Leprosy: diagnosis and management in a developed setting.

Leprosy remains an important global health concern, but little has been published about its diagnosis and management in developed settings. It has been postulated that delay in diagnosis is common in developed settings. We reviewed all the cases of leprosy seen at a major tertiary referral centre between 1999 and 2013 and demonstrated that delay in diagnosis is common, especially when patients present with symptoms of leprosy reactions rather than classical symptoms, such as hypo-pigmented hypo-aesthetic skin lesions and neuropathy.

Experience with high frequency oscillation ventilation during the 2009 H1N1 influenza pandemic in Australia and New Zealand.

During the 2009 H1N1 pandemic, large numbers of patients had severe respiratory failure. High frequency oscillation ventilation was used as a salvage technique for profound hypoxaemia. Our aim was to compare this experience with high frequency oscillation ventilation during the 2009 H1N1 pandemic with the same period in 2008 by performing a three-month period prevalence study in Australian and New Zealand intensive care units. The main study end-points were clinical demographics, care delivery and survival. Nine intensive care units contributed data. During 2009 there were 22 H1N1 patients (17 adults, five children) and 10 non-H1N1 patients (five adults, five children), while in 2008, 18 patients (two adults, 16 children) received high frequency oscillation ventilation. The principal non-H1N1 high frequency oscillation ventilation indication was bacterial or viral pneumonia (56%). For H1N1 patients, the median duration of high frequency oscillation ventilation was 3.7 days (interquartile range 1.8 to 5) with concomitant therapies including recruitment manoeuvres (22%), prone ventilation (41%), inhaled prostacyclins (18%) and inhaled nitric oxide (36%). Seven patients received extracorporeal membrane oxygenation, six having H1N1. Three patients had extracorporeal membrane oxygenation concurrently, two as salvage therapy following the commencement of high frequency oscillation ventilation. In 2008, no high frequency oscillation ventilation patient received extracorporeal membrane oxygenation. Overall hospital survival was 77% in H1N1 patients, while survival in patients having adjunctive extracorporeal membrane oxygenation was similar to those receiving high frequency oscillation ventilation alone (65% compared to 71%, P = 1.00). Survival rates were comparable to published extracorporeal membrane oxygenation outcomes. High frequency oscillation ventilation was used successfully as a rescue therapy for severe respiratory failure. High frequency oscillation ventilation was only available in a limited number of intensive care units during the H1N1 pandemic.

The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible for its anti-inflammatory action in arthritis.

OBJECTIVE: In countries where parasitic infections are endemic, autoimmune disease is relatively rare, leading to the hypothesis that parasite-derived immunomodulators may protect against its development. Consistent with this, we have previously demonstrated that ES-62, a 62 kDa phosphorylcholine (PC)-containing glycoprotein that is secreted by filarial nematodes, can exert anti-inflammatory action in the murine collagen-induced arthritis (CIA) model and human rheumatoid arthritis-derived synovial tissue cultures. As a first step to developing ES-62-based drugs, the aim of this study was to determine whether the PC-moiety of ES-62 was responsible for its anti-inflammatory actions. METHODS: We compared the anti-inflammatory activity of a PC-free form of recombinant ES-62 (rES-62) and a synthetic PC-ovalbumin conjugate (OVA-PC) with that of native ES-62 in the CIA model and synovial tissues from patients with rheumatoid arthritis. RESULTS: The anti-inflammatory actions of ES-62 in CIA appear to be dependent on the PC moiety as indicated by the reduction in severity of disease and also suppression of collagen-specific T helper 1 cytokine production observed when testing OVA-PC, but not rES-62. Interestingly, the anti-inflammatory activity of PC did not correlate with a reduction in anti-collagen IgG2a levels. Also, the ES-62-mediated suppression of interferon-gamma from human patient tissues could be mimicked by OVA-PC but not rES-62 or ovalbumin. CONCLUSIONS: In countries where filariasis is endemic the reduced detection of inflammatory diseases, such as rheumatoid arthritis may be because of the anti-inflammatory action of the PC moieties of ES-62. PC may thus provide the starting point for the development of novel, safe immunomodulatory therapies.

Phosphorylcholine mimics the effects of ES-62 on macrophages and dendritic cells.

Modulation of macrophage/dendritic cell (DC) cytokine production by the filarial nematode phosphorylcholine (PC)-containing product, ES-62, is mediated by Toll-like receptor (TLR) 4 and signal transduction depends on the TLR adaptor MyD88. Intriguingly, comparison of TLR4 knock-out (ko) mice with TLR4 mutant C3H/HeJ mice indicates that ES-62 cytokine responses are not dependent on the Pro712 residue of TLR4, which is crucial for the response to bacterial lipopolysaccharide (LPS). Because other immunomodulatory effects of ES-62 have been attributed to PC we have now investigated, using PC conjugated to ovalbumin (PC-Ova), whether PC is responsible for the interaction of ES-62 with TLR4. PC-Ova mimicked the modulation of interleukin (IL)-12 production by ES-62 in a TLR4- and MyD88-dependent manner and as with native ES-62, PC-Ova effects were not dependent on Pro712. Furthermore, both native ES-62 and PC-Ova suppressed Akt phosphorylation, whereas neither altered the activation of p38 or Erk MAP kinases. To rule out any role for the ES-62 protein component, we tested a PC-free recombinant ES-62 (rES-62) generated in the yeast Pichia pastoris. Surprisingly, rES-62 also modulated IL-12 production, but in a TLR4/MyD88-independent manner. Furthermore, rES-62 strongly activated both the p38 and Erk MAP kinases and Akt. However, recent biophysical analysis suggests there are differences in folding/shape between native and rES-62 and hence data obtained with the latter should be treated with caution. Nevertheless, although our study indicates that PC is likely to be primarily responsible for the modulation of cytokine production observed with native ES-62, an immunomodulatory role for the protein component cannot be ruled out.