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We report two cationic silver‐based coordination polymers with N‐donating quinoxaline as the linker. [Ag(quinoxaline)+] [–O3S(CH2)2SO3–]0.5·2H2O (which we denote as SLUG‐37 for University of California, Santa Cruz, structure No. 37; quinoxaline = C8H6N2) and [Ag(quinoxaline)+][CH3CO2–] (SLUG‐38) were solved by single‐crystal X‐ray diffraction and further characterized by several solid‐state techniques. Both structures consist of cationic 1D Ag‐quinoxaline chains arranged into π‐stacked layers, with charge‐balancing anions residing in the interlamellar space. The materials can be synthesized hydrothermally as well as in higher yield by reflux or room temperature conditions. The luminescent behavior of SLUG‐37 exhibits a strong white emission making it potentially useful as white LEDs. [ABSTRACT FROM AUTHOR]

Aims To characterize the association with Type 2 diabetes of known Type 2 diabetes risk variants in people in Malaysia of Malay, Chinese and Indian ancestry who participated in the Malaysian Cohort project. Methods We genotyped 1604 people of Malay ancestry (722 cases, 882 controls), 1654 of Chinese ancestry (819 cases, 835 controls) and 1728 of Indian ancestry (851 cases, 877 controls). First, 62 candidate single-nucleotide polymorphisms previously associated with Type 2 diabetes were assessed for association via logistic regression within ancestral groups and then across ancestral groups using a meta-analysis. Second, estimated odds ratios were assessed for excess directional concordance with previously studied populations. Third, a genetic risk score aggregating allele dosage across the candidate single-nucleotide polymorphisms was tested for association within and across ancestral groups. Results After Bonferroni correction, seven individual single-nucleotide polymorphisms were associated with Type 2 diabetes in the combined Malaysian sample. We observed a highly significant excess in concordance of effect directions between Malaysian and previously studied populations. The genetic risk score was strongly associated with Type 2 diabetes in all Malaysian groups, explaining from 1.0 to 1.7% of total Type 2 diabetes risk variance. Conclusion This study suggests there is substantial overlap of the genetic risk alleles underlying Type 2 diabetes in Malaysian and other populations. [ABSTRACT FROM AUTHOR]

The methylation status of human spermatozoa has been examined in relation to the isopycnic density of these cells and their tendency to spontaneously default to an apoptotic state. DNA methylation was evaluated using three independent procedures: high-pressure liquid chromatography, flow cytometry and immunocytochemistry. All three techniques revealed that poor-quality spermatozoa recovered from the low-density region of Percoll gradients were characterised by a global hypermethylation of their DNA. Hypermethylation was visualised with an anti-5-methylcytosine antibody as punctate areas of cross-reactivity randomly distributed throughout the chromatin. Immunocytochemical evidence was also obtained suggesting that the sperm mitochondrial genome exists in a heavily methylated state, as a possible buffer against unscheduled transcription. Defective human spermatozoa were also shown to exhibit a tendency to default to an apoptotic state characterised by an increase in annexin V binding. The measurement of annexin V binding levels in individual sperm populations was found to be highly correlated with sperm vitality ( P < 0.001) and the methylation status of their DNA ( P < 0.001). We conclude that the generation of defective, apoptotic human spermatozoa is associated with disorders of spermatogenesis that lead to a global hypermethylation of their nuclear DNA. [ABSTRACT FROM AUTHOR]

Vilain RE, Dudding T, Braye SG, Groombridge C, Meldrum C, Spigelman AD, Ackland S, Ashman L, Scott RJ. Can a familial gastrointestinal tumour syndrome be allelic with Waardenburg syndrome? Familial gastrointestinal stromal tumours (GISTs) are rare but otherwise well-characterized tumour syndromes, most commonly occurring on a background of germline-activating mutations in the tyrosine kinase receptor c-KIT. The associated clinical spectrum reflects the constitutive activation of this gene product across a number of cell lines, generating gain-of-function phenotypes in interstitial cells of Cajal (GIST and dysphagia), mast cells (mastocytosis) and melanocytes (hyperpigmentation). We report a three-generation kindred harbouring a c-KIT germline-activating mutation resulting in multifocal GISTs, dysphagia and a complex melanocyte hyperpigmentation and hypopigmentation disorder, the latter with features typical of those observed in Waardenburg type 2 syndrome (WS2F). Sequencing of genes known to be causative for WS [microphthalmia transcription factor ( MITF), Pax3, Sox10, SNAI2] failed to show any candidate mutations to explain this complex cutaneous depigmentation phenotype. Our case report conclusively expands the clinical spectrum of familial GISTs and shows a hitherto unrecognized link to WS. Possible mechanisms responsible for this novel cause of WS2F will be discussed. [ABSTRACT FROM AUTHOR]

Objective There is evidence that estrogens and some of their metabolites are involved in endometrial cancer pathogenesis. As estrogens mediate their effects via the estrogen receptors, ESR1 and ESR2, the objective of this investigation was to determine whether six single nucleotide polymorphisms (SNPs) in these two genes were over-represented in a population of endometrial cancer patients compared with a healthy matched control population, thereby associating differences in these genes with endometrial cancer. Design The study is a case–control investigation large enough to detect a two-fold increased risk, assuming a dominant genetic model, with P = 0.05 and 80% power. Setting The study and control populations were all from the Hunter-New England region of New South Wales, Australia collected between the years 1992 and 2005. Population The study consisted of 191 endometrial cancer patients and 291 healthy controls matched for gender and age. Methods Two SNPs in ESR1 and four SNPs in ESR2 were genotyped using PCR-based restriction fragment length polymorphism analysis and real-time PCR. Odds ratios were calculated using unconditional logistic regression and SIMHAP was used for haplotype analysis, adjusting for potential endometrial cancer risk factors. Kaplan–Meier survival analysis, Cox regression and t tests were used to examine the patient’s age of diagnosis of endometrial cancer and genotype. Main outcome measures Over-representation of ESR1 and ESR2 polymorphisms in the endometrial cancer population compared with the control population indicates an involvement in the development and/or progression of disease. Results Two ESR1 (rs2234693 and rs9340799) and two ESR2 (rs1255998 and rs944050) polymorphisms were associated with an increased risk of endometrial cancer. Following adjustment for risk factors, the association with the ESR1 and ESR2 polymorphisms (rs2234693, rs1255998 and rs944050) remained highly significant. Haplotype analysis revealed that carriers of the ESR1 haplotype (variant alleles; rs2234693 and rs9340799) and the ESR2 haplotype (variant allele; rs1255998 and wild-type alleles; rs944050, rs4986938 and rs1256049) were at an increased risk (OR 1.862, P = 0.013 and OR 1.918, P = 0.046 respectively). This risk was even greater in women carrying both risk haplotypes (OR 5.041, P = 0.007). Conclusions Our data suggest that the ESR1 (rs2234693 and rs9340799) and the ESR2 (rs1255998 and rs944050) polymorphisms may be associated with an increased risk of developing endometrial cancer. [ABSTRACT FROM AUTHOR]

Atlantic salmon ( Salmo salar) was once native to Lake Ontario, however, its numbers rapidly declined following colonisation by Europeans and the species was extirpated by 1896. Government agencies surrounding Lake Ontario are currently undertaking a variety of studies to assess the feasibility of reintroducing Atlantic salmon. We released hatchery-reared adult Atlantic salmon into a Lake Ontario tributary to examine spawning interactions between this species and fall-spawning exotic salmonids found in the same stream. Chinook salmon, coho salmon and brown trout were observed interacting with spawning Atlantic salmon in nearly one-quarter of our observation bouts, with chinook salmon interacting most frequently. Whereas a previous investigation found that chinook salmon caused elevated agonistic behaviour and general activity by spawning Atlantic salmon, the present study found that interspecific courtship was the most common form of exotic interaction with spawning Atlantic salmon. In particular, we observed precocial male Chinook salmon courting female Atlantic salmon and defending the female against approach by male Atlantic salmon. We discuss the potential implications of these interactions on the Lake Ontario Atlantic salmon reintroduction programme. [ABSTRACT FROM AUTHOR]

Scott RJ, Poos MS, Noakes DLG, Beamish FWH. Effects of exotic salmonids on juvenile Atlantic salmon behaviour. Ecology of Freshwater Fish 2005. © Blackwell Munksgaard, 2005 We examined the effects of two salmonid species, chinook salmon ( Oncorhynchus tschwaytscha) and brown trout ( Salmo trutta), both exotic species to Lake Ontario, on behaviour and foraging success of juvenile Atlantic salmon ( S. salar), a native species to Lake Ontario, in an artificial stream. We found that both exotic species have effects on Atlantic salmon behaviour, but that neither had an effect on foraging success. These results may explain why the Atlantic salmon re-introduction programme in Lake Ontario has had little success, as more than 3 million exotic salmonids are released in Lake Ontario streams annually. [ABSTRACT FROM AUTHOR]

: To assess the pharmacokinetics of alosetron, its effect on in vivo enzyme activities, and influence of demographic factors during repeated dosing. : Thirty healthy men and women received 1 mg oral alosetron twice-daily for 29.5 days and a single oral dose of a metabolic probe cocktail before and on the last day of alosetron dosing. Serum alosetron concentrations were measured on days 1, 8, 15, 22 and 29. Probe-substrate and metabolite concentrations were measured after each cocktail dose. : Alosetron accumulation in serum was negligible. Exposure to alosetron did not alter probe-metabolite/substrate ratios associated with CYP2C19, 2E1, 2C9, or 3A4 activity, but modestly decreased those associated with CYP1A2 and N-acetyltransferase activity. Systemic exposure to alosetron was higher in women, positively correlated with age and body mass index, and negatively correlated with CYP1A2 activity. Incidence of constipation was higher in women, but not associated with alosetron concentration. : Single dose data can reliably predict the pharmacokinetics of alosetron after repeated doses. Alosetron exhibits limited potential for inhibition of cytochrome P450-mediated metabolism. Interindividual differences in alosetron pharmacokinetics associated with demographic factors may be related to strong dependence on metabolism by CYP1A2. [ABSTRACT FROM AUTHOR]

Scott RJ. Assortative mating between adjacent populations of threespine stickleback ( Gasterosteus aculeatus). Ecology of Freshwater Fish 2004: 13: 1–7. © Blackwell Munksgaard, 2004 The idea that sexual selection can lead to rapid evolution of premating isolation among independent populations (speciation) has been controversial, but is rapidly gaining acceptance among many evolutionary biologists as empirical examples accumulate. A survey of male signals and female preferences (mate recognition systems, MRSs) across the contact zone between divergent populations of threespine stickleback ( Gasterosteus aculeatus) in Conner Creek, WA, revealed a spatial pattern of MRSs that is consistent with speciation via sexual selection. Females from locations that possessed melanic males preferred melanic males whereas females from populations possessing typical mosaic males (red chin, blue iris, and blue-green dorsum) preferred mosaic males. I argue that sensory drive sexual selection, acting through geographically varying spectral properties, is responsible for the observed population differences and premating isolation between the adjacent populations. [ABSTRACT FROM AUTHOR]

Thompson E, Meldrum CJ, Crooks R, McPhillips M, Thomas L, Spigelman AD, Scott RJ. Hereditary non-polyposis colorectal cancer and the role of hPMS2 and hEXO1 mutations. Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant, inherited condition that is characterized primarily by the development of early-onset colorectal cancer and a number of other epithelial malignancies. The underlying genetic basis of the disease is associated with a breakdown of DNA-mismatch repair. There are many genes involved in DNA-mismatch repair, and five of them have been implicated in HNPCC. Two of the genes ( hMSH2 and hMLH1) account for the majority of HNPCC families (approximately 60%), and it is not known what the exact contributions of the remaining three genes ( hPMS1, hPMS2, and hMSH6) are in relation to this condition. In addition, a sixth gene ( hEXO1) has been associated with a disease phenotype that is consistent with HNPCC. Current estimates suggest that all four of these genes, combined, may account for up to 5% of families. In this report, we examine the contribution of hPMS2 and hEXO1 to a well-defined set of families that fulfill the diagnostic criteria for HNPCC. The genes, hPMS2 and hEXO1, were studied by denaturing high performance liquid chromatography (DHPLC) analysis in 21 families that have previously been determined not to have mutations in hMSH2 or hMLH1. hPMS2 accounts for a small proportion of HNPCC families, and none were deemed to be associated with hEXO1. Mutations in hPMS2 appear to account for a small proportion of families adhering to the Amsterdam II criteria, whereas hEXO1 does not appear to be associated with HNPCC. [ABSTRACT FROM AUTHOR]

Summary: A key step in pollen formation is the segregation of the products of male meiosis into a tetrad of microspores, each of which develops into a pollen grain. Separation of microspores does not occur in tetraspore (tes) mutants of Arabidopsis thaliana, owing to the failure of male meiotic cytokinesis. tes mutants thus generate large ‘tetraspores’ containing all the products of a single meiosis. Here, we report the positional cloning of the TES locus and details of the role played by the TES product in male cytokinesis. The predicted TES protein includes an N-terminal domain homologous to kinesin motors and a C-terminus with little similarity to other proteins except for a small number of plant kinesins. These include the Arabidopsis HINKEL protein and NACK1 and two from tobacco (Nishihama et al ., 2002), which are involved in microtubule organization during mitotic cytokinesis. Immunocytochemistry shows that the characteristic radial arrays of microtubules associated with male meiotic cytokinesis fail to form in tes mutants. The TES protein therefore is likely to function as a microtubule-associated motor, playing a part either in the formation of the radial arrays that establish spore domains following meiosis, or in maintaining their stability. [ABSTRACT FROM AUTHOR]

Summary 1. Several genetically modified herbicide-tolerant (GMHT) crops have cleared most of the regulatory hurdles required for commercial growing in the United Kingdom. However, concerns have been expressed that their management will have negative impacts on farmland biodiversity as a result of improved control given by the new herbicide regimes of the arable plants that support farmland birds and other species of conservation value. 2. The Farm-Scale Evaluations (FSE) project is testing the null hypothesis that there is no difference between the management of GMHT varieties of beet, oilseed rape and maize and that of comparable conventional varieties in their effect on the abundance and diversity of arable plants and invertebrates. The FSE also aims to estimate the magnitude and consider the implications of any differences that are found. 3. The experimental design of the FSE is a randomized block, with two treatments allocated at random to half-fields. The target sample is around 60–75 fields for each crop, selected to represent variation of geography and intensity of management across Britain. The experimental crops are managed by commercial farmers as if under commercial conditions. 4. Biodiversity indicators have been selected from plants and terrestrial invertebrates to identify differences between crop management regimes that may result in important ecological changes over larger scales of space and time. Field sampling is at fixed points, mainly along transects from the field boundary, starting before the crop is sown and continuing into following crops. 5. Synthesis and applications. The FSE is best considered as an investigation into the effects of contrasting crop management regimes on farmland biodiversity, rather than a study of the effects of genetic modification. It could become a model for future studies of ecological effects of the way we use and manage agricultural land. [ABSTRACT FROM AUTHOR]

Summary Few Arabidopsis mutants defective in early male or female germline development have been reported. A novel extinction screen has been devised which permits the identification of mutants deficient in the earliest stages of anther development. Using mutagenized plants carrying GUS reporter constructs driven by tapetal-specific promoters originally derived from Brassica genes, a wide spectrum of mutants have been identified in Arabidopsis, ranging from those defective in archesporial cell differentiation to others expressed later in development. Crosses between these lines and known anther development mutants have enabled the identification of lines carrying mutations in genes expressed during very early anther formation. Initial characterization reveals these early mutants fall into two classes, gne (GUS-negative) 1-like, and gne2-like. Members of the gne1 mutant class initiate all four layers of the anther wall and an appropriate number of sporogenous cells; however, as development proceeds the tapetal and middle-layer cells enlarge, eventually crushing the sporogenous cells. The gne2 class anthers are disrupted at an earlier stage, with the middle and tapetal layers failing to form, and an excess of sporogenous cells developing until the germline aborts late in meiosis II. Analysis of these mutants has already raised questions about the accuracy of current models of angiosperm anther development. [ABSTRACT FROM AUTHOR]

The article presents the authors' insights on the role of evidence-based medicine (EBM) in biomarkers. According to the authors, EBM provides methodological issues on biomarker development, validation and application which includes random measurement error, proper model analysis, and translation to clinical practice. Moreover, they mention the use of randomized controlled trials (RCTs) to prove the use of EBM application in clinical practices.

The article discusses the findings of a study of the frequency and nature of hMSH6 germline mutations in Polish patients with colorectal, endometrial and ovarian cancers. A description of the experimental setup and measurement method is given. A chart is presented that shows hMSH6 germlike alterations and pedigree data on the families with detected abnormalities. The study suggests that hMSH6 examination be considered for probands with multiple primary tumors.

Presents a letter to the editor in response to articles on genetic testing in cancer research, published in the "Internal Medicine Journal."

Poly­[tin(II)-μ-phenyl­phospho­nato], [Sn(C6H5O3P)] n, was synthesized solvothermally at 423 K and crystallized in the monoclinic system, space group Cc. The inorganic layers consist of alternating pyramidal Sn and tetrahedral P centers, joined by doubly bridging O atoms. The corner-sharing SnO3 and PO3C6H5 polyhedra define a corrugated layer of six-membered rings. The layers are connected along the unique b axis by interdigitated phenyl rings of the phenyl­phospho­nate groups. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about the mutational analysis of genes.

The title compound, [HgBr2(C10H8N2O2)], has an Hg atom surrounded by two Br atoms and two O atoms from a chelating BipyO2 ligand (BipyO2 is 2,2′-bipyridine N, N′-dioxide), forming a severely distorted tetrahedron. In addition, two weak Hg⋯Br bonds link these complexes into a chain. [ABSTRACT FROM AUTHOR]

Colorless needlelike single crystals of the title compound are hydrothermally synthesized from aqueous solutions of Sb(OAc)3 and H2SO4 (autoclave, 150 °C, 72 h, 87% yield). [ABSTRACT FROM AUTHOR]

The title compound, [HgI2(C10H8N2O2)], is a further example of a mercury halide complex of the chelating BipyO2 ligand (BipyO2 is 2,2′-bipyridine N, N′-dioxide). As observed for similar compounds, the coordination polyhedron of the Hg atom is a severely distorted tetrahedron, in which Hg is coordinated by two I atoms and two O atoms of the ligand. [ABSTRACT FROM AUTHOR]

In the crystal structure of the title compound, [HgCl2(C10H8N2O2)], the Hg atom has severely distorted tetrahedral coordination by two Cl atoms and by two O atoms of the chelating ligand. Additional weak Hg⋯Cl bonds link the mol­ecules into a chain. [ABSTRACT FROM AUTHOR]

Aims: The use of multiple probe substrates to evaluate the activity of drug metabolizing enzymes requires that there are no inter-substrate interactions. As part of a series of studies to develop a clinically useful collection of probe substrates that could be given alone or in any combination, we observed an interaction between midazolam (MDZ) and another component of the six-drug cocktail. Published data indicated that the interacting component was likely to be chlorzoxazone. This was investigated as part of a second study. The data relating to the interaction from both studies are reported here., Methods: Both studies were performed in 16 healthy subjects. All treatments were given orally after an overnight fast. In study 1, which was performed to a four-period, open, crossover design, subjects received on separate occasions MDZ 5 mg, diclofenac 25 mg, a four drug cocktail (caffeine 100 mg, mephenytoin 100 mg, debrisoquine 10 mg and chlorzoxazone 250 mg) and a six drug cocktail (caffeine 100 mg, mephenytoin 100 mg, debrisoquine 10 mg, chlorzoxazone 250 mg, diclofenac 25 mg and MDZ 5 mg). In study 2, which was performed to a two-period, open, crossover design, subjects received a five drug cocktail (as the six drug cocktail in the first study, but without chlorzoxazone and with diclofenac dose increased to 50 mg) and a six drug cocktail (as five drug cocktail, with chlorzoxazone 250 mg). In both studies, blood samples were taken for measurement of plasma MDZ and 1-hydroxy MDZ (1-OH MDZ) concentrations. In study 1, blood samples were taken up to 12 h post-dose while in study 2 a single sample was taken 2 h after dosing. In study 1, the potential interaction between MDZ and the other components of the six drug cocktail was assessed by comparing AUClast ratios (1-OH MDZ/MDZ) between the two treatments. Additionally, a single sampling timepoint of 2 h post-dose for determination of concentration, rather than AUC, ratios was established. The 2 h plasma concentration ratios from studies 1 and 2 were combined and a pooled analysis performed to compare ratios within each study (to determine the change in ratio when MDZ was dosed with and without chlorzoxazone) and between studies (to determine the consistency of the ratios when MDZ was given either as part of the two six drug cocktails or when given alone and as part of the five drug cocktail)., Results: In study 1, both the AUClast ratio and the 2 h post-dose plasma concentration ratio were reduced when MDZ was given as part of the six drug cocktail in comparison with those for MDZ alone. This was the result of an increase in MDZ, rather than decrease in 1-OH MDZ, concentrations and was considered to result from a reduction in first pass metabolism of MDZ. The geometric mean AUClast values (with 95% CI) for MDZ were 95.6 (79.0, 115.7) and 160.4 (133.6, 192.6) microg l(-1) h when given alone and as part of the six drug cocktail, respectively. The corresponding values for 1-OH MDZ were 789.6 (697.6, 893.6) and 791.4 (701.7, 892.6) microg l(-1) h. The ratio of adjusted geometric mean AUClast ratios for the two treatments was 1.82 (90% CI 1.48, 2.23, P < 0.001). The pooled plasma 1-OH MDZ/MDZ ratio data from both studies showed that the differences in MDZ metabolism observed in study 1 were replicated in study 2. The adjusted geometric mean 1-OH MDZ/MDZ ratios when MDZ was given alone and as part of the six drug cocktail were 7.79 and 4.59, respectively, for study 1 (ratio 1.70, 95% CI 1.36, 2.11, P < 0.001) and 7.64 and 4.60 for study 2 (ratio 1.66, 95% CI 1.34, 2.06, P < 0.001). These data indicate that when given orally chlorzoxazone interacts with MDZ, increasing plasma MDZ concentrations. In contrast, there was no difference between the plasma 1-OH MDZ/MDZ ratios when MDZ was given alone and as part of the five drug cocktail indicating that there were no interactions between MDZ and any of the other components of that cocktail., Conclusions: Chlorzoxazone appears to significantly influence the pharmacokinetics of oral MDZ, probably through inhibition of first pass metabolism by CYP3A in the GI tract. Data from these studies and literature evidence showing a further interaction between chlorzoxazone and CYP1A2 substrates and questions concerning the specificity of chlorzoxazone as a probe substrate for CYP2E1, indicate that the use of chlorzoxazone in multisubstrate probe cocktails should be avoided.