Blood viscosity: effects of mental stress and relations to autonomic nervous system function and insulin sensitivity

We studied effects of mental stress on whole-blood viscosity (WBV) and blood pressure (BP), and relations between WBV and autonomic nervous system activity and insulin sensitivity. We measured WBV (rotational rheometer), plasma noradrenaline (NA), finger BP, heart rate variability (HRV) and baroreflex sensitivity (BRS; transfer technique) during hyperinsulinaemic glucose clamp and mental arithmetic stress test (MST) in 20 men with high ( > or =140/90 mmHg) and 21 men with normal (< or =115/75 mmHg) screening BP, and 10 women regardless of screening BP (all normotensive). WBV and NA increased during the MST, while HRV and BRS decreased. During the MST, WBV (all shear rates) and the response ((delta)WBV) (low shear) were higher in men with high compared to normal screening BP (p<0.05). In men, WBV correlated positively with NA and negatively with HRV, BRS and insulin sensitivity. The diastolic BP response ((delta)DBP) was independently explained by high-shear (delta)WBV (p<0.05) and (delta)NA (p<0.0001), and (delta)WBV independently by (delta)DBP (p<0.05). WBV is related to increased sympathetic activity, impaired vagal cardiac control and low insulin sensitivity in young adults. The haemorheological effect of mental stress is increased in young men with high screening BP and may be mediated by the acute increase in BP.     

Level of satisfaction during mammography screening in relation to discomfort, service provided, level of pain and breast compression

Purpose

The purpose of the present study was to identify the factors having the largest influence on the patients, experiences of mammography screening and if these factors can be generalised for different centres.

Material and methods

Three-hundred-and-ninety-three women attending mammography examination during two randomly selected days at four screening centres in the Southern Health Region of Norway were approached. A questionnaire designed to survey socio-demographic variables and their experience with mammography screening was distributed upon attendance. The answers to the questionnaire were related to the level of breast compression which was recorded for every patient. Statistical analyses were performed to assess women's satisfaction, discomfort and level of pain during mammography screening.

Results

Eighty-two percent (324/393) completed the questionnaire. Ninety-one percent were ‘satisfied’ or ‘very satisfied’ with the service at the mammography screening centres. Still, 80% reported high level of discomfort related to the examination. ‘Moderate’, ‘strong’ or ‘intense’ pain during breast compression was reported by 25% of the women. Mean breast compression ranged from 8.5 ± 1.2 kg to15.7 ± 2.2 kg. In all, 23% of women experienced strong and intense pain at a compression of more than 16 kg, while none of the women experienced strong or intense pain for compression less than 8 kg.

Conclusion

Our results concur with earlier studies showing high level of satisfaction among Norwegian women undergoing breast screening. The present study clearly demonstrates that the level of compression is vital to the patients' experience of pain, but do not seem to influence their level of satisfaction with the procedure.     

Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity

P38alpha is a protein kinase that regulates the expression of inflammatory cytokines, suggesting a role in the pathogenesis of diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Here, we describe the preclinical pharmacology of pamapimod, a novel p38 mitogen-activated protein kinase inhibitor. Pamapimod inhibited p38alpha and p38beta enzymatic activity, with IC(50) values of 0.014 +/- 0.002 and 0.48 +/- 0.04 microM, respectively. There was no activity against p38delta or p38gamma isoforms. When profiled across 350 kinases, pamapimod bound only to four kinases in addition to p38. Cellular potency was assessed using phosphorylation of heat shock protein-27 and c-Jun as selective readouts for p38 and c-Jun NH(2)-terminal kinase (JNK), respectively. Pamapimod inhibited p38 (IC(50), 0.06 microM), but inhibition of JNK was not detected. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) alpha production by monocytes, interleukin (IL)-1beta production in human whole blood, and spontaneous TNFalpha production by synovial explants from RA patients. LPS- and TNFalpha-stimulated production of TNFalpha and IL-6 in rodents also was inhibited by pamapimod. In murine collagen-induced arthritis, pamapimod reduced clinical signs of inflammation and bone loss at 50 mg/kg or greater. In a rat model of hyperalgesia, pamapimod increased tolerance to pressure in a dose-dependent manner, suggesting an important role of p38 in pain associated with inflammation. Finally, an analog of pamapimod that has equivalent potency and selectivity inhibited renal disease in lupus-prone MRL/lpr mice. Our study demonstrates that pamapimod is a potent, selective inhibitor of p38alpha with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases.     

Long-term effects of a losartan- compared with an atenolol-based treatment regimen on carotid artery plaque development in hypertensive patients with left ventricular hypertrophy: ICARUS, a LIFE substudy

In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, there was a 25% risk reduction for stroke with angiotensin receptor blocker-based therapy (losartan) as compared with beta-blocker-based therapy (atenolol) despite comparable blood pressure reductions. This substudy examines treatment effects on the amount and density of atherosclerotic lesions in the common carotid arteries and the carotid bulb in 81 patients during 3 years of treatment. There were no statistically significant changes in the amount of carotid plaque in patients treated with losartan compared with an atenolol-based treatment program. A statistically nonsignificant increase in plaque density and index (average of plaque amount and density) was seen in the atenolol group compared with those treated with losartan. The small number of patients evaluated may have limited the power to detect a difference in outcome. The difference in carotid plaque index increase between the treatment groups during 3 years of treatment could not be statistically linked to specific treatments in the present substudy.     

Connexin43 acts as a colorectal cancer tumor suppressor and predicts disease outcome

This article is the first to show that loss of connexin43 (Cx43) expression in colorectal tumors is correlated with significantly shorter relapse-free and overall survival. Cx43 was further found to negatively regulate growth of colon cancer cells, in part by enhancing apoptosis. In addition, Cx43 was found to colocalize with β-catenin and reduce Wnt signaling. The study represents the first evidence that Cx43 acts as a colorectal cancer tumor suppressor and that loss of Cx43 expression during colorectal cancer development is associated with reduced patient survival. The study has important implications for the assessment of Cx43 as a prognostic marker and target in colorectal cancer prevention and therapy. Gap junctions consist of intercellular channels that permit direct transfer of ions and small molecules between adjacent cells. The gap junction channel protein Cx43 plays important roles in cell growth control and differentiation and is frequently dysregulated in human cancers. However, the functional importance and clinical relevance of Cx43 in cancer development has remained elusive. Here, we show that Cx43 is downregulated or aberrantly localized in colon cancer cell lines and colorectal carcinomas, which is associated with loss of gap junction intercellular communication. The in situ protein expression of Cx43 was analyzed in colorectal tumors in a cohort of 674 patients and related to established clinicopathological variables and survival. A subgroup of the patients had weak or no expression of Cx43 in tumors. Loss of Cx43 expression was significantly correlated with shorter relapse-free and overall survival. Loss of Cx43 further identified a high-risk subgroup among stage I and stage II patients with reduced relapse-free and overall survival. Ectopic expression of Cx43 in the colon cancer cell line HT29 was associated with reduced growth in monolayer and soft agar cultures and in tumor xenografts. Cx43 was found to colocalize with β-catenin and negatively regulate the Wnt signaling pathway, and expression of Cx43 was associated with increased levels of apoptosis. Altogether, these data indicate that Cx43 is a colorectal cancer tumor suppressor protein that predicts clinical outcome.