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Scientific irrigation is of great significance to plant seed production. With two excellent native plant species in desert steppe,科学灌溉对植物种子生产具有重要意义。本研究以荒漠草原优良乡土植物沙芦草和牛枝子为对象,以充分灌溉为对照,探究不同生育时期亏缺灌溉对两种牧草种子生产和水分利用效率的影响。结果表明: 与对照相比,亏缺灌溉下两种植物土壤含水率下降,其中沙芦草土壤含水率下降主要发生在0～60 cm土层,牛枝子土壤水分下降未出现明显的分层现象。亏缺灌溉下沙芦草种子产量各构成因子差异均显著,开花期亏缺灌溉种子产量最高;牛枝子仅生殖枝数、小花数和荚果数差异显著,种子产量各处理差异不显著。相关分析显示,沙芦草种子产量与生殖枝数(

Schizophrenia is a major mental disorder with a wide range of psychiatric symptoms. This study explored the structure of psychiatric symptoms of schizophrenia using network analysis in a large representative Asian sample based on a survey of clinical features and treatment used in schizophrenia patients across 15 countries/territories in Asia.Data on the demographic characteristics and psychiatric symptoms in schizophrenia patients were extracted from the dataset of the fourth Research on Asia Psychotropic Prescription for Antipsychotics (REAP-AP) project. The presence of the following psychiatric symptoms including delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms, social/occupational dysfunction, verbal aggression, physical aggression, and affective symptoms were analyzed.A total of 3681 patients were included. The network analysis revealed that verbal aggression, hallucinations, and social/occupational dysfunction were the most central symptoms, while the connections between social/occupational dysfunction and verbal aggression, and between hallucinations and disorganized speech were the two strongest edges. There were significant gender differences in the network structure based on the network structure invariance test (M=0.74, P = 0.03) and invariant edge strength test. The positive correlation between verbal aggression and hallucinations was significantly stronger in the female network than that in the male network (P = 0.03), while a negative correlation between affective symptoms and negative symptoms was found in the female, but not the male network (P 0.01).Central symptoms including verbal aggression, hallucinations, and socio-occupational dysfunction should be addressed in developing targeted treatment strategy for schizophrenia patients.

Pyoderma gangrenosum is an uncommon ulcerative cutaneous lesion manifesting as rapidly progressing single or multiple skin ulcers. Permanent stoma in inflammatory bowel disease patients remains an independent risk of pyoderma gangrenosum. In the current report, we describe a case of pyoderma gangrenosum in a post-colostomy ulcerative colitis patient with chronic hepatitis B. Pyoderma gangrenosum began seemingly as peristomal dermatitis that rapidly developed into painful ulcerations with subsequent appearance of sterile pustules and ulcerations in the left lower leg. The patient significantly improved after active management with prednisolone, antiviral therapy with entecavir, and wound dressings. Our case suggests that physicians and surgeons should have a high index of suspicion of pyoderma gangrenosum in post-colostomy ulcerative colitis patients who develop peristomal dermatitis.

Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves disease (GD) by promoting autoreactive B-cell activation. Objective Evaluate efficacy and safety of a human, blocking, nondepleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD. Design Open-label, phase II proof-of-concept study. Setting Multicenter. Patients Fifteen with GD. Intervention Patients received 5 doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in 7 of 15 (47%) patients. Free and total triiodothyronine and thyroxine normalized in 7 patients who did not receive any rescue medication with antithyroid drugs (ATD), and 2/15 (13.3%) showed normal thyrotropin. Six (40%) patients required ATD. Four of 7 responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L vs 4.0 IU/L, 66% reduction; P < 0.001) and TSH-R-Ab levels normalized in 4 (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P < 0.001). Twelve (80.0%) patients reported at least 1 adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. Conclusion Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of iscalimab should be further tested.

Background: We conducted this meta-analysis to compare the efficacy and safety of imiquimod with other treatments in patients with basal cell carcinoma (BCC).Methods: A comprehensive literature search was performed in the database of PubMed, Embase, and Web of Science, focusing on studies that evaluated the efficacy and safety profile of BCC patients who were treated with imiquimod. The main outcome measures included histological/composite clearance rate, success rate, complete response rate, tumor free survival, and adverse events. Results were expressed as risk ratio (RR) with 95% confidence intervals (CIs). Pooled estimates were calculated using a fixed-effects or random-effects model according to the heterogeneity among studies.Results: A total of 13 studies involving 4256 patients were included in this meta-analysis. Imiquimod was associated with significantly higher histological clearance rate and composite clearance rate. Moreover, imiquimod also significantly increased complete response rate but had no effect in the success rate and probability of tumor free survival, as compared with other treatments. There were more patients with imiquimod developed adverse events than those with other treatments.Conclusion: The present meta-analysis indicated the effects of imiquimod in improving the histological/composite clearance rates as compared with other treatments.

Coated zinc oxide nanoparticles (ZnO-NPs) are more commonly applied in commercial products but current risk assessments mostly focus on bare ZnO-NPs. To investigate the impacts of surface coatings, this study examined acute and chronic toxicities of six chemicals, including bare ZnO-NPs, ZnO-NPs with three silane coatings of different hydrophobicity, zinc oxide bulk particles (ZnO-BKs), and zinc ions (Zn-IONs), toward a marine copepod

Absorption, metabolism, and excretion (AME) of licogliflozin, a sodium-glucose co-transporters (SGLTs) 1 and 2 inhibitor, were studied in male rats, dogs, and healthy male volunteers and reported.Oral absorption of licogliflozin was rapid (tmax < 1 h) with absorption estimated at 87%, 100% and 77% in rats, dogs and humans, respectively.Excretion of licogliflozin-related radioactivity was rapid and nearly complete following oral administration with total radioactivity recovery ranging from 73% in dogs, 92.5% in humans, to 100% in rats. Dose-related radioactivity was excreted in both urine and faeces with urinary excretion playing a slightly more important role in humans (∼56%) than in animal species (∼19–41%).Elimination of licogliflozin was predominantly via metabolism with the majority of the radioactivity dose (∼54–74%) excreted as metabolites across species.The principal biotransformation pathways involved direct glucuronidation and oxidation across all species. In humans, direct glucuronidation to M17 and M27 was the major pathway observed, accounting for ∼38% of the dose in excreta while oxidative metabolism also contributed to >29% of the dose in excreta. Oxidative pathways were predominant in animal species. Absorption, metabolism, and excretion (AME) of licogliflozin, a sodium-glucose co-transporters (SGLTs) 1 and 2 inhibitor, were studied in male rats, dogs, and healthy male volunteers and reported. Oral absorption of licogliflozin was rapid (tmax < 1 h) with absorption estimated at 87%, 100% and 77% in rats, dogs and humans, respectively. Excretion of licogliflozin-related radioactivity was rapid and nearly complete following oral administration with total radioactivity recovery ranging from 73% in dogs, 92.5% in humans, to 100% in rats. Dose-related radioactivity was excreted in both urine and faeces with urinary excretion playing a slightly more important role in humans (∼56%) than in animal species (∼19–41%). Elimination of licogliflozin was predominantly via metabolism with the majority of the radioactivity dose (∼54–74%) excreted as metabolites across species. The principal biotransformation pathways involved direct glucuronidation and oxidation across all species. In humans, direct glucuronidation to M17 and M27 was the major pathway observed, accounting for ∼38% of the dose in excreta while oxidative metabolism also contributed to >29% of the dose in excreta. Oxidative pathways were predominant in animal species.

Background Omalizumab has been proposed as a possible effective treatment of chronic spontaneous urticaria (CSU). Study question We aimed to access the efficacy and safety of omalizumab in the treatment of CSU based on qualified, randomized controlled trials (RCTs). Data sources PubMed, the Cochrane library, and Embase databases. Study design Computerized search by index words was performed to identify qualified RCTs, and relevant literature sources were also searched. Result Nine RCTs were included in the meta-analysis with 1612 patients in the omalizumab group and 1251 patients in the placebo group. Compared with the placebo group, omalizumab significantly decreased the weekly itch score after therapy [Weighted Mean Difference (WMD), -3.94; 95% confidence interval (CI), -4.64 to -3.24], the weekly hive score (WMD, -5.27; 95% CI, -6.17 to -4.38), the dermatology life quality index (DLQI; WMD, -3.58; 95% CI, -4.66 to -2.50), and the urticaria activity score over 7 days (UAS7; WMD, -9.51; 95% CI, -10.94 to -8.08). There was no significant difference in the incidence of adverse events (AE) [relative risk (RR), 1.01; 95% CI, 0.91-1.12], serious AE (RR, 0.85; 95% CI, 0.57-1.27), and severe AE (RR, 0.83; 95% CI, 0.60-1.14) between the 2 groups. Compared with the placebo, omalizumab significantly decreased the weekly itch score and weekly hive score after therapy in patients receiving 75, 150, and 300 mg omalizumab, respectively. DLQI was significantly reduced in patients receiving 150 and 300 mg of omalizumab, respectively. In all the subgroup of UAS7, omalizumab significantly decreased the score compared with the placebo. Only patients receiving 600-mg omalizumab had a significantly higher AE incidence versus placebo. There was no significant difference in serious and severe AE between the 2 groups. Conclusion Omalizumab caused a significantly greater reduction in weekly itch score, weekly hive score, DLQI, and UAS7 in CSU patients than the placebo. However, high-quality, multicenter RCTs with a larger sample size are needed to confirm the safety of omalizumab, and whether AEs are caused by omalizumab or other factors.

Acer davidii Franch. and A. morrisonense Hayata are two important forest tree species (Aceraceae) endemic to mainland China and the Taiwan area, respectively. To investigate population structure and interspecific differentiation between them, we characterized a set of novel microsatellite markers using Illumina sequencing technology. The cross-species amplification analysis showed that 11 out of 21 polymorphic SSR primers of A. davidii also exhibited polymorphisms in A. morrisonense. At the species level, A. davidii has a slightly higher genetic diversity (mean observed heterozygosity, HO = 0.180) than A. morrisonense (HO = 0.119). AMOVA showed that most of the variations in A. davidii occurred among individuals within populations and within individuals. Bayesian clustering analyses demonstrated that the two maple species formed two clear genetic lineages. PCoA showed that A. davidii and A. morrisonense were significantly divided into two genetic groups. In addition, asymmetrical weaker gene flow was detected among the two forest tree species. These results suggest that the long term geographic isolation between the mainland and Taiwan may have resulted in a high level of genetic differentiation between these two important maple species.

Treatment with licogliflozin, a dual sodium-glucose co-transporter (SGLT)1/2-inhibitor, is associated with increased stool frequency and loose stools, attributed to SGLT1 inhibition. To investigate the effect of carbohydrate content and supplements on licogliflozin-induced stools, a randomized, open-label, two-part (N = 24/part), three-period crossover study was carried out in overweight or obese adults. Significantly higher (P < 0.01) change from baseline in 3-day total number of bowel movements was observed following 3 days of licogliflozin treatment (50 mg q.d.) together with a 50% carbohydrate meal compared with a 25% and 0% carbohydrate meal. The number of stools with Bristol Stool Chart score of 6 or 7 was also significantly lower following a 0% carbohydrate meal. Supplementation with psyllium 6 g or calcium carbonate 1 g had no effect on stool changes following treatment. Licogliflozin was generally safe and well-tolerated. Loose stool associated with licogliflozin treatment and ingestion of meals can be managed by reducing the carbohydrate content of meals taken with licogliflozin.

Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 µg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases.

Objective: Graves’ disease (GD) is an autoimmune disorder characterized by thyrotropin receptor autoantibody (TSHR-Ab)-mediated pathology, leading to hyperthyroidism. To date there is no pharmacotherapy that addresses the underlying pathogenesis. The CD40-CD154 (CD40L) co-stimulatory pathway plays an important role in the pathogenesis of GD by promoting auto-reactive B cell activation and intrathyroidal ectopic lymphoid structure formation and function. Iscalimab (CFZ533) is a fully human, blocking and non-depleting anti-CD40 monoclonal antibody. The purpose of this study was to investigate the efficacy and safety of Iscalimab in patients with Graves’ hyperthyroidism. Methods: In total, fifteen patients with Graves’ hyperthyroidism were enrolled in an open label Phase I proof-of concept study and all completed the trial. Each patient received five doses of Iscalimab at 10 mg/kg IV over 12 weeks. We assessed the effects of Iscalimab on thyroid-related hormones (baseline TSH, free and total T3/T4) and autoantibodies (TSHR-Ab) over 36 weeks following the first dose of Iscalimab. Safety, pharmacokinetics, soluble CD40 levels in plasma, free CD40 on whole blood CD19-positive B cells, and CXCL13 were also assessed. Results: Based on the CD40 occupancy and plasma levels of soluble CD40, the intervention resulted in full CD40 engagement for up to 20 weeks (12-week treatment + 8 week follow up). A clinical response and biochemical euthyroidism was observed in seven out of 15 (46.7%) by Day 211. Free T3/T4 normalized in seven (46.7%) patients who did not received any rescue medication with anti-thyroid drugs. Two further patients (13.3%) did not normalize but did not require rescue medication. In contrast, six (40%) patients required rescue medication with anti-thyroid drugs by Day 141. No patients achieved normalization of TSH by Day 85, however, two out of 15 patients (13.3%) showed normal TSH by Day 169. The levels of free thyroid hormones and TSHR-Ab levels declined over time up to Day 211. The mean levels of TSHR-Ab declined from 15.3 IU/L (baseline) to 9.4 IU/L at Day 85 (35% reduction, P

Objective To assess the bioequivalence of vildagliptin/metformin fixeddose combination (FDC) tablets (50/250 mg and 50/500 mg) to free combinations of vildagliptin and metformin and the effect of food on the pharmacokinetics (PK) of vildagliptin and metformin following administration of 50/500 mg FDC tablets. Methods Two openlabel, randomized, single-center, singledose, 2-period crossover studies were conducted in Japanese healthy male volunteers. Participants were administered vildagliptin/ metformin FDC tablets (study I: 50/250 mg, study II: 50/500 mg) or their free combinations under fasted condition. Food effect (standard Japanese breakfast: fat, 20 - 30% with ~ 600 kcal in total) was assessed during an additional period in study II (50/500 mg). PK parameters (AUC, C(max), t(max), t(1/2)) were calculated for vildagliptin and metformin. Results In both studies, vildagliptin/metformin FDC tablets were bioequivalent to their respective free combinations. Administration of FDC tablets after meals had no effect on vildagliptin PK parameters. The rate of absorption of metformin decreased when administered under fed condition, as reflected by a prolonged t(max) (3 hours in fasted state vs. 4 hours in fed state) and decrease in C(max) by 26%, however, the extent of absorption (AUC(last)) was similar to that in the fasted state. Conclusions Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the C(max) of metformin by 26%, while AUC(last) was unchanged, consistent with previous reports. No food effect was observed on the C(max) or AUC(last) of vildagliptin. Thus, food had no clinically relevant effects on the PK of metformin or vildagliptin.

Historical geological and climatic events are the most important drivers of population expansions/contractions, range shifts, and interspecific divergence in plants. However, the species divergence and spatiotemporal population dynamics of alpine cold-tolerant herbal plants in the high-altitude Qinghai-Tibetan Plateau (QTP) and adjacent areas remain poorly understood. In this study, we investigated population evolutionary history of four endangered Notopterygium herb species in the QTP and adjacent regions. We sequenced 10 nuclear loci, 2 mitochondrial DNA regions, and 4 chloroplast DNA regions in a total of 72 natural populations from the 4 species, and tested the hypothesis that the population history of these alpine herbs was markedly affected by the Miocene–Pliocene QTP uplifts and Quaternary climatic oscillations. We found that the four Notopterygium species had generally low levels of nucleotide variability within populations. Molecular dating and isolation-with-migration analyses suggested that Notopterygium species diverged ~1.74–7.82 million years ago and their differentiation was significantly associated with recent uplifts of the eastern margin of the QTP. In addition, ecological niche modeling and population history analysis showed that N. incisum and N. franchetii underwent considerable demographic expansions during the last glacial period of the Pleistocene, whereas a demographic contraction and a expansion occurred for N. forrestii and N. oviforme during the antepenultimate interglacial period and penultimate glacial period, respectively. These findings highlight the importance of geological and climatic changes during the Miocene–Pliocene and Pleistocene as causes of species divergence and changes in population structure within cold-tolerant herbs in the QTP biodiversity hotspot., This work was co-supported by the National Natural Science Foundation of China (31470400), the Shaanxi Provincial Key Laboratory Project of Department of Education (grant number 17JS135), and the Open Foundation of Key Laboratory of Resource Biology and Biotechnology in Western China (Ministry of Education) (Number ZSK2017007).

BACKGROUND There is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS Patients with obesity (BMI, 35-50 kg/m2 ) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 - 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE24 ) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY3-36 , and GIP), insulin and glucagon. RESULTS Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P

Periploca forrestii Schltr. (P. forrestii) is a species used in Traditional Chinese Medicine (TCM) known as &ldquo, Miao medicine&rdquo, and has a long history of use in the treatment of rheumatism, rheumatoid arthritis (RA), and joint pain. The present study aimed to evaluate the anti-arthritis effects of the cardenolide-rich and caffeoylquinic acid-rich fractions (CDLFs and CQAFs) of P. forrestii in collagen-induced arthritic (CIA) rats, and defined the mechanisms of therapeutic action in MH7A cells treated with TNF-&alpha, Serum rheumatoid factor (RF), TNF-&alpha, IL-6, IL-1&beta, PGE2, NO, SOD, and MDA were determined by ELISA or other commercially assay kits. Histopathological changes in ankle joint tissues were examined. The mRNA expressions of IL-1&beta, IL-6, COX-2, and iNOS in MH7A cells were measured by qRT-PCR assays. In addition, the expressions of iNOS, COX-2, and p65 proteins, and the phosphorylation of I&kappa, B&alpha, p38, ERK1/2, and JNK proteins in MH7A cells were analyzed by Western blot. The results showed that CDLF and CQAF could suppress the paw swelling in CIA rats at different doses (125 mg/kg, 250 mg/kg, and 500 mg/kg). Histopathological examination suggests that the CDLF and CQAF significantly relieved the damage of the structure of the ankle joint in CIA rats. In addition, serum RF, TNF-&alpha, PGE2, NO, and MDA were decreased, along with increased activity of serum SOD. Furthermore, CDLF and CQAF downregulated the expressions of IL-1&beta, IL-6, COX-2, iNOS, and p65, and inhibited the phosphorylation of I&kappa, p38, ERK1/2, and JNK in MH7A cells treated with TNF-&alpha, These findings demonstrated that both CDLF and CQAF exhibited anti-arthritic activity, which might be associated with their inhibitory effects on the NF-&kappa, B and MAPK signaling pathways.

Background: LIK066 is a potent dual inhibitor of SGLT1/2 (IC50: 20.6 and 0.58 nM for SGLT1 and SGLT2). We studied mechanistic effects of dual SGLT1/2 inhibition of SGLT1 in the gut and SGLT1/2 in the kidneys. Methods: Effects of LIK066 on weight, glucose and a variety of incretin hormones (GLP-1, PYY, GIP, glucagon, insulin) were investigated in: 1) a single dose cross-over study in T2DM, 2) a 14 day randomized, double-masked study in T2DM, 3) a 12-week randomized, double-masked, placebo-controlled study in obese subjects with normoglycemia (NG) or dysglycemia (DG; HbA1c: ≥5.7% and Results: LIK066 (2.5, 30, 300 mg single dose) significantly reduced glucose excursion and insulin secretion (p1.5-fold; p50%; p Conclusions: LIK066 treatment leads to favorable changes in a variety of metabolic hormones (increased GLP-1, PYY and glucagon, reduced GIP, glucose and insulin), all contributing to WL effects of LIK066. The dual inhibition of SGLT1/2 in both the gut and kidneys is an attractive strategy for obesity or diabetes treatment. Disclosure Y. He: None. W.G. Haynes: Employee; Self; AstraZeneca. C.D. Meyers: Employee; Self; Janssen Research & Development. A. Amer: Employee; Self; Novartis Pharmaceuticals Corporation. Stock/Shareholder; Self; Novartis AG. Y. Zhang: Employee; Self; Novartis Pharmaceuticals Corporation. P.C. Mahling: None. A.E. Mendonza: None. S. Ma: None. W. Chutkow: Employee; Self; Novartis Pharmaceuticals Corporation. E.S. Bachman: None.

The whole chloroplast genome (cp DNA) sequence of Acer davidii Franch has been characterized from Illumina pair-end sequencing. The complete cpDNA was 157,044 bp in length, containing a large single copy region (LSC) of 85,410 bp and a small single copy region (SSC) of 18,112 bp, which were separated by a pair of 26,761 bp inverted repeat regions (IRs). The cpDNA contained 134 genes, including 86 protein-coding genes (78 PCG species), forty tRNA genes (31 tRNA species) and eight ribosomal RNA genes (four rRNA species). The most of gene species occur as a single copy, while 21 gene species occur in double copies. The overall AT content of A. davidii cpDNA is 62.1 %, while the corresponding values of the LSC, SSC and IR regions are 63.9, 67.7 and 57.3 %, respectively. The phylogenetic analysis suggested that the sampled Acer species formed a monophyletic clade, and the cpDNA of A. davidii is closely related to that of congeneric A. morrisonense.

Species identification and discrimination is the basis of biodiversity research. In general, it is considered that numerous nucleotide variations (e.g., whole chloroplast genomes) can identify species with higher resolution than a few loci, e.g., partial chloroplast or nuclear gene fragments. In this study, we tested this hypothesis by sampling population genetics samples of the endangered herb genus Notopterygium. We sequenced the complete plastomes, five nuclear gene regions, three chloroplast DNA fragments, and a nuclear internal transcribed spacer (nrITS) region for 18 populations sampled throughout most of the geographic ranges of all six Notopterygium species. Species identification analysis showed that four DNA barcodes (matK, rbcL, trnS-trnG, and nrITS) and/or combinations of these markers achieved Notopterygium species discrimination at higher resolution than the general plastomes and nuclear gene sequences. In particular, nrITS had the highest discriminatory power among all of the individual markers. Molecular data sets and morphological evidence indicated that all six Notopterygium species could be reclassified unambiguously to four putative species clades. N. oviforme and N. franchetii had the closest relationship. Molecular dating showed that the origin and divergence of Notopterygium species was significantly associated with geological and climatic fluctuations during the middle of the Pliocene. In conclusion, our results suggest that a few nucleotide variations can achieve species discrimination with higher resolution than numerous plastomes and general nuclear gene fragments when discerning related Notopterygium species.

PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China’s registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2–4, the incidence of febrile neutropenia, and the safety. A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3–4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan–Meier analysis (n = 49, P = 0.153). PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

In the present study, the SDA (specific denitrification activity) and SMA (specific methanogenic activity) in Start up of mixotrophic anammox reactor was optimized by applying the response surface method (RSM). The purpose of this work was to find the optimal combination of C/N ratio, influent ammonium (NH4+-N) and volatile suspended solid (VSS) with respect to minmum the SDA and SMA. Based on the RSM results, the quadratic model developed for the responses indicated that optimal conditions were C/N ratio of 0.5, influent NH4+-N content of 200mg L-1, and VSS content of 59.31g L-1. Under this conditions, the SDA and SMA were minimize and found to be 0.05 mmol N2 (g VSS d)-1, 0.017 mmol N2 (g VSS d)-1, respectively

To compare the effect of early tracheotomy (ET) and late tracheotomy (LT) on ventilator-associated pneumonia (VAP) incidence and short-term mortality in critically ill patients who received mechanical ventilation.We searched databases of PubMed, Embase, and others for randomized controlled trials (RCTs) that compared ET (≤ 8 days after admission to the intensive care unit, initiation of translaryngeal intubation, or initiation of mechanical ventilation) with LT (≥ 6 days) in critically ill patients.The overall odds ratio (OR) was estimated by traditional meta-analysis. In addition, cumulative meta-analysis was conducted by adding 1 study at a time in the order of year of publication.A total of 11 RCTs involving 1436 patients (708 in the ET group and 728 in the LT group) were included in this analysis. Early tracheotomy could significantly reduce the short-term mortality (OR = 0.74; 95% confidence interval [CI] [0.58, 0.95]) but did not reduce the VAP incidence (OR = 0.70; 95% CI [0.47, 1.04]). The cumulative meta-analysis showed that evidence of the benefit of ET on VAP incidence was unstable over time. In contrast, the difference in short-term mortality was stable from the first appearance during the cumulative meta-analysis.Early tracheotomy could improve short-term mortality but did not alter VAP incidence. Many factors may be responsible for the unstable results during cumulative meta-analysis, and further study is still needed to explore the optimal timing of tracheotomy.

In this paper, twenty-two compounds including twenty-one flavonoids ( 1 – 21 ) and one alkaloid ( 22 ) were isolated from Panzeria alaschanica , in which seventeen flavonoids ( 1 – 2 , 5 – 11 , 13 – 20 ) were isolated from P. alaschanica and four flavonoid p -coumaroylglucosides ( 15 – 18 ) from the genus Panzeria for the first time. The occurrence of flavonoid p -coumaroylglucosides and alkaloids might be employed as the common characteristic constituents of the genera Panzeria , Leonurus , Lagochilus , Lagopsis and Marrubium .

Reactive oxygen species (ROS) is a normal metabolic product of cellular respiration, but too much ROS can induce cell apoptosis. Here, we used N-acetylcysteine (NAC) to inhibit ROS activity to explore the effects of NAC on silica-induced pulmonary fibrosis in rats and provide evidence for study on the mechanism of silicosis. 24 adult male Sprague-Dawley rats weighing 180-220 g were randomly divided into three groups with eight rats in each group. Silicosis model group and NAC group were adopted non-tracheal exposure method of disposable intrapulmonary injection of 50 g/L, silica suspension 1 mL to establish animal silicosis model, NAC group treated with 600 mg/kg NAC by gavage from the right day of modeling, all animals were sacrificed after 28 days. The level of ROS contents and mitochondrial transmembrane potential changes of AM, the mRNA expression level of type I and type III procollagen, cytochrome C, cysteinyl aspartate specific protease-9 and caspase-3 were detected. The severity of pathological changes and pulmonary fibrosis were observed by pathologic specimens. It was showed that ROS contents and MTP changes were lower in the NAC group compared with the silicosis model group, other indexes were lower in the NAC group than the model group, but higher than those of the control group, the degree of lung fibrotic lesions observed from the pathological slices showed the same trend. These data indicated that NAC can reduce ROS content of AM in silica exposure rats, the mitochondrial apoptosis pathway can also be inhibited, the severity of pulmonary fibrosis alleviated as a result.

OBJECTIVE The kidney plays a key role in both the metabolism and excretion of vildagliptin. This study was designed to investigate the effects of varying degrees of renal impairment (RI) on the pharmacokinetics of vildagliptin. METHODS A total of 96 subjects were enrolled, and each subject received vildagliptin 50 mg dosed orally once daily for 14 days. Vildagliptin and metabolite concentrations in plasma and urine were measured on Days 1 and 14. RESULTS Compared to age-, gender-, BMI-matched subjects with normal renal function, the mean AUC of vildagliptin after 14 days in patients with mild, moderate, and severe RI increased by 40%, 71%, and 100%, respectively, and the Cmax of vildagliptin showed similar and minimal increases of 37%, 32% and 36%, respectively. CONCLUSIONS These pharmacokinetics results suggest that 50 mg once daily is an appropriate dose and recommended for patients with moderate and severe renal impairment.

Public Administration (PA) as a field of study in China has made tremendous strides over the last three decades. This paper provides an overview of PA research in China from a sample of 2,877 articles published in six top PA journals in mainland China and Taiwan between 1998 and 2008. Our analysis based on these journal publications reveals several critical shortcomings of PA research in China in research reporting, approaches, and methodologies, pointing to a long journey ahead before the full potential of such research can be unleashed. Our comparison of journal publications between mainland China and Taiwan suggests that scholars in Taiwan have made great strides in improving quality of research in a short period of time, and that such experience could provide their colleagues across the Taiwan Strait with valuable insights into the future direction of the field.

This study compared the demographics, clinical characteristics, and antidepressant prescription patterns between Asian patients aged 50 years and older attending psychiatric hospitals and those attending general hospitals.In total, 955 patients (604 in general hospitals, 351 in psychiatric hospitals) aged 50 years or older treated with antidepressants in 10 Asian countries and territories were examined. Patients' demographics, clinical features, and prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure.Binary logistic regression revealed that high income and diagnosis of schizophrenia were independently associated with psychiatric hospital treatment, whereas outpatient care, diagnosis of anxiety disorders, and multiple major medical conditions were independently associated with general hospital treatment. In addition, tetracyclic and noradrenergic and specific serotonergic antidepressants were more likely to be prescribed in general hospitals.Older adults treated with antidepressants showed different demographic and clinical features between general hospitals and psychiatric hospitals in Asia.

Combined with sewage disposal characteristics and content networking technology, Constructing the relatively flexible structure, the price is relatively cheap,reliable performance of sewage treatment monitoring system. Improve the sewage disposal automation and informationization level and the ability of the key sources of pollution monitoring and environmental incident coping,The environmental protection,energy saving and emission reduction is of great significance.

SummaryObjective To compare the clinical efficacy and safety of combining flumetasone ointment with 308-nm excimer laser therapy vs. 308-nm excimer laser monotherapy for the treatment of psoriasis vulgaris. Method Forty patients with psoriasis vulgaris were recruited; 20 were treated with flumetasone ointment plus 308-nm excimer laser therapy, and the other 20 received only excimer laser monotherapy. The flumetasone ointment was applied topically twice a day, and laser treatments were scheduled twice weekly for a total of 10 treatments. Clinical efficacy was evaluated in a blinded manner by two independent physicians using photographs taken before and after treatment. Results Of the 40 patients who received and completed the entire course of therapy, the psoriasis area and severity index score was improved by 82.51 ± 11.24% and 72.01 ± 20.94% in the combination group and laser group, respectively (P > 0.05), and the average cumulative dose was 5.06 ± 2.20 j/cm2 in the combination group and 7.75 ± 2.25 j/cm2 in the laser-only group, respectively (P

Objective To assess the effects of meal timing on the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin in Japanese patients with Type 2 diabetes. Methods In this open-label, single-center crossover study, 12 Japanese patients with Type 2 diabetes were randomized to twice-daily vildagliptin 50 mg, administered 30 min before or immediately before breakfast and dinner for 7 days. After a 7-day washout period, patients received the other regimen. Blood samples were collected for the determination of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1) and glucose. Results Vildagliptin absorption appeared slower when administered 30 min before rather than immediately before meals (tmax absolute range: 1.00 - 2.00 h vs. 0.33 - 1.58 h). Vildagliptin Cmax and AUC0-8 h were essentially the same irrespective of meal timing (geometric mean ratio: Cmax 1.08 (90% CI; 0.92 - 1.26); AUC0-8 h 0.97 (90% CI; 0.91 - 1.05)). Meal timing did not affect pharmacodynamics; complete DPP-4 inhibition (> 90%) was sustained for 8 h post-dose, and plasma active glucagon-like peptide-1 levels increased 2 - 3-fold from baseline. Fasting plasma glucose (FPG) and postprandial plasma glucose (PPPG) reductions from baseline did not differ significantly with meal timing (30 min before vs. immediately before: FPG, -8.9 vs. -5.8 mg/dl; adjusted AUE0-4 h, -67.0 vs. -51.0 mg×h/dl). Vildagliptin was well tolerated. Conclusions Dosing 30 min or immediately before meals did not affect vildagliptin pharmacokinetics or pharmacodynamics in Japanese patients with Type 2 diabetes.

Vildagliptin is an orally active, potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor, shown to be effective and well tolerated in patients with type 2 diabetes mellitus (T2DM) as either monotherapy or in combination with other anti-diabetic agents. Vildagliptin possesses several desirable pharmacokinetic properties that contribute to its lower variability and low potential for drug interaction. Following oral administration, vildagliptin is rapidly and well absorbed with an absolute bioavailability of 85%. An approximately dose-proportional increase in exposure to vildagliptin over the dose range of 25-200 mg has been reported. Food does not have a clinically relevant impact on the pharmacokinetics of vildagliptin, and it can be taken without regard to food. Vildagliptin is minimally bound to plasma proteins (9.3%) and, on the basis of a volume of distribution of 71 L, it is considered to distribute extensively into extravascular spaces. Renal clearance of vildagliptin (13 L/h) accounts for 33% of the total body clearance after intravenous administration (41 L/h). The primary elimination pathway is hydrolysis by multiple tissues/organs. The DPP-4 enzyme contributes to the formation of the major hydrolysis metabolite, LAY151; therefore, vildagliptin is also a substrate of DPP-4. Vildagliptin has a low potential for drug interactions, as cytochrome P450 (CYP) enzymes are minimally (1.6%) involved in the overall metabolism. Clinical pharmacokinetic studies have reported the lack of drug interaction with several drugs (metformin, pioglitazone, glyburide, simvastatin, amlodipine, valsartan, ramipril, digoxin and warfarin) that are likely to be frequently co-administered to patients with T2DM. In particular, vildagliptin does not affect the pharmacokinetics of pioglitazone, glyburide, warfarin and simvastatin; therefore, it is not expected to affect the pharmacokinetics of a drug that is a substrate for CYP2C8, CYP2C9 or CYP3A4. In the elderly, vildagliptin exposure increases by approximately 30%, which is considered to be mostly attributable to compromised renal function in the elderly population and is not considered to be clinically relevant. Vildagliptin has been demonstrated to be efficacious, safe and well tolerated in elderly patients with T2DM without dose adjustment. In subjects with varying degrees of renal impairment, vildagliptin exposure increases by approximately 2-fold; however, the increase in the exposure does not correlate with the severity of renal impairment. The lack of a clear correlation between the increased exposure and the severity of renal impairment is considered to be attributable to the fact that the kidneys contribute to both the excretion and the hydrolysis metabolism of vildagliptin. Hepatic impairment, gender, body mass index (BMI) and ethnicity do not have an influence on the pharmacokinetics of vildagliptin. These findings suggest that vildagliptin can be used in a diverse patient population without dose adjustment. Oral administration of vildagliptin to patients with T2DM completely inhibits DPP-4 activity at a variety of doses. The onset of DPP-4 inhibition is rapid, and the duration of DPP-4 inhibition is dose dependent. Vildagliptin is a potent inhibitor of the DPP-4 enzyme, with a concentration required to achieve 50% DPP-4 inhibition (IC(50)) of 4.5 nmol/L in patients with T2DM. Similar potency of DPP-4 inhibition by vildagliptin has been reported in different ethnic groups, indicating that ethnicity does not affect the pharmacodynamics of vildagliptin. Vildagliptin significantly increases the active glucagon-like peptide 1 (GLP-1) levels by approximately 2- to 3-fold and glucose-dependent insulinotropic polypeptide (GIP) levels by approximately 5-fold, and significantly suppresses the postprandial glucagon levels in response to a meal or following an oral glucose tolerance test (OGTT) in patients with T2DM. Vildagliptin significantly reduces both fasting and postprandial glucose levels over the dose range of 50-100 mg daily (administered either once daily or twice daily), and there are no substantial additional benefits of doses greater than 50 mg twice daily. The primary clinical dosing regimen is 50 mg twice daily as monotherapy or in combination with metformin. Vildagliptin increases the insulin levels following an OGTT and an intravenous glucose tolerance test (IVGTT), and the stimulation of insulin secretion is glucose dependent. Vildagliptin has been shown to improve beta-cell function on the basis of pharmacodynamic modelling taking the reduced glucose levels into account. The improvement of beta-cell function by vildagliptin has been confirmed after chronic treatment with vildagliptin for up to 2 years. Reduction of the endogenous glucose production appears to contribute to the glucose-lowering effects. Unlike the GLP-1 receptor agonists, vildagliptin does not affect gastric emptying, and this is consistent with the favourable gastrointestinal safety profile. Vildagliptin improves the sensitivity of the alpha cell to glucose in patients with T2DM by enhancing the alpha-cell responsiveness to both suppressive effects of hyperglycaemia and stimulatory effects of hypoglycaemia. Consistently, a lower incidence of hypoglycaemic events with vildagliptin is reported when it is used as either monotherapy or in combination with other anti-diabetic agents, such as metformin or insulin, as compared with a sulphonylurea. Numerous long-term clinical trials of up to 2 years have demonstrated that vildagliptin 50 mg once daily or twice daily is effective, safe and well tolerated in patients with T2DM as either monotherapy or in combination with a variety of other anti-diabetic agents.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Vildagliptin is a novel antidiabetic agent that acts by inhibiting dipeptidyl peptidase IV (DPP-4). • DPP-4 inhibition results in higher active concentrations of incretin hormone, glucagon-like peptide 1 (GLP-1), leading to reduced glucose concentrations. • Mechanism-based modelling of the pharmacokinetics (PK) of vildagliptin and its DPP-4 inhibition effects in type 2 diabetic patients has not been performed. WHAT THIS STUDY ADDS • Population pharmacokinetic modelling of the vildagliptin concentrations from three different doses indicated the presence of a small saturable elimination pathway for vildagliptin. • Simultaneous population modelling of the pharmacokinetics and DPP-4 activity in patients with type 2 diabetes after treatment with vildagliptin revealed: 1) Saturable binding of vildagliptin to DPP-4 in plasma and tissues and partial hydrolysis of vildagliptin by DPP-4. 2) Vildagliptin is both an inhibitor and a substrate for DPP-4. AIMS To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology. METHODS Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling. RESULTS A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h−1 (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%). CONCLUSIONS Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Vildagliptin is a potent and selective inhibitor of dipeptidylpeptidase-IV (DPP-4). • DPP-4 inhibition leads to increased active glucagon-like peptide 1 (GLP-1) concentrations and decreased plasma glucose in patients with type 2 diabetes. WHAT THIS STUDY ADDS • No mechanism-based population PD modelling has been conducted to understand the effects of vildagliptin on active GLP-1, glucose and insulin. • Active GLP-1 concentrations could be described by secretion of active GLP-1 from the gut in response to a meal and elimination by DPP-4 and an additional non-saturable elimination pathway. • The effects of vildagliptin on glucose and insulin are primarily via enhanced GLP-1 concentrations which could be modelled by its effects on insulin secretion and peripheral insulin sensitivity. • Parallelized S-ADAPT but not NONMEM VI proved to be an excellent choice for estimating a complex population model such as the current PK/PD model. AIM To build a mechanism-based population pharmacodynamic model to describe and predict the time course of active GLP-1, glucose and insulin in type 2 diabetic patients after treatment with various doses of vildagliptin. METHODS Vildagliptin concentrations, DPP-4 activity, active GLP-1, glucose and insulin concentrations from 13 type 2 diabetic patients after oral vildagliptin doses of 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. The population PK/PD model was developed utilizing the MC-PEM algorithm in parallelized S-ADAPT version 1.56. RESULTS In the PD model, active GLP-1 production was stimulated by gastrointestinal intake of nutrients. Active GLP-1 was primarily metabolized by DPP-4 and an additional non-saturable pathway. Increased plasma glucose stimulated secretion of insulin which stimulated utilization of glucose. Active GLP-1 stimulated both glucose-dependent insulin secretion and insulin-dependent glucose utilization. Complete inhibition of DPP-4 resulted in an approximately 2.5-fold increase of active GLP-1 half-life. CONCLUSIONS The effects of vildagliptin in patients with type 2 diabetes on several PD endpoints were successfully described by the proposed model. The mechanisms of vildagliptin on glycaemic control could be evaluated from a variety of aspects such as effects of DPP-4 on GLP-1, effects of GLP-1 on insulin secretion and effects on hepatic and peripheral insulin sensitivity. The present model can be used to predict the effects of other dosage regimens of vildagliptin on DPP-4 inhibition, active GLP-1, glucose and insulin concentrations, or can be modified and applied to other incretin-related anti-diabetes therapies.

Based on the measurement of train speed, this paper briefly describes the basic principle of Doppler speed measurement and the design of speed measurement system. By the analysis of test signal which simulates the actual speed signal and comparison of the simulation results, the AR power spectrum estimation algorithm is selected as the model of speed measurement system, and the Burg method is selected to evaluate the Doppler frequency. Then the effect of parameters such as sampling frequency, length of the input vector, FFT length and estimation order on power spectrum estimation are analyzed, the optimization principles of the parameters are defined. Finally, the determined method is simulated with a high-noise, multi-jamming signal and has good results. The accuracy, stability and immunity are proved by the simulation.

Objective: To investigate the clinical efficacy and safety of the treatment of vitiligo using a 308 nm excimer laser. Method: Thirty-six patients with 44 vitiligo patches were treated using a 308 nm excimer laser, which was performed twice a week, for a total of 30 treatments. The therapeutic efficacy and safety were then evaluated. Results: After 30 treatments: (1) 27/44 patches (61.4%) achieved more than 75% repigmentation, 4/44 lesions (9.1%) showed 51–75% repigmentation, 10/44 (22.7%) showed 26–50% repigmentation and 3/44 (6.8%) showed 1–25% repigmentation. (2) Of the 44 patches of vitiligo, 20/27 (74.1%) lesions on the face/neck, 9/9 (100%) on the trunk and 2/8 (25.0%) on the extremities showed ≥50% repigmentation. The repigmentation (≥50%) in face/neck and trunk were much higher than that in the extremities (P2 years were 100.0% and 46.2% (P

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Genetic polymorphisms of VKORC1 and CYP2C9 are known to influence warfarin dosage. * Recent studies among Caucasians showed that polymorphisms of CYP4F2 also play a role in warfarin pharmacogenetics. * The contribution of CYP4F2 variants to the variability inwarfarin dose requirement in Chinese subjects remains to be investigated. WHAT THIS STUDY ADDS * This research was to study the effect of CYP4F2 variants on warfarin requirements in the Han Chinese population. * This study developed a multiple regression model including CYP2C9, VKORC1 3673G>A, CYP4F2 genotypes and age, weight, combination use of amiodarone which could explain 56.1% of the individual variability in warfarin dose CYP4F2 could explain 4% of the variance in warfarin dose. * We found that one novel genotypic polymorphism 5417G>T for Asp36Tyr, which was identified as an important marker of warfarin resistance, was absent in the Han Chinese population in our study. AIMS The objective of this study was to assess the effect of the CYP4F2 on the daily stable warfarin dose requirement in Han Chinese patients with mechanical heart valve replacement (MHVR). METHODS From March 2007 to November 2008, 222 Han Chinese MHVR patients were recruited in our study. VKORC1 3673G>A, 5417G>T, CYP2C9*3 and CYP4F2 rs2108622 were genotyped by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Polymorphisms of VKORC1 9041G>A were detected by direct sequencing. Multiple linear regression analysis was used to investigate the contribution of CYP4F2. RESULTS The CYP4F2 rs2108622 CT/TT group took a significantly higher stable warfarin dose (3.2 mg day(-1)) than the CC group (2.9 mg day(-1), 95% CI 0.2, 1.0, P= 0.033). The multiple linear regression model included VKORC1 3673G>A, CYP2C9, CYP4F2 genotypes and clinical characteristics. The model could explain 56.1% of the variance in stable warfarin dose in Han Chinese patients with MHVR. CYP4F2 contributed about 4% to the variance in the warfarin dose. There was no variation in the SNPs of VKORC1 5417G>T. CONCLUSION CYP4F2 is a minor significant factor of individual variability in the stable warfarin dose in Han Chinese patients with MHVR. The effect of CYP2C9 and VKORC1 genotypes on variability in the stable warfarin dose had also been confirmed.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Vildagliptin is an orally active, potent inhibitor of dipeptidyl peptidase IV and was developed for the treatment of type 2 diabetes. • In clinical trials, once or twice daily dosing with vildagliptin (up to 100 mg day−1) has been shown to reduce endogenous glucose production and fasting plasma glucose in patients with type 2 diabetes. • The comparative efficacy of vildagliptin under a morning vs. evening dosing regimen has not previously been determined. WHAT THIS STUDY ADDS • Once daily dosing with vildagliptin 100 mg for 28 days improved glycaemic control in patients with type 2 diabetes independent of whether vildagliptin was administered in the morning or evening. • Morning or evening dosing with vildagliptin had similar effects on 24 h glycaemic control and plasma concentrations of the hormones insulin, glucagon and glucagon-like peptide 1. AIM This randomized, double-blind, crossover study compared post-prandial hormonal and metabolic effects of vildagliptin, (an oral, potent, selective inhibitor of dipeptidyl peptidase IV [DPP-4]) administered morning or evening in patients with type 2 diabetes. METHODS Forty-eight patients were randomized to once daily vildagliptin 100 mg administered before breakfast or before dinner for 28 days then crossed over to the other dosing regimen. Blood was sampled frequently after each dose at baseline (day −1) and on days 28 and 56 to assess pharmacodynamic parameters. RESULTS Vildagliptin inhibited DPP-4 activity (>80% for 15.5 h post-dose), and increased active glucagon-like peptide-1 compared with placebo. Both regimens reduced total glucose exposure compared with placebo (area under the 0–24 h effect–time curve [AUE(0,24 h)]: morning −467 mg dl−1 h, P= 0.014; evening −574 mg dl−1 h, P= 0.003) with no difference between regimens (P= 0.430). Reductions in daytime glucose exposure (AUE(0,10.5 h)) were similar between regimens. Reduction in night-time exposure (AUE(10.5,24 h) was greater with evening than morning dosing (−336 vs.−218 mg dl−1 h, P= 0.192). Only evening dosing significantly reduced fasting plasma glucose (−13 mg dl−1, P= 0.032) compared with placebo. Insulin exposure was greater with evening dosing (evening 407 µU ml−1 h; morning 354 µU ml−1 h, P= 0.050). CONCLUSIONS Both morning and evening dosing of once daily vildagliptin 100 mg significantly reduced post-prandial glucose in patients with type 2 diabetes; only evening dosing significantly decreased fasting plasma glucose. Although evening dosing with vildagliptin 100 mg tended to decrease night-time glucose exposure more than morning dosing, both regimens were equally effective in reducing 24 h mean glucose exposure (AUE(0,24 h)) in patients with type 2 diabetes.

The biosynthesis study of antibiotics saframycin (SFM) in Streptomyces lavendulae and safracin (SAC) in Pseudomonas fluorescens demonstrated that 3-hydroxy-5-methyl-O-methyltyrosine (3h5mOmTyr), a nonproteinogenic amino acid, is the precursor of the tetra hydroisoquinoline molecular core. In the biosynthetic gene cluster of SAC/SFM, sacD/sfmD encodes a protein with high homology to each other but no sequence similarity to other known enzymes; sacF/sfmM2 and sacG/sfmM3 encode methyltransferases for C-methylation and O-methylation; and sacE/sfmF encodes a small protein with significant sequence similarity to the MbtH-like proteins, which are frequently found in the biosynthetic pathways of nonribosomal peptide antibiotics and siderophores. To address their function, the biosynthetic cassette of 3h5mOmTyr was heterologously expressed in S. coelicolor and P. putida, and an in-frame deletion and complementation in trans were carried out. The results revealed that (i) SfmD catalyzes the hydroxylation of aromatic rings; (ii) sacD/sacF/sacG in the SAC gene cluster and sfmD/sfmM2/sfmM3 in the SFM cluster are sufficient for the biosynthesis of 3h5mOmTyr; and (iii) the mbtH-like gene is not required for the biosynthesis of the 3h5mOmTyr precursor.

Vildagliptin is an orally effective, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled, time-lagged, parallel-group study in a total of 60 healthy Chinese participants. Single- and multiple-dose pharmacokinetics and pharmacodynamics, and safety and tolerability of vildagliptin were assessed following administration of 25, 50, 100, or 200 mg qd, or 50 mg bid. Vildagliptin was rapidly absorbed (tmax 1.5-2.0 hours) across the dose range of 25 to 200 mg and was quickly eliminated with a terminal elimination half-life (t1/2) of approximately 2 hours. Consistent with the short t1/2, no accumulation of vildagliptin was observed following the administration of multiple doses (accumulation factors were 1.00-1.05 across the 25- to 200-mg dose range). Vildagliptin AUC and Cmax values increased in an approximately dose-proportional fashion (dose proportionality constant beta 1.00-1.16). Administration of vildagliptin 25 to 200 mg led to rapid and near-complete (>95%) inhibition of DPP-4 activity for at least 4 hours after dosing, which was associated with increases in plasma active glucagon-like peptide-1 of up to 2- to 3-fold compared with placebo. The duration of DPP-4 inhibition increased with dose. Glucose and insulin levels were not affected by vildagliptin in healthy participants, consistent with the fact that the glucose-lowering effects of vildagliptin occur in a glucose-dependent fashion. Vildagliptin was well tolerated at the highest tested dose of 200 mg qd. Vildagliptin 25 to 200 mg qd exhibits approximately dose-proportional pharmacokinetics with no evidence of accumulation after multiple dosing in healthy Chinese participants. Vildagliptin demonstrates potent inhibition of DPP-4 activity with excellent tolerability at doses of up to and including 200 mg qd.

Context: Dipeptidyl-peptidase-IV (DPP-4) inhibition increases endogenous GLP-1 activity resulting in improved glycemic control in patients with type 2 diabetes mellitus. The metabolic response may be explained in part by extra-pancreatic mechanisms. Objective: We tested the hypothesis that DPP-4 inhibition with vildagliptin elicits changes in adipose tissue and skeletal muscle metabolism. Design: Randomized, double blind, crossover study. Setting: Academic clinical research center. Patients: Twenty patients with type 2 diabetes, body mass index between 28 and 40 kg/m2. Intervention: Seven days treatment with the selective DPP-4 inhibitor vildagliptin or placebo. Standardized test meal on day seven. Main Outcome Measures: Venous DPP-4 activity, catecholamines, free fatty acids, glycerol, glucose, (pro)insulin; dialysate glucose, lactate, pyruvate, glycerol. Results: Fasting and postprandial venous insulin, glucose, glycerol, triglycerides and free fatty acid concentrations were not different with vildagliptin and with placebo. Vildagliptin augmented the postprandial increase in plasma norepinephrine. Furthermore, vildagliptine increased dialysate glycerol and lactate concentrations in adipose tissue while suppressing dialysate lactate and pyruvate concentration in skeletal muscle. The respiratory quotient increased with meal ingestion but was consistently lower with vildagliptin. Conclusions: Our study is the first to suggest that DPP-4 inhibition augments postprandial lipid mobilization and oxidation. The response may be explained by sympathetic activation rather than a direct effect on metabolic status.

The pulp and paper industry is under regulatory pressure to reduce the volume of its water usage and wastewater discharge. To provide more efficient use of water resources and to minimise wastewater discharge, the design of water allocation networks has recently received increasing attention. Water system integration is often applied in the petroleum and chemical industry but much less so in the pulp and paper industry. We proposed a general methodology, nonlinear programming (NLP), for the design of optimal water use networks in a paper mill. The NLP requires specification of the lower and upper bounds on the contaminant concentrations flowing in and out of each process unit. This method can be effectively used to optimize the water network and minimise fresh water consumption and wastewater discharge in a paper mill. The minimised wastewater flows into a bio-treatment system where it is regenerated and can be reused for papermaking. We successfully achieved zero discharge of wastewater without affecting...