A Repurposing Strategy for Hsp90 Inhibitors Demonstrates Their Potency against Filarial Nematodes

Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties.     

A computational model of the development of separate representations of facial identity and expression in the primate visual system

Experimental studies have provided evidence that the visual processing areas of the primate brain represent facial identity and facial expression within different subpopulations of neurons. For example, in non-human primates there is evidence that cells within the inferior temporal gyrus (TE) respond primarily to facial identity, while cells within the superior temporal sulcus (STS) respond to facial expression. More recently, it has been found that the orbitofrontal cortex (OFC) of non-human primates contains some cells that respond exclusively to changes in facial identity, while other cells respond exclusively to facial expression. How might the primate visual system develop physically separate representations of facial identity and expression given that the visual system is always exposed to simultaneous combinations of facial identity and expression during learning? In this paper, a biologically plausible neural network model, VisNet, of the ventral visual pathway is trained on a set of carefully-designed cartoon faces with different identities and expressions. The VisNet model architecture is composed of a hierarchical series of four Self-Organising Maps (SOMs), with associative learning in the feedforward synaptic connections between successive layers. During learning, the network develops separate clusters of cells that respond exclusively to either facial identity or facial expression. We interpret the performance of the network in terms of the learning properties of SOMs, which are able to exploit the statistical indendependence between facial identity and expression.     

Likely health outcomes for untreated acute febrile illness in the tropics in decision and economic models; a Delphi survey

Background

Modelling is widely used to inform decisions about management of malaria and acute febrile illnesses. Most models depend on estimates of the probability that untreated patients with malaria or bacterial illnesses will progress to severe disease or death. However, data on these key parameters are lacking and assumptions are frequently made based on expert opinion. Widely diverse opinions can lead to conflicting outcomes in models they inform.

Methods and Findings

A Delphi survey was conducted with malaria experts aiming to reach consensus on key parameters for public health and economic models, relating to the outcome of untreated febrile illnesses. Survey questions were stratified by malaria transmission intensity, patient age, and HIV prevalence. The impact of the variability in opinion on decision models is illustrated with a model previously used to assess the cost-effectiveness of malaria rapid diagnostic tests. Some consensus was reached around the probability that patients from higher transmission settings with untreated malaria would progress to severe disease (median 3%, inter-quartile range (IQR) 1–5%), and the probability that a non-malaria illness required antibiotics in areas of low HIV prevalence (median 20%). Children living in low transmission areas were considered to be at higher risk of progressing to severe malaria (median 30%, IQR 10–58%) than those from higher transmission areas (median 13%, IQR 7–30%). Estimates of the probability of dying from severe malaria were high in all settings (medians 60–73%). However, opinions varied widely for most parameters, and did not converge on resurveying.

Conclusions

This study highlights the uncertainty around potential consequences of untreated malaria and bacterial illnesses. The lack of consensus on most parameters, the wide range of estimates, and the impact of variability in estimates on model outputs, demonstrate the importance of sensitivity analysis for decision models employing expert opinion. Results of such models should be interpreted cautiously. The diversity of expert opinion should be recognised when policy options are debated.     

Sequence variation does not confound the measurement of plasma PfHRP2 concentration in African children presenting with severe malaria

ABSTRACT: BACKGROUND: Plasmodium falciparum histidine-rich protein PFHRP2 measurement is used widely for diagnosis, and more recently for severity assessment in falciparum malaria. The Pfhrp2 gene is highly polymorphic, with deletion of the entire gene reported in both laboratory and field isolates. These issues potentially confound the interpretation of PFHRP2 measurements. METHODS: Studies designed to detect deletion of Pfhrp2 and its paralog Pfhrp3 were undertaken with samples from patients in seven countries contributing to the largest hospital-based severe malaria trial (AQUAMAT). The quantitative relationship between sequence polymorphism and PFHRP2 plasma concentration was examined in samples from selected sites in Mozambique and Tanzania. RESULTS: There was no evidence for deletion of either Pfhrp2 or Pfhrp3 in the 77 samples with lowest PFHRP2 plasma concentrations across the seven countries. Pfhrp2 sequence diversity was very high with no haplotypes shared among 66 samples sequenced. There was no correlation between Pfhrp2 sequence length or repeat type and PFHRP2 plasma concentration. CONCLUSIONS: These findings indicate that sequence polymorphism is not a significant cause of variation in PFHRP2 concentration in plasma samples from African children. This justifies the further development of plasma PFHRP2 concentration as a method for assessing African children who may have severe falciparum malaria. The data also add to the existing evidence base supporting the use of rapid diagnostic tests based on PFHRP2 detection.     

Grampian Health Board's joint drug formulary.

OBJECTIVE--To develop a model for creating a joint general practice-hospital formulary, using the example of ulcer healing drugs. DESIGN--A joint formulary development group produced draft guidelines based on an earlier hospital formulary, which were sent to interested local general practitioners for consultation. Revised guidelines were then drawn up and forwarded to the health board''s medicines committee for approval and distribution. SETTING--Grampian Health Board. SUBJECTS--Nine members of joint formulary development group plus local general practitioners who were invited to comment on a list of 11 ulcer healing drugs. MAIN OUTCOME MEASURE--Degree of coincidence of drugs selected by hospital doctors and general practitioners. RESULTS--The ulcer healing drugs selected by the panel of general practitioners and by hospital doctors were highly coincident. The cost of one day''s treatment with drugs varied considerably between hospital and general practice--for example, one drug cost 46p in hospital and 1 pounds in general practice and another cost 1.26 pounds in hospital and 1.01 pounds in general practice. Overall, six drugs cost more in hospital and five cost more in general practice. CONCLUSIONS--A joint formulary for use in hospitals and general practice in a health board can be devised fairly simply by consultation as virtually the same drugs are used in both types of practice. It should influence the health board''s expenditure on drugs and affect the choice of drugs when a patient is discharged from hospital or is referred to any hospital in the region.     

Ecology of Allis Shad Alosa alosa and Twaite Shad Alosa fallax in the Solway Firth, Scotland

The basis of this study were 132 adult Allis Shad and 150 Twaite Shad collected as bycatches from salmon stake nets in Scotland on the north side of the Solway Firth. Most (60%) of the Allis Shad were immature fish 2–3 years of age (mean length 305 mm). Mature males were younger (3–5 years) and smaller (mean length 421 mm) than females (4–6 years and 481 mm mean length). The largest Allis Shad was a female of 515 mm and 2183 g. In contrast, almost all the Twaite Shad were mature, the males younger (3–5 years) and smaller (mean length 341 mm) than the females (4–6 years and 364 mm mean length). The largest Twaite Shad was a female of 400 mm and 1213 g. The food of Allis Shad consisted mainly of small zooplankton with some fish and larger Crustacea. Fine vegetable fragments were common in the stomachs and attributed to filter feeding. The food of Twaite Shad was mainly small fish with some Crustacea. Mature Allis Shad of both sexes with large gonads (maximum female GSI: 20.63) were found throughout the spring and summer but no definite evidence of local spawning was obtained. Mature Twaite Shad of both sexes with large gonads (maximum female GSI: 23.32) were found until early July, thereafter most of the fish were spent. It appears that Twaite Shad spawn locally in June. Some hybrids between the two species were found.