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Purpose. The aim of this study was to establish the relationship between known cognitive factors and levels of pain and disability in patients with idiopathic chronic neck pain. Method. Ninety-four patients referred for physiotherapy because of chronic neck pain completed measures of pain, disability, catastrophising, pain-related fear, pain vigilance and awareness and self-efficacy beliefs. Hierarchical multiple regression analyses were then performed to establish whether the cognitive factors were significant determinants of levels of pain and disability. Results. The cognitive measures were significantly related to levels of pain and disability, explaining 23% of the variance in pain intensity and 30% of the variance in disability. Specifically, greater catastrophising (β = 0.37, p < 0.05) and lower pain vigilance and awareness (β = − 0.32, p < 0.05) were associated with greater pain intensity. Moreover, greater catastrophising (β = 0.26, p < 0.05) and lower functional self-efficacy beliefs (β = − 0.34, p < 0.001) were significantly associated with greater levels of disability. Conclusions. Cognitive factors were strongly related to levels of pain and disability in patients with chronic neck pain. In view of this, targeting the modification of these cognitive factors should be an integral part of therapy when treating patients with idiopathic chronic neck pain. [ABSTRACT FROM AUTHOR]

Northern ungulates contend with Setaria yehi and Rumenfilaria andersoni , filarioid nematodes that are transmitted by ectoparasitic blood-feeding arthropods, which can result in animal and population level impacts. Setaria yehi microfilariae can be detected in fresh blood samples using a modified Knott's test, or by postmortem detection by genetic sampling or through the retrieval of adult specimens in the peritoneal cavity. In this study we validated a novel qPCR for detection of S . yehi DNA in blood samples of moose ( Alces alces ). Additionally, we compared quantitative values from modified Knott's test to detect both S. yehi and R. andersoni from both fresh and frozen blood samples. Species-specific primers targeting a 121-base pair fragment of the cytochrome oxidase c subunit 1 ( cox1 ) of S. yehi , and a species-specific probe were designed. The qPCR had a detection threshold of 0.157 pg/μL of parasite DNA. We collected 166 blood samples from wild moose captured on the Kenai Peninsula, Alaska from 2019 to 2022. Matching blood aliquots were tested by modified Knott's test and subjected to DNA extraction for subsequent qPCR. Quantitatively, blood samples had an average S. yehi microfilaremia (mf) of 472.2 mf/mL (0-14,490 mf/mL) and R. andersoni of 72.9 mf/mL (0.0-5071.5 mf/mL). Qualitatively, 32.53% ( n  = 54) of samples tested positive for S. yehi in each of the tests, and 37.35% ( n  = 62) when both tests were combined, with very good agreement between the results from Knott's test and qPCR ( kappa = 0.90). The validation of the qPCR test for S. yehi allows for faster, less labor-intensive diagnosis and epidemiological surveillance of this emerging parasite in moose and other cervid hosts., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Background: Following the outbreak of the Covid-19 pandemic and associated social distancing requirements, Pain Services were no longer able to deliver face-to-face Pain Management Programmes (PMP). As an alternative, the Bury Integrated Pain Service developed an interactive, online programme, delivered via Microsoft Teams videoconferencing technology. However, the efficacy of such programmes is unclear. The aim of this project was to assess whether comparable results were observed with online PMPs as with face-to-face PMPs., Methods: A non-inferiority study comparing patients attending an online PMP to a historical cohort of patients attending face-to-face PMPs. Analyses of variance were performed to assess between group differences and chi squared tests to compare the proportion of patients making clinically meaningful changes in pain, musculoskeletal health, anxiety, depression and self-efficacy., Results: 24% of patients (n = 9) deemed suitable for the online PMP were unable to participate due to technological difficulties. This resulted in 28 people attending the online PMP. Greater mean reductions in anxiety (GAD-7 mean difference = 1.9; p < 0.05) and depression (PHQ-9 mean difference 3.3; p < 0.05) were observed with face-to-face PMP and a greater proportion of patients made clinically meaningful improvements in musculoskeletal health (face-to-face = 13; online = 5), anxiety (face-to-face = 7; online = 1), and depression (face-to-face = 11; online = 2)., Conclusions: Some patients appear to obtain significant benefit from online PMPs, but this appeared to be to a lesser extent than face-to-face PMPs. It is possible that factors related to the experience of the pandemic influenced these results. However, online PMPs appear to show some promise and further research is warranted to explore the value of online PMPs., (© 2024 The Author(s). Musculoskeletal Care published by John Wiley & Sons Ltd.)

Moose ( Alces alces ) in boreal habitats feed and rest where they are exposed to Dipteran flies and the parasites they carry. We collected 31,905 flies during the summer from 12 habituated moose on the Kenai Peninsula, Alaska. Moose flies, Haematobosca alcis (Snow), Diptera: Muscidae-a species that completes its entire life cycle on or around moose-accounted for 91% of flies collected; the reminder of the flies collected included mosquitoes (Culicidae), black flies (Simuliidae), and deer flies (Tabanidae). Flies impose physiological costs for moose, e.g., vectors for parasites such as Legworm ( Onchocerca spp.) which causes sores on the hind legs of moose. We found that the number of sores present on the hind legs of moose is positively correlated with body fat, which suggests a correlation between gains of energy and damage from flies. We also found that the number of sores is negatively correlated with serum albumin, which is indicative of an inflammatory response and body protein being used to repair injuries from flies and parasites. The number or type of flies present on a Moose were not correlated with the concentration of corticosteroids in saliva or feces. Flies do not elicit a stress response in moose even though the costs of repairing wounds and resisting infections of those wounds likely reduce gains of protein from summer foraging. Moose can tolerate the injuries from biting flies with regular gains from summer foraging but exposure to insect-borne parasites poses a risk to reproduction and survival., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society of Mammalogists.)

Moose ( Alces alces ) in the boreal forest habitats of Alaska are unlike other northern ungulates because they tolerate high densities of flies (Diptera) even though flies cause wounds and infections during the warm summer months. Moose move to find food and to find relief from overheating (hyperthermia) but do they avoid flies? We used GPS collars to measure the rate of movement (m⋅h -1 ) and the time spent (min⋅day -1 ) by enclosed moose in four habitats: wetlands, black spruce, early seral boreal forest, and late seral boreal forest. Fly traps were used in each habitat to quantify spatio-temporal abundance. Average daily air temperatures increased into July when peak biomass of forage for moose was greatest in early seral boreal forest habitats (424.46 vs. 25.15 kg⋅ha -1 on average in the other habitats). Average daily air temperatures were 1.7°C cooler in black spruce than other habitats, but fly abundance was greatest in black spruce (approximately 4-fold greater on average than the other habitats). Moose increased their movement rate with counts of biting flies (mosquitoes, black flies, horse and deer flies), but not non-biting flies (coprophagous flies). However, as air temperature increased (above 14.7°C) moose spent more time in fly-abundant black spruce, than early seral boreal forest, showing great tolerance for mosquitoes. Warm summer temperatures appear to cause moose to trade-off foraging in fly-sparse habitats for resting and dissipating heat in shady, wet habitats with abundant flies that adversely affect the fitness of moose., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

AbstractUngulates can respond to changes in food supply by altering foraging behavior, digestive function, and metabolism. A multifaceted response to an environmental change is considered robust. Short seasons of plant growth make herbivores sensitive to changes in food supply because maintenance and production must be accomplished in less time with fewer options in a more fragile response. Caribou live at high latitudes where short summers constrain their response to changes in food supply. We measured the ability of female caribou to resist and tolerate changes in the quality and quantity of their food supply during winter and summer. Caribou resisted changes in food abundance and quality by changing food intake and physical activity with changes in daily temperature within each season. Peak food intake rose by 134% from winter pregnancy to summer lactation (98 vs. 229 g kg -0.75 d -1 ), as digestible requirements to maintain the body increased by 85% for energy (1,164 vs. 2,155 kJ kg -0.75 d -1 ) and by 266% for N (0.79 vs. 2.89 g N kg -0.75 d -1 ). Caribou required a diet with a digestible content of 12 kJ g -1 and 0.8% N in pregnancy, 18 kJ g -1 and 1.9% N in early lactation, and 11 kJ g -1 and 1.2% N in late lactation, which corresponds with the phenology of the wild diet. Female caribou tolerated restriction of ad lib. food intake to 58% of their energy requirement (680 vs. 1,164 kJ kg -0.75 d -1 ) during winter pregnancy and to 84% of their energy requirement (1,814 vs. 2,155 kJ kg -0.75 d -1 ) during summer lactation without a change in stress level, as indicated by fecal corticosterone concentration. Conversely, caribou can respond to increased availability of food with a spare capacity to process digestible energy and N at 123% (2,642 vs. 2,155 kJ kg -0.75 d -1 ) and 145% (4.20 vs. 2.89 g N kg -0.75 d -1 ) of those respective requirements during lactation. Robust responses to changes in food supply allow caribou to sustain reproduction, which would buffer demographic response. However, herds may decline when thresholds of behavioral resistance and physiological tolerance are frequently exceeded. Therefore, the challenge for managing declining populations of caribou and other robust species is to identify declines in robustness before their response becomes fragile.

Measurements of reproductive and stress-related hormones in keratinous tissues (e.g. hair, claws, hooves, baleen) can provide a record of stress and reproductive response in wildlife. We evaluated a method to collect keratin tissue from hooves of immobilized moose ( Alces alces ) and validated enzyme immunoassays for measuring cortisol and progesterone in hooves and hair. We also measured the annual growth and wear rates of moose hooves. Progesterone (range: 1.0-43.7 pg/mg) and cortisol (range: 0.05-2.9 pg/mg) were measurable and showed variation among hoof samples and moose. Pregnant females had twice as high progesterone concentrations (18.00 ± 3.73 pg/mg) from hoof sample locations post breeding compared to non-pregnant moose (9.40 ± 0.25 pg/mg). Annual hoof growth differed between the front (5.58 ± 0.12 cm) and rear (4.73 ± 0.13 cm) hooves and varied by season with higher growth rates during summer which decreased into autumn and winter. Adult female hooves represented between 1.6 and 2.1 years of growth and included up to two reproductive cycles. We established a method to estimate hoof growth rate and applied this to postmortem samples and were able to detect previous pregnancies. Shoulder guard hairs grew between August and March including during late gestation; however, hair progesterone concentrations (range: 2-107.1 pg/mg) were not related to reproductive state. Hair cortisol concentrations in our study (range: 0.2-15.9 pg/mg) were within the range of values previously reported for cervids. Our study supports the use of hooves for longitudinal sampling and measuring reproductive and stress-related hormones, providing a new tool for tracking reproductive events and understanding what variables may contribute to population level changes in reproduction., Competing Interests: All authors acknowledge that regarding this manuscript there is no conflict of interest to declare., (© The Author(s) 2023. Published by Oxford University Press and the Society for Experimental Biology.)

Long-standing reports of open sores on the hind legs of moose (Alces alces) have been recorded in Alaska (as well as Canada, Europe, and Michigan), eliciting concerns about causes and infection. We used histological and genomic methods to investigate the sores from 20 adult moose on the Kenai Peninsula, Alaska. We paired this with thermal imagery and molt scoring of adult moose to further describe sore formation and understand its timing. Severe, ulcerative and eosinophilic dermatitis was found in all moose with sores present, and microfilariae within intraepidermal pustules were additionally found in four samples. Genetic analysis of sores from moose revealed a previously unknown genetic lineage of Onchocerca. Adult moose molt and lose their barrier of protection against flies in June and July during peak fly activity, leaving them vulnerable and allowing the development of sores. In summary, our results indicate that the cause for the sores on the hindleg of moose is a previously unknown genetic lineage of Onchocerca, probably transmitted by black flies, in timing with the molt cycle of adult moose. These sores leave moose exposed to pathogens, making them vulnerable, and challenging their health and fitness., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Benedict et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Most research exploring the relationship between cognitive factors (catastrophizing and self-efficacy beliefs) and levels of pain, disability and fatigue in patients with chronic widespread pain has been performed in multidisciplinary environments. It is less clear whether these associations are valid in other clinical environments. This study therefore aimed to establish whether changes in cognitive factors were related to changes in pain, disability and fatigue among patients treated in a physiotherapy-led symptom management programme., Design: A longitudinal pre-post treatment study. Regression analyses were performed with change in pain, disability, physical and mental fatigue as the dependent measures. Demographics, change in pain and fatigue (when not dependent variables) and cognitive factors were entered as independent variables. β values were calculated for the final model., Setting: Two out-patient physiotherapy departments in Manchester, UK., Participants: Fifty patients with persistent widespread pain., Intervention: A physiotherapist-led symptom management programme., Main Outcome Measures: Disability (Fibromyalgia Impact Questionnaire), Pain (Numeric Pain Rating Scale and Fatigue (Chalder Fatigue Scale) RESULTS: Significant changes in disability, fatigue and cognitive factors were observed after treatment. Changes in self-efficacy beliefs (β=-0.38, P<0.05) and catastrophizing (β=0.41, P<0.05) were significantly related to reductions in disability. There was no significant relationship between change in the cognitive variables and change in pain or fatigue., Conclusions: Self-efficacy beliefs and catastrophizing were important determinants of change in disability, but not pain or fatigue among patients with chronic widespread pain attending physiotherapy. Cognitively-informed physiotherapy appeared to be effective in reducing disability and fatigue and modifying cognitive factors. Such interventions may offer an effective treatment option for patients with chronic widespread pain and future randomised controlled trials are required to fully assess this., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Management of large herbivores depends on providing habitats for forage supply and refuge from risks of temperature, predation and disease. Moose ( Alces alces ) accumulate body energy and nutrient stores during summer, while reducing the impact of warm temperatures through physiological and behavioural thermoregulation. Building on the animal indicator concept, we used rumen temperature sensors and GPS collars on captive moose ( n  = 6) kept in large natural enclosures to evaluate how behaviour and habitat selection influence the rate of change in rumen temperature during the growing season on the Kenai Peninsula, Alaska, USA. We compared movement and habitat selection of individual females during tolerance days (daily amplitude in rumen temperature was ≥1.2°C in 24 h) with those of control days (daily amplitude in rumen temperature was < 1.2°C) before and after the tolerance day. Moose moved more during tolerance days (172 m • h -1 ; 95% confidence intervals (CI)  = 149-191 m • h -1 ) than on control days (151 m • h -1 ; 95% CI = 128-173 m • h -1 ). The rate of change in rumen temperature (°C • h -1 ) declined with low to moderate movement rates that were probably associated with foraging in all habitats. Movement only increased the rate of change in rumen temperature at high activity (~ > 500 m • h -1 ). Additionally, the relationship between rate of change in rumen temperature and movement rate was different during tolerance and control days in open meadow and wetland habitats. In all habitats except wetlands, the rate of change in rumen temperature increased while resting, which probably is a result of diet-induced thermogenesis. Our study demonstrates that the behavioural choices of moose on the landscape are associated with the rate of change in rumen temperature and their ability to thermoregulate. Wildlife managers must consider high-value habitats where wildlife can employ both behavioural and physiological mechanisms to tolerate warm ambient conditions in a landscape of forage, predators and pests., (© The Author(s) 2021. Published by Oxford University Press and the Society for Experimental Biology.)

We tested the concept that moose (Alces alces) begin to show signs of thermal stress at ambient air temperatures as low as 14 °C. We determined the response of Alaskan female moose to environmental conditions from May through September by measuring core body temperature, heart rate, respiration rate, rate of heat loss from exhaled air, skin temperature, and fecal and salivary glucocorticoids. Seasonal and daily patterns in moose body temperature did not passively follow the same patterns as environmental variables. We used large changes in body temperature (≥1.25 °C in 24hr) to indicate days of physiological tolerance to thermal stressors. Thermal tolerance correlated with high ambient air temperatures from the prior day and with seasonal peaks in solar radiation (June), ambient air temperature and vapor pressure (July). At midday (12:00hr), moose exhibited daily minima of body temperature, heart rate and skin temperature (difference between the ear artery and pinna) that coincided with daily maxima in respiration rate and the rate of heat lost through respiration. Salivary cortisol measured in moose during the morning was positively related to the change in air temperature during the hour prior to sample collection, while fecal glucocorticoid levels increased with increasing solar radiation during the prior day. Our results suggest that free-ranging moose do not have a static threshold of ambient air temperature at which they become heat stressed during the warm season. In early summer, body temperature of moose is influenced by the interaction of ambient temperature during the prior day with the seasonal peak of solar radiation. In late summer, moose body temperature is influenced by the interaction between ambient temperature and vapor pressure. Thermal tolerance of moose depends on the intensity and duration of daily weather parameters and the ability of the animal to use physiological and behavioral responses to dissipate heat loads., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Most research exploring the relationship between cognitive factors and pain, disability and fatigue in patients with persistent pain/fatigue has been performed in multi disciplinary environments. It is unclear whether these associations are consistent in other contexts. This study therefore aimed to establish the relationships between these factors in patients with persistent pain/fatigue referred for physiotherapy treatment., Design: Cross-sectional observational study assessing the association between cognitive factors (self-efficacy and catastrophizing) and levels of pain, disability, mental fatigue and physical fatigue in patients with persistent pain/fatigue disorders. Data were analysed using regression analyses., Setting: Two out-patient physiotherapy departments, Manchester, UK., Participants: 166 patients with persistent pain and fatigue disorders chronic widespread pain, fibromyalgia and chronic fatigue syndrome/myalgic encephalopathy)., Main Outcome Measures: Disability was assessed using the Fibromyalgia Impact Questionnaire, whilst mental and physical fatigue were assessed with the sub-scales of the Chalder Fatigue Scale. Pain intensity was measured with a Numeric Pain Rating Scale, self-efficacy with the Chronic Pain Self-efficacy Questionnaire and catastrophizing with the Pain Catastrophizing Scale., Results: Cognitive factors were significantly associated with pain (self-efficacy beliefs β=-0.30, P<0.05; catastrophizing β=0.24, P<0.05) and disability (self-efficacy beliefs β=-0.62, P<0.05), but not fatigue., Conclusions: Similar associations were observed in patients referred to physiotherapy as to those observed in patients treated in multi disciplinary clinical environments. Self-efficacy beliefs appear to be particularly strong determinants of disability, but exert a lesser influence over pain or fatigue. Targeting self-efficacy may be an effective method to reduce disability in patients with persistent pain and fatigue disorders., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose : The prevention of falls and fall-related fractures following menopause is an important health initiative. The Fracture Prevention Screening Algorithm (FPSA) uniquely uses fracture risk to prompt fall risk assessment to classify both fall and fracture risk in individuals. The purpose of this study was to determine whether use of the FPSA accurately predicted self-reported falls in post-menopausal women over one year. Methods : 142 postmenopausal women were recruited. Based on Fracture Risk Assessment Tool (FRAX®) scores, women with a ≥3% 10-year probability of hip fracture (high risk), or who self-identified as having balance problems or a fall history, underwent the Functional Gait Assessment (FGA) to estimate fall risk (high risk = ≤22/30). This allowed classification on the FPSA into one of four risk categories: low fall/low fracture risk; low fall/high fracture risk; high fall/low fracture risk; high fall/high fracture risk. Participants were contacted monthly for one year to determine fall and injury occurrence. Results : Fall/injury surveillance was conducted with 136 subjects over one year. Compared to women in the low fall/low fracture risk group, both high fall risk groups demonstrated significantly greater fall rates. Falls were 81-89% more likely in women with FGA scores of 22/30 or less. All injuries were rare events across all risk strata and did not differ between risk groups. Conclusion : These findings support the use of fracture risk as a trigger for fall screening to comprehensively classify risk in post-menopausal women as proposed by the FPSA.

Food intake may limit the ability of browsing mammals to gain body mass during the growing season when the leaves and stems of woody plants are most abundant. Moose are highly productive browsers with high demands for energy and nutrients, particularly during lactation. Using an indigestible marker, we estimated dry matter intake of free ranging adult female moose with and without calves over three growing seasons. During the same period, we analyzed forage quality. Intakes were highest in late spring (280 ± 19 g·kg-0.75·d-1) when forage quality peaked; however, intakes declined by 39% throughout the summer as temperatures increased and as acid detergent fiber content of browse increased. Digestibility of dry matter declined over summer from 71% to 57% among browse. Intakes were similar for moose with and without calves. Heat loads may impair the ability of moose to consume sufficient energy and nutrients. Warming and habitat change can adversely affect browser populations when poor forage qualities and low dry matter intakes combine to suppress digestible intakes of energy and nutrients., Competing Interests: The authors have declared that no competing interests exist.

The purpose of this research is to describe Texas educator sexual misconduct (ESM) by examining 8 years of sanctions issued to educators (N = 1415) for either sexual misconduct or inappropriate relationships with students or minors. We first examine Texas ESM from the perspective of quality database construction and then describe the demographic characteristics of educators sanctioned for ESM between 2008 and 2016. Differences in the demographic characteristics of educators sanctioned for ESM vary according to the definition of ESM employed by the state education agency. Younger and early career educators are more likely to engage in inappropriate relationships with students or minors, whereas older and later-career teachers are more likely to engage in sexual misconduct as that term is defined by the state education agency. Over one-third of educators sanctioned for ESM were either new to the profession or new to their school district when sanctioned. Recommendations are offered for database construction, policy, and practice.

Purpose: To establish whether different processes underpin changes in disability in people with neck pain who underwent two types of active physiotherapy intervention., Materials and Methods: This study was a sub-analysis of a randomized controlled trial assessing whether the addition of Interactive Behavioral Modification Therapy (a cognitively informed physiotherapy treatment) to a Progressive Neck Exercise Program improved outcome in patients with chronic neck pain. Regression analyses were performed to determine the extent to which demographics, changes in pain, and changes in certain cognitive factors were related to changes in disability., Results: In the progressive neck exercise group, changes in levels of pain intensity were the only factor significantly related to change in disability, explaining 33% of the variance. In the interactive behavioral modification therapy group, changes in pain intensity, and catastrophizing together explained 54% of the variance in change in disability. Only changes in catastrophizing displayed a significant β value in the final model., Conclusions: Different processes appear to underpin changes in disability in patients undergoing cognitively informed physiotherapy to those undergoing a primarily exercise-based approach. Implications for rehabilitation Certain cognitive factors are known to be related to levels of disability in patients with chronic neck pain Specifically targeting these factors results in more patients making a clinically meaningful reduction in disability Different processes appear to underpin reductions in disability when people with neck pain are treated with cognitively informed physiotherapy to when treated with exercise alone, which may account for why more patients improve when treated in this manner. Reductions in catastrophizing appear to be particularly important and efforts should be made to assess and treat catastrophic thoughts in people with chronic neck pain.

Objectives: Chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) is a chronic illness which can cause significant fatigue, pain and disability. Activity pacing is frequently advocated as a beneficial coping strategy, however, it is unclear whether pacing is significantly associated with symptoms in people with CFS/ME. The first aim of this study was therefore to explore the cross-sectional associations between pacing and levels of pain, disability and fatigue. The second aim was to explore whether changes in activity pacing following participation in a symptom management programme were related to changes in clinical outcomes., Design: Cross-sectional study exploring the relationships between pacing, pain, disability and fatigue (n=114) and pre-post treatment longitudinal study of a cohort of patients participating in a symptom management programme (n=35)., Setting: Out-patient physiotherapy CFS/ME service., Participants: One-hundred and fourteen adult patients with CFS/ME., Main Outcome Measures: Pacing was assessed using the chronic pain coping inventory. Pain was measured using a Numeric Pain Rating Scale, fatigue with the Chalder Fatigue Scale and disability with the Fibromyalgia Impact Questionnaire., Results: No significant associations were observed between activity pacing and levels of pain, disability or fatigue. Likewise, changes in pacing were not significantly associated with changes in pain, disability or fatigue following treatment., Conclusions: Activity pacing does not appear to be a significant determinant of pain, fatigue or disability in people with CFS/ME when measured with the chronic pain coping index. Consequently, the utility and measurement of pacing require further investigation., (Copyright © 2017 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

Introduction: Osteoarthritis of the knee (OAK) can result in significant disability and previous authors have suggested that cognitive and falls-related factors may be significant determinants of function. However, no previous studies have considered the relative influence of these factors when the effects of symptoms related to OAK are also considered. Additionally, it is plausible that falls-related factors exert a greater influence in patients who have previously fallen., Methods: Fifty-eight patients were recruited from an outpatient physiotherapy department. They completed measures of physical function, pain, stiffness, physical symptoms, fear avoidance, perceived consequences of falling, fear of falling and self-efficacy beliefs. Variables exhibiting significant correlations with disability were entered into a regression model. β Values were also calculated for the final model to allow the relative contribution of each variable to be established when all variables were considered. Sub-analysis was then performed using only data from patients who had previously fallen, to establish whether cognitive and falls-related factors exerted a stronger influence in this group., Results: Pain, stiffness and joint symptoms significantly explained 75% of the variance in disability. The cognitive and falls-related variables did not significantly explain any additional variance. Only pain and stiffness exhibited significant β values in the final model. Similar findings were observed in the sub-analysis with the participants who had previously fallen, with only pain and stiffness explaining significant variance (77%) or exhibiting significant β values., Discussion: The current findings suggested that cognitive and falls-related factors are not significantly related to disability in patients with OAK. By contrast, pain and stiffness were strongly associated with disability. This suggests that targeting cognitive and falls-related factors is unlikely significantly to improve outcome in these patients., (Copyright © 2016 John Wiley & Sons, Ltd.)

Chronic neck pain can result in significant levels of disability. Physiotherapy treatments often aim to modify cognitive factors and this approach benefits some, but not all, patients. Research from other pain conditions suggests that acceptance may be related to disability; however, it is unclear whether these associations exist in patients with neck pain. Moreover, it is unclear to what extent other cognitive factors are related to acceptance. Feasibly, if these factors are related, existing treatments may already be indirectly modifying acceptance. The aim of this study was therefore to establish the associations between acceptance and disability, and between acceptance and other cognitive factors. Cross-sectional data were collected from 149 patients and regression analyses were carried out. In the first analysis, disability was the dependent variable and the proportion of variance explained by two acceptance subscales (activities engagement and pain willingness) was calculated. In the second analyses, the acceptance subscales were the dependent variables. Measures of pain-related fear, catastrophizing and pain vigilance and awareness were entered as explanatory variables and the proportion of variance explained was calculated. In the first analysis, acceptance explained 18% of variance in disability (P<0.001). In the second analysis, cognitive factors explained 7% (P<0.05) of variance in activities engagement and 58% (P<0.001) of pain willingness. On this basis, treatments that enhance acceptance may reduce disability. Moreover, as cognitive factors were strongly related to pain willingness, but not activity engagement, alternative treatments may be required to maximize acceptance. Further studies are warranted to assess acceptance-based treatments in patients with neck pain.

Objectives: To assess the efficacy of three different exercise programmes in treating rotator cuff tendinopathy/shoulder impingement syndrome., Design: Parallel group randomised clinical trial., Setting: Two out-patient NHS physiotherapy departments in Manchester, United Kingdom., Participants: 120 patients with shoulder pain of at least three months duration. Pain was reproduced on stressing the rotator cuff and participants had full passive range of movement at the shoulder., Interventions: Three dynamic rotator cuff loading programmes; open chain resisted band exercises (OC) closed chain exercises (CC) and minimally loaded range of movement exercises (ROM)., Main Outcomes: Change in Shoulder Pain and Disability Index (SPADI) score and the proportion of patients making a Minimally Clinically Important Change (MCIC) in symptoms 6 weeks after commencing treatment., Results: All three programmes resulted in significant decreases in SPADI score, however there were no significant differences between the groups. Participants making a MCIC in symptoms were similar across all groups, however more participants deteriorated in the ROM group. Dropout rate was higher in the CC group, but when only patients completing treatment were considered more patients in the CC group made a meaningful reduction in pain and disability., Conclusions: Open chain, closed chain and range of movement exercises all seem to be effective in bringing about short term changes in pain and disability in patients with rotator cuff tendinopathy. ISRCTN76701121., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Objectives: To determine whether adding a physiotherapist-led cognitive-behavioural intervention to an exercise programme improved outcome in patients with chronic neck pain (CNP)., Design: Multicentre randomised controlled trial., Setting: Four outpatient physiotherapy departments., Participants: Fifty-seven patients with CNP. Follow-up data were provided by 39 participants [57% of the progressive neck exercise programme (PNEP) group and 79% of the interactive behavioural modification therapy (IBMT) group]., Interventions: Twenty-eight subjects were randomised to the PNEP group and 29 subjects were randomised to the IBMT group. IBMT is underpinned by cognitive-behavioural principles, and aims to modify cognitive risk factors through interactive educational sessions, graded exercise and progressive goal setting., Main Outcome Measures: The main outcome measure was disability, measured by the Northwick Park Questionnaire (NPQ). Secondary outcomes were the Numeric Pain Rating Scale (NPRS), Pain Catastrophising Scale, Tampa Scale for Kinesiophobia (TSK), Chronic Pain Self-efficacy Scale (CPSS) and the Pain Vigilance and Awareness Questionnaire., Results: No significant between-group differences in disability were observed (mean NPQ change: PNEP=-7.2, IBMT=-10.2). However, larger increases in functional self-efficacy (mean CPSS change: PNEP=1.0, IBMT=3.2) and greater reductions in pain intensity (mean NPRS change: PNEP=-1.0, IBMT=-2.2; P<0.05) and pain-related fear (mean TSK change: PNEP=0.2, IBMT=-4.7, P<0.05) were observed with IBMT. Additionally, a significantly greater proportion of participants made clinically meaningful reductions in pain (25% vs 55%, P<0.05) and disability (25% vs 59%, P<0.05) with IBMT., Conclusions: The primary outcome did not support the use of cognitive-behavioural physiotherapy in all patients with CNP. However, superior outcomes were observed for several secondary measures, and IBMT may offer additional benefit in some patients., Clinical Trial Registration Number: ISRCTN27611394., (Copyright © 2015 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

The objective of the current study was to establish an in vitro screen and a highly sensitive analytical assay to delineate key physicochemical properties that favor compound bioaccumulation in the L3 life stage of a Haemonchus contortus isolate. Time-dependent studies revealed that absorption and elimination kinetics during the first 6 hr of exposure were sufficient to achieve maximum bioaccumulation for the majority of compounds tested. In subsequent studies, the larvae were incubated for 6 hr in a medium containing 146 compounds (5 μM initial concentration), including both human and veterinary medicines, characterized by a broad range of physicochemical properties. Bioaccumulation of the compounds by the nematodes was determined, and multiple physicochemical descriptors were selected for correlation. Data analysis using Bayes classification model and partial least-square regression revealed that clogD7.4, rotatable bond, E-state, and hydrogen bond donor each correlated with compound bioaccumulation in H. contortus L3. The finding that lipophilicity was critical for transcuticle compound permeation was consistent with previous studies in other parasitic species and in adult H. contortus . The finding of additional physicochemical properties that contribute to compound conformational flexibility, polarity, and electrotopological state shed light on the mechanisms governing transcuticle permeation. The relatively poor correlation between transcuticle and transmembrane permeation indicated the distinct mechanisms of compound permeation, likely due to the different constituents, and their contributions to overall transport function, of the lipid membranes and the porous collagen barrier of the nematode cuticle. Our study, for the first time, establishes a high-throughput screen for compound bioaccumulation in a parasitic nematode and further elucidates physicochemical factors governing transcuticular permeation of compounds. Application of this methodology will help explain the basis for discrepancies observed in receptor binding and whole organism potency assays and facilitate incorporation of drug delivery principles in the design of candidate anthelmintics.

Objectives were to evaluate the administration of an anti-gonadotropin releasing factor (GnRF) analog on suppression of estrus, consistency of feed intake, and growth performance in market gilts and to investigate the impact the physiological changes would have on carcass characteristics and fresh meat quality. Gonadotropin releasing factor stimulates the anterior pituitary to release luteinizing hormone that acts on the ovary to induce follicle development and indirectly initiates ovulation. Improvest (Zoetis, Kalamazoo, MI) contains an incomplete version of naturally occurring GnRF and causes the production of anti-GnRF antibodies that bind to the GnRF receptor and thus render GnRF inactive. This in turn suppresses estrus in female pigs. Gilts were initially separated into 10 blocks based on age and then within each block allotted to a pen (n = 114; 5 pigs/pen) based on BW. Gilts received the first dose at 12 wk of age and the second dose at 16 wk of age, were exposed to a boar daily from 20 to 26 wk of age, and were slaughtered at 26 wk of age (10 wk after second dose). Meat quality was analyzed on the 2 gilts closest to pen average ending live weight in 5 of the 10 blocks. Pen served as the experimental unit for all data analysis. During the 15-wk finishing period, ADG was 0.03 kg greater (P < 0.01) and G:F was 0.009 greater (P = 0.02) in gilts administered GnRF suppression (treated) compared with untreated gilts (control). The majority of improvements in growth performance were observed from 16 to 20 wk of age (4 wk after second dose), as ADG was 0.07 kg greater (P < 0.001) and G:F was 0.021 greater (P < 0.01) in treated gilts compared with control gilts. Ovarian weights were reduced (P < 0.0001) by 64.15% and gilts exhibiting puberty were reduced by 87.80% (P < 0.001) in treated gilts compared with control gilts. Back fat depth was 3.78 mm greater (P < 0.0001) and estimated lean was 1.31 percentage units less (P < 0.0001) in treated gilts compared with control gilts. With the exception of subjective color, there were no differences (P ≥ 0.12) in meat quality parameters between treated and control gilts. Subjective color was darker (P = 0.03) in treated gilts compared with control gilts. These data suggest market gilts treated with an anti-GnRF analog had suppressed estrus and episodical changes in ADFI, while they had improved feed efficiency, increased ADG, and increased back fat depth when compared with gilts without an anti-GnRF analog treatment.

Startect(®) is a novel anthelmintic combination of derquantel and abamectin. It is hypothesized that derquantel and abamectin interact pharmacologically. We investigated the effects of derquantel, abamectin and their combination on somatic muscle nicotinic acetylcholine receptors and pharyngeal muscle glutamate gated chloride receptor channels of Ascaris suum. We used muscle-strips to test the effects of abamectin, derquantel, and abamectin+derquantel together on the contraction responses to different concentrations of acetylcholine. We found that abamectin reduced the response to acetylcholine, as did derquantel. In combination (abamectin+derquantel), inhibition of the higher acetylcholine concentration response was greater than the predicted additive effect. A two-micropipette current-clamp technique was used to study electrophysiological effects of the anthelmintics on: (1) acetylcholine responses in somatic muscle and; (2) on l-glutamate responses in pharyngeal preparations. On somatic muscle, derquantel (0.1-30μM) produced a potent (IC50 0.22, CI 0.18-0.28μM) reversible antagonism of acetylcholine depolarizations. Abamectin (0.3μM) produced a slow onset inhibition of acetylcholine depolarizations. We compared effects of abamectin and derquantel on muscle preparations pretreated for 30min with these drugs. The effect of the combination was significantly greater than the predicted additive effect of both drugs at higher acetylcholine concentrations. On the pharynx, application of derquantel produced no significant effect by itself or on responses to abamectin and l-glutamate. Abamectin increased the input conductance of the pharynx (EC50 0.42, CI 0.13-1.36μM). Our study demonstrates that abamectin and derquantel interact at nicotinic acetylcholine receptors on the somatic muscle and suggested synergism can occur., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To delineate the relative extent to which specific cognitive factors are related to levels of pain and disability in patients with chronic whiplash-associated disorder., Design: Cross-sectional observation study., Setting: Three secondary care physiotherapy departments in the Greater Manchester region of the UK., Participants: All patients with chronic whiplash-associated disorder referred to the participating departments were invited to take part in the study. In total, 124 patients were invited to participate, and 63 (51%) agreed to do so. Complete data were available for 55 (44%) of those invited to participate in the study., Main Outcome Measures: Pain and disability, as assessed by the Neck Disability Index., Results: Cognitive factors were strongly related to levels of disability (R(2) change=0.39, P<0.001). Specifically, greater catastrophising (beta=0.41, P<0.01) and lower functional self-efficacy beliefs (beta=-0.47, P<0.001) were significantly related to greater levels of disability. Significant univariate correlations were seen between the cognitive factors and current pain intensity. However, no significant associations were seen between the cognitive factors and current pain intensity in the multivariate analysis., Conclusions: Interventions which aim to reduce catastrophising and enhance functional self-efficacy beliefs should be included alongside conventional physiotherapy interventions when treating patients with chronic whiplash-associated disorder., (Copyright 2009 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

As research funding becomes more competitive, it will be imperative for researchers to break the mentality of a single laboratory/single research focus and develop an interdisciplinary research team aimed at addressing real world challenges. Members of this team may be at the same institution, may be found regionally, or may be international. However, all must share the same passion for a topic that is bigger than any individual's research focus. Moreover, special consideration should be given to the professional development issues of junior faculty participating in interdisciplinary research teams. While participation may be "humbling" at times, the sheer volume of research progress that may be achieved through interdisciplinary collaboration, even in light of a short supply of grant dollars, is remarkable., (Copyright 2009 Elsevier Inc. All rights reserved.)

Biochemical and biophysical research tools are used to define the developmental dynamics of numerous cell lineages from a variety of tissues relevant to meat quality. With respect to the adipose cell lineage, much of our present understanding of adipogenesis and lipid metabolism was initially determined through the use of these methods, even though the in vitro or molecular environments are far removed from the tissues of meat animals. This concise review focuses on recent cellular and molecular biology-related research with adipocytes, and how the research might be extended to the endpoint of altering red meat quality. Moreover, economic and policy impacts of such in animal production regimens is discussed. These issues are important, not only with respect to palatability, but also to offer enhanced health benefits to the consumer by altering content of bioactive components in adipocytes.

The performance of 14 primary clinical display monitor workstations in use in the Radiology Department of a large acute NHS Trust was assessed using the methods and guidelines described by the American Association of Physicists in Medicine Task Group 18. Tests undertaken included the measurement of ambient light, display uniformity, luminance ratio, luminance response, maximum luminance and spatial resolution. Four display monitors failed to meet at least one of the test's guideline tolerances. In addition a number of display monitors were found to be operating at settings that might reduce their useful life span. These devices were either replaced or recalibrated by the installers, or were subject to local adjustment to ensure applicable standards were met. Consequently the study suggests that quality assurance testing of display monitors used for image reporting is necessary and valuable to ensure that images are viewed at an appropriate standard.

The Specific Molecular Identification of Life Experiment (SMILE) instrument (Sims et al. Planet. Space Science 2005, 53, 781-791) proposes to use specific molecular receptors for the detection of organic biomarkers on future astrobiology missions (e.g., to Mars). Such receptors will be used in assays with fluorescently labeled assay reagents. A key uncertainty of this approach is whether the fluorescent labels used in the system will survive exposure to levels of solar and galactic particle radiation encountered during a flight to Mars. Therefore, two fluorescent dyes (fluorescein and Alexa Fluor 633) have been exposed to low-energy proton and alpha radiation with total fluences comparable or exceeding that expected during an unshielded cruise to Mars. The results of these initial experiments are presented, which show that both dyes retain their fluorescent properties after irradiation. No significant alteration in the absorption and emission wavelengths or the quantum yields of the dyes with either radiation exposure was found. These results suggest other structurally similar fluorophores will likely retain their fluorescent properties after exposure to similar levels of proton and alpha radiation. However, more extensive radiation fluorophore testing is needed before their suitability for astrobiology missions to Mars can be fully confirmed.

Allatostatins are the largest family of known arthropod neuropeptides. To date more than 150 different arthropod type-A allatostatins have been identified and are characterized by the C-terminal signature, (Y/F)XFG(L/I)amide. Using specific allatostatin antisera, positive immunoreactivity has been identified within the central and peripheral nervous systems of the flatworm (platyhelminth) Procerodes littoralis and the roundworm (nematode) Panagrellus redivivus. Comparative analyses of the allatostatin-like immunoreactivity and that of other known helminth neuropeptides (FMRFamide-like peptides [FLPs]) indicate differences in the distribution of these peptide families. Specific differences in neuropeptide distribution have been noted within the pharyngeal innervation of flatworms and in the cephalic papillary neurons of nematodes. In arthropods, type-A allatostatins have functions that include potent myoactivity. In this study, seven members of the allatostatin superfamily induced concentration-dependent contractions of flatworm muscle fibres. Pharmacological studies indicate that these peptides do not interact with muscle-based FLP receptors. The type-A allatostatins, therefore, represent the second family of neuropeptides that induce muscle contraction in flatworms. Although the majority of arthropod type-A allatostatins examined did not affect the somatic body wall muscle or the ovijector of the pig nematode, Ascaris suum, two type-A allatostatins (GDGRLYAFGLamide and DRLYSFGLamide) exhibited significant inhibitory effects on the A. suum ovijector at 10 microM. These data suggest that allatostatin-like peptides and receptors occur in helminths. Further, although arthropod type-A allatostatins display inter-phyla activities, their receptors are less compelling as potential targets for broad-spectrum parasiticides (endectocides) than FLP receptors.

The interrelationships between physicochemical properties, absorption and potency of 2-desoxoparaherquamide and five analogs, representing a new anthelmintic class, were evaluated in in vitro and in vivo assays. At pH 7.5, rates of drug absorption by the gastrointestinal nematode Haemonchus contortus and jird small intestine, parameterized by the permeability coefficient, P(e), ranged from 1.2-2.4 x 10(-4) cm/min (nematode) to 2.5-5.5 x 10(-3) cm/min (jird). In the jird intestine, absorption was pH-dependent, with P(e) at pH 7.5 being twice that at pH 4.5, reflecting the negative influence of protonation on transport of these weakly basic molecules. Each compound rapidly paralyzed H. contortus during in vitro exposure to therapeutically relevant concentrations (1-10 microm). The kinetics of drug action on motility in vivo mirrored their in vitro effects; motility concentrations were reduced in nematodes collected from jird stomach 3 h following oral drug dosing, by which time > or =50% clearance of the parasites had occurred. The nematode/medium partition coefficient K ranged from 10.1 to 16.1, consistent with the lipophilic nature of the compounds. The time required to reduce motility in vitro by 50% (t50*) and P(e) were used to determine C(n)*, the concentration of drug in the nematode at t50*, as an indicator of intrinsic potency. In the jird, the apparent potencies of the compounds were insensitive to route of administration (i.e. oral = i.v. = i.p. = i.m.) for H. contortus and two other gastrointestinal nematodes, Ostertagia ostertagi and Trichostrongylus colubriformis; topical administration, however, required three to 10-fold higher doses for equivalent efficacy.

FMRFamide-related peptides are common to a wide variety of invertebrate species, including helminths and arthropods. In arthropods, five distinct FMRFamide-related peptide subfamilies are recognised: the myosuppressins, extended-FLRFamides, -FMRFamides, -RFamides, and sulfakinins, members of which induce potent and diverse myotropic effects. Whilst >80 FMRFamide-related peptides have been identified in nematodes, only four FMRFamide-related peptides have been characterised from flatworms. The Ascaris suum ovijector/body wall bioassay and the Procerodes littoralis muscle fibre bioassay have proved both reliable and sensitive systems for assessing the functional activities of FMRFamide-related peptides in vitro, and data describing the effects of native FMRFamide-related peptides in these systems are rapidly accumulating. This is the first study to determine the cross-phyla activities of non-native FMRFamide-related peptides in both nematode and flatworm species. In the present study, the effects of 10 arthropod FMRFamide-related peptides (leucomyosuppressin [pQDVDHVFLRFamide], schistoFLRFamide [PDVDHVFLRFamide] and truncated analogues [HVFLRFamide and VFLRFamide], lobster peptide I [TNRNFLRFamide], lobster peptide II [SDRNFLRFamide], manducaFLRFamide II [GNSFLRFamide], manducaFLRFamide III [DPSFLRFamide], calliFMRFamide 4 [KPNQDFMRFamide] and perisulfakinin [EQFDDY(SO(3)H)GHMRFamide]), representing the five subfamilies, were examined on the body wall and ovijector of the parasitic porcine nematode, A. suum and dispersed muscle fibres from the free-living turbellarian, P. littoralis. The muscle activity of the ovijector was found to be modulated significantly by each of the arthropod FMRFamide-related peptides tested; the effects were concentration-dependent, reversible and repeatable. All but one (perisulfakinin) of the 10 arthropod FMRFamide-related peptides examined modulated significantly the activity of A. suum body wall muscle. In addition, all of the arthropod FMRFamide-related peptides examined induced potent concentration-dependent contractions of P. littoralis muscle fibres. These results reveal similarities in the ligand requirement(s) between FMRFamide-related peptide receptors within the Phyla Arthropoda, Nematoda and Platyhelminthes, and indicate significant receptor promiscuity, which highlights the potential of FMRFamide-related peptide receptors as legitimate targets for novel endectocidal agents.

Caenorhabditis elegans possesses 22 FMRFamide-like peptide (flp) genes predicted to encode 60 different FMRFamide-related peptides with a range of C-terminal signatures. Peptides from five flp genes (1, 6, 8, 9 and 14) are known to modulate the ovijector of Ascaris suum in vitro. This study examines the physiological effects of peptides from the remaining 17 flp genes such that the variety of FMRFamide-related peptide-induced ovijector response types can be delineated. Five categories of response were identified according to the pattern of changes in contractile behaviour and baseline tension. Peptides encoded on 16 flp genes (1, 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 20) had qualitatively similar inhibitory (response type 1) actions, with the lowest activity thresholds (1 nM) recorded for peptides with FIRFamide or FLRFamide C-terminal signatures. Peptides encoded on four flp genes (2, 18, 19 and 21), and on the A. suum afp-1 gene, had excitatory actions on the ovijector (response type 2), with PGVLRFamides having the lowest activity threshold (1 nM). An flp-2 peptide (LRGEPIRFamide) induced a transient contraction of the ovijector (activity threshold, 10nM) that was designated response type 3. Response type 4 comprised a transient contraction followed by an extended period of inactivity and was observed with peptides encoded on flp-5 (AGAKFIRFamide, APKPKFIRFamide), flp-8 (KNEFIRFamide) and flp-22 (SPSAKWMRFamide). SPSAKWMRFamide was the most potent peptide tested with an activity threshold of 0.1 nM. A single peptide (AMRNALVRFamide; activity threshold 0.1 microM), encoded on flp-11, induced response type 5, a shortening of the ovijector coupled with an increase in contraction frequency. Although most flp genes encode structurally related peptides that trigger one of the five ovijector response types, flp-2 and flp-11 co-encode FMRFamide-related peptides that induce distinct responses. Within the ovijector of A. suum FaRPs play a complex role involving at least five receptor subtypes or signalling pathways.

Prospects for discovering new antiparasitic drugs for veterinary medicine in the coming century will be determined by economic, social and scientific factors. Consolidation in the pharmaceutical industry in general, and the animal health industry in particular, changes the business conditions in which drug discovery for veterinary medicine occurs. Social pressures on traditional animal agriculture and companion animal ownership have shifted the interest of animal companies primarily to pet medicine. Antiparasitic drug discovery is more than ever targeted to the most lucrative market segments, but the excellence of available drugs, and the apparent lack of resistance in important parasites, reduces industrial motivation to invest in parasitology. Veterinary parasitologists in academia will still have the chance to interact with their industrial counterparts in the traditional ways of supporting drug discovery and development. Nonetheless, there are many new opportunities to expand the research horizons of veterinary parasitology to strengthen the case for retaining a significant presence in the animal health industry.

Patch-clamp recordings from muscle- and cuticle-facing hypodermal membranes of the gastrointestinal nematode Ascaris suum reveal a high-conductance, voltage- sensitive Ca(2+) -dependent Cl(-) channel. The hypodermal channel has a conductance of 195 pS in symmetrical 160 mM NaCl. The open probability of the channel is highly voltage-sensitive, and channel activity is not observed when Ca(2+) is reduced to <100 microM. The channel is permeable to organic anions that are major end-products of carbohydrate metabolism in A. suum, including acetate, butyrate and 2-methylvalerate. The conductances and relative permeabilities of these organic anions are inversely related to size, with 2-methylvalerate being only approximately 3% as permeable as Cl(-). The diameter of the channel pore was 12.3+/-0.2 A, calculated from the relative permeability coefficients of Cl(-) and the organic anions. Results of this study are consistent with the hypothesis that the large conductance anion channel in A. suum hypodermal membranes provides a low energy pathway for organic anion excretion from the hypodermal compartment, followed by diffusion across the aqueous channels of the cuticle matrix.

KHEYLRF-NH(2) (AF2) is a FMRFamide-related peptide (FaRP) present in parasitic and free-living nematodes. At concentrations as low as 10 pM, AF2 induces a biphasic tension response, consisting of a transient relaxation followed by profound excitation, in neuromuscular strips prepared from Ascaris suum. In the present study, the effects of AF2 on cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP) and inositol-1,4,5-triphosphate (IP(3)) levels were measured following muscle tension recordings from 2 cm neuromuscular strips prepared from adult A. suum. AF2 induced a concentration- and time-dependent increase in cAMP, beginning at 1 nM; cAMP levels increased by 84-fold following 1 h exposure to 1 microM AF2. cGMP and IP(3) levels were unaffected by AF2 at concentrations

Beta-sialons are ceramic phases occurring in the SiO(2)-Si(3)N(4)-AlN-Al(2)O(3) system. A series of samples with differing compositions has been investigated by magic-angle spinning nuclear magnetic resonance (NMR) spectroscopy and powder X-ray diffraction (XRD). Although the constituent nitrogen nuclei occupy positions of low symmetry in the beta-sialon structure, 14N NMR spectra could be recorded for the samples examined. The origin of the 14N signal could be traced to the presence of an aluminium nitride (AlN) impurity phase with the help of 27Al NMR and XRD results. Similarly, the existence of Al(2)O(3) grains could be readily detected for a number of samples. Thus, the combination of 14N and 27Al NMR is shown to be an especially effective tool in identifying and characterizing impurity phases in sialon ceramics, complementing the results obtained from standard XRD analysis., (Copyright 2002 Elsevier Science (USA))

FMRFamide-related peptides are widespread among the Nematoda. Among them is a family of extended PNFLRFamide peptides encoded on the flp-1 peptide precursor gene in Caenorhabditis elegans. The most studied peptide from this series is SDPNFLRFamide (PF1). Each residue in this peptide was sequentially substituted with either alanine or the corresponding d-isomer of the native amino acid in order to define structure-function relationships in this peptide using an Ascaris suum muscle tension assay. In general, substitutions in the N-terminal tetrapeptide had only minor consequences for efficacy, while substitutions in the C-terminal tetrapeptide caused more dramatic changes. Such substitutions typically markedly diminished efficacy, but d-isomer substitution at either position 5 (Phe) or 6 (Leu) converted the inhibitory activity of the prototype into excitation. In addition, it has been evident that KPNFLRFamide and SDPNFLRFamide, though encoded on flp-1 and sharing a PNFLRFamide hexapeptide, act through different receptors. KPNFLRFamide directly gates a chloride channel in A. suum muscle cells, while SDPNFLRFamide acts through nitric oxide synthase to open K+ channels in the same tissue. The use of K+ channel blockers and nitric oxide synthase inhibitors in electrophysiological experiments employing A. suum muscle membranes allowed the unambiguous conclusion that the N-terminal lysine is absolutely required for activation of the chloride channel and excludes interaction with the SDPNFLRFamide receptor.

Here we describe the actions of the peptide Lys-Pro-Asn-Phe-Ile-Arg-Phe-NH(2), or PF4, on inside-out membrane patches (n=164), recorded from vesicles derived from Ascaris suum somatic muscle cells. We observed numerous, small-amplitude Cl(-) channels in the membrane patches. The conductance of the Cl(-) channels ranged from 1.09 to 7.07 pS, the open probability (P(open)) ranged from 0.047+/-0.015 (mean+/-S.E.M.) at 0 microM PF4 to 0.156+/-0.026 at 0.1 microM PF4. The channel mean open time was more variable and prolonged at negative potentials than when the membrane patch was clamped at positive potentials: at 0.03 microM PF4, the mean open time (+/-S.E.M) at -80 mV was 522+/-333 ms; at+80 mV, it was 25+/-7 ms. When patches were isolated from the parent vesicle, there were no changes in channel characteristics, suggesting that the channels function without the involvement of cytoplasmic components. Similarly, the channel characteristics were not affected by the G-protein inhibitor, guanosine-5'-O-(2-thiodiphosphate), indicating that the ion channels do not require a G-protein to function. These data indicate that the PF4-activated Cl(-) channels function independently of intracellular signal transducers and are, therefore, directly gated by PF4.

Paraherquamide is a novel natural anthelmintic product with a mode of action that is incompletely characterized. Nicotine and cholinergic-anthelmintic agonists of different chemical classes were used to produce contraction in Ascaris muscle strips. Paraherquamide and a semisynthetic derivative, 2-deoxy-paraherquamide, antagonized these responses. Analysis of the actions of the antagonists was made using the simple competitive model and nonlinear regression to estimate the pK(B) values of the antagonists. The analysis was tested using Clark plots. The pK(B) values for paraherquamide were: nicotine, 5.86 +/- 0.14; levamisole, 6.61 +/- 0.19; pyrantel, 6.50 +/- 0.11; and bephenium, 6.75 +/- 0.15. The pK(B) of nicotine was significantly different from the pK(B) values for levamisole, pyrantel, and bephenium, showing that paraherquamide can distinguish a subtype of cholinergic receptors sensitive to nicotine and a subtype of cholinergic receptors sensitive to levamisole, pyrantel, and bephenium. The pK(B) values for 2-deoxy-paraherquamide were: levamisole, 5.31 +/- 0.13; pyrantel, 5.63 +/- 0.10; and bephenium, 6.07 +/- 0.13. The Clark plots of the antagonism illustrated the degree of fit to the competitive model for 2-deoxy-paraherquamide. 2-Deoxy-paraherquamide selectively antagonized the effects of bephenium; the pK(B) values of levamisole and pyrantel were significantly different from the pK(B) of bephenium. Paraherquamide and 2-deoxy-paraherquamide are selective competitive cholinergic antagonists that distinguish subtypes of cholinergic receptor in Ascaris muscle corresponding to nicotine-, levamisole-, and bephenium-sensitive receptors.

Oxindole alkaloids in the paraherquamide/marcfortine family exhibit broad-spectrum anthelmintic activity that includes drug-resistant strains of nematodes. Paraherquamide (PHQ), 2-deoxoparaherquamide (2DPHQ), and close structural analogs of these compounds rapidly induce flaccid paralysis in parasitic nematodes in vitro, without affecting adenosine triphosphate (ATP) levels. The mechanism of action of this anthelmintic class was investigated using muscle tension and microelectrode recording techniques in isolated body wall segments of Ascaris suum. None of the compounds altered A. suum muscle tension or membrane potential. However, PHQ blocked (when applied before) or reversed (when applied after) depolarizing contractions induced by acetylcholine (ACh) and the nicotinic agonists levamisole and morantel. These effects were mimicked by the nicotinic ganglionic blocker mecamylamine, suggesting that the anthelmintic activity of PHQ and marcfortines is due to blockade of cholinergic neuromuscular transmission. The effects of these compounds were also examined on subtypes of human nicotinic ACh receptors expressed in mammalian cells with a Ca2+ flux assay. 2DPHQ blocked nicotinic stimulation of cells expressing alpha3 ganglionic (IC50 approximately 9 microm) and muscle-type (IC50 approximately 3 microm) nicotinic cholinergic receptors, but was inactive at 100 microm vs. the alpha7 CNS subtype. PHQ anthelmintics are nicotinic cholinergic antagonists in both nematodes and mammals, and this mechanism appears to underlie both their efficacy and toxicity.

Current problems of drug resistance in parasites and pests demand the identification of new targets and their exploitation through novel drug design and development programs. Neuropeptide signaling systems in helminths (nematodes and platyhelminths = worms) and arthropods are well developed and complex, play a crucial role in many aspects of their biology, and appear to have significant potential as targets for novel drugs. The best-known neuropeptide family in invertebrates is the FMRFamide-related peptides (FaRPs). Amongst many roles, FaRPs potently influence motor function. The genome sequencing projects of Drosophila melanogaster and Caenorhabditis elegans have revealed unexpected complexity within the FaRPergic systems of arthropods and nematodes, although available evidence for platyhelminths indicates structural and functional simplicity. Regardless of these differences, FaRPs potently modulate motor function in arthropods, nematodes and platyhelminths and there appears to be at least some commonality in the FaRPergic signaling systems therein. Moreover, there is now increasing evidence of cross-phyla activity for individual FaRPs, providing clear signals of opportunities for target selection and the identification and development of broad-spectrum drugs.

Three distinct chemical classes for the control of gastrointestinal nematodes are available: benzimidazoles, imidazothiazoles, and macrocyclic lactones. The relentless development of drug resistance has severely limited the usefulness of such drugs and the search for a new class of compounds preferably with a different mode of action is an important endeavor. Marcfortine A (1), a metabolite of Penicillium roqueforti, is structurally related to paraherquamide A (2), originally isolated from Penicillium paraherquei. Chemically the two compounds differ only in one ring; in marcfortine A, ring G is six-membered and carries no substituents, while in paraherquamide A, ring G is five-membered with methyl and hydroxyl substituents at C14. Paraherquamide A (2) is superior to marcfortine A as a nematocide. 2-Desoxoparaherquamide A (PNU-141962, 53) has excellent nematocidal activity, a superior safely profile, and is the first semi-synthetic member of this totally new class of nematocides that is a legitimate candidate for development. This review describes the chemistry, efficacy and mode of action of PNU-141962.