Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study.

BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes. METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort). FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4. INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care. FUNDING: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

Closely packed, low reorganization energy π-extended postfullerene acceptors for efficient polymer solar cells.

New organic semiconductors are essential for developing inexpensive, high-efficiency, solution-processable polymer solar cells (PSCs). PSC photoactive layers are typically fabricated by film-casting a donor polymer and a fullerene acceptor blend, with ensuing solvent evaporation and phase separation creating discrete conduits for photogenerated holes and electrons. Until recently, n-type fullerene acceptors dominated the PSC literature; however, indacenodithienothiophene (IDTT)-based acceptors have recently enabled remarkable PSC performance metrics, for reasons that are not entirely obvious. We report two isomeric IDTT-based acceptors 3,9-bis(2-methylene-(3-(1,1-dicyanomethylene)-benz-(5, 6)indanone))-5,5,11,11-tetrakis(4-nonylphenyl)-dithieno[2,3-d:2',3'-d']-s-indaceno[1,2-b:5,6-b']di-thiophene (ITN-C9) and 3,9-bis(2-methylene-(3-(1,1-dicyanomethylene)-benz(6,7)indanone))-5,5,11,11-tetrakis(4-nonylphenyl)-dithieno[2,3-d:2',3'-d']-s-indaceno[1,2-b:5,6-b']dithiophene (ITzN-C9) that shed light on the exceptional IDTT properties vis-à-vis fullerenes. The neat acceptors and blends with fluoropolymer donor poly{[4,8-bis[5-(2- ethylhexyl)-4-fluoro-2-thienyl]benzo[1,2-b:4,5-b']dithiophene2,6-diyl]-alt-[2,5-thiophenediyl[5,7-bis(2-ethylhexyl)-4,8-dioxo4H,8H-benzo[1,2-c:4,5-c']dithiophene-1,3-diyl]]} (PBDB-TF) are investigated by optical spectroscopy, cyclic voltammetry, thermogravimetric analysis, differential scanning calorimetry, single-crystal X-ray diffraction, photovoltaic response, space-charge-limited current transport, atomic force microscopy, grazing incidence wide-angle X-ray scattering, and density functional theory-level quantum chemical analysis. The data reveal that ITN-C9 and ITzN-C9 organize such that the lowest unoccupied molecular orbital-rich end groups have intermolecular π-π distances as close as 3.31(1) Å, with electronic coupling integrals as large as 38 meV, and internal reorganization energies as small as 0.133 eV, comparable to or superior to those in fullerenes. ITN-C9 and ITzN-C9 have broad solar-relevant optical absorption, and, when blended with PBDB-TF, afford devices with power conversion efficiencies near 10%. Performance differences between ITN-C9 and ITzN-C9 are understandable in terms of molecular and electronic structure distinctions via the influences on molecular packing and orientation with respect to the electrode.

Phenotypic and genotypic profile of clinical and animal multidrug-resistant Salmonella enterica isolates from Mexico.

AIMS: The objective of this study was to obtain a phenotypic and genotypic profile of Salmonella enterica including multidrug-resistant (MDR) isolates from food-producing animals and clinical isolates, as well as their genetic relatedness in two different States of Mexico (Jalisco and State of Mexico). METHODS AND RESULTS: A total of 243 isolates were evaluated in terms of antimicrobial resistance (AMR) and related genes through a disk diffusion method and PCR respectively; we found 16 MDR isolates, all of them harbouring the blaCMY gene but not qnr genes, these isolates represent less than 10% of the collection. The pulsed-field gel electrophoresis revealed a higher genotypic similitude within isolates of State of Mexico than Jalisco. CONCLUSIONS: A low percentage of Salmonella isolates were resistant to relevant antibiotics in human health, nevertheless, the AMR and involved genes were similar despite the different serovars and origin of the isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: This investigation provided an insight of the current status of AMR of Salmonella isolates in two States of Mexico and pinpoint the genes involved in AMR and their epidemiological relationship, the information could help to determine an adequate therapy in human and veterinary medicine.

Adipose tissue and serum CCDC80 in obesity and its association with related metabolic disease.

Coiled-coil domain-containing 80 (CCDC80) is an adipocyte-secreted protein that modulates glucose homeostasis in response to diet-induced obesity in mice. The objective of this study is to analyze the link between human CCDC80 and obesity. CCDC80 protein expression was assessed in paired visceral (VAT) and subcutaneous (SAT) adipose tissue from 10 subjects (BMI range 22.4-38.8 kg/m2). Circulating CCDC80 levels were quantified in serum samples from two independent cross-sectional cohorts comprising 33 lean and 15 obese (cohort 1) and 32 morbid obese (cohort 2) male subjects. Insulin sensitivity, insulin secretion and blood neutrophil count were quantified in serum samples from both cohorts. Additionally, circulating free IGF-1 levels and oral glucose tolerance tests (OGTT) were assessed in cohort 1 whereas C-reactive protein levels and degree of atherosclerosis and hepatic steatosis were studied in cohort 2. In lean subjects, total CCDC80 protein content assessed by immunoblotting was lower in VAT than in SAT. In obese patients, CCDC80 was increased in VAT (P<0.05), but equivalent in SAT compared with lean counterparts. In cohort 1, serum CCDC80 correlated negatively with the acute insulin response to glucose and IGF1 levels, and positively with blood neutrophil count, independently of BMI, but not with insulin sensitivity. In cohort 2, serum CCDC80 was positively linked to the inflammatory biomarker C-reactive protein (r=0.46; P=0.009), atherosclerosis (carotid intima-media thickness, r=0.62; P<0.001) and hepatic steatosis (ANOVA P=0.025). Overall, these results suggest for the first time that CCDC80 may be a component of the obesity-altered secretome in VAT and could act as an adipokine whose circulant levels are linked to glucose tolerance derangements and related to inflammation-associated chronic complications.

Decreased lipid metabolism but increased FA biosynthesis are coupled with changes in liver microRNAs in obese subjects with NAFLD.

BACKGROUND/OBJECTIVE: Many controversies regarding the association of liver miRNAs with obesity and nonalcoholic fatty liver diseases (NAFLD) call for additional validations. This study sought to investigate variations in genes and hepatic miRNAs in a sample of obese patients with or without NAFLD and human hepatocytes (HH). SUBJECTS/METHODS: A total of 60 non-consecutive obese women following bariatric surgery were recruited. Subjects were classified as NAFLD (n=17), borderline (n=24) and controls (n=19) with normal enzymatic profile, liver histology and ultrasound assessments. Profiling of 744 miRNAs was performed in 8 obese women with no sign of hepatic disease and 11 NAFLD patients. Additional validation and expression of genes related to de novo fatty acid (FA) biosynthesis, uptake, transport and ß-oxidation; glucose metabolism, and inflammation was tested in the extended sample. Induction of NAFLD-related genes and miRNAs was examined in HepG2 cells and primary HH treated with palmitic acid (PA), a combination of palmitate and oleic acid, or high glucose, and insulin (HG) mimicking insulin resistance in NAFLD. RESULTS: In the discovery sample, 14 miRNAs were associated with NAFLD. Analyses in the extended sample confirmed decreased miR-139-5p, miR-30b-5p, miR-122-5p and miR-422a, and increased miR-146b-5p in obese subjects with NAFLD. Multiple linear regression analyses disclosed that NAFLD contributed independently to explain miR-139-5p (P=0.005), miR-30b-5p (P=0.005), miR-122-5p (P=0.021), miR-422a (P=0.007) and miR-146a (P=0.033) expression variance after controlling for confounders. Decreased miR-122-5p in liver was associated with impaired FA usage. Expression of inflammatory and macrophage-related genes was opposite to decreased miR-30b-5p, miR-139-5p and miR-422a, whereas increased miR-146b-5p was associated with FABP4 and decreased glucose metabolism and FA mobilization. In partial agreement, PA (but not HG) led to decreased miR-139-5p, miR-30b-5p, miR-422a and miR-146a in vitro, in parallel with increased lipogenesis and FA transport, decreased glucose metabolism and diminished FA oxidation. CONCLUSION: This study confirms decreased liver glucose and lipid metabolism but increased FA biosynthesis coupled with changes in five unique miRNAs in obese patients with NAFLD.

Neuroinflammation in obesity: circulating lipopolysaccharide-binding protein associates with brain structure and cognitive performance.

BACKGROUND/OBJECTIVES: Growing evidence implicates neuroinflammation in the pathogenesis of diet-induced obesity and cognitive dysfunction in rodent models. Obesity is associated with reduced white matter integrity and cognitive decline. Circulating lipopolysaccharide binding protein (LBP) concentration is known to be increased in patients with obesity. Here, we aimed to evaluate whether circulating LBP is associated longitudinally with white matter structure and cognitive performance according to obesity status. SUBJECTS/METHODS: This longitudinal study analyzed circulating LBP (ELISA), DTI-metrics (axial diffusivity (L1), fractional anisotropy (FA) and radial diffusivity (RD)) in specific regions of the white matter of 24 consecutive middle-aged obese subjects (13 women) and 20 healthy volunteers (10 women) at baseline and two years later. Digit Span Test (DST) was used as a measure of working memory/short-term verbal memory. RESULTS: Circulating LBP concentration was associated with FA and L1 values of several white matter regions both at baseline and follow-up. The associations remained significant after controlling for age, BMI, fat mass and plasma high sensitivity C-reactive protein. Importantly, the increase in LBP over time impacted negatively on FA and L1 values and on DST performance. CONCLUSIONS: Circulating LBP associates with brain white matter integrity and working memory/short-term verbal memory in both obese and non-obese subjects.

Molecular aggregation of naphthalimide organic semiconductors assisted by amphiphilic and lipophilic interactions: a joint theoretical and experimental study.

Amphiphilic and lipophilic donor-acceptor naphthalimide-oligothiophene assemblies exhibiting almost identical intramolecular properties, but differing in their intermolecular interactions, have been synthesized. Here we analyze the effect of replacing the normally used lipophilic alkyl chains with hydrophilic ones in directing molecular aggregation from an antiparallel to a parallel stacking. This different molecular packing of the amphiphilic, NIP-3TAmphi, and lipophilic, NIP-3TLipo, systems is assessed by electronic spectroscopies, scanning electronic microscopy and DFT quantum-chemical calculations. Theoretical calculations indicate that the presence of amphiphilic interactions promotes a face-to-face parallel arrangement of neighbor molecules, which induces improved electronic coupling and therefore enhances the charge transport ability and photoconducting properties of this type of materials. Time of flight and photoconducting measurements are used to determine the impact of the amphiphilic and lipophilic interactions on their possible performance in optoelectronic devices.

Tuning of the Electronic Levels of Oligothiophene-Naphthalimide Assemblies by Chemical Modification.

Inversion of the connections of amidine linkers combined with controlled oligothiophene chain catenation in oligothiophene-naphthalimide assemblies provides an efficient method to tune the HOMO and LUMO values in this type of assemblies. This modification also suppresses the intramolecular charge transfer (ICT) band normally found in this type of derivatives, also delocalizing the frontier molecular orbitals over the whole conjugated skeleton. The resultant assemblies were used in the fabrication of field-effect transistors, which showed well-balanced ambipolar transport.

Benzotrithiophene versus Benzo/Naphthodithiophene Building Blocks: The Effect of Star-Shaped versus Linear Conjugation on Their Electronic Structures.

The synthesis, characterization, and optical properties of a novel star-shaped oligothiophene with a central rigid trithienobenzene (BTT) core and diketopyrrolopyrrole (DPP) units are reported and compared with homologous linear systems based on the benzodithiophene (BDT) and the naphthodithiophene (NDT) units end capped with DPPs. This comparison is aimed at elucidating the effect of the star-shaped configuration versus linear conformation on the optical and electrical properties. Electronic and vibrational spectroscopies, together with transient absorption spectroscopy, scanning electronic microscopy, and DFT calculations are used to understand not only the molecular properties of these semiconductors, but also to analyze the supramolecular aggregation in these derivatives. We conclude that although the subject star-shaped derivative is not optimal in terms of π-conjugation, its extended BTT unit significantly favors intermolecular π-stacking interactions, which is interesting for their applications in devices. Field-effect transistors and solar cells were fabricated with these new molecular semiconductors and the performance difference discussed.

Synthesis of Perylene Imide Diones as Platforms for the Development of Pyrazine Based Organic Semiconductors.

There is a great interest in peryleneimide (PI)-containing compounds given their unique combination of good electron accepting ability, high abosorption in the visible region, and outstanding chemical, thermal, and photochemical stabilities. Thus, herein we report the synthesis of perylene imide derivatives endowed with a 1,2-diketone functionality (PIDs) as efficient intermediates to easily access peryleneimide (PI)-containing organic semiconductors with enhanced absorption cross-section for the design of tunable semiconductor organic materials. Three processable organic molecular semiconductors containing thiophene and terthiophene moieties, PITa, PITb, and PITT, have been prepared from the novel PIDs. The tendency of these semiconductors for molecular aggregation have been investigated by NMR spectroscopy and supported by quantum chemical calculations. 2D NMR experiments and theoretical calculations point to an antiparallel π-stacking interaction as the most stable conformation in the aggregates. Investigation of the optical and electrochemical properties of the materials is also reported and analyzed in combination with DFT calculations. Although the derivatives presented here show modest electron mobilities of ∼10-4 cm2V-1s-1, these preliminary studies of their performance in organic field effect transistors (OFETs) indicate the potential of these new building blocks as n-type semiconductors.

Circulating irisin levels and coronary heart disease: association with future acute coronary syndrome and major adverse cardiovascular events.

INTRODUCTION: Irisin is a newly discovered myokine, associated with 'browning' of the white adipose tissue, obesity, insulin resistance and metabolic syndrome. The purpose of this study is to evaluate circulating irisin as a predictor of acute coronary syndromes (ACSs) and major adverse cardiovascular events (MACE). METHODS: Sub-study 1: a case-control study, nested within the Veteran's Affairs Normative Ageing Study, evaluating circulating irisin levels in 88 ACS cases and 158 age- and sampling year-matched controls, as a predictor of ACS. Sub-study 2: a prospective cohort study, where 103 participants with established coronary artery disease were stratified by circulating irisin levels at the time they received percutaneous coronary interventions (PCIs) and were followed for the development of MACE. RESULTS: Study 1: there was no association between irisin levels and ACS in otherwise healthy individuals (odds ratio: 1.00 95% confidence interval: (0.99-1.00)). Study 2: the incidence of MACE was significantly lower in the first irisin tertile compared with the second and third (incidence rate 0 vs 0.92 (0.51-1.61) vs 0.57 (0.28-1.14) events per 1000 person-days; P < 0.01). This was primarily driven by the lower incidence of unstable angina (incidence rate 0 vs 0.61 (0.31-1.22) vs 0.43 (0.19-0.96) per 1000 person-days; P = 0.01). CONCLUSION: This is the first study to date that demonstrates that, although circulating irisin levels do not predict the development of ACS in healthy individuals, increased irisin levels are associated with the development of MACE in patients with established coronary artery disease after PCI.

CIDEC/FSP27 and PLIN1 gene expression run in parallel to mitochondrial genes in human adipose tissue, both increasing after weight loss.

OBJECTIVE: FSP27 KO mice showed enhanced expression of mitochondrial genes, increased mitochondrial activity and smaller lipid droplets. Here, we aimed to investigate lipid droplet protein (CIDEC/FSP27 and perilipinA (PLIN1)) gene expression in human adipose tissue in association with obesity, insulin resistance and mitochondrial gene expression. DESIGN AND SUBJECTS: In cohort 1, CIDEC/FSP27, PLIN1, adipogenic (FASN, ACACA, PPARG, GLUT4) and mitochondrial (PPARGC1A, PPARGC1B, TFAM, MT-CO3) gene expression were analyzed in 171 adipose tissue samples (88 visceral adipose tissue (VAT) and 83 subcutaneous adipose tissue (SAT) depots) and in a time course experiment in human subcutaneous and visceral preadipocytes using real-time PCR. In cohort 2, the effects of bariatric surgery-induced weight loss were also evaluated in six caucasian morbidly obese women. Additionally, in cohort 2 FSP27 and PLIN1 protein levels were measured using western blotting. RESULTS: CIDEC/FSP27 (1.03±0.52 vs 0.49±0.23 relative gene expression unit (R.U.), P<0.0001) and PLIN1 (1.32±0.82 vs 0.63±0.42 R.U., P<0.0001) gene were significantly more expressed in SAT than in VAT. In VAT, CIDEC/FSP27 and PLIN1 gene expression decreased with body mass index, percent fat mass, fasting glucose, fasting insulin, HOMA and were positively associated with adipogenic (PPARG, GLUT4, FASN and ACACA) and mitochondrial biogenesis (PPARGC1A, PPARGC1B, TFAM and MT-CO3)-related genes. Mitochondrial gene expression increased during adipocyte differentiation in parallel to FSP27 and PLIN1 and other adipogenic genes. After bariatric surgery-induced weight loss, PLIN1 and CIDEC/FSP27 gene and protein expression in SAT increased significantly in parallel to adipogenic and mitochondrial genes. CONCLUSION: These findings suggest a positive functional interaction between CIDEC/FSP27, PLIN1 and mitochondrial biogenesis-related genes in human adipose tissue.

Inflammation and insulin resistance exert dual effects on adipose tissue tumor protein 53 expression.

OBJECTIVE: The purpose of this study was to investigate the expression of human adipose tissue protein 53 (p53) in subjects who varied widely in terms of obesity and insulin resistance. We also analyzed different in vivo and in vitro models to try to comprehend the associations found in humans. METHODS: p53 was analyzed in human adipose and isolated adipocytes, in high fat-fed and GLP-1R KO mice, during in vitro adipogenesis, and in adipocytes after high glucose, rosiglitazone and inflammatory conditions. The effects of surgery-induced weight loss and ex vivo metformin were also evaluated. RESULTS: Omental (OM) p53 gene expression (+27%, P=0.001) and protein (+11%, P=0.04) were increased in obese subjects and high fat diet-induced obese mice (+86%, P=0.018). Although the obesity-associated inflammatory milieu was associated with increased OM p53, this was negatively related to insulin resistance and glycated hemoglobin, and positively with biomarkers for insulin sensitivity. Multiple linear regression analyses revealed that glycated hemoglobin (P<0.0001) and body mass index (P=0.048) contributed independently to explain 13.7% (P<0.0001) of the OM p53 variance. Accordingly, the improvement of insulin sensitivity with surgery-induced weight loss (+51%, P=0.01) and metformin (+42%, P=0.02) led to increased adipose p53. While the glucose-intolerant GLP-1R KO mice showed decreased mesenteric p53 (-45.4%, P=0.017), high glucose led to decreased p53 in pre-adipocytes (-27%, P<0.0001). Inflammatory treatments led to increased p53 (+35%, P<0.0001), while Rs downregulated this expression (-40%, P=0.005) in mature adipocytes. CONCLUSION: Inflammation and insulin resistance exert dual effects on adipose p53, which seems to be the final result of these opposing forces.

Effects of delay sequence in a delay discounting task.

Delay discounting refers to the decrease in subjective value of a reward as the delay until its receipt increases. In the present study we assessed the effects of the sequence of delay blocks (increasing or decreasing) on discounting and the data systematicity using a titrating procedure with human participants. All participants completed the delay discounting task in both an increasing and decreasing sequence of delays. Delays ranged from one day to ten years. We found steeper discounting when the delays were presented in an increasing sequence compared with when they were presented in a decreasing sequence. We also found steeper discounting when participants completed the increasing sequence condition first. Our results agree with other findings reported in the literature and suggest that delay discounting may be affected by prior and subsequent experience.

The lung innate immune gene surfactant protein-D is expressed in adipose tissue and linked to obesity status.

BACKGROUND: Surfactant protein-D (SFTPD) is a component of the lung innate immunity that enhances clearance of pathogens and modulates inflammatory responses. An inverse association of putative, lung-derived circulating SFTPD with obesity has been reported but no information is available concerning possible SFTPD gene expression in human adipose tissue. METHODS: SFTPD gene expression was analyzed in human omental (OM; n=156) and subcutaneous (SC; n=106) adipose tissue, and in isolated fat cells (n=12) in association with measures of obesity and glucose tolerance. RESULTS: SFTPD gene was expressed in human adipose tissue and adipocytes. This expression was decreased in OM and SC adipose tissue from obese subjects with (-47%, P<0.0001; and -37%, P=0.048) and without (-34%, P=0.001; and -22%, P=0.08; respectively) type 2 diabetes when compared with the control group. Indeed, OM SFTPD was inversely associated with body mass index (r=-0.33, P<0.0001), percent fat mass (r=-0.36, P<0.0001), waist perimeter (r=-0.26, P=0.002), diastolic blood pressure (r=-0.21, P=0.018) and fasting glucose (r=-0.21, P=0.012); and positively linked to the expression of insulin receptor substrate 1 (IRS1; r=0.25, P=0.004), perilipin A (PLIN; r=0.38, P=0.007) and fatty acid synthase (FASN; r=0.36, P<0.0001). Accordingly, increased SFTPD (4.5-fold, P=0.02) was detected in isolated adipocytes when compared with the stromal-vascular cell fraction, in parallel to IRS1, FASN and PLIN. CONCLUSIONS: Both OM and SC adipose tissue (mainly mature adipocytes) express SFTPD. This expression decreases with obesity and impaired glucose tolerance.

Liver, but not adipose tissue PEDF gene expression is associated with insulin resistance.

OBJECTIVE: Recent studies linked circulating pigment epithelium-derived factor (PEDF) to obesity-associated insulin resistance, but the main source of circulating PEDF is unknown. We aimed to investigate liver and adipose tissue PEDF gene expression in association with obesity and insulin resistance. DESIGN, SUBJECTS AND METHODS: Three (two cross-sectional and one longitudinal) independent cohorts have been studied, for adipose tissue (n=80 and n=30) and liver gene expression (n=32 and n=14). Effects of high glucose and cytokines on HepG2 cell line were also investigated. PEDF gene expression and circulating PEDF were analyzed using real-time PCR and ELISA, respectively. RESULTS: In a first cohort of subjects, PEDF relative gene expression was higher in subcutaneous (SC) than in omental (OM) adipose tissue (P<0.0001) being also higher in mature adipocytes compared with stromo-vascular cells (P<0.0001). However, OM PEDF relative gene expression was decreased in morbidly obese subjects (P=0.01). Both OM PEDF and OM PEDF receptor (PEDFR) correlated positively with lipogenic and lipolytic genes, and with genes implicated in the lipid vacuole formation. Circulating PEDF levels were not associated with fat PEDF gene expression. In the second cohort, SC PEDF was decreased in subjects with type 2 diabetes and did not change significantly after weight loss. We next explored circulating PEDF in association with markers of liver-related insulin resistance injury (alanine aminotransferase, r=0.59, P=0.001). Interestingly, liver PEDF gene expression increased with obesity and insulin resistance in men, being significantly associated with fasting glucose and glycated hemoglobin in two independent cohorts. In fact, high glucose led to increased PEDF in HepG2 cells, while inflammatory stimuli present in the adipose tissue environment downregulated PEDF. CONCLUSION: Liver, but not adipose tissue, might be the source of increased circulating PEDF linked to insulin resistance.

Molecular and electronic-structure basis of the ambipolar behavior of naphthalimide-terthiophene derivatives: implementation in organic field-effect transistors.

A new family of naphthalimide-fused thienopyrazine derivatives for ambipolar charge transport in organic field-effect transistors is presented. Their electronic and molecular structures were elucidated through optical and vibrational spectroscopy aided by DFT calculations. The results indicate that these compounds have completely planar molecular skeletons which promote good film crystallinity and low reorganization energies for both electron and hole transport. Their performance in organic field-effect transistors is compared with twisted and planar naphthaleneamidine monoimide-fused terthiophenes in order to understand the origin of ambipolarity in this new series of molecular semiconductors.

Quality of life in patients with non-muscle invasive bladder tumor undergoing adjuvant intravesical treatment.

INTRODUCTION: The objective of the study was to establish a possible relationship between mitomycin-C (MMC) and bacillus Calmette-Guérin (BCG) treatments and quality of life impairment. MATERIAL AND METHODS: Quasi-experimental, prospective, and longitudinal study including patients undergoing adjuvant treatment in NMIBC. The Short form-12 (SF-12) and Urogenital Distress Inventory-6 (UDI-6) questionnaires were used to measure quality of life. Questionnaire scores were compared between cases with MMC and BCG before induction (M1), at 4 weeks (M2) and at 2 months (M3). RESULTS: Of the 90 patients enrolled, 54 were in the BCG group and 36 in the MMC group. It was found that BCG patients had worse perceived physical quality of life compared to MMC patients in M2 (OR:2.59, p=0.046). In addition, significant changes were found in the urinary quality of life of patients on MMC treatment between the different time points (UDI-6 score: 33.33 in M1, 27.78 in M2 and 16.67 in M3, p=0.001). CONCLUSIONS: There are no differences in urinary quality of life between patients treated with MMC and BCG. Patients with MMC show a significant recovery of urinary quality of life from the completion of the induction course, which becomes even more significant after 2 months. In addition, BCG-treated patients have worse physical quality of life after 4 weeks of treatment than those treated with MMC.

Type I iodothyronine 5'-deiodinase mRNA and activity is increased in adipose tissue of obese subjects.

Differentiation and metabolism of adipose tissue are modulated by thyroid hormones (THs), but relatively little is known about the metabolism of THs in this tissue. Expression of the genes for type I iodothyronine 5'-deiodinase (D1), leptin (LEP) and stearoyl-CoA desaturase 1 (SCD-1) was evaluated in omental (OM) and subcutaneous (SC) fat using a cohort of 70 humans. Activities of iodothyronine deiodinases (D1, D2 and D3) were assessed in a randomly selected subpopulation of 19 subjects. D1 expression was upregulated in both OM (P=0.011) and SC (P=0.003) fat of obese subjects. Concomitantly, OM (P=0.002) and SC (P=0.028) LEP expression were increased in obesity, associated with both D1 mRNA (r=0.315, P=0.014) and activity (r=0.647, P=0.023) and inversely related to SCD-1 (r=-0.266, P=0.034) expression in SC fat. Also D1 (but not D2 and D3) activity was increased in OM (∼fourfold, P=0.010) and SC (∼eightfold, P=0.004) fat of obese when compared with non-obese subjects and correlated in both OM (r=0.528, P=0.036) and SC (r=0.749, P=0.005) fat with body mass index. Our results document increased D1 gene expression and activity in adipose tissue of obese humans and suggest a role of 3,5,3'-triiodo-L-thyronine formed by D1 in response to leptin in the modulation of adipose tissue metabolism.