Predictive Value of Depressive Symptoms for All-Cause Mortality: Findings From the PRIME Belfast Study Examining the Role of Inflammation and Cardiovascular Risk Markers

OBJECTIVES: To improve understanding about the potential underlying biological mechanisms in the link between depression and all-cause mortality and to investigate the role that inflammatory and other cardiovascular risk factors may play in the relationship between depressive symptoms and mortality.

METHODS: Depression and blood-based biological markers were assessed in the Belfast PRIME prospective cohort study (N = 2389 men, aged 50-59 years) in which participants were followed up for 18 years. Depression was measured using the 10-item Welsh Pure Depression Inventory. Inflammation markers (C-reactive protein [CRP], neopterin, interleukin [IL]-1 receptor antagonist [IL-1Ra], and IL-18) and cardiovascular-specific risk factors (N-terminal pro-b-type natriuretic peptide, midregion pro-atrial natriuretic peptide, midregion pro-adrenomedullin, C-terminal pro-endothelin-1 [CT-proET]) were obtained at baseline. We used Cox proportional hazards modeling to examine the association between depression and biological measures in relation to all-cause mortality and explore the mediating effects.

RESULTS: During follow-up, 418 participants died. Higher levels of depressive symptoms were associated with higher levels of CRP, IL-1Ra, and CT-proET. After adjustment for socioeconomic and life-style risk factors, depressive symptoms were significantly associated with all-cause mortality (hazard ratio = 1.10 per scale unit, 95% confidence interval = 1.04-1.16). This association was partly explained by CRP (7.3%) suggesting a minimal mediation effect. IL-1Ra, N-terminal pro-b-type natriuretic peptide, midregion pro-atrial natriuretic peptide, midregion pro-adrenomedullin, and CT-proET contributed marginally to the association between depression and subsequent mortality.

CONCLUSIONS: Inflammatory and cardiovascular risk markers are associated with depression and with increased mortality. However, depression and biological measures show additive effects rather than a pattern of meditation of biological factors in the association between depression and mortality.

A Role for Behavior in the Relationships Between Depression and Hostility and Cardiovascular Disease Incidence, Mortality, and All-Cause Mortality: the Prime Study

BACKGROUND: Behavioral factors are important in disease incidence and mortality and may explain associations between mortality and various psychological traits.

PURPOSE: These analyses investigated the impact of behavioral factors on the associations between depression, hostility and cardiovascular disease(CVD) incidence, CVD mortality, and all-cause mortality.

METHODS: Data from the PRIME Study (N = 6953 men) were analyzed using Cox proportional hazards models, following adjustment for demographic and biological CVD risk factors, and other psychological traits, including social support.

RESULTS: Following initial adjustment, both depression and hostility were significantly associated with both mortality outcomes (smallest SHR = 1.24, p < 0.001). Following adjustment for behavioral factors, all relationships were attenuated both when accounting for and not accounting for other psychological variables. Associations with all-cause mortality remained significant (smallest SHR = 1.14, p = 0.04). Of the behaviors included, the most significant contribution to outcomes was found for smoking, but a role was also found for fruit and vegetable intakes and high alcohol consumption.

CONCLUSIONS: These findings demonstrate well-known associations between depression, hostility, and mortality and suggest the potential importance of behaviors in explaining these relationships.

NAA and STS effects on bract survival time, carbohydrate content, respiration rate and carbohydrate balance of potted Bougainvillea spectabilis Willd

The aims of this work were to deepen the knowledge on the physiology of bract abscission in Bougainvillea spectabilis ‘Killie Campbell’ plants, in what relates to respiration and carbon balance. Using the effects induced by Silver Thiosulphate (STS) and/or Naphtalene Acetic Acid (NAA, at high concentration: 500 mg.l-1) on bract abscission under interior conditions, the relationship between bract survival time (longevity) and, respiration rate or carbohydrate levels, was investigated. Treatments that included NAA were the ones that reduced significantly bract abscission. Unexpectedly, the higher the levels of bract soluble and total carbohydrates, measured at day 10 postproduction (PP), the higher the abscission of bracts. These results show, for the first time, that abscission can positively correlate with non structural carbohydrates levels in the organ that abscise. Bract respiration rate was significantly affected by treatment and postproduction day (PP). Treatments that had higher bract respiration rates (WATER and STS) also had higher levels of non structural carbohydrates in the bracts. Bract respiration rate decreased from day 10 to day 17 PP by approximately 50% (on average of all treatments) and was negatively correlated with bract survival time. In the carbon balance per gram of bract dry weight, the treatments WATER and STS, showed the largest decrease in the content of total carbohydrates and had the highest consumption of carbohydrates through respiration. So, these were the bracts that needed to import a higher amount of carbohydrates per gram of bract dry weight. In the carbon balance for the whole mass of bracts and adjacent stems in an average plant, the treatments WATER and STS continued to allow for the largest decreases in total carbohydrate during postproduction. However, and contradicting the results per gram of bract dry weight, the highest total consumption of carbohydrates by respiration was obtained for the NAA and STS+NAA treatments. It makes sense that bracts that last longer have lower individual carbon consumption while, at the plant level, the increased number of remaining bracts causes a higher overall expenditure. Respiration rate has been used as an indicator of flower longevity, this correlation is here extended for the flower+bract system. Plants that had higher bract respiration rates, most probably, had a higher flow of carbohydrates through the bracts (and flowers), which, in the end, was sensed as a higher carbohydrate level.

Top Three Pharmacogenomics and Personalized Medicine Applications at the Nexus of Renal Pathophysiology and Cardiovascular Medicine.

Pharmacogenomics is a field with origins in the study of monogenic variations in drug metabolism in the 1950s. Perhaps because of these historical underpinnings, there has been an intensive investigation of 'hepatic pharmacogenes' such as CYP450s and liver drug metabolism using pharmacogenomics approaches over the past five decades. Surprisingly, kidney pathophysiology, attendant diseases and treatment outcomes have been vastly under-studied and under-theorized despite their central importance in maintenance of health, susceptibility to disease and rational personalized therapeutics. Indeed, chronic kidney disease (CKD) represents an increasing public health burden worldwide, both in developed and developing countries. Patients with CKD suffer from high cardiovascular morbidity and mortality, which is mainly attributable to cardiovascular events before reaching end-stage renal disease. In this paper, we focus our analyses on renal function before end-stage renal disease, as seen through the lens of pharmacogenomics and human genomic variation. We herein synthesize the recent evidence linking selected Very Important Pharmacogenes (VIP) to renal function, blood pressure and salt-sensitivity in humans, and ways in which these insights might inform rational personalized therapeutics. Notably, we highlight and present the rationale for three applications that we consider as important and actionable therapeutic and preventive focus areas in renal pharmacogenomics: 1) ACE inhibitors, as a confirmed application, 2) VDR agonists, as a promising application, and 3) moderate dietary salt intake, as a suggested novel application. Additionally, we emphasize the putative contributions of gene-environment interactions, discuss the implications of these findings to treat and prevent hypertension and CKD. Finally, we conclude with a strategic agenda and vision required to accelerate advances in this under-studied field of renal pharmacogenomics with vast significance for global public health.

Macronutrients and energy balance in obesity.

Energy balance is the difference between metabolizable energy intake and total energy expenditure. Energy intake is difficult to measure accurately; changes in body weight, for example, are not a good measure of the adequacy of energy intake, because fluctuations in body weight are common even if the overall trend is toward weight loss. It is now customary to assess energy requirements indirectly from total energy expenditure. Total energy expenditure consists of basal metabolism, postprandial thermogenesis, and physical activity. Energy expenditure is related to both body weight and body composition. A reduction in total energy expenditure accompanies weight loss, because basal metabolic rate decreases with the loss of lean tissue mass. Similarly, with weight gain, there is an increase in basal metabolic rate, because lean tissue mass grows to support the increase in fat tissue mass. Excess energy intake over energy expenditure causes weight gain and an accompanying increase in total energy expenditure. Following a period of adaptation, total energy expenditure will match energy intake and body weight will stabilize at a higher level. This same relationship holds for weight loss. Respiratory quotient (measured in steady state) is an indication of the proportion of energy expenditure derived from fat and carbohydrate oxidation. Over long periods of time, fat balance is equivalent to energy balance, as an excess of fat intake over fat oxidation causes fat storage.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Sodium and potassium balance depends on αENaC expression in connecting tubule.

Mutations in α, β, or γ subunits of the epithelial sodium channel (ENaC) can downregulate ENaC activity and cause a severe salt-losing syndrome with hyperkalemia and metabolic acidosis, designated pseudohypoaldosteronism type 1 in humans. In contrast, mice with selective inactivation of αENaC in the collecting duct (CD) maintain sodium and potassium balance, suggesting that the late distal convoluted tubule (DCT2) and/or the connecting tubule (CNT) participates in sodium homeostasis. To investigate the relative importance of ENaC-mediated sodium absorption in the CNT, we used Cre-lox technology to generate mice lacking αENaC in the aquaporin 2-expressing CNT and CD. Western blot analysis of microdissected cortical CD (CCD) and CNT revealed absence of αENaC in the CCD and weak αENaC expression in the CNT. These mice exhibited a significantly higher urinary sodium excretion, a lower urine osmolality, and an increased urine volume compared with control mice. Furthermore, serum sodium was lower and potassium levels were higher in the genetically modified mice. With dietary sodium restriction, these mice experienced significant weight loss, increased urinary sodium excretion, and hyperkalemia. Plasma aldosterone levels were significantly elevated under both standard and sodium-restricted diets. In summary, αENaC expression within the CNT/CD is crucial for sodium and potassium homeostasis and causes signs and symptoms of pseudohypoaldosteronism type 1 if missing.

Did Dumbo suffer a heart attack? independent association between earlobe crease and cardiovascular disease.

BACKGROUND: Earlobe crease (ELC) has been associated with cardiovascular diseases (CVD) or risk factors (CVRF) and could be a marker predisposing to CVD. However, most studies studied only a small number of CVRF and no complete assessment of the associations between ELC and CVRF has been performed in a single study. METHODS: Population-based study (n = 4635, 46.7 % men) conducted between 2009 and 2012 in Lausanne, Switzerland. RESULTS: Eight hundred six participants (17.4 %) had an ELC. Presence of ELC was associated with male gender and older age. After adjusting for age and gender (and medication whenever necessary), presence of ELC was significantly (p < 0.05) associated with higher levels of body mass index (BMI) [adjusted mean ± standard error: 27.0 ± 0.2 vs. 26.02 ± 0.07 kg/m(2)], triglycerides [1.40 ± 0.03 vs. 1.36 ± 0.01 mmol/L] and insulin [8.8 ± 0.2 vs. 8.3 ± 0.1 μIU/mL]; lower levels of HDL cholesterol [1.61 ± 0.02 vs. 1.64 ± 0.01 mmol/L]; higher frequency of abdominal obesity [odds ratio and (95 % confidence interval) 1.20 (1.02; 1.42)]; hypertension [1.41 (1.18; 1.67)]; diabetes [1.43 (1.15; 1.79)]; high HOMA-IR [1.19 (1.00; 1.42)]; metabolic syndrome [1.28 (1.08; 1.51)] and history of CVD [1.55 (1.21; 1.98)]. No associations were found between ELC and estimated cardiovascular risk, inflammatory or liver markers. After further adjustment on BMI, only the associations between ELC and hypertension [1.30 (1.08; 1.56)] and history of CVD [1.47 (1.14; 1.89)] remained significant. For history of CVD, further adjustment on diabetes, hypertension, total cholesterol and smoking led to similar results [1.36 (1.05; 1.77)]. CONCLUSION: In this community-based sample ELC was significantly and independently associated with hypertension and history of CVD.

ERP and cardiovascular correlates of source memory discrimination in older and younger adults /

There is much evidence to support an age-related decline in source memory ability. However, the underlying mechanisms responsible for this decline are not well understood. The current study was carried out to determine the electrophysiological correlates of source memory discrimination in younger and older adults. Event-related potentials (ERPs) and continuous electrocardiographic (ECG) data were collected from younger (M= 21 years) and older (M= 71 years) adults during a source memory task. Older adults were more likely to make source memory errors for recently repeated, non-target words than were younger adults. Moreover, their ERP records for correct trials showed an increased amplitude in the late positive (LP) component (400-800 msec) for the most recently presented, non-target stimuli relative to the LP noted for target items. Younger adults showed an opposite pattern, with a large LP component for target items, and a much smaller LP component for the recently repeated non-target items. Computation of parasympathetic activity in the vagus nerve was performed on the ECG data (Porges, 1985). The resulting measure, vagal tone, was used as an index of physiological responsivity. The vagal tone index of physiological responsivity was negatively related to the LP amplitude for the most recently repeated, non-target words in both groups, after accounting for age effects. The ERP data support the hypothesis that the tendency to make source memory errors on the part of older adults is related to the ability to selectively control attentional processes during task performance. Furthermore, the relationship between vagal tone and ERP reactivity suggests that there is a physiological basis to the heightened reactivity measured in the LP response to recently repeated non-target items such that, under decreased physiological resources, there is an impairment in the ability to selectively inhibit bottom-up, stimulus based properties in favour of task-related goals in older adults. The inconsistency of these results with other explanatory models of source memory deficits is discussed. It is concluded that the data are consistent with a physiological reactivity model requiring inhibition of reactivity to irrelevant, but perceptually-fluent, stimuli.

Hyperosmotic Stress and the Impact on Metabolite Formation and Redox Balance in Saccharomyces cerevisiae and Saccharomyces bayanus strains

Wine produced using an appassimento-type process represents a new and exciting innovation for the Ontario wine industry. This process involves drying grapes that have already been picked from the vine, which increases the sugar content due to dehydration and induces a variety of changes both within and on the surface of the grapes. Increasing sugar contents in musts subject wine yeast to conditions of high osmolarity during alcoholic fermentations. Under these conditions, yeast growth can be inhibited, target alcohol levels may not be attained and metabolic by-products of the hyperosmotic stress response, including glycerol and acetic acid, may impact wine composition. The further metabolism of acetic acid to acetylCoA by yeast facilitates the synthesis of ethyl acetate, a volatile compound that can also impact wine quality if present in sufficiently high concentrations. The first objective of this project was to understand the effect of yeast strain and sugar concentration on fermentation kinetics and metabolite formation, notably acetic acid and ethyl acetate, during fermentation in appassimento-type must. Our working hypotheses were that (1) the natural isolate Saccharomyces bayanus would produce less acetic acid and ethyl acetate compared to Saccharomyces cerevisiae strain EC-1118 fermenting the high and low sugar juices; (2) the wine produced using the appassimento process would contain higher levels of acetic acid and lower levels of ethyl acetate compared to table wine; (3) and the strains would be similar in the kinetic behavior of their fermentation performances in the high sugar must. This study determined that the S. bayanus strain produced significantly less acetic acid and ethyl acetate in the appassimento wine and table wine fermentations. Differences in acetic acid and ethyl acetate production were also observed within strains fermenting the two sugar conditions. Acetic acid production was higher in table wine fermented by S. bayanus as no acetic acid was produced in appassimento-style wine, and 1.4-times higher in appassimento wine fermented by EC-1118 over that found in table wine. Ethyl acetate production was 27.6-times higher in table wine fermented by S. bayanus, and 5.2-times higher by EC-1118, compared to that in appassimento wine. Sugar utilization and ethanol production were comparable between strains as no significant differences were determined. The second objective of this project was to bring a method in-house for measuring the concentration of pyridine nucleotides, NAD+, NADP+, NADH and NADPH, in yeast cytosolic extract. Development of this method is of applicative interest for our lab group as it will enable the redox balance of the NAD+/ NADH and NADP+/ NADPH systems to be assessed during high sugar fermentations to determine their respective roles as metabolic triggers for acetic acid production. Two methods were evaluated in this study including a UV-endpoint method using a set of enzymatic assay protocols outlined in Bergmeyer (1974) and a colorimetric enzyme cycling method developed by Sigma-Aldrich® using commercial kits. The former was determined to be limited by its low sensitivity following application to yeast extract and subsequent coenzyme analyses, while the latter was shown to exhibit greater sensitivity. The results obtained from the kits indicated high linearity, accuracy and precision of the analytical method for measuring NADH and NADPH, and that it was sensitive enough to measure the low coenzyme concentrations present in yeast extract samples. NADtotal and NADPtotal concentrations were determined to be above the lower limit of quantification and within the range of the respective calibration curves, making this method suitable for our research purposes.

Alley cropping of willows and grassland for bioenergy provision: productivity, tree-crop interactions and energy balance

The demand for biomass for bioenergy has increased rapidly in industrialized countries in the recent years. Biogenic energy carriers are known to reduce CO2 emissions. However, the resource-inefficient production of biomass often caused negative impacts on the environment, e.g. biodiversity losses, nitrate leaching, and erosion. The detrimental effects evolved mainly from annual crops. Therefore, the aim of modern bioenergy cropping systems is to combine yield stability and environmental benefits by the establishment of mixed-cropping systems. A particular emphasis is on perennial crops which are perceived as environmentally superior to annual crops. Agroforestry systems represent such mixed perennial cropping systems and consist of a mix of trees and arable crops or grassland within the same area of land. Agroforestry practices vary across the globe and alley cropping is a type of agroforestry system which is well adapted to the temperate zone, with a high degree of mechanization. Trees are planted in rows and crops are planted in the alleyways, which facilitates their management by machinery. This study was conducted to examine a young alley cropping system of willows and two grassland mixtures for bioenergy provision under temperate climate conditions. The first part of the thesis identified possible competition effects between willows and the two grassland mixtures. Since light seemed to be the factor most affecting the yield performance of the understory in temperate agroforestry systems, a biennial in situ artificial shade experiment was established over a separate clover-grass stand to quantify the effects of shade. Data to possible below- and aboveground interactions among willows and the two grassland mixtures and their effects on productivity, sward composition, and quality were monitored along a tree-grassland interface within the alleys. In the second part, productivity of the alley cropping system was examined on a triennial time frame and compared to separate grassland and willow stands as controls. Three different conversion technologies (combustion of hay, integrated generation of solid fuel and biogas from biomass, whole crop digestion) were applied to grassland biomass as feedstock and analyzed for its energetic potential. The energetic potential of willow wood chips was calculated by applying combustion as conversion technique. Net energy balances of separate grassland stands, agroforestry and pure willow stands evaluated their energy efficiency. Results of the biennial artificial shade experiment showed that severe shade (80 % light reduction) halved grassland productivity on average compared to a non-shaded control. White clover as heliophilous plant responded sensitively to limited radiation and its dry matter contribution in the sward decreased with increasing shade, whereas non-leguminous forbs (mainly segetal species) benefited. Changes in nutritive quality could not be confirmed by this experiment. Through the study on interactions within the alleys of the young agroforestry system it was possible to outline changes of incident light, soil temperature and sward composition of clover-grass along the tree-grassland interface. Nearly no effects of trees on precipitation, soil moisture and understory productivity occurred along the interface during the biennial experiment. Considering the results of the productivity and the net energy yield alley cropping system had lower than pure grassland stands, irrespective of the grassland seed mixture or fertilization, but was higher than that for pure willow stands. The comparison of three different energetic conversion techniques for the grassland biomass showed highest net energy yields for hay combustion, whereas the integrated generation of solid fuel and biogas from biomass (IFBB) and whole crop digestion performed similarly. However, due to the low fuel quality of hay, its direct combustion cannot be recommended as a viable conversion technique, whereas IFBB fuels were of a similar quality to wood chip from willow.

An integrated model of soil-canopy spectral radiances, photosynthesis, fluorescence, temperature and energy balance

This paper presents the model SCOPE (Soil Canopy Observation, Photochemistry and Energy fluxes), which is a vertical (1-D) integrated radiative transfer and energy balance model. The model links visible to thermal infrared radiance spectra (0.4 to 50 μm) as observed above the canopy to the fluxes of water, heat and carbon dioxide, as a function of vegetation structure, and the vertical profiles of temperature. Output of the model is the spectrum of outgoing radiation in the viewing direction and the turbulent heat fluxes, photosynthesis and chlorophyll fluorescence. A special routine is dedicated to the calculation of photosynthesis rate and chlorophyll fluorescence at the leaf level as a function of net radiation and leaf temperature. The fluorescence contributions from individual leaves are integrated over the canopy layer to calculate top-of-canopy fluorescence. The calculation of radiative transfer and the energy balance is fully integrated, allowing for feedback between leaf temperatures, leaf chlorophyll fluorescence and radiative fluxes. Leaf temperatures are calculated on the basis of energy balance closure. Model simulations were evaluated against observations reported in the literature and against data collected during field campaigns. These evaluations showed that SCOPE is able to reproduce realistic radiance spectra, directional radiance and energy balance fluxes. The model may be applied for the design of algorithms for the retrieval of evapotranspiration from optical and thermal earth observation data, for validation of existing methods to monitor vegetation functioning, to help interpret canopy fluorescence measurements, and to study the relationships between synoptic observations with diurnally integrated quantities. The model has been implemented in Matlab and has a modular design, thus allowing for great flexibility and scalability.

Amniotic fluid and umbilical cord plasma corticotropin-releasing factor (CRF), CRF-binding protein, adrenocorticotropin, and cortisol concentrations in intraamniotic infection and inflammation at term

Context: Pregnant tissues express corticotropin-releasing factor (CRF), a peptide modulating fetal and placental ACTH and cortisol secretion. These actions are modulated by the locally expressed CRF-binding protein (CRF-BP). Objective: The objective of the study was to determine whether CRF, CRF-BP, ACTH, and cortisol concentrations change in amniotic fluid and umbilical cord plasma in the presence of intraamniotic infection/inflammation (IAI) in women with spontaneous labor at term. Design: This was a cross-sectional study. Setting: The study was conducted at a tertiary referral center for obstetric care. Patients: Patients included women in active labor at term with (n = 39) and without (controls; n = 78) IAI. Main Outcome Measures: Amniotic fluid and umbilical cord plasma concentrations of CRF, CRF-BP, ACTH, and cortisol measured by RIA and immunoradiometric assays were measured. Results: In patients with IAI, amniotic fluid CRF (0.97 +/- 0.18 ng/ml) and CRF-BP (33.06 +/- 5.54 nmol/liter) concentrations were significantly (P < 0.001) higher than in controls (CRF: 0.32 +/- 0.04 ng/ml; CRF-BP: 14.69 +/- 2.79 ml). The umbilical cord plasma CRF and CRF-BP concentrations were significantly (P < 0.001 for all) higher in women with IAI than in controls (CRF: 2.96 +/- 0.35 ng/ml vs. 0.38 +/- 0.18 ng/ml; CRF-BP: 152.12 +/- 5.94 nmol/liter vs. 106.9 +/- 5.97 nmol/liter). In contrast, amniotic fluid and umbilical cord plasma ACTH and cortisol concentrations did not differ between groups. Conclusions: Amniotic fluid and umbilical cord plasma CRF and CRF-BP concentrations are increased in women with spontaneous labor at term and IAI. CRF-BP may modulate CRF actions on ACTH and cortisol secretion, playing a pivotal role in limiting the inflammatory process and thus avoiding an overactivation of the fetal/placental hypothalamus-pituitary-adrenal axis at birth.