An approach for evaluating the effects of dietary fiber polysaccharides on the human gut microbiome and plasma proteome

Increases in snack consumption associated with Westernized lifestyles provide an opportunity to introduce nutritious foods into poor diets. We describe two 10-wk-long open label, single group assignment human studies that measured the effects of two snack prototypes containing fiber preparations from two sustainable and scalable sources; the byproducts remaining after isolation of protein from the endosperm of peas and the vesicular pulp remaining after processing oranges for the manufacture of juices. The normal diets of study participants were supplemented with either a pea- or orange fiber-containing snack. We focused our analysis on quantifying the abundances of genes encoding carbohydrate-active enzymes (CAZymes) (glycoside hydrolases and polysaccharide lyases) in the fecal microbiome, mass spectrometric measurements of glycan structures (glycosidic linkages) in feces, plus aptamer-based assessment of levels of 1,300 plasma proteins reflecting a broad range of physiological functions. Computational methods for feature selection identified treatment-discriminatory changes in CAZyme genes that correlated with alterations in levels of fiber-associated glycosidic linkages; these changes in turn correlated with levels of plasma proteins representing diverse biological functions, including transforming growth factor type β/bone morphogenetic protein-mediated fibrosis, vascular endothelial growth factor-related angiogenesis, P38/MAPK-associated immune cell signaling, and obesity-associated hormonal regulators. The approach used represents a way to connect changes in consumer microbiomes produced by specific fiber types with host responses in the context of varying background diets.

Advances in our understanding of the role of the gut microbiome in regulating many aspects of human physiology hold the promise of evolving our view of human nutrition by establishing mechanistic connections between the foods we consume and how they affect health status. One manifestation of this effort is a series of studies, performed on well-phenotyped cohorts, that seek to relate features of gut microbial community composition (organisms, genes), dietary practices, and pre- and postprandial cardiometabolic responses to test meals (1–4). A key question raised by these initiatives relates to the nature of the “bioactive” components of foods. Specifically, what are the nutrients utilized by various gut community members or microbiome-encoded metabolic pathways? What products are produced by biotransformation of these nutrients? How are these products linked to specific host physiologic (or pathophysiologic) processes?Plant-derived dietary fibers represent a “poster child” for these efforts and illustrate the formidable challenges faced. The health benefits of dietary fibers are widely known, as is their inadequate representation in Western diets. However, natural fibers are structurally complex and highly diverse. They contain numerous, typically undefined polysaccharide structures and largely unspecified protein, lipid, and small molecule constituents. Their composition varies as a function of their origin (food staple and cultivar), the different methods employed to recover them from these sources, as well as the different techniques used to incorporate them into processed foods with acceptable organoleptic properties (5). Moreover, analyzing the host effects of metabolism of different fibers is confounded by the fact that there is substantial intra- and interpersonal variation in microbiome configuration (6, 7).Snacking is becoming an ever more dominant feature of daily life worldwide and thus provides an opportunity to introduce nutritious ingredients, such as fibers, into diets. However, obtaining structure-activity relationships for specific fiber types and their corresponding targets in the gut community is foundational for designing snack foods that evoke and/or reinforce microbiome responses that are beneficial to the host.Degradation of dietary polysaccharides is a function primarily performed by bacterial carbohydrate-active enzymes (CAZymes). The gut microbiome harbors tens of thousands of CAZyme genes belonging to at least 136 glycoside hydrolase (GH) and 29 polysaccharide lyase (PL) families [extrapolated and updated from El Kaoutari et al. (8)]. In contrast, the human genome only contains 98 GH and no PL genes (9), of which <20% contribute to the processing of dietary glycans.In the current study, we test the effects of dietary supplementation with two snack food prototypes, one containing pea fiber and the other orange fiber, in two pilot studies of overweight and obese individuals consuming their normal, unrestricted diets. Our strategy was to focus on fiber-associated changes in the abundances of microbial GH and PL genes to determine whether responses to the pea or orange fiber prototypes in the gut microbiome and host are decipherable against a background of varying dietary practices and starting microbiome configurations. Higher order singular value decomposition (10) was utilized as a feature selection tool to identify treatment-discriminating changes in GH and PL gene representation. Mass spectrometric assays of the levels of fecal glycan structures (glycosidic linkages) were subsequently performed and the results were correlated with changes in the abundances of treatment-discriminating GH and PL genes with known or predicted substrate specificities. Our analysis concluded by measuring changes in levels of 1,305 plasma proteins in each study participant as a function of fiber treatment and applying computational tools to identify links between these microbiome and plasma proteome changes in response to fiber consumption. Our results provide an approach, using pilot human studies, for selecting specific fiber preparations, plus informative microbiome and host biomarkers, that can be advanced to proof-of-concept clinical trials which assess their capacity for precise manipulation of microbiome and host features.     

Changes in Liver Congestion in Patients with Budd–Chiari Syndrome following Endovascular Interventions: Assessment with Transient Elastography

Purpose

Transient elastography (TE) is routinely used for noninvasive staging of hepatic fibrosis. The objective of the present study was to investigate the role of TE (FibroScan) in determining changes in liver congestion in patients with Budd–Chiari syndrome (BCS) treated by endovascular interventions and determine the effects of pretreatment Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) fibrosis score on posttreatment liver stiffness (LS).

Radiation exposure from head computed tomography scans in pediatric trauma

Background

We have previously reported that children receive significantly less radiation exposure after abdominal and/or pelvis computed tomography (CT) scanning for acute appendicitis when performed at our children's hospital (CH) rather than at outside hospitals (OH). In this study, we compare the amount of radiation children receive from head CTs for trauma done at OH versus those at our CH.

Methods

A retrospective chart review was performed on all children transferred to our hospital after receiving a head CT for trauma at an OH between July 2012 and December 2012. These children were then blindly case matched based on date, age, and gender to children at our CH.

Results

There were 50 children who underwent head CT scans for trauma at 28 OH. There were 21 females and 29 males in each group. Average age was 7.01 ± 0.5 y at the OH and 7.14 ± 6.07 at our CH (P = 0.92). Average weight was 30.81 ± 4.69 kg at the OH and 32.69 ± 27.21 kg at our CH (P = 0.81). Radiation measures included dose length product (671.21 ± 22.6 mGycm at OH versus 786.28 ± 246.3 mGycm at CH, P = 0.11) and CT dose index (53.4 ± 2.26 mGy at OH versus 49.2 ± 12.94 mGy at CH, P = 0.56).

Conclusions

There is no significant difference between radiation exposure secondary to head CTs for traumatic injuries performed at OH and those at a dedicated CH.     

Rigid and flexible docking studies on PPAR-γ agonists: key interactions for a better antihyperglycemic activity and in silico pharmacodynamic activity versus experimental in vivo activity

We report both automated rigid and flexible ligand docking simulations performed on fifty peroxisome proliferator-activated receptor (PPAR-γ) agonists, namely, glitazones. The binding conformations and binding affinities of these agonists were obtained by the use of the Autodock 4.1 with Lamarckian genetic algorithm (LGA). All the 50 flexible docks are considered as well-docked as all of them were bound to the ligand binding domain of PPAR-γ. The predicted binding affinity values (pKa) were found to have some degree of correlation with their experimental in vivo activity values. The head group hydrogen bond interactions via H323 and H449 histidine residues were found to play a significant role. The results obtained will be valuable in designing newer selective PPAR-γ agonists.     

The Role of Iron in Hepatitis C Infection

Iron overload of varying degrees is common among patients with chronic hepatitis C. The clinical significance of this iron overload is uncertain. Studies that have evaluated the effect of hepatic iron stores on the response to anti-viral treatment or on the natural history of chronic hepatitis C have found variable results depending on the technique used to measure hepatic iron stores and the degree of iron overload present among the study population. We have tried to comprehensively analyze the literature regarding the clinical interaction between iron overload and the natural history of chronic hepatitis C. The one clear relationship that emerges is that pre treatment serum ferritin inversely correlates with the odds of achieving sustained virological(SVR) response after combination interferon ribavirin treatment. We have also reviewed the limited literature that reports the effect of therapeutic phlebotomy to reverse iron overload among patients with chronic hepatitis C. A small meta-analysis of 6 prospective randomized trials and a subsequent seventh trial do suggest that phlebotomy to induce iron depletion enhances the likelihood of achieving (SVR) after anti-viral therapy. However, these studies are primarily in patients receiving interferon monotherapy, which is of course now obsolete. Finally, a few small studies suggest that therapeutic phlebotomy to induce iron depletion reduces liver transaminase levels and may improve histology, and perhaps even reduce the risk of hepato-cellular carcinoma. Prospective randomized controlled trials of phlebotomy among patients with advanced hepatitis C and iron overload are needed.     

The association of environmental,meteorological, and pollen count variables with asthma-related emergency department visits and hospitalizations in the Bronx

Objective: To better understand how meteorological variables, air quality variables, and pollen counts collectively contribute to asthma-related emergency department visits (AREDV) and asthma-related hospitalizations (ARH) among pediatric and adult patients in the New York City borough of the Bronx. Methods: The numbers of daily adult and pediatric AREDV and ARH from 2001 to 2008 were obtained from three Bronx hospitals. After removing outliers, interpolating missing data, and standardizing variable values by scaling the data using z-scores, data were analyzed using Spearman rank tests and linear regression models for the full year and each season. Results: There were a total of 42,065 AREDV and 1,664 ARH at both Bronx hospitals. With the exception of a spring peak in AREDVs, AREDVs and ARHs follow a cyclical pattern, climbing in the fall, plateauing in the winter, dropping in the spring, and reaching a low in the summer. Among the 11 air quality, meteorological, and pollen count variables, temperature and tree pollen made the greatest contribution to AREDV with scaled coefficients of –0.337 and 0.311 respectively; equating to an additional AREDV for every 5.0-unit decrease in temperature and an additional AREDV for every 186.0-unit increase in tree pollen. These two variables were confirmed to have independent associations with AREDV prior to the data interpolation. Grass pollen was also found to have a relatively large contribution to AREDV during the summer with a scaled coefficient of 0.314, equating to an additional AREDV for every 2.3-unit increase in grass pollen. Conclusion: There are distinct peaks of increased AREDVs that are closely associated with increased tree pollen counts in the spring and decreasing temperatures in the fall. Early anticipation of these air quality, meteorological, and pollen factor changes based on ongoing surveillance could potentially guide clinical practice and minimize AREDVs in the Bronx.     

Gemcitabine Hydrochloride-Loaded Functionalised Carbon Nanotubes as Potential Carriers for Tumour Targeting

The objective of the present work was to formulate gemcitabine hydrochloride loaded functionalised carbon nanotubes to achieve tumour targeted drug release and thereby reducing gemcitabine hydrochloride toxicity. Multiwalled carbon nanotubes were functionalised using 1,2-distearoylphosphatidyl ethanolamine-methyl polyethylene glycol conjugate 2000. Optimised ratio 1:2 of carbon nanotubes:1,2-distearoylphosphatidyl ethanolamine-methyl polyethylene glycol conjugate 2000 was taken for loading of gemcitabine hydrochloride. The formulation was evaluated for different parameters. The results showed that maximum drug loading efficiency achieved was 41.59% with an average particle size of 188.7 nm and zeta potential of −10−1 mV. Scanning electron microscopy and transmission electron microscopy images confirmed the tubular structure of the formulation. The carbon nanotubes were able to release gemcitabine hydrochloride faster in acidic pH than at neutral pH indicating its potential for tumour targeting. Gemcitabine hydrochloride release from carbon nanotubes was found to follow Korsmeyer-Peppas kinetic model with non-Fickian diffusion pattern. Cytotoxic activity of formulation on A549 cells was found to be higher in comparison to free gemcitabine hydrochloride. Stability studies indicated that lyophilised samples of the formulation were more stable for 3 months under refrigerated condition than at room temperature. Thus carbon nanotubes can be promising carrier for the anticancer drug gemcitabine hydrochloride.     

Serum ionized magnesium and calcium levels in adult patients with seizures

Objective. Prior studies have been equivocal about whether or not serum levels of the divalent ions calcium and magnesium are altered during different types of seizures. Magnesium is a potential modulator of seizure activity because of its ability to antagonize the excitatory calcium influx through the N‐methyl‐D‐aspartate (NMDA) receptor. We hypothesize that serum ionized levels of calcium (Ca²⁺) and magnesium (Mg²⁺) would be altered significantly during certain types of seizures. Material and methods. A convenience sample of seizure patients presenting to an emergency department (ED) were enrolled in this prospective study. Novel ion‐selective electrodes were used to measure Ca²⁺ and Mg²⁺. Data were reported as mean values±standard deviations. Group comparisons were analyzed by ANOVA with post‐hoc testing using the Bonferroni, or the Fisher exact test, where appropriate, α = 0.05 (two‐tailed). Results. Forty‐nine patients with seizure and 32 healthy racially matched controls were included in the study. Seizure patients had a significantly (p<0.001) lower mean Mg²⁺, but not total serum Mg and a significantly (p<0.001) higher Ca²⁺/Mg²⁺ ratio than that in controls. Conclusions. We were able to show significantly lower Mg²⁺ and higher ionized Ca²⁺/Mg²⁺ ratios in seizure patients compared with a racially matched control group.