Usual interstitial pneumonia and smoking-related interstitial fibrosis display epithelial to mesenchymal transition in fibroblastic foci

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

The impact of physical activity on mitigation of health care costs related to diabetes mellitus: findings from developed and developing settings Diabetes mellitus and physical exercise

Over the last decades, the prevalence of diabetes mellitus (DM) has been increasing globally such that nowadays the disease constitutes an important outcome related to early mortality among adults. In parallel with the high prevalence, healthcare costs related to DM treatment have increased significantly, exacerbating its burden on modern society. The scientific literature points out that obesity and physical inactivity have a central role in the development of most DM cases. In fact, either physical exercise practice or an increase in the level of physical activity, constitute relevant tools in the guidelines for treatment of the disease. On the other hand, the effect of physical activity on the economic consequences of DM is not completely clear. The identification of the actual burden of lifestyle changes on the reduction of healthcare costs related to DM is relevant, primarily for developing nations, where it could represent a cheaper strategy for treating the disease and its complications than paying for drug treatment, which is commonly related to collateral effects. That being said, the prevention of DM and other diseases and consequently the mitigation of the costs related to these outcomes seem to depend essentially on the promotion of healthy habits. The aim of the present review was therefore to discuss recent evidence on the effects of physical activity/exercise on mitigation of health care cost related to DM.

Increased DNA damage is related to maternal blood glucose levels in the offspring of women with diabetes and mild gestational hyperglycemia

This study aimed at correlating maternal blood glucose levels with DNA damage levels in the offspring of women with diabetes or mild gestational hyperglycemia (MGH). Based on oral glucose tolerance test results and glycemic profiles, 56 pregnant women were allocated into 3 groups: nondiabetes, MGH, and diabetes. The offspring of these women (56 infants) were also evaluated. Maternal peripheral blood and umbilical cord blood samples were collected and processed for biochemical and DNA damage analysis by the comet assay. A positive correlation between maternal blood glucose mean and increased offspring DNA damage levels was observed. Hyperglycemia played a role in offspring DNA damage, but other diabetes-induced complications were also involved. Increased maternal blood glucose levels can lead to increased offspring DNA damage levels. Therefore, the monitoring, control, and treatment of pregnant women with diabetes and MGH are highly important to ensure a risk-free pregnancy and healthy infants.

Experimental diabetes modulates collagen remodelling of joints in rats

The aim of this study was to evaluate extracellular matrix components in articular cartilage, ligaments and synovia in an experimental model of diabetes. Young Wistar rats were divided into a streptozotocin-induced (STZ; 35 mg/kg) diabetic group (DG; n=15) and a control group (CG; n=15). Weight, blood glucose and plasma anti-carboxymethyllysine were measured 70 days after STZ infusions. Knee joints, patellar ligaments, and lateral and medial collateral ligaments were isolated and stained with hematoxylineosin and Picrosirius. The total collagen content was determined by morphometry. Immunofluorescence was employed to evaluate types I, III, and V collagen in ligaments and synovial tissues and types II and XI collagen in cartilage. Results: Higher blood glucose levels and plasma anti-carboxymethyllysine were observed in DG rats when compared to those in CG rats. The final weight was significantly lower in the DG rats than in the CG rats. Histomorphometric evaluation depicted a small quantity of collagen fibers in ligaments and articular cartilage in DG rats, as well as increased collagen in synovial tissue. There was a decrease in cartilage proteoglycans in DG rats when compared with CG rats. Immunofluorescence staining revealed an increase of collagen III and V in ligaments, collagen XI in cartilage, and collagen I in synovial tissue of DG rats compared with CG rats. Conclusion: The ligaments, cartilage and synovia are highly affected following STZ-induced diabetes in rats, due the remodeling of collagen types in these tissues. This process may promote the degradation of the extracellular matrix, thus compromising joint function. Our data may help to better understand the pathogenesis of joint involvement related to diabetes.

Noninvasive assessment of exercise-related intramyocellular acetylcarnitine in euglycemia and hyperglycemia in patients with type 1 diabetes using ¹H magnetic resonance spectroscopy: a randomized single-blind crossover study

Intramyocellular acetylcarnitine (IMAC) is involved in exercise-related fuel metabolism. It is not known whether levels of systemic glucose influence IMAC levels in type 1 diabetes.

Diabetes-related knowledge among medical and nursing house staff

To assess the diabetes-related knowledge of medical and nursing house staff with particular focus on inpatient diabetes management and insulin therapy.

A subset of metzincins and related genes constitutes a marker of human solid organ fibrosis

Metzincins and functionally related genes play important roles in extracellular matrix remodeling both in healthy and fibrotic conditions. We recently presented a transcriptomic classifier consisting of 19 metzincins and related genes (MARGS) discriminating biopsies from renal transplant patients with or without interstitial fibrosis/tubular atrophy (IF/TA) by virtue of gene expression measurement (Roedder et al., Am J Transplant 9:517-526, 2009). Here we demonstrate that the same algorithm has diagnostic value in non-transplant solid organ fibrosis. We used publically available microarray datasets of 325 human heart, liver, lung, kidney cortex, and pancreas microarray samples (265 with fibrosis, 60 healthy controls). Expression of nine commonly differentially expressed genes was confirmed by TaqMan low-density arrays (Applied Biosystems, USA) in 50 independent archival tissue specimens with matched histological diagnoses to microarray patients. In separate and in combined, integrated microarray data analyses of five datasets with 325 samples, the previously published MARGS classifier for renal post-transplant IF/TA had a mean AUC of 87% and 82%, respectively. These data demonstrate that the MARGS gene panel classifier not only discriminates IF/TA from normal renal transplant tissue, but also classifies solid organ fibrotic conditions of human pancreas, liver, heart, kidney, and lung tissue samples with high specificity and accuracy, suggesting that the MARGS classifier is a cross-platform, cross-organ classifier of fibrotic conditions of different etiologies when compared to normal tissue.

HCV-related advanced fibrosis/cirrhosis: randomized controlled trial of pegylated interferon alpha-2a and ribavirin

In patients with hepatitis C virus (HCV)-related advanced fibrosis/cirrhosis, 30% of sustained HCV clearance has been reported with pegylated interferon alpha-2a (PEG-IFN) alone, but the efficacy and tolerability of the PEG-IFN/ribavirin (RBV) combination remain poorly defined. A total of 124 treatment-naïve patients with biopsy proved HCV-related advanced fibrosis/cirrhosis (Ishak score F4-F6, Child-Pugh score < or =7) were randomized to 48 weeks of PEG-IFN (180 microg sc weekly) and standard dose of RBV (1000/1200 mg po daily, STD) or PEG-IFN (180 microg sc weekly) and low-dose of RBV (600/800 mg po daily, LOW). Sustained virologic response (SVR) rates with PEG-IFN/STD RBV (52%) were higher--albeit not significantly--than that with PEG-IFN/LOW RBV (38%, P = 0.153). In multivariate analysis, genotype 2/3 and a baseline platelet count > or =150 x 10(9)/L were independently associated with SVR. The likelihood of SVR was < 7% if viraemia had not declined by > or =2 log or to undetectable levels after 12 weeks. Nine adverse events in the STD RBV and 15 in the LOW RBV group were classified as severe (including two deaths); dose reductions for intolerance were required in 78% and 57% (P = 0.013), and treatment was terminated early in 23% and 27% of patients (P = n.s.). The benefit/risk ratio of treating compensated HCV-cirrhotics with STD PEG-IFN/RBV is favourable.

TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure. Subtle inter-patient genetic variation and environmental factors combine to determine variation in disease progression. A common non-synonymous polymorphism in TM6SF2 (rs58542926 c.449 C>T, p.Glu167Lys) was recently associated with increased hepatic triglyceride content, but whether this variant promotes clinically relevant hepatic fibrosis is unknown. Here we confirm that TM6SF2 minor allele carriage is associated with NAFLD and is causally related to a previously reported chromosome 19 GWAS signal that was ascribed to the gene NCAN. Furthermore, using two histologically characterized cohorts encompassing steatosis, steatohepatitis, fibrosis and cirrhosis (combined n=1,074), we demonstrate a new association, independent of potential confounding factors (age, BMI, type 2 diabetes mellitus and PNPLA3 rs738409 genotype), with advanced hepatic fibrosis/cirrhosis. These findings establish new and important clinical relevance to TM6SF2 in NAFLD.

Age Related Differences in Individual Quality of Life Domains in Youth with Type 1 Diabetes.

BACKGROUND: Investigating individual, as opposed to predetermined, quality of life domains may yield important information about quality of life. This study investigated the individual quality of life domains nominated by youth with type 1 diabetes. METHODS: Eighty young people attending a diabetes summer camp completed the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting interview, which allows respondents to nominate and evaluate their own quality of life domains. RESULTS: The most frequently nominated life domains were 'family', 'friends', 'diabetes', 'school', and 'health' respectively; ranked in terms of importance, domains were 'religion', 'family', 'diabetes', 'health', and 'the golden rule'; ranked in order of satisfaction, domains were 'camp', 'religion', 'pets', and 'family' and 'a special person' were tied for fifth. Respondent age was significantly positively associated with the importance of 'friends', and a significantly negatively associated with the importance of 'family'. Nearly all respondents nominated a quality of life domain relating to physical status, however, the specific physical status domain and the rationale for its nomination varied. Some respondents nominated 'diabetes' as a domain and emphasized diabetes 'self-care behaviors' in order to avoid negative health consequences such as hospitalization. Other respondents nominated 'health' and focused more generally on 'living well with diabetes'. In an ANOVA with physical status domain as the independent variable and age as the dependent variable, participants who nominated 'diabetes' were younger (M = 12.9 years) than those who nominated 'health' (M = 15.9 years). In a second ANOVA, with rationale for nomination the physical status domain as the independent variable, and age as the dependent variable, those who emphasized 'self care behaviors' were younger (M = 11.8 years) than those who emphasized 'living well with diabetes' (M = 14.6 years). These differences are discussed in terms of cognitive development and in relation to the decline in self-care and glycemic control often observed during adolescence. CONCLUSIONS: Respondents nominated many non-diabetes life domains, underscoring that QOL is multidimensional. Subtle changes in conceptualization of diabetes and health with increasing age may reflect cognitive development or disease adjustment, and speak to the need for special attention to adolescents. Understanding individual quality of life domains can help clinicians motivate their young patients with diabetes for self-care. Future research should employ a larger, more diverse sample, and use longitudinal designs.

Exercise during pregnancy and gestational diabetes related adverse effects: a randomized controlled trial

Ejercicio, embarazo y diabetes

Interaction of the Ras-related protein associated with diabetes Rad and the putative tumor metastasis suppressor NM23 provides a novel mechanism of GTPase regulation

Rad is the prototypic member of a new class of Ras-related GTPases. Purification of the GTPase-activating protein (GAP) for Rad revealed nm23, a putative tumor metastasis suppressor and a development gene in Drosophila. Antibodies against nm23 depleted Rad-GAP activity from human skeletal muscle cytosol, and bacterially expressed nm23 reconstituted the activity. The GAP activity of nm23 was specific for Rad, was absent with the S105N putative dominant negative mutant of Rad, and was reduced with mutations of nm23. In the presence of ATP, GDP⋅Rad was also reconverted to GTP⋅Rad by the nucleoside diphosphate (NDP) kinase activity of nm23. Simultaneously, Rad regulated nm23 by enhancing its NDP kinase activity and decreasing its autophosphorylation. Melanoma cells transfected with wild-type Rad, but not the S105N-Rad, showed enhanced DNA synthesis in response to serum; this effect was lost with coexpression of nm23. Thus, the interaction of nm23 and Rad provides a potential novel mechanism for bidirectional, bimolecular regulation in which nm23 stimulates both GTP hydrolysis and GTP loading of Rad whereas Rad regulates activity of nm23. This interaction may play important roles in the effects of Rad on glucose metabolism and the effects of nm23 on tumor metastasis and developmental regulation.

A yeast artificial chromosome-based map of the region of chromosome 20 containing the diabetes-susceptibility gene, MODY1, and a myeloid leukemia related gene.

We have generated a physical map of human chromosome bands 20q11.2-20q13.1, a region containing a gene involved in the development of one form of early-onset, non-insulin-dependent diabetes mellitus, MODY1, as well as a putative myeloid tumor suppressor gene. The yeast artificial chromosome contig consists of 71 clones onto which 71 markers, including 20 genes, 5 expressed sequence tags, 32 simple tandem repeat DNA polymorphisms, and 14 sequence-tagged sites have been ordered. This region spans about 18 Mb, which represents about 40% of the physical length of 20q. Using this physical map, we have refined the location of MODY1 to a 13-centimorgan interval (approximately equal to 7 Mb) between D20S169 and D20S176. The myeloid tumor suppressor gene was localized to an 18-centimorgan interval (approximately equal to 13 Mb) between RPN2 and D20S17. This physical map will facilitate the isolation of MODY1 and the myeloid tumor suppressor gene.

Local and systemic delivery of a novel group of inhibitors of transglutaminase enzyme: A potential approach for treating of catheter-related complications and liver fibrosis

The present thesis investigates targeted (locally and systemically) delivery of a novel group of inhibitors of enzyme transglutaminases (TGs). TGs are a widely distributed group of enzymes that catalyse the formation of isopeptide bonds between the y-carboxamide group of protein-bound glutamines and the a-amino group of protein-bound lysines or polyamines. The first group of the novel inhibitors tested were the tluorescently labelled inhibitors of Factor XIIIa (FXIIIa). These small, non-toxic inhibitors have the potential to prevent stabilisation of thrombi by FXIIIa and consequently increase the natural rate of thrombolysis, in addition it reduces staphylococcal colonisation of catheters by inhibiting their FXIIIa¬mediated cross-linking to blood clot proteins on the central venous catheter (CVCs) surface. The aim of this work was to incorporate the FXIIIa inhibitor either within coating of polyurethane (PU) catheters or to integrate it into silicone catheters, so as to reduce the incidence of thrombotic occlusion and associated bacterial infection in CVCs. The initial work focused on the incorporation of FXIIIa inhibitors within polymeric coatings of PU catheters. After defining the key characteristics desired for an effective polymeric-coating, polyvinylpyrrolidone (PVP), poly(lactic-co-glycolic acid) (PLGA) or their combination were studies as polymers of choice for coating of the catheters_ The coating was conducted by dip-coating method in a polymer solution containing the inhibitor. Upon incubation of the inhibitor-and polymer-coated strips in buffer, PVP was dissolved instantly, generating fast and significant drug release, whilst PLGA did not dissolve, yielding a slow and an insufficient amount of drug release. Nevertheless, the drug release profile was enhanced upon employing a blend solution of PVP and PLGA. The second part of the study was to incorporate the FXIIIa inhibitor into a silicone elastomer; results demonstrated that FXIIIa inhibitor can be incorporated and released from silicone by using citric acid (CA) and sodium bicarbonate (SB) as additives and the drug release rate can be controlled by the amount of incorporated additives in the silicone matrix. Furthermore, it was deemed that the inhibitor was still biologically active subsequent to being released from the silicone elastomer strips. Morphological analysis confirmed the formation of channels and cracks inside the specimens upon the addition of CA and SB. Nevertheless, the tensile strength, in addition to Young's modulus of silicone elastomer strips, decreased constantly with an increasing amount of amalgamated CA/ SB in the formulations. According to our results, incorporation of FXIIIa inhibitor into catheters and other medical implant devices could offer new perspectives in preventing bio-material associated infections and thrombosis. The use of tissue transglutaminase (T02) inhibitor for treating of liver fibrosis was also investigated. Liver fibrosis is characterized by increased synthesis and decreased degradation of the extracellular matrix (ECM). Transglutaminase-mediated covalent cross-linking is involved in the stabilization of ECM in human liver fibrosis. Thus, TG2 inhibitors may be used to counteract the decreased degradation of the ECM. The potential of a liposome based drug delivery system for site specific delivery of the fluorescent TG2 inhibitor into the liver was investigated; results indicated that the TG2 inhibitor can be successfully integrated into liposomes and delivered to the liver, therefore demonstrating that liposomes can be employed for site-specific delivery of TG2 inhibitors into the liver and TG2 inhibitor incorporating liposomes could offer a new approach in treating liver fibrosis and its end stage disease cirrhosis.