Neutrophil extracellular traps promote cancer-associated inflammation and myocardial stress.

Cancer is associated with systemic pathologies that contribute to mortality, such as thrombosis and distant organ failure. The aim of this study was to investigate the potential role of neutrophil extracellular traps (NETs) in myocardial inflammation and tissue damage in treatment-naïve individuals with cancer. Mice with mammary carcinoma (MMTV-PyMT) had increased plasma levels of NETs measured as H3Cit-DNA complexes, paralleled with elevated coagulation, compared to healthy littermates. MMTV-PyMT mice displayed upregulation of pro-inflammatory markers in the heart, myocardial hypertrophy and elevated cardiac disease biomarkers in the blood, but not echocardiographic heart failure. Moreover, increased endothelial proliferation was observed in hearts from tumor-bearing mice. Removal of NETs by DNase I treatment suppressed the myocardial inflammation, expression of cardiac disease biomarkers and endothelial proliferation. Compared to a healthy control group, treatment-naïve cancer patients with different malignant disorders had increased NET formation, which correlated to plasma levels of the inflammatory marker CRP and the cardiac disease biomarkers NT-proBNP and sTNFR1, in agreement with the mouse data. Altogether, our data indicate that NETs contribute to inflammation and myocardial stress during malignancy. These findings suggest NETs as potential therapeutic targets to prevent cardiac inflammation and dysfunction in cancer patients.

Excessive daytime sleepiness, morning tiredness and major adverse cardiovascular events in patients with chronic coronary syndrome.

BACKGROUND: Sleep-related breathing disorders (SRBDs), particularly obstructive sleep apnoea, are associated with increased cardiovascular (CV) risk. However, it is not known whether individual questions used for SRBD screening are associated with major adverse CV events (MACE) and death specifically in patients with chronic coronary syndrome (CCS). METHODS: Symptoms associated with SRBD were assessed by a baseline questionnaire in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. The patients reported the frequency (never/rarely, sometimes, often and always) of: 1) loud snoring; 2) more than one awakening/night; 3) morning tiredness (MT); 4) excessive daytime sleepiness (EDS); or 5) gasping, choking or apnoea when asleep. In adjusted Cox regression models, associations between the frequency of SRBD symptoms and CV outcomes were assessed with never/rarely as reference. RESULTS: During a median follow-up time of 3.7 years, 1,588 MACE events (541 CV deaths, 749 nonfatal myocardial infarctions [MI] and 298 nonfatal strokes) occurred. EDS was associated (hazard ratio [HR], 95% confidence interval [CI]) with increased risk of MACE (sometimes 1.14 [1.01-1.29], often 1.19 [1.01-1.40] and always 1.43 [1.15-1.78]), MI (always 1.61 [1.17-2.20]) and all-cause death (often 1.26 [1.05-1.52] and always 1.71 [1.35-2.15]). MT was associated with higher risk of MACE (often 1.23 [1.04-1.45] and always 1.46 [1.18-1.81]), MI (always 1.61 [1.22-2.14]) and all-cause death (always 1.54 [1.20-1.98]). The other SRBD-related questions were not consistently associated with worse outcomes. CONCLUSIONS: In patients with CCS, gradually higher levels of EDS and MT were independently associated with increased risk of MACE, including mortality.

Psychosocial stress and major cardiovascular events in patients with stable coronary heart disease.

OBJECTIVES: Assess the risk of ischaemic events associated with psychosocial stress in patients with stable coronary heart disease (CHD). METHODS: Psychosocial stress was assessed by a questionnaire in 14 577 patients (median age 65.0, IQR 59, 71; 81.6% males) with stable CHD on optimal secondary preventive therapy in the prospective randomized STABILITY clinical trial. Adjusted Cox regression models were used to assess associations between individual stressors, baseline cardiovascular risk factors and outcomes. RESULTS: After 3.7 years of follow-up, depressive symptoms, loss of interest and financial stress were associated with increased risk (hazard ratio, 95% confidence interval) of CV death (1.21, 1.09-1.34; 1.15, 1.05-1.27; and 1.19, 1.08-1.30, respectively) and the primary composite end-point of CV death, nonfatal MI or nonfatal stroke (1.21, 1.13-1.30; 1.19, 1.11-1.27; and 1.17, 1.10-1.24, respectively). Living alone was related to higher risk of CV death (1.68, 1.38-2.05) and the primary composite end-point (1.28, 1.11-1.48), whereas being married as compared with being widowed, was associated with lower risk of CV death (0.64, 0.49-0.82) and the primary composite end-point (0.81, 0.67-0.97). CONCLUSIONS: Psychosocial stress, such as depressive symptoms, loss of interest, living alone and financial stress, were associated with increased CV mortality in patients with stable CHD despite optimal medical secondary prevention treatment. Secondary prevention of CHD should therefore focus also on psychosocial issues both in clinical management and in future clinical trials.

MHC variability supports dog domestication from a large number of wolves: high diversity in Asia.

The process of dog domestication is still somewhat unresolved. Earlier studies indicate that domestic dogs from all over the world have a common origin in Asia. So far, major histocompatibility complex (MHC) diversity has not been studied in detail in Asian dogs, although high levels of genetic diversity are expected at the domestication locality. We sequenced the second exon of the canine MHC gene DLA-DRB1 from 128 Asian dogs and compared our data with a previously published large data set of MHC alleles, mostly from European dogs. Our results show that Asian dogs have a higher MHC diversity than European dogs. We also estimated that there is only a small probability that new alleles have arisen by mutation since domestication. Based on the assumption that all of the currently known 102 DLA-DRB1 alleles come from the founding wolf population, we simulated the number of founding wolf individuals. Our simulations indicate an effective population size of at least 500 founding wolves, suggesting that the founding wolf population was large or that backcrossing has taken place.

Serum calcium is independently associated with insulin sensitivity measured with euglycaemic-hyperinsulinaemic clamp in a community-based cohort.

AIMS/HYPOTHESIS: Diabetes mellitus type 2 is associated with altered calcium metabolism. Moreover, in diseases with supranormal serum calcium levels, such as primary hyperparathyroidism, the prevalence of diabetes is increased. Relatively little is known about the relationship between serum calcium concentration and the underlying causes of diabetes-insulin resistance and defective insulin secretion-in the normocalcaemic general population. MATERIALS AND METHODS: We investigated associations between serum calcium concentration and insulin sensitivity and secretion in a population-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men, n = 961). Insulin sensitivity index (M/I; glucose disposal rate [M] divided by mean insulin concentration [I]) was assessed using euglycaemic-hyperinsulinaemic clamp, and insulin secretion was estimated from the early insulin response (EIR) during an OGTT. RESULTS: In a multivariable linear regression model adjusting for BMI, physical activity, smoking, consumption of tea, alcohol, coffee and dietary calcium, serum phosphate and serum creatinine, 1 SD increase in serum calcium was associated with 0.17 mg kg(-1) min(-1) (mU/l)(-1) x 100 (0.024 mg kg(-1) min(-1) [pmol/l](-1) x 100) decrease in M/I (p = 0.01). The results remained robust in individuals with normal fasting glucose, normal glucose tolerance and serum calcium within the normal range (n = 413, regression coefficient for 1 SD increase -0.45, p = 0.001). Serum calcium was not associated with EIR. Dietary intake of calcium was not independently associated with insulin sensitivity or EIR. CONCLUSION/INTERPRETATION: Our data support the notion that endogenous calcium may be involved early in the development of diabetes and that this effect is mediated mainly through effects on insulin sensitivity rather than defective insulin secretion. Dietary intake of calcium does not seem to influence insulin sensitivity.

Positive effect of parathyroidectomy on bone mineral density in mild asymptomatic primary hyperparathyroidism.

OBJECTIVES: Patients with mild primary hyperparathyroidism (pHPT) often appear asymptomatic, and have previously been regarded as not requiring treatment. However, increased cardiovascular morbidity and dyslipidaemia have also been recognized in mild pHPT, which also seem to be normalized after parathyroidectomy. The present study explores whether postmenopausal women with mild pHPT have decreased bone mineral density (BMD) compared with age-matched healthy controls, and the effects on BMD of parathyroidectomy. DESIGN, SUBJECTS AND INTERVENTION: A population-based health screening of 5202 postmenopausal women identified 87 overtly asymptomatic patients with mild pHPT as well as age-matched healthy controls. A 5-year follow-up included 49 cases who had undergone parathyroidectomy. BMD was measured with DXA at the femoral neck, the lumbar spine and the total body. RESULTS: At study entry, BMD was 5-6% lower in the lumbar spine (L2-L4) and femoral neck in cases compared with matched controls. After the 5-year follow-up, BMD increased in L2-L4 by 2.9% (P = 0.002) in the parathyroidectomized cases and remained stable in the femoral neck. However, femoral neck BMD increased 4.1% (P = 0.013) for cases <67 years old (50% of the cohort). CONCLUSION: In accordance with recent NIH guidelines for pHPT treatment, the level of BMD per se in the investigated group of patients justifies parathyroidectomy in almost half of the cases with mild pHPT. Surgery could be expected to increase BMD in L2-L4 to the level of the controls, to increase femoral neck BMD in patients <67 years of age and to preserve femoral neck BMD in the elderly population.

Subcutaneous adipose tissue: a source of lactate production after glucose ingestion in humans.

The in vivo kinetics of lactate and pyruvate in the extracellular space of subcutaneous adipose tissue after glucose ingestion were investigated in healthy volunteers by the use of a microdialysis sampling technique. Comparison was made with the metabolite levels in venous plasma. The absolute subcutaneous tissue concentrations of lactate and pyruvate were estimated in the fasting state by perfusion with varying lactate- and pyruvate-containing solutions. An equilibrium with the surrounding extracellular fluid was found for both lactate and pyruvate in concentrations similar to those in venous plasma. After glucose ingestion there was an increase in the circulating levels of glucose, lactate, and pyruvate, which returned to base-line values within 3 h. There was a more marked increase in lactate in subcutaneous adipose tissue than in venous blood, and the adipose tissue lactate remained elevated for at least 3 h. In contrast, pyruvate levels increased much less in subcutaneous fat than in venous blood. The addition of isoproterenol (which inhibits adipose tissue glucose metabolism) to the tissue perfusate lowered the subcutaneous tissue lactate levels significantly but did not affect the subcutaneous pyruvate levels. These data suggest that human subcutaneous adipose tissue is a source of in vivo lactate production after glucose ingestion. Since lactate is thought to be a major substrate for glycogen synthesis in the liver, the present findings may provide evidence of a new and important role of the adipose tissue metabolism in the regulation of whole body glucose homeostasis in humans.

In vivo subcutaneous adipose tissue glucose kinetics after glucose ingestion in obesity and fasting.

The kinetic pattern of subcutaneous adipose tissue extracellular glucose following glucose ingestion was investigated in vivo with a microdialysis technique in normal-weight (n = 21) and obese subjects (n = 18) before and after a 7-day fast (n = 9). A dialysis probe (4 x 0.5 mm) was implanted subcutaneously, and was continuously perfused (5 microliters/min). The tissue dialysate glucose concentration was determined in 15-min samples before and during a period of 180 min after a 75-g oral glucose load. A comparison was made between the tissue dialysate concentrations and the venous blood glucose levels. In all study groups the increase in subcutaneous tissue dialysate glucose following glucose ingestion paralleled that in blood, with a time-lag of up to 15 min. In the normal-weight subjects the maximum relative increase in abdominal adipose tissue dialysate glucose was 25% higher (p less than 0.005) than the corresponding blood glucose level, and the total relative glucose level (area under curve, AUC) in abdominal fat was 20% (p less than 0.01) higher than in blood. In contrast, the kinetics of gluteal subcutaneous tissue dialysate and blood glucose levels were similar. In the obese patients before the fasting period the maximum relative glucose level in abdominal fat was almost twice as high as in blood (p less than 0.005), and the total glucose level (AUC) was 50% higher than the blood glucose AUC (p less than 0.005). After the fast, on the other hand, almost identical relative dynamics of abdominal subcutaneous tissue and blood glucose levels were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Some evidence in support of a relationship between human auditory signal-detection performance and the phase of the alpha cycle.

This study concerned the hypothesis presented by Lindsley in 1961 that human sensorimotor performance should vary with the phase of the alpha cycle. Although there have been a number of studies which have supported this hypothesis, there has been no work from a modality other than the visual modality. Since eye tremor is correlated in phase and frequency with the alpha rhythm, these visual results might be explained by the peripheral eye tremor and not necessarily by the central alpha rhythm. The present study measured human auditory signal-detection performance at four different phases of the temporally (T5-linked mastoids) measured alpha rhythm. These four different phases were defined on an a priori basis by a computer algorithm. Detection performance was significantly better at the negative peak of this alpha cycle than at the positive peak, but there was no significant difference between the positively and negatively going zero cross performances. These results are consistent with the Lindsley hypothesis.

Microdialysis of subcutaneous adipose tissue in vivo for continuous glucose monitoring in man.

Subcutaneous adipose tissue extracellular glucose was investigated in vivo in man with a microdialysis technique. A small dialysis probe (4 or 10 x 0.5 mm) was implanted subcutaneously, and was perfused continuously with a micro-infusion pump. Dialysate samples were collected in 15-min periods. A transient yield of ATP was recorded immediately after insertion of the probe; thereafter ATP was almost undetectable. During steady-state conditions the tissue dialysate glucose concentration remained constant for at least 2 h, which indicated that there was no drainage of glucose from the interstitial fluid to the tissue dialysate. Simultaneous dialysis of venous blood and subcutaneous fat in rats showed that the recovery of glucose from the adipose tissue interstitial fluid to the dialysate was only 20% of that from blood. However, in vivo dialysis of human adipose tissue with glucose-containing solutions produced an equilibrium with the extracellular space at a glucose concentration that was similar to the blood glucose concentration. After oral glucose ingestion and following i.v. insulin and glucose administration the relative variations in subcutaneous glucose closely resembled those in blood glucose. It is concluded that the subcutaneous implantation of the presently used small dialysis device causes only minor and transient traumatic effects. The dialysis recovery of glucose is lower in adipose tissue than in blood. However, the relative kinetics of subcutaneous tissue dialysate glucose are closely related to variations in the blood glucose concentration, and thus may be used for monitoring of glycaemic control in man.

Splanchnic and renal exchange of infused fructose in insulin-deficient type 1 diabetic patients and healthy controls.

Fructose raises blood glucose and lactate levels in normal as well as diabetic man, but the tissue origin (liver and/or kidney) of these responses and the role of insulin in determining the end products of fructose metabolism have not been fully established. Splanchnic and renal substrate exchange was therefore examined during intravenous infusion of fructose or saline in six insulin-deficient type I diabetics who fasted overnight and in five healthy controls. Fructose infusion resulted in similar arterial concentrations and regional uptake of fructose in the two groups. Splanchnic glucose output increased threefold in the diabetics but remained unchanged in controls in response to fructose infusion, and the arterial glucose concentration rose more in diabetics (+5.5 mmol/liter) than in controls (+0.5 mmol/liter). Splanchnic uptake of both lactate and pyruvate increased twofold in response to fructose infusion in the diabetics. In contrast, a consistent splanchnic release of both lactate and pyruvate was seen during fructose infusion in controls. In diabetics fructose-induced hyperglycemia was associated with no net renal glucose exchange, while there was a significant renal glucose production during fructose infusion in the controls. In both groups fructose infusion resulted in renal output of lactate and pyruvate. In the diabetics this release corresponded to the augmented uptake by splanchnic tissues. In two diabetic patients given insulin infusion, all responses to fructose infusion were normalized. Fructose infusion in diabetics did not influence either splanchnic ketone body production or its relationship to splanchnic FFA inflow. We conclude that in insulin-deficient, mildly ketotic type I diabetes, (a) both the liver, by virtue of lactate, pyruvate, and fructose-derived gluconeogenesis, and the kidneys , by virtue of fructose-derived lactate and pyruvate production, contribute to fructose-induced hyperglycemia; (b) outcome of hepatic fructose metabolism; and (c) fructose does not exert an antiketogenic effect. These data suggest that while total fructose metabolism is not altered in diabetics, intermediary hepatic fructose metabolism is dependent on the presence of insulin.