Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC.

Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC.

Nematic Phase of Polar Unsymmetrical Bent-Core Molecules.

In liquid crystalline systems, the presence of polar groups at lateral or terminal positions is fundamentally and technologically important. Bent-core nematics composed of polar molecules with short rigid cores usually exhibit highly disordered mesomorphism with some ordered clusters that favourably nucleate within. Herein, we have systematically designed and synthesized two new series of highly polar bent-core compounds comprised of two unsymmetrical wings, highly electronegative -CN and -NO2 groups at one end, and flexible alkyl chains at the other end. All the compounds showed a wide range of nematic phases composed of cybotactic clusters of smectic-type (Ncyb ). The birefringent microscopic textures of the nematic phase were accompanied by dark regions. Further, the cybotactic clustering in the nematic phase was characterized via temperature-dependent XRD studies and dielectric spectroscopy. Besides, the birefringence measurements demonstrated the ordering of the molecules in the cybotactic clusters upon lowering the temperature. DFT calculations illustrated the favourable antiparallel arrangement of these polar bent-core molecules as it minimizes the large net dipole moment of the system.

Neuroprotective effect of standardized extracts of three Lactuca sativa Linn. varieties against 3-NP induced Huntington's disease like symptoms in rats.

OBJECTIVES: The study was aimed to evaluate the efficacy of three commonly consumed Lactuca sativa (LS) Linn. varieties viz., Grand rapid, Lollo rosso and Iceberg (Asteraceae) against 3-NP induced HD like symptoms in rats. METHODS: Ethanol extracts of leaves of three LS varieties were prepared, and standardized on the basis of quercetin content using HPLC. These extracts (100 and 200 mg kg, p.o. for 20 days) were evaluated for their neuroprotective effect against 3-NP (10 mg/kg, i.p. for 14 days) induced neurotoxicity in male Wistar rats. The extract that exhibited maximum activity was successively fractionated using hexane, ethyl acetate, n-butanol and aqueous in increasing order of polarity. These fractions were also evaluated (dose equivalent to the dose of the extract of LS variety exhibiting maximum activity) for their neuroprotective effect. The protective effect of extracts and fractions was evaluated using different behavioral (rota rod, actophotometer, beam walk and Morris water maze) and biochemical (malondialdehyde, nitrite, superoxide dismutase, catalase and reduced glutathione) parameters. RESULTS: 3-NP elicit marked deterioration in motor coordination, locomotor activity and memory in comparison to control group. Standardized ethanol extract of grand rapid (200 mg/kg) exhibited maximum activity amongst the three tested varieties. Therefore, its fractions were also evaluated, and n-butanol fraction (40 mg/kg) exhibited maximum attenuation of 3-NP induced HD like symptoms which was evident from improved behavioral and biochemical parameters. DISCUSSION: The results exhibit that LS (Grand rapid variety) prophylaxis mitigated 3-NP induced neurotoxicity and HD like symptoms in rats due to its potent antioxidant potential.

Chemically realistic coarse-grained models for polyelectrolyte solutions.

Polyelectrolyte solutions are of considerable scientific and practical importance. One of the most widely studied polymer is polystyrene sulfonate (PSS), which has a hydrophobic backbone with pendant charged groups. A polycation with similar chemical structure is poly(vinyl benzyltri methyl) ammonium (PVBTMA). In this work, we develop coarse-grained (CG) models for PSS and PVBTMA with explicit CG water and with sodium and chloride counterions, respectively. We benchmark the CG models via a comparison with atomistic simulations for single chains. We find that the choice of the topology and the partial charge distribution of the CG model, both play a crucial role in the ability of the CG model to reproduce results from atomistic simulations. There are dramatic consequences, e.g., collapse of polyions, with injudicious choices of the local charge distribution. The polyanions and polycations exhibit a similar conformational and dynamical behavior, suggesting that the sign of the polyion charge does not play a significant role.

Importance of feature construction in machine learning for phase transitions.

Machine learning is an important tool in the study of the phase behavior from molecular simulations. In this work, we use un-supervised machine learning methods to study the phase behavior of two off-lattice models, a binary Lennard-Jones (LJ) mixture and the Widom-Rowlinson (WR) non-additive hard-sphere mixture. The majority of previous work has focused on lattice models, such as the 2D Ising model, where the values of the spins are used as the feature vector that is input into the machine learning algorithm, with considerable success. For these two off-lattice models, we find that the choice of the feature vector is crucial to the ability of the algorithm to predict a phase transition, and this depends on the particular model system being studied. We consider two feature vectors, one where the elements are distances of the particles of a given species from a probe (distance-based feature) and one where the elements are +1 if there is an excess of particles of the same species within a cut-off distance and -1 otherwise (affinity-based feature). We use principal component analysis and t-distributed stochastic neighbor embedding to investigate the phase behavior at a critical composition. We find that the choice of the feature vector is the key to the success of the unsupervised machine learning algorithm in predicting the phase behavior, and the sophistication of the machine learning algorithm is of secondary importance. In the case of the LJ mixture, both feature vectors are adequate to accurately predict the critical point, but in the case of the WR mixture, the affinity-based feature vector provides accurate estimates of the critical point, but the distance-based feature vector does not provide a clear signature of the phase transition. The study suggests that physical insight into the choice of input features is an important aspect for implementing machine learning methods.

Nutritional requirements for the elderly in India: A status paper.

Advances in the medical field and healthcare sector during the last few decades have resulted in increased longevity. Increased lifespans have in turn led to a rapid global rise of the elderly population. However, ensuring the health and quality of life, especially in the context of chronic age-related ailments, among the growing geriatric population is a challenge. Ageing is associated with several changes in body composition including a decline in the lean body mass usually accompanied by an increase in body fat content which have a bearing on the nutrient requirements for the elderly. The nutrient requirements currently recommended for Indian adults are primarily computed using a factorial approach, that considers the cumulative loss of nutrients and is adjusted for optimal body weights and bioavailability. It is logical that physiological and metabolic changes associated with ageing influence several of these factors: body weight, lean mass, energy expenditure, nutrient retention and bioavailability and thus alter nutrient requirements compared to the adult population. Acknowledging these age-related changes, some international organizations have suggested nutrient requirements specific to the elderly. Given the contextual differences in physiology, caution needs to be exercised in adopting these guidelines for the Indian elderly. In addition, in the Indian context, there is sparse information on the diet and nutrient intakes vis-à -vis nutritional status and physiology of the elderly. This status paper highlights some of the pertinent issues related to nutritional requirements for the elderly that advocate a need for deriving nutritional requirements for the elderly in India.

Discovery of small molecule inhibitors of Plasmodium falciparum apicoplast DNA polymerase.

Malaria is caused by infection with protozoan parasites of the Plasmodium genus, which is part of the phylum Apicomplexa. Most organisms in this phylum contain a relic plastid called the apicoplast. The apicoplast genome is replicated by a single DNA polymerase (apPOL), which is an attractive target for anti-malarial drugs. We screened small-molecule libraries (206,504 compounds) using a fluorescence-based high-throughput DNA polymerase assay. Dose/response analysis and counter-screening identified 186 specific apPOL inhibitors. Toxicity screening against human HepaRG human cells removed 84 compounds and the remaining were subjected to parasite killing assays using chloroquine resistant P. falciparum parasites. Nine compounds were potent inhibitors of parasite growth and may serve as lead compounds in efforts to discover novel malaria drugs.

Protocolized approach saves the limb in peripheral arterial injury: A decade experience.

PURPOSE: Outcomes of peripheral arterial injury (PAI) depend on various factors, such as warm ischemia time and concomitant injuries. Suboptimal prehospital care may lead to delayed presentation, and a lack of dedicated trauma system may lead to poorer outcome. Also, there are few reports of these outcomes. The aim of this study was to review our experience of PAI management for more than a decade, and identify the predictors of limb loss in these patients. METHODS: This is a retrospective analysis of prospectively maintained database of trauma admissions at a level I trauma center from January 2008 to December 2019. Patients with acute upper limb arterial injuries or lower limb arterial injuries at or above the level of popliteal artery were included. Association of limb loss with ischemia time, mechanism of injury and concomitant injuries was studied using multiple logistic regressions. Statistical analysis was performed using STATA version 15.0 (Stata Corp LLC, Texas). RESULTS: Out of 716 patients with PAI, the majority (92%) were young males. Blunt trauma was the most common mechanism of injury. Median ischemia time was 4 h (interquartile range 2-7 h). Brachial artery (28%) was the most common injured vessel followed by popliteal artery (18%) and femoral artery (17%). Limb salvage rate was 78%. Out of them, 158 (22%) patients needed amputation, and 53 (7%) had undergone primary amputation. The majority (86%) of patients who required primary or secondary amputations had blunt trauma. On multivariate analysis, blunt trauma, ischemia time more than 6 h and concomitant venous, skeletal, and soft tissue injuries were associated with higher odds of amputation. CONCLUSION: Over all limb salvage rates was 78% in our series. Blunt mechanism of injury and associated skeletal and soft tissue injury, ischemia time more than 6 h portend a poor prognosis. Injury prevention, robust prehospital care, and rapid referral to specialized trauma center are few efficient measures, which can decrease the morbidity associated with vascular injury.

Photo-Responsive Behavior of Azobenzene Based Polar Hockey-Stick-Shaped Liquid Crystals.

A study on the photoswitching behavior of azobenzene-based polar hockey-stick-shaped liquid crystals (HSLCs) has been presented. Two new series of five phenyl rings based polar HSLCs have been designed and synthesized. Solution state photoisomerization of the synthesized materials was investigated thoroughly via UV-visible and 1 H NMR spectroscopic techniques, whereas solid-state photochromic behavior was elucidated via physical color change of the materials, solid-state UV-visible study, powder XRD, and FE-SEM techniques. The materials exhibited decent photochromic behavior for different potential applications. The thermal phase behavior of the superstructural assembly has been characterized via polarizing optical microscopy (POM), differential scanning calorimetry (DSC), and temperature-dependent small and wide-angle X-ray scattering (SAXS/WAXS) studies. Depending upon the length of the terminal alkyl chain, nematic (N) and partially bilayer smectic A (SmAd ) phases were observed. DFT calculations revealed the favorable anti-parallel arrangement of the polar molecules that substantiate the formation of SmAd phase.

National Landscape of Unplanned 30-Day Readmission Rates for Acute Non-hemorrhagic Diverticulitis: Insight from National Readmission Database.

BACKGROUND: Early readmissions are an important indicator of the quality of care. Limited data exist describing hospital readmissions in acute diverticulitis. The study aimed to describe unplanned, 30-day readmissions among adult acute diverticulitis patients and to assess readmission predictors. METHODS: We analyzed the 2013 and 2014 United States National Readmission Database and identified acute diverticulitis admissions using administrative codes in adult patients older than 18 years of age. Our primary outcome was a 30-day, unplanned readmission rate. We used Chi-square tests, t tests, and Wilcoxon rank-sum tests for descriptive analyses and survey logistic regression to calculate adjusted odds ratios (aORs) and 95% confidence intervals for associations with readmissions adjusting for confounders. RESULTS: In the cohort of 364,511 hospitalizations with acute diverticulitis, as the primary diagnosis on index admission, 31,420 (8.6%) had at least one unplanned 30-day readmission. Sixty percent of the readmissions occurred within the first 2 weeks of the index admission. The most common reasons for unplanned 30-day readmission were due to diverticulitis of the colon (41.5%), postoperative infection (4.2%), septicemia (3.6%), intestinal infection due to Clostridium difficile (3%), and other digestive system complications such bleeding or fistula (2.8%). Multivariable analysis showed advance age (> 75 years), discharge against medical advice, comorbidities (renal failure, coronary artery disease, atrial fibrillation, congestive heart failure, hypertension, diabetes, obesity, weight loss, chronic lung disease, malignancy), blood transfusion, Medicare and Medicaid insurance, and increased length of stay (> 3 days) were associated with significantly higher odds for readmission. Patients who have undergone abdominal surgery during index admission were 31% less likely to get readmitted. CONCLUSIONS: On a national level, 1 in 11 hospitalizations for acute diverticulitis was followed by unplanned readmission within 30 days with most admissions occurring in the first 2 weeks. Multiple modifiable and non-modifiable factors influencing readmission rates were noted. Further studies should examine if strategies that address these predictors can decrease readmissions.

Chiral Bent-Shaped Molecules Exhibiting Unusually Wide Range of Blue Liquid-Crystalline Phases and Multistimuli-Responsive Behavior.

Recently, an unprecedented observation of polar order, thermochromic behavior, and exotic mesophases in new chiral, bent-shaped systems with a -CH3 moiety placed at the transverse position of the central core was reported. Herein, a homologous series of compounds with even-numbered carbon chains from n=4 to 18 were synthesized, in which -Cl was substituted for -CH3 at the kink position and a drastic modification in the phase structure of the bent-shaped molecule was observed. An unusual stabilization of the cubic blue phase (BP) over a wide range of 16.4 °C has been witnessed. Two homologues in this series (1-12 and 1-14) exhibit an interesting phase sequence consisting of BPI/II, chiral nematic, twist grain boundary, smectic A, and smectic X (SmX) phases. The higher homologues (1-16 and 1-18) stabilize the SmX phase enantiotropically over the entire temperature range. Crystal structure analysis confirmed the bent molecular architecture, with a bent angle of 148°, and revealed the presence of two different molecular conformations in an asymmetric unit of compound 1-4. A DFT study corroborated that the -Cl moiety at the central core of the molecule led to an increase in the dipole moment along the transverse direction, which, in turn, facilitated the unusual stabilization of frustrated structures. Crystal polymorphism has been evidenced in three homologues (1-10, 1-12, and 1-14) of the series. On the application of mechanical pressure through grinding, compound 1-10 transformed from a bright yellow crystalline solid to a dark orange-green amorphous solid, which reversed upon dropwise addition of dichloromethane, indicating reversible mechanochromism in this class of compounds. In addition, excellent thermochromic behavior has been observed for compound 1-10 with a controlled temperature-color combination.

Microrheology to probe smectic clusters in bent-core nematic liquid crystals.

Many bent-core nematic liquid crystals exhibit unusual physical properties due to the presence of smectic clusters, known as "cybotactic" clusters, in the nematic phase. Here, we investigate the effect of these clusters on the complex shear modulus (G*(ω)) of two asymmetric bent-core liquid crystals using a microrheological technique. The compound with a shorter hydrocarbon chain (8OCH3) exhibits only a nematic (N) phase whereas the compound with a longer chain (16OCH3) exhibits both nematic (N) and smectic-A (SmA) phases. The rheological results are correlated with the measurements of curvature elastic constants. Our results show that the directional shear modulus of 16OCH3, just above the SmA to N phase transition temperature, is strikingly different than that of 8OCH3, owing to the smectic clusters. An approximate size of the clusters is estimated using a simple model. Therefore, microrheological studies on bent-core nematic liquid crystals are very useful in extracting information about underlying smectic clusters.

Determinants of low birth weight in India: An investigation from the National Family Health Survey.

OBJECTIVE: This study aimed to estimate the change in prevalence of low birth weight (LBW) over the last decade in India and to identify its associated factors-biological, demographic, socio-economic, and programmatic. METHODS: We used the data from the National Family Health Survey of 2005-2006 (NFHS-3) and 2015-2016 (NFHS-4). The sample of this study included 11 300 children from NFHS-3 and 99 894 from NFHS-4 data; all these children were the last full-term singleton live-births, born within the last 3 years prior to the survey. RESULTS: In India, the prevalence of LBW has significantly declined from 20.4% (95%CI 19.4-21.4) to 16.4% (95% CI 16.1-16.8) in the last decade. The prevalence of LBW remained high in girl children (OR = 1.2, 95% CI 1.2-1.3; P < .001), whose mothers were adolescent (OR = 1.2, 95% CI 1.1-1.3; P < .001), and were stunted (OR = 1.3, 95% CI 1.3-1.3; P < .001). Prevalence of LBW declined among second or higher birth order child (OR = 0.8, 95% CI 0.8-0.9; P < .001), whose mothers educated up to secondary level and above (OR = 0.6 to 0.8), belonged to rich wealth quintiles (OR = 0.9 to 0.8), were from rural area (OR = 0.9, 95% CI 0.9-1.0; P < .001), received better nutrition and adequate antenatal care (OR = 0.8, 95% CI 0.8-0.8; P < .001), and were from eastern, northeastern, and southern regions of India (OR = 0.9 to 0.5). CONCLUSION: Although the prevalence of LBW in India has declined over the past decade, the extent of the decline is modest. In the coming years, health programs in India need to gear up with greater convergence between maternal health services and maternal nutrition to reduce LBW.

National trends of endoscopic retrograde cholangiopancreatography utilization and outcomes in decompensated cirrhosis.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) can be challenging in patients with decompensated cirrhosis (DC) due to increased risk of adverse events related to liver dysfunction. Limited data exist regarding its national utilization in patients with DC. We aim to determine the trends in utilization and outcomes of ERCP among patients with DC in US hospitalizations. METHODS: We identified hospitalizations undergoing ERCP (diagnostic and therapeutic) between 2000 and 2013 from the National Inpatient Sample (NIS) database and used validated ICD9-CM codes to identify DC hospitalizations. We utilized Cochrane-Armitage test to identify changes in trends and multivariable survey regression modeling for adjusted odds ratios (aOR) for adverse outcomes and mortality predictors. RESULTS: There were 43782 cases of ERCPs performed in DC patients during the study period. Absolute number of ERCPs performed in this population from 2000 to 2013 showed an upward trend; however, the proportion of DC patients undergoing ERCP remained stable. We noted significant decrease in utilization of diagnostic ERCP and an increase of therapeutic ERCPs (P < 0.01). There was a significant decrease in the mean length of stay for DC patients undergoing ERCP from 8.2 days in 2000 to 7.2 days in 2013 (P < 0.01) with an increase in the mean cost of hospitalization from $17053 to $19825 (P < 0.001). Mortality rates showed a downward trend from 2000 to 2013 from 13.6 to 9.6% (P < 0.01). Increasing age, Hispanic race, diagnosis of hypertension and diabetes mellitus, and private insurance were related to adverse discharges(P < 0.01). Increasing age, presence of hepatic encephalopathy, and sepsis were associated with higher mortality (P < 0.01). CONCLUSIONS: There is an increasing trend in therapeutic ERCP utilization in DC hospitalizations nationally. There is an overall decrease in mortality in DC hospitalizations undergoing ERCP. This improvement in mortality suggests improvement in both procedural technique and peri-procedural care as well as overall decreasing mortality in cirrhosis.

A case of cervical spinal mass with cord compression and rib bone metastasis from presumably burned-out seminomatous testicular germ cell tumor.

Most germ cell tumors are located in the gonads however there are instances where these tumors are located elsewhere in which are termed extragonadal germ cell tumors. When primary lesion of the testicular tumor has regressed, the term "burned-out testicular tumor" has been proposed. We herein report the first case of burned-out seminoma of the testis presenting as a cervical spinal mass causing cord compression with bone metastasis.

Synergistic cross-talk of hedgehog and interleukin-6 signaling drives growth of basal cell carcinoma.

Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin-6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis-regulatory sequences by co-binding of GLI and STAT3 to common HH-IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI-driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH-IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

Impact of amphiphilic molecules on the structure and stability of homogeneous sphingomyelin bilayer: Insights from atomistic simulations.

Modulation of lipid membrane properties due to the permeation of amphiphiles is an important biological process pertaining to many applications in the field of pharmaceutics, toxicology, and biotechnology. Sphingolipids are both structural and functional lipids that constitute an important component of mechanically stable and chemically resistant outer leaflets of plasma membranes. Here, we present an atomistic molecular dynamics simulation study to appreciate the concentration-dependent effects of small amphiphilic molecules, such as ethanol, acetone, and dimethyl sulfoxide (DMSO), on the structure and stability of a fully hydrated homogeneous N-palmitoyl-sphingomyelin (PSM) bilayer. The study reveals an increase in the lateral expansion of the bilayer along with disordering of the hydrophobic lipid tails on increasing the concentration of ethanol. At higher concentrations of ethanol, rupturing of the bilayer is quite evident through the analysis of partial electron density profiles and lipid tail order parameters. For ethanol containing systems, permeation of water molecules in the hydrophobic part of the bilayer is allowed through local defects made due to the entry of ethanol molecules via ethanol-ethanol and ethanol-PSM hydrogen bonds. Moreover, the extent of PSM-PSM hydrogen bonding decreases with increasing ethanol concentration. On the other hand, acetone and DMSO exhibit minimal effects on the stability of the PSM bilayer at their lower concentrations, but at higher concentrations they tend to enhance the stability of the bilayer. The simulated potential of mean force (PMF) profiles for the translocation of the three solutes studied reveal that the free-energy of transfer of an ethanol molecule across the PSM lipid head region is lower than that for acetone and DMSO molecules. However, highest free-energy rise in the core hydrophobic part of the bilayer is observed for the DMSO molecule, whereas the ethanol and acetone PMF profiles show a lower barrier in the hydrophobic region of the bilayer.

Bulk and interfacial structures of reline deep eutectic solvent: A molecular dynamics study.

We apply all-atom molecular dynamics simulations to describe the bulk morphology and interfacial structure of reline, a deep eutectic solvent comprising choline chloride and urea in 1:2 molar ratio, near neutral and charged graphene electrodes. For the bulk phase structural investigation, we analyze the simulated real-space radial distribution functions, X-ray/neutron scattering structure functions, and their partial components. Our study shows that both hydrogen-bonding and long-range correlations between different constituents of reline play a crucial role to lay out the bulk structure of reline. Further, we examine the variation of number density profiles, orientational order parameters, and electrostatic potentials near the neutral and charged graphene electrodes with varying electrode charge density. The present study reveals the presence of profound structural layering of not only the ionic components of reline but also urea near the electrodes. In addition, depending on the electrode charge density, the choline ions and urea molecules render different orientations near the electrodes. The simulated number density and electrostatic potential profiles for reline clearly show the presence of multilayer structures up to a distance of 1.2 nm from the respective electrodes. The observation of positive values of the surface potential at zero charge indicates the presence of significant nonelectrostatic attraction between the choline cation and graphene electrode. The computed differential capacitance (Cd) for reline exhibits an asymmetric bell-shaped curve, signifying different variation of Cd with positive and negative surface potentials.

Hepatocyte glutathione peroxidase-1 deficiency improves hepatic glucose metabolism and decreases steatohepatitis in mice.

AIMS/HYPOTHESIS: In obesity oxidative stress is thought to contribute to the development of insulin resistance, non-alcoholic fatty liver disease and the progression to non-alcoholic steatohepatitis. Our aim was to examine the precise contributions of hepatocyte-derived H2O2 to liver pathophysiology. METHODS: Glutathione peroxidase (GPX) 1 is an antioxidant enzyme that is abundant in the liver and converts H2O2 to water. We generated Gpx1 lox/lox mice to conditionally delete Gpx1 in hepatocytes (Alb-Cre;Gpx1 lox/lox) and characterised mice fed chow, high-fat or choline-deficient amino-acid-defined (CDAA) diets. RESULTS: Chow-fed Alb-Cre;Gpx1 lox/lox mice did not exhibit any alterations in body composition or energy expenditure, but had improved insulin sensitivity and reduced fasting blood glucose. This was accompanied by decreased gluconeogenic and increased glycolytic gene expression as well as increased hepatic glycogen. Hepatic insulin receptor Y1163/Y1163 phosphorylation and Akt Ser-473 phosphorylation were increased in fasted chow-fed Alb-Cre;Gpx1 lox/lox mice, associated with increased H2O2 production and insulin signalling in isolated hepatocytes. The enhanced insulin signalling was accompanied by the increased oxidation of hepatic protein tyrosine phosphatases previously implicated in the attenuation of insulin signalling. High-fat-fed Alb-Cre;Gpx1 lox/lox mice did not exhibit alterations in weight gain or hepatosteatosis, but exhibited decreased hepatic inflammation, decreased gluconeogenic gene expression and increased insulin signalling in the liver. Alb-Cre;Gpx1 lox/lox mice fed a CDAA diet that promotes non-alcoholic steatohepatitis exhibited decreased hepatic lymphocytic infiltrates, inflammation and liver fibrosis. CONCLUSIONS/INTERPRETATION: Increased hepatocyte-derived H2O2 enhances hepatic insulin signalling, improves glucose control and protects mice from the development of non-alcoholic steatohepatitis.

Infective Endocarditis in Hemodialysis Patients.

BACKGROUND AND AIM OF THE STUDY: Infective endocarditis (IE) is a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD). The study aim was to evaluate the demographic, clinical, microbiological and inpatient mortality data of IE in hemodialysis patients. METHODS: Data were analyzed for all IE patients admitted to the authors' 800-bed tertiary care hospital between January 2001 and December 2014. These data included demographics, comorbidities, clinical and microbiological characteristics, echocardiographic findings, complications, outcomes, and in-patient mortality. RESULTS: A total of 296 patients, including 52 on hemodialysis, was admitted with a diagnosis of IE. The median age of patients with ESRD (28 females, 24 males) was 55.9 ± 15.47 years. The prevalences of comorbidities such as hypertension (80%) and diabetes mellitus (46%) were significantly higher in ESRD patients, whereas other comorbidities were similarly distributed in both groups. The mitral valve was the most commonly involved (55.8%), followed by aortic (21.7%), tricuspid (21.2%) and pulmonary (1.9%) valves. Staphylococcus aureus was the most common organism (40%), followed by Enterococcus sp. (13.7%), Gram-negative staphylococci (13.7%), coagulase-negative staphylococci (11.5%), and Streptococcus sp. (5.7%). Polymicrobes were found in 11.5% of patients and cultures were negative in 19%. The mean ejection fraction in these patients was 42 ± 4.19% and the mean area of vegetation was 63.5 ± 40 mm2. The in-hospital course of 11 patients was complicated by embolic events, while three patients had acute heart failure and one patient had heart block secondary to IE. A total of four patients (7.7%) died during the index hospitalization. CONCLUSIONS: IE in patients receiving chronic hemodialysis is a very frequent occurrence. Its diagnosis is complex and its presence should be considered in all hemodialysis patients with bacteremia. In the present study the etiology was shown to be multifactorial, with the mitral valve being the most commonly involved and S. aureus the most common organism.