Differences in the Direction of Change of Cerebral Function Parameters Are Evident over Three Years in HIV-Infected Individuals Electively Commencing Initial cART

BackgroundChanges in cerebral metabolite ratios (CMR) measured on ¹H-MRS and changes in cognitive function (CF) are described in subjects commencing combination antiretroviral therapy (cART), although the dynamics of such changes are poorly understood.MethodsNeuroasymptomatic, HIV-infected subjects electively commencing cART were eligible. CMR were assessed in three anatomical voxels and CF assessed at baseline, week 48 and week 144. Overall differences in absolute change in CMRs and CF parameters between 0–48 and 48–144 weeks were assessed.ResultsTwenty-two subjects completed study procedures. Plasma HIV-RNA was <50 copies/mL in all at week 48 and in all, but two subjects at week 144. In general, between weeks 0–48 a rise in N-acetyl-aspartate(NAA)/Creatine(Cr) ratio and a decline in myo-Inositol(mI)/Cr ratio were observed. Between weeks 48–144, small rises in NAA/Cr ratio were observed in two anatomical voxels, whereas a rise in mI/Cr ratio was observed in all anatomical locations (0.31 (0.66) and -0.27 (1.35) between weeks 0–48 and 0.13 (0.91) and 1.13 (1.71) between weeks 48–144 for absolute changes in NAA/Cr and mI/Cr (SD) in frontal-grey voxel, respectively). Global CF score improved between weeks 0–48 and then declined between weeks 48–144 (0.63 (1.16) and -0.63 (0.1.41) for mean absolute change (SD) between weeks 0–48 and weeks 48–144, respectively).ConclusionsThe direction of change of cerebral function parameters differs over time in HIV-infected subjects commencing cART, highlighting the need for long-term follow-up in such studies. The changes we have observed between weeks 48–144 may represent the initial development of cerebral toxicities from cART.     

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

The interaction of p53 and MDM2 is modulated by the phosphorylation of p53. This mechanism is key to activating p53, yet its molecular determinants are not fully understood. To study the spatiotemporal characteristics of this molecular process we carried out Brownian dynamics simulations of the interactions of the MDM2 protein with a p53 peptide in its wild type state and when phosphorylated at Thr18 (pThr18) and Ser20 (pSer20). We found that p53 phosphorylation results in concerted changes in the topology of the interaction landscape in the diffusively bound encounter complex domain. These changes hinder phosphorylated p53 peptides from binding to MDM2 well before reaching the binding site. The underlying mechanism appears to involve shift of the peptide away from the vicinity of the MDM2 protein, peptide reorientation, and reduction in peptide residence time relative to wild-type p53 peptide. pThr18 and pSr20 p53 peptides experience reduction in residence times by factors of 13.6 and 37.5 respectively relative to the wild-type p53 peptide, indicating a greater role for Ser20 phosphorylation in abrogating p53 MDM2 interactions. These detailed insights into the effect of phosphorylation on molecular interactions are not available from conventional experimental and theoretical approaches and open up new avenues that incorporate molecular interaction dynamics, for stabilizing p53 against MDM2, which is a major focus of anticancer drug lead development.     

Barriers to partnership working in public health: a qualitative study

Background

Public health provision in England is undergoing dramatic changes. Currently established partnerships are thus likely to be significantly disrupted by the radical reforms outlined in the Public Health White Paper. We therefore explored the process of partnership working in public health, in order to better understand the potential opportunities and threats associated with the proposed changes.

Methodology/Principal Findings

70 participants took part in an in-depth qualitative study involving 40 semi-structured interviews and three focus group discussions. Participants were senior and middle grade public health decision makers working in Primary Care Trusts, Local Authorities, Department of Health, academia, General Practice and Hospital Trusts and the third sector in England. Despite mature arrangements for partnership working in many areas, and much support for joint working in principle, many important barriers exist. These include cultural issues such as a lack of shared values and language, the inherent complexity of intersectoral collaboration for public health, and macro issues including political and resource constraints. There is particular uncertainty and anxiety about the future of joint working relating to the availability and distribution of scarce and diminishing financial resources. There is also the concern that existing effective collaborative networks may be completely disrupted as the proposed changes unfold. The extent to which the proposed reforms might mitigate or potentiate these issues remains unclear. However the threats currently remain more salient than opportunities.

Conclusions

The current re-organisation of public health offers real opportunity to address some of the barriers to partnership working identified in this study. However, significant threats exist. These include the breakup of established networks, and the risk of cost cutting on effective public health interventions.     

A mouse model of Haemophilus ducreyi infection (chancroid)

Abstract Six- to 8-week-old CBA mice were inoculated intradermally and/or subcutaneously on each flank with one of 3 strains of Haemophilus ducreyi , 2 of these being recent isolates and the other a reference strain. Pustular nodules developed at all sites the day after 10⁷ organisms had been given. Severe ulceration similar to chancroid occurred in about half of the lesions which took at least 13 days to heal. All three strains of H. ducreyi were isolated from the mice during the first week. The model is invaluable in helping to understand the pathogenicity of H. ducreyi as well as the immunopathogenesis and other aspects of chancroid.     

Development and evaluation of the polymerase chain reaction to detect Mycoplasma genitalium

The polymerase chain reaction (PCR) was developed to detect Mycoplasma genitalium. Oligonucleotide primers were used to amplify a 374 bp region of the attachment protein of the mycoplasma. DNA from three strains of M. genitalium tested gave a characteristic PCR product which was not seen with DNA from any other source. As little as 10(-15) g of M. genitalium DNA could be detected and it was found in the vagina of progesterone-treated BALB/c mice inoculated with M. genitalium organisms later than they could be cultured from this site, but not in mice that never became colonised vaginally.