Short-rib polydactyly and jeune syndromes are caused by mutations in WDR60

Short-rib polydactyly syndromes (SRPS I-V) are a group of lethal congenital disorders characterized by shortening of the ribs and long bones, polydactyly, and a range of extraskeletal phenotypes. A number of other disorders in this grouping, including Jeune and Ellis-van Creveld syndromes, have an overlapping but generally milder phenotype. Collectively, these short-rib dysplasias (with or without polydactyly) share a common underlying defect in primary cilium function and form a subset of the ciliopathy disease spectrum. By using whole-exome capture and massive parallel sequencing of DNA from an affected Australian individual with SRPS type III, we detected two novel heterozygous mutations in WDR60, a relatively uncharacterized gene. These mutations segregated appropriately in the unaffected parents and another affected family member, confirming compound heterozygosity, and both were predicted to have a damaging effect on the protein. Analysis of an additional 54 skeletal ciliopathy exomes identified compound heterozygous mutations in WDR60 in a Spanish individual with Jeune syndrome of relatively mild presentation. Of note, these two families share one novel WDR60 missense mutation, although haplotype analysis suggested no shared ancestry. We further show that WDR60 localizes at the base of the primary cilium in wild-type human chondrocytes, and analysis of fibroblasts from affected individuals revealed a defect in ciliogenesis and aberrant accumulation of the GLI2 transcription factor at the centrosome or basal body in the absence of an obvious axoneme. These findings show that WDR60 mutations can cause skeletal ciliopathies and suggest a role for WDR60 in ciliogenesis.

Altered formalin-induced pain and Fos induction in the periaqueductal grey of preadolescent rats following neonatal LPS exposure

Animal and human studies have demonstrated that early pain experiences can produce alterations in the nociceptive systems later in life including increased sensitivity to mechanical, thermal, and chemical stimuli. However, less is known about the impact of neonatal immune challenge on future responses to noxious stimuli and the reactivity of neural substrates involved in analgesia. Here we demonstrate that rats exposed to Lipopolysaccharide (LPS; 0.05 mg/kg IP, Salmonella enteritidis) during postnatal day (PND) 3 and 5 displayed enhanced formalin-induced flinching but not licking following formalin injection at PND 22. This LPS-induced hyperalgesia was accompanied by distinct recruitment of supra-spinal regions involved in analgesia as indicated by significantly attenuated Fos-protein induction in the rostral dorsal periaqueductal grey (DPAG) as well as rostral and caudal axes of the ventrolateral PAG (VLPAG). Formalin injections were associated with increased Fos-protein labelling in lateral habenula (LHb) as compared to medial habenula (MHb), however the intensity of this labelling did not differ as a result of neonatal immune challenge. These data highlight the importance of neonatal immune priming in programming inflammatory pain sensitivity later in development and highlight the PAG as a possible mediator of this process

Muscular activity and fatigue in lower-limb and trunk muscles during different sit-to-stand tests

Sit-to-stand (STS) tests measure the ability to get up from a chair, reproducing an important component of daily living activity. As this functional task is essential for human independence, STS performance has been studied in the past decades using several methods, including electromyography. The aim of this study was to measure muscular activity and fatigue during different repetitions and speeds of STS tasks using surface electromyography in lower-limb and trunk muscles. This cross-sectional study recruited 30 healthy young adults. Average muscle activation, percentage of maximum voluntary contraction, muscle involvement in motion and fatigue were measured using surface electrodes placed on the medial gastrocnemius (MG), biceps femoris (BF), vastus medialis of the quadriceps (QM), the abdominal rectus (AR), erector spinae (ES), rectus femoris (RF), soleus (SO) and the tibialis anterior (TA). Five-repetition STS, 10-repetition STS and 30-second STS variants were performed. MG, BF, QM, ES and RF muscles showed differences in muscle activation, while QM, AR and ES muscles showed significant differences in MVC percentage. Also, significant differences in fatigue were found in QM muscle between different STS tests. There was no statistically significant fatigue in the BF, MG and SO muscles of the leg although there appeared to be a trend of increasing fatigue. These results could be useful in describing the functional movements of the STS test used in rehabilitation programs, notwithstanding that they were measured in healthy young subjects.

Canadian Stroke Best Practice Recommendations: Mood, Cognition and Fatigue Following Stroke practice guidelines, update 2015

Every year, approximately 62 000 people with stroke and transient ischemic attack are treated in Canadian hospitals, and the evidence suggests one-third or more will experience vascular-cognitive impairment, and/or intractable fatigue, either alone or in combination. The 2015 update of the Canadian Stroke Best Practice Recommendations: Mood, Cognition and Fatigue Module guideline is a comprehensive summary of current evidence-based recommendations for clinicians in a range of settings, who provide care to patients following stroke. The three consequences of stroke that are the focus of the this guideline (poststroke depression, vascular cognitive impairment, and fatigue) have high incidence rates and significant impact on the lives of people who have had a stroke, impede recovery, and result in worse long-term outcomes. Significant practice variations and gaps in the research evidence have been reported for initial screening and in-depth assessment of stroke patients for these conditions. Also of concern, an increased number of family members and informal caregivers may also experience depressive symptoms in the poststroke recovery phase which further impact patient recovery. These factors emphasize the need for a system of care that ensures screening occurs as a standard and consistent component of clinical practice across settings as stroke patients transition from acute care to active rehabilitation and reintegration into their community. Additionally, building system capacity to ensure access to appropriate specialists for treatment and ongoing management of stroke survivors with these conditions is another great challenge.

A description of neck motor performance, neck pain, fatigue, and mental effort while driving in a sample with chronic whiplash-associated disorders

Objective: Individuals with chronic whiplash-associated disorders (WADs) often note driving as a difficult task. This study’s aims were to (1) compare, while driving, neck motor performance, mental effort, and fatigue in individuals with chronic WAD against healthy controls and (2) investigate the relationships of these variables and neck pain to self-reported driving difficulty in the WAD group. Design: This study involved 14 participants in each group (WAD and control). Measures included self-reported driving difficulty and measures of neck pain intensity, overall fatigue, mental effort, and neck motor performance (head rotation and upper trapezius activity) while driving a simulator. Results: The WAD group had greater absolute path of head rotation in a simulated city area and used greater mental effort (P = 0.04), but there were no differences in other measures while driving compared with the controls (all P Q 0.05). Self-reported driving difficulty correlated moderately with neck pain intensity, fatigue level, and maximum velocity of head rotation while driving in the WAD group (all P G 0.05). Conclusions: Individuals with chronic WAD do not seem to have impaired neck motor performance while driving yet use greater mental effort. Neck pain, fatigue, and maximum head rotation velocity could be potential contributors to self-reported driving difficulty in this group.

A longitudinal study of health-related quality of life, fatigue and physical activity in chronic kidney disease patients

This study assessed the health-related quality of life (HRQoL), fatigue and physical activity levels of 28 persons with chronic kidney disease (CKD) on initial administration of an erythropoietin stimulating agent, and at 3 months, 6 months and 12 months. The sample comprised of 15 females and 13 males whose ages ranged from 31 to 84 years. Physical activity was measured using the Human Activity Profile (HAP): Self-care, Personal/Household work, Entertainment/Social, Independent exercise. Quality of life was measured using the SF-36 which gives scores on physical health (physical functioning, role-physical, bodily pain and general health) and mental health (vitality, social functioning, role-emotional and emotional well-being). Fatigue was measured by the Fatigue Severity Scale (FSS). Across all time points the renal sample engaged in considerably less HAP personal/household work activities and entertainment/social activities compared to healthy adults. The normative sample engaged in three times more independent/exercise activities compared to renal patients. One-way Repeated measures ANOVAs indicated a significant change over time for SF-36 scales of role physical, vitality, emotional well-being and overall mental health. There was a significant difference in fatigue levels over time [F(3,11) = 3.78, p<.05]. Fatigue was highest at baseline and lowest at 6 months. The more breathlessness the CKD patient reported, the fewer activities undertaken and the greater the reported level of fatigue. There were no significant age differences over time for fatigue or physical activity. Age differences were only found for SF-36 mental health at 3 months (t=-2.41, df=14, p<.05). Those younger than 65 years had lower emotional well-being compared to those aged over 65. Males had poorer physical health compared to females at 12 months. There were no significant gender differences on mental health at any time point. In the management of chronic kidney disease, early detection of a person’s inability to engage in routine activities due to fatigue is necessary. Early detection would enable timely interventions to optimise HRQoL and independent exercise.

Psychological distress and pain reporting in Australian coal miners

BACKGROUND: Coal mining is of significant economic importance to the Australian economy. Despite this fact, the related workforce is subjected to a number of psychosocial risks and musculoskeletal injury, and various psychological disorders are common among this population group. Because only limited research has been conducted in this population group, we sought to examine the relationship between physical (pain) and psychological (distress) factors, as well as the effects of various demographic, lifestyle, and fatigue indicators on this relationship. METHODS: Coal miners (N = 231) participated in a survey of musculoskeletal pain and distress on-site during their work shifts. Participants also provided demographic information (job type, age, experience in the industry, and body mass index) and responded to questions about exercise and sleep quality (on- and off-shift) as well as physical and mental tiredness after work. RESULTS: A total of 177 workers (80.5%) reported experiencing pain in at least one region of their body. The majority of the sample population (61.9%) was classified as having low-level distress, 28.4% had scores indicating mild to moderate distress, and 9.6% had scores indicating high levels of distress. Both number of pain regions and job type (being an operator) significantly predicted distress. Higher distress score was also associated with greater absenteeism in workers who reported lower back pain. In addition, perceived sleep quality during work periods partially mediated the relationship between pain and distress. CONCLUSION: The study findings support the existence of widespread musculoskeletal pain among the coal-mining workforce, and this pain is associated with increased psychological distress. Operators (truck drivers) and workers reporting poor sleep quality during work periods are most likely to report increased distress, which highlights the importance of supporting the mining workforce for sustained productivity.

What about me? Avoiding fatigue and gaining personal time in the work to leisure transition in work-life balance initiatives

Fatigue and overwork are problems experienced by numerous employees in many industry sectors. Focusing on improving work-life balance can frame the ‘problem’ of long work hours to resolve working time duration issues. Flexible work options through re-organising working time arrangements is key to developing an organisational response for delivering work-life balance and usually involves changing the internal structure of work time. This study examines the effect of compressed long weekly working hours and the consequent ‘long break’ on work-life balance. Using Spillover theory and Border theory, this research considers organisational and personal determinants of overwork and fatigue. It concludes compressed long work hours with a long break provide better work-life balance. Further, a long break allows gaining ‘personal time’ and overcoming fatigue.

Future developments in chest pain diagnosis and management

Much of the focus of research on patients with chest pain is directed at technological advances in the diagnosis and management of acute coronary syndrome (ACS), pulmonary embolism (PE), and acute aortic dissection (AAD), despite there being no significant difference at 4 years as regards mortality, ongoing chest pain, and quality of life between patients presenting to the emergency department with noncardiac chest pain and those with cardiac chest pain. This article examines future developments in the diagnosis and management of patients with suspected ACS, PE, AAD, gastrointestinal disease, and musculoskeletal chest pain.

An examination of monotony and hypovigilance, independent of fatigue : relevance to road safety

Driving is a vigilance task, requiring sustained attention to maintain performance and avoid crashes. Hypovigilance (i.e., marked reduction in vigilance) while driving manifests as poor driving performance and is commonly attributed to fatigue (Dinges, 1995). However, poor driving performance has been found to be more frequent when driving in monotonous road environments, suggesting that monotony plays a role in generating hypovigilance (Thiffault & Bergeron, 2003b). Research to date has tended to conceptualise monotony as a uni-dimensional task characteristic, typically used over a prolonged period of time to facilitate other factors under investigation, most notably fatigue. However, more often than not, more than one exogenous factor relating to the task or operating environment is manipulated to vary or generate monotony (Mascord & Heath, 1992). Here we aimed to explore whether monotony is a multi-dimensional construct that is determined by characteristics of both the task proper and the task environment. The general assumption that monotony is a task characteristic used solely to elicit hypovigilance or poor performance related to fatigue appears to have led to there being little rigorous investigation into the exact nature of the relationship. While the two concepts are undoubtedly linked, the independent effect of monotony on hypovigilance remains largely ignored. Notwithstanding, there is evidence that monotony effects can emerge very early in vigilance tasks and are not necessarily accompanied by fatigue (see Meuter, Rakotonirainy, Johns, & Wagner, 2005). This phenomenon raises a largely untested, empirical question explored in two studies: Can hypovigilance emerge as a consequence of task and/or environmental monotony, independent of time on task and fatigue? In Study 1, using a short computerised vigilance task requiring responses to be withheld to infrequent targets, we explored the differential impacts of stimuli and task demand manipulations on the development of a monotonous context and the associated effects on vigilance performance (as indexed by respone errors and response times), independent of fatigue and time on task. The role of individual differences (sensation seeking, extroversion and cognitive failures) in moderating monotony effects was also considered. The results indicate that monotony affects sustained attention, with hypovigilance and associated performance worse in monotonous than in non-monotonous contexts. Critically, performance decrements emerged early in the task (within 4.3 minutes) and remained consistent over the course of the experiment (21.5 minutes), suggesting that monotony effects can operate independent of time on task and fatigue. A combination of low task demands and low stimulus variability form a monotonous context characterised by hypovigilance and poor task performance. Variations to task demand and stimulus variability were also found to independently affect performance, suggesting that monotony is a multi-dimensional construct relating to both task monotony (associated with the task itself) and environmental monotony (related to characteristics of the stimulus). Consequently, it can be concluded that monotony is multi-dimensional and is characterised by low variability in stimuli and/or task demands. The proposition that individual differences emerge under conditions of varying monotony with high sensation seekers and/or extroverts performing worse in monotonous contexts was only partially supported. Using a driving simulator, the findings of Study 1 were extended to a driving context to identify the behavioural and psychophysiological indices of monotony-related hypovigilance associated with variations to road design and road side scenery (Study 2). Supporting the proposition that monotony is a multi-dimensional construct, road design variability emerged as a key moderating characteristic of environmental monotony, resulting in poor driving performance indexed by decrements in steering wheel measures (mean lateral position). Sensation seeking also emerged as a moderating factor, where participants high in sensation seeking tendencies displayed worse driving behaviour in monotonous conditions. Importantly, impaired driving performance was observed within 8 minutes of commencing the driving task characterised by environmental monotony (low variability in road design) and was not accompanied by a decline in psychophysiological arousal. In addition, no subjective declines in alertness were reported. With fatigue effects associated with prolonged driving (van der Hulst, Meijman, & Rothengatter, 2001) and indexed by drowsiness, this pattern of results indicates that monotony can affect driver vigilance, independent of time on task and fatigue. Perceptual load theory (Lavie, 1995, 2005) and mindlessness theory (Robertson, Manly, Andrade, Baddley, & Yiend, 1997) provide useful theoretical frameworks for explaining and predicting monotony effects by positing that the low load (of task and/or stimuli) associated with a monotonous task results in spare attentional capacity which spills over involuntarily, resulting in the processing of task-irrelevant stimuli or task unrelated thoughts. That is, individuals – even when not fatigued - become easily distracted when performing a highly monotonous task, resulting in hypovigilance and impaired performance. The implications for road safety, including the likely effectiveness of fatigue countermeasures to mitigate monotony-related driver hypovigilance are discussed.

Exercise for health : a randomized, controlled trial evaluating impact of a pragmatic, translational exercise intervention on quality of life, function and treatment-related side effects following breast cancer

Purpose Exercise for Health was a randomized, controlled trial designed to evaluate two modes of delivering (face-to-face [FtF] and over-the-telephone [Tel]) an 8-month translational exercise intervention, commencing 6-weeks post-breast cancer surgery (PS). Methods Outcomes included quality of life (QoL), function (fitness and upper-body) and treatment-related side effects (fatigue, lymphoedema, body mass index, menopausal symptoms, anxiety, depression and pain). Generalised estimating equation modelling determined time (baseline [5-weeks PS], mid-intervention [6-months PS], post-intervention [12-months PS]), group (FtF, Tel, Usual Care [UC]) and time-by-group effects. 194 women representative of the breast cancer population were randomised to the FtF (n=67), Tel (n=67) and UC (n=60) groups. Results: There were significant (p<0.05) interaction effects on QoL, fitness and fatigue, with differences being observed between the treatment groups and the UC group. Trends observed for the treatment groups were similar. The treatment groups reported improved QoL, fitness and fatigue over time and changes observed between baseline and post-intervention were clinically relevant. In contrast, the UC group experienced no change, or worsening QoL, fitness and fatigue, mid-intervention. Although improvements in the UC group occurred by 12-months post-surgery, the change did not meet the clinically relevant threshold. There were no differences in other treatment-related side-effects between groups. Conclusion This translational intervention trial, delivered either face-to-face or over-the-telephone, supports exercise as a form of adjuvant breast cancer therapy that can prevent declines in fitness and function during treatment and optimise recovery post-treatment.

Neurological drugs and opioids for pain management

20.1 Epilepsy and an introduction to drugs used to treat 20.1.1 Introduction to epilepsy 20.1.2 Treatment of partial seizures 20.1.3 Treatment of generalised seizures 20.1.4 Treatment of status epilepticus 20.2 Neurodegenerative disorders; principles of treatment 20.2.1 Introduction to neurodegenerative disorders 20.2.2 Parkinson’s disease 20.2.2.1 Introduction to Parkinson’s disease 20.2.2.2 Dopaminergic system 20.2.2.3 Treatment to enhance the dopaminergic system 20.2.2.4 Treatment to inhibit the cholinergic system 20.2.3 Dementia/Alzheimer’s disease 20.2.3.1 Introduction to Alzheimer’s disease 20.2.3.2 Treatment of Alzheimer’s disease 20.2.4 Amyotrophic lateral sclerosis 43.4.1 Introduction 43.4.2 Treatment 20.3. Pain and opioid analgesics 20.3.1 Introduction to pain and analgesia 20.3.2 Introduction to opioids 20.3.3 Tolerance and physical dependence 20.3.4 Effects of opioids 20.3.5 Agonists at opioid μ receptors 20.3.6 Toxicity to opioids This section deals with the neurologic drugs. The neurologic drugs are used to treat epilepsy and neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. The opioids for pain management are also discussed in this section.

How do perceptions of risk associated with driving while fatigued and perceptions of effectiveness of countermeasures effect willingness to engage in fatigue reducing countermeasures?

Sleep-related and fatigue-related driving is an important contributory factor in fatal and serious injury crashes - Accounts for approx 19% - Similar in magnitude to drink driving

The prevalence and perception of pain amongst hospital in-patients

The aim of this paper is to describe the prevalence and perceptions of pain and pain management amongst hospital in-patients. A cross-sectional descriptive survey of 205 patients was conducted. Presence and severity of pain was assessed using verbal descriptor and visual analogue scales, and perceptions of pain were assessed using multi-item scales. Although the severity of pain reported was consistent across age groups and clinical areas, women in the study sample were significantly more likely to report high levels of pain than men. Differences in how men and women communicate their pain were observed, with women indicating that they were less willing to ask for help with their pain. Results suggest that pain continues to be an important problem for a large number of men and women in hospital, and that the experience of pain impacts negatively upon their well-being. Gender differences in the experience of and response to pain remain important considerations for clinical nurses who have major responsibilities for the management of pain in hospitalized patients.

The relationship between hip-abductor strength and the magnitude of pelvic drop in patients with low back pain

Context: It has been theorized that a positive Trendelenburg test (TT) indicates weakness of the stance hip-abductor (HABD) musculature, results in contralateral pelvic drop, and represents impaired load transfer, which may contribute to low back pain. Few studies have tested whether weakness of the HABDs is directly related to the magnitude of pelvic drop (MPD). Objective: To examine the relationship between HABD strength and MPD during the static TT and during walking for patients with nonspecific low back pain (NSLBP) and healthy controls (CON). A secondary purpose was to examine this relationship in NSLBP after a 3-wk HABD-strengthening program. Design: Quasi-experimental. Setting: Clinical research laboratory. Participants: 20 (10 NSLBP and 10 CON). Intervention: HABD strengthening. Main Outcome Measures: Normalized HABD strength, MPD during TT, and maximal pelvic frontal-plane excursion during walking. Results: At baseline, the NSLBP subjects were significantly weaker (31%; P = .03) than CON. No differences in maximal pelvic frontal-plane excursion (P = .72), right MPD (P = 1.00), or left MPD (P = .40) were measured between groups. During the static TT, nonsignificant correlations were found between left HABD strength and right MPD for NSLBP (r = -.32, P = .36) and CON (r = -.24, P = .48) and between right HABD strength and left MPD for NSLBP (r = -.24, P = .50) and CON (r = -.41, P = .22). Nonsignificant correlations were found between HABD strength and maximal pelvic frontal-plane excursion for NSLBP (r = -.04, P = .90) and CON (r = -.14, P = .68). After strengthening, NSLBP demonstrated significant increases in HABD strength (12%; P = .02), 48% reduction in pain, and no differences in MPD during static TT and maximal pelvic frontal-plane excursion compared with baseline. Conclusions: HABD strength was poorly correlated to MPD during the static TT and during walking in CON and NSLBP. The results suggest that HABD strength may not be the only contributing factor in controlling pelvic stability, and the static TT has limited use as a measure of HABD function.