Jennifer L.J. Heaney

Ageing, depression, anxiety, social support and the diurnal rhythm and awakening response of salivary cortisol.

The present study compared the cortisol awakening response and diurnal rhythm in 24 young healthy students and 48 community-dwelling older adults. The associations with diurnal cortisol and depression, anxiety and social support were also examined in relation to age. Salivary cortisol was measured over the course of one day: immediately upon awakening, 30 min later, and then 3h, 6h, 9h and 12h post-awakening. Participants completed a questionnaire measuring symptoms of anxiety and depression and social support was assessed. Older adults exhibited a significantly reduced awakening response, overall cortisol levels, area under the curve (AUC) and diurnal slopes than younger adults, resulting in a flatter diurnal rhythm. Younger adults with higher depression scores had significantly higher overall cortisol and higher levels upon awakening and 30 min post-awakening. In the younger adults, anxiety and depression correlated positively with AUC and the cortisol awakening response (CAR). Older adults with lower social support had a reduced AUC where younger adults with lower social support displayed a larger AUC. These findings suggest that the diurnal rhythm and awakening response of salivary cortisol are significantly reduced in older adults and the associations between anxiety, depression and social support and diurnal cortisol vary with age.

Disordered eating behaviour is associated with blunted cortisol and cardiovascular reactions to acute psychological stress

Research suggests a potential dysregulation of the stress response in individuals with bulimia nervosa. This study measured both cardiovascular and cortisol reactions to a standardised laboratory stress task in individuals identified as showing disordered eating behaviour to determine whether dysregulation of the stress response is characteristic of the two branches of the stress response system. Female students (N=455) were screened using two validated eating disorder questionnaires. Twelve women with disordered eating, including self-induced vomiting, and 12 healthy controls were selected for laboratory stress testing. Salivary cortisol and cardiovascular activity, via Doppler imaging and semi-automatic blood pressure monitoring, were measured at resting baseline and during and after exposure to a 10-min mental arithmetic stress task. Compared to controls the disordered eating group showed blunted cortisol, cardiac output, heart rate, and stroke volume reactions to the acute stress, as well as an attenuated vasodilatory reaction. These effects could not be accounted for in terms of group differences in stress task performance, subjective task impact/engagement, age, BMI, neuroticism, cardio-respiratory fitness, or co-morbid exercise dependence. Our findings suggest that disordered eating is characterised by a dysregulation of the autonomic stress-response system. As such, they add further weight to the general contention that blunted stress reactivity is characteristic of a number of maladaptive behaviours and states.

Preliminary evidence that exercise dependence is associated with blunted cardiac and cortisol reactions to acute psychological stress

Low or blunted cardiovascular and cortisol reactions to acute psychological stress have been shown to characterise those with a tobacco or alcohol dependency. The present study tested the hypothesis that exercise dependency would be similarly associated with blunted reactivity. Young female exercisers (N=219) were screened by questionnaire for exercise dependence. Ten women with probable exercise dependence and 10 non dependent controls were selected for laboratory stress testing. Cardiovascular activity and salivary cortisol were measured at rest and in response to a 10-min mental arithmetic stress task. The exercise dependent women showed blunted cardiac reactions to the stress task and blunted cortisol at 10, 20, and 30 minute post stress exposure. These effects could not be accounted for in terms of group differences in stress task performance, nor could the cardiac effects be attributed to group differences in cardio-respiratory fitness. It would seem that low stress reactivity is characteristic of a wide range of dependencies, and is not confined to substance dependence. Our results offer further support for the hypothesis that blunted stress reactivity may be a peripheral marker of a central motivational dysregulation.

Relationships and cardiovascular risk: Perceived spousal ambivalence in specific relationship contexts and its links to inflammation

OBJECTIVES Although perceiving ones social ties as sources of ambivalence has been linked to negative health outcomes, the more specific contexts by which such relationships influence health remain less studied. We thus examined if perceived spousal relationship quality in three theoretically important contexts (i.e., support, capitalization, everyday life) predicted inflammation. METHOD Ninety-four married couples completed measures of perceived spousal positivity and negativity in support, capitalization, and everyday contexts. These scores were used to derive an index of relationship ambivalence whereby interactions were rated as containing both positive and negative aspects. Serum levels of IL-6, fibrinogen, and CRP were assessed from plasma. RESULTS Perceiving ambivalence toward ones spouse in a support context was linked to greater inflammation even when considering health behaviors, relationship-specific romantic attachment style, spouse negativity/positivity ratings, and overall marital satisfaction. Perceiving ambivalence toward a spouse during capitalization predicted higher fibrinogen levels only, whereas no links were found with perceived spousal ambivalence in everyday life contexts. CONCLUSION Perceptions of ambivalence during support may be a particularly important relational context in which marital ties influence health.

Ageing, physical function, and the diurnal rhythms of cortisol and dehydroepiandrosterone

The present study examined the relationship between ageing, physical function and the diurnal rhythms of cortisol and dehydroepiandrosterone (DHEA). Participants were 36 community dwelling older adults aged between 65 and 86 years old. Salivary cortisol and DHEA were measured over the course of one day: immediately upon awakening, 30 min later, and then 3 h, 6 h, 9 h and 12 h post-awakening. Participants completed the Nottingham extended activities of daily living index, the Berg Balance Scale and their handgrip strength was assessed. Older participants had a significantly higher cortisol area under the curve (AUC), lower overall DHEA levels, lower DHEA AUC, a decreased diurnal slope of decline and increased cortisol:DHEA ratio. Lower diurnal cortisol levels were associated with poorer performance on the Berg Balance Scale and lower handgrip strength, and those with a flattened DHEA diurnal profile reported less independence in carrying out daily tasks. These associations withstood adjustment for age. In conclusion, this study suggests an association between cortisol, DHEA, ageing and physical function.

Aging, Health Behaviors, and the Diurnal Rhythm and Awakening Response of Salivary Cortisol

Background/Study Context: The cortisol diurnal rhythm has previously been examined in relation to age and health behaviors. However, less is known about the relationship between multiple health behaviors and diurnal cortisol in the context of aging, where it is possible that the impact of health behaviors on cortisol varies as a function of age. This study compared the awakening response and diurnal rhythm of cortisol in young versus older adults in relation to health behaviors. Methods: Twenty-four young students (aged 18–22) and 48 community-dwelling older adults (aged 65–88) completed an assessment of health behaviors (exercise, smoking, sleep, diet, alcohol) over the past year. Salivary cortisol was measured over the course of 1 day: immediately upon awakening, 30 min later, and then 3, 6, 9, and 12 h post awakening. Repeated measures/univariate analysis of variance (ANOVA) was used to test main effects of age and health behaviors, and any interaction effects in relation to diurnal cortisol. Results: Older adults displayed significantly reduced cortisol upon awakening, a lower cortisol awakening response, and a flatter diurnal profile represented by a reduced area under the curve and cortisol slope. There was also a significant interaction of age, cortisol, and diet; younger adults with a higher fat and lower fruit and vegetable intake exhibited the flattened diurnal cortisol phenotype of the older adults. Conclusion: These findings suggest that the diurnal rhythm and awakening response of salivary cortisol is significantly reduced in older adults and that variations in the cortisol diurnal rhythm of younger adults are associated with dietary factors. Younger adults with a poor quality of food intake may be vulnerable to a reduction in the amplitude of the cortisol diurnal profile and this may have implications for other aspects of health.

Physical Activity, Life Events Stress, Cortisol, and DHEA: Preliminary Findings That Physical Activity May Buffer Against the Negative Effects of Stress

The present study examined the relationship between habitual physical activity, life events stress, the diurnal rhythms of cortisol and DHEA, and the cortisol:dehydroepiandrosterone (DHEA) ratio in older adults. Thirty-six participants aged ≥ 65 reported their habitual physical activity, and indicated if a particular event happened to them in the past year (stress incidence) and how stressful they perceived the event to be (stress severity). Older adults with higher stress severity demonstrated a significantly higher cortisol:DHEA ratio. Individuals with higher stress incidence scores and who did not participate in aerobic exercise had a significantly higher cortisol:DHEA ratio and flatter DHEA diurnal rhythm compared with those who regularly participated in aerobic exercise. In conclusion, life events stress may have a negative impact on the cortisol:DHEA ratio in older adults. Under conditions of high stress exposure, exercise may protect older adults from an increased cortisol:DHEA ratio and flatter DHEA diurnal rhythm.

Development of a rapid and quantitative lateral flow assay for the simultaneous measurement of serum κ and λ immunoglobulin free light chains (FLC): inception of a new near-patient FLC screening tool

Abstract Background: Serum free light chains (FLC) are sensitive biomarkers used for the diagnosis and management of plasma cell dyscrasias, such as multiple myeloma (MM), and are central to clinical screening algorithms and therapy response criteria. We have developed a portable, near-patient, lateral-flow test (Seralite®) that quantitates serum FLC in 10 min, and is designed to eliminate sample processing delays and accelerate decision-making in the clinic. Methods: Assay interference, imprecision, lot-to-lot variability, linearity, and the utility of a competitive-inhibition design for the elimination of antigen-excess (‘hook effect’) were assessed. Reference ranges were calculated from 91 healthy donor sera. Preliminary clinical validation was conducted by retrospective analysis of sera from 329 patients. Quantitative and diagnostic results were compared to Freelite®. Results: Seralite® gave a broad competitive-inhibition calibration curve from below 2.5 mg/L to above 200 mg/L, provided good assay linearity (between 1.6 and 208.7 mg/L for κ FLC and between 3.5 and 249.7 mg/L for λ FLC) and sensitivity (1.4 mg/L for κ FLC and 1.7 mg/L for λ FLC), and eliminated anomalous results from antigen-excess. Seralite® gave good diagnostic concordance with Freelite® (Roche Hitachi Cobas C501) identifying an abnormal FLC ratio and FLC difference in 209 patients with newly diagnosed MM and differentiating these patients from normal healthy donors with polyclonal FLC. Conclusions: Seralite® sensitively quantitates FLC and rapidly identifies clinical conditions where FLC are abnormal, including MM.

Serum free light chains are reduced in endurance trained older adults: Evidence that exercise training may reduce basal inflammation in older adults

Traditionally, free light chains (FLCs) are used as key serum biomarkers in the diagnosis and monitoring of plasma cell malignancies, but polyclonal FLCs can also be used as an accurate real-time indicator of immune-activation and inflammation. The primary aim of the present study was to assess the effects of exercise training status on serum FLCs in older adults, and secondly, to examine if training status moderated serum FLC responses to acute exercise. Kappa and lambda serum FLC levels were measured in 45 healthy older adults (aged ≥ 60 years) who were either sedentary, physically active or endurance trained. FLCs were measured at baseline and in response to an acute bout of submaximal exercise. The endurance trained group had significantly lower levels of kappa and lambda serum FLCs compared with physically active or sedentary elderly adults; these effects were independent of age, BMI and renal function. There was no significant difference in whole immunoglobulins between groups. Exercise training status had no effect on serum FLC responses to acute exercise, which were marginal. In conclusion, endurance training was associated with lower FLC levels compared with less physically active individuals. These findings suggest that long-term endurance training may be beneficial in reducing basal inflammation in older adults as well as elevated FLCs present in inflammatory and autoimmune conditions, often associated with ageing. FLCs may serve as a useful biomarker for monitoring the efficacy of exercise intervention studies in healthy and clinical populations.

Response comparison of multiple myeloma and monoclonal gammopathy of undetermined significance to the same anti-myeloma therapy: a retrospective cohort study

BACKGROUND Multiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), which is usually only treated by a form of anti-multiple myeloma therapy if it is causing substantial disease through deposition of secreted M proteins. However, studies comparing how MGUS and multiple myeloma plasma cell clones respond to these therapies are scarce. Biclonal gammopathy multiple myeloma is characterised by the coexistence of an active multiple myeloma clone and a benign MGUS clone, and thus provides a unique model to assess the responses of separate clones to the same anti-multiple myeloma therapy, in the same patient, at the same time. We aimed to identify how MGUS and multiple myeloma plasma cell clones responded to anti-multiple myeloma therapy in patients newly diagnosed with biclonal gammopathy multiple myeloma. METHODS In this retrospective cohort study, we identified patients with biclonal gammopathy multiple myeloma by central laboratory analysis of 6399 newly diagnosed patients with multiple myeloma enrolled in three UK clinical trials (Myeloma IX, Myeloma XI, and TEAMM) between July 7, 2004, and June 2, 2015. In addition to the inclusion criteria of these trials, our study necessitated at trial entry the presence of two distinct M proteins in immunofixation electrophoresis. The primary endpoint was difference in response achieved with anti-multiple myeloma therapy on MGUS (which we defined as M2) and multiple myeloma (M1) clones-overall, within patients, and between therapy types-with international therapy response criteria assessed with χ2 analyses. We analysed by intention to treat. FINDINGS 44 patients with biclonal gammopathy multiple myeloma with IgG or IgA MGUS clones were subsequently identified from the three trials and then longitudinally monitored. 41 (93%) of M1 clones had a response to therapy (either complete response, very good partial response, partial response, or minor response) compared with only 28 (64%) of M2 clones (p=0·0010). For the 20 patients who received intensive therapy, there was no difference between the proportion of responding clones in M1 (19 [95%]) and M2 (15 [75%], p=0·13). However, for the 17 patients who received non-intensive therapy, 16 (94%) of M1 clones had a response compared with ten [59%] of M2 clones (p=0·031). When examining clones within the same patient, 30 (68%) of 44 individual patients had different levels of responses within the M1 and M2 clones. One patient exhibited M2 progression to myeloma and subsequently died. INTERPRETATION These results show that, in patients with biclonal gammopathy multiple myeloma, anti-multiple myeloma therapies exert a greater depth of response against multiple myeloma plasma cell clones than MGUS plasma cell clones. Although some MGUS clones exhibited a complete response, many did not respond, which suggests that the underlying features that render multiple myeloma plasma cells susceptible to therapy are present in only some MGUS plasma cell clones. To determine MGUS clone susceptibly to therapy, future studies might seek to identify, with biclonal gammopathy multiple myeloma as an investigative model, the genetic and epigenetic alterations that affect whether MGUS plasma cell clones are responsive to anti-multiple myeloma therapy. FUNDING National Institute of Health Research, Medical Research Council, and Cancer Research UK.