Role of the enterocyte in fructose-induced hypertriglyceridaemia

Abstract: Dietary fructose has been linked to an increased post-prandial triglyceride (TG) level, which is an established independent risk factor for cardiovascular disease. Although much research has focused on the effects of fructose consumption on liver-derived very-low density lipoprotein (VLDL), emerging evidence also suggests that fructose may raise post-prandial TG levels by affecting the metabolism of enterocytes of the small intestine. Enterocytes have become well recognised for their ability to transiently store lipids following a meal and to thus control post-prandial TG levels according to the rate of chylomicron (CM) lipoprotein synthesis and secretion. The influence of fructose consumption on several aspects of enterocyte lipid metabolism are discussed, including de novo lipogenesis, apolipoprotein B48 and CM-TG production, based on the findings of animal and human isotopic tracer studies. Methodological issues affecting the interpretation of fructose studies conducted to date are highlighted, including the accurate separation of CM and VLDL. Although the available evidence to date is limited, disruption of enterocyte lipid metabolism may make a meaningful contribution to the hypertriglyceridaemia often associated with fructose consumption

Association of the tumor necrosis factor-alpha promoter polymorphism with change in triacylglycerol response to sequential meals

Background: Reported associations between Tumor Necrosis Factor-alpha (TNFA) and the postprandial triacylglycerol (TAG) response have been inconsistent, which could be due to variations in the TNFA gene, meal fat composition or participant’s body weight. Hence, we investigated the association of TNFA polymorphism (−308G → A) with body mass index (BMI) and postprandial lipaemia and also determined the impact of BMI on the association of the polymorphism with postprandial lipaemia. Methods: The study participants (n = 230) underwent a sequential meal postprandial study. Blood samples were taken at regular intervals after a test breakfast (t = 0, 49 g fat) and lunch (t =330 min, 29 g fat) to measure fasting and postprandial lipids, glucose and insulin. The Metabolic Challenge Study (MECHE) comprising 67 Irish participants who underwent a 54 g fat oral lipid tolerance test was used as a replication cohort. The impact of genotype on postprandial responses was determined using general linear model with adjustment for potential confounders. Results: The -308G → A polymorphism showed a significant association with BMI (P = 0.03) and fasting glucose (P = 0.006), where the polymorphism explained 13 % of the variation in the fasting glucose. A 30 % higher incremental area under the curve (IAUC) was observed for the postprandial TAG response in the GG homozygotes than A-allele carriers (P = 0.004) and the genotype explained 19 % of the variation in the IAUC. There was a non-significant trend in the impact of BMI on the association of the genotype with TAG IAUC (P = 0.09). These results were not statistically significant in the MECHE cohort, which could be due to the differences in the sample size, meal composition, baseline lipid profile, allelic diversity and postprandial characterisation of participants across the two cohorts. Conclusions: Our findings suggest that TNFA -308G → A polymorphism may be an important candidate for BMI, fasting glucose and postprandial TAG response. Further studies are required to investigate the mechanistic effects of the polymorphism on glucose and TAG metabolism, and determine whether BMI is an important variable which should be considered in the design of future studies. Trial registration: NCT01172951

Insufficient Impact: Limited Implementation of Federal Regulatory Changes to Methadone and Buprenorphine Access in Arizona During COVID-19

Introduction: This study examined the impact of federal regulatory changes on methadone and buprenorphine treatment during COVID-19 in Arizona. Methods: A cohort study of methadone and buprenorphine providers from September 14, 2021 to April 15, 2022 measured the proportion of 6 treatment accommodations implemented at 3 time periods: before COVID-19, during Arizona's COVID-19 shutdown, and at the time of the survey completion. Accommodations included (1) telehealth, (2) telehealth buprenorphine induction, (3) increased multiday dosing, (4) license reciprocity, (5) home medications delivery, and (6) off-site dispensing. A multilevel model assessed the association of treatment setting, rurality, and treatment with accommodation implementation time. Results: Over half (62.2%) of the 74-provider sample practiced in healthcare settings not primarily focused on addiction treatment, 19% practiced in methadone clinics, and 19% practiced in treatment clinics not offering methadone. Almost half (43%) were unaware of the regulatory changes allowing treatment accommodation. Telehealth was most frequently reported, increasing from 30% before COVID-19 to 80% at the time of the survey. Multiday dosing was the only accommodation substantially retracted after COVID-19 shutdown: from 41% to 23% at the time of the survey. Providers with higher patient limits were 2.5–3.2 times as likely to implement telehealth services, 4.4 times as likely to implement buprenorphine induction through telehealth, and 15.2–20.9 times as likely to implement license reciprocity as providers with lower patient limits. Providers of methadone implemented 12% more accommodations and maintained a higher average proportion of implemented accommodations during the COVID-19 shutdown period but were more likely to reduce the proportion of implemented accommodations (a 17-percentage point gap by the time of the survey). Conclusions: Federal regulatory changes are not sufficient to produce a substantive or sustained impact on provider accommodations, especially in methadone medical treatment settings. Practice change interventions specific to treatment settings should be implemented and studied for their impact

Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial

Copyright @ Queen’s Printer and Controller of HMSO 2012. This work was produced by Sharples et al. under the terms of a commissioning contract issued by the Secretary of State for Health.Objective: To assess the clinical effectiveness and cost-effectiveness of endosonography (followed by surgical staging if endosonography was negative), compared with standard surgical staging alone, in patients with non-small cell lung cancer (NSCLC) who are otherwise candidates for surgery with curative intent. Design: A prospective, international, open-label, randomised controlled study, with a trialbased economic analysis. Setting: Four centres: Ghent University Hospital, Belgium; Leuven University Hospitals,Belgium; Leiden University Medical Centre, the Netherlands; and Papworth Hospital, UK. Participants: Inclusion criteria: known/suspected NSCLC, with suspected mediastinal lymph node involvement; otherwise eligible for surgery with curative intent; clinically fit for endosonography and surgery; and no evidence of metastatic disease. Exclusion criteria: previous lung cancer treatment; concurrent malignancy; uncorrected coagulopathy; and not suitable for surgical staging. Interventions: Study patients were randomised to either surgical staging alone (n = 118) or endosonography followed by surgical staging if endosonography was negative (n = 123). Endosonography diagnostic strategy used endoscopic ultrasound-guided fine-needle aspiration combined with endobronchial ultrasound-guided transbronchial needle aspiration, followed by surgical staging if these tests were negative. Patients with no evidence of mediastinal metastases or tumour invasion were referred for surgery with curative intent. If evidence of malignancy was found, patients were referred for chemoradiotherapy. Main outcome measures: The main clinical outcomes were sensitivity (positive diagnostic test/nodal involvement during any diagnostic test or thoracotomy) and negative predictive value (NPV) of each diagnostic strategy for the detection of N2/N3 metastases, unnecessary thoracotomy and complication rates. The primary economic outcome was cost–utility of the endosonography strategy compared with surgical staging alone, up to 6 months after randomisation, from a UK NHS perspective. Results: Clinical and resource-use data were available for all 241 patients, and complete utilities were available for 144. Sensitivity for detecting N2/N3 metastases was 79% [41/52; 95% confidence interval (CI) 66% to 88%] for the surgical arm compared with 94% (62/66; 95% CI 85% to 98%) for the endosonography strategy (p = 0.02). Corresponding NPVs were 86% (66/77; 95% CI 76% to 92%) and 93% (57/61; 95% CI 84% to 97%; p = 0.26). There were 21/118 (18%) unnecessary thoracotomies in the surgical arm compared with 9/123 (7%) in the endosonography arm (p = 0.02). Complications occurred in 7/118 (6%) in the surgical arm and 6/123 (5%) in the endosonography arm (p = 0.78): one pneumothorax related to endosonography and 12 complications related to surgical staging. Patients in the endosonography arm had greater EQ-5D (European Quality of Life-5 Dimensions) utility at the end of staging (0.117; 95% CI 0.042 to 0.192; p = 0.003). There were no other significant differences in utility. The main difference in resource use was the number of thoracotomies: 66% patients in the surgical arm compared with 53% in the endosonography arm. Resource use was similar between the groups in all other items. The 6-month cost of the endosonography strategy was £9713 (95% CI £7209 to £13,307) per patient versus £10,459 (£7732 to £13,890) for the surgical arm, mean difference £746 (95% CI –£756 to £2494). The mean difference in quality-adjusted life-year was 0.015 (95% CI –0.023 to 0.052) in favour of endosonography, so this strategy was cheaper and more effective. Conclusions: Endosonography (followed by surgical staging if negative) had higher sensitivity and NPVs, resulted in fewer unnecessary thoracotomies and better quality of life during staging, and was slightly more effective and less expensive than surgical staging alone. Future work could investigate the need for confirmatory mediastinoscopy following negative endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the diagnostic accuracy of EUS-FNA or EBUS-TBNA separately and the delivery of both EUSFNA or EBUS-TBNA by suitably trained chest physicians.This project was funded by the NIHR Health Technology Assessment programm

Oxygen-Enhanced MRI Accurately Identifies, Quantifies, and Maps Tumor Hypoxia in Preclinical Cancer Models.

There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (ΔR1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ΔR1, termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast-enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic

Capsular profiling of the Cronobacter genus and the association of specific Cronobacter sakazakii and C. malonaticus capsule types with neonatal meningitis and necrotizing enterocolitis

Background: Cronobacter sakazakii and C. malonaticus can cause serious diseases especially in infants where they are associated with rare but fatal neonatal infections such as meningitis and necrotising enterocolitis. Methods: This study used 104 whole genome sequenced strains, covering all seven species in the genus, to analyse capsule associated clusters of genes involved in the biosynthesis of the O-antigen, colanic acid, bacterial cellulose, enterobacterial common antigen (ECA), and a previously uncharacterised K-antigen. Results: Phylogeny of the gnd and galF genes flanking the O-antigen region enabled the defining of 38 subgroups which are potential serotypes. Two variants of the colanic acid synthesis gene cluster (CA1 and CA2) were found which differed with the absence of galE in CA2. Cellulose (bcs genes) were present in all species, but were absent in C. sakazakii sequence type (ST) 13 and clonal complex (CC) 100 strains. The ECA locus was found in all strains. The K-antigen capsular polysaccharide Region 1 (kpsEDCS) and Region 3 (kpsMT) genes were found in all Cronobacter strains. The highly variable Region 2 genes were assigned to 2 homology groups (K1 and K2). C. sakazakii and C. malonaticus isolates with capsular type [K2:CA2:Cell+] were associated with neonatal meningitis and necrotizing enterocolitis. Other capsular types were less associated with clinical infections. Conclusion: This study proposes a new capsular typing scheme which identifies a possible important virulence trait associated with severe neonatal infections. The various capsular polysaccharide structures warrant further investigation as they could be relevant to macrophage survival, desiccation resistance, environmental survival, and biofilm formation in the hospital environment, including neonatal enteral feeding tubes

An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo

General Form of the Color Potential Produced by Color Charges of the Quark

Constant electric charge $e$ satisfies the continuity equation $\partial_\mu j^{\mu}(x)= 0$ where $j^\mu(x)$ is the current density of the electron. However, the Yang-Mills color current density $j^{\mu a}(x)$ of the quark satisfies the equation $D_\mu[A] j^{\mu a}(x)= 0$ which is not a continuity equation ($\partial_\mu j^{\mu a}(x)\neq 0$) which implies that a color charge $q^a(t)$ of the quark is not constant but it is time dependent where $a=1,2,...8$ are color indices. In this paper we derive general form of color potential produced by color charges of the quark. We find that the general form of the color potential produced by the color charges of the quark at rest is given by \Phi^a(x) =A_0^a(t,{\bf x}) =\frac{q^b(t-\frac{r}{c})}{r}\[\frac{{\rm exp}[g\int dr \frac{Q(t-\frac{r}{c})}{r}] -1}{g \int dr \frac{Q(t-\frac{r}{c})}{r}}\]_{ab} where $dr$ integration is an indefinite integration, ~~ $Q_{ab}(\tau_0)=f^{abd}q^d(\tau_0)$, ~~$r=|{\vec x}-{\vec X}(\tau_0)|$, ~~$\tau_0=t-\frac{r}{c}$ is the retarded time, ~~$c$ is the speed of light, ~~${\vec X}(\tau_0)$ is the position of the quark at the retarded time and the repeated color indices $b,d$(=1,2,...8) are summed. For constant color charge $q^a$ we reproduce the Coulomb-like potential $\Phi^a(x)=\frac{q^a}{r}$ which is consistent with the Maxwell theory where constant electric charge $e$ produces the Coulomb potential $\Phi(x)=\frac{e}{r}$.Comment: Final version, two more sections added, 45 pages latex, accepted for publication in JHE

Surface electrons at plasma walls

In this chapter we introduce a microscopic modelling of the surplus electrons on the plasma wall which complements the classical description of the plasma sheath. First we introduce a model for the electron surface layer to study the quasistationary electron distribution and the potential at an unbiased plasma wall. Then we calculate sticking coefficients and desorption times for electron trapping in the image states. Finally we study how surplus electrons affect light scattering and how charge signatures offer the possibility of a novel charge measurement for dust grains.Comment: To appear in Complex Plasmas: Scientific Challenges and Technological Opportunities, Editors: M. Bonitz, K. Becker, J. Lopez and H. Thomse

Serum Lipid Changes after Short Term SIPC Therapy for Lower Limb Lymphedema

Lymphedema is a ubiquitous chronic disease with various suggested treatment options, but no definite treatment. Using (Sequential) Intermittent Pneumatic Compression (SIPC) is one of the most appropriate non-surgical treatments without any noticeable complications. In this study, we evaluated the serum lipids changes following SIPC. Participants included 40 lower limb lymphedema patients who underwent High Pressure SIPC for a period of 48 hrs. Pre and Post SIPC serum lipids changes were evaluated. Though, there was some increase in the serum level of cholesterol and triglyceride, none of the patients had the values above the normal range. We concluded that, the fluid entering the serum during SIPC, contain large molecules such as lipids, which increases serum lipid levels. However this phenomenon does not have any significant complication for the patients