The ability of pollutants to affect human health is a major concern, justified by the wide demonstration that reproductive functions are altered by endocrine disrupting chemicals. The definition of ...endocrine disruption is today extended to broader endocrine regulations, and includes activation of metabolic sensors, such as the peroxisome proliferator-activated receptors (PPARs). Toxicology approaches have demonstrated that phthalate plasticizers can directly influence PPAR activity. What is now missing is a detailed molecular understanding of the fundamental basis of endocrine disrupting chemical interference with PPAR signaling. We thus performed structural and functional analyses that demonstrate how monoethyl-hexyl-phthalate (MEHP) directly activates PPARγ and promotes adipogenesis, albeit to a lower extent than the full agonist rosiglitazone. Importantly, we demonstrate that MEHP induces a selective activation of different PPARγ target genes. Chromatin immunoprecipitation and fluorescence microscopy in living cells reveal that this selective activity correlates with the recruitment of a specific subset of PPARγ coregulators that includes Med1 and PGC-1α, but not p300 and SRC-1. These results highlight some key mechanisms in metabolic disruption but are also instrumental in the context of selective PPAR modulation, a promising field for new therapeutic development based on PPAR modulation.
To determine the diagnostic accuracy of a new point-of-care assay detecting anti-deamidated gliadin peptides in celiac disease (CD) patients.
One-hundred-and-twelve patients (age range: 1.8-79.2 ...years old) with clinical symptoms suggestive of CD and/or first-degree relatives (FDR) of CD patients (n = 66), and confirmed CD on a gluten-free diet (GFD) (n = 46), were prospectively enrolled in the study at Gastroenterology outpatient clinics for adult patients and from the Gastroenterology Consultation Ward at the Pediatric Department of the University Hospital of Geneva. Written informed consent was obtained from all subjects enrolled. The study received approval from the local ethics committee. The original CD diagnosis had been based on serum-positive IgA anti-tissue transglutaminase enzyme-linked immunosorbent assay (ELISA) (QuantaLite™, Inova Diagnostics, San Diego, CA, United States) and on biopsy results. Serum samples from all study participants were tested by the new CD lateral flow immunochromatographic assay (CD-LFIA) device, Simtomax® Blood Drop (Augurix SA, BioArk, Monthey, Switzerland) to detect immunoglobulin (Ig)A and IgG antibodies against deamidated gliadin peptides. The diagnostic performance was evaluated using receiver operating characteristic curves with 95%CIs. A cut-off of 2 on the Rann colorimetric scale was used to calculate the device's sensitivity and specificity.
CD-LFIA was highly accurate in detecting untreated celiac patients. In the group of patients with CD symptoms and/or FDR, eight new cases of CD were detected by ELISA and biopsy. All of these new cases were also correctly identified by CD-LFIA. The test yielded four false positive and four false negative results. The false positive results were all within the groups with clinical symptoms suggestive of CD and/or FDR, whereas the false negative results were all within the GFD group. The test yeld a sensitivity of 78.9% (95%CI: 54.4-93.9) and specificity of 95.7% (95%CI: 89.4-98.8), and the area under the curve reached 0.893 (95%CI: 0.798-0.988). The Kappa coefficient, calculated according to the values obtained by two readers from the same device, was of 0.96 (SE: 0.06). When the GFD patients were excluded from the analysis, the area under the curve reached 0.989 (95%CI: 0.971-1.000) and the Kappa coefficient, calculated according to the values obtained by two readers from the same device, became 0.96 (SE: 0.07). Furthermore, using the Rann scale cut-off of 2 without the GFD patients, sensitivity was 100% and specificity was 93.1% (95%CI: 83.3-98.1).
The new CD-LFIA rapid screening test shows good diagnostic accuracy, sensitivity and specificity, and may rule out CD in patients with CD-related symptoms.
To analyse the gastrostomy procedures performed in HNC patients admitted to Coltea Clinical Hospital in order to underline the similarities and differences to the data published worldwide.
Our ...retrospective study contains 64 HNC cases that met the inclusion criteria between 2008 and 2011.
The study group presents numerous specific characteristics (a larger number of cases aged over 55 than younger patients; elective use of classic gastrostomy instead of newer techniques; approximately two thirds of the gastrostomies were performed in patients with laryngeal carcinoma; only one third approximately of the cases benefited from prophylactic gastrostomy; etc.).
22% of the gastrostomies were made after the appearance of a pharyngocutaneous fistula. Therefore we will begin a future prospective study in order to ascertain the value of prophylactic PEG in preventing the appearance of pharyngocutaneous fistulas.
The paper provides another insight into the pipeline risk assessment for in-service pressure piping containing defects. Beside of the traditional analytical approximation methods or sampling-based ...methods safety index and failure probability of pressure piping containing defects will be obtained based on a novel type of support vector machine developed in a
minimax manner. The safety index or failure probability is carried out based on a binary classification approach. The procedure named
classification reliability procedure, involving a link between artificial intelligence and reliability methods was developed as a user-friendly computer program in MATLAB language. To reveal the capacity of the proposed procedure two comparative numerical examples replicating a previous related work and predicting the failure probabilities of pressured pipeline with defects were presented.
The serological diagnosis of celiac disease (CD) often relies on the presence of anti-tissue transglutaminase (tTG) IgA autoantibodies. Patients suffering from selective IgA deficiency (IgAD) are ...often not aware of their IgA deficiency and are tested as CD negative, delaying considerably the diagnosis. The detection of IgG against deamidated gliadin peptides (DGP) has high specificity and better sensitivity than IgG anti-tTG. A multi-analytic lateral-flow immunochromatographic assay (CD-LFIA) based on the detection of IgA and IgG anti-DGP and total IgA was shown to have a good diagnostic accuracy for CD. The aim of this study was to evaluate the clinical accuracy of its use in children suffering from IgAD.
45 IgAD children ranging from 1.1 to 17.4 years and suspected of CD or having high CD risk factors were referred from outpatient clinics located in the area of Rhone-Alpes (France) to the Hospices Civils de Lyon, Paediatric Hospital-Gastroenterology-Hepatology- Nutrition Department for further CD investigations. The CD investigations, including the sample collection, were performed within the Paediatric Hospital-Gastroenterology-Hepatology- Nutrition Department, and the serological testing was performed at the Lyon-Sud Hospital-Immunology Laboratory. The diagnosis of CD was based on IgG anti-tTG serology, biopsy results and patient follow-up. The serum samples were retrospectively tested on the CD-LFIA test.
A total of eight (8) patients were diagnosed as new CD. All were correctly identified by the CD-LFIA. The test yielded four (4) false positive results. Two patients with positive IgG anti-tTG were negative on CD-LFIA, but were classified as CD negative based on biopsy results and patient follow-up. The remaining 33 patients were found negative by both methods. The specificity and sensitivity of CD-LFIA was of 89.2% 74.6-97.0 and of 100% 63.1-100 respectively. The negative predictive value (NPV) was of 100% 89.4-100, and the Likelihood Ratio for Negative Test (LR-) was of 0 0.0-0.91.
CD-LFIA is a useful, non-invasive and rapid tool to rule out CD in primary care paediatric patients having CD-related symptoms and IgAD. Patients having a positive CD-LFIA result could be then readily directed to secondary care setting for further evaluation by standard serology and biopsy.
Peroxisome proliferator-activated receptor γ (PPARγ) is an essential regulator of adipocyte differentiation, maintenance, and survival. Deregulations of its functions are associated with metabolic ...diseases. We show here that deletion of one PPARγ allele not only affected lipid storage but, more surprisingly, also the expression of genes involved in glucose uptake and utilization, the pentose phosphate pathway, fatty acid synthesis, lipolysis, and glycerol export as well as in IR/IGF-1 signaling. These deregulations led to reduced circulating adiponectin levels and an energy crisis in the WAT, reflected in a decrease to nearly half of its intracellular ATP content. In addition, there was a decrease in the metabolic rate and physical activity of the PPARγ⁺/⁻ mice, which was abolished by thiazolidinedione treatment, thereby linking regulation of the metabolic rate and physical activity to PPARγ. It is likely that the PPARγ⁺/⁻ phenotype was due to the observed WAT dysfunction, since the gene expression profiles associated with metabolic pathways were not affected either in the liver or the skeletal muscle. These findings highlight novel roles of PPARγ in the adipose tissue and underscore the multifaceted action of this receptor in the functional fine tuning of a tissue that is crucial for maintaining the organism in good health.
The peroxisome proliferator-activated receptor γ (PPARγ) plays a major role in fat tissue development and physiology. Mutations in the gene encoding this receptor have been associated to disorders in ...lipid metabolism. A thorough investigation of mice in which one PPARγ allele has been mutated reveals that male PPARγ heterozygous (PPARγ +/−) mice exhibit a reduced body size associated with decreased body weight, reflecting lean mass reduction. This phenotype is reproduced when treating the mice with a PPARγ- specific antagonist. Monosodium glutamate treatment, which induces weight gain and alters body growth in wild-type mice, further aggravates the growth defect of PPARγ +/− mice. The levels of circulating GH and that of its downstream effector, IGF-I, are not altered in mutant mice. However, the IGF-I mRNA level is decreased in white adipose tissue (WAT) of PPARγ +/− mice and is not changed by acute administration of recombinant human GH, suggesting an altered GH action in the mutant animals. Importantly, expression of the gene encoding the suppressor of cytokine signaling-2, which is an essential negative regulator of GH signaling, is strongly increased in the WAT of PPARγ +/− mice. Although the relationship between the altered GH signaling in WAT and reduced body size remains unclear, our results suggest a novel role of PPARγ in GH signaling, which might contribute to the metabolic disorder affecting insulin signaling in PPARγ mutant mice.
We report the final measurement of the neutrino oscillation parameters Δm322 and sin2 θ23 using all data from the MINOS and MINOS+ experiments. These data were collected using a total exposure of ...23.76 × 1020 protons on target producing νμ and νμ beams and 60.75 kt yr exposure to atmospheric neutrinos. The measurement of the disappearance of νμ and the appearance of νe events between the Near and Far detectors yields ... and ... at 68% C.L. for normal (inverted) hierarchy. (ProQuest: ... denotes formulae omited.).
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