Cellular conditions that modulate the fungicidal activity of occidiofungin.

AIMS: To identify cellular conditions that significantly alter susceptibility of Saccharomyces cerevisiae, Candida albicans and Candida glabrata to the antimicrobial peptide, occidiofungin. METHODS AND RESULTS: Genetic and pharmacological approaches were used to determine a role for calcium signalling in occidiofungin sensitivity profiles for S. cerevisiae, C. albicans and C. glabrata strains of yeast. Minimum inhibitory concentration (MIC) and drop assays found that extracellular calcium resulted in a fourfold resistance, and this was independent of an intact calmodulin-calcineurin signalling pathway. A similar resistance was found in the presence of magnesium but not other cations. Occidiofungin was found to be ineffective against cells in a quiescent state when measured by MIC, drop assay and short-term time-kill assays. A similar resistance pattern was detected for S. cerevisiae cultures pre-exposed to cycloheximide or placed in depleted media conditions. CONCLUSIONS: Extracellular calcium results in fungal tolerance to occidiofungin bioactivity outside of the calmodulin-calcineurin pathway. In addition, the resistance of quiescent cells suggests that active cellular growth is a requirement for occidiofungin's mechanism of action. SIGNIFICANCE AND IMPACT OF THE STUDY: The identification of cellular conditions that have a role in the activity of occidiofungin provided insight into potential cellular targets of this novel antifungal.

Feasibility of a rural palliative supportive service.

INTRODUCTION: Healthcare models for the delivery of palliative care to rural populations encounter common challenges: service gaps, the cost of the service in relation to the population, sustainability, and difficulty in demonstrating improvements in outcomes. Although it is widely agreed that a community capacity-building approach to rural palliative care is essential, how that approach can be achieved, evaluated and sustained remains in question. The purpose of this community-based research project is to test the feasibility and identify potential outcomes of implementing a rural palliative supportive service (RPaSS) for older adults living with life-limiting chronic illness and their family caregiver in the community. This paper reports on the feasibility aspects of the study. METHODS: RPaSS is being conducted in two co-located rural communities with populations of approximately 10 000 and no specialized palliative services. Participants living with life-limiting chronic illness and their family caregivers are visited bi-weekly in the home by a nurse coordinator who facilitates symptom management, teaching, referrals, psychosocial and spiritual support, advance care planning, community support for practical tasks, and telephone-based support for individuals who must commute outside of the rural community for care. Mixed-method collection strategies are used to collect data on visit patterns; healthcare utilization; family caregiver needs; and participant needs, functional performance and quality of life. RESULTS: A community-based advisory committee worked with the investigative team over a 1-year period to plan RPaSS, negotiating the best fit between research methods and the needs of the community. Recruitment took longer than anticipated with service capacity being reached at 8 months. Estimated service capacity of one nurse coordinator, based on bi-weekly visits, is 25 participants and their family caregivers. A total of 393 in-person visits and 53 telephone visits were conducted between January 2013 and May 2014. Scheduled in-person visit duration showed a mean of 67 minutes. During this same time period only 19 scheduled visits were declined, and there was no study attrition except through death, indicating a high degree of acceptability of the intervention. The primary needs that were addressed during these visits have been related to chronic disease management, and the attending physical symptoms were addressed through teaching and support. The use of structured quality of life and family caregiver needs assessments has been useful in facilitating communication, although some participants experienced the nature of the questions as too personal in the early stages of the relationship with the nurse coordinator. CONCLUSIONS: Findings from this study illustrate the feasibility of providing home-based services for rural older adults living with life-limiting chronic illness. The RPaSS model has the potential to smooth transitions and enhance quality of life along the disease trajectory and across locations of care by providing a consistent source of support and education. This type of continuity has the potential to foster the patient- and family-centered approach to care that is the ideal of a palliative approach. Further, the use of a rural community capacity-building approach may contribute to sustainability, which is a particularly important part of rural health service delivery.

Stakeholder perspectives on transitions of nursing home residents to hospital emergency departments and back in two Canadian provinces.

Major gaps exist in our understanding of transitions in care for older persons living in nursing homes. The purpose of the study was to identify key elements, from multiple stakeholder perspectives, that influence the success of transitions experienced by nursing home residents when they required transfer to a hospital emergency department. This interpretive descriptive study was conducted in two cities in the Canadian provinces of British Columbia and Alberta. Data were collected from 71 participants via focus groups and individual interviews with nursing home residents, family members, and professional healthcare providers working in nursing homes, emergency departments, and emergency medical services. Transcripts were analyzed using constant comparison. The elements contributing to the success of transitions reflected a patient- and family-centered approach to care. Transitions were influenced by the complex interplay of multiple elements that included: knowing the resident; critical geriatric knowledge and skilled assessment; positive relationships; effective communication; and timeliness. When one or more of the elements was absent or compromised, the success of the transition was also compromised. There was consistency about the importance of all the identified elements across all stakeholder groups whether they are residents, family members, or health professionals in nursing homes, emergency departments or emergency medical services. Aspects of many of these elements are modifiable and suggest viable targets for interventions aimed at improving the success of transitions for this vulnerable population.

Gamma-aminobutyric acid (GABA)-B receptor 1 in cerebellar cortex of essential tremor.

Some reports suggest cerebellar dysfunction as the basis of essential tremor (ET). Several drugs with the action of gamma-aminobutyric acid (GABA) are known to improve ET. Autopsy studies were performed on brains from nine former patients followed at the Movement Disorders Clinic Saskatchewan, Canada, and compared with five normal control brains. We aimed to measure the concentration of GABA B receptor 1 (GBR1) in the brains of patients who had had ET and to compare them to the GABA concentration in brains of controls. Western blot was used to determine the expression of GBR1 in cerebellar cortex tissue. We found that compared to the controls, the ET brains had three different patterns of GBR1 protein concentration--two with high, four comparable, and three with marginally low levels. There was no association between the age of onset, severity or duration of tremor, the response to alcohol or other drugs and GBR1 level. Thus, we conclude that our study does not support that GBR1 is involved in ET. Further studies are needed to verify these results.

Essential tremor is not dependent upon cerebellar Purkinje cell loss.

UNLABELLED: The pathophysiology of essential tremor (ET) is unknown but recent studies report that the majority of ET cases has cerebellar Purkinje cell (PC) degeneration and its sequelae. OBJECTIVE: To perform PC counts in ET, and normal and Parkinson's disease (PD) controls to determine the relationship of PC loss to ET. METHODS: All ET cases and PD controls were followed at our clinic. Normal controls had no history of neurological disease and had normal standard neuropathological studies. The PC counts were done by a neuropathologist who was blinded to the clinical diagnosis. Three different methods were used for counting PC; section through any part of the PC, through any part of the PC nucleus, and through any part of PC nucleolus. The counts were done in five non-contiguous microscopic fields. RESULTS: 59 brains were studied. These included 12 ET, 41 PD controls, and six normal controls. The mean age at death was 82.7 in ET, 79.1 in PD, and 75.7 years in the normal controls. The mean duration of symptoms was 34 years in ET and 15.7 years in the PD cases. The mean PC counts through any part of the neuron were 64.8 in ET, 56.2 in PD, and 58.0 in normal controls. Differences were not significant. CONCLUSION: Cerebellar PC loss does not distinguish ET from controls. It is concluded that PC loss is neither a pathological basis for, nor the distinctive feature of ET.

Validating the CANRISK prognostic model for assessing diabetes risk in Canada's multi-ethnic population.

INTRODUCTION: Despite high rates of undiagnosed diabetes and prediabetes, suitable risk assessment tools for estimating personal diabetes risk in Canada are currently lacking. METHODS: We conducted a cross-sectional screening study that evaluated the accuracy and discrimination of the new Canadian Diabetes Risk Assessment Questionnaire (CANRISK) for detecting diabetes and prediabetes (dysglycemia) in 6223 adults of various ethnicities. All participants had their glycemic status confirmed with the oral glucose tolerance test (OGTT). We developed electronic and paper-based CANRISK scores using logistic regression, and then validated them against reference standard blood tests using test-set methods. We used area under the curve (AUC) summary statistics from receiver operating characteristic (ROC) analyses to compare CANRISK with other alternative risk-scoring models in terms of their ability to discern true dysglycemia. RESULTS: The AUC for electronic and paper-based CANRISK scores were 0.75 (95% CI: 0.73-0.78) and 0.75 (95% CI: 0.73-0.78) respectively, as compared with 0.66 (95% CI: 0.63-0.69) for the Finnish FINDRISC score and 0.69 (95% CI: 0.66-0.72) for a simple Obesity model that included age, BMI, waist circumference and sex. CONCLUSION: CANRISK is a statistically valid tool that may be suitable for assessing diabetes risk in Canada's multi-ethnic population. CANRISK was significantly more accurate than both the FINDRISC score and the simple Obesity model.

Cerebellar Purkinje cell loss is not pathognomonic of essential tremor.

BACKGROUND: Most of the literature on pathology of essential tremor (ET) has reported no consistent abnormalities. Some recent studies however indicate that cerebellar Purkinje cell (PC) loss is the pathological basis of ET in most patients. OBJECTIVE: To compare cerebellar PC loss in ET, with normal and tremor dominant Parkinson's disease [PD] control brains. METHODS: Cerebellar PC counts were performed in seven ET, six PD and two normal control brains. Three different counting methods - sectioned through nucleolus, through nucleus and through any part of PC body, were used to count the PC. RESULTS: There were individual differences in the PC counts both in the ET and the PD cases. In all three subgroups, there was a reduction in the number of PC with advancing age. When the individuals of comparable age in the three subgroups were considered, there was no clear distinction between ET, PD and normal control subjects. There was no association between the degree of PC loss and the severity or the duration of ET. CONCLUSION: Our study militates against the hypothesis that PC loss is pathognomonic of ET.

Impacts on non-human biota from a generic geological disposal facility for radioactive waste: some key assessment issues.

This paper provides an overview of key issues associated with the application of currently available biota dose assessment methods to consideration of potential environmental impacts from geological disposal facilities. It explores philosophical, methodological and practical assessment issues and reviews the implications of test assessment results in the context of recent and on-going challenges and debates.

Canopy penetration and deposition of barrier sprays from electrostatic and conventional sprayers.

An experimental study was conducted to investigate the usefulness of electrostatic and conventional sprayers for barrier applications. Two conventional and three electrostatic sprayers were used in the study. Usefulness of the sprayers was rated based on penetration of spray into and deposition onto 2 sides of leaves on natural vegetation. Bifenthrin (Talstar adulticide) was applied at labeled rate, fluorescent dye was added to the tank mix as tracer, and all sprayers applied the dye and insecticide at the same rate. The results indicated that sprayers producing larger droplets produced significantly higher deposition on vegetation in barrier applications than the sprayers producing smaller droplets. Sprayers with higher air velocity at the nozzle discharge proved significantly better for barrier sprays than the sprayers with lower air velocity. Electrostatic sprayers did not show any improvement in deposition on vegetation or in penetration into vegetation over the conventional sprayers. There was no difference in deposition between truck-mounted and backpack sprayers.

Course in Parkinson disease subtypes: A 39-year clinicopathologic study.

BACKGROUND: Individual variations in the course of Lewy body Parkinson disease (PD) are well known. Patients have been classified into different clinical subtypes to identify differences in the course among the subgroups. Several studies indicate that the outcome is more favorable in tremor dominant (TD) cases but others report no difference. A majority of progression studies are based on cross-sectional single point data or short-term clinical observations. The lack of longitudinally followed autopsy-confirmed PD cohort remains a major weakness in the literature. Biochemical studies of brain indicate most pronounced abnormalities in akinetic/rigid (AR) and the least in TD cases. We postulate that PD course in these subtypes is concordant with the biochemical findings. OBJECTIVE: To compare the course in TD, mixed (MX), and AR subtypes of PD. METHODS: Longitudinal clinical follow-up and autopsy studies were performed on 166 patients with PD over 39 years (1968-2006). Patients were classified into TD, AR, and MX based on the entire clinical course. Only the pathologically confirmed PD cases were included. RESULTS: Sixty-six percent of cases had MX, 26% AR, and 8% TD profile. The age at onset was younger (p < 0.001) and progression to Hoehn & Yahr stage 4 was slower (p = 0.016) in the TD cases. Dementia was most common in AR (p = 0.039) and the least common in TD. In general, the course was most favorable in TD, followed by MX and AR subgroups. CONCLUSION: The three subtypes of Parkinson disease have different courses which are concordant with the differences in brain biochemical abnormalities.

Vascular pathology in male Lewis rats following short-term, low-dose rotenone administration.

The long-term administration of low doses of rotenone has been used to produce a model of Parkinson disease (PD) in rats. However, only about 50% of similarly treated rats develop the PD-like syndrome, with many dying during the first few days of treatment. The lesions in male Lewis rats that became moribund or died after short-term, low-dose rotenone administration are described. Dosed rats had fibrinoid change and acute hemorrhage involving small arteries and arterioles of the brain and lungs. The thalamus, hypothalamus, and medulla oblongata were most frequently and severely affected. Blood vessels in the brain of some male Lewis rats appeared acutely susceptible to the effects of rotenone. Understanding the selective nature of the fibrinoid change and hemorrhage might explain how rotenone produces PD-like signs and lesions in rats, and it might also provide the basis for a model of intraparenchymal hemorrhagic cerebrovascular disease (i.e., hemorrhagic strokes) in humans.

Samplers for evaluation and quantification of ultra-low volume space sprays.

A field study was conducted to explore the suitability of 5 pesticide deposition samplers for airborne spray and ground deposits from ultra-low-volume (ULV) space sprays. Samplers included horizontally stretched stationary cotton ribbons at 2 heights, rotating ribbon, rotating Teflon slides, and filter paper. Slides were also used for droplet-size analysis. A set of 7 samplers of each type was placed at 1, 7, 15, 25, 40, 65, and 90 m from the spray line along the spray swath. Water and BVA13 oil with fluorescent dyes as tracers were sprayed with the use of a truck-mounted ULV sprayer at dusk and dawn. Results suggest that the horizontal and rotating cotton ribbons are best for quantification of airborne spray and filter paper is best for ground deposition collection. The rotating slide samplers only detected the BVA13 oil-based sprays.

Rural-urban differences in the effects on mental well-being of caring for people with stroke or dementia.

BACKGROUND: Rural and urban differences in the effects of care-giving are not well documented. This paper reports data on 122 carers for people with stroke or dementia living in rural and urban settings in Wales. METHOD: Carers completed a postal questionnaire, including the SF-12v2 Health Survey. Definitions of rural and urban were based on the Urban/Rural Indicator from the Office of National Statistics (ONS) All Fields Postcode Directory 2004. RESULTS: Carers' mean Mental Component Summary (MCS) score (adjusted for age and sex) was one standard deviation below the population mean (-12.03). Male carers living in urban areas reported better mental health than male carers in rural areas (p<0.05) and female carers in both settings (p<0.05). A full model and a parsimonious model were developed, using MCS scores as outcome variables. In the full model sitting service provision in rural and urban locations was linked to better carer mental health, while support from friends and family was linked to better mental health for urban carers only. CONCLUSION: Our findings indicate the existence of both gender and location differences in carer experiences.

Parkinsonism, Lrrk2 G2019S, and tau neuropathology.

Lrrk2 G2019S is predominantly associated with alpha-synuclein-immunopositive Lewy body pathology. We have identified Family SK where Lrrk2 G2019S segregates with slowly progressive parkinsonism and the affected proband has tau-immunopositive neurofibrillary tangle pathology. Thus alpha-synucleinopathy and tauopathy, the predominant pathologies associated with parkinsonism, may be alternate outcomes of the same underlying genetic cause. Intriguingly, we observe no evidence of a direct interaction between either the tau or alpha-synuclein protein with Lrrk2.

Susceptibility of pseudomonas aeruginosa to cefepime versus ceftazidime in patients with cystic fibrosis.

STUDY OBJECTIVES: To compare the susceptibility of respiratory cultures of Pseudomonas aeruginosa obtained from patients with cystic fibrosis to cefepime versus ceftazidime. The pattern of cumulative resistance of P aeruginosa to cefepime in patients who had received at least one treatment course of cefepime between two sputum cultures was also characterized. DESIGN: Prospective consecutive data collection. SETTING: University-affiliated cystic fibrosis clinic and medical center. PATIENTS: Eighty patients with cystic fibrosis who had at least one sputum culture positive for P aeruginosa with reported microbiologic susceptibilities to cefepime and ceftazidime. INTERVENTION: Patient data was collected and analyzed. Measurements and Main Results. Two hundred and thirty-one P aeruginosa isolates were collected over 6 months. A total of 16.4% and 8.7% of the isolates were nonsusceptible to cefepime and ceftazidime, respectively (p=0.01). In eight patients who had not received cefepime before the study period, nonsusceptibility was 11.8% and 27.2% before and after exposure to cefepime, respectively. CONCLUSIONS: Susceptibility of P. aeruginosa isolates in patients with cystic fibrosis was lower with cefepime than with ceftazidime. Follow-up surveillance to determine changes in susceptibility of P aeruginosa isolates to cefepime is warranted.

Carers of older people with dementia: assessment and the Carers Act.

The Carers (Recognition and Services) Act 1995 came into force on 1 April 1996. It entitles carers who are providing substantial amounts of care on a regular basis to an assessment of their needs and ability to care. Local authorities are required to take the results of this assessment into account when making decisions about services. This paper reports the key findings of a two-year study, conducted in Wales, that evaluated the process and outcomes of assessments carried out under the auspices of the Carers Act. The findings offer insights to policy makers and practitioners and profile how care managers assess carers' needs. In addition, the paper describes carers' qualitative experiences of the assessment process and the difficulties care managers encounter in translating into practice the policy emphasis on supporting carers. It is suggested that separate carer assessments are not an established feature of care management practice and that care managers lack an explicit framework to direct the assessment of carers' needs.