Optimization of trans-Resveratrol bioavailability for human therapy

We have developed an innovative soluble galenic form to overcome the low absorption of trans-Resveratrol (t-Res) as a dry powder. We present here data on pharmacokinetics, bioavailability, and toxicity of t-Res in human volunteers treated with this soluble form, plus additional data on biological effects in rodents. Fifteen healthy volunteers of both sexes received 40 mg of t-Res in two forms, the soluble formulation (caplets) and the original powder (capsules), in a crossover design. Blood samples were collected at 15 min, 30 min, and every hour for 5 h. Plasma concentrations of t-Res and its metabolites were analyzed by liquid chromatography and mass spectrometry. The single dose (40 mg) of the soluble t-Res was well absorbed and elicited biologically efficient blood levels (0.1–6 μM) for several hours, despite metabolization into glucuronide and sulfate conjugates coupled to renal elimination. In contrast, t-Res administered as a dry powder barely elicited efficient blood levels for a short duration. The new formulation led to 8.8-fold higher t-Res levels in plasma versus the powder. t-Res metabolism was not modified and neither intolerance nor toxicity were observed during the study and the following week. The soluble formulation elicited a robust anti-inflammatory effect in various tissues of mice fed a high-fat diet, while dry powder t-Res was almost inactive. Our data suggest that significant improvements in t-Res bioavailability and efficiency can be obtained by this soluble galenic form, also allowing lower doses. The use of t-Res in human therapy is thus greatly facilitated and the toxicity risk is reduced.     

Limnichthys polyactis,a new species of blennioid fish from New Zealand,with notes on the taxonomy and distribution of other Creediidae (including Limnichthyidae)

Abstract

Limnichthys polyactis n.sp., from the North Island of New Zealand, differs from its nearest relative, the more widespread L. rendahli Parrott, in having a shorter preanal distance (the origin of the anal fin precedes the origin of the dorsal fin, as in the other four species of Limnichthys), fewer cirri along the lower jaw, a shorter snout, and fewer vertebrae. The deepest known occurrence of L. polyactis is 6 m, compared to at least 165 m for L. rendahli. It is suggested that the families Creediidae and Limnichthyidae be combined, the former name having precedence. Notes are given on the taxonomy and distribution of the 13 recognised species, and characters for their separation are keyed.     

Location and timing of Asian carp spawning in the Lower Missouri River

We sampled for eggs of Asian carps, (bighead carp Hypophthalmichthys nobilis, silver carp H. molitrix, and grass carp Ctenopharyngodon idella) in 12 sites on the Lower Missouri River and in six tributaries from the months of May through July 2005 and May through June 2006 to examine the spatial and temporal dynamics of spawning activity. We categorized eggs into thirty developmental stages, but usually they could not be identified to species. We estimated spawning times and locations based on developmental stage, temperature dependent rate of development and water velocity. Spawning rate was higher in the daytime between 05:00 and 21:00 h than at night. Spawning was not limited to a few sites, as has been reported for the Yangtze River, where these fishes are native, but more eggs were spawned in areas of high sinuosity. We employ a sediment transport model to estimate vertical egg concentration profiles and total egg fluxes during spawning periods on the Missouri River. We did not identify substantial spawning activity within tributaries or at tributary confluences examined in this study.     

Structure and activity of the NAD(P)+‐dependent succinate semialdehyde dehydrogenase YneI from Salmonella typhimurium

Aldehyde dehydrogenases are found in all organisms and play an important role in the metabolic conversion and detoxification of endogenous and exogenous aldehydes. Genomes of many organisms including Escherichia coli and Salmonella typhimurium encode two succinate semialdehyde dehydrogenases with low sequence similarity and different cofactor preference (YneI and GabD). Here, we present the crystal structure and biochemical characterization of the NAD(P)⁺‐dependent succinate semialdehyde dehydrogenase YneI from S. typhimurium. This enzyme shows high activity and affinity toward succinate semialdehyde and exhibits substrate inhibition at concentrations of SSA higher than 0.1 mM. YneI can use both NAD⁺ and NADP⁺ as cofactors, although affinity to NAD⁺ is 10 times higher. High resolution crystal structures of YneI were solved in a free state (1.85 Å) and in complex with NAD⁺ (1.90 Å) revealing a two domain protein with the active site located in the interdomain interface. The NAD⁺ molecule is bound in the long channel with its nicotinamide ring positioned close to the side chain of the catalytic Cys268. Site‐directed mutagenesis demonstrated that this residue, as well as the conserved Trp136, Glu365, and Asp426 are important for activity of YneI, and that the conserved Lys160 contributes to the enzyme preference to NAD⁺. Our work has provided further insight into the molecular mechanisms of substrate selectivity and activity of succinate semialdehyde dehydrogenases. © 2012 Wiley Periodicals, Inc.     

Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis

Background:

There is an increased risk of venous thromboembolism among women taking oral contraceptives. However, whether there is an additional risk among women with polycystic ovary syndrome (PCOS) is unknown.

Methods:

We developed a population-based cohort from the IMS LifeLink Health Plan Claims Database, which includes managed care organizations in the United States. Women aged 18–46 years taking combined oral contraceptives and who had a claim for PCOS (n = 43 506) were matched, based on a propensity score, to control women (n = 43 506) taking oral contraceptives. Venous thromboembolism was defined using administrative coding and use of anticoagulation. We used Cox proportional hazards models to assess the relative risk (RR) of venous thromboembolism among users of combined oral contraceptives with and without PCOS.

Results:

The incidence of venous thromboembolism among women with PCOS was 23.7/10 000 person-years, while that for matched controls was 10.9/10 000 person-years. Women with PCOS taking combined oral contraceptives had an RR for venous thromboembolism of 2.14 (95% confidence interval [CI] 1.41–3.24) compared with other contraceptive users. The incidence of venous thromboembolism was 6.3/10 000 person-years among women with PCOS not taking oral contraceptives; the incidence was 4.1/10 000 person-years among matched controls. The RR of venous thromboembolism among women with PCOS not taking oral contraceptives was 1.55 (95% CI 1.10–2.19).

Interpretation:

We found a 2-fold increased risk of venous thromboembolism among women with PCOS who were taking combined oral contraceptives and a 1.5-fold increased risk among women with PCOS not taking oral contraceptives. Physicians should consider the increased risk of venous thromboembolism when prescribing contraceptive therapy to women with PCOS.Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. The National Institutes of Health criteria estimates its prevalence in the United States to be between 6% and 10%, while the Rotterdam criteria estimates the prevalence to be as high as 15%.¹ Although its cause is not entirely known, the diagnostic criteria include oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries.² Women often present with clinical manifestations of high androgen levels, including facial hair growth (hirsutism), acne vulgaris and hair loss on the scalp. Previous studies reported the prevalence of impaired glucose tolerance to be 31.1%–35.2% and the prevalence of type 2 diabetes to be 7.5%–9.8% among women with PCOS.^3,4 A recent consensus workshop reported that the prevalence of several known risk factors for cardiovascular disease (hypertension, diabetes, abdominal obesity, psychological factors, smoking, altered apoA1/ApoB ratios) are doubled among women with PCOS compared with matched controls.^1,5Combined oral contraceptives are the mainstay treatment for PCOS. However, they are also known to elevate the risk of venous thromboembolism and cardiovascular disease.⁶ To date, contraceptive studies involving women with PCOS have focused mainly on efficacy, evaluating the effect of combined oral contraceptives on the reduction of hirsutism and hyperandrogenism.^7,8 Two studies assessed the metabolic effects of combined oral contraceptives in PCOS, but these studies had small sample sizes and could not evaluate for cardiovascular events.^9,10Although women with PCOS have an increase in both cardiovascular risk factors and subclinical cardiovascular disease,¹¹ recent guidelines have concluded there are no data in the literature assessing the association between the use of oral contraceptives and cardiovascular disease among women with PCOS.² Because combined oral contraceptives are the mainstay treatment, our objective was to determine whether women with PCOS taking combined oral contraceptives have a greater risk of venous thromboembolism compared with other contraceptive users. We also examined whether women with PCOS not taking oral contraceptives had an increased risk of venous thromboembolism compared with the general population.     

Identifying human-rhesus macaque gene orthologs using heterospecific SNP probes

We genotyped a Chinese and an Indian-origin rhesus macaque using the Affymetrix Genome-Wide Human SNP Array 6.0 and cataloged 85,473 uniquely mapping heterospecific SNPs. These SNPs were assigned to rhesus chromosomes according to their probe sequence alignments as displayed in the human and rhesus reference sequences. The conserved gene order (synteny) revealed by heterospecific SNP maps is in concordance with that of the published human and rhesus macaque genomes.Using these SNPs' original human rs numbers, we identified 12,328 genes annotated in humans that are associated with these SNPs, 3674 of which were found in at least one of the two rhesus macaques studied. Due to their density, the heterospecific SNPs allow fine-grained comparisons, including approximate boundaries of intra- and extra-chromosomal rearrangements involving gene orthologs, which can be used to distinguish rhesus macaque chromosomes from human chromosomes.     

Role of hydrophobicity in bacterial adherence to carbon nanostructures and biofilm formation

The role of cell and surface hydrophobicity in the adherence of the waterborne bacterium Mycobacterium smegmatis to nanostructures and biofilm formation was investigated. Carbon nanostructures (CNs) were synthesized using a flame reactor and deposited on stainless steel grids and foils, and on silicon wafers that had different initial surface hydrophobicities. Surface hydrophobicity was measured as the contact angle of water droplets. The surfaces were incubated in suspensions of isogenic hydrophobic and hydrophilic strains of M. smegmatis and temporal measurements of the numbers of adherent cells were made. The hydrophobic, rough mutant of M. smegmatis adhered more readily and formed denser biofilms on all surfaces compared to its hydrophilic, smooth parent. Biofilm formation led to alterations in the hydrophobicity of the substratum surfaces, demonstrating that bacterial cells attached to CNs are capable of modifying the surface characteristics.     

The calculation of structural,elastic and phase stability properties of minerals using first principles techniques: A comparison of HF,DFT and Hybrid functional treatments of exchange and correlation

We benchmark the performance of four treatments of electron exchange and correlation in the prediction of structural and elastic properties of a range of minerals. The treatments used are the Hartree-Fock (HF) theory, the local density approximation (LDA) and the generalised gradient approximation (GGA) to the density functional theory (DFT) and Becke's three parameter hybrid functional (B3LYP). We find that the hybrid functional, B3LYP method yields computed elastic properties in significantly better agreement to experiment than HF or DFT-LDA and performs at least as well, if not better than the most successful DFT-GGA functionals. We suggest that B3LYP is a simple, reliable and computationally efficient tool for the ab initio simulation of mineral systems.