Search

J.R. and G.A.B. thank GlaxoSmithKline (GSK) and the Engineering and Physical Sciences Research Council (EPSRC) for an industrial CASE studentship. MMA is supported by a studentship from the government of Libya, and MAU by a studentship from the Petroleum Technology Development Fund (PTDF), Abuja, Nigeria. A selective mono-N-arylation strategy of amidines under Chan-Lam conditions is described. During the reaction optimization phase, the isolation of a mononuclear Cu(II) complex provided unique mechanistic insight into the operation of Chan-Lam mono-N-arylation. The scope of the process is demonstrated, and then applied to access the first mono-N-arylated analogues of pentamidine. Sub-micromolar activity against kinetoplastid parasites was observed for several analogues with no cross-resistance in pentamidine and diminazene-resistant trypanosome strains and against Leishmania mexicana. A fluorescent mono-N-arylated pentamidine analogue revealed rapid cellular uptake, accumulating in parasite nuclei and the kinetoplasts. The DNA binding capability of the mono-N-arylated pentamidine series was confirmed by UV-melt measurements using AT-rich DNA. This work highlights the potential to use Chan-Lam mono-N-arylation to develop therapeutic leads against diamidine-resistant trypanosomiasis and leishmaniasis. Publisher PDF

Background: Rigidity of upper and lower limbs in Parkinson9s disease (PD) is typically assessed via a clinical rating scale that is subject to biases inherent to human perception. Methodologies and systems to systematically quantify changes in rigidity associated with angular position (stiffness) or velocity (viscous damping) are needed to enhance our understanding of PD pathophysiology and objectively assess therapies. New method: We developed a robotic system and a model-based approach to estimate viscous damping and stiffness of the elbow. Our methodology enables the subject to freely rotate the elbow, while torque perturbations tailored to identify the arm dynamics are delivered. The viscosity and stiffness are calculated based on the experimental data using least-squares optimization. Results: We validated our technique using computer simulations of the arm dynamics and experiments with a nonhuman primate model of PD in the presence and absence of deep brain stimulation (DBS) therapy. Computer simulations of the arm demonstrate that the proposed approach can accurately estimate viscous damping and stiffness. The experimental data show that both viscosity and stiffness significantly decreased when DBS was delivered. Comparison with existing methods: Computer simulations and experiments showed that stiffness and viscosity measurements obtained with the proposed methodology could better differentiate changes in rigidity than scores previously used for research, including the work score, impulse score, and modified Unified Parkinson9s Disease Rating Scale (mUPDRS). Conclusions: The proposed estimation method is suitable to quantify the effect of therapies on viscous damping and stiffness and study the pathophysiological mechanisms underlying rigidity in PD.

Peptidomimetics designed to target voltage‐gated sodium channels have attracted significant attention as potential analgesics. However, voltage‐gated sodium channel (VGSC)‐blocking activity of these compounds has mainly been assessed using rat and/or mice homologs. In this study, we developed a novel series of conformationally constrained peptidomimetic analogues of the μ‐conotoxin KIIIA and assessed their activity against human VGSCs. Two of the mimetics block the currents of hNav1.4 and hNav1.6 channels. NMR derived structures of the mimetics provided excellent insight into the structural requirements for bioactivity. A lactam‐constrained analogue, previously reported to be active in mice, did not block the corresponding human VGSC. This work highlights important differences in VGSCs between species and validates the potential of peptidomimetics as human analgesics.

Modified peptides, such as stapled peptides, which replicate the structure of α-helical protein segments, represent a potential therapeutic advance. However, the 3D solution structure of these stapled peptides is rarely explored beyond the acquisition of circular dichroism (CD) data to quantify bulk peptide helicity; the detailed backbone structure, which underlies this, is typically undefined. Diastereomeric stapled peptides based on helical sections of three proteins (αSyn, Cks1 and CK1α) were generated; their overall helicity was quantified by CD; and the most helical peptide from each series was selected for structural analysis. Solution-phase models for the optimised peptides were generated using NMR-derived restraints and a modified CHARMM22 force field. Comparing these models with PDB structures allowed deviation between the stapled peptides and critical helical regions to be evaluated. These studies demonstrate that CD alone is not sufficient to assess the structural fidelity of a stapled peptide.

Background. Rates of gender-based violence (GBV) in South Africa (SA) are among the highest in the world. In societies where social ideals of masculinity encourage male dominance and control over women, gender power imbalances contribute to male perpetration and women’s vulnerability. The drivers that cause men to perpetrate GBV and those that lead to HIV overlap and interact in multiple and complex ways. Multiple risk and protective factors for GBV perpetration by males operate interdependently at a number of levels; at the individual level, these include chronic anxiety and depression, which have been shown to lead to risky sexual behaviours.Objectives. (i) To examine psychosocial risk factors (symptoms of anxiety and depression) as well as protective factors (social support and self-esteem) as self-reported by a cohort of males in rural KwaZulu-Natal (KZN) Province, SA; and (ii) to determine whether there are differences in anxiety, depression, social support and self-esteem between perpetrators and non-perpetrators.Methods. A cross-sectional study using quasi-probability cluster sampling of 13 of 28 wards in Harry Gwala District, KZN. Participants were then randomly chosen from each ward proportionate to size.Results. The participants were relatively young (median age 22 years); over half were schoolgoers, and 91.3% had never married. Over 43% of the sample reported clinical levels of anxiety and depressive symptoms on the Brief Symptom Inventory. Rates of GBV perpetration were 60.9%, 23.6% and 10.0% for psychological abuse, non-sexual physical violence and sexual violence, respectively. GBV perpetration was associated with higher depression, higher anxiety, lower self-esteem and lower social support.Conclusions. Interventions to address GBV need to take modifiable individual-level factors into account.

A range of 4-substituted prolines can be rapidly synthesized from a protected glycine Schiff base in only four steps and in 27-55% overall yield. Phase transfer catalysis allows direct access to both enantiomeric series, and the relative stereochemistry at the 4-position is readily controlled (>10:1 dr) through the choice of hydrogenation conditions.

A range of 4-substituted prolines can be rapidly synthesized from a protected glycine Schiff base in only four steps and in 27–55% overall yield. Phase transfer catalysis allows direct access to both enantiomeric series, and the relative stereochemistry at the 4-position is readily controlled (>10:1 dr) through the choice of hydrogenation conditions.

(1965). Lymnaea natalensis and fascioliasis in Ghana. Annals of Tropical Medicine & Parasitology: Vol. 59, No. 3, pp. 320-326.

(1965). A note on intestinal schistosomiasis and the snail hosts in Ghana. Annals of Tropical Medicine & Parasitology: Vol. 59, No. 3, pp. 312-319.

On the basis of observations of school children described in Part I, a model for the infective process of S. haematobium in man in the Misungwi area of Tanzania is put forward. On the basis of steady challenge by cercariae, effective concomitant immunity, exponential death of worm pairs, the observed variance of egg output at age 10, and constant ranking by infection level in early life, the behaviour of egg output patterns with age in the community is predicted. Expected curves of output are compared with those observed in cross-sectional survey of over 4,000 people at Misungwi. Agreement is close. This provides additional evidence for the occurrence of concomitant immunity to S. haematobium in man and suggests that immunity cannot be disregarded in epidemiological models of the infection. It is suggested that there are 3 phases in an age-cohort's experience of endemic infection: acquisition and increase of infection, a phase of decreasing worm load combined with concomitant immunity, and a steady state phase, with loss of immunity and reinfection balancing, in later life. The need for better data on the nature of human immunity to schistosomiasis becomes apparent.

Summary A clinical examination of 1,675 children in three different locations in rural parts of Northern Rhodesia showed a high incidence of blindness and of other eye symptoms and skin changes generally ascribed to vitamin A deficiency. In order to verify this observation, plasmalevels of vitamin A and carotene were measured in 183 preschool and school children in these areas. Very low values of both vitamin A and carotene were found in a high proportion of unselected cases. It is our view, based on these observations, that lack of vitamin A is a significant health problem. It is thought to be a principal factor in the great number of eye diseases and blindness and is a factor in the poor general health status and in the high mortality rate (30 to 50 per cent) of these children by causing a lowered resistance to infectious diseases and parasitic infestations. Great improvements could accordingly beachieved by providing more carotene-containing foods in the diet such as red palm oil and by growing more vegetables rich in carotene. To change the diet and eating habits is not easy, but considerable success could be achieved by instruction of the children in the schools and by developing school gardens.

In 1962, the author conducted a preliminary investigation of bilharziasis in the Republic of the Congo (Brazzaville), at the request of the Government, in order to review existing information and work done on bilharziasis, to assess the prevalence and distribution of the disease, to make observations on the potential snail hosts, and to propose further suitable studies and control measures.Although little time was available for this study, it appears reasonable to conclude that Schistosoma haematobium is confined to a few foci in the west of the country, the main snail host being a new subspecies of Bulinus (B.) truncatus. Intestinal bilharziasis is apparently very rare, but systematic stool surveys have not been done; S. mansoni may be, or become, endemic at Dolisie, where Biomphalaria camerunensis is abundant. The main factors governing the restricted distribution of bilharziasis are discussed.Bilharziasis control appears to merit relatively low priority compared with that due to several other diseases, and the author concludes that bilharziasis is unlikely to become widespread in future years unless there is major environmental change, although the intensity of transmission may increase in some present endemic foci.