The combined association of psychological distress and socioeconomic status with all-cause mortality: a national cohort study.

Background Psychological distress and low socioeconomic status (SES) are recognized risk factors for mortality. The aim of this study was to test whether lower SES amplifies the effect of psychological distress on all-cause mortality. Methods We selected 66 518 participants from the Health Survey for England who were 35 years or older, free of cancer and cardiovascular disease at baseline, and living in private households in England from 1994 to 2004. Selection used stratified random sampling, and participants were linked prospectively to mortality records from the Office of National Statistics (mean follow-up, 8.2 years). Psychological distress was measured using the 12-item General Health Questionnaire, and SES was indexed by occupational class. Results The crude incidence rate of death was 14.49 (95% CI, 14.17-14.81) per 1000 person-years. After adjustment for age and sex, psychological distress and low SES category were associated with increased mortality rates. In a stratified analysis, the association of psychological distress with mortality differed with SES (likelihood ratio test–adjusted P < .001), with the strongest associations being observed in the lowest SES categories. Conclusions The detrimental effect of psychological distress on mortality is amplified by low SES category. People in higher SES categories have lower mortality rates even when they report high levels of psychological distress. Psychological distress is becoming recognized increasingly as a risk factor for mortality and a trigger for cardiovascular disease (CVD) events.1- 3 Socioeconomic status (SES) is also a recognized determinant of health status: in developed countries, lower SES levels signal worse health. Even in the most affluent countries, people in lower SES levels have considerably shorter life expectancies and more disease than people in higher SES levels,4- 6 and low SES levels are associated with a high risk for CVD and death in developed countries, such as England.7 People in higher SES categories may have greater economic, social, and psychological resources and better coping strategies for dealing with adversity.8 These assets may be acquired through learning or better access to resources. Consequently, when both risk factors are present (high levels of psychological distress and low SES levels), we can argue that the resulting effect on mortality is not the mere sum of the two (additive effect) but that some extra risk may appear (multiplicative effect). We therefore hypothesized that SES can operate as an amplifier of psychological distress and that the effect of psychological distress on mortality would be greater in groups with lower compared with higher SES levels. As a consequence, vulnerable populations of adults may be more susceptible to the detrimental effects of psychological distress and may have unmet health care needs. Identifying people who are more vulnerable to the health consequences of psychological distress may have clinical and public health implications. For example, questionnaires such as the 12-item General Health Questionnaire (GHQ-12) could be of value in systematic screening by family physicians with the aim of improving the recognition rate of common mental disorders and thereby reducing the risk for CVD and other fatal conditions. We sought to analyze the association of psychological distress and low SES levels on the incidence of all-cause mortality, with an emphasis on the interaction between both risk factors

Objectively assessed physical activity, adiposity, and inflammatory markers in people with type 2 diabetes.

OBJECTIVE: Inflammatory processes may play an important role in the development of acute coronary syndromes in people with type 2 diabetes; thus, strategies to control inflammation are of clinical importance. We examined the cross-sectional association between objectively assessed physical activity and inflammatory markers in a sample of people with type 2 diabetes. METHODS: Participants were 71 men and 41 women (mean age=63.9±7 years), without a history of cardiovascular disease, drawn from primary care clinics. Physical activity was objectively measured using waist-worn accelerometers (Actigraph GT3X) during waking hours for seven consecutive days. RESULTS: We observed inverse associations between moderate-to-vigorous physical activity (per 10 min) with plasma interleukin-6 (B=-0.035, 95% CI -0.056 to -0.015), interleukin-1ra (B=-0.033, 95% CI -0.051 to -0.015), and monocyte chemotactic protein-1 (B=-0.011, 95% CI -0.021 to 0.000). These associations largely persisted in multivariable adjusted models, although body mass index considerably attenuated the effect estimate. CONCLUSIONS: These data demonstrate an inverse association between physical activity and inflammatory markers in people with type 2 diabetes

Blunted glucocorticoid and mineralocorticoid sensitivity to stress in people with diabetes.

Psychological stress may contribute to type 2 diabetes but mechanisms are still poorly understood. In this study, we examined whether stress responsiveness is associated with glucocorticoid and mineralocorticoid sensitivity in a controlled experimental comparison of people with type 2 diabetes and non-diabetic participants. Thirty-seven diabetes patients and 37 healthy controls underwent psychophysiological stress testing. Glucocorticoid (GR) and mineralocorticoid sensitivity (MR) sensitivity were measured by dexamethasone- and prednisolone-inhibition of lipopolysaccharide (LPS)-induced interleukin (IL) 6 levels, respectively. Blood pressure (BP) and heart rate were monitored continuously, and we periodically assessed salivary cortisol, plasma IL-6 and monocyte chemotactic protein (MCP-1). Following stress, both glucocorticoid and mineralocorticoid sensitivity decreased among healthy controls, but did not change in people with diabetes. There was a main effect of group on dexamethasone (F(1,74)=6.852, p=0.013) and prednisolone (F(1,74)=7.295, p=0.010) sensitivity following stress at 45 min after tasks. People with diabetes showed blunted stress responsivity in systolic BP, diastolic BP, heart rate, IL-6, MCP-1, and impaired post-stress recovery in heart rate. People with Diabetes had higher cortisol levels as measured by the total amount excreted over the day and increased glucocorticoid sensitivity at baseline. Our study suggests that impaired stress responsivity in type-2 diabetes is in part due to a lack of stress-induced changes in mineralocorticoid and glucocorticoid sensitivity

Assessing the translational feasibility of pharmacological drug memory reconsolidation blockade with memantine in quitting smokers.

RATIONALE: Preclinical reconsolidation research offers the first realistic opportunity to pharmacologically weaken the maladaptive memory structures that support relapse in drug addicts. N-methyl D-aspartate receptor (NMDAR) antagonism is a highly effective means of blocking drug memory reconsolidation. However, no research using this approach exists in human addicts. OBJECTIVES: The objective of this study was to assess the potential and clinical outcomes of blocking the reconsolidation of cue-smoking memories with memantine in quitting smokers. METHODS: Fifty-nine dependent and motivated to quit smokers were randomised to one of three groups receiving the following: (1) memantine with or (2) without reactivation of associative cue-smoking memories or (3) reactivation with placebo on their target quit day in a double-blind manner. Participants aimed to abstain from smoking for as long as possible. Levels of smoking and FTND score were assessed prior to intervention and up to a year later. Primary outcome was latency to relapse. Subjective craving measures and attentional bias to smoking cues were assessed in-lab. RESULTS: All study groups successfully reduced their smoking up to 3 months. Memantine in combination with smoking memory reactivation did not affect any measure of smoking outcome, reactivity or attention capture to smoking cues. CONCLUSIONS: Brief exposure to smoking cues with memantine did not appear to weaken these memory traces. These findings could be due to insufficient reconsolidation blockade by memantine or failure of exposure to smoking stimuli to destabilise smoking memories. Research assessing the treatment potential of reconsolidation blockade in human addicts should focus on identification of tolerable drugs that reliably block reward memory reconsolidation and retrieval procedures that reliably destabilise strongly trained memories

ILB® attenuates clinical symptoms and serum biomarkers of oxidative/nitrosative stress and mitochondrial dysfunction in patients with Amyotrophic Lateral Sclerosis

Oxidative/nitrosative stress and mitochondrial dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS), an invariably fatal progressive neurodegenerative disease. Here, as an exploratory arm of a phase II clinical trial (EudraCT Number 2017-005065-47), we used high performance liquid chromatography(HPLC) to investigate changes in the metabolic profiles of serum from ALS patients treated weekly for 4 weeks with a repeated sub-cutaneous dose of 1 mg/kg of a proprietary low molecular weight dextran sulphate, called ILB®. A significant normalization of the serum levels of several key metabolites was observed over the treatment period, including N-acetylaspartate (NAA), oxypurines, biomarkers of oxidative/nitrosative stress and antioxidants. An improved serum metabolic profile was accompanied by significant amelioration of the patients' clinical conditions, indicating a response to ILB® treatment that appears to be mediated by improvement of tissue bioenergetics, decrease of oxidative/nitrosative stress and attenuation of (neuro)inflammatory processes

Hostility and physiological responses to acute stress in people with type 2 diabetes.

OBJECTIVE: Hostility is associated with cardiovascular mortality and morbidity, and one of the mechanisms may involve heightened reactivity to mental stress. However, little research has been conducted in populations at high risk for cardiovascular disease. The aim of the present study was to assess the relationship between hostility and acute stress responsivity in individuals with Type 2 diabetes. METHODS: A total of 140 individuals (median age [standard deviation] 63.71 [7.00] years) with Type 2 diabetes took part in laboratory-based experimental stress testing. Systolic blood pressure, diastolic blood pressure, heart rate, plasma interleukin-6 (IL-6), and salivary cortisol were assessed at baseline, during two stress tasks, and 45 and 75 minutes later. Cynical hostility was assessed using the Cook Medley Cynical Hostility Scale. RESULTS: Participants with greater hostility scores had heightened increases in IL-6 induced by the acute stress tasks (B = 0.082, p = .002), independent of age, sex, body mass index, smoking, household income, time of testing, medication, and baseline IL-6. Hostility was inversely associated with cortisol output poststress (B = -0.017, p = .002), independent of covariates. No associations between hostility and blood pressure or heart rate responses were observed. CONCLUSIONS: Hostile individuals with Type 2 diabetes may be susceptible to stress-induced increases in inflammation. Further research is needed to understand if such changes increase the risk of cardiovascular disease in this population

Planar AFM macro-probes to study the biomechanical properties of large cells and 3D cell spheroids

The ability to measure mechanical response of cells under applied load is essential for developing more accurate models of cell mechanics and mechanotransduction. Living cells have been mechanically investigated by several approaches. Among them, atomic force microscopy (AFM) is widely used thanks to its high versatility and sensitivity. In the case of large cells or 3D multicellular aggregates, standard AFM probes may not be appropriate to investigate the mechanical properties of the whole biological system. Owing to their size, standard AFM probes can compress only a single somatic cell or part of it. To fill this gap, we have designed and fabricated planar AFM macro-probes compatible with commercial AFM instruments. The probes are constituted of a large flat compression plate, connected to the chip by two flexible arms, whose mechanical characteristics are tuned for specific biological applications. As proof of concept, we have used the macro-probes to measure the viscoelasticity of large spherical biological systems, which have a diameter above 100 \u3bcm: human oocytes and 3D cell spheroids. Compression experiments are combined with visual inspection, using a side-view configuration imaging, which allows us to monitor the sample morphology during the compression and to correlate it with the viscoelastic parameters. Our measurements provide a quantitative estimate of the relaxation times of such biological systems, which are discussed in relation to data present in literature. The broad applicability of the AFM macro-probes can be relevant to study the biomechanical features in any biological process involving large soft materials. Statement of Significance: The understanding of the role of physical factors in defining cell and tissue functions requires to develop new methods or improve the existing ones to accurately measure the biomechanical properties. AFM is a sensitive and versatile tool to measure the mechanical features from single proteins to single cells. When cells or cell aggregates exceed few tens of microns, AFM suffers from limitations. On these biological systems the control of the contact area and the application of a precise uniform compression becomes crucial. A modification of the standard cantilevers fabrication allowed us obtaining AFM macro-probes, having large planar contact area and spring constant suitable for biological investigations. They were demonstrated valuable to characterize the mechanical properties of large hierarchical biological systems

Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multicentre nation-wide cohort

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusion-dependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX).We developed a multicentre follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95%CI=6.3-13.1). Multiple Cox regression analysis identified 3 key predictors: age showed a positive log-linear effect (adjusted HR for 50% increase=1.2, 95%CI=1.1-1.3, P=0.005), the serum concentration of thyrotropin (TSH) showed a positive linear effect (adjusted HR for 1 mIU/L increase=1.3, 95%CI=1.1-1.4, P