Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1

Diseases caused by the apicomplexan protozoans Toxoplasma gondii and Cryptosporidium parvum are a major health concern. The life cycle of these parasites is regulated by a family of calcium-dependent protein kinases (CDPKs) that have no direct homologues in the human host. Fortuitously, CDPK1 from both parasites contains a rare glycine gatekeeper residue adjacent to the ATP-binding pocket. This has allowed creation of a series of C3-substituted pyrazolopyrimidine compounds that are potent inhibitors selective for CDPK1 over a panel of human kinases. Here we demonstrate that selectivity is further enhanced by modification of the scaffold at the C1 position. The explanation for this unexpected result is provided by crystal structures of the inhibitors bound to CDPK1 and the human kinase c-SRC. Furthermore, the insight gained from these studies was applied to transform an alternative ATP-competitive scaffold lacking potency and selectivity for CDPK1 into a low nanomolar inhibitor of this enzyme with no activity against SRC.     

Managing the Placebo Effect: Enhancing the Signal-to-Noise Ratio

Confirming the absence of the placebo response has been the bane of researchers throughout the ages. Thus, the gold standard of research methodology is the evidence for a treatment modality provided by a prospective randomized controlled trial. The “control” arm of a trial is the arm in which the placebo has been administered. Increasing evidence from basic science and clinical research is pointing to the fact that the placebo response may have some biological basis that can translate into enduring therapeutic benefit. Have our placebo-controlled trials simply compared one treatment effect to the treatment effect of the “placebo”? Thus, the “δ” is relative treatment effect; perhaps this may provide some insight as to why some treatment response is low compared to a relatively strong placebo response. How can we use this knowledge to create more robust clinical designs that help establish true treatment effect? This article aims to provide an overview of the contemporary insight into the placebo response.     

Novel myosin heavy chain immunohistochemical double staining developed for the routine diagnostic separation of I, IIA and IIX fibers

The different histochemical ATPase properties of myosins separating the muscle fiber types have been utilized in diagnostic muscle biopsy routine for more than four decades. The ATPase staining method is rather laborious and has several disadvantages, such as weakening of staining over time and non-specific staining of capillaries, making the distinction of extremely atrophic muscle fibers difficult. We have developed a reliable and advanced immunohistochemical myosin double staining method for the identification of fiber types, including highly atrophic fibers in routine diagnostics. With this double staining method, we are able to distinguish among type I (ATPase type 1), IIA (ATPase type 2A), IIX (ATPase type 2B) and remodeled ATPase type 2C fibers expressing both fast and slow myosins using a one slide technique. Immunohistochemical double staining of myosin heavy chain isoforms can be used as an alternative for the conventional ATPase staining method in routine histopathology. The method provides even more detailed information of fast fiber subtypes and highly atrophic fibers on one single slide.     

Urinary (1)H-NMR metabonomics study on intervention effects of soya milk in Africans

Metabonomics is an important tool in understanding the toxicological or therapeutic effects of interventions by analysing metabolic profiles and interpreting complex multi‐dimensional spectroscopic/spectrometric data using multivariate data analysis. The objectives of this study were to evaluate the metabolic changes following a short‐term 5 day soya milk intervention, and to investigate factors that influence soy‐phytoestrogen metabolism focused on Africans based in either UK or Nigeria. ¹H‐NMR metabonomics was applied to analyse urine samples collected at four phases I–IV (pre, days 3 and 5, and post) of the soy‐intervention from African volunteers (n = 40 in total). Individual proton NMR spectra were visually and statistically assessed using multivariate analyses (MVA): principal component analysis (PCA) and (orthogonal‐) partial‐least square–discriminant analysis ((O‐) PLS‐DA). In addition, 22 endogenous metabolites were quantified using a Chenomx NMR suite. The results showed the levels of analysed endogenous metabolites (creatinine adjusted) present ranged from 4 µ m to 12 m m with large inter‐subject variances in acetate, acetone, lactate and trimethylamine. The MVA results showed high inter‐individuality and sampling variances based on PCA score plots, and demonstrated soy metabolism to be significantly influenced by location and gender by both PLS‐DA and O‐PLS‐DA. Copyright © 2011 John Wiley & Sons, Ltd.     

New paradigm old thinking: the case for emergency obstetric care in the prevention of maternal mortality in Nigeria

Background  

The continuing burden of maternal mortality, especially in developing countries has prompted a shift in paradigm from the traditional risk assessment approach to the provision of access to emergency obstetric care services for all women who are pregnant. This study assessed the knowledge of maternity unit operatives at the primary and secondary levels of care about the concept of emergency obstetric care (EmOC) and investigated the contents of antenatal care (ANC) counseling services they delivered to clients. It also described the operatives' preferred strategies and practices for promoting safe motherhood and averting maternal mortality in South-west Nigeria.     

Correlates of physicians' attitudes toward communication with HIV/AIDS patients in Ile-Ife,Nigeria

Objectives The study assessed physicians' perceptions of HIV/AIDS patients and identified the determinants of physicians' attitudes toward communication with HIV/AIDS patients in Ile-Ife, Nigeria.

Methods A semi-structured questionnaire was used to elicit information from 110 physicians in a cross-sectional survey, while in-depth interviews were conducted with 10 people living with HIV/AIDS (PLWHA) who had been previously admitted under the care of the physicians. Univariate, bivariate and multivariate analyzes were conducted.

Results Although most physicians perceived PLWHA positively and 58% of them displayed a positive attitude toward communication with PLWHA under their care, the expectations of the patients concerning HIV/AIDS communication were not being met. Only 43% of physicians expressed any degree of comfort engaging PLWHA in lengthy discussions or communicating the diagnosis of HIV to patients. The strongest correlates of physicians' positive attitude were previous exposure to HIV/AIDS counseling, the number of HIV/AIDS patients treated per month, the number of years spent in the care of PLWHA, and the gender of the physicians (p < 0.05).

Conclusions Physicians in Ile-Ife, Nigeria are not adequately equipped by way of training to effectively meet the expectations of their patients concerning HIV/AIDS communication. The large number of PLWHA in the country calls for urgent attention to address this important aspect of care.