Inadequate glucose control in type 2 diabetes is associated with impaired lung function and systemic inflammation: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Inadequate glucose control may be simultaneously associated with inflammation and decreased lung function in type 2 diabetes. We evaluated if lung function is worse in patients with inadequate glucose control, and if inflammatory markers are simultaneously increased in these subjects.</p> <p>Methods</p> <p>Subjects were selected at the Colombian Diabetes Association Center in Bogotá. Pulmonary function tests were performed and mean residual values were obtained for forced expiratory volume (FEV₁₎, forced vital capacity (FVC) and FEV₁/FVC, with predicted values based on those derived by Hankinson et al. for Mexican-Americans. Multiple least-squares regression was used to adjust for differences in known determinants of lung function. We measured blood levels of glycosylated hemoglobin (HBA_1c), interleukin 6 (IL-6), tumor necrosis factor (TNF-α), fibrinogen, ferritin, and C-reactive protein (C-RP).</p> <p>Results</p> <p>495 diabetic patients were studied, out of which 352 had inadequate control (HBA_1c> 7%). After adjusting for known determinants of lung function, those with inadequate control had lower FEV₁(-75.4 mL, IC95%: -92, -59; P < 0.0001) and FVC (-121 mL, IC95%: -134, -108; P < 0,0001) mean residuals, and higher FEV₁/FVC (0.013%, IC95%: 0.009, 0.018, P < 0.0001) residuals than those with adequate control, as well as increased levels of all inflammatory markers (P < 0.05), with the exception of IL-6.</p> <p>Conclusions</p> <p>Subjects with type 2 diabetes and inadequate control had lower FVC and FEV₁than predicted and than those of subjects with adequate control. It is postulated that poorer pulmonary function may be associated with increased levels of inflammatory mediators.</p

Age-specific prevalence of the metabolic syndrome defined by the International Diabetes Federation and the National Cholesterol Education Program: the Norwegian HUNT 2 study

<p>Abstract</p> <p>Background</p> <p>The 2005 International Diabetes Federation (IDF) definition of the metabolic syndrome was designed to be useful worldwide, but to date few prevalence studies have used that definition in European populations. We estimated the age- and sex-stratified prevalence of IDF-defined metabolic syndrome in a county of Norway and compared it with the prevalence estimated using the revised National Cholesterol Education Program-Adult Treatment Panel-III definition (2005 ATP III).</p> <p>Methods</p> <p>Cross-sectional analysis of 10,206 participants aged 20–89 years in the Nord-Trøndelag Health Study 1995–97 (HUNT 2).</p> <p>Results</p> <p>Prevalence of IDF-defined metabolic syndrome was 29.6% (95% CI: 28.8 to 30.5), compared to 25.9% (95% CI: 25.0 to 26.7) using the 2005 ATP III criteria. The prevalence of IDF-defined metabolic syndrome increased from 11.0% in the 20–29 years age group to 47.2% in the 80–89 years group in men, and from 9.2% to 64.4% for women in the corresponding age groups. Among men and women aged ≥60 years, the IDF criteria classified 56.7% and 75.0%, respectively, as having central obesity, and 89.3% and 90.9%, respectively, as being hypertensive.</p> <p>Conclusion</p> <p>According to both definitions, the prevalence of the metabolic syndrome increased strongly with age. The IDF and the American Heart Association/National Heart, Lung, and Blood Institute guidelines for clinical management of metabolic syndrome would classify a high proportion of elderly Norwegians as in need of overall risk assessment for cardiovascular disease.</p

Resistance of HNSCC cell models to pan-FGFR inhibition depends on the EMT phenotype associating with clinical outcome

Background: Focal adhesion signaling involving receptor tyrosine kinases (RTK) and integrins co-controls cancer cell survival and therapy resistance. However, co-dependencies between these receptors and therapeutically exploitable vulnerabilities remain largely elusive in HPV-negative head and neck squamous cell carcinoma (HNSCC). Methods: The cytotoxic and radiochemosensitizing potential of targeting 10 RTK and β1 integrin was determined in up to 20 3D matrix-grown HNSCC cell models followed by drug screening and patient-derived organoid validation. RNA sequencing and protein-based biochemical assays were performed for molecular characterization. Bioinformatically identified transcriptomic signatures were applied to patient cohorts. Results: Fibroblast growth factor receptor (FGFR 1–4) targeting exhibited the strongest cytotoxic and radiosensitizing effects as monotherapy and combined with β1 integrin inhibition, exceeding the efficacy of the other RTK studied. Pharmacological pan-FGFR inhibition elicited responses ranging from cytotoxicity/radiochemosensitization to resistance/radiation protection. RNA sequence analysis revealed a mesenchymal-to-epithelial transition (MET) in sensitive cell models, whereas resistant cell models exhibited a partial epithelial-to-mesenchymal transition (EMT). Accordingly, inhibition of EMT-associated kinases such as EGFR caused reduced adaptive resistance and enhanced (radio)sensitization to FGFR inhibition cell model- and organoid-dependently. Transferring the EMT-associated transcriptomic profiles to HNSCC patient cohorts not only demonstrated their prognostic value but also provided a conclusive validation of the presence of EGFR-related vulnerabilities that can be strategically exploited for therapeutic interventions. Conclusions: This study demonstrates that pan-FGFR inhibition elicits a beneficial radiochemosensitizing and a detrimental radioprotective potential in HNSCC cell models. Adaptive EMT-associated resistance appears to be of clinical importance, and we provide effective molecular approaches to exploit this therapeutically

Frequent loss of endothelin-3 (EDN3) expression due to epigenetic inactivation in human breast cancer

Introduction: Endothelin (EDN) signalling plays a crucial role in cell differentiation, proliferation and migration processes. There is compelling evidence that altered EDN signalling is involved in carcinogenesis by modulating cell survival and promoting invasiveness. To date, most reports have focused on the oncogenic potential of EDN1 and EDN2, both of which are overexpressed in various tumour entities. Here, we aimed at a first comprehensive analysis on EDN3 expression and its implication in human breast cancer. Methods: EDN3 mRNA expression was assessed by Northern blotting in normal human tissues (n = 9) as well as in matched pairs of normal and tumourous tissues from breast specimens (n = 50). EDN3 mRNA expression in breast cancer was further validated by real-time polymerase chain reaction (PCR) (n = 77). A tissue microarray was used to study EDN3 protein expression in breast carcinoma (n = 150) and normal breast epithelium (n = 44). EDN3 promoter methylation was analysed by methylation-specific PCR in breast cell lines (n = 6) before and after demethylating treatment, normal breast tissues (n = 17) and primary breast carcinomas (n = 128). EDN3 expression and methylation data were statistically correlated with clinical patient characteristics and patient outcome. Results: Loss of EDN3 mRNA expression in breast cancer, as initially detected by array-based expression profiling, could be confirmed by Northern blot analysis (> 2-fold loss in 96%) and real-time PCR (> 2-fold loss in 78%). Attenuated EDN3 expression in breast carcinoma was also evident at the protein level (45%) in association with adverse patient outcome in univariate (P = 0.022) and multivariate (hazard ratio 2.0; P = 0.025) analyses. Hypermethylation of the EDN3 promoter could be identified as the predominant mechanism leading to gene silencing. Reversion of the epigenetic lock by 5-aza-2'-deoxycytidine and trichostatin A resulted in EDN3 mRNA reexpression in vitro. Furthermore, EDN3 promoter hypermethylation was detected in 70% of primary breast carcinomas with significant association to loss of EDN3 mRNA expression (P = 0.005), whilst normal matched breast tissues revealed no EDN3 promoter methylation. Conclusions EDN3 is a frequent target of epigenetic inactivation in human breast cancer, potentially contributing to imbalanced EDN signalling commonly found in this disease. The clinical implication supports the view that EDN3, in contrast to EDN1 and EDN2, may act as natural tumour suppressor in the human mammary gland

Type I Gaucher disease with exophthalmos and pulmonary arteriovenous malformation

BACKGROUND: Gaucher disease type I, the non-neuropathic type, usually presents in adulthood with hepatosplenomegaly. We report here an adult with type I Gaucher disease presented with unusual and severe clinical manifestations. CASE PRESENTATION: Hepatosplenomegaly, bone crisis and fractures occurred at early childhood, and splenectomy was performed at the age of 5. Exophthalmos with increase in retrobulbar space was noted when the patient was 30. Cerezyme infusion started at the age of 32; but unfortunately, pulmonary arteriovenous malformation with dyspnea and hypoxemia was found two years later. Gene analysis revealed V375L/L444P mutations in the β-glucocerebrosidase gene. CONCLUSION: Although both eye and lung diseases have been associated with Gaucher disease, this is the first reported demonstration of exophthalmos and pulmonary arteriovenous malformation in the same patient. This case may therefore present an extremely severe and unusual form of type I Gaucher disease

Memory-experience gap in early adolescents' happiness reports

Studies among adult populations show that estimates of how happy one has felt in the past tend to be more positive than average happiness as assessed using time sampling techniques. This ‘memory-experience gap’ is attributed to cognitive biases, among which fading affect bias. In this paper we report a study among 352 pupils of a secondary school in the Netherlands. These youngsters reported subsequently: 1) how happy they had felt yesterday, 2) how happy they had felt during the last month, 3) what they had done the previous day and 4) how the

Democratization and foreign policy in Southeast Asia: the case of the ASEAN Inter-Parliamentary Myanmar Caucus

This is an Author's Accepted Manuscript of an article published in Cambridge Review of International Affairs Vol. 22, Iss. 3, 2009 as published in the CAMBRIDGE REVIEW OF INTERNATIONAL AFFAIRS, 2009, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/09557570903104008

An appeal to the global health community for a tripartite innovation: an ‘‘Essential Diagnostics List,’’ ‘‘Health in All Policies,’’ and ‘‘See-Through 21st Century Science and Ethics"

Diagnostics spanning a wide range of new biotechnologies, including proteomics, metabolomics, and nanotechnology, are emerging as companion tests to innovative medicines. In this Opinion, we present the rationale for promulgating an ‘‘Essential Diagnostics List.’’ Additionally, we explain the ways in which adopting a vision for ‘‘Health in All Policies’’ could link essential diagnostics with robust and timely societal outcomes such as sustainable development, human rights, gender parity, and alleviation of poverty. We do so in three ways. First, we propose the need for a new, ‘‘see through’’ taxonomy for knowledge-based innovation as we transition from the material industries (e.g., textiles, plastic, cement, glass) dominant in the 20th century to the anticipated knowledge industry of the 21st century. If knowledge is the currency of the present century, then it is sensible to adopt an approach that thoroughly examines scientific knowledge, starting with the production aims, methods, quality, distribution, access, and the ends it purports to serve. Second, we explain that this knowledge trajectory focus on innovation is crucial and applicable across all sectors, including public, private, or public–private partnerships, as it underscores the fact that scientific knowledge is a co-product of technology, human values, and social systems. By making the value systems embedded in scientific design and knowledge co-production transparent, we all stand to benefit from sustainable and transparent science. Third, we appeal to the global health community to consider the necessary qualities of good governance for 21st century organizations that will embark on developing essential diagnostics. These have importance not only for science and knowledge based innovation, but also for the ways in which we can build open, healthy, and peaceful civil societies today and for future generations

Mindful breath awareness meditation facilitates efficiency gains in brain networks: A steady-state visually evoked potentials study

The beneficial effects of mindfulness-based therapeutic interventions have stimulated a rapidly growing body of scientific research into underlying psychological processes. Resulting evidence indicates that engaging with mindfulness meditation is associated with increased performance on a range of cognitive tasks. However, the mechanisms promoting these improvements require further investigation. We studied changes in behavioural performance of 34 participants during a multiple object tracking (MOT) task that taps core cognitive processes, namely sustained selective visual attention and spatial working memory. Concurrently, we recorded the steady-state visually evoked potential (SSVEP), an EEG signal elicited by the continuously flickering moving objects, and indicator of attentional engagement. Participants were tested before and after practicing eight weeks of mindful breath awareness meditation or progressive muscle relaxation as active control condition. The meditation group improved their MOT-performance and exhibited a reduction of SSVEP amplitudes, whereas no such changes were observed in the relaxation group. Neither group changed in self-reported positive affect and mindfulness, while a marginal increase in negative affect was observed in the mindfulness group. This novel way of combining MOT and SSVEP provides the important insight that mindful breath awareness meditation may lead to refinements of attention networks, enabling more efficient use of attentional resources

Differential regulation of neurotrophin expression in human bronchial smooth muscle cells

BACKGROUND: Human bronchial smooth muscle cells (HBSMC) may regulate airway inflammation by secreting cytokines, chemokines and growth factors. The neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), have been shown to be elevated during airway inflammation and evoke airway hyperresponsiveness. We studied if HBSMC may be a source of NGF, BDNF and NT-3, and if so, how inflammatory cytokines may influence their production. METHODS: Basal and cytokine (IL-1β, IFN-γ, IL-4)-stimulated neurotrophin expression in HBSMC cultured in vitro was quantified. The mRNA expression was quantified by real-time RT-PCR and the protein secretion into the cell culture medium by ELISA. RESULTS: We observed a constitutive NGF, BDNF and NT-3 expression. IL-1β stimulated a transient increase of NGF, while the increase of BDNF had a later onset and was more sustained. COX-inhibitors (indomethacin and NS-398) markedly decreased IL-1β-stimulated secretion of BDNF, but not IL-1β-stimulated NGF secretion. IFN-γ increased NGF expression, down-regulated BDNF expression and synergistically enhanced IL-1β-stimulated NGF expression. In contrast, IL-4 had no effect on basal NGF and BDNF expression, but decreased IL-1β-stimulated NGF expression. NT-3 was not altered by the tested cytokines. CONCLUSION: Taken together, our data indicate that, in addition to the contractile capacity, HBSMC can express NGF, BDNF and NT-3. The expression of these neurotrophins may be differently regulated by inflammatory cytokines, suggesting a dynamic interplay that might have a potential role in airway inflammation