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Deformation predictions in high Concrete Face Rockfill Dams tend to underestimate observed settlements due to scale effect and breakage phenomena that cannot be adequately captured by laboratory tests. This paper presents a Visco-Elasto-Perfectly Plastic (VEPP) model for predicting deformations in high Concrete Face Rockfill Dams (CFRDs) that addresses these challenges incorporating explicitly key rockfill parameters like grain size and post-compaction porosity, which influence both the non-linear elastic and plastic behaviors of rockfill. The VEPP model enables deformation prediction while using standard laboratory test results. The model's effectiveness was demonstrated through its application to the 233 m high Shuibuya Dam, the tallest CFRD in the world. The VEPP model predictions closely align with observed deformations throughout the dam's construction, impoundment, and early operational stages. By using physically meaningful parameters, the model reduces the uncertainty associated with the empirical assessment of model parameters using back-analysis from similar projects. While the VEPP model offers improved predictive accuracy, particularly during early design phases, further advancements could be achieved by refining the creep formulation and accounting for grain size evolution during construction. This approach has the potential to optimize the design and construction of future high CFRD. [ABSTRACT FROM AUTHOR]

Context: Periodontitis confers an increased risk of developing type 2 diabetes and, in patients with obesity, it might interfere with the incretin axis. The effect of periodontal treatment on glucoregulatory hormones remains unknown.Objective: To evaluate the effect of periodontal treatment on incretin axis in obese and lean nondiabetic individuals.Setting: King's College Dental Hospital and Institute, London, UK.Participants and Methods: The metabolic profile of obese and normal-body-mass-index individuals affected by periodontitis was studied at baseline, 2, and 6 months after intensive periodontal treatment, by measuring plasma insulin, glucagon, glucagon-like peptide-1(GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) and markers of systemic inflammation and oxidative stress.Main Outcome Measure(s): Circulating levels of incretins and inflammatory markers.Results: At baseline, periodontal parameters were worse for obese than nonobese; this was accompanied by higher levels of circulating high-sensitivity C-reactive protein (hs-CRP), insulin, and GLP-1. The response to periodontal treatment was less favorable in the obese group, without significant variations of hs-CRP or malondialdehyde. Glucoregulatory hormones changed differently after treatment: while insulin and glucagon did not vary at 2 and 6 months, GLP-1 and GIP significantly increased at 6 months in both groups. In particular, GLP-1 increased more rapidly in obese participants, while the increase of GIP followed similar trends across visits in both groups.Conclusions: Nonsurgical treatment of periodontitis is associated with increased GLP-1 and GIP levels in nonobese and obese patients; changes in GLP-1 were more rapid in obese participants. This might have positive implications for the metabolic risk of these individuals. [ABSTRACT FROM AUTHOR]

Insulin resistance is a key marker of both obesity and GH excess. The purpose of the study was to assess the role of GH on p53-mediated insulin resistance of male mice with obesity due to a high-fat diet. C57BL/6J × CBA male mice fed on a high-fat diet (Obe) were studied; male mice fed a normal diet (Lean) or transgenic mice for bovine GH under the same genetic background (Acro) served as controls. The convergence of p53 and GH pathways was evaluated by Western blot. Obe mice had insulin resistance, which was sustained by a selective increased expression of p53 in adipose tissue. Normal insulin sensitivity was restored, and adipose p53 expression normalized when the GH pathway was blocked. Only the adipose p53 expression was sensitive to the GH blockage, which occurred through the p38 pathway. Adipose tissue of Obe mice had a coordinate overexpression of suppressors of cytokine signal 1-3 and signal transducers and activators of transcription-1, -3, and -5b, not different from that of Acro mice, suggesting an increased sensitivity of adipose tissue to GH. On the contrary, Lean mice were unaffected by changes of GH action. GH seems to be necessary for the increased adipose p53 expression and for insulin resistance of obese mice.

GH has antiapoptotic effects on several cells. However, the antiapoptotic mechanisms of GH on colonic mucosa cells are not completely understood. Peroxisome proliferator activated receptor-gamma (PPARgamma) activation enhances apoptosis, and a link between GH and PPARgamma in the colonic epithelium of acromegalic patients has been suggested. We investigated the effects of GH and of PPARgamma ligands on apoptosis in colonic cancer cell lines. Colonic cells showed specific binding sites for GH, and after exposure to 0.05-50 nm GH, their apoptosis reduced by 45%. The antiapoptotic effect was due to either GH directly or GH-dependent local production of IGF-1. A 55-85% reduction of PPARgamma expression was observed in GH-treated cells, compared with controls (P < 0.05). However, treatment of the cells with 1-50 microm ciglitazone (cig), induced apoptosis and reverted the antiapoptotic effects of GH by increasing the programmed cell death up to 3.5-fold at 30 min and up to 1.7-fold at 24 h. Expression of Bcl-2 and TNF-related apoptosis-induced ligand was not affected by either GH or cig treatment, whereas GH reduced the expression of Bax, which was increased by cig treatment. In addition, GH increased the expression of signal transducer and activator of transcription 5b, which might be involved in the down-regulation of PPARgamma expression. In conclusion, GH may exert a direct antiapoptotic effect on colonic cells, through an increased expression of signal transducer and activator of transcription 5b and a reduction of Bax and PPARgamma. The reduced GH-dependent apoptosis can be overcome by PPARgamma ligands, which might be useful chemopreventive agents in acromegalic patients, who have an increased colonic polyps prevalence.

Acromegalic patients have an increased prevalence of colonic neoplasms and lower peroxisome proliferator-activated receptor gamma (PPARgamma) levels, the latter acting as a tumor suppressor gene. In this study we evaluated the expression of PPARgamma in the biopsy samples of the polyps and outside polyps colonic mucosa from seven patients with active, untreated acromegaly, 11 with cured disease, and 15 controls. Serum GH and IGF-I levels were higher in patients with untreated acromegaly than in those with acromegaly in remission or controls (P = 0.003 and P = 0.002, respectively) The expression of PPARgamma mRNA (mean +/- SE) was 1) mucosa outside polyps, 24,188 +/- 3,254 transcripts in the controls, 22,432 +/- 2,006 transcripts in acromegaly in remission, and 1,952 +/- 342 transcripts in untreated acromegaly (P < 0.0001 vs. controls and acromegaly in remission); and 2) polyps mucosa, 1,554 +/- 236 transcripts in the controls, 1,112 +/- 143 in acromegaly in remission, and 1,570 +/- 251 in untreated acromegaly (P = NS among polyps groups and mucosa outside polyps of untreated acromegaly; P < 0.0001 vs. mucosa outside polyps of controls and acromegaly in remission). Eighty-five percent of the cells in the mucosa outside polyps from controls or acromegaly in remission were positive at immunohistochemistry, at variance with 45% of the cells from polyps mucosa from each group and from those of mucosa outside polyps of untreated acromegaly (P = 0.0002). In conclusion, patients with untreated acromegaly have reduced expression of PPARgamma in the mucosa outside polyps, which might be reversed by curing the disease; conversely, patients with acromegaly in remission have the same low levels of expression of PPARgamma in the polyps mucosa as untreated acromegaly or controls, supporting the concept that reduced expression of PPARgamma might be an early event in colonic tumorigenesis.

Unlabelled: Acromegalic patients have an increased prevalence of colonic polyps, due to the elevated serum insulin like growth factor (IGF)-I levels. The mechanisms underlying this process are poorly understood. Peroxisome proliferator activated receptor (PPAR)gamma, a nuclear receptor that regulates adipocyte differentiation, is highly expressed in the human colonic mucosa, where it induces growth inhibition and cell differentiation. In the present study we evaluated the expression of PPARgamma in the bioptic samples of colonic mucosa from 22 patients with acromegaly (Acro) and 13 normal subjects (CONTROLS) matched for age and sex. Among Acro patients, 10 had active, untreated disease (AcroUntr), 6 were in remission after surgery (AcroRem), and 6 had active disease under treatment with somatostatin analogs (AcroSMSa). Serum GH and IGF-I (mean +/- SD) levels were as follows: AcroUntr: GH, 36 +/- 40 microg/l; IGF-I, 769 +/- 298 microg/l; AcroRem: GH, 1.0 +/- 1.3 microg/l; IGF-I, 248 +/- 96 microg/l; AcroSMSa: GH, 7.8 +/- 12 microg/l; IGF-I, 429 +/- 221 microg/l;, Controls: GH, 0.8 +/- 0.7 microg/l; IGF-I, 203 +/- 67 microg/l. In the CONTROLS the level of expression of PPARgamma mRNA was 15230 +/- 891 transcripts. Patients with AcroUntr had 2750 +/- 688 transcripts of PPARgamma. (p < 0.0001) vs. CONTROLS); patients AcroSMSa had 4629 +/- 1286 transcripts of PPARgamma. (p = NS vs AcroUntr, p = 0.0002 vs. CONTROLS); patients with AcroRem had 8261 +/- 2481 transcripts of PPARgamma (p = 0.008 vs. AcroUntr, p = NS vs. AcroSMSa, p = 0.007 vs. CONTROLS). A significant inverse correlation was found between serum IGF-I concentrations and the level of expression of PPARgamma (r = 0.43, p = 0.03). In conclusion, patients with active Acro have a reduced expression of PPARgamma in the colonic mucosa, which appears be related to the increased serum IGF-I levels and might lead to an increased prevalence of colonic polyps.