Do we know how scabies outbreaks in residential and nursing care homes for the elderly should be managed? A systematic review of interventions using a novel approach to assess evidence quality.

Currently no national guidelines exist for the management of scabies outbreaks in residential or nursing care homes for the elderly in the United Kingdom. In this setting, diagnosis and treatment of scabies outbreaks is often delayed and optimal drug treatment, environmental control measures and even outcome measures are unclear. We undertook a systematic review to establish the efficacy of outbreak management interventions and determine evidence-based recommendations. Four electronic databases were searched for relevant studies, which were assessed using a quality assessment tool drawing on STROBE guidelines to describe the quality of observational data. Nineteen outbreak reports were identified, describing both drug treatment and environmental management measures. The quality of data was poor; none reported all outcome measures and only four described symptom relief measures. We were unable to make definitive evidence-based recommendations. We draw on the results to propose a framework for data collection in future observational studies of scabies outbreaks. While high-quality randomised controlled trials are needed to determine optimal drug treatment, evidence on environmental measures will need augmentation through other literature studies. The quality assessment tool designed is a useful resource for reporting of outcome measures including patient-reported measures in future outbreaks.

FTIR study of secondary structure changes in Epidermal Growth Factor by gold nanoparticle conjugation.

Conformation of protein is vital to its function, but may get affected when processing to manufacture products. It is therefore important to understand structural changes during each step of production. In this study, we investigate secondary structure changes in the targeting protein Epidermal Growth Factor (EGF) during synthesis of theranostic bifunctional nanoparticle, devised for Photodynamic therapy of breast cancer. We acquired FTIR spectra of EGF; unconjugated, post treatment with α-lipoic acid, attached to gold nanoparticle, and bound to the bifunctional nanoprobe. We observed decreasing disordered structures and turns, and increasing loops, as the synthesis process progressed. There was an overall increase in ß-sheets in final product compared to pure EGF, but this increase was not linear and fluctuated. Previous crystal structure studies on EGF-EGFR complex have shown loops and ß-sheets to be important in the binding interaction. Since our study found increase in these structures in the final product, no adverse effect on binding function of EGF was expected. This was confirmed by functional assays. Such studies may help modify synthesis procedures, and thus secondary structures of proteins, enabling increased functionality and optimum results.

Surge-type and surge-modified glaciers in the Karakoram.

Glaciers in the Karakoram exhibit irregular behavior. Terminus fluctuations of individual glaciers lack consistency and, unlike other parts of the Himalaya, total ice mass remained stable or slightly increased since the 1970s. These seeming anomalies are addressed through a comprehensive mapping of surge-type glaciers and surge-related impacts, based on satellite images (Landsat and ASTER), ground observations, and archival material since the 1840s. Some 221 surge-type and surge-like glaciers are identified in six main classes. Their basins cover 7,734 ± 271 km2 or ~43% of the total Karakoram glacierised area. Active phases range from some months to over 15 years. Surge intervals are identified for 27 glaciers with two or more surges, including 9 not previously reported. Mini-surges and kinematic waves are documented and surface diagnostic features indicative of surging. Surge cycle timing, intervals and mass transfers are unique to each glacier and largely out-of-phase with climate. A broad class of surge-modified ice introduces indirect and post-surge effects that further complicate tracking of climate responses. Mass balance in surge-type and surge-modified glaciers differs from conventional, climate-sensitive profiles. New approaches are required to account for such differing responses of individual glaciers, and effectively project the fate of Karakoram ice during a warming climate.

First demonstration of surface enhanced-stimulated Raman spectroscopy (SE-SRS) using low-power CW sources.

Using commercially available nanoparticles, continuous wave Surface-Enhanced Stimulated Raman spectroscopy (CW SE-SRS) is demonstrated for the first time using two Ti:Sapphire lasers producing a pump beam (785 nm, 100 mW) and appropriately varying probe/Stokes beams (860-870 nm, 120 mW). The Ti-Sapphire lasers are co-pumped by a 10 W low noise 532 nm Spectra Physics Millennia laser. Pulsed SE-SRS is also demonstrated using a Coherent Chameleon Ultra laser for the Stokes/probe (863-871 nm) beam and a Coherent Ultra II as the pump laser (785 nm). In both cases lock-in techniques are used to extract the small signal (1 in 109) successfully. These experiments convincingly demonstrate that SRS with CW sources is possible using appropriate nanoparticles, and this realization creates opportunities for a wider range of stimulated Raman spectroscopy applications.

Synthesis and characterization of gold nanostructured Chorin e6 for Photodynamic Therapy.

Photodynamic therapy is an alternative treatment for cancer based on cellular uptake of a photosensitizer, illuminated with an appropriate wavelength in the presence of oxygen. A cascade of reactions generates reactive oxygen species leading to cell death. Using carbodiimide chemistry, chlorin e6 (Ce6) was covalently bonded to thiourea, and (via the sulphur end group) to gold nanoparticles (AuNPs), forming the Ce6-AuNP complex. Ce6 absorbs in the range 650-680nm, where the coefficient of biological tissue absorption is low (part of the therapeutic window), which is ideal for biological application. Transmission Electron Microscopy, UV-vis spectroscopy, Fourier transform Infrared Spectroscopy and Zeta potential measurements were completed to characterize the Ce6-AuNP complex. The bare AuNPs have an average diameter of 18±4nm. A line of human breast carcinoma cells (MDA-MB-468) was used to determine whether Ce6 functionalization to AuNPs potentiate its activity. Trypan blue assays were used to assess cell viability. In the absence of light, Ce6 either alone or bounded to AuNPs was not cytotoxic. When irradiated at 660nm, the cytotoxicity of Ce6-AuNP was higher than Ce6 alone for MDA-MB-468 cells using 4h incubation. AuNPs without Ce6 showed no cytotoxic.

Zoonotic diseases in South American camelids in England and Wales.

The number of South American camelids (SACs) in England and Wales is increasing and with this comes a risk of new and emerging infections. Although classified as livestock, these animals are also treated as pets and may be in regular contact with humans. This paper reviews zoonotic diseases that have been identified in SACs in England and Wales, and which pose a potential risk to human health. We also highlight the importance of surveillance continuing to capture information on infections in SACs for the protection of both public and animal health.

Risk factors for acute toxoplasmosis in England and Wales.

Over 300 cases of acute toxoplasmosis are confirmed by reference testing in England and Wales annually. We conducted a case-control study to identify risk factors for Toxoplasma gondii infection to inform prevention strategies. Twenty-eight cases and 27 seronegative controls participated. We compared their food history and environmental exposures using logistic regression to calculate odds ratios (OR) and 95% confidence intervals in a model controlling for age and sex. Univariable analysis showed that the odds of eating beef (OR 10·7, P < 0·001), poultry (OR 6·4, P = 0·01) or lamb/mutton (OR 4·9, P = 0·01) was higher for cases than controls. After adjustment for potential confounders a strong association between beef and infection remained (OR 5·6, P = 0·01). The small sample size was a significant limitation and larger studies are needed to fully investigate potential risk factors. The study findings emphasize the need to ensure food is thoroughly cooked and handled hygienically, especially for those in vulnerable groups.

The management of scabies outbreaks in residential care facilities for the elderly in England: a review of current health protection guidelines.

Commonly thought of as a disease of poverty and overcrowding in resource-poor settings globally, scabies is also an important public health issue in residential care facilities for the elderly (RCFE) in high-income countries such as the UK. We compared and contrasted current local Health Protection Team (HPT) guidelines for the management of scabies outbreaks in RCFE throughout England. We performed content analysis on 20 guidelines, and used this to create a quantitative report of their variation in key dimensions. Although the guidelines were generally consistent on issues such as the treatment protocols for individual patients, there was substantial variation in their recommendations regarding the prophylactic treatment of contacts, infection control measures and the roles and responsibilities of individual stakeholders. Most guidelines did not adequately address the logistical challenges associated with mass treatment in this setting. We conclude that the heterogeneous nature of the guidelines reviewed is an argument in favour of national guidelines being produced.

The Hematopoietic Stem and Progenitor Cell Cistrome: GATA Factor-Dependent cis-Regulatory Mechanisms.

Transcriptional regulators mediate the genesis and function of the hematopoietic system by binding complex ensembles of cis-regulatory elements to establish genetic networks. While thousands to millions of any given cis-element resides in a genome, how transcriptional regulators select these sites and how site attributes dictate functional output is not well understood. An instructive system to address this problem involves the GATA family of transcription factors that control vital developmental and physiological processes and are linked to multiple human pathologies. Although GATA factors bind DNA motifs harboring the sequence GATA, only a very small subset of these abundant motifs are occupied in genomes. Mechanistic studies revealed a unique configuration of a GATA factor-regulated cis-element consisting of an E-box and a downstream GATA motif separated by a short DNA spacer. GATA-1- or GATA-2-containing multiprotein complexes at these composite elements control transcription of genes critical for hematopoietic stem cell emergence in the mammalian embryo, hematopoietic progenitor cell regulation, and erythroid cell maturation. Other constituents of the complex include the basic helix-loop-loop transcription factor Scl/TAL1, its heterodimeric partner E2A, and the Lim domain proteins LMO2 and LDB1. This chapter reviews the structure/function of E-box-GATA composite cis-elements, which collectively constitute an important sector of the hematopoietic stem and progenitor cell cistrome.

In vitro characterisation of the fermentation profile and prebiotic capacity of gold-fleshed kiwifruit.

A new Actinidia chinensis gold-fleshed kiwifruit cultivar 'Zesy002' was tested to investigate whether it could positively modulate the composition of the human colonic microbiota. Digested Zesy002 kiwifruit was added to in vitro pH-controlled anaerobic batch fermenters that were inoculated with representative human faecal microbiota. Alterations to the gut microbial ecology were determined by 16S rRNA gene sequencing and metabolic end products were measured using gas chromatography and liquid chromatography - mass spectrometry. Results indicated a substantial shift in the composition of bacteria within the gut models caused by kiwifruit supplementation. Zesy002 supplemented microbiota had a significantly higher abundance of Bacteroides spp., Parabacteroides spp. and Bifidobacterium spp. after 48 h of fermentation compared with the start of the fermentation. Organic acids from kiwifruit were able to endure simulated gastrointestinal digestion and were detectable in the first 10 h of fermentation. The fermentable carbohydrates were converted to beneficial organic acids with a particular predilection for propionate production, corresponding with the rise in Bacteroides spp. and Parabacteroides spp. These results support the claim that Zesy002 kiwifruit non-digestible fractions can effect favourable changes to the human colonic microbial community and primary metabolites, and demonstrate a hitherto unknown effect of Zesy002 on colonic microbiota under in vitro conditions.

Prolonged clinical remissions in patients with relapsed or refractory follicular lymphoma treated with autologous stem cell transplantation incorporating rituximab.

Three sequential phase II trials were conducted with different immunotherapy approaches to enhance the outcome of autologous transplant (high-dose therapy and autologous stem cell transplantation (HDT/ASCT)) for recurrent follicular lymphoma. Seventy-three patients were enrolled from 1996 to 2009. Patients received HDT/ASCT combined with (1) interferon-α 3 MU/m(2) subcutaneously (SC) three times per week (TIW) for 2 years post-ASCT, (2) rituximab (R) 375 mg/m(2) for in vivo purging 3-5 days pre-stem cell collection and 2 × 4 weekly R at 2 and 6 months post-ASCT, respectively, or (3) three infusions of R pre-stem cell collection followed by 6× R weekly and interferon-α 3 MU/m(2) SC TIW. Although not statistically significant, progression-free survival (PFS) for patients who received rituximab was 56.4 and 49.1% at 5 and 10 years compared to 36 and 21% in those who did not receive rituximab. Molecular relapse post-HDT/ASCT was the strongest predictor of PFS in a multivariate analysis. Molecular relapse was coincident with or preceded clinical relapses in 84% of patients who relapsed­median of 12 months (range 0-129 months). Adverse events included secondary malignancy, transformation to diffuse large B cell lymphoma, prolonged mostly asymptomatic hypogammaglobulinemia, and pulmonary fibrosis. The long-term toxicity profile must be considered when selecting patients for this treatment.

Scabies outbreaks in residential care homes: factors associated with late recognition, burden and impact. A mixed methods study in England.

Scabies is an important public health problem in residential care homes. Delayed diagnosis contributes to outbreaks, which may be prolonged and difficult to control. We investigated factors influencing outbreak recognition, diagnosis and treatment, and staff experiences of outbreak control, identifying areas for intervention. We carried out a semi-structured survey of managers, affected residents and staff of seven care homes reporting suspected scabies outbreaks in southern England over a 6-month period. Attack rates ranged from 2% to 50%, and most cases had dementia (37/39, 95%). Cases were diagnosed clinically by GPs (59%) or home staff (41%), none by dermatologists. Most outbreaks were attributable to avoidably late diagnosis of the index case. Participants reported considerable challenges in managing scabies outbreaks, including late diagnosis and recognition of outbreaks; logistically difficult mass treatment; distressing treatment processes and high costs. This study demonstrates the need for improved support for care homes in detecting and managing these outbreaks.

The effect of different feed delivery methods on time to consume feed and the resulting changes in postprandial metabolite concentrations in horses.

Management techniques that reduce the insulin response to feeding in horses have application in preventing insulin resistance (IR) and potential associations (e.g., laminitis). Eight mature idle horses of BCS between 5 and 6.5 and with no previous indication of IR were fed a meal of concentrate under 4 feed delivery treatments in a repeated Latin Square design. Treatments were all based on a bucket of equal dimensions. The treatments included a control (CON) and 3 treatments hypothesized to increase time to consume feed (TCF): mobile obstacles above the feed (BALL), stationary obstacles below the feed (WAFF), and feed with water added (WTR). Jugular venous blood samples were taken at feed delivery, every 10 min for the first hour, and then every 30 min until 300 min after feed delivery. The TCF was different across treatment and was greater (P < 0.05) for BALL and WAFF when compared with CON and WTR. Glucose and insulin concentrations increased after feeding (P < 0.05) and tended to differ among treatments (P < 0.10). Peak insulin and glucose concentrations were affected by treatment as were the time to peak insulin and the area under the curve of insulin (P < 0.05). Therefore, feed delivery methods that include obstacles effectively increase TCF and attenuate postprandial glucose and insulin concentrations. A second experiment was designed to determine if the TCF changes associated with BALL and WAFF in Exp. 1 remain effective over a 4-d period. Four horses with no recent or regular history of consuming concentrates were fed concentrate meals for 4 consecutive d using the same treatments described in Exp. 1 and a Latin square design. Horses were subject to a 4-d adaptation period and were randomly assigned to 4-d treatment periods using the 4 previously described treatments. During adaptation, TCF decreased over time (P = 0.02). After adaptation, WAFF had greater TCF when compared with CON and WTR (P < 0.05) whereas WTR had the lowest TCF overall. Using obstacles to increase TCF on a daily basis may be an effective method to reduce postprandial glucose and insulin concentrations, thereby decreasing the risk of IR development in horses.

Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance.

AIMS/HYPOTHESIS: Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known. METHODS: We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed. RESULTS: The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic-euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1). CONCLUSIONS/INTERPRETATION: These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity.

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity.

AIMS/HYPOTHESIS: Obesity-related insulin resistance is associated with accumulation of bioactive lipids in skeletal muscle. The AMP-activated protein kinase (AMPK) regulates lipid oxidation in muscle by inhibiting acetyl-CoA carboxylase-2 (ACC2) and increasing mitochondrial biogenesis. We investigated whether reduced levels of muscle AMPK promote lipid accumulation and insulin resistance during high-fat feeding. METHODS: Male C57/BL6 wild-type mice and transgenic littermates overexpressing an alpha2AMPK kinase-dead (KD) in muscle were fed control or high-fat diet. Whole-body glucose homeostasis was assessed by glucose and insulin tolerance tests, and by measuring fasting and fed serum insulin and glucose. Insulin action in muscle was determined by measuring 2-deoxy-[(3)H]glucose uptake and Akt phosphorylation in incubated soleus and extensor digitorum longus muscles. Muscle triacylglycerol, diacylglycerol and ceramide content was measured by thin-layer chromatography. Mitochondrial proteins were measured by immunoblotting. RESULTS: KD mice had reduced skeletal muscle alpha2AMPK activity (50% in gastrocnemius and >80% in soleus and extensor digitorum longus) and ACC2 Ser228 phosphorylation (90% in gastrocnemius). High-fat feeding increased body mass and adiposity, and impaired insulin and glucose tolerance; however, there were no differences between wild-type and KD littermates. High-fat feeding impaired insulin-stimulated muscle glucose uptake and Akt-phosphorylation, while increasing muscle triacylglycerol, diacylglycerol (p = 0.07) and ceramide, but these effects were not exacerbated in KD mice. In response to high-fat feeding, mitochondrial proteins were increased to similar levels in wild-type and KD muscles. CONCLUSIONS/INTERPRETATION: Obesity-induced lipid accumulation and insulin resistance were not exacerbated in AMPK KD mice, suggesting that reduced levels of muscle alpha2AMPK do not promote insulin resistance in the early phase of obesity-related diabetes.

Assessing the risk from emerging infections.

Emerging infections pose a constant threat to society and can require a substantial response, thus systems to assess the threat level and inform prioritization of resources are essential. A systematic approach to assessing the risk from emerging infections to public health in the UK has been developed. This qualitative assessment of risk is performed using algorithms to consider the probability of an infection entering the UK population, and its potential impact, and to identify knowledge gaps. The risk assessments are carried out by a multidisciplinary, cross-governmental group of experts working in human and animal health. This approach has been piloted on a range of infectious threats identified by horizon scanning activities. A formal risk assessment of this nature should be considered for any new or emerging infection in humans or animals, unless there is good evidence that the infection is neither a recognized human disease nor a potential zoonosis.

Sex differences in emotionality in C3H/HeH mice, with hypogonadal mutant to distinguish activational effects of gonadal hormones.

The C3H/HeH mouse strain has a mutant hypogonadal (hpg) variant, providing an animal model to examine the activational effects of sex hormones because reproductive maturation is arrested at a neonatal stage. Thus in the adult mouse, the circulating concentrations of sex steroids are extremely low. The present study used a series of tests to distinguish sex differences in behaviour: open field, locomotor activity, hyponeophagia, and novel location recognition. The results showed some evidence for a role of sex hormones in emotionality underscoring the potential utility of the hpg model, to distinguish activational effects in the C3H/HeH strain. However, the direction that the sex differences took varied by task: whilst males showed the predicted sex difference of relatively greater anxiety in the open field, hyponeophagia tests suggested higher emotionality in females. The hpg mice of both sexes showed a reduction in anxiety measured as hyponeophagia. Overall it can be concluded that this set of experiments supports the potential of the hpg model to investigate hormonal influences on emotionality.

Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism.

BACKGROUND AND PURPOSE: Although CB(1) receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPAR alpha and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection. EXPERIMENTAL APPROACH: Assays of PPAR alpha occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPAR alpha activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPAR alpha gene-disrupted mice. KEY RESULTS: The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPAR alpha ligand binding domain and to increase PPAR alpha-driven transcriptional activity. The high affinity synthetic CB(1/2) cannabinoid agonist WIN 55212-2 bound to PPAR alpha equipotently with the PPARalpha agonist fenofibrate, and stimulated PPARalpha-mediated gene transcription. The phytocannabinoid delta 9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPAR alpha-null mice. OEA treatment also led to increased expression of the NFkappa B-inhibitory protein, Ikappa B, in mouse cerebral cortex, while expression of the NFkappa B-regulated protein COX-2 was inhibited. CONCLUSIONS AND IMPLICATIONS: These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPAR alpha and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.