Interference by Carbohydrate Substrates, Flavonoids, and Monosaccharide Derivatives on Bacterial β-D-Glucuronidase Assays

Most commercially available test kits for water and foodstuffs use β-galactosidase activity for coliforms and β-glucuronidase activity for Escherichia coli. We tested the effects on the β-glucuronidase activity of E. coli W3110 of substances usually present in foods and several synthetic pharmaceutical compounds. Thirteen substances were tested: three carbohydrates, four flavonoids, five monosaccharide derivatives, and dimethyl sulphoxide. In a minimum medium without any other carbon source, glucose (0.1 mM), quercetin (0.1 mM), silymarin (10 mg/L), D-gluconic acid (0.01 mM), D-gluconic acid lactone (0.01 mM), isopropyl-β-D-thiogalacto pyranoside (1 mM), p-nitrophenyl β-D-glucuronide (1 mM), and DMSO (1 M) completely inhibited E. coli glucuronidase activity at the above concentrations. However, the following compounds stimulated E. coli glucuronidase activity within the ranges of concentrations shown: glucose (0.0001–0.01 mM), lactose and sucrose (>0.1 mM), D-saccharic acid 1,4 lactone (0.0001–0.1 mM), p-nitrophenyl β-D-glucuronide (0.001–0.01 mM) and DMSO (2–500 mM). In a rich culture medium that contained other carbon sources (lauryl tryptose broth) E. coli glucuronidase activity in the presence of the extra nutrients was unaffected by the test substances and therefore, under normal conditions in water or foods, they should not interfere with E. coli assays based on measurements of β-glucuronidase activity. Received: 17 February 1998/Accepted: 1 July 1998     

Pharmacokinetic–Pharmacodynamic Modeling of the Hydroxy Lerisetron Metabolite L6-OH in Rats: An Integrated Parent–Metabolite Model

Purpose The twofold aim of this study was to characterize in vivo in rats the pharmacokinetics (PK) and pharmacodynamics (PD) of L6-OH, a metabolite of lerisetron with in vitro pharmacological activity, and evaluate the extent to which L6-OH contributes to the overall effect. Methods The PK of L6-OH was determined directly postmetabolite i.v. dose (PK-1), and also simultaneously for L (lerisetron concentration) and for generated L6-OH after lerisetron dose (200 μg kg⁻¹, i.v.), using Nonlinear Mixed Effects Modeling with an integrated parent–metabolite PK model (PK-2). Surrogate effect was measured by inhibition of serotonin-induced bradycardia. Protein binding was assayed via ultrafiltration and all quantification was performed via liquid chromatography-electrospray ionization-mass spectrometry. Results L6-OH showed elevated plasma and renal clearances, and volume of distribution (PK-1). The in vivo potency (PD) of L6-OH was high (EC₅₀ = 0.098 ng mL⁻¹ and EC_50unbound = 0.040 ng mL⁻¹). Total clearance for L (PK-2) in the presence of generated L6-OH (CL_L = CL_→L6-OH + CL_n) was 0.0139 L min⁻¹. Most of this clearance was L6-OH formation (F_c = 99.6%), but only an 8.6% fraction of L6-OH was released into the bloodstream. The remainder undergoes biliar and fecal elimination. The parameters estimated from PK-2 were used to predict concentrations of L6-OH (Cp_L6) generated after a lerisetron therapeutic dose (10 μg kg⁻¹) in the rat. These concentrations are needed for the PD model and are below the quantification limit. Cp_L6max was less than the EC₅₀ of L6-OH. Conclusions We conclude that after lerisetron administration, L6-OH is extensively formed in the rat but it is quickly eliminated; therefore, besides being equipotent with the parent drug, the L6-OH metabolite does not influence the effect of lerisetron.     

Epidemiological features,resistance genes,and clones among community-onset methicillin-resistant Staphylococcus aureus (CO-MRSA) isolates detected in northern Spain

Twenty-nine community-onset methicillin-resistant Staphylococcus aureus (CO-MRSA) isolates were prospectively selected according to epidemiological criteria among 374 MRSA isolates collected in our laboratory during 2009–2010 in order to determine which community-associated MRSA (CA-MRSA) and healthcare-associated MRSA (HA-MRSA) clones are circulating in the community in northern Spain. PVL genes were detected in 5 strains (17.2%) that belonged to SCCmec type IV or V and to the agr group I (ST8 and ST2050), agr group II (ST121), and agr group III (ST30 and ST852). These strains were isolated from patients with different clinical manifestations such as urinary tract infection, abscess, or pneumonia, and most of them belonged to emergency department patients with no history of visits to General Practitioners (GPs) in the year before the isolation. We considered that the prevalence of CA-MRSA in community-onset isolates was low (17.2%). A high proportion of the CO-MRSA strains (58.6%) were ST125-MRSA-IVc (CC5), responsible for most of the infections caused by HA-MRSA strains in Spain. This endemic clone is also circulating in the community of northern Spain as we could demonstrate in this study. Antimicrobial resistance was found in spa type t067 isolates linked to the presence of ant(4′)-Ia and msr(A). Most of the CO-MRSA isolates in this study corresponded to spa types more associated to the hospital environment, suggesting the interchange of genetic lineages of MRSA among community and hospital niches.     

Biochemical markers of myocardial remodelling in hypertensive heart disease

The intricate mechanisms responsible for the structural remodelling of the myocardium that facilitates the evolution to heart failure in hypertensive patients, namely in those with left ventricular hypertrophy, requires from clinicians the utilization of a multibiomarker approach for short-term and long-term stratification as well as prognostication of patients. Biochemical markers may also help to identify patients with no clinical evidence of hypertensive heart disease, and provide information about the need for more aggressive therapy during different stages of the disease, and potentially provide valuable biochemical data for the specialist. Although there is a continuous and complex interplay between biochemical and imaging markers, perhaps their use will also have the potential to modify the medical management of patients with hypertensive heart disease and therapeutic decision-making by tailoring a targeted therapy according to the predominant mechanism of myocardial remodelling. This article will review in brief the most relevant information on a panel of circulating molecules that may accomplish the criteria required to be considered as biochemical markers of the cardiomyocyte and non-cardiomyocyte structural changes that occur in the hypertensive myocardium.     

Adherence to the Mediterranean diet reduces mortality in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain)

Epidemiological studies show that adherence to a Mediterranean diet (MD) increases longevity; however, few studies are restricted to Mediterranean populations or explore the effect of a MD pattern that directly incorporates olive oil. Therefore the relationship between adherence to the MD and mortality was studied within the the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). The EPIC-Spain analysis included 40 622 participants (37·7?% males) aged 29-69 years who were recruited from five Spanish regions in 1992-1996. During a mean follow-up of 13·4 years, 1855 deaths were documented: 913 from cancer, 399 from CVD, 425 from other causes and 118 from unknown causes of death. Risk of all-cause and cause-specific mortality was assessed according to the level of adherence to a relative MD (rMED) score, measured using an 18-unit scale incorporating nine selected dietary components. A high compared with a low rMED score was associated with a significant reduction in mortality from all causes (hazard ratio (HR) 0·79; 95?% CI 0·69, 0·91), from CVD (HR 0·66; 95?% CI 0·49, 0·89), but not from overall cancer (HR 0·92; 95?% CI 0·75, 1·12). A 2-unit increase in rMED score was associated with a 6?% (P?相似文献