High prevalence of non-alcoholic fatty liver disease and metabolic risk factors in Guatemala: A population-based study.

BACKGROUND: There are no data on the prevalence of non-alcoholic fatty liver disease (NAFLD) in general population samples in Guatemala or in other Central American countries. The prevalence and distribution of NAFLD and its associated risk factors were evaluated in a population-based sample of adults in Guatemala. METHODS: Cross-sectional study of 411 men and women 40 years of age or older residing in urban and rural areas of Guatemala. Metabolic outcomes included obesity, central obesity, hypercholesterolemia, diabetes, and metabolic syndrome (MetS). Liver disease outcomes included elevated liver enzymes, elevated Fatty Liver Index (FLI), and elevated FIB-4 score. RESULTS: The overall prevalence of obesity, central obesity, diabetes, and MetS were 30.9, 74.3, 21.6, and 64.2%, respectively. The fully-adjusted prevalence ratios (95% CI) for obesity, central obesity, diabetes, and MetS comparing women to men were 2.83 (1.86-4.30), 1.72 (1.46-2.02), 1.18 (1.03-1.34), and 1.87 (1.53-2.29), respectively. The overall prevalence of elevated liver enzymes (ALT or AST), elevated FLI, and elevated FIB-4 scores were 38.4, 60.1, and 4.1%, respectively. The fully-adjusted prevalence ratios (95% CI) for elevated liver enzymes (either ALT or AST) and elevated FLI score comparing women to men were 2.99 (1.84-4.86) and 1.47 (1.18-1.84), respectively. CONCLUSIONS: The prevalence of metabolic abnormalities and liver outcomes in this general population study was very high. The prevalence of metabolic and liver abnormalities was particularly high among women, an observation that could explain the atypical 1:1 male to female ratio of liver cancer in Guatemala.

Soft X-Ray Second Harmonic Generation as an Interfacial Probe.

Nonlinear optical processes at soft x-ray wavelengths have remained largely unexplored due to the lack of available light sources with the requisite intensity and coherence. Here we report the observation of soft x-ray second harmonic generation near the carbon K edge (∼284 eV) in graphite thin films generated by high intensity, coherent soft x-ray pulses at the FERMI free electron laser. Our experimental results and accompanying first-principles theoretical analysis highlight the effect of resonant enhancement above the carbon K edge and show the technique to be interfacially sensitive in a centrosymmetric sample with second harmonic intensity arising primarily from the first atomic layer at the open surface. This technique and the associated theoretical framework demonstrate the ability to selectively probe interfaces, including those that are buried, with elemental specificity, providing a new tool for a range of scientific problems.

Exogenous Carbohydrate Reduces Cortisol Response from Combined Mental and Physical Stress.

Combined mental and physical stress is associated with exacerbated cortisol production which may increase risk for the progression of cardiovascular disease in individuals working in high-stress occupations (e.g., firefighters, military personnel, etc.). Carbohydrate (CHO) ingestion prior to physical stress may attenuate cortisol concentrations. This project was the first to investigate the effect of CHO ingestion on cortisol response from combined mental and physical stress. 16 men 21-30 years old were randomly assigned a 6.6% CHO beverage or non-CHO control 15 min prior to performing a dual-concurrent-stress challenge. This consisted of physical stress (i.e., steady state exercise) combined with computerized mental challenges. Blood was sampled 70, 40, and 15 min before exercise, immediately at onset of exercise, 10, 20, 30, 35 min during exercise, and 15, 30, 45, and 60 min after exercise. There was a significant main effect for treatment regarding mean cortisol concentrations (F=5.30, P=0.0219). The total area under curve for cortisol was less when CHO was ingested (T7=4.07, P=0.0048). These findings suggest that CHO ingestion immediately prior to combined mental and physical stress may attenuate cortisol responses.

Metrological challenges for measurements of key climatological observables, Part 4: Atmospheric relative humidity.

Water in its three ambient phases plays the central thermodynamic role in the terrestrial climate system. Clouds control Earth's radiation balance, atmospheric water vapour is the strongest "greenhouse" gas, and non-equilibrium relative humidity at the air-sea interface drives evaporation and latent heat export from the ocean. In this paper, we examine the climatologically relevant atmospheric relative humidity, noting fundamental deficiencies in the definition of this key observable. The metrological history of this quantity is reviewed, problems with its current definition and measurement practice are analysed, and options for future improvements are discussed in conjunction with the recent seawater standard TEOS-10. It is concluded that the International Bureau of Weights and Measures, (BIPM), in cooperation with the International Association for the Properties of Water and Steam, IAPWS, along with other international organisations and institutions, can make significant contributions by developing and recommending state-of-the-art solutions for this long standing metrological problem, such as are suggested here.

Metrological challenges for measurements of key climatological observables: Oceanic salinity and pH, and atmospheric humidity. Part 1: Overview.

Water in its three ambient phases plays the central thermodynamic role in the terrestrial climate system. Clouds control Earth's radiation balance, atmospheric water vapour is the strongest "greenhouse" gas, and non-equilibrium relative humidity at the air-sea interface drives evaporation and latent heat export from the ocean. On climatic time scales, melting ice caps and regional deviations of the hydrological cycle result in changes of seawater salinity, which in turn may modify the global circulation of the oceans and their ability to store heat and to buffer anthropogenically produced carbon dioxide. In this paper, together with three companion articles, we examine the climatologically relevant quantities ocean salinity, seawater pH and atmospheric relative humidity, noting fundamental deficiencies in the definitions of those key observables, and their lack of secure foundation on the International System of Units, the SI. The metrological histories of those three quantities are reviewed, problems with their current definitions and measurement practices are analysed, and options for future improvements are discussed in conjunction with the recent seawater standard TEOS-10. It is concluded that the International Bureau of Weights and Measures, BIPM, in cooperation with the International Association for the Properties of Water and Steam, IAPWS, along with other international organisations and institutions, can make significant contributions by developing and recommending state-of-the-art solutions for these long standing metrological problems in climatology.

Sustainability assessment of electrokinetic bioremediation compared with alternative remediation options for a petroleum release site.

Sustainable management practices can be applied to the remediation of contaminated land to maximise the economic, environmental and social benefits of the process. The Sustainable Remediation Forum UK (SuRF-UK) have developed a framework to support the implementation of sustainable practices within contaminated land management and decision making. This study applies the framework, including qualitative (Tier 1) and semi-quantitative (Tier 2) sustainability assessments, to a complex site where the principal contaminant source is unleaded gasoline, giving rise to a dissolved phase BTEX and MTBE plume. The pathway is groundwater migration through a chalk aquifer and the receptor is a water supply borehole. A hydraulic containment system (HCS) has been installed to manage the MTBE plume migration. The options considered to remediate the MTBE source include monitored natural attenuation (MNA), air sparging/soil vapour extraction (AS/SVE), pump and treat (PT) and electrokinetic-enhanced bioremediation (EK-BIO). A sustainability indictor set from the SuRF-UK framework, including priority indicator categories selected during a stakeholder engagement workshop, was used to frame the assessments. At Tier 1 the options are ranked based on qualitative supporting information, whereas in Tier 2 a multi-criteria analysis is applied. Furthermore, the multi-criteria analysis was refined for scenarios where photovoltaics (PVs) are included and amendments are excluded from the EK-BIO option. Overall, the analysis identified AS/SVE and EK-BIO as more sustainable remediation options at this site than either PT or MNA. The wider implications of this study include: (1) an appraisal of the management decision from each Tier of the assessment with the aim to highlight areas for time and cost savings for similar assessments in the future; (2) the observation that EK-BIO performed well against key indicator categories compared to the other intensive treatments; and (3) introducing methods to improve the sustainability of the EK-BIO treatment design (such as PVs) did not have a significant effect in this instance.

Effect of fertilizer formulation and bioaugmentation on biodegradation and leaching of crude oils and refined products in soils.

The effects of soil characteristics and oil types as well as the efficacy of two fertilizer formulations and three bioaugmentation packages in improving the bioremediation of oil-contaminated soils were assessed as a means of ex situ treatment selection and optimization through seven laboratory microcosm studies. The influence of bioremediation on leaching of oil from the soil was also investigated. The studies demonstrated the benefits ofbiostimulation to overcome nutrient limitation, as most of the soils were nutrient depleted. The application of both liquid and pelleted slow-release N and P fertilizers increased both the hydrocarbon biodegradation rates (by a factor of 1.4 to 2.9) and the percentage of hydrocarbon mass degraded (by > 30% after 12 weeks and 80% after 37 weeks), when compared with the unamended soils. Slow-release fertilizers can be particularly useful when multiple liquid applications are not practical or cost-effective. Bioaugmentation products containing inoculum plus fertilizer also increased biodegradation by 20% to 37% compared with unamended biotic controls; however, there was no clear evidence of additional benefits due to the inocula, compared with fertilizer alone. Therefore biostimulation is seen as the most cost-effective bioremediation strategy for contaminated soils with the levels of crude oil and refined products used in this study. However, site-specific considerations remain essential for establishing the treatability of oil-contaminated soils.

Lysis of ras oncogene-transformed cells by specific cytotoxic T lymphocytes elicited by primary in vitro immunization with mutated ras peptide.

Ras protooncogenes are activated by characteristic point mutations in a wide variety of malignancies. The expressed p21ras proteins are oncogenic by virtue of single substituted amino acids, usually at position 12 or 61 of the 189-residue p21ras protein. In the current study, the ability of class I major histocompatibility complex (MHC)-restricted T cells to recognize the altered segment of a transforming p21ras protein and to lyse cells transformed by the corresponding ras oncogene was examined. Synthetic ras peptides encompassing the common activating substitution of leucine for glutamine at position 61 were constructed with an amino acid motif appropriate for binding to the H-2Kb murine class I MHC molecule. Cytotoxic T lymphocytes (CTL) specific for bound ras leucine 61 peptide were elicited by in vitro immunization of normal lymphocytes with synthetic peptides. The ras peptide-induced CTL specifically lysed syngeneic fibroblasts transformed by an activated ras gene encoding oncogenic p21ras protein containing the same single amino acid substitution. Thus, in some circumstances, mutated p21ras protein can serve as a tumor-specific antigen.

The vitronectin receptor alpha v beta 3 binds fibronectin and acts in concert with alpha 5 beta 1 in promoting cellular attachment and spreading on fibronectin.

The vitronectin receptor (alpha v beta 3) is a member of the integrin superfamily of adhesive protein receptors that mediate a wide spectrum of adhesive cellular interactions, including attachment to vitronectin, von Willebrand factor, fibrinogen, and thrombospondin. We have studied the binding of fibronectin to the purified vitronectin receptor, and the role of this receptor in the attachment of cells to fibronectin. A solid-phase microtiter assay was developed to investigate the binding properties of the vitronectin receptor. Purified alpha v beta 3 bound fibronectin with high affinity in a saturable, divalent cation-dependent manner. Binding was inhibited by soluble vitronectin, by RGD-containing peptides, and by LM609, a monoclonal antibody against the vitronectin receptor known to inhibit the binding of adhesive proteins to alpha v beta 3. Immunoinhibition experiments showed that M21 human melanoma cells, which express the fibronectin receptor, alpha 5 beta 1, as well as alpha v beta 3, used both of these integrins to attach and spread on fibronectin. In support of this finding, M21-L cells, a variant cell line that specifically lacks alpha v beta 3 but expresses alpha v beta 1, attached and spread poorly on fibronectin. In addition, alpha v beta 3 from surface-labeled M21 cells was retained, and selectively eluted by RGDS from a fibronectin affinity column. These results indicate that alpha v beta 3 acts in concert with alpha 5 beta 1 in promoting fibronectin recognition by these cells. We conclude that fibronectin binds to the alpha v beta 3 vitronectin receptor specifically and with high affinity, and that this interaction is biologically relevant in supporting cell adhesion to matrix proteins.

Early events elicited by bombesin and structurally related peptides in quiescent Swiss 3T3 cells. I. Activation of protein kinase C and inhibition of epidermal growth factor binding.

Addition of bombesin to quiescent cultures of Swiss 3T3 cells caused a rapid increase in the phosphorylation of an Mr 80,000 cellular protein (designated 80k). The effect was both concentration and time dependent; enhancement in 80k phosphorylation could be detected as early as 10 s after the addition of peptide. Recently, a rapid increase in the phosphorylation of an 80k cellular protein after treatment with phorbol esters or diacylglycerol has been shown to reflect the activation of protein kinase C in intact fibroblasts (Rozengurt, E., A. Rodriguez-Pena, and K. A. Smith, 1983, Proc. Natl. Acad. Sci. USA., 80:7244-7248; Rozengurt, E., A. Rodriguez-Pena, M. Coombs, and J. Sinnett-Smith, 1984, Proc. Natl. Acad. Sci. USA., 81:5748-5752). The 80k phosphoproteins generated in response to bombesin and to phorbol 12,13-dibutyrate were identical as judged by one- and two-dimensional PAGE and by peptide mapping after partial proteolysis with Staphylococcus aureus V8 protease. In addition, prolonged pretreatment of 3T3 cells with phorbol 12,13-dibutyrate, which leads to the disappearance of protein kinase C activity, blocked the ability of bombesin to stimulate 80k. Bombesin also caused a rapid (1 min) inhibition of 125I-labeled epidermal growth factor (125I-EGF) binding to Swiss 3T3 cells. The inhibition was both concentration and temperature dependent and resulted from a marked decrease in the affinity of the EGF receptor for its ligand. Peptides structurally related to bombesin, including gastrin-releasing peptide, also stimulated 80k phosphorylation and inhibited 125I-EGF binding; both effects were selectively blocked by a novel bombesin antagonist. These results strongly suggest that these responses are mediated by specific high-affinity receptors that recognize the peptides of the bombesin family in Swiss 3T3 cells. While an increase in cytosolic Ca2+ concentration does not mediate the bombesin inhibition of 125I-EGF binding, the activation of protein kinase C in intact Swiss 3T3 cells by peptides of the bombesin family may lead to rapid inhibition of the binding of 125I-EGF to its cellular receptor.

Early events elicited by bombesin and structurally related peptides in quiescent Swiss 3T3 cells. II. Changes in Na+ and Ca2+ fluxes, Na+/K+ pump activity, and intracellular pH.

The amphibian tetradecapeptide, bombesin, and structurally related peptides caused a marked increase in ouabain-sensitive 86Rb+ uptake (a measure of Na+/K+ pump activity) in quiescent Swiss 3T3 cells. This effect occurred within seconds after the addition of the peptide and appeared to be mediated by an increase in Na+ entry into the cells. The effect of bombesin on Na+ entry and Na+/K+ pump activity was concentration dependent with half-maximal stimulation occurring at 0.3-0.4 nM. The structurally related peptides litorin, gastrin-releasing peptide, and neuromedin B also stimulated ouabain-sensitive 86Rb+ uptake; the relative potencies of these peptides in stimulating the Na+/K+ pump were comparable to their potencies in increasing DNA synthesis (Zachary, I., and E. Rozengurt, 1985, Proc. Natl. Acad. Sci. USA., 82:7616-7620). Bombesin increased Na+ influx, at least in part, through an Na+/H+ antiport. The peptide augmented intracellular pH and this effect was abolished in the absence of extracellular Na+. In addition to monovalent ion transport, bombesin and the structurally related peptides rapidly increased the efflux of 45Ca2+ from quiescent Swiss 3T3 cells. This Ca2+ came from an intracellular pool and the efflux was associated with a 50% decrease in total intracellular Ca2+. The peptides also caused a rapid increase in cytosolic free calcium concentration. Prolonged pretreatment of Swiss 3T3 cells with phorbol dibutyrate, which causes a loss of protein kinase C activity (Rodriguez-Pena, A., and E. Rozengurt, 1984, Biochem. Biophys. Res. Commun., 120:1053-1059), greatly decreased the stimulation of 86Rb+ uptake and Na+ entry by bombesin implicating this phosphotransferase system in the mediation of part of these responses to bombesin. Since some activation of monovalent ion transport by bombesin was seen in phorbol dibutyrate-pretreated cells, it is likely that the peptide also stimulates monovalent ion transport by a second mechanism.

Endogenous carbon in carbonaceous meteorites.

Seven carbonaceous chondrites have been analyzed for soluble organic compounds, carbonate, and residual carbon. Carbon-13/carbon-12 isotopic mneasurements on these fractions gave the following values relative to a marine carbonate standard: carbonate, +40 to +70 per mil; residual carbon, -15 to -17 per mil; soluble organic material, -17 to -27 per mil, with one value of -5.5 per mil. These values are interpreted to indicate that carbonate, residual carbon, and part of the extractable organic material are endogenous to these meteorites.

Concentration and isotopic composition of carbon and sulfur in apollo 11 lunar samples.

The concentration of carbon and sulfur in six samples ranged between 20 to 200 and 650 to 2300 parts per million, respectively. Carbon was present in gaseous, volatilizable, and nonvolatile forms, and terrestrial contaminants were recognized. Sulfur appeared to exist only as acid-volatile sulfide. The bulk fines contain a high concentration of carbon and a low concentration of sulfur. They are always enriched in the heavier isotope carbon-13 or sulfur-34. The fine-grained basaltic rocks show the reverse relation; lowest carbon, highest sulfide concentrations, and no apparent enrichment in heavy isotopes. The breccias are of intermediate composition.

Radioimmunoassay for prostaglandins.

Antibodies to prostaglandin were obtained by immunization of rabbits with PGA(1), PGA(2), and PGE(1), protein conjugates of prostaglandins. The antibodies demonstrated specificity toward both the cyclopentane ring and the aliphatic side chains. With the use of these antibodies a highly sensitive radio-immunoassay capable of measuring less than picomolar amounts of PGA1, PGA2, and PGE1 has been developed.

Selective dose escalation of chemoradiotherapy for locally advanced esophageal cancer.

This phase II study assessed the use of concurrent continuous infusion of 5-fluorouracil and weekly carboplatin plus paclitaxel with selective radiation dose escalation for patients with localized esophageal cancer. Patients with esophageal carcinoma were staged by thoracic and abdominal computed tomography, endoscopic ultrasound, and positron emission tomography scans. Patients received a continuous infusion of 5-fluorouracil 225 mg/m(2) on days 1 to 38 and intravenous paclitaxel 45 mg/m(2) and carboplatin AUC 2 on days 1, 8, 15, 22, 29, and 36. Radiotherapy was delivered in 1.8-Gy fractions, 5 d/wk for 5.5 weeks. Six to 8 weeks after initial therapy, patients without metastatic progression but with a positive biopsy, or less than partial response received a 9-Gy boost with the same concurrent chemotherapy. Twenty-four patients were enrolled: 18 patients were enrolled initially; 6 additional patients were enrolled following a protocol amendment designed to reduce the esophagitis by adding the radioprotectant amifostine. Median follow-up was 30 months. Twenty (83%) patients had adenocarcinomas of the lower esophagus/gastroesophageal junction. Seventeen patients (81%) attained at least a partial response. Six patients received boost treatment. At 4 years, overall survival was 28%, cause-specific survival was 38%, locoregional control was 61%, and distant metastasis-free survival was 52%. Radiation delays ranged from 0 to 62 days (median, 8 d), primarily owing to esophagitis. In total, 28% of patients developed esophageal strictures requiring dilatations. There were no differences in esophageal strictures, local control, or survival with the addition of amifostine.

Cellular immune responses to platelet factor 4 and heparin complexes in patients with heparin-induced thrombocytopenia.

Essentials The immunogenesis of Heparin-induced thrombocytopenia (HIT) is not well understood. Immunization to platelet factor 4 (PF4)-heparin occurs early in life, before any heparin exposure. PF4 and PF4-heparin complexes induce the proliferation of CD14+ cells. Reduced levels of regulatory cytokines contribute to immune dysregulation in HIT. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin characterized by thrombocytopenia and thrombotic complications. HIT is caused by pathogenic antibodies that bind to complexes of platelet factor 4 (PF4) and heparin, leading to platelet activation and inducing a hypercoagulable state. Previous studies have shown immunity to PF4-heparin complexes occurs early in life, even before heparin exposure; however, the immunogenesis of HIT is not well characterized. Objectives To investigate cellular proliferation in response to PF4-heparin complexes in patients with HIT. Patients/Methods Peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 30), postoperative cardiac surgery patients who had undergone cardiopulmonary bypass (CPB) (n = 17) and patients with confirmed HIT (n = 41) were cultured with PF4 and PF4-heparin complexes. Cellular proliferation was assessed by [3 H]thymidine uptake and 5-ethynyl-2'-deoxyuridine detection. Results and Conclusions PBMCs proliferated in the presence of PF4, and this was enhanced by the addition of heparin in all study groups. CPB and HIT patients showed significantly greater proliferative responses than healthy controls. PBMC proliferation was antigen-specific, depended on the presence of platelets, and only CD14+ cells were identified as proliferating cells. Culture supernatants were tested for the levels of regulatory cytokines, and both CPB and HIT patients produced significantly lower levels of interleukin-10 and transforming growth factor-ß1 than healthy controls. These findings further demonstrate cellular immune sensitization to PF4-heparin complexes occurs before heparin exposure, and suggests immune dysregulation can contribute to HIT.

The local immune response to Escherichia coli O and K antigen in experimental pyelonephritis.

Although the systemic and local immune response to the O antigen of Escherichia coli has been well characterized, little information is available on the immune response to K anigen. Experimental hematogenous pyelonephritis was produced with Escherichia coli 06 K13 H1 and the serum and local (intrarenal) antibody response to O and K antigens was determined with the enzyme-linked immunosorbent assay. Both local and serum antibody responses to the K antigen were significantly less than that to the O antigen. The K antigen induced low titer IgM and IgG antibody responses in fewer than one-half of the animals and did not induce a local IgA response in any animal. In contrast, the O antigen induced local antibody responses in each of the immunoglobulin classes in all animals from day 9 of infection. Similarly, the serum IgM and IgG antibody titers to the K antigen were significantly less than those evoked in response to the O component of the Escherichia coli. No serum IgA anti-K antibodies were detected. These observations helf clarify the roles of these two antigens in pyelonephritis. Although the K antigen of Escherichia coli functions as a virulence factor in upper urinary tract infections, this antigen does not elicit a significant immune response, whereas the O antigen does induce a significant antibody response which could be of protective or diagnostic benefit.

Alterations in cyclic adenosine monophosphate metabolism in human bronchial asthma. I. Leukocyte responsiveness to -adrenergic agents.

In an effort to better define the role of betaadrenergic blockade in human bronchial asthma, peripheral blood leukocytes and lymphocytes from individuals with this condition were studied for possible alterations in cyclic AMP metabolism. Using a previously described radioimmunoassay to measure cyclic AMP, cells from asthmatic subjects were shown to have a highly significant decrease in their cyclic AMP response to beta-adrenergic agents (isoproterenol, norepinephrine, and epinephrine) by comparison with normal control cells. The alteration in responsiveness was most marked at the time of severe active asthma and returned toward normal during periods of clinical remission. Evidence was presented to indicate that the reduced response in cells from asthmatic individuals was not due to marked alterations in the proportion of T and B lymphocytes. Five normal volunteers were treated with an oral bronchodilator preparation containing theophylline and ephedrine over a 2 wk period without a significant change in the lymphocyte cyclic AMP response. These results provide unambiguous evidence for altered adrenergic responsiveness in bronchial asthma and indicate that purified peripheral blood lymphocytes should be a suitable in vitro system for further elucidation of the abnormality. Despite the reduction in catecholamine responsiveness in the asthmatic population as a whole, major alterations were largely restricted to individuals with severe, chronic asthma. Conclusive evidence for beta-adrenergic blockade in individuals who have not had recent asthmatic symptoms was not obtained, casting some doubt on the theory that bronchial asthma is due to a congenital derangement of cyclic AMP metabolism. Moreover, transient episodes of bronchospasm were often accompanied by a normal cyclic AMP response indicating that episodes of asthma frequently occur in the absence of easily demonstrable adrenergic blockade.