The use of formative research to inform the design of a seasonal malaria chemoprevention intervention in northern Nigeria

BACKGROUND:Experience of seasonal malaria chemoprevention (SMC) is growing in the Sahel sub-region of Africa, though there remains insufficient evidence to recommend a standard deployment strategy. In 2012, a project was initiated in Katsina state, northern Nigeria, to design an appropriate and effective community-based delivery approach for SMC, in consultation with local stakeholders. Formative research (FR) was conducted locally to explore the potential feasibility and acceptability of SMC and to highlight information gaps and practical considerations to inform the intervention design. METHODS:The FR adopted qualitative methods; 36 in-depth interviews and 18 focus group discussions were conducted across 13 target groups active across the health system and within the community. Analysis followed the 'framework' approach. The process for incorporating the FR results into the project design was iterative which was initiated by a week-long 'intervention design' workshop with relevant stakeholders. RESULTS:The FR highlighted both supportive and hindering factors to be considered in the intervention design. Malaria control was identified as a community priority, the community health workers were a trusted resource and the local leadership exerted strong influence over household decisions. However, there were perceived challenges with quality of care at both community and health facility levels, referral linkage and supportive supervision were weak, literacy levels lower than anticipated and there was the potential for suspicion of 'outside' interventions. There was broad consensus across target groups that community-based SMC drug delivery would better enable a high coverage of beneficiaries and potentially garner wider community support. A mixed approach was recommended, including both community fixed-point and household-to-household SMC delivery. The FR findings were used to inform the overall distribution strategy, mechanisms for integration into the health system, capacity building and training approaches, supportive interventions to strengthen the health system, and the social mobilization strategy. CONCLUSIONS:Formative research played a valuable role in exploring local socio-cultural contexts and health system realities. Both opportunities and challenges for the introduction of SMC delivery were highlighted, which were appropriately considered in the design of the project

Active Site Design in a Chemzyme: Development of a Highly Asymmetric and Remarkably Temperature-Independent Catalyst for the Imino Aldol Reaction**

The asymmetric aldol reaction of an enolate or enolate equivalent with an imine is a reaction of established synthetic importance for the synthesis of chiral amines in general and bamino esters in particular. [1] The development of chiral catalysts for this reaction has proven to be a difficult task and had eluded all attempts until recently when Kobayashi and co-workers examined imines derived from o-aminophenol. [2±4] Their method involves the catalysis of the reactions of these imines and ketene acetals with a catalyst generated from zirconium(iv) tert-butoxide and two equivalents of (R)-6,6'-dibromoBINOL (BINOL 1,1'-binaphth-2-ol). Our interest in the synthesis of chiral amines led us to investigate the use of VAPOL-derived catalysts A comparison of catalysts prepared from BINOL, 6,6'-dibromoBINOL and VAPOL ligands on the asymmetric induction in the reaction of the phenyl-substituted imine 1 and acetal 2 is summarized in [2] The VAPOL catalyst could be prepared in either methylene chloride or toluene, but for solubility reasons, the BINOL catalysts were prepared in methylene chloride. The VAPOL and Br 2 BINOL catalysts were superior to the BINOL catalyst at À 45 8C. The asymmetric induction dropped for the Br 2 BINOL catalyst when the temperature was raised from À 45 8C to room temperature, but curiously, the asymmetric induction for the VAPOL catalyst was essentially unchanged over this same temperature range. Only a small drop-off is noted (85 % ee) when the temperature is raised to 41 8C and the substrate-to-catalyst ratio is raised to 200:1 (entry 5). Both the R enantiomers of BINOL and Br 2 BINOL ligands give the R enantiomer of the product 3, whereas with the VAPOL ligand, it is the S enantiomer that gives the R product. This reversal is not unexpected given the structures of the ligands where the zirconium is in the minor groove of the BINOL ligands and in the major groove of the VAPOL ligand. [2g] It is clear from the examination of space-filling CPK models that it is possible to bind two VAPOL ligands to one zirconium atom but only with a facial arrangement of the four oxygen atoms as is illustratred by structure 6 in Scheme 1. This is supported by 1 H NMR experiments on a catalyst generated from zirconium tetraisopropoxide and VAPOL in the presence of two equivalents of N-methyl imidiazole. A clean spectrum is only observed with two equivalents of VAPOL relative to zirconium and the spectrum is consistent with a single C 2 -symmetrical species were performed by using the TEXSAN [13] crystallographic software package. Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-153832. Copies of the data can be obtained free of charge on application to CCDC

Endothelin-1: The yin and yang on vascular function

Abstract: Endothelin-1 (ET-1) is a vasoconstrictor secreted by endothelial cells, which acts as the natural counterpart of the vasodilator nitric oxide (NO). ET-1 contributes to vascular tone and regulates cell proliferation through activation of ETA and ETB receptors. Physical factors such as shear stress, or stimuli including thrombin, epinephrine, angiotensin II, growth factors, cytokines and free radicals enhance secretion of ET-1. By contrast, mediators like nitric oxide (NO), cyclic GMP, atrial natriuretic peptide, and prostacyclin reduce the release of endogenous ET-1. Thus, under normal conditions, the effects of the ET-1 are carefully regulated through inhibition or stimulation of ET-1 release from endothelium. Endothelial dysfunction is one of the earliest landmarks of vascular abnormalities. Altered function of endothelium may result from absolute decrease in bioavailability of NO as well as from relative augment in ET- 1 synthesis, release or activity. Imbalance in the production of vasodilator and vasoconstrictor agents may contribute to the onset of hemodynamic disorders. Since dysregulation of the endothelin system is important in the pathogenesis of several cardiovascular diseases, the ETA and ETB receptors are attractive therapeutic targets for disorders associated with elevated ET- 1 levels. ET receptor antagonists may be regarded as disease-modifying agents thanks to their ability to preserve endothelial integrity when the endothelin system is overactive. This review summarizes the current knowledge on the role of ET-1 in experimental hypertension and describes recent findings on the involvement of MAPK signalling pathways in ET-1 release in hypertension associated with insulin resistance. Moreover, therapeutic applications of ET-1 receptor blockers are also discussed