Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

OBJECTIVE OF THE STUDY: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. METHODOLOGY AND PRINCIPAL FINDINGS: Streptozotocin (STZ)-induced diabetes in apolipoprotein E(-/-) mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. CONCLUSIONS: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications

Systematic study of constitutive cyclo-oxygenase-2 expression: role of NFκB and NFAT transcriptional pathways

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system

Swedish snuff and incidence of cardiovascular disease. A population-based cohort study

<p>Abstract</p> <p>Background</p> <p>The relationship between smoking and an increased incidence of cardiovascular diseases is well known. Whether smokeless tobacco (snuff) is related to myocardial infarction (MI) or stroke is still controversial. Aim of this study was to explore whether snuff users have an increased incidence of MI or stroke.</p> <p>Methods</p> <p>A total of 16 754 women and 10 473 men (aged 45–73 years), without history of cardiovascular disease (CVD), belonging to the population-based "Malmö Diet and Cancer" study were examined. Incidence of MI and stroke were monitored over 10.3 years.</p> <p>Results</p> <p>Snuff was used by 737 (7.0%) men and 75 (0.4%) women, respectively. Among men, snuff was significantly associated with low occupation level, single civil status, high BMI and with current and former smoking. In women, snuff was associated with lower systolic blood pressure. A total of 964 individuals (3.5%), i.e.544 men (5.3%) and 420 (2.5%) women suffered a MI during the follow-up period. The corresponding numbers of incident stroke cases were 1048, i.e. 553 men (5.3%) and 495 (3.0%) women, respectively. Snuff was not associated with any statistically significant increased risk of MI or stroke in men or women. The relative risks (RR) in male snuff users compared to non-users were 1.05 (95% confidence interval (CI): 0.8–1.4, p = 0.740) for incident MI and 0.97 (0.7–1.4, p = 0.878) for stroke, after taking age and potential confounders into account. In women none of the 420 (2.5%) women who were snuff users had a MI and only one suffered a stroke during the follow-up.</p> <p>Conclusion</p> <p>Several life-style risk factors were more prevalent in snuff-users than in non-users. However, the present study does not support any relationship between snuff and incidence of cardiovascular disease in men.</p

Fibromyalgia and neuropathic pain - differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia

<p>Abstract</p> <p>Background</p> <p>Patients with diabetic neuropathy (DPN) and fibromyalgia differ substantially in pathogenetic factors and the spatial distribution of the perceived pain. We questioned whether, despite these obvious differences, similar abnormal sensory complaints and pain qualities exist in both entities. We hypothesized that similar sensory symptoms might be associated with similar mechanisms of pain generation. The aims were (1) to compare epidemiological features and co-morbidities and (2) to identify similarities and differences of sensory symptoms in both entities.</p> <p>Methods</p> <p>The present multi-center study compares epidemiological data and sensory symptoms of a large cohort of 1434 fibromyalgia patients and 1623 patients with painful diabetic neuropathy. Data acquisition included standard demographic questions and self-report questionnaires (MOS sleep scale, PHQ-9, Pain<it>DETECT</it>). To identify subgroups of patients with characteristic combinations of symptoms (sensory profiles) a cluster analysis was performed using all patients in both cohorts.</p> <p>Results</p> <p>Significant differences in co-morbidities (depression, sleep disturbance) were found between both disorders. Patients of both aetiologies chose very similar descriptors to characterize their sensory perceptions. Burning pain, prickling and touch-evoked allodynia were present in the same frequency. Five subgroups with distinct symptom profiles could be detected. Two of the subgroups were characteristic for fibromyalgia whereas one profile occurred predominantly in DPN patients. Two profiles were found frequently in patients of both entities (20-35%).</p> <p>Conclusions</p> <p>DPN and fibromyalgia patients experience very similar sensory phenomena. The combination of sensory symptoms - the sensory profile - is in most cases distinct and almost unique for each one of the two entities indicating aetiology-specific mechanisms of symptom generation. Beside the unique aetiology-specific sensory profiles an overlap of sensory profiles can be found in 20-35% of patients of both aetiologies.</p

Population structure and genetic history of Tibetan Terriers

International audienceAbstractBackgroundTibetan Terrier is a popular medium-sized companion dog breed. According to the history of the breed, the western population of Tibetan Terriers includes two lineages, Lamleh and Luneville. These two lineages derive from a small number of founder animals from the native Tibetan Terrier population, which were brought to Europe in the 1920s. For almost a century, the western population of Tibetan Terriers and the native population in Tibet were reproductively isolated. In this study, we analysed the structure of the western population of Tibetan Terriers, the original native population from Tibet and of different crosses between these two populations. We also examined the genetic relationships of Tibetan Terriers with other dog breeds, especially terriers and some Asian breeds, and the within-breed structure of both Tibetan Terrier populations.ResultsOur analyses were based on high-density single nucleotide polymorphism (SNP) array (Illumina HD Canine 170 K) and microsatellite (18 loci) genotypes of 64 Tibetan Terriers belonging to different populations and lineages. For the comparative analysis, we used 348 publicly available SNP array genotypes of dogs from other breeds. We found that the western population of Tibetan Terriers and the native Tibetan Terriers clustered together with other Asian dog breeds, whereas all other terrier breeds were grouped into a separate group. We were also able to differentiate the western Tibetan Terrier lineages (Lamleh and Luneville) from the native Tibetan Terrier population.ConclusionsOur results reveal the relationships between the western and native populations of Tibetan Terriers and support the hypothesis that Tibetan Terrier belongs to the group of ancient dog breeds of Asian origin, which are close to the ancestors of the modern dog that were involved in the early domestication process. Thus, we were able to reject the initial hypothesis that Tibetan Terriers belong to the group of terrier breeds. The existence of this native population of Tibetan Terriers at its original location represents an exceptional and valuable genetic resource

Overexpression of podocalyxin-like protein is an independent factor of poor prognosis in colorectal cancer

Background:Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and poor prognosis in several forms of cancer. In this study, we investigated the prognostic impact of PODXL expression in colorectal cancer (CRC).Methods:Using tissue microarrays and immunohistochemistry, PODXL expression was evaluated in 536 incident CRC cases from a prospective, population-based cohort study. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the impact of PODXL expression on cancer-specific survival (CSS) and overall survival (OS).Results:High PODXL expression was significantly associated with unfavourable clinicopathological characteristics, a shorter CSS (hazard ratio (HR)=1.98; 95% confidence interval (CI) 1.38-2.84, P<0.001) and 5-year OS (HR=1.85; 95% CI 1.29-2.64, P=0.001); the latter remaining significant in multivariate analysis (HR=1.52; 95% CI 1.03-2.25, P=0.036). In addition, in curatively resected stage III (T1-4, N1-2, M0) patients (n=122) with tumours with high PODXL expression, a significant benefit from adjuvant chemotherapy was demonstrated (p(interaction) =0.004 for CSS and 0.015 for 5-year OS in multivariate analysis).Conclusion:Podocalyxin-like 1 expression is an independent factor of poor prognosis in CRC. Our results also suggest that PODXL may be a useful marker to stratify patients for adjuvant chemotherapy

Long-term follow-up after cancer rehabilitation using high-intensity resistance training: persistent improvement of physical performance and quality of life

The short-term beneficial effects of physical rehabilitation programmes after cancer treatment have been described. However, little is known regarding the long-term effects. The purpose of this study was to investigate the long-term effects of high-intensity resistance training compared with traditional recovery. A total of 68 cancer survivors who completed an 18-week resistance training programme were followed for 1 year. During the 1-year follow-up, 19 patients dropped out (14 due to recurrence of cancer). The remaining 49 patients of the intervention group were compared with a group of 22 patients treated with chemotherapy in the same period but not participating in any rehabilitation programme. Outcome measures were muscle strength, cardiopulmonary function, fatigue, and health-related quality of life. One year after completion of the rehabilitation programme, the outcome measures in the intervention group were still at the same level as immediately after rehabilitation. Muscle strength at 1 year was significantly higher in patients who completed the resistance training programme than in the comparison group. High-intensity resistance training has persistent effects on muscle strength, cardiopulmonary function, quality of life, and fatigue. Rehabilitation programmes for patients treated with chemotherapy with a curative intention should include high-intensity resistance training in their programme