ss)(L /kg) and AUC((0-∞))(µg·h /mL) values were 2.85, 0.99, 2.72 and 10.34, respectively. After intramuscular administration, valnemulin was rapidly absorbed with a C(max) of 2.2 µg/mL achieved at 0.43 h (t(max)), and the absolute bioavailability (F) was 88.81%; and for the oral route the same parameters were 0.66 ± 0.15 µg/mL, 1.54 ± 0.27 h and 74.42%. A multiple-peak phenomenon was present after oral administration. The plasma profile of valnemulin exhibited a secondary peak during 2-6 h and a tertiary peak at 32 h. The favorable PK behavior, such as the wide distribution, slow elimination and acceptable bioavailability indicated that it is likely to be effective in chickens.

Dexamethasone alters the expression of genes related to the growth of skeletal muscle in chickens (Gallus gallus domesticus).

Glucocorticoids (GCs) are involved in the muscle wasting caused by trauma, inactivity, and stress. In the present study, three experiments were conducted to investigate the effect of GCs on the expression of genes related to muscle development in chickens. Broilers at 7 or 35 days of age were subjected to dexamethasone (DEX) treatment (2 mg/kg body mass (BM)) for 3 or 7 days. The expression levels of genes such as IGF1, IGF1 receptor, MSTN, WW domain containing E3 ubiquitin (UB) protein ligase 1, myogenic determining factor, and myogenic factor 5 were measured. The results showed that BM gain was significantly suppressed by DEX treatment. The plasma level of insulin was increased (P<0.05) by DEX treatment at feeding, whereas IGF1 was decreased (P<0.05). The expression of genes in the IGF1, myostatin, and UB-proteasome (UBP) pathways were altered by DEX treatment in age- and exposure time-related ways. These results suggest that GCs suppress IGF1 and upregulate myostatin and/or activated myostatin and the UBP pathway, which might be the source of the effect of GCs on muscle development.

A physiologically based pharmacokinetic model for valnemulin in rats and extrapolation to pigs.

A flow-limited, physiologically based pharmacokinetic (PBPK) model for predicting the plasma and tissue concentrations of valnemulin after a single oral administration to rats was developed, and then the data were extrapolated to pigs so as to predict withdrawal interval in edible tissues. Blood/tissue pharmacokinetic data and blood/tissue partition coefficients for valnemulin in rats and pigs were collected experimentally. Absorption, distribution and elimination of the drug were characterized by a set of mass-balance equations. Model simulations were achieved using a commercially available software program. The rat PBPK model better predicted plasma and tissue concentrations. The correlation coefficients of the predicted and experimentally determined values for plasma, liver, kidney, lung and muscle were 0.96, 0.94, 0.96, 0.91 and 0.91, respectively. The rat model parameters were extrapolated to pigs to estimate valnemulin residue withdrawal interval in edible tissues. Correlation (R(2) ) between predicted and observed liver, kidney and muscle were 0.95, 0.97 and 0.99, respectively. Based on liver tissue residue profiles, the pig model estimated a withdrawal interval of 10 h under a multiple oral dosing schedule (5.0 mg/kg, twice daily for 7.5 days). PBPK models, such as this one, provide evidence of the usefulness in interspecies PK data extrapolation over a range of dosing scenarios and can be used to predict withdrawal interval in pigs.

Pharmacological studies on the sedative-hypnotic effect of Semen Ziziphi spinosae (Suanzaoren) and Radix et Rhizoma Salviae miltiorrhizae (Danshen) extracts and the synergistic effect of their combinations.

Semen Ziziphi spinosae (Suanzaoren in China) and Radix et Rhizoma Salviae miltiorrhizae (Danshen in China) are conventional herbal drugs in traditional Chinese medicine and have been used widely for the treatment of insomnia. In the present study, the sedative-hypnotic activity of the active fractions extracted from Suanzaoren and Danshen were studied using the method of pentobarbital-induced sleep in the mouse model. Qualitative analysis of the standardized extracts was carried out by HPLC-DAD. The results showed that the water extract of Suanzaoren (SWE) (400 and 800 mg/kg body wt.) and the ether extract of Danshen (DTT) (300 and 600 mg/kg body wt.) can shorten sleep latency significantly, increase sleeping time and prolong movement convalescence time induced by sodium pentobarbital (55 mg/kg body wt.) administration in mice. Furthermore, the combination of SWE and DTT showed significant synergistic effect (p<0.05) in decreasing sleep latency and increasing sleeping time, but not in prolonging the movement convalescence time, which might be helpful for energy recovery in the treatment of insomnia. The results suggest that SWE, DTT, and the combination of SWE and DTT possess significant sedative-hypnotic activity, which supports the popular use of Suanzaoren and Danshen for treatment of insomnia and provide the basis for new drug discovery. Furthermore, the results demonstrate that the combination of SWE and DTT may be preferable for the treatment of insomnia.

Association of haemoglobin level with morbidity and mortality of patients with locally advanced oesophageal carcinoma undergoing radiotherapy--a secondary analysis of three consecutive clinical phase III trials.

AIMS: To investigate the strength of association between anaemia and overall survival, locoregional control, and late radiation complications in patients with locally advanced oesophageal carcinoma undergoing radiotherapy with or without chemotherapy and hyperthermia. MATERIALS AND METHODS: Between March 1996 and December 2002, 303 patients with locally advanced squamous cell carcinoma of oesophagus enrolled in three consecutive prospective phase III trials conducted in our department were included in this study. These patients received one of the following four irradiation schedules: late course accelerated hyperfractionated (LCAF) radiotherapy alone, LCAF combined with concurrent chemotherapy, LCAF combined with hyperthermia, and continuous accelerated hyperfractionated (CAHF) radiotherapy according to each protocol. According to the haemoglobin levels measured before radiotherapy, patients were stratified to normal haemoglobin group (> or = 12.0 g/dl for men, or > or = 11.0 g/dl for women) or anaemic group (< 12.0 g/dl for men, or < 11.0 g/dl for women). Overall survival, locoregional control rate and late irradiation toxicity were estimated by Kaplan-Meier method. RESULTS: Of 303 eligible patients, 243 patients (80.2%) had normal haemoglobin level and 60 patients (19.8%) were anaemic. The 5-year overall survival was 39% in patients with normal haemoglobin level, whereas, 22%, with anaemia patients (P = 0.001). The 5-year locoregional control rate at 5 years was 68% in patients with normal haemoglobin, versus 62%, with anaemia patients (P = 0.050). The 5-year rate of radiation toxicity of grade 3 or greater was 29% in patients with normal haemoglobin level, but it was 8%, with anaemic patients (P = 0.033). From multivariate analyses, T stage, location of tumour and haemoglobin level were found to be independent predictors for survival. T stage, gender and haemoglobin level were independent predictors for locoregional control. It was also detected that age and haemoglobin level played as independent predictors for development of radiation toxicity. CONCLUSIONS: For patients with locally advanced oesophageal carcinoma undergone irradiation, anaemia associated a statistically significant reduction in survival and locoregional control rates, but also decreased radiation toxicity rates. Therefore, haemoglobin level should be considered as a stratification variable in prospective clinical trials.