Phonon spectrum and thermoelectric properties of square/octagon structure of bismuth monolayer.

First-principles calculation and Boltzmann transport theory have been combined to comparatively investigate the band structure, phonon spectrum, lattice thermal conductivity, electronic transport property, Seebeck coefficient, and figure of merit of square/octagon (s/o)-bismuth monolayer. Calculations reveal that the thermoelectric properties of s/o-bismuth monolayer are better than that of ß-bismuth monolayer, which should be mainly due to the low lattice thermal conductivity and weakened coupling of electrons and phonons. It is also found that the phonon frequency and group velocity could play dominant roles in determining the magnitude of the lattice thermal conductivity of s/o-bismuth monolayer. Furthermore, the Seebeck coefficient and figure of merit of s/o-bismuth monolayer are higher than those of ß-bismuth monolayer. The derived results are in good agreement with other theoretical results in the literature, and could provide a deep understanding of thermoelectric properties of the bismuth monolayer materials.

ANO1 relieves pressure overload-induced myocardial fibrosis in mice by inhibiting TGF-ß/Smad3 signaling pathway.

OBJECTIVE: The aim of this study was to measure the expression of anoctamin 1 (ANO1) in myocardial tissues of mice with pressure overload-induced myocardial fibrosis, and to further investigate the effect of ANO1 on myocardial fibrosis in mice and its mechanism. MATERIALS AND METHODS: A total of 40 male C57/B6 mice aged 6-8 weeks old were divided into 2 groups using a random number table, namely sham operation group (Sham group, n=20) and thoracic aortic constriction group (TAC group, n=20). Meanwhile, 20 ANO1 transgenic (TG) mice aged 6-8 weeks old were enrolled for TAC as TAC + ANO1 TG group. At 8 weeks after TAC, ejection fraction (EF%) and fraction shortening (FS%) in each group of mice were detected via echocardiography. Western blotting and immunofluorescence staining assays were conducted to measure the protein expression of ANO1 in myocardial tissues of mice in each group. The pathological changes in myocardial tissues of mice were evaluated through hematoxylin-eosin (H&E) staining. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) assay was performed to measure the messenger ribonucleic acid (mRNA) expression levels of hypertrophy markers atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in myocardial tissues of mice in each group. The deposition of collagen fibers in heart tissues was determined by Masson staining assay. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) staining assay was carried out to detect the apoptosis of myocardial cells and fibroblasts in heart tissues. Additionally, the protein expressions of oxidative stress markers superoxide dismutase 1 (SOD1) and 4-hydroxynonenal (4-HNE) in myocardial tissues were detected as well. Finally, Western blotting was employed to detect the effect of ANO1 overexpression on the expression of transforming growth factor-ß (TGF-ß)/Smad3 signaling pathway-related proteins in myocardial tissues of mice. RESULTS: At 8 weeks after TAC, ANO1 expression was overtly reduced in myocardial tissues of mice (p<0.05). Echocardiographic results showed that ANO1 overexpression significantly alleviated TAC-induced cardiac function deterioration in mice (p<0.05). The mRNA expression levels of ANP and BNP in myocardial tissues of TAC + ANO1 TG group were evidently lower than those in TAC group (p<0.05). Meanwhile, myocardial interstitial collagen deposition was significantly ameliorated in TAC + ANO1 TG group compared with TAC group (p<0.05). ANO1 overexpression notably mitigated the apoptosis of myocardial cells and oxidative stress in mice with cardiac pressure overload (p<0.05). Western blotting results further indicated that after overexpression of ANO1, the protein levels of TGF-ß and phosphorylated Smad3 (p-Smad3) were significantly inhibited in mice undergoing TAC (p<0.05). CONCLUSIONS: In the case of cardiac pressure overload in mice, ANO1 is lowly expressed in myocardial tissues. Meanwhile, its overexpression is able to attenuate pressure overload-induced myocardial fibrosis in mice by repressing the TGF-ß/smad3 signaling pathway. All our findings indicate that ANO1 can serve as a potential gene target for the treatment of myocardial fibrosis in the future.

A microfabricated low-profile wideband antenna array for terahertz communications.

While terahertz communications are considered to be the future solutions for the increasing demands on bandwidth, terahertz equivalents of radio frequency front-end components have not been realized. It remains challenging to achieve wideband, low profile antenna arrays with highly directive beams of radiation. Here, based on the complementary antenna approach, a wideband 2 × 2 cavity-backed slot antenna array with a corrugated surface is proposed. The approach is based on a unidirectional antenna with a cardiac radiation pattern and stable frequency characteristics that is achieved by integrating a series-resonant electric dipole with a parallel-resonant magnetic dipole. In this design, the slots work as magnetic dipoles while the corrugated surface radiates as an array of electric dipoles. The proposed antenna is realized at 1 THz operating frequency by stacking multiple metallized layers using the microfabrication technology. S-parameter measurements of this terahertz low-profile metallic antenna array demonstrate high efficiency at terahertz frequencies. Fractional bandwidth and gain are measured to be 26% and 14 dBi which are consistent with the simulated results. The proposed antenna can be used as the building block for larger antenna arrays with more directive beams, paving the way to develop high gain low-profile antennas for future communication needs.

Application value of stomach filling ultrasonography and intravenous contrast agents in diagnosis of advanced gastric cancer.

OBJECTIVE: To explore the imaging characteristics and clinical application value of gastric filling ultrasound combined with an intravenous contrast agent (double contrast ultrasonography, DCUS) in the diagnosis of advanced gastric carcinoma. PATIENTS AND METHODS: Totally 48 patients with advanced gastric carcinoma were confirmed by endoscopic biopsy and then administrated with DCUS and enhanced magnetic resonance examination before treatment. Retrospective analysis was conducted based on the characteristics of their ultrasonic images, and the results of diagnosis were compared and analyzed between the DCUS technology and the enhanced magnetic resonance examination. RESULTS: The DCUS technology showed rapid positive development in the arterial phase and rapid negative development in the portal phase at all foci of advanced gastric carcinomas. The initiation time in the arterial phase was (19.35±4.82) s, the peak value was (31.41±4.23) dB, and the expurgation time was (41.71±7.03) s. The accuracy rates of the DCUS diagnosis and the enhanced magnetic resonance diagnosis of advanced gastric cancer were 87.5% and 66.7% respectively, with statistical differences (p<0.05). CONCLUSIONS: DCUS had specific fast-in and fast-out characteristics and high accuracy in diagnosing the advanced gastric cancer and so could be used as an effective means to the diagnosis of the disease in clinic.

Cost-effectiveness of Lamivudine, Telbivudine, Adefovir Dipivoxil and Entecavir on decompensated hepatitis B virus-related cirrhosis.

OBJECTIVE: To evaluate the cost-effectiveness of lamivudine (LMV), telbivudine (LdT), adefovir dipivoxil (ADV) and entecavir (ETV) on decompensated hepatitis B virus-related cirrhosis. PATIENTS AND METHODS: 1332 patients with decompensated hepatitis B virus-related cirrhosis were randomly assigned into 5 groups with different clinical treatment including LMV treatment, LdT treatment, ADV treatment, LMV+ADV treatment and ETV treatment. And then the liver function, Child-Pugh scores, sero-conversion of HBeAg/HBeAb, polymerase gene mutations, cost-effectiveness, incremental cost-effectiveness and side effects were investigated and further analyzed. RESULTS: LMV, ADV, LdT, LMV+ADV and ETV were all effective on decreasing Child-Pugh scores and conversing negatively hepatitis B virus (HBV) DNA and HBeAg, whereas LMV+ADV and ETV more effective than LMV, ADV and LdT. HBV DNA polymerase genotypic mutations were rare in the 5 groups. The less mutation rate was found in the LMV+ADV and ETV group than in the LMV, ADV and LdT group. Compared to the cost-effectiveness and incremental cost-effectiveness ratio, ETV was the optimal selection, LMV+ADV was the alternative selection and LMV was the cheapest option. The side effects of the 5 plans were all rare and could be controlled. CONCLUSIONS: LMV, ADV, LdT, LMV+ADV and ETV were all effective on treatment of decompensated hepatitis B virus-related cirrhosis whereas ETV and LMV+ADV were recommended.

Gastrodin suppresses BACE1 expression under oxidative stress condition via inhibition of the PKR/eIF2α pathway in Alzheimer's disease.

The expression of ß-site APP-cleaving enzyme 1 (BACE1) is increased in the brain of late-onset sporadic Alzheimer's disease (AD) and oxidative stress may be the potential cause of this event. The phenolic glucoside gastrodin (Gas), a main component of a Chinese herbal medicine Gastrodia elata Blume, has been demonstrated to display antioxidant activity and suppresses BACE1 expression. However, the mechanisms by which Gas suppresses BACE1 expression are not clear. Morris water maze test was performed to assess the effect of Gas treatment on memory impairments in Tg2576 mice. The level of oxidative stress in the brain of Tg2576 mice was determined by measuring the superoxide dismutase (SOD) activity, catalase (CAT) activity, and the levels of malondialdehyde (MDA) and ROS. In vivo and in vitro, we detected the expression levels of BACE1, pPKRThr446, PKR, pPERKThr981, PERK, peIF2αSer51, and eIF2α using western blot analysis. We found that Gas improved learning and memory abilities of Tg2576 transgenic mice and attenuated intracellular oxidative stress in hippocampi of Tg2576 mice. We discovered that the expression levels of BACE1, activated PKR (pPKRThr446) and activated eIF2α (peIF2αSer51) were elevated in the brains of Tg2576 mice and hydrogen peroxide (H2O2)-stimulated SH-SY5Y cells. Moreover, peptide PKR inhibitor (PRI) and Gas down-regulated BACE1 expression in Tg2576 mice and H2O2-stimulated SH-SY5Y cells by inhibiting activation of PKR and eIF2α. Gas alleviates memory deficits in mice and suppresses BACE1 expression by inhibiting the protein kinase/Eukaryotic initiation factor-2α (PKR/eIF2α) pathway. The research suggested that Gas may develop as an drug candidate in neurodegenerative diseases.

Clinical herbal interactions with conventional drugs: from molecules to maladies.

Clinical studies and case reports have identified a number of herb-drug interactions potentiated by the concurrent use of herbal medicines with prescription drugs. The purpose of this paper is to discuss the mechanisms and clinical implications of such herb-drug interactions by reviewing published human studies. Both pharmacokinetic and pharmacodynamic components may be involved in herbdrug interactions, although metabolic induction or inhibition is a common underlying mechanism for many herb-drug interactions. Drugs that have a high potential to interact with herbal medicines usually have a narrow therapeutic index, including warfarin, digoxin, cyclosporine, tacrolimus, amitriptyline, midazolam, indinavir, and irinotecan. Many of them are substrates of cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). Herbal medicines that are reported to interact with drugs include garlic (Allium sativum), ginger (Zingiber officinale), ginkgo (Ginkgo biloba), ginseng (Panax ginseng), and St. John's wort (Hypericum perforatum). For example, garlic has been shown to increase the clotting time and international normalized ratio (INR) of warfarin, cause hypoglycaemia when taken with chlorpropamide, and reduce the area under the plasma concentration-time curve (AUC) and maximum concentration of saquinavir in humans. Similarly, case reports have demonstrated that ginkgo may potentiate bleeding when combined with warfarin or aspirin, increases blood pressure when combined with thiazide diuretics, and has even led to a coma when combined with trazodone, a serotonin antagonist and reuptake inhibitor used to treat depression. Furthermore, ginseng reduced the blood levels of warfarin and alcohol as well as induced mania if taken concomitantly with phenelzine, a non-selective and irreversible monoamine oxidase inhibitor used as an antidepressant and anxiolytic agent. Lastly, multiple herb-drug interactions have been identified with St. John's wort that involve significantly reduced AUC and blood concentrations of warfarin, digoxin, indinavir, theophylline, cyclosporine, tacrolimus, amitriptyline, midazolam, and phenprocoumon. The clinical consequence of herb-drug interactions varies, from being well-tolerated to moderate or serious adverse reactions, or possibly life-threatening events. Undoubtedly, the early and timely identification of herb-drug interactions is imperative to prevent potentially dangerous clinical outcomes. Further well-designed studies are warranted to address the mechanisms and clinical significance of important herb-drug interactions.

Pharmacokinetic profiles of anticancer herbal medicines in humans and the clinical implications.

A number of herbal medicines are increasingly used by cancer patients worldwide, despite the fact that the clinical evidence that supports their use to fight cancer is weak or lacking. Pharmacokinetic studies have been integrated into modern drug development, but they are generally not needed for herbal remedies. To update our knowledge in this field, this paper highlights the pharmacokinetic properties of anticancer herbal medicines and the clinical relevance. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase ((all from inception to May 2011). An extensive literature search indicatesthat there are limited data on the pharmacokinetic properties of anticancer herbal medicines in humans. There are increasing pharmacokinetic studies of anticancer herbal remedies, but these studies are mainly focused on a small number of herbal medicines including curcumin, ginseng, ginkgo, ginger and milk thistle. For an anticancer herbal medicine, the pharmacological activity is gained when the active agents or the active metabolites reach and sustain proper levels at their sites of action. Both the dose levels and pharmacokinetic processes of active herbal components in the body determine their target-site concentrations and thus the anticancer effect. In this regard, a safe and optimal use of anticancer herbal medicines requires a full understanding of their pharmacokinetic profiles. To optimize the use of anticancer herbal remedies, further studies to explore their pharmacokinetic properties and the relevance to pharmacodynamics and toxicity in humans are certainly warranted.

Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1).

Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse P-gp/Abcb1a structure has been determined and this has significantly enhanced our understanding of the structure-activity relationship (SAR) of mammalian ABC transporters. This paper highlights our current knowledge on the structural and functional properties and the SAR of human MRP1/ABCC1. Although the crystal structure of MRP1/ABCC1 has yet to be resolved, the current topological model of MRP1/ABCC1 contains two transmembrane domains (TMD1 and TMD2) each followed by a nucleotide binding domain (NBD) plus a third NH2-terminal TMD0. MRP1/ABCC1 is expressed in the liver, kidney, intestine, brain and other tissues. MRP1/ABCC1 transports a structurally diverse array of important endogenous substances (e.g. leukotrienes and estrogen conjugates) and xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions and lipids. Cells that highly express MRP1/ABCC1 confer resistance to a variety of natural product anticancer drugs such as vinca alkaloids (e.g. vincristine), anthracyclines (e.g. etoposide) and epipodophyllotoxins (e.g. doxorubicin and mitoxantrone). MRP1/ABCC1 is associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. However, most compounds that efficiently reverse P-gp/ABCB1-mediated multidrug resistance have only low affinity for MRP1/ABCC1 and there are only a few effective and relatively specific MRP1/ABCC1 inhibitors available. A number of site-directed mutagenesis studies, biophysical and photolabeling studies, SAR and QSAR, molecular docking and homology modeling studies have documented the role of multiple residues in determining the substrate specificity and inhibitor selectivity of MRP1/ABCC1. Most of these residues are located in the TMs of TMD1 and TMD2, in particular TMs 4, 6, 7, 8, 10, 11, 14, 16, and 17, or in close proximity to the membrane/cytosol interface of MRP1/ABCC1. The exact transporting mechanism of MRP1/ABCC1 is unclear. MRP1/ABCC1 and other multidrug transporters are front-line mediators of drug resistance in cancers and represent important therapeutic targets in future chemotherapy. The crystal structure of human MRP1/ABCC1 is expected to be resolved in the near future and this will provide an insight into the SAR of MRP1/ABCC1 and allow for rational design of anticancer drugs and potent and selective MRP1/ABCC1 inhibitors.

Clinical drugs undergoing polymorphic metabolism by human cytochrome P450 2C9 and the implication in drug development.

CYP2C9 metabolizes more than 100 clinically used drugs including phenytoin, S-warfarin, tolbutamide, glipizide, diclofenac, and losartan with varying contributions. CYP2C9 is considered one of the most important CYPs, with substrate specificity typical of many new chemical entities (i.e. lipophilic bases). A large interindividual variation has been identified for the CYP2C9 activity and for the clinical response to the therapeutics metabolised by the enzyme. So far, at least 33 variants of CYP2C9 (*2 through to *34) have been identified. CYP2C9 is one of the clinically significant drug metabolising enzymes that demonstrates genetic variants with significant phenotype and clinical outcomes. This review updates our current knowledge on the polymorphic metabolism of drugs by CYP2C9 and discusses its implications in drug development. The authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Genetics Abstracts (CSA), SCOPUS, Chemical Abstracts, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to October 31 2010). A comprehensive literature search has identified 32 drugs that are subject to CYP2C9-mediated polymorphic metabolism. Drugs that are subject to polymorphic metabolism with clinical significance include nine nonsteroidal anti-inflammatory agents, six sulfonylurea antidiabetic drugs and, most critically, three oral coumarin anticoagulants. Polymorphisms in CYP2C9 have the potential to affect the clearance and clinical response of CYP2C9 substrate drugs with low therapeutic indices such as warfarin, phenytoin, and certain antidiabetic drugs. Warfarin has served as a model drug of how pharmacogenetics can be employed to achieve maximum efficacy and minimum toxicity. Minimizing interindividual variability in drug exposure due to CYP2C9 polymorphisms is an important goal in drug development and discovery.

Biodegradation of organic compounds from coking wastewater with UASB reactor.

The UASB reactor was applied for biodegradation of organic compounds in coking wastewater. The influent pH ranged between 6.8 and 7.2, and stirring speed and temperature were controlled at 2 r/min and 30±1°C, respectively. The reactor was successfully started up in 133 days. When the influent COD was 2,600 mg/L (VLR was 2.6 kg/m(3) d), the removal rate of COD was about 54% and the effluent VFA was below 400 mg/L. GC/MS analysis indicated that the coking wastewater mainly contained aniline, phenol, o-phenol, p-cresol, benzoic acid, indole, quinoline etc. Twenty four kinds of organic compounds were detected in the influent, and 20 kinds of organic compounds were completely removed in the UASB reactor. The biodegradation of organic compounds followed Grau second-order kinetics. It was proved to be an effective and feasible method for coking wastewater anaerobic treatment.

Disposition pathways and pharmacokinetics of herbal medicines in humans.

Pharmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper updates our current knowledge on the disposition pathways and pharmacokinetic properties of commonly used herbal medicines in humans. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to May 2010). Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. There are increasing pharmacokinetic studies of herbal remedies, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, sculcap, curcumin, echinacea, ginseng, ginkgo, and ginger. The pharmacokinetic data of a small number of purified herbal ingredients, including anthocyanins, berberine, catechins, curcumin, lutein and quercetin, are available. For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. For a herbal medicine, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action. Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of an herbal remedy. In this regard, a safe and optimal use of herbal medicines requires a full understanding of their pharmacokinetic profiles. To optimize the use of herbal remedies, further clinical studies to explore their biological fate including the disposition pathways and kinetics in the human body are certainly needed.

Widespread but small-scale changes in the structural and dynamic properties of vaccinia virus poly(A) polymerase upon association with its processivity factor in solution.

Vaccinia virus poly(A) polymerase (VP55) has been analyzed via hydrogen-deuterium exchange (HDX) mass spectrometry in the absence and presence of its processivity factor, VP39, to improve our understanding of the mechanism by which processivity is impressed on the polymerase. For 119 peptic peptides covering 74.1% of VP55, the extent of HDX at 900 s was interpreted in the context of parameters deduced from the VP55-VP39 X-ray crystal structure. While HDX exhibited a degree of correlation with the mean SASA of whole residues within each peptide segment, HDX was generally more active than expected from either the SASA or hydrogen bonding status of the exchangeable amide proton, indicating a significant molecular dynamics contribution to amide proton deprotection. Peptic peptides undergoing either more or less HDX than expected were distributed throughout VP55 and showed consistency between multiple overlapping peptides. VP39 had a net, marginal cooling effect on VP55, indicating a possible restriction of VP55's flexibility. VP39's cooling effect was most extensive within the central domain of VP55's three domains, while a patch within VP55's C-terminal domain showed an increased level of HDX in the presence of VP39. Langevin dynamics all-atom simulations of VP55 motions showed slower relaxation to equilibrium in the absence of VP39. At equilibrium, regions showing extremes of variation in simulated atomic fluctuation were localized within VP55's N- and C-terminal domains, and VP39 had a predominantly cooling effect on VP55. Broadly, across VP55's peptic peptides, a mild negative correlation was noted between the extent to which deuteration was more active than predicted from the structure and the amplitudes of the simulated atomic fluctuation and/or degree of disorder at equilibrium.

Genetic polymorphism of the human cytochrome P450 2C9 gene and its clinical significance.

Human cytochrome P450 2C9 (CYP2C9) accounts for approximately 20% of total hepatic CYP content and metabolizes approximately 15% clinically used drugs including S-warfarin, tolbutamide, phenytoin, losartan, diclofenac, and celecoxib. To date, there are at least 33 variants of CYP2C9 (*1B through to *34) being identified. CYP2C9*2 and CYP2C9*3 differ from the wild-type CYP2C9*1 by a single point mutation: CYP2C9*2 is characterised by a 430C>T exchange in exon 3 resulting in an Arg144Cys amino acid substitution, whereas CYP2C9*3 shows an exchange of 1075A>C in exon 7 causing an Ile359Leu substitution in the catalytic site of the enzyme. CYP2C9*2 is frequent among Caucasians with approximately 1% of the population being homozygous carriers and 22% heterozygous. The corresponding figures for the CYP2C9*3 allele are 0.4% and 15%, respectively. Worldwide, a number of other variants have also to be considered. The CYP2C9 polymorphisms are relevant for the efficacy and adverse effects of numerous nonsteroidal anti-inflammatory agents, sulfonylurea antidiabetic drugs and, most critically, oral anticoagulants belonging to the class of vitamin K epoxide reductase inhibitors. Numerous clinical studies have shown that the CYP2C9 polymorphism should be considered in warfarin therapy and practical algorithms how to consider it in therapy are available. These studies have highlighted the importance of the CYP2C9*2 and *3 alleles. Warfarin has served as a practical example of how pharmacogenetics can be utilized to achieve maximum efficacy and minimum toxicity. Polymorphisms in CYP2C9 have the potential to affect the toxicity of CYP2C9 drugs with somewhat lower therapeutic indices such as warfarin, phenytoin, and certain antidiabetic drugs. CYP2C9 is one of the clinically significant drug metabolising enzymes that demonstrates genetic variants with significant phenotype and clinical outcomes. Genetic testing of CYP2C9 is expected to have a role in predicting drug clearance and implementing individualized pharmacotherapy. Prospective clinical studies with large samples are required to establish gene-dose and gene-effect relatiohsips for CYP2C9.

A novel rat model of chronic heart failure following myocardial infarction.

In this report, we describe an improved method for the establishment of reproducible congestive heart failure (CHF) in a rat model. The area of myocardial infarction (MI) after ligation of the left anterior descending (LAD) coronary artery was quantified. Histological changes, heart function detected by echocardiography and isolated Langendorff perfusion, and selected biochemical factors were monitored after ligation of the LAD. Contrary to previous beliefs, thoracotomy in the second intercostal space provided a much better visualization of and easier access to the LAD and significantly reduced the mortality rate. Surface electrocardiogram (ECG) showed that the S-T interval was arched raised upward immediately after ligation. Typical morphological and functional changes of CHF were observed after LAD ligation. Cardiomyocytes in the infarcted zone were depleted and deranged. Biochemical analysis and enzyme-linked immunosorbent assay (ELISA) showed that superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and nitric oxide (NO) levels were significantly lowered in rats with MI than in the normal and sham groups, whereas serum malondialdehyde (MDA), MB isoenzyme of creatine kinase (CK-MB), cardiac troponin (cTnT) and C-reactive protein (CRP) levels were elevated. After MI, N-terminal pro-brain natriuretic peptide (NT-proBNP) was increased but insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF) in culture supernatant were lower than in the normal and sham groups. We present an improved model for maximal reproducibility of experimental CHF in rats which allows the study of molecular and physiological variables in relation to CHF.

Unbalanced translocation in an adult patient with premature ovarian failure and mental retardation detected by spectral karyotyping and array-comparative genomic hybridization.

BACKGROUND: There are only three cases of unbalanced translocation (X;1) reported in childhood in the literature, while no such phenotypic information is available in adults. MATERIALS AND METHODS: To delineate the phenotype-genotype relationship of unbalanced translocation (X;1) in adulthood, we reported here a 20-year-old female with an unbalanced translocation (X;1) which was determined by spectral karyotyping, array-comparative genomic hybridization and subtelomeric fluorescence in situ hybridization (FISH). RESULTS: The phenotype of partial trisomy 1 and partial monosomy X of the present case was much attenuated, including premature ovarian failure, mental retardation, class I obesity, mild dysmorphism and delayed secondary sexual characteristics. The breakpoints of the unbalanced translocation were accurately located at Xq28 and 1q32.1. The large amplification on Chromosome 1 q arm was found to involve 312 genes and the deletion on Chromosome X q arm also involved 141 genes. Overall, genes associated with physiological process (47 genes), cellular process (33), development (23), response to stimulus (1) and reproduction (1) were observed in the amplification on Chromosome 1 q arm. In addition, genes related to physiological process (23 genes), cellular process (13), development (6) and response to stimulus (2) were observed in the large deletion on chromosome X q arm. Late-replication studies revealed the existence of skewed X inactivation in the derivative X chromosome. CONCLUSIONS: The phenotype of partial monosomy X and partial trisomy 1q is much attenuated in case of unbalanced translocation (X;1) in adulthood probably owing to skewed X inactivation in derivative X chromosome.

Up-regulated renal expression of TNF-alpha signalling adapter proteins in lupus glomerulonephritis.

The role of tumour necrosis factor (TNF-alpha) signalling adapters in lupus nephritis (LN) is poorly understood. This study investigated renal expression of TNF-alpha and TNF signalling adapter proteins, including TNF receptor-associated death domain protein (TRADD), receptor-interacting protein (RIP) and TNF receptor-associated factor-2 (TRAF-2) in patients with LN. The renal expression of proliferating cell nuclear antigen (PCNA) and CD68 was also measured. The study showed that glomerular and tubular expression of TNF-alpha, TRADD, RIP and TRAF-2 was significantly up-regulated in class III and IV LN in which the intense staining was observed on the crescents, proximal and distal tubules and interstitial mononuclear cells. The number of PCNA-positive cells and CD68-positive cells (macrophages) was increased obviously in class III and IV LN. There was a correlation between the expression levels of TNF-alpha, TRADD, RIP, TRAF-2 and the number of PCNA-positive or CD68-positive cells and active index of renal pathology. These findings suggest that TNF-alpha and TNF-alpha adapters in patients with LN play a role in immunopathogenic injury via transmitting abnormal cell proliferating and proinflammatory signals. The findings have provided further insights into the role of TNF-alpha and its adapter proteins in the pathogenesis of LN and have important therapeutic implications.

Chemistry and bioactivity of Flos Magnoliae, a Chinese herb for rhinitis and sinusitis.

Flos Magnoliae (FM, Chinese name: Xin-yi) is one of the most commonly used Chinese medicinal herbs. It has a long history of clinical use for managing rhinitis, sinusitis and headache. More than 20 different FM species have been used clinically, which makes species identification and evaluation of pharmacological effects of individual chemical ingredients difficult. In this review, we have summarized the current knowledge on FM phytochemistry and its bioactivity activities. The bioactive compounds in FM include both lipid and water-soluble components. More than 90% of the essential components of FM species are terpenoids, including monoterpenes and sesquiterpenes. Lignans and neolignans including tetrahydrofurofuran, tetrahydrofuran and aryltetralin are also present in FM species. A small number of water-soluble compounds have been isolated from Magnolia flower buds, including a benzylisoquinoline alkaloid magnoflorine, an ester ethyl-E-p-hydroxyl-cinnamate and a flavonoid biondnoid. A wide range of pharmacological actions of FM have been reported, including anti-allergy, anti-inflammation and anti-microbial activity. The structure-activity relationship analysis revealed the influence of methylation at position 5 on the 3,7-dioxabicyclo-(3,3,0)-octane backbone of six lignans in antagonistic activities against platelet-activating factor. In addition, the trans stereoisomer fargesin had a much lower bioactivity than the cis stereoisomer demethoxyaschantin. Recent studies have been directed towards the isolation of other bioactive compounds. Further studies on FM may help to develop new anti-inflammatory and anti-allergic drugs.

Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition.

1. P-glycoprotein (P-gp/MDR1), one of the most clinically important transmembrane transporters in humans, is encoded by the ABCB1/MDR1 gene. Recent insights into the structural features of P-gp/MDR1 enable a re-evaluation of the biochemical evidence on the binding and transport of drugs by P-gp/MDR1. 2. P-gp/MDR1 is found in various human tissues in addition to being expressed in tumours cells. It is located on the apical surface of intestinal epithelial cells, bile canaliculi, renal tubular cells, and placenta and the luminal surface of capillary endothelial cells in the brain and testes. 3. P-gp/MDR1 confers a multi-drug resistance (MDR) phenotype to cancer cells that have developed resistance to chemotherapy drugs. P-gp/MDR1 activity is also of great clinical importance in non-cancer-related drug therapy due to its wide-ranging effects on the absorption and excretion of a variety of drugs. 4. P-gp/MDR1 excretes xenobiotics such as cytotoxic compounds into the gastrointestinal tract, bile and urine. It also participates in the function of the blood-brain barrier. 5. One of the most interesting characteristics of P-gp/MDR1 is that its many substrates vary greatly in their structure and functionality, ranging from small molecules such as organic cations, carbohydrates, amino acids and some antibiotics to macromolecules such as polysaccharides and proteins. 6. Quite a number of single nucleotide polymorphisms have been found for the MDR1 gene. These single nucleotide polymorphisms are associated with altered oral bioavailability of P-gp/MDR1 substrates, drug resistance, and a susceptibility to some human diseases. 7. Altered P-gp/MDR1 activity due to induction and/or inhibition can cause drug-drug interactions with altered drug pharmacokinetics and response. 8. Further studies are warranted to explore the physiological function and pharmacological role of P-gp/MDR1.