Association of the MDR1 (ABCB1) gene 3435C> T polymorphism with male infertility

Infertility is a common problem affecting one in six couples, and in 30% of infertile couples, the male factor is a major cause due to defective sperm quality. P-glycoprotein (P-gp), a product of the MDR1 (ABCB1) gene, may be a link between genetic and environmental factors contributing to the development of male infertility because pesticides (P-gp substrates) are well established factors of male infertility. The aim of the present study was to examine the effect of the MDR1 gene 3435C>T polymorphism on male infertility. In total, 162 male patients undergoing semen analysis due to initial infertility workup were included in the study. The control group consisted of 191 healthy males with proven fertility. MDR1 3435C>T genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Assessment of MDR1 genotypes among the infertile men showed that 17.9% of subjects were carriers of the CC genotype, 58.0% were CT and 24.1% were TT. Among fertile men, 30.4% of subjects were characterised by the CC genotype, 49.7% were CT and 19.9% were TT. In addition, the frequency of carriers of at least one T allele (i.e., CT and TT genotypes) among infertile and fertile subjects was 82.1% and 69.6%, respectively. The risk of infertility was significantly elevated by two-fold in individuals carrying at least one T allele (CT and TT genotypes: p = 0.009, OR = 2.00, 95% CI: 1.20–3.32). Furthermore, this elevated risk was still found when considering each of the CT and TT genotypes alone (TT genotype: p = 0.027, OR = 2.05, 95% CI: 1.09–3.86; CT genotype: p = 0.013, OR = 1.98, 95% CI: 1.16–3.36). This preliminary report suggests that P-gp may play some role in male infertility, mediating detrimental effects of environmental factors.     

Deborah Dunsire：万事皆有可能

继19位制药界的女精英被保健女企业家协会（HBA）推选为年度杰出女性后,千年制约CEO Deborah Dunsire近日被宣布当选为2009年HBA的年度女性。     

Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2

In addition to its role in megakaryocyte production, signaling initiated by thrombopoietin (TPO) activation of its receptor, myeloproliferative leukemia virus protooncogene (c-Mpl, or Mpl), controls HSC homeostasis and self-renewal. Under steady-state conditions, mice lacking the inhibitory adaptor protein Lnk harbor an expanded HSC pool with enhanced self-renewal. We found that HSCs from Lnk-/- mice have an increased quiescent fraction, decelerated cell cycle kinetics, and enhanced resistance to repeat treatments with cytoablative 5-fluorouracil in vivo compared with WT HSCs. We further provide genetic evidence demonstrating that Lnk controls HSC quiescence and self-renewal, predominantly through Mpl. Consistent with this observation, Lnk-/- HSCs displayed potentiated activation of JAK2 specifically in response to TPO. Biochemical experiments revealed that Lnk directly binds to phosphorylated tyrosine residues in JAK2 following TPO stimulation. Of note, the JAK2 V617F mutant, found at high frequencies in myeloproliferative diseases, retains the ability to bind Lnk. Therefore, we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence.     

Solutions, techniques and pressure in wound cleansing

This information on best practice discusses the evidence on the use of solutions, techniques and pressure in wound cleansing. The article has been reproduced with the permission of the Joanna Briggs Institute (JBI). The article (JBI 2006a), which updates and supersedes the 2003 information sheet of the same name, has been derived from a systematic review conducted in 2004 (Fernandez et al 2004). The primary references on which this information sheet is based are available in the systematic review reports to members of the JBI via the website: www.joannabriggs.edu.au     

Identification of hydrolytically stable and selective P2Y(1) receptor agonists

P2Y nucleotide receptors (P2YRs) are attractive pharmaceutical targets. Most P2YR agonists proposed as drugs consist of a nucleotide scaffold, but their use is limited due to their chemical and enzymatic instabilities. To identify drug candidates, we developed non-hydrolyzable P2YR agonists. We synthesized ATP-beta,gamma-CH(2) analogues 2-4, and evaluated their chemical and metabolic stabilities and activities at P2Y(1,2,4,6) receptors. Analogues 2-4 exhibited t(1/2) values of 14.5-65 h in gastric juice pH. They were completely resistant to alkaline phosphatase for 30 min at 37 degrees C and slowly hydrolyzed in human blood serum (t(1/2) 12.7-71.9 h). In comparison to ATP, analogues 2-4 were barely hydrolyzed by nucleoside triphosphate diphosphohydrolases, NTPDase1,2,3,8 (< 8% hydrolysis), and nucleotide pyrophosphatases, NPP1,3 (< or = 10% hydrolysis). Analogues 2 and 4B were selective agonists of the P2Y(1)R with EC(50)s of 0.08 and 17.2 microM, respectively. These features make analogues 2 and 4B potential therapeutic agents for health disorders involving the P2Y(1)R.     

Parallel analysis of mucosally derived B- and T-cell responses to an oral typhoid vaccine using simplified methods

There is a great need for simple methods for analysis of immune responses to mucosal vaccines that can be used on small blood volumes in field trials in both children and adults. We have investigated if mucosally derived B- and T-cell responses can be monitored in parallel by analysis of antibodies and T-cell effector molecules in culture supernatants from circulating blood lymphocytes obtained from orally vaccinated Swedes. Immunization with a live oral model vaccine, i.e. Salmonellaenterica serovar Typhi Ty21a, gave rise to secretion of typhoid specific IgA and IgM antibodies from peripheral blood mononuclear cells (PBMCs) and this response could be equally well detected by ELISA and ELISPOT 7 days after vaccination. The ELISA based assay could be further simplified by using buffy coat cells, but not by using whole blood or frozen PBMCs. Vaccine induced T-cell responses appeared later than the B-cell responses, but could be detected by ELISA assessment of IFN-γ and granzymes in supernatants from antigen stimulated PBMCs 21 days after vaccination. Thus, both B- and T-cell responses could be detected using simple ELISA based assays that would be practical to use in large-scale vaccine trials.     

Evidence-based policy-making: The implications of globally-applicable research for context-specific problem-solving in developing countries

In the past 15 or so years, the “evidence-based medicine” (EBM) framework has become increasingly institutionalized, facilitating its transfer across the globe. In the late 1990s, the basic principles of EBM began to have a marked influence in a number of non-clinical public policy arenas. Policy-makers working in these areas are now being urged to move away from developing policies according to political ideologies to a more legitimate approach based on “scientific fact,” a process termed “evidence-based policy-making” (EBPM). The conceptual diffusion of EBM to non-clinical arenas has exposed epistemologically destabilizing views regarding the definition of “science,” particularly as it relates to the demands of global versus national/sub-national policy-making. Using the maternal and neonatal subfield as an ethnographic case-study, this paper explores the effects of these divergences on EBPM in 5 developing countries (Bangladesh, Burkina Faso, Ghana, Malawi and Nepal). In doing so, our analysis aims to explain why EBPM has thus far had a limited impact in the area of context-specific programmatic policy-development and implementation at the national and sub-national levels. Results highlight that the political contexts in which EBPM is played out promote uniformity of methodological and policy approaches, despite the fact that disciplinary diversity is being called for repeatedly in the public health literature. Even in situations where national EBPM diverges from international priorities, national evidence-based policies are found to hold little weight in countering global policy interests, which some informants claim are themselves legitimated, rather than informed, by evidence. Informants also highlight the way interpretations of research findings are shaped by the broader political context within which donors set priorities and distribute limited resources – contexts that are driven by the need to provide generalisable research recommendations based on scientifically replicable methods. Added to this are clear rifts between senior and junior-level experts within countries that constrain national and sub-national research agendas from serving as tools for empowered knowledge production and problem-solving. We conclude by arguing for diverse forms of research that can more effectively address context-specific problems. While such diversity may render EBPM more conflict-ridden, debate is by no means an undesirable characteristic in any evolving system of knowledge, for it has the potential to foster critical insight and localized change.     

Noninvasive measurement of the cerebral blood flow response in human lateral geniculate nucleus with arterial spin labeling fMRI

To date, functional magnetic resonance imaging (fMRI) studies of the lateral geniculate nucleus (LGN) have primarily focused on measures of the blood oxygenation level dependent (BOLD) signal. Arterial spin labeling (ASL) is an MRI method that can provide direct measures of functional cerebral blood flow (CBF) changes. Because CBF is a well-defined physiological quantity that contributes to BOLD contrast, CBF measures can be used to improve the quantitative interpretation of fMRI studies. However, due in part to the low intrinsic signal-to-noise ratio of the ASL method, measures of functional CBF changes in the LGN are challenging and have not previously been reported. In this study, we demonstrate the feasibility of using ASL fMRI to measure the CBF response of the LGN to visual stimulation on a 3 T MRI system. The use of background suppression and physiological noise reduction techniques allowed reliable detection of LGN activation in all five subjects studied. The measured percent CBF response during activation ranged from 40 to 100%, assuming no interaction between the left and right LGN.