Differential association of insulin resistance with cognitive and somatic symptoms of depression.

AIM: To examine the associations of depressive symptoms with insulin resistance, evaluating somatic and cognitive depressive symptoms separately. METHODS: A total of 328 individuals (mean age 60 years) referred for exercise stress testing, taking part in the Mechanisms and Outcomes of Silent Myocardial Ischemia study, completed the Beck Depression Inventory II. A fasting venous blood sample was collected for assessments of insulin and glucose level; the HOMA-IR (homeostatic model assessment of insulin resistance) was calculated. In principal component analysis, Beck Depression Inventory II items were forced to load onto two components (somatic and cognitive depressive symptoms). Adjusting for age, sex, BMI, medication use, smoking, physical activity, diabetes and cardiovascular disease, general linear model analyses were conducted to examine the associations between the components and log HOMA-IR . RESULTS: Principal component analysis showed that nine items loaded onto a cognitive depressive symptoms component and 10 items loaded onto a somatic depressive symptoms component. When examined separately, both components were significantly associated with log HOMA-IR however, when including both components simultaneously in the model, only somatic depressive symptoms remained significantly associated with log HOMA-IR. Back-transformed, a one-unit change in somatic depressive symptoms was associated with a 1.07 (95% CI 1.002, 1.14) change in HOMA-IR and a one-unit change in cognitive depressive symptoms was associated with a 1.03 (95% CI 0.97, 1.14) change in HOMA-IR. CONCLUSION: Somatic depressive symptoms seem to be more strongly associated with insulin resistance than do cognitive depressive symptoms. Monitoring somatic depressive symptoms may be more appropriate than monitoring cognitive depressive symptoms among depressed individuals with high insulin resistance.

The role of ischaemia and pain in the blood pressure response to exercise stress testing in patients with coronary heart disease.

Silent myocardial ischaemia is a common phenomenon in patients with coronary heart disease. However, very little is known about the underlying mechanisms of silent ischaemia. One potential pathway that may contribute to this absence of pain is increased blood pressure. The main aim of the current study was to assess the associations among blood pressure, pain and ischaemia in patients undergoing a standard exercise stress test. We hypothesized that patients who experienced chest pain during exercise would have lower baseline and peak blood pressures compared to those who did not experience chest pain. A total of 1,355 patients (418 women) who underwent a single-photon emission computed tomography treadmill exercise stress test and had not experienced a cardiac event in the past 2 weeks participated in the current study. Myocardial perfusion defects were assessed at rest and during the stress challenge. Systolic blood pressure (SBP), diastolic blood pressure, heart rate (HR) and rate pressure product (RPP) were assessed during rest and at peak exercise. There were no main effects of either pain or ischaemia on the baseline cardiovascular variables. Peak exercise data revealed main effects of pain on SBP, RPP and HR, and main effects of ischaemia on SBP and RPP, controlling for age, sex, baseline level, medication status and cardiac history. These findings suggest that acute rather than chronic increases in blood pressure may be one mechanism to explain the phenomena of silent myocardial ischaemia in cardiac patients, and may potentially provide a target for future treatment strategies.

Mutational analysis of the kinetics and thermodynamics of transcription factor NF-kappaB homodimerisation.

Dimeric transcription factors of the NF-kappaB/Rel family are sequence-specific DNA-binding proteins that mediate the inducible expression of immunologically important eukaryotic genes by competing for kappaB sites. The kinetic and thermodynamic components of these interactions were probed by mutation of the subunit interface of the p50 homodimer, a paradigm for other family members. Guided by the crystal structure, we selected the side chains of five key residues (R255, Y270, L272, A311 and V313) for individual and combinatorial truncation, with the aim of generating a mutant panel. Homodimerisation was assessed indirectly by measurement of DNA binding with an optical biosensor in order to unmask the relative contributions of each residue. Surface plasmon resonance revealed that a unanimous bias for a palindromic kappaB site over an asymmetric one was mainly the result of a slower dissociation rate for the DNA/homodimer complex in the case of the palindromic kappaB site. Y270 and L272 were individually the most critical residues in homodimerisation. DNA binding was abolished when all five residues were substituted, which reinforces the notion that only a subset of residues contributes crucial dimer-forming contacts. The role of Y270 was unique, since its mutation to glycine dramatically slowed both the association and dissociation rates for DNA binding. Surprisingly, R255 was shown to be of little importance in the stability of the p50 homodimer, despite its apparent participation in a salt bridge at the dimer interface. Our results suggest that binding modes inferred from structural data should be treated cautiously.