There is debate in Australia and New Zealand around the appropriate use of illness severity scoring systems in Australasian intensive care units. The international benchmark is the Acute Physiological and Chronic Health Evaluation (APACHE) system. In order to compare the performance of recent APACHE releases, we audited 2080 sequential patients admitted between 1 January 2006 and 31 March 2008 to the Middlemore Hospital intensive care unit, Auckland, New Zealand. We compared the predictive performance of the proprietary APACHE II, IIIh, IIIj and IV releases, and the performance of a 'localised' version of APACHE II containing re-estimated coefficients derived from a legacy dataset (7703 sequential patients admitted between 1 January 1997 and 31 December 2005). Discrimination assessed by receiver operating characteristic curves was highest with the APACHE III and IV releases, and significantly better than the APACHE II releases. Calibration assessed by the Hosmer-Lemeshow statistic was poor with all releases, although it was best with APACHE IV and 'localised' version of the APACHE II release. Overall accuracy assessed by the Brier Mean Probability score and Shapiro's R statistic was best with APACHE IV. Our study suggests the possibility of improved prediction in moving to APACHE IV from older releases, although broader multicentre study within the Australian and New Zealand critical care community is warranted. Our study also suggests localisation of the APACHE system offers further opportunity to improve prediction, although these improvements may not be major without ground-up development of a new risk prediction model within our local critical care setting.

NLRs (nucleotide-binding domain leucine-rich-repeat-containing receptors; NOD-like receptors) are a class of pattern recognition receptor (PRR) that respond to host perturbation from either infectious agents or cellular stress. The function of most NLR family members has not been characterized and their role in instructing adaptive immune responses remains unclear. NLRP10 (also known as PYNOD, NALP10, PAN5 and NOD8) is the only NLR lacking the putative ligand-binding leucine-rich-repeat domain, and has been postulated to be a negative regulator of other NLR members, including NLRP3 (refs 4-6). We did not find evidence that NLRP10 functions through an inflammasome to regulate caspase-1 activity nor that it regulates other inflammasomes. Instead, Nlrp10(-/-) mice had a profound defect in helper T-cell-driven immune responses to a diverse array of adjuvants, including lipopolysaccharide, aluminium hydroxide and complete Freund's adjuvant. Adaptive immunity was impaired in the absence of NLRP10 because of a dendritic cell (DC) intrinsic defect in emigration from inflamed tissues, whereas upregulation of DC costimulatory molecules and chemotaxis to CCR7-dependent and -independent ligands remained intact. The loss of antigen transport to the draining lymph nodes by a subset of migratory DCs resulted in an almost absolute loss in naive CD4(+) T-cell priming, highlighting the critical link between diverse innate immune stimulation, NLRP10 activity and the immune function of mature DCs.

BACKGROUND: Complex anal fistulas remain a challenge for the colorectal surgeon. The anal fistula plug has been developed as a simple treatment for fistula-in-ano. We present and evaluate our experience with the Surgisis anal fistula plug from two centres. METHODS: Data were prospectively collected and analysed from consecutive patients undergoing insertion of a fistula plug between January 2007 and October 2009. Fistula plugs were inserted according to a standard protocol. Data collected included patient demographics, fistula characteristics and postoperative outcome. RESULTS: Forty-four patients underwent insertion of 62 plugs (27 males, mean age 45.6 years), 25 of whom had prior fistula surgery. Mean follow-up was 10.5 months Twenty-two patients (50%) had successful healing following the insertion of plug with an overall success rate of 23 out of 62 plugs inserted (35%). Nineteen out of 29 patients healed following first-time plug placement, whereas repeated plug placement was successful in 3 out of 15 patients (20%; p = 0.0097). There was a statistically significant difference in the healing rate between patients who had one or less operations prior to plug insertion (i.e. simple fistulas) compared with patients who needed multiple operations (18 out of 24 patients vs. 4 out of 20 patients; p = 0.0007). CONCLUSIONS: Success of treatment with the Surgisis anal fistula plug relies on the eradication of sepsis prior to plug placement. Plugs inserted into simple tracts have a higher success rate, and recurrent insertion of plugs following previous plug failure is less likely to be successful. We suggest the fistula plug should remain a first-line treatment for primary surgery and simple tracts.

OBJECTIVE: Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin α(M)(complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.METHODS: The authors examined several markers in the ICAM1-ICAM4-ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case-control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene-gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed.RESULTS: The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (OR(meta)=1.16, 95% CI 1.11 to 1.22; p=4.88×10(-10) and OR(meta)=1.67, 95% CI 1.55 to 1.79; p=3.32×10(-46), respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10(-5)).CONCLUSION: These findings are the first to suggest that an ICAM-integrin-mediated pathway contributes to susceptibility to SLE.

Iron is an essential cofactor for both mycobacterial growth during infection and for a successful protective immune response by the host. The immune response partly depends on the regulation of iron by the host, including the tight control of expression of the iron-storage protein, ferritin. BCG vaccination can protect against disease following Mycobacterium tuberculosis infection, but the mechanisms of protection remain unclear. To further explore these mechanisms, splenocytes from BCG-vaccinated guinea pigs were stimulated ex vivo with purified protein derivative from M. tuberculosis and a significant down-regulation of ferritin light- and heavy-chain was measured by reverse-transcription quantitative-PCR (P≤0.05 and ≤0.01, respectively). The mechanisms of this down-regulation were shown to involve TNFα and nitric oxide. A more in depth analysis of the mRNA expression profiles, including genes involved in iron metabolism, was performed using a guinea pig specific immunological microarray following ex vivo infection with M. tuberculosis of splenocytes from BCG-vaccinated and naïve guinea pigs. M. tuberculosis infection induced a pro-inflammatory response in splenocytes from both groups, resulting in down-regulation of ferritin (P≤0.05). In addition, lactoferrin (P≤0.002), transferrin receptor (P≤0.05) and solute carrier family 11A1 (P≤0.05), were only significantly down-regulated after infection of the splenocytes from BCG-vaccinated animals. The results show that expression of iron-metabolism genes is tightly regulated as part of the host response to M. tuberculosis infection and that BCG-vaccination enhances the ability of the host to mount an iron-restriction response which may in turn help to combat invasion by mycobacteria.

Prolonged intermittent renal replacement therapy (PIRRT) is a recently defined acute modality for critically ill patients, and in theory combines the superior detoxification and haemodynamic stability of continuous renal replacement therapy (CRRT) with the operational convenience and low cost of intermittent haemodialysis (iHD). We performed a retrospective cohort study for all critically ill adults treated with renal replacement therapy at our centre in Auckland, New Zealand from 1 January 2002 to 31 December 2008. The exposure of interest was modality (PIRRT, CRRT, iHD). Primary and secondary outcomes were patient mortality determined at hospital discharge and 90 days post renal replacement therapy inception, respectively. Co-variates included co-morbidity and baseline illness severity measured by Acute Physiology and Chronic Health Evaluation IV and Sepsis-Related Organ Failure Assessment (SOFA) and time-varying illness severity measured by daily SOFA scores. We used Marginal Structural Modelling to estimate mortality risk adjusting for both time-varying illness severity and modality exposure. A total of 146 patients with 633 treatment-days had sufficient data for modelling. With PIRRT as the reference, the adjusted hazard ratios for patient hospital mortality were 1.31 (0.60 to 2.90) for CRRT and 1.22 (0.21 to 2.29) for iHD. Corresponding estimates for mortality at 90 days were 0.96 (0.39 to 2.36) and 2.22 (0.49 to 10.11), respectively, reflecting the poorer longer-term prognosis of patients still on iHD at hospital discharge with delayed or non-recovery of acute kidney injury. Our study supports the recent increased use of PIRRT, which within limits can be regarded as safe and effective.

Reasons for performing study: Idiopathic headshaking is often a facial pain syndrome, but a diagnostic protocol has not been described. In a previous study, caudal compression of the infraorbital nerve for treatment offered a fair success rate, but low case numbers and short follow-up time were limitations. Objectives: To describe a diagnostic protocol for headshaking, examining the role of bilateral local analgesia of the posterior ethmoidal nerve (PET block). To report longer-term follow-up after surgery of the original cases and further cases and to determine whether changes to the technique influence success rates and complications. Methods: Records of horses that had undergone PET block and caudal compression surgery at 3 hospitals were reviewed. Modifications to the surgical technique included placing additional coils into the infraorbital canal and/or performing concurrent laser cautery of the nerve. Follow-up information was obtained by telephone contact with owners. Results: The PET block was performed in 27 horses, with a positive result in 23 of 27 (85%). Surgery was performed in 58 horses. A successful outcome was initially achieved in 35 of 57 (63%) horses, but recurrence occurred between 9 and 30 months later in 9 (26%). Surgery was repeated in 10 of 31 (32%) horses. Final success rate, considering only response to the last performed surgery, was 28 of 57 (49%) horses with median follow-up time of 18 months (range 2-66 months). Nose-rubbing was reported post operatively in 30 of 48 (63%) horses. This resolved in all but 4 horses, which were subjected to euthanasia. Response to PET block or change in surgical technique did not appear to influence outcome or complications. Conclusions and potential relevance: The diagnostic protocol described is recommended for the investigation of headshakers. Caudal compression offers the best prognosis for a successful outcome compared with other treatments, for horses in which the only alternative is euthanasia. Surgical treatment of the disorder requires refinement, and the pathogenesis of the disorder requires investigation.

We describe a previously unknown assemblage of seamount-associated megabenthos that has by far the highest peak biomass reported in the deep-sea outside of vent communities. The assemblage was found at depths of 2-2.5 km on rocky geomorphic features off the southeast coast of Australia, in an area near the Sub-Antarctic Zone characterised by high rates of surface productivity and carbon export to the deep-ocean. These conditions, and the taxa in the assemblage, are widely distributed around the Southern mid-latitudes, suggesting the high-biomass assemblage is also likely to be widespread. The role of this assemblage in regional ecosystem and carbon dynamics and its sensitivities to anthropogenic impacts are unknown. The discovery highlights the lack of information on deep-sea biota worldwide and the potential for unanticipated impacts of deep-sea exploitation.

Mutation of ptsP encoding EI(Ntr) of the PTS(Ntr) system in Rhizobium leguminosarum strain Rlv3841 caused a pleiotropic phenotype as observed with many bacteria. The mutant formed dry colonies and grew poorly on organic nitrogen or dicarboxylates. Most strikingly the ptsP mutant had low activity of a broad range of ATP-dependent ABC transporters. This lack of activation, which occurred post-translationally, may explain many of the pleiotropic effects. In contrast proton coupled transport systems were not inhibited in a ptsP mutant. Regulation by PtsP also involves two copies of ptsN that code for EIIA(Ntr), resulting in a phosphorylation cascade. As in Escherichia coli, the Rlv3841 PTS(Ntr ) system also regulates K(+) homeostasis by transcriptional activation of the high affinity ATP dependent K(+) transporter KdpABC. This involves direct interaction of a two component sensor regulator pair KdpDE with unphosphorylated EIIA(Ntr). Critically, ptsP mutants, which cannot phosphorylate PtsN1 or PtsN2, had a fully activated KdpABC transporter. This is the opposite pattern from that observed with ABC transporters which apparently require phosphorylation of PtsN. These results suggest that ATP-dependent transport might be regulated via PTS(Ntr) responding to the cellular energy charge. ABC transport may be inactivated at low energy charge, conserving ATP for essential processes including K(+) homeostasis. © 2012 Blackwell Publishing Ltd.

The bioavailability of ingested silver nanoparticles (AgNPs) depends in large part on initial particle size, shape and surface coating, properties which will influence aggregation, solubility and chemical composition during transit of the gastrointestinal tract. Citrate-stabilized AgNPs were exposed to synthetic human stomach fluid (SSF)(pH 1.5) and changes in size, shape, zeta potential, hydrodynamic diameter and chemical composition were determined during a 1h exposure period using Surface Plasmon Resonance (SPR), High Resolution Transmission Electron Microscopy/Energy Dispersive X-ray Spectroscopy (TEM/EDS), Dynamic Light Scattering (DLS) and X-ray Powder Diffraction (XRD) combined with Rietveld analysis. Exposure of AgNPs to SSF produced a rapid decrease in the SPR peak at 414nm and the appearance of a broad absorbance peak in the near infrared (NIR) spectral region. During exposure to SSF, changes in zeta potential, aggregation and morphology of the particles were also observed as well as production of silver chloride which appeared physically associated with particle aggregates.