Lead Diversification 2: application to P38, gMTP and lead compounds

Lead Diversification is a new technology platform developed at Pfizer for the functionalization of drug molecules using C-H activation. We describe its application to some drug programs such as P38 and gMTP and the development of some new plate based screens including a fluorination screen.     

The metabolic syndrome: prevalence, associated factors, and impact on survival among older persons in rural Bangladesh

Objectives

To describe the prevalence of the metabolic syndrome (MetS) among older persons in rural Bangladesh, to investigate whether the prevalence varies by age, sex, literacy, marital status, nutritional status and socio-economic status, and to assess the impact of MetS on survival.

Methods

The study consisted of 456 persons who were aged ≥60 years living in a rural area of Bangladesh during July 2003–March 2004. Data were collected through interview, clinical examination, and laboratory tests, and their survival status until 30^th June 2009 was ascertained through the Matlab surveillance system. We defined MetS following the NCEP ATP III criteria, with minor modifications, i.e., presence of any three of the following: hypertension (BP ≥130/85 mm Hg); random blood glucose (RBG) level ≥7.0 mmol/L; hyper-triglyceridemia (≥2.28 mmol/L); low level of HDL-cholesterol (<1.04 mmol/L for men and <1.29 mmol/L for women); and BMI ≥25.0 kg/m². Data were analysed with logistic regressions for the influential factors of MetS, and with Cox models for the association of MetS with the survival status.

Findings

The overall prevalence of MetS was 19.5%, 20.8% in women, and 18.0% in men. Asset-index and nutritional status were independently associated with MetS. During 4.93 years of follow-up, 18.2% died. In the presence of high RBG, MetS has a significant negative effect on survival (69.4% vs 95.2%, log rank p = 0.02).

Conclusion

This study highlights the importance of the metabolic syndrome in rural Bangladesh. Our findings suggest that there is a need for screening programmes involving the metabolic syndrome to prevent diabetes and cardiovascular diseases.     

Critical role for a stage-specific actin in male exflagellation of the malaria parasite

Male gametogenesis occurs directly after uptake of malaria parasites by the mosquito vector and leads to the release of eight nucleated flagellar gametes. Here, we report that one of the two parasite actin isoforms, named actin II, is essential for this process. Disruption of actin II in Plasmodium berghei resulted in viable asexual blood stages, but male gametogenesis was specifically inhibited. Upon activation, male gametocyte DNA was replicated normally and axonemes assembled, but egress from the host cell was inhibited, and axoneme motility abolished. The major actin isoform, actin I, displayed dual localization to the cytoplasm and the nucleus in male gametocytes. After activation actin I was found to be restricted to the cytoplasm. In actII(-) mutant parasites, this re-localization was abolished and actin I remained in both cellular compartments. These findings reveal vital and pleiotropic functions for the actin II isoform in male gametogenesis of the malaria parasite.     

Conversion of Exogenous Cholesterol into Glycoalkaloids in Potato Shoots,Using Two Methods for Sterol Solubilisation

Steroidal glycoalkaloids (SGA) are toxic secondary metabolites naturally occurring in the potato, as well as in certain other Solanaceous plant species, such as tomato, eggplant and pepper. To investigate the steroidal origin of SGA biosynthesis, cut potato shoots were fed cholesterol labelled with deuterium (D) in the sterol ring structure (D₅- or D₆-labelled), or side chain (D₇-labelled), and analysed after three or five weeks. The labelled cholesterol and presence of D-labelled SGA were analysed by GC-MS and LC-MS/MS, respectively. When feeding D-labelled cholesterol solubilised in Tween-80, labelled cholesterol in free form became present in both leaves and stems, although the major part was recovered as steryl esters. Minor amounts of D-labelled SGA (α-solanine and α-chaconine) were identified in cholesterol-treated shoots, but not in blank controls, or in shoots fed D₆-27-hydroxycholesterol. Solubilising the labelled cholesterol in methyl-β-cyclodextrin instead of Tween-80 increased the levels of labelled SGA up to 100-fold, and about 1 mole% of the labelled cholesterol was recovered as labelled SGA in potato leaves. Both side chain and ring structure D labels were retained in SGA, showing that the entire cholesterol molecule is converted to SGA. However, feeding side chain D₇-labelled cholesterol resulted in D₅-labelled SGA, indicating that two hydrogen atoms were released during formation of the SGA nitrogen-containing ring system. Feeding with D₇-sitosterol did not produce any labelled SGA, indicating that cholesterol is a specific SGA precursor. In conclusion, we have demonstrated a superior performance of methyl-β-cyclodextrin for delivery of cholesterol in plant tissue feeding experiments, and given firm evidence for cholesterol as a specific sterol precursor of SGA in potato.     

Waveguide evanescent field scattering microscopy: bacterial biofilms and their sterilization response via UV irradiation

Waveguide Evanescent Field Scattering (WEFS) microscopy is introduced as a new and simple tool for label‐free, high contrast imaging of bacteria and bacteria sensors. Bacterial microcolonies and single bacteria were discriminated both by their bright field images and by their evanescent scattering intensity. By comparing bright field images with WEFS images, the proportion of planktonic: sessile (i.e., “floating”: attached) bacteria were measured. Bacteria were irradiated with UV light, which limited their biofilm forming capability. A quantitative decrease in attachment of individual, sessile bacteria and in attached, microcolony occupied areas was easily determined within the apparent biofilms with increasing UV dose. WEFS microscopy is an ideal tool for providing rapid quantitative data on biofilm formation. (© 2014 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Impact of a Participatory Intervention with Women’s Groups on Psychological Distress among Mothers in Rural Bangladesh: Secondary Analysis of a Cluster-Randomised Controlled Trial

Background

Perinatal common mental disorders (PCMDs) are a major cause of disability among women and disproportionately affect lower income countries. Interventions to address PCMDs are urgently needed in these settings, and group-based and peer-led approaches are potential strategies to increase access to mental health interventions. Participatory women’s health groups led by local women previously reduced postpartum psychological distress in eastern India. We assessed the effect of a similar intervention on postpartum psychological distress in rural Bangladesh.

Method

We conducted a secondary analysis of data from a cluster-randomised controlled trial with 18 clusters and an estimated population of 532,996. Nine clusters received an intervention comprising monthly meetings during which women’s groups worked through a participatory learning and action cycle to develop strategies for improving women’s and children’s health. There was one group for every 309 individuals in the population, 810 groups in total. Mothers in nine control clusters had access to usual perinatal care. Postpartum psychological distress was measured with the 20-item Self Reporting Questionnaire (SRQ-20) between six and 52 weeks after delivery, during the months of January to April, in 2010 and 2011.

Results

We analysed outcomes for 6275 mothers. Although the cluster mean SRQ-20 score was lower in the intervention arm (mean 5.2, standard deviation 1.8) compared to control (5.3, 1.2), the difference was not significant (β 1.44, 95% CI 0.28, 3.08).

Conclusions

Despite promising results in India, participatory women’s groups focused on women’s and children’s health had no significant effect on postpartum psychological distress in rural Bangladesh.