Orthodontic tooth movement and de novo synthesis of proinflammatory cytokines.

Interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) are proinflammatory cytokines that are thought to play a role in bone remodeling, bone resorption, and new bone deposition. In the present work, in situ hybridization was performed to measure the messenger RNA expression of IL-1beta, IL-6, and TNF-alpha at 3, 7, and 10 days after the application of orthodontic force on the maxillary first molars of 12 rats. The contralateral side and 3 untreated rats served as controls. Measurements of the messenger RNA expression were selected as the means to investigate the role of orthodontic force in de novo synthesis of proinflammatory cytokines. After the application of force, the induction of IL-1beta and IL-6 was observed to reach a maximum on day 3 and to decline thereafter. No messenger RNA induction of either cytokine was measured in the control teeth. The messenger RNA expression of TNF-alpha was not detected at any time point of this study in the experimental or contralateral sides or in the control animals. Our data support the hypothesis that these proinflammatory cytokines may play important roles in bone resorption after the application of orthodontic force.     

Electrical neuromodulation therapy for inflammatory bowel disease

Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal (GI) tract. It has financial and quality of life impact on patients. Although there has been a significant advancement in treatments, a considerable number of patients do not respond to it or have severe side effects. Therapeutic approaches such as electrical neuromodulation are being investigated to provide alternate options. Although bioelectric neuromodulation technology has evolved significantly in the last decade, sacral nerve stimulation (SNS) for fecal incontinence remains the only neuromodulation protocol commonly utilized use for GI disease. For IBD treatment, several electrical neuromodulation techniques have been studied, such as vagus NS, SNS, and tibial NS. Several animal and clinical experiments were conducted to study the effectiveness, with encouraging results. The precise underlying mechanisms of action for electrical neuromodulation are unclear, but this modality appears to be promising. Randomized control trials are required to investigate the efficacy of intrinsic processes. In this review, we will discuss the electrical modulation therapy for the IBD and the data pertaining to it.     

The Role of Dual-Phase Cone-Beam CT in Predicting Short-Term Response after Transarterial Chemoembolization for Hepatocellular Carcinoma

Purpose

To identify computational and qualitative features derived from dual-phase cone-beam CT that predict short-term response in patients undergoing transarterial chemoembolization for hepatocellular carcinoma (HCC).

A phased approach for assessing combined effects from multiple stressors

We present a phased approach for evaluating the effects of physical, biological, chemical, and psychosocial stressors that may act in combination. Although a phased concept is common to many risk-based approaches, it has not been explicitly outlined for the assessment of combined effects of multiple stressors. The approach begins with the development of appropriate conceptual models and assessment end points. The approach then proceeds through a screening stage wherein stressors are evaluated with respect to their potential importance as contributors to risk. Stressors are considered individually or as a combination of independent factors with respect to one or more common assessment end points. As necessary, the approach then proceeds to consider interactions among stressors. We make a distinction between applications that begin with effects of concern (effects based) or with specific stressors (stressor based). We describe a number of tools for use within the phased approach. The methods profiled are ones that have been applied to yield results that can be communicated to a wide audience. The latter characteristic is considered especially important because multiple stressor problems usually involve exposures to communities or to ecologic regions with many stakeholders.     

Critical assessment of the current guidelines for the management and treatment of morbidly obese patients

An interdisciplinary panel of specialists met in Mallorca in the first European Symposium on Morbid Obesity entitled; "Morbid Obesity, an Interdisciplinary Approach". During the two and half days of the meeting, the participants discussed several aspects related to pathogenesis, evaluation, and treatment of morbid obesity. The expert panel included basic research scientists, dietitians and nutritionists, exercise physiologists, endocrinologists, psychiatrists, cardiologists, pneumonologists, anesthesiologists, and bariatric surgeons with expertise in the different weight loss surgeries. The symposium was sponsored by the Balearic Islands Health Department; however, this statement is an independent report of the panel and is not a policy statement of any of the sponsors or endorsers of the Symposium. The prevalence of morbid obesity, the most severe state of the disease, has become epidemic. The current recommendations for the therapy of the morbidly obese comes as a result of a National Institutes of Health (NIH) Consensus Conference held in 1991 and subsequently reviewed in 2004 by the American Society for Bariatric Surgery. This document reviews the work-up evaluation of the morbidly obese patient, the current status of the indications for bariatric surgery and which type of procedure should be recommended; it also brings up for discussion some important real-life clinical practice issues, which should be taken into consideration when evaluating and treating morbidly obese patients. Finally, it also goes through current scientific evidence supporting the potential effectiveness of medical therapy as treatment of patients with morbid obesity.     

A Systems Biology Approach Reveals Converging Molecular Mechanisms that Link Different POPs to Common Metabolic Diseases

Background:

A number of epidemiological studies have identified statistical associations between persistent organic pollutants (POPs) and metabolic diseases, but testable hypotheses regarding underlying molecular mechanisms to explain these linkages have not been published.

Objectives:

We assessed the underlying mechanisms of POPs that have been associated with metabolic diseases; three well-known POPs [2,3,7,8-tetrachlorodibenzodioxin (TCDD), 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB 153), and 4,4´-dichlorodiphenyldichloroethylene (p,p´-DDE)] were studied. We used advanced database search tools to delineate testable hypotheses and to guide laboratory-based research studies into underlying mechanisms by which this POP mixture could produce or exacerbate metabolic diseases.

Methods:

For our searches, we used proprietary systems biology software (MetaCore™/MetaDrug™) to conduct advanced search queries for the underlying interactions database, followed by directional network construction to identify common mechanisms for these POPs within two or fewer interaction steps downstream of their primary targets. These common downstream pathways belong to various cytokine and chemokine families with experimentally well-documented causal associations with type 2 diabetes.

Conclusions:

Our systems biology approach allowed identification of converging pathways leading to activation of common downstream targets. To our knowledge, this is the first study to propose an integrated global set of step-by-step molecular mechanisms for a combination of three common POPs using a systems biology approach, which may link POP exposure to diseases. Experimental evaluation of the proposed pathways may lead to development of predictive biomarkers of the effects of POPs, which could translate into disease prevention and effective clinical treatment strategies.

Citation:

Ruiz P, Perlina A, Mumtaz M, Fowler BA. 2016. A systems biology approach reveals converging molecular mechanisms that link different POPs to common metabolic diseases. Environ Health Perspect 124:1034–1041; http://dx.doi.org/10.1289/ehp.1510308     

Application of physiologically-based pharmacokinetic modeling to investigate the toxicological interaction between chlorpyrifos and parathion in the rat

Environmental exposure is usually due to the presence of multiple chemicals. In most cases, these chemicals interact with each other at both pharmacokinetic and pharmacodynamic toxicity mechanisms. In the absence of data, joint toxicity assessment of a mixture is based on default dose or response additivity. Although, the concept of additivity is mostly accepted at low dose levels, these levels need to be determined quantitatively to validate the use of additivity as an absence of any possible synergistic or antagonistic interactions at low environmental exposure levels. The doses at which interaction becomes significant define the interaction threshold. In most cases, estimation of these low-dose interaction thresholds experimentally is economically costly and challenging because of the need to use a large number of laboratory animals. Computational toxicology methods provide a feasible alternative to establish interaction thresholds. For example, a physiologically based pharmacokinetic (PBPK) model was developed to estimate an interaction threshold for the joint toxicity between chlorpyrifos and parathion in the rat. Initially, PBPK models were developed for each chemical to estimate the blood concentrations of their respective metabolite. The metabolite concentrations in blood out-put was then linked to acetylcholinesterase kinetics submodel. The resulting overall PBPK model described interactions between these pesticides at two levels in the organism: (a) the P450 enzymatic bioactivation site, and (b) acetylcholinesterase binding sites. Using the overall model, a response surface was constructed at various dose levels of each chemical to investigate the mechanism of interaction and to calculate interaction threshold doses. The overall model simulations indicated that additivity is obtained at oral dose levels below 0.08mg/kg of each chemical. At higher doses, antagonism by enzymatic competitive inhibition is the mode of interaction.