Nutritional immunity describes the host-driven manipulation of essential micronutrients, including iron, zinc and manganese. To withstand nutritional immunity and proliferate within their hosts, pathogenic microbes must express efficient micronutrient uptake and homeostatic systems. Here we have elucidated the pathway of cellular zinc assimilation in the major human fungal pathogen Candida albicans. Bioinformatics analysis identified nine putative zinc transporters: four cytoplasmic-import Zip proteins (Zrt1, Zrt2, Zrt3 and orf19.5428) and five cytoplasmic-export ZnT proteins (orf19.1536/Zrc1, orf19.3874, orf19.3769, orf19.3132 and orf19.52). Only Zrt1 and Zrt2 are predicted to localise to the plasma membrane and here we demonstrate that Zrt2 is essential for C. albicans zinc uptake and growth at acidic pH. In contrast, ZRT1 expression was found to be highly pH-dependent and could support growth of the ZRT2-null strain at pH 7 and above. This regulatory paradigm is analogous to the distantly related pathogenic mould, Aspergillus fumigatus, suggesting that pH-adaptation of zinc transport may be conserved in fungi and we propose that environmental pH has shaped the evolution of zinc import systems in fungi. Deletion of C. albicans ZRT2 reduced kidney fungal burden in wild type, but not in mice lacking the zinc-chelating antimicrobial protein calprotectin. Inhibition of zrt2Δ growth by neutrophil extracellular traps was calprotectin-dependent. This suggests that, within the kidney, C. albicans growth is determined by pathogen-Zrt2 and host-calprotectin. As well as serving as an essential micronutrient, zinc can also be highly toxic and we show that C. albicans deals with this potential threat by rapidly compartmentalising zinc within vesicular stores called zincosomes. In order to understand mechanistically how this process occurs, we created deletion mutants of all five ZnT-type transporters in C. albicans. Here we show that, unlike in Saccharomyces cerevisiae, C. albicans Zrc1 mediates zinc tolerance via zincosomal zinc compartmentalisation. This novel transporter was also essential for virulence and liver colonisation in vivo. In summary, we show that zinc homeostasis in a major human fungal pathogen is a multi-stage process initiated by Zrt1/Zrt2-cellular import, followed by Zrc1-dependent intracellular compartmentalisation.

Background Several authors have documented the problem of sex offenders and abusers with intellectual disability. With the advent of community care policies, alternative systems for treatment and management are needed to deal with the problems associated with this client group. The current paper describes such a service which attempts to maintain clients' community placements. Methods A database was set up drawing on information from a wide variety of professions. Data are reported on 62 sex offenders and abusers with intellectual disability. Results Information is reported on age, IQ, mental illness, medication, referral characteristics, current and previous sexual offending, forensic status and the range of problems identified during assessment. Re-offending data are reported up to 4 years following discharge. Reoffending rates increase from 4% after 1 year to 21% after 4 years. Unplanned discharge was significantly associated with re-offending. Conclusions It is possible to set up a relatively cost-effective community service for sex offenders with intellectual disability. In terms of re-offending, the outcomes for this service are favourable when compared to the outcomes for alternative disposals reported in the literature.

The ideal procedural sedation drug for emergency department (ED) use would be easily titrated, rapid in onset, brief in duration, and provide sedation and analgesia without respiratory or hemodynamic compromise. Although many agents have been tried, no single drug fits this profile. The authors evaluated the comparative effectiveness and safety of propofol versus propofol/ketamine combination for procedural sedation using bispectral index monitoring for measuring depth of sedation. A prospective, randomized case series of patients undergoing procedural sedation for fracture manipulation was studied in a Level 1 trauma center emergency department. Patients were randomized to a propofol (P) group with a target dose of 0.5 to 1.5 mg/kg or a propofol/ketamine (P/K) group with a target dose of both ketamine and propofol of 0.75 mg/kg. Procedural success, bispectral index (BIS) score, adverse effects, recovery time, and vital signs were measured. Twenty-eight patients were enrolled. The P/K group experienced a smaller decline in systolic blood pressure (1.6% versus 12.5%) and BIS score at goal sedation (77 versus 61), a smaller difference between baseline and goal sedation BIS score (18.78 ± 10 versus 34.64 ± 11) and a lower mean propofol dose (92.5 ± 58 versus 177.27 ± 11 mg). No patient in either group experienced respiratory depression or required any intervention. The combination of propofol and ketamine provides an attractive combination for procedural sedation in the emergency department. Compared to propofol alone, "ketofol" results in less hypotension, better sedation, and enhanced patient comfort and safety.

In some respects, this cohort of female offenders shows similar characteristics to their male counterparts. However, there are higher levels of mental illness, higher levels of sexual abuse and lower levels of re-offending. It is hypothesized that as females constitute such a low percentage of referrals, it suggests that women with ID do not show the same levels of sexually abusive behaviour or aggressive behaviour--the two most frequent reasons for male referral. Therefore, an intervening variable such as mental illness may indeed be a significant factor. Lower re-offending rates may indicate the success of interventions directed at psychological problems and mental illness.