Breathlessness and inflammation: potential relationships and implications.

PURPOSE OF REVIEW: Breathlessness and chronic inflammation both span a wide range of disease contexts and hold prognostic significance. The possibility of a causal relationship between the two has been hypothesized. The aims of this article are to review the intersections between breathlessness and inflammation in the literature, describe potential mechanisms connecting the two phenomena, and discuss the potential clinical implications of a causal relationship. RECENT FINDINGS: There is a very limited literature exploring the relationship between systemic inflammation and breathlessness in chronic obstructive pulmonary disease, heart failure, and cancer. One large study in cancer patients is suggestive of a weak association between self-reported breathlessness and inflammation. Studies exploring the relationship between inflammation and Medical Research Council Dyspnoea grade in chronic obstructive pulmonary disease patients have produced inconsistent findings. Although a causal relationship has not yet been proven, there is evidence to support the existence of potential mechanisms mediating a relationship. This evidence points to a role for the skeletal muscle and stress hormone systems. SUMMARY: There is much progress to be made in this area. Interventional studies, evaluating the impact of anti-inflammatory interventions on breathlessness, are needed to help determine whether a causal relationship exists. If proven, this relationship might have important implications for both the treatment and impact of breathlessness.R.R. was funded by a National Institute for Health Research (NIHR) Doctoral Research Fellowship Award from January 2013–December 2015

Targeting neuroendocrine abnormalities in Parkinson’s disease with exercise

Parkinson’s Disease (PD) is a prevalent and complex age-related neurodegenerative condition for which there are no disease-modifying treatments currently available. The pathophysiological process underlying PD remains incompletely understood but increasing evidence points to multiple system dysfunction. Interestingly, the past decade has produced evidence that exercise not only reduces signs and symptoms of PD but is also potentially neuroprotective. Characterizing the mechanistic pathways that are triggered by exercise and lead to positive outcomes will improve understanding of how to counter disease progression and symptomatology. In this review, we highlight how exercise regulates the neuroendocrine system, whose primary role is to respond to stress, maintain homeostasis and improve resilience to aging. We focus on a group of hormones – cortisol, melatonin, insulin, klotho, and vitamin D – that have been shown to associate with various non-motor symptoms of PD, such as mood, cognition, and sleep/circadian rhythm disorder. These hormones may represent important biomarkers to track in clinical trials evaluating effects of exercise in PD with the aim of providing evidence that patients can exert some behavioral-induced control over their disease

The cortisol awakening response predicts same morning executive function: results from a 50-day case study

A relationship between individual differences in trait estimates of the cortisol-awakening response (CAR) and indices of executive function (EF) has been reported. However, it is difficult to determine causality from such studies. The aim of the present study was to capitalise upon state variation in both variables to seek stronger support for causality by examining daily co-variation. A 50 days researcher–participant case study was employed, ensuring careful adherence to the sampling protocol. A 24-year-old healthy male collected saliva samples and completed an attention-switching index of EF on the morning of each study day. Subsidiary control measures included wake time, sleep duration, morning fatigue, and amount of prior day exercise and alcohol consumption. As the CAR preceded daily measurement of EF, we hypothesised that, over time, a greater than average CAR would predict better than average EF. This was confirmed by mixed regression modelling of variation in cortisol concentrations, which indicated that the greater the increase in cortisol concentrations from 0 to 30 min post-awakening (CAR) the better was subsequent EF performance at 45 min post-awakening (t = 2.29, p = 0.024). This effect was independent of all potential confounding measures. Results are discussed in terms of implications for the understanding of the relationship between the CAR and the cognitive function, and the previously suggested role of the CAR in “boosting” an individual’s performance for the day ahead

Assessment of the cortisol awakening response: Real-time analysis and curvilinear effects of sample timing inaccuracy

The cortisol awakening response (CAR) is typically measured in the domestic setting. Moderate sample timing inaccuracy has been shown to result in erroneous CAR estimates and such inaccuracy has been shown partially to explain inconsistency in the CAR literature. The need for more reliable measurement of the CAR has recently been highlighted in expert consensus guidelines where it was pointed out that less than 6% of published studies provided electronic-monitoring of saliva sampling time in the post-awakening period. Analyses of a merged data-set of published studies from our laboratory are presented. To qualify for selection, both time of awakening and collection of the first sample must have been verified by electronic-monitoring and sampling commenced within 15 min of awakening. Participants (n = 128) were young (median age of 20 years) and healthy. Cortisol values were determined in the 45 min post-awakening period on 215 sampling days. On 127 days, delay between verified awakening and collection of the first sample was less than 3 min (‘no delay’ group); on 45 days there was a delay of 4–6 min (‘short delay’ group); on 43 days the delay was 7–15 min (‘moderate delay’ group). Cortisol values for verified sampling times accurately mapped on to the typical post-awakening cortisol growth curve, regardless of whether sampling deviated from desired protocol timings. This provides support for incorporating rather than excluding delayed data (up to 15 min) in CAR analyses. For this population the fitted cortisol growth curve equation predicted a mean cortisol awakening level of 6 nmols/l (±1 for 95% CI) and a mean CAR rise of 6 nmols/l (±2 for 95% CI). We also modelled the relationship between real delay and CAR magnitude, when the CAR is calculated erroneously by incorrectly assuming adherence to protocol time. Findings supported a curvilinear hypothesis in relation to effects of sample delay on the CAR. Short delays of 4–6 min between awakening and commencement of saliva sampling resulted an overestimated CAR. Moderate delays of 7–15 min were associated with an underestimated CAR. Findings emphasize the need to employ electronic-monitoring of sampling accuracy when measuring the CAR in the domestic setting

'Well London' and the benefits of participation: results of a qualitative study nested in a cluster randomised trial

Background: Well London is a multicomponent community engagement and coproduction programme designed to improve the health of Londoners living in socioeconomically deprived neighbourhoods. To evaluate outcomes of the Well London interventions, a cluster randomised trial (CRT) was conducted that included a longitudinal qualitative component, which is reported here. The aim is to explore in depth the nature of the benefits to residents and the processes by which these were achieved. Methods: The 1-year longitudinal qualitative study was nested within the CRT. Purposive sampling was used to select three intervention neighbourhoods in London and 61 individuals within these neighbourhoods. The interventions comprised activities focused on: healthy eating, physical exercise and mental health and well-being. Interviews were conducted at the inception and following completion of the Well London interventions to establish both if and how they had participated. Transcripts of the interviews were coded and analysed using Nvivo. Results: Positive benefits relating to the formal outcomes of the CRT were reported, but only among those who participated in project activities. The extent of benefits experienced was influenced by factors relating to the physical and social characteristics of each neighbourhood. The highest levels of change occurred in the presence of: (1) social cohesion, not only pre-existing but also as facilitated by Well London activities; (2) personal and collective agency; (3) involvement and support of external organisations. Where the physical and social environment remained unchanged, there was less participation and fewer benefits. Conclusions: These findings show interaction between participation, well-being and agency, social interactions and cohesion and that this modulated any benefits described. Pathways to change were thus complex and variable, but personal well-being and local social cohesion emerged as important mediators of change

Stressful life events are associated with low secretion rates of immunoglobulin A in saliva in the middle aged and elderly

Whether chronic stress experience is related to down-regulation of secretory immunoglobulin A (S-IgA) was tested in two substantial cohorts, one middle-aged (N = 640) and one elderly (N = 582), comprising similar numbers of men (N = 556) and women (N = 666) and manual (N = 606) and non-manual (N = 602) workers. Participants indicated from a list of major stressful life events up to six they had experienced in the previous two years. They also rated how disruptive and stressful the events were, at the time and now, as well as their perceived seriousness; the products of these impact values and event frequency were adopted as measures of stress load. From unstimulated 2-minute saliva samples, saliva volume and S-IgA concentration were measured, and S-IgA secretion rate determined as their product. There was a negative association between the stress load measures and S-IgA secretion rate, still evident following adjustment for such variables as smoking and saliva volume. The associations also withstood adjustment for sex, cohort, and household occupational status. Although these associations are small in terms of the amount of variance explained, they nonetheless suggest that chronic stress experience either decreases IgA production by the local plasma cells or reduces the efficiency with which S-IgA is transported from the glandular interstitium into saliva. Given the importance of S-IgA in immune defence at mucosal surfaces and the frequency with which infections are initiated at these surfaces, S-IgA down-regulation could be a means by which chronic stress increases susceptibility to upper respiratory tract infection

Post awakening salivary cortisol secretion and trait well-being: The importance of sample timing accuracy

Indices of post awakening cortisol secretion (PACS), include the rise in cortisol(cortisol awakening response: CAR) and overall cortisol concentrations (e.g. area under the curve with reference to ground: AUCg) in the first 30—45 min. Both are commonly investigated in relation to psychosocial variables. Although sampling within the domestic setting is ecologically valid, participant non-adherence to the required timing protocol results in erroneous measurement of PACS and this may explain discrepancies in the literature linking these measures to trait well-being (TWB). We have previously shown that delays of little over 5 min(between awakening and the start of sampling) to result in erroneous CAR estimates. In this study, we report for the first time on the negative impact of sample timing inaccuracy (verified by electronic-monitoring) on the efficacy to detect significant relationships between PACS and TWB when measured in the domestic setting.Healthy females (N = 49, 20.5 ± 2.8 years) selected for differences in TWB collected saliva samples (S1—4) on 4 days at 0, 15, 30, 45 min post awakening, to determine PACS. Adherence to the sampling protocol was objectively monitored using a combination of electronic estimates of awakening (actigraphy) and sampling times (track caps).Relationships between PACS and TWB were found to depend on sample timing accuracy. Lower TWB was associated with higher post awakening cortisol AUCg in proportion to the mean sample timing accuracy (p 5 min between awakening and collection of sample 1 (median = 8 min delay), negatively impacts on the sensitivity of analysis to detect associations between PACS and TWB