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.

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.

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.

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.

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.

Catastrophic landslide deposits in the karakoram himalaya.

In July 1986, three catastrophic landslides deposited about 20 x 10(6) cubic meters of debris on Bualtar Glacier in the Karakoram Himalaya. A sudden acceleration and superficial breakup of the glacier provided an opportunity to examine the fresh deposits in depth. Beneath a surface layer of large boulders, finer materials, mainly sand and silt, made up half of the total volume. The fine materials were formed during the rock avalanche from mostly intact, massive rock of the source zone. Velocity estimates suggest that this disaggregation occurred in less than 2 minutes. Coarse materials remained in bands of uniform lithology, but the fine materials had diffused throughout the landslides. A small amount of carbonate appears to have been calcined by frictional heating, presumably at the base of the initial sliding masses. These observations are relevant to understanding the mechanisms of catastrophic landslides. Other nearby rock avalanche deposits indicate that landslides are an important geomorphic process in the area and that they pose a continuing risk to human activity.

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.

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.

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.

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.

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.

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.

Transient NMDA receptor inactivation provides long-term protection to cultured cortical neurons from a variety of death signals.

NMDA receptor antagonists, such as (+)-5-methyl-10, 11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801), potently block glutamate-induced neuronal death in myriad in vitro cell models and effectively attenuate ischemic damage in vivo. In this report, a novel role for MK-801 and other NMDA receptor antagonists in preconditioning neurons to withstand a wide range of subsequent lethal insults is described. A brief 30 min exposure to 0.1 microM MK-801, applied up to 96 hr before a "lethal" insult, protected primary cortical neurons from a diverse group of neurotoxic agents, including NMDA, beta-amyloid, staurosporine, etoposide, and oxygen-glucose deprivation. This neuroprotective preconditioning by MK-801 arose from transient NMDA receptor inactivation, because the noncompetitive NMDA receptor antagonists memantine and nylindin and the competitive antagonist AP-5 gave similar effects. MK-801 protection was dependent on new protein synthesis during the first 2 hr, but not from 2 to 5 hr, after MK-801 exposure. The MK-801 transient did not alter the ability of NMDA to trigger normally lethal [Ca(2+)](i) influx 48 hr later, but it did block early downstream signaling events coupled to NMDA neurotoxicity, including PKC inactivation and the activation of calpain. Moreover, MK-801 protected neurons from staurosporine-induced apoptosis, although caspase activation in these cells was unimpeded. It is likely that the stress associated with transient inactivation of NMDA receptors triggered a rapid compensatory survival response that provided long-term protection from a spectrum of insults, inducing apoptotic and nonapoptotic death. The possibility that MK-801 preconditioning blocks an event common to seemingly diverse death mechanisms suggests it will be an important tool for obtaining a clearer understanding of the salient molecular events at work in neuronal death and survival pathways.

Sequential chemotherapy and radiation for nasopharyngeal cancer: absence of long-term benefit despite a high rate of tumor response to chemotherapy.

Between April 1981 and December 1983, patients with locoregional carcinoma of the nasopharynx were treated with two courses of chemotherapy administered before radiation therapy. Chemotherapy consisted of methotrexate, bleomycin, and cisplatin, which were administered at 3-week intervals, and radiation therapy was scheduled to commence 3 weeks after the start of the second course. Forty-nine of 51 consecutive patients were treated; only one patient progressed on chemotherapy, and of 36 patients with measurable neck nodes, eight had complete and 19 had partial clearance (greater than 50% decrease in cross-sectional area) of these nodes when assessed before initiation of radiotherapy. Despite the high rate of tumor response (75%; 95% confidence limits, 59% to 91%), the actuarial survival and disease-free survival curves were almost identical to those recorded for a consecutive group of 140 historical controls of similar stage distribution treated with radiation alone. This chemotherapy provided a high rate of tumor remission, but did not appear to convey long-term benefit to patients when used before radiation therapy.