Summary Objective To examine the pain experience of people with hip or knee osteoarthritis (OA), particularly changes over time and most distressing features. Method Focus groups in individuals aged ...40+ years with painful hip or knee OA obtained detailed descriptions of OA pain from early to late disease. A modified Patient Generated Index (PGI) was used to assess the features of OA pain that participants found most distressing. Content analysis was performed to examine response patterns; descriptive statistics were used to summarize PGI responses. Results Mean age of the 143 participants (52 hip OA; 91 knee OA) was 69.5 years (47–92 years); 60.8% were female and 93.7% Caucasian. Participants described two distinct types of pain – a dull, aching pain, which became more constant over time, punctuated increasingly with short episodes of a more intense, often unpredictable, emotionally draining pain. The latter, but not the former, resulted in significant avoidance of social and recreational activities. From PGI responses, distressing pain features were: the pain itself (particularly intense and unpredictable pain) and the pain's impact on mobility, mood and sleep. Conclusions Two distinct pain types were identified. Intermittent intense pain, particularly when unpredictable, had the greatest impact on quality of life.
π-Conjugated polymers that are electrochemically cycled in ionic liquids have enhanced lifetimes without failure (up to 1 million cycles) and fast cycle switching speeds (100 ms). We report results ...for electrochemical mechanical actuators, electrochromic windows, and numeric displays made from three types of π-conjugated polymers: polyaniline, polypyrrole, and polythiophene. Experiments were performed under ambient conditions, yet the polymers showed negligible loss in electroactivity. These performance advantages were obtained by using environmentally stable, room-temperature ionic liquids composed of 1-butyl-3-methyl imidazolium cations together with anions such as tetrafluoroborate or hexafluorophosphate.
The abuse of drugs is now an epidemic globally whose control has been mainly through rehabilitation. The demand for drug abuse rehabilitation has not been matched with the available capacity ...resulting in limited placement of addicts into rehabilitation. In this paper, we model limited rehabilitation through the Hill function incorporated into a system of nonlinear ordinary differential equations. Not every member of the community is equally likely to embark on drug use, risk structure is included to help differentiate those more likely (high risk) to abuse drugs and those less likely (low risk) to abuse drugs. It is shown that the model has multiple equilibria, and using the centre manifold theory, the model exhibits the phenomenon of backward bifurcation whose implications to rehabilitation are discussed. Sensitivity analysis and numerical simulations are performed. The results show that saturation in rehabilitation will in the long run lead to the escalation of drug abuse. This means that limited access to rehabilitation has negative implications in the fight against drug abuse where rehabilitation is the main form of control. This suggests that increased access to rehabilitation is likely to lower the drug abuse epidemic.
This paper reviews the aging mechanisms and stresses that affect porcelain suspension-type insulators. Procedures and criteria for determining the overall condition of inservice porcelain suspension ...insulators on an aged line are described so that a decision can be made on their suitability for continued service or to replace the insulators.
Hyperinsulinemia concurrent with hypoglycemia is one of a myriad of physiological changes typically experienced by lactating dairy cows exposed to heat stress, the consequences of which are not yet ...well defined or understood. Therefore, the objective of this experiment was to separate the production-related effects of hyperinsulinemia with hypoglycemia from those of a hyperthermic environment. Multiparous lactating Holstein cows (n = 23; 58 ± 4 d in milk, 3.1 ± 0.3 lactations) were housed in temperature-controlled rooms and all were subjected to 4 experimental periods as follows: (1) thermoneutral (TN; temperature-humidity index of 65.1 ± 0.2; d 1–5), (2) TN + hyperinsulinemic-hypoglycemic clamp (HHC; insulin infused at 0.3 µg/kg of BW per h, glucose infused to maintain 90 ± 10% of baseline blood glucose for 96 h; d 6–10), (3) heat stress (HS; temperature-humidity index of 72.5 ± 0.2; d 16–20), and (4) HS + euglycemic clamp (EC; glucose infused to reach 100 ± 10% of TN baseline blood glucose for 96 h; d 21–25). Cows were fed and milked twice daily. Feed refusals were collected once daily for calculation of daily dry matter intake, and milk samples were collected at the beginning and end of each period for component analyses. Circulating insulin concentrations were measured in daily blood samples, whereas glucose concentrations were measured more frequently and variably in association with clamp procedures. Rectal temperatures and respiration rates were greater during HS than TN, as expected, and states of hyperinsulinemia and hypoglycemia were successfully induced by the HHC and high ambient temperatures (HS and EC). Feed intake differed based upon thermal environment as it was similar during TN and HHC periods, and declined for HS and EC. Milk production was not entirely reflective of feed intake as it was greatest during TN, intermediate during HHC, and lowest during HS and EC. All milk components differed with the experimental period, primarily in response to the thermal environment. Interestingly, TN baseline glucose concentrations were highly correlated with the change in glucose from TN to HS, and were related to glycemic status during HS. Furthermore, although few in number, those cows that failed to become hypoglycemic during HS tended to have a greater reduction in milk yield. The work presented here addresses a critical knowledge gap by broadening our understanding of the physiological response to heat stress and the related changes in glycemic state. This broadened understanding is fundamental for the development of novel, innovative management strategies as the dairy industry is compelled to become increasingly efficient in spite of global warming.
Abstract
Background
A common polymorphism (R577X) in the
ACTN3
gene results in the complete absence of the Z-disc protein α-actinin-3 from fast-twitch muscle fibres in ~ 16% of the world’s ...population. This single gene polymorphism has been subject to strong positive selection pressure during recent human evolution. Previously, using an
Actn3KO
mouse model, we have shown in fast-twitch muscles, eccentric contractions at
L
0
+ 20% stretch did not cause eccentric damage. In contrast,
L
0
+ 30% stretch produced a significant ~ 40% deficit in maximum force; here, we use isolated single fast-twitch skeletal muscle fibres from the
Actn3KO
mouse to investigate the mechanism underlying this.
Methods
Single fast-twitch fibres are separated from the intact muscle by a collagenase digest procedure. We use label-free
second harmonic generation
(SHG) imaging, ultra-fast video microscopy and skinned fibre measurements from our
MyoRobot
automated biomechatronics system to study the morphology, visco-elasticity, force production and mechanical strength of single fibres from the
Actn3KO
mouse. Data are presented as means ± SD and tested for significance using ANOVA.
Results
We show that the absence of α-actinin-3 does not affect the visco-elastic properties or myofibrillar force production. Eccentric contractions demonstrated that chemically skinned
Actn3KO
fibres are mechanically weaker being prone to breakage when eccentrically stretched. Furthermore, SHG images reveal disruptions in the myofibrillar alignment of
Actn3KO
fast-twitch fibres with an increase in Y-shaped myofibrillar branching.
Conclusions
The absence of α-actinin-3 from the Z-disc in fast-twitch fibres disrupts the organisation of the myofibrillar proteins, leading to structural weakness. This provides a mechanistic explanation for our earlier findings that in vitro intact
Actn3KO
fast-twitch muscles are significantly damaged by
L
0
+ 30%, but not
L
0
+ 20%, eccentric contraction strains. Our study also provides a possible mechanistic explanation as to why α-actinin-3-deficient humans have been reported to have a faster decline in muscle function with increasing age, that is, as sarcopenia reduces muscle mass and force output, the eccentric stress on the remaining functional α-actinin-3 deficient fibres will be increased, resulting in fibre breakages.
Reliable and repeatable experimental generation of high-g shock environments is a long-standing problem which faces significant difficulty. The shock levels experienced by various defense-related ...structural and mechanical components are not always easily obtained in the true environments but are known to span a significant range of peak accelerations and pulse durations. The reproduction of these high-g shock levels in a controlled setting is highly important but also quite complicated. A system which is characterized by substantial energy output, a high level of precision, and adjustability is ideal for producing the varying and intense conditions experienced by structures and components subjected to shock loads.
The Blast Simulator, a complex experimental device which simulates explosive blasts without the use of explosive materials, has proven to be an appropriate tool for this application. The system uses high-precision, computer-controlled hydraulic actuators to fire a piston mounted with various impact materials at high velocities into the specified test article. In the developed experimental series, a cylindrical steel specimen is launched by the Blast Simulator from a set of custom pedestals into a catcher pit. The response of the test article to the impact is acquired and analyzed using the shock response spectrum. The results are used to display the capabilities of the Blast Simulator to induce a wide range of shocks on the test article and display the effectiveness of the device as a shock loading tool.
•Developed new experimental method for shock loading of structures.•Examined the effects of varying experimental parameters on the shock pulse.•Compared various shock loads using the shock response spectrum.•Created a range of shocks on a structural specimen using the new methodology.
Abstract
Background
Adolescent depression can place a young person at high risk of recurrence and a range of psychosocial and vocational impairments in adult life, highlighting the importance of ...early recognition and prevention. Parents/carers are well placed to notice changes in their child’s emotional wellbeing which may indicate risk, and there is increasing evidence that modifiable factors exist within the family system that may help reduce the risk of depression and anxiety in an adolescent. A randomised controlled trial (RCT) of the online personalised ‘Partners in Parenting’ programme developed in Australia, focused on improving parenting skills, knowledge and awareness, showed that it helped reduce depressive symptoms in adolescents who had elevated symptom levels at baseline. We have adapted this programme and will conduct an RCT in a UK setting.
Methods
In total, 433 family dyads (parents/carers and children aged 11–15) will be recruited through schools, social media and parenting/family groups in the UK. Following completion of screening measures of their adolescent’s depressive symptoms, parents/carers of those with elevated scores will be randomised to receive either the online personalised parenting programme
or
a series of online factsheets about adolescent development and wellbeing. The primary objective will be to test whether the personalised parenting intervention reduces depressive symptoms in adolescents deemed at high risk, using the parent-reported Short Mood & Feelings Questionnaire. Follow-up assessments will be undertaken at 6 and 15 months and a process evaluation will examine context, implementation and impact of the intervention. An economic evaluation will also be incorporated with cost-effectiveness of the parenting intervention expressed in terms of incremental cost per quality-adjusted life year gained.
Discussion
Half of mental health problems emerge before mid-adolescence and approximately three-quarters by mid-20s, highlighting the need for effective preventative strategies. However, few early interventions are family focused and delivered online. We aim to conduct a National Institute for Health and Care Research (NIHR) funded RCT of the online personalised ‘Partners in Parenting’ programme, proven effective in Australia, targeting adolescents at risk of depression to evaluate its effectiveness, cost-effectiveness and usability in a UK setting.
Trial registration {2a}
ISRCTN63358736. Registered 18 September 2019.
Summary Background The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2·0 Gy over 5 weeks, but there is a long history of non-standard regimens ...delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2·0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy. Methods Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2·0 Gy over 5 weeks or 40 Gy in 15 fractions of 2·67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. Findings 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6·0 years (IQR 5·0–6·2) the rate of local-regional tumour relapse at 5 years was 2·2% (95% CI 1·3–3·1) in the 40 Gy group and 3·3% (95% CI 2·2 to 4·5) in the 50 Gy group, representing an absolute difference of −0·7% (95% CI −1·7% to 0·9%)—ie, the absolute difference in local-regional relapse could be up to 1·7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy. Interpretation A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.
BACKGROUND AND PURPOSE The lung adenocarcinoma cell line, A549, undergoes epithelial‐mesenchymal cell transition (EMT) in response to TGF‐β. Glucocorticoids do not prevent the EMT response, but TGF‐β ...induced resistance to the cytokine‐regulatory action of glucocorticoids. We sought to characterize the impairment of glucocorticoid response in A549 cells.
EXPERIMENTAL APPROACH A549 cells were exposed to TGF‐β for up to 96 h before glucocorticoid treatment and challenge with IL‐1α to assess glucocorticoid regulation of IL‐6 and CXCL8 production. Nuclear localization of the glucocorticoid receptor α (GRα) was ascertained by immunofluorescence and Western blotting. Transactivation of the glucocorticoid response element (GRE) was measured with a transfected GRE‐secreted human placental alkaline phosphatase reporter.
KEY RESULTS TGF‐β (40–400 pM) reduced the maximum inhibitory effect of dexamethasone on IL‐1α‐induced IL‐6 and CXCL8 production. The impaired glucocorticoid response was detected with 4 h of TGF‐β (40 pM) exposure (and 4 h IL‐1α to induce CXCL8 expression) and therefore was not secondary to EMT, a process that requires longer incubation periods and higher concentrations of TGF‐β. TGF‐β also impaired dexamethasone regulation of granulocyte‐macrophage colony‐stimulating factor in thrombin‐stimulated BEAS‐2B epithelial cells. Impaired regulation of CXCL8 was associated with markedly reduced GRE transactivation and reduced induction of mRNA for IκBα, the glucocorticoid‐inducible leucine zipper and the epithelial sodium channel (SCNN1A). The expression, cellular levels and nuclear localization of GRα were reduced by TGF‐β.
CONCLUSIONS AND IMPLICATIONS We have identified mechanisms underlying the impairment of responses to glucocorticoids by TGF‐β in the A549 and BEAS‐2B cell lines.
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