Risk factors associated with the Motoric Cognitive Risk syndrome: A meta-analysis of data from a cross-national study.

BACKGROUND: Identifying risk factors associated with the Motoric Cognitive Risk (MCR) syndrome (a pre-dementia syndrome) can assist in developing risk reduction strategies and interventions to delay progression to dementia. Tailored interventions require comparisons of high- and middle-income countries to determine if the same or different risk factors should be targeted. We examined risk factors associated with MCR in seven Health and Retirement Studies with harmonized measures. METHODS: Data from adults aged ≥65 years (n = 20,036, mean age 71.2(SD 6.2)-80.1(SD 4.1)) from the U.S. Health and Retirement Study, English Longitudinal Study of Aging, Survey of Health, Aging and Retirement in Europe, China Health and Retirement Longitudinal Study, Harmonized Diagnostic Assessment of Dementia for Longitudinal Aging Study in India, Mexican Health and Aging Study, and Brazilian Longitudinal Study of Aging was included. MCR was defined as the presence of cognitive complaints and slow gait (no mobility disability and dementia). Associations of demographic [education], medical [hypertension, diabetes, heart disease, obesity, stroke, Parkinson's, falls], psychological [depressive symptoms, psychiatric problems], sensorimotor [grip strength, hearing], and behavioral factors [smoking, sedentariness, sleep], with prevalent MCR were examined using age- and sex-adjusted logistic regression models. A meta-analysis was performed to compare risk factors for MCR in high- versus middle-income countries. RESULTS: Except for depressive symptoms and weak grip strength, different risk factor clusters were associated with individual studies. Poor sleep, hearing, weak grip, and multiple falls emerged as novel associations with MCR. When grouped by income, some risk factors (i.e., education) were associated with MCR in high- and middle-income countries. Others (i.e., obesity) were specific to high-income countries. CONCLUSIONS: This cross-sectional, cross-national study identified new, shared, and specific risk factors associated with MCR in high- and middle-income countries, providing insights to develop public health approaches and interventions to forestall the onset of dementia in those with MCR.

Systematic review of global functioning and quality of life in people with psychotic disorders.

AimsPeople with psychotic disorders face impairments in their global functioning and their quality of life (QoL). The relationship between the two outcomes has not been systematically investigated. Through a systematic review, we aim to explore the presence and extent of associations between global functioning and QoL and establish whether associations depend on the instruments employed. METHODS: In May 2016, ten electronic databases were searched using a two-phase process to identify articles in which associations between global functioning and QoL were assessed. Basic descriptive data and correlation coefficients between global functioning and QoL instruments were extracted, with the strength of the correlation assessed according to the specifications of Cohen 1988. Results were reported with reference to the Meta-analysis of Observational Studies in Epidemiology guidelines and PRISMA standards. A narrative synthesis was performed due to heterogeneity in methodological approaches. RESULTS: Of an initial 15 183 non-duplicate articles identified, 756 were deemed potentially relevant, with 40 studies encompassing 42 articles included. Fourteen instruments for measuring global functioning and 22 instruments for measuring QoL were used. Twenty-nine articles reported linear associations while 19 assessed QoL predictors. Correlations between overall scores varied in strength, primarily dependent on the QoL instrument employed, and whether QoL was objectively or subjectively assessed. Correlations observed for objective QoL measures were consistently larger than those observed for subjective measures, as were correlations for an interviewer than self-assessed QoL. When correlations were assessed by domains of QoL, the highest correlations were found for social domains of QoL, for which most correlations were moderate or higher. Global functioning consistently predicted overall QoL as did depressive and negative symptoms. CONCLUSIONS: This review is the first to explore the extent of associations between global functioning and QoL in people with psychotic disorders. We consistently found a positive association between global functioning and QoL. The strength of the association was dependent on the QoL instrument employed. QoL domains strongly associated with global functioning were highlighted. The review illustrates the extensive array of instruments used for the assessment of QoL and to a lesser extent global functioning in people with psychotic disorders and provides a framework to understand the different findings reported in the literature. The findings can also inform the future choice of instruments by researchers and/or clinicians. The observed associations reassure that interventions for improving global functioning will have a positive impact on the QoL of people living with a psychotic disorder.

Epothilone D accelerates disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

AIMS: Degeneration of the distal neuromuscular circuitry is a hallmark pathology of Amyotrophic Lateral Sclerosis (ALS). The potential for microtubule dysfunction to be a critical pathophysiological mechanism in the destruction of this circuitry is increasingly being appreciated. Stabilization of microtubules to improve neuronal integrity and pathology has been shown to be a particularly favourable approach in other neurodegenerative diseases. We present evidence here that treatment with the microtubule-targeting compound Epothilone D (EpoD) both positively and negatively affects the spinal neuromuscular circuitry in the SOD1G93A mouse model of ALS. METHODS: SOD1G93A mice were treated every 5 days with 2 mg/kg EpoD. Evaluation of motor behaviour, neurological phenotype and survival was completed, with age-dependent histological characterization also conducted, using the thy1-YFP mouse. Motor neuron degeneration, axonal integrity, neuromuscular junction (NMJ) health and gliosis were also assessed. RESULTS: EpoD treatment prevented loss of the spinal motor neuron soma, and distal axon degeneration, early in the disease course. This, however, was not associated with protection of the NMJ synapse and did not improve motor phenotype or clinical progression. EpoD administration was also found to be neurotoxic at later disease stages. This was evidenced by accelerated motor neuron cell body loss, increasing gliosis, and was associated with detrimental outcomes to motor behaviour, clinical assessment and survival. CONCLUSIONS: The results suggest that EpoD accelerates disease progression in the SOD1G93A mouse model of ALS, and highlights that the pathophysiological involvement of microtubules in ALS is an evolving and underappreciated phenomenon.

An in-vitro investigation into the efficacy of disinfectants used in the duck industry against Salmonella.

In 2010, 81 confirmed cases of Salmonella Typhimurium DT8 were reported across England and Northern Ireland - an increase of 26% from 2009 and 41% since 2008. Five cases were hospitalized and one death reported, with a strong association found between cases and the consumption of duck eggs. Once present on farms, Salmonella may become persistent and can survive for long periods of time in residual organic matter, increasing risk of infection for follow-on flocks if cleaning and disinfection is not carried out effectively. The aim of this study was to investigate the efficacy of a range of disinfectants used by the duck industry against Salmonella using laboratory models. Sixteen products were selected from seven chemical groups and the Minimum Inhibitory Concentration and Minimum Bactericidal Concentrations determined. Each product was also tested at the recommended general orders (GO) concentration using a faecal suspension model to mimic boot dips and a surface contamination model to simulate contaminated building fabric and equipment. In the faecal suspension model, all products were effective at 2 × GO concentration, and activity was more inconsistent at GO concentration. At 0.5 × GO concentration, iodine-based and quaternary-ammonium-compound-based products were significantly less effective than products within other chemical groups (P < 0.001). Glutaraldehyde-based products were significantly more effective than the other products in the surface contamination tests (P < 0.001). Chlorocresol-based products were found to be most effective for use in boot dips and aldehyde-based products for surface disinfection, although there was variability between products within a chemical group.

Modifications to the INSM1 promoter to preserve specificity and activity for use in adenoviral gene therapy of neuroendocrine carcinomas.

The INSM1 gene encodes a transcriptional repressor that is exclusively expressed in neuronal and neuroendocrine tissue during embryonic development that is re-activated in neuroendocrine tumors. Using the 1.7 kbp INSM1 promoter, an adenoviral HSV thymidine kinase gene therapy was tested for the treatment of neuroendocrine tumors. An unforeseen interference on the INSM1 promoter specificity from the adenoviral genome was observed. Attempts were made to protect the INSM1 promoter from the influence of essential adenoviral sequences and to further enhance the tissue specificity of the INSM1 promoter region. Using the chicken ß-globin HS4 insulator sequence, we eliminated off-target tissue expression from the Ad-INSM1 promoter-luciferase2 constructs in vivo. In addition, inclusion of two copies of the mouse nicotinic acetylcholine receptor (n(AchR)) neuronal-restrictive silencer element (NRSE) reduced nonspecific activation of the INSM1 promoter both in vitro and in vivo. Further, inclusion of both the HS4 insulator with the n(AchR) 2 × NRSE modification showed a two log increase in luciferase activity measured from the NCI-H1155 xenograft tumors compared with the original adenovirus construct. The alterations increase the therapeutic potential of adenoviral INSM1 promoter-driven suicide gene therapy for the treatment of a variety of neuroendocrine tumors.

Persistence and clearance of different Salmonella serovars in buildings housing laying hens.

We investigated factors associated with persistence of different Salmonella serovars in buildings housing laying hens in Great Britain using survival analysis. A total of 264 incidents of Salmonella detection occurring between July 1998 and August 2007 in 152 houses were recorded. For incidents involving Salmonella Enteritidis (SE), both the rodent score of the house and the type of house were positively associated with persistence. For non-SE serovars, only the type of house was associated with persistence. Persistence of SE in the houses was longest (>15 months) in step-cage and cage-scraper houses when high levels of rodents were present, and lowest in non-cage and cage-belt houses. We estimated that 42% (95% CI 23.3-63.1) of SE incidents may be cleared during the lay period, and this was related to elimination of rodents from the houses. From January 2009, EU legislation will ban the sale of fresh eggs from SE-positive and S. Typhimurium-positive flocks over their remaining lifespan. If infection is eliminated from such flocks, they would cease to represent a public health risk.

Observations related to the Salmonella EU layer baseline survey in the United Kingdom: follow-up of positive flocks and sensitivity issues.

A follow-on study was carried out on 23 holdings identified as Salmonella positive in the 2004/2005 European Union (EU) baseline survey of Salmonella in laying hens. Eleven of 13 cage and 4/7 floor houses remained positive for Salmonella when the new flock was tested, and from 10/13 cage and 3/7 floor houses a Salmonella of the same serovar/phage type as found in the EU survey was isolated. There was a high correlation between the level of contamination in the houses at the time of the EU survey and in the follow-on flock. On seven occasions the house identified as positive in the EU survey was sampled after cleaning and disinfection but before a new flock was placed, and in all of them Salmonella could be isolated from the houses. The observed number of infected houses in infected holdings suggests that the holding-level prevalence in the United Kingdom would be about 21% higher than the results obtained in the EU survey.

Comparison of environmental sampling methods for detecting Salmonella in commercial laying flocks in the UK.

AIMS: To investigate the performance of the Salmonella National Control Programme (NCP) sampling/testing methods in laying flocks of domestic fowl. METHODS AND RESULTS: Eighty-five visits were made to 69 flocks representative of the main production systems (cage, barn and free-range) infected with Salmonella. In each visit, three methodologies were compared: (i) the European Union (EU) baseline survey method (five faeces and two dust samples); (ii) an in-house (Veterinary Laboratories Agency, VLA) 'wet' method that involved collecting 10 dust and 10 faeces samples into jars with buffered peptone water; and (iii) a method involving two samples of pooled faeces and one of dust (cultured as one sample of each type), which has been adopted for the NCP for laying flocks across the EU. CONCLUSIONS: The 'wet' method was the most sensitive, and the NCP the least, although individual NCP samples were the most sensitive ones. SIGNIFICANCE AND IMPACT OF THE STUDY: The apparent lower sensitivity of the NCP method may be compensated by repeated sampling of flocks (twice during rear and several times during lay). Sampling using VLA methodology should be advocated for farms aiming to disclose low-level Salmonella before restrictions on the sale of eggs from Salmonella Enteritidis or Salmonella Typhimurium-infected flocks are in place.

Semiquantitative assessment of the distribution of Salmonella in the environment of caged layer flocks.

AIMS: To evaluate a semiquantitative technique for the enumeration of Salmonella in the environment of layer flocks and to compare findings with those of a standard qualitative technique. METHODS AND RESULTS: Samples were taken from faeces, floor dust, dust on cages, feeders and egg belts. After mixing with buffered peptone water, serial dilutions were prepared and culture was performed using pre-enrichment, then plating on semisolid selective and solid isolation media. Comparison with a qualitative pre-enrichment technique indicated a similar sensitivity for both methods despite smaller sample sizes. The numbers of Salmonella detected for a site or sample type did not correlate closely with the prevalence of positive samples. CONCLUSIONS: The sensitive detection and quantification of Salmonella in the flock environment is practicable with the technique described. Quantitative data in many cases do not correlate with qualitative findings. SIGNIFICANCE AND IMPACT OF THE STUDY: The significance of certain environmental factors and interventions in the maintenance and dissemination of Salmonella in poultry houses may be over- or under-represented by prevalence data alone. The technique described allows the issue of poultry house contamination to be examined from a new perspective.

The insulinoma-associated 1: a novel promoter for targeted cancer gene therapy for small-cell lung cancer.

The insulinoma-associated 1 (INSM1) gene is expressed exclusively during early embryonal development, but has been found re-expressed at high levels in neuroendocrine tumors. The regulatory region of the INSM1 gene is therefore a potential candidate for regulating expression of a therapeutic gene in transcriptionally targeted cancer gene therapy against neuroendocrine tumors. We analyzed expression of a reporter gene from a 1.7 kb region of the INSM1 promoter in a large number of small-cell lung cancer (SCLC) cell lines. This INSM1 promoter region showed very high levels of expression in most of the SCLC cell lines and expression was absent in cell lines of non-neuroendocrine origin. Inclusion of the general transcriptional enhancer from SV40 compromised the specificity of the promoter and did not enhance transcription in most of the SCLC cell lines. For comparison, the region of the gastrin releasing peptide (GRP) previously suggested for SCLC gene therapy was analyzed in a similar manner. High expression was observed for a number of cell lines, but unlike for the INSM1 promoter, reporter gene expression from the GRP promoter did not correlate to the relative GRP mRNA levels, demonstrating that this region may not contain all necessary regulatory elements. Expression of the suicide gene herpes simplex virus thymidine kinase (HSV-TK) from the INSM1 promoter in combination with treatment with the prodrug ganciclovir (GCV) caused a significant increase in GCV sensitivity specifically in INSM1-expressing cell lines. The INSM1 promoter is therefore a potential novel tool for transcriptionally targeted gene therapy for neuroendocrine tumors.

The role of ultrasound-guided fine-needle aspiration biopsy in the previously treated patient with thyroid cancer.

The aim of the present study was to evaluate the effectiveness of ultrasound-guided fine-needle aspiration in detecting locoregional recurrence in previously treated patients with thyroid cancer. A retrospective analysis of ultrasound-guided fine-needle aspiration (FNA) biopsy was carried out for suspected recurrence of thyroid cancer over a 5-year period at a single institution. There were 37 biopsies in 37 patients. Each patient's ultrasound report, cytology report and medical notes were examined to determine the result of the biopsy and the patient's outcome. There were 29 true-positives, 6 true-negatives, 1 false-negative and 1 inadequate biopsy. Ultrasound-guided FNA, therefore, had a sensitivity of 96.7%, specificity of 100% and overall accuracy of 97.2% in detecting recurrence. Ultrasound-guided FNA is an accurate method of identifying suspected recurrence.

Effects of vaccination and other preventive methods for Salmonella enteritidis on commercial laying chicken farms.

The effect of introducing vaccinated commercial laying chickens on to farms, which previously had laying flocks that were infected with Salmonella Enteritidis, was investigated by sampling faeces and environmental samples, and in some cases spent hens. In 15 of 17 free-range flocks vaccination eliminated any evidence of infection. In 11 barn egg production flocks, vaccination produced similar results in four flocks on one farm but infection persisted in seven flocks on other farms. Vaccination of two consecutive cage layer flocks led to a gradual disappearance of the infection, but in 18 other flocks there was evidence of infection after vaccination. In one continuously occupied cage layer house, treatment by competitive exclusion was followed by a gradual disappearance of S Enteritidis in faeces and a substantial reduction in its levels in the environment. On four barn egg production sites disinfection with a formaldehyde, glutaraldehyde and quaternary ammonium compound disinfectant eliminated Salmonella species even though birds housed subsequently were not vaccinated. In three flocks that had been vaccinated for four years, S Enteritidis was still present. In most cases the poor performance of the vaccine was associated with severe rodent control problems and a poor standard of cleaning and disinfection.

Observations on the distribution and persistence of Salmonella enterica serovar enteritidis phage type 29 on a cage layer farm before and after the use of competitive exclusion treatment.

1. A continuously occupied cage layer house, which had been linked with a human outbreak of Salmonella Enteritidis PT29, was investigated to assess the distribution of contamination and the options for control. 2. The presence and persistence of Salmonella before and after application of competitive exclusion (CE) treatment was investigated by culturing samples from faeces, the environment, spent hens and eggs, and use of an ELISA to detect egg yolk antibodies. 3. A high prevalence of Salmonella was found in faecal and environmental samples before CE treatment was used but this reduced to minimal levels after treatment. 4. Egg yolk antibody assay suggested that although treated birds showed reduced excretion of Salmonella there was no difference between these and non-treated birds in terms of seroprevalence. 5. Contamination of the egg packing plant disappeared following CE. 6. Chicks and pullets in separate accommodation on site remained Salmonella free throughout despite no precautions being taken to avoid transmission of infection from the laying flock. 7. The rapid and substantial reduction in Salmonella in faeces, birds and the environment following the introduction of CE treatment suggests that further controlled field studies would be justified.

Molecular fingerprinting evidence of the contribution of wildlife vectors in the maintenance of Salmonella Enteritidis infection in layer farms.

AIMS: To provide molecular fingerprinting evidence of the contribution of wildlife vectors in the on-farm epidemiology of Salmonella Enteritidis infections. METHODS AND RESULTS: Salmonella Enteritidis strains were isolated from wildlife and from farm environment samples collected in 10 egg layer farms. Isolates were typed using plasmid profiling, XbaI-pulsed field gel electrophoresis and PstI-SphI ribotyping. In all 10 farms we were able to identify the same S. Enteritidis clones in wildlife vectors and farm environment. On several occasions the same clones were found before and after cleansing and disinfecting the farm premises. Also in some instances the same clones were present in mice samples, egg contents and spent hens. CONCLUSIONS: Definitive molecular evidence for the involvement of several wildlife species (mice, rats, flies, litter beetles and foxes) in the maintenance of S. Enteritidis infection on farms has been presented. Failures in biosecurity seriously compromise the control of this pathogen on laying farms. SIGNIFICANCE AND IMPACT OF THE STUDY: This paper reports on the use of molecular tools for the study of the epidemiology of S. Enteritidis. It gives useful information to be considered in control programmes for this organism on poultry farms.

Investigations into possible alternative decontamination methods for Salmonella enteritidis on the surface of table eggs.

Investigations into various alternative techniques for decontamination of the surfaces of artificially contaminated shell eggs were carried out. Ionized air, exposure to ozone in a dry atmosphere and use of a commercial herbal antibacterial product were not effective. Application of ozone in a humid environment was only partially effective but a commercial ionized water anolyte was highly effective in eliminating Salmonella from egg surfaces.

Observations on Salmonella contamination of commercial laying farms before and after cleaning and disinfection.

Little is known about the effectiveness of the cleaning and disinfection methods in use on commercial laying farms in Great Britain. Samples were taken from poultry house structures and equipment of five cage layer flocks, five barn egg production flocks and two free-range flocks. In the free-range houses there was a decrease in Salmonella after cleaning and disinfection, although the soil in the paddocks remained contaminated. In the barn and especially the cage layer houses, significant residual contamination remained on the surfaces of buildings and equipment. Wildlife pests were also found to be carrying Salmonella in the disinfected houses and free-range paddocks.

Investigation of Salmonella contamination and disinfection in farm egg-packing plants.

AIMS: As part of a field-based study of the distribution and persistence of Salmonella infection on commercial egg-laying farms, sampling was carried out on one or more occasions in egg-packing areas of 12 farms infected with Salm. Enteritidis. METHODS AND RESULTS: Salmonellas were isolated by cultural methods. Contamination was common, with Salmonella being found in 23.1% of floor swab samples, 30.8% of grading tables, 23.1% of conveyor belts or rollers and 23.8% of candlers. Four farms were sampled after cleaning and disinfection of packing plants had been carried out on the previous day, and residual contamination was found on 6.9% of samples from grading tables, 16.0% holding/sorting tables, 12.6% of conveyors or rollers, 16.7% of vacuum egg lifters, 21.4% of floor surfaces and 5.0% of egg store floor surfaces. Sterilized eggs passed through five farm packing plants showed a contamination rate of at least 16/5,948 (0.3%) egg passages. CONCLUSIONS: It is apparent that contamination in egg-packing plants may be a significant contributory factor to external contamination of shell eggs, and improved methods of cleaning and disinfecting egg-handling equipment are required. SIGNIFICANCE AND IMPACT OF THE STUDY: The presence of Salmonella contamination in egg-packing plants presents a contamination hazard for eggs from Salmonella-free flocks. Samples from equipment in the packing plant could also be used for screening for detection of Salmonella in the throughout of the plant.

The efficacy of Salenvac, a Salmonella enterica subsp. Enterica serotype Enteritidis iron-restricted bacterin vaccine, in laying chickens.

The protective effect of two vaccination regimes using Salenvac, a commercially available iron-restricted Salmonella enterica subsp. Enterica serotype Enteritidis PT4 bacterin vaccine, was verified in laying birds. Immunization was intramuscular at 1 day old and again at 4 weeks of age (V2), or at 1 day and 4 weeks with a third dose at 18 weeks of age (V3). Challenge S. Enteritidis (5 to 7.5); x 10(7) colony forming units) was given intravenously at 8, 17, 23, 30 and 59 weeks of age. For all age groups, both vaccination regimes reduced significantly the number of tissues and faecal samples that were culture positive for the challenge strain. For laying birds, fewer eggs (P < 0.001) were culture positive for S. Enteritidis after challenge from vaccinated laying birds (56/439 batches of eggs) than unvaccinated birds (99/252 batches). The data give compelling evidence that the vaccine is efficacious and may contribute to the reduction of layer infection and egg contamination.

A laboratory study of an inactivated bivalent iron restricted Salmonella enterica serovars Enteritidis and Typhimurium dual vaccine against Typhimurium challenge in chickens.

A commercial inactivated iron restricted Salmonella Typhimurium and Salmonella Enteritidis vaccine was used to vaccinate chicks at 1 day and again at 4 weeks of age, with challenge by a high and a low dose of S. Typhimurium given either orally or by contact with seeder birds inoculated orally with a high dose of S. Typhimurium. In all three challenge regimes, the shedding of challenge strain was reduced significantly (p < 0.05) in vaccinated birds compared with unvaccinated controls. Vaccination reduced colonisation of internal organs after challenge by contact seeder birds. However, no effect of vaccination upon colonisation of internal organs after either high or low oral challenge was apparent. In conclusion, the data indicate that the vaccine should be a useful tool in the control of S. Typhimurium infection in chickens.