[Relationship between inorganic elements in rhizosphere soil and rhizome radial striations in Ligusticum chuanxiong].

The study is aimed to reveal the fluctuation of the inorganic elements in the rhizosphere soil of Ligusticum chuanxiong during their whole growth period, and explore the relationship between that fluctuation and the formation of radial striations character in the rhizomes. During the cultivation period of L. chuanxiong, the rhizosphere soil samples were taken regularly, and the content of 26 inorganic elements were determined by X-ray fluorescence spectrometry(XRF). Then the difference between the radial striations and un-radial striations rhizomes were analyzed for their fluctuation of the inorganic elements. The results showed that there were different "key period" and "key elements" in the rhizosphere elements content of L. chuanxiong rhizome with radial and un-radial striations, and different element coordination and antagonistic relationship. The key fluctuation period of rhizosphere elements in un-radial striations group were in 0-60 and 60-150 days, of which 22 elements such as Na, Mg, Al were the key elements in 0-60 days, and 5 elements such as Sr, Hf, Pb, Co, Ce were the key elements in 60-150 days. The key fluctuation period of rhizosphere elements in radial striations group were in 0-60 and 210-270 days, of which four elements such as Na, Co, Ce, As are the key change elements in 0-60 days, and 18 elements such as Mg, Al, Si are the key change elements in 210-270 days. At the same time, the study showed that the fluctuation of inorganic elements in rhizosphere soil coincided with the growth and development process of L. chuanxiong and the key period of the formation of "radial striations rhizome". The key stage which the rapid growth of lateral buds of rhizome affected the formation of radial striations is 60-150 days after planting, while the increase of Sr and Co elements is likely to be an important reason for the expansion of lateral buds of rhizome and the failure to form typical "radial striations rhizome" in un-radial striations group.

Relationship Between Sunitinib Pharmacokinetics and Administration Time: Preclinical and Clinical Evidence.

BACKGROUND AND OBJECTIVE: Circadian rhythms may influence the pharmacokinetics of drugs. This study aimed to elucidate whether the pharmacokinetics of the orally administered drug sunitinib are subject to circadian variation. METHODS: We performed studies in male FVB-mice aged 8-12 weeks, treated with single-dose sunitinib at six dosing times. Plasma and tissue samples were obtained for pharmacokinetic analysis and to monitor messenger RNA (mRNA) expression of metabolizing enzymes and drug transporters. A prospective randomized crossover study was performed in which patients took sunitinib once daily at 8 a.m., 1 p.m., and 6 p.m at three subsequent courses. Patients were blindly randomized into two groups, which determined the sequence of the sunitinib dosing time. The primary endpoint in both studies was the difference in plasma area under the concentration-time curve (AUC) of sunitinib and its active metabolite SU12662 between dosing times. RESULTS: Sunitinib and SU12662 plasma AUC in mice followed an ~12-h rhythm as a function of administration time (p ≤ 0.04). The combined AUC from time zero to 10 h (AUC10) was 14-27 % higher when sunitinib was administered at 4 a.m. and 4 p.m. than at 8 a.m. and 8 p.m. Twenty-four-hour rhythms were seen in the mRNA levels of drug transporters and metabolizing enzymes. In 12 patients, sunitinib trough concentrations (C trough) were higher when the drug was taken at 1 p.m. or 6 p.m. than when taken at 8 a.m. (C trough-1 p.m. 66.0 ng/mL; C trough-6 p.m. 58.9 ng/mL; C trough-8 a.m. 50.7 ng/mL; p = 0.006). The AUC was not significantly different between dosing times. CONCLUSIONS: Our results indicate that sunitinib pharmacokinetics follow an ~12-h rhythm in mice. In humans, morning dosing resulted in lower C trough values, probably resulting from differences in elimination. This can have implications for therapeutic drug monitoring.

Bilateral collicular interaction: modulation of auditory signal processing in frequency domain.

In the ascending auditory pathway, the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from a variety of lower auditory nuclei, intrinsic projections within the IC, contralateral IC through the commissure of the IC and the auditory cortex. All these connections make the IC a major center for subcortical temporal and spectral integration of auditory information. In this study, we examine bilateral collicular interaction in the modulation of frequency-domain signal processing of mice using electrophysiological recording and focal electrical stimulation. Focal electrical stimulation of neurons in one IC produces widespread inhibition and focused facilitation of responses of neurons in the other IC. This bilateral collicular interaction decreases the response magnitude and lengthens the response latency of inhibited IC neurons but produces an opposite effect on the response of facilitated IC neurons. In the frequency domain, the focal electrical stimulation of one IC sharpens or expands the frequency tuning curves (FTCs) of neurons in the other IC to improve frequency sensitivity and the frequency response range. The focal electrical stimulation also produces a shift in the best frequency (BF) of modulated IC (ICMdu) neurons toward that of electrically stimulated IC (ICES) neurons. The degree of bilateral collicular interaction is dependent upon the difference in the BF between the ICES neurons and ICMdu neurons. These data suggest that bilateral collicular interaction is a part of dynamic acoustic signal processing that adjusts and improves signal processing as well as reorganizes collicular representation of signal parameters according to the acoustic experience.

Effect of soybean protein on novel cardiovascular disease risk factors: a randomized controlled trial.

BACKGROUND/OBJECTIVES: Cardiovascular disease (CVD) is the leading cause of death in the United States and the world. Clinical trials have suggested that soybean protein lowers lipids and blood pressure. The effect of soybean protein on novel CVD risk factors has not been well studied. The objective of this study was to examine the effect of soybean protein on biomarkers of inflammation, endothelial dysfunction and adipocytokines. SUBJECTS/METHODS: The effect of 8 weeks of 40 g of soybean protein supplement (89.3 mg isoflavones), 40 g of milk protein supplement and 40 g of complex carbohydrate placebo was examined in a randomized, placebo-controlled, double-blind, three-phase crossover trial among adults in New Orleans, Louisiana and Jackson, Mississippi. Plasma levels of inflammation biomarkers (C-reactive protein, interleukin-6, tumor necrosis factor-α), endothelial dysfunction biomarkers (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, thrombomodulin) and adipocytokines (high-molecular weight adiponectin, leptin, resistin) were measured at baseline and at the end of each intervention using immunoturbidimetric and enzyme-linked immunosorbent assay techniques. RESULTS: Soy protein supplementation resulted in a significant mean net change (95% confidence interval) in plasma E-selectin of -3.93 ng/ml (-7.05 to -0.81 ng/ml; P=0.014) compared with milk protein, and in plasma leptin of -2089.8 pg/ml (-3689.3 to -490.3 pg/ml; P=0.011) compared with carbohydrate. There were no significant changes in any other risk factors. CONCLUSIONS: Soy protein supplementation may reduce levels of E-selectin and leptin. Further research is warranted to investigate the mechanisms through which protein may confer protective effects on novel CVD risk factors.

Ceftaroline fosamil: a cephalosporin with activity against methicillin-resistant Staphylococcus aureus.

BACKGROUND: Ceftaroline is a cephalosporin with expanded gram-positive activity recently approved for clinical uses by the US Food and Drug Administration. OBJECTIVE: This article provides an overview of the in vitro and in vivo activities, mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of ceftaroline. METHODS: Relevant information was identified through a search of PubMed (1990-April 2011), EMBASE (1990-April 2011), International Pharmaceutical Abstracts (1970-April 2011), and Google Scholar using the key words ceftaroline, PPI-0903, PPI-0903M, T-91825, and TAK-599. A review of the reference lists of identified articles, a search of the US Food and Drug Administration Web site, and posters and abstracts from scientific meetings yielded additional publications. RESULTS: In vitro, ceftaroline exhibits activity against most aerobic gram-positive isolates, common aerobic gram-negative respiratory pathogens, and some gram-positive anaerobes. The MIC range for most Staphylococcus aureus isolates, including vancomycin-resistant strains was between ≤0.008 and 4 µg/mL. In Phase III studies (CANVAS 1 and CANVAS 2), ceftaroline was found to be noninferior to vancomycin + aztreonam for the treatment of complicated skin and skin-structure infections, with a clinical cure rate of 91.6% among clinically evaluable patients (ceftaroline versus vancomycin + aztreonam: difference, -1.1; 95% CI, -4.2 to 2.0; P = NS). Ceftaroline's efficacy has also been assessed for the treatment of community-acquired pneumonia in 2 Phase III studies (FOCUS 1 and FOCUS 2) and was equivalent to ceftriaxone, with cure rates of 84.3% and 77.7%, respectively, among clinically evaluable patients in the combined analysis (ceftaroline versus ceftriaxone: difference, 6.7; 95% CI, 1.6 to 11.8). The recommended dosage for patients 18 years and older is 600 mg IV every 12 hours. Dosage adjustment is necessary in patients with renal impairment (creatinine clearance ≤50 mL/min). The pharmacokinetic properties of ceftaroline in patients with hepatic impairments are currently unavailable. Ceftaroline appeared to be well tolerated generally. The most frequently (>3%) reported adverse events were nausea, headaches, diarrhea, pruritus, rash, and insomnia; all were usually mild to moderate, self-limiting, and of little clinical significance. CONCLUSIONS: Ceftaroline is a cephalosporin with broad gram-positive activity, including Methicillin-resistant S aureus and vancomycin-resistant S aureus. Its gram-negative activity includes common respiratory pathogens and members of the Enterobacteriaceae. Clinical trials have reported that ceftaroline was noninferior to ceftriaxone, and vancomycin + aztreonam for the treatment of community-acquired pneumonia and complicated skin and skin-structure infections, respectively.

Efficient tetanus toxoid immunization on vitamin D supplementation.

BACKGROUND/OBJECTIVES: Vitamin D mediates immunomodulatory functions, and its deficiency has been associated with an increased prevalence of immunological diseases. The supplementation of vitamin D might be therapeutically beneficial, for example, in lupus erythematosus patients. However, its affect on established recall immune responses is undefined. SUBJECTS/METHODS: In all, 32 individuals were randomized in a placebo controlled, double-blind setting, and received vitamin D (daily 2000 IU) for 10 weeks followed by tetanus toxoid (TT) booster immunization. RESULTS: During vitamin D supplementation the median 25-hydroxyvitamin D serum concentration increased to 80.3 nM, which as expected decreased in the placebo group to 29.1 nM during the ultraviolet-deprived winter months. The TT-specific immunoglobulin G (IgG) boost efficiency was marginal higher in the vitamin D group (P = 0.04). The increase of the 25-hydroxyvitamin D levels correlated with the increase of TT-IgG serum concentrations. The induction of specific serum IgA and specific antibody secreting cells was comparable between both groups. Accordingly, the TT-specific and polyclonally triggered T-cell cytokine profiles were stable as well. CONCLUSIONS: Vitamin D supplementation was successful and booster immunization induced efficiently specific antibodies titers.

Genetic correlation of blood pressure responses to dietary sodium and potassium intervention and cold pressor test in Chinese population.

We examined the genetic association between blood pressure (BP) responses to dietary sodium and potassium intervention and to cold pressor test (CPT) in a large family-based dietary feeding study. The dietary intervention and CPT were conducted among 1906 participants in rural China. The dietary intervention included three 7-day periods of low-sodium feeding (51.3 mmol per day), high-sodium feeding (307.8 mmol per day) and high-sodium feeding plus potassium supplementation (60 mmol per day). BP responses to high-sodium intervention had strong genetic correlations (ρ(G)) with both BP responses to low sodium (ρ(G)=-0.43 to -0.54, P-values=0.0005 to 0.03) and to potassium supplementation (ρ(G)=-0.41 to -0.49, P-values=0.001 to 0.005) interventions. Most environmental correlations between BP responses to various dietary interventions were significant. The ρ(G) between BP responses to CPT and to high-sodium intervention and potassium supplementation were statistically significant. For example, the ρ(G) between maximum BP responses to CPT and BP responses to high-sodium intervention was 0.37 (P=0.006) for systolic BP (SBP) and 0.41 (P=0.002) for diastolic BP (DBP). The ρ(G) between maximum BP responses to CPT and BP responses to potassium intervention was -0.42 (P=0.001) for SBP and -0.46 (P=0.001) for SBP. Our study suggests that there are common genetic determinants that influence BP responses to dietary sodium and potassium interventions and to CPT.

The expression of the open reading frame of Arabidopsis CAX1, but not its cDNA, confers metal tolerance in yeast.

The biochemical properties and regulation of several plant CAX (CAtion eXchanger)-type vacuolar Ca2+/H+ exchangers have been extensively analysed in yeast expression assays. In the present study, we compare and contrast the phenotypes of yeast cells expressing the CAX1 cDNA and open reading frame (ORF). We report that the CAX1 ORF, but not the cDNA containing the 3'-untranslated region (UTR), was able to confer Ca2+ tolerance when expressed in a Ca2+-sensitive yeast mutant. Additionally, only yeasts expressing the N-terminal truncated CAX1 ORF were able to grow on high Mn2+ media, suggesting that removal of the 3'-UTR altered activity. However, removal of the 3'-UTR from another CAX did not alter the yeast phenotypes. Expression studies demonstrated that expressing the CAX1 ORF in yeast elevates CAX1 RNA and protein levels. Our results suggest that the 3'-UTR modulates expression of CAX1 in yeast.

Besifloxacin: a topical fluoroquinolone for the treatment of bacterial conjunctivitis.

BACKGROUND: Besifloxacin is a topical ophthalmic fluoroquinolone that was approved by the US Food and Drug Administration (FDA) in May 2009 for the treatment of bacterial conjunctivitis caused by susceptible bacterial strains. OBJECTIVE: This article provides an overview of the pharmacology, clinical efficacy, and tolerability of ophthalmic besifloxacin when used for the treatment of bacterial conjunctivitis. METHODS: Relevant reports pertaining to the pharmacology, efficacy, and tolerability of besifloxacin were identified through a search of MEDLINE (1985-December 2009) and International Pharmaceutical Abstracts (1985-December 2009) using the terms besifloxacin, BOL-303224-A, ophthalmic fluoroquinolones, and bacterial conjunctivitis. Additional publications were identified by reviewing the reference lists of identified articles and searching the FDA Web site. RESULTS: Besifloxacin has potent in vitro inhibitory activity against most common ocular bacterial pathogens (MIC90 values generally < or =4 microg/mL), including Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. In an ocular pharmacokinetic study in 64 healthy volunteers, the C(max) in tears (mean [SD], 610 [540] microg/mL) was reached 10 minutes after a single ocular instillation of besifloxacin; concentrations > or =1.6 microg/g of tear were sustained for at least 24 hours; and the elimination t(1/2) was ~3.4 hours. In a study in 24 patients with a clinical diagnosis of bilateral bacterial conjunctivitis, systemic exposure (C(max)) after administration of besifloxacin ophthalmic suspension 3 times daily for 5 days was <0.5 ng/mL. In 2 randomized, double-masked, vehicle-controlled clinical trials, besifloxacin ophthalmic suspension was well tolerated and significantly more efficacious than vehicle in achieving clinical resolution (73.3% vs 43.1%, respectively, in one of the studies [P < 0.001]; 45.2% vs 33.0% in the other [P = 0.008]) and microbial eradication (88.3% vs 60.3% [P < 0.001] and 91.5% vs 59.7% [P < 0.001], respectively). In a randomized, double-masked, parallel-group, noninferiority trial comparing besifloxacin ophthalmic suspension 0.6% with moxifloxacin ophthalmic solution 0.5%, besifloxacin was found to be noninferior to moxifloxacin (predefined cutoff for noninferiority = -15), with no significant differences in rates of clinical resolution (58.3% and 59.4%, respectively; 95% CI, -9.48 to 7.29) or microbial eradication (93.3% and 91.1%; 95% CI, -2.44 to 6.74). Besifloxacin was generally well tolerated in these clinical trials, with the most common (> or =1.5%) ocular adverse events being nonspecific conjunctivitis (2.6%), blurred vision (2.1%), bacterial conjunctivitis (1.8%), and eye pain (1.5%). The recommended dose of besifloxacin is 1 drop in the affected eye(s) 3 times daily (4-12 hours apart) for 7 days. CONCLUSION: Besifloxacin ophthalmic suspension 0.6% appeared to be well tolerated in the populations studied and was efficacious in the treatment of bacterial conjunctivitis caused by susceptible isolates.

Telavancin: a lipoglycopeptide antimicrobial for the treatment of complicated skin and skin structure infections caused by gram-positive bacteria in adults.

BACKGROUND: Telavancin, a lipoglycopeptide antibiotic, is a semisynthetic derivative of vancomycin. It was approved by the US Food and Drug Administration (FDA) in 2009 for the treatment of complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. OBJECTIVE: This article summarizes the pharmacology, in vitro and in vivo activity, pharmacokinetic properties, and clinical efficacy and tolerability of telavancin. METHODS: Relevant information was identified through a search of MEDLINE (1966-August 2010), Iowa Drug Information Service (1966-August 2010), International Pharmaceutical Abstracts (1970-August 2010), and Google Scholar using the terms telavancin, lipoglycopeptide, and TD-6424. Abstracts and posters from scientific meetings, as well as documents submitted by the manufacturer of telavancin to the FDA as part of the approval process, were consulted. In vivo and in vitro experimental and clinical studies and review articles that provided information on the activity, mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of telavancin were reviewed. RESULTS: In vitro, telavancin has potent activity against S aureus, including methicillin-resistant strains; Streptococcus pneumoniae; and vancomycin-susceptible enterococci with MICs generally <1 µg/mL. Telavancin appears to have a dual mechanism of action, inhibiting cell wall formation and disrupting the cell membrane. In Phase III studies (ATLAS 1 and ATLAS 2), telavancin was found to be noninferior to vancomycin, with clinical cure rates of 88.3% and 87.1%, respectively, in clinically evaluable patients in the treatment of cSSSIs (difference, 1.2%; 95% CI, -2.1 to 4.6; P = NS). The effectiveness of telavancin in the treatment of hospital-acquired pneumonia was assessed in 2 Phase III studies (ATTAIN 1 and ATTAIN 2). Preliminary findings were that the effectiveness of telavancin was not significantly different from that of vancomycin, with cure rates of 82.7% and 80.9% in the clinically evaluable population, respectively (difference, 1.8%; 95% CI, -4.1 to 7.7; P = NS). The most commonly (>10%) reported adverse events included taste disturbances, nausea, headache, vomiting, foamy urine, constipation, and insomnia. CONCLUSION: In clinical trials, the effectiveness of telavancin was not significantly different from that of vancomycin in the treatment of cSSSIs, and telavancin was generally well tolerated.

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.

Gene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three two-marker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

In vitro formation of oropharyngeal biofilms on silicone rubber treated with a palladium/tin salt mixture.

Adhesion of yeasts and bacteria to silicone rubber is one of the first steps in the biodeterioration of indwelling, silicone rubber voice prostheses. In this paper, silicone rubber, so-called "Groningen button," voice prostheses were treated with a colloidal palladium/tin solution to form a thin metal coat intended to discourage biofilm formation. First it was demonstrated that this treatment did not negatively affect the airflow resistance of the prostheses or induce any cytotoxicity. Subsequently, palladium/tin-treated voice prostheses were placed in a modified Robbins device together with untreated control prostheses to evaluate biofilm formation. Biofilms were formed by inoculating the device for 3 days with the total cultivable microflora obtained from an explanted, malfunctioning voice prosthesis supplemented with separately isolated yeasts (Candida albicans and Candida tropicalis). After 3 days the device was perfused three times daily with growth medium and phosphate-buffered saline. The device was allowed to drain between perfusions to better mimic the conditions in the oropharynx (moist but not always fully wetted). After 9 days the total number of bacterial and fungal colony-forming units on the prostheses were determined microbiologically, and scanning electron micrographs were taken of the valve sides. Biofilm formation was significantly less on the heavily treated palladium/tin prostheses than it was on the untreated prostheses although some ingrowing microcolonies also were observed on the treated prostheses. The spread of the biofilms was smaller on the treated prostheses than on the untreated ones.

The effect of water, ascorbic acid, and cranberry derived supplementation on human urine and uropathogen adhesion to silicone rubber.

In this study, urine was collected from groups of volunteers following the consumption of water, ascorbic acid, or cranberry supplements. Only ascorbic acid intake consistently produced acidic urine. Photospectroscopy data indicated that increased water consumption produced urine with lower protein content. Surface tension measurements of the collected urine showed that both water and cranberry supplementation consistently produced urine with surface tensions higher than the control or urine collected following ascorbic acid intake. These urine samples were also employed to study uropathogen adhesion to silicone rubber in a parallel plate flow chamber. Urine obtained after ascorbic acid or cranberry supplementation reduced the initial deposition rates and numbers of adherent Escherichia coli and Enterococcus faecalis, but not Pseudomonas aeruginosa, Staphylococcus epidermidis, or Candida albicans. Conversely, urine obtained from subjects with increased water intake vastly increased the initial deposition rates and numbers of adherent E. coli and E. faecalis (P < 0.05).

Detachment of linking film bacteria from enamel surfaces by oral rinses and penetration of sodium lauryl sulphate through an artificial oral biofilm.

The biofilm mode of growth protects plaque micro-organisms against environmental attacks, such as from antimicrobials or detergents. Dental plaque is linked to enamel through the adhesion of initial colonizers. Once this link is disrupted, the entire plaque mass adhering to it detaches. Experiments in a parallel-plate flow chamber demonstrated that bacteria adhering to saliva-coated enamel could not be stimulated to detach by perfusion of the flow chamber with two traditional mouthrinses (Corsodyl and Scope), whereas perfusion with a prebrushing rinse (Plax) or its detergent components stimulated detachment from saliva-coated enamel of a wide variety of bacterial strains. Following perfusion of the flow chamber with the mouthrinses, little additional detachment of adhering bacteria by the passage of a liquid-air interface occurred. After perfusion with the prebrushing rinse, however, significant numbers of still-adhering bacteria could be stimulated to detach by passage of a liquid-air interface, indicating that Plax had weakened their adhesive bond. The ability of Plax or its detergent components to detach plaque bacteria is not always obvious from in vivo experiments, and reports on its clinical efficacy are inconsistent. Likely, antimicrobials or detergents are unable to penetrate the plaque and reach the linking film bacteria, as demonstrated here by Fourier transform infrared spectroscopy.