Issues in the Pharmacokinetics of Trichloroethylene and Its Metabolites

Much progress has been made in understanding the complex pharmacokinetics of trichloroethylene (TCE). Qualitatively, it is clear that TCE is metabolized to multiple metabolites either locally or into systemic circulation. Many of these metabolites are thought to have toxicologic importance. In addition, efforts to develop physiologically based pharmacokinetic (PBPK) models have led to a better quantitative assessment of the dosimetry of TCE and several of its metabolites. As part of a mini-monograph on key issues in the health risk assessment of TCE, this article is a review of a number of the current scientific issues in TCE pharmacokinetics and recent PBPK modeling efforts with a focus on literature published since 2000. Particular attention is paid to factors affecting PBPK modeling for application to risk assessment. Recent TCE PBPK modeling efforts, coupled with methodologic advances in characterizing uncertainty and variability, suggest that rigorous application of PBPK modeling to TCE risk assessment appears feasible at least for TCE and its major oxidative metabolites trichloroacetic acid and trichloroethanol. However, a number of basic structural hypotheses such as enterohepatic recirculation, plasma binding, and flow- or diffusion-limited treatment of tissue distribution require additional evaluation and analysis. Moreover, there are a number of metabolites of potential toxicologic interest, such as chloral, dichloroacetic acid, and those derived from glutathione conjugation, for which reliable pharmacokinetic data is sparse because of analytical difficulties or low concentrations in systemic circulation. It will be a challenge to develop reliable dosimetry for such cases

Matrix Metalloproteinase Expression in Contusional Traumatic Brain Injury: A Paired Microdialysis Study.

Matrix metalloproteinases (MMPs) are extracellular enzymes that have been implicated in the pathophysiology of blood-brain barrier (BBB) breakdown, contusion expansion, and vasogenic edema after traumatic brain injury (TBI). Specifically, in focal injury models, increased MMP-9 expression has been observed in pericontusional brain, and MMP-9 inhibitors reduce brain swelling and final lesion volume. The aim of this study was to examine whether there is a similarly localized increase of MMP concentrations in patients with contusional TBI. Paired microdialysis catheters were inserted into 12 patients with contusional TBI (with or without associated mass lesion) targeting pericontusional and radiologically normal brain defined on admission computed tomography scan. Microdialysate was pooled every 8 h and analyzed for MMP-1, -2, -7, -9, and -10 using a multiplex immunoassay. Concentrations of MMP-1, -2, and -10 were similar at both monitoring sites and did not show discernible temporal trends. Overall, there was a gradual increase in MMP-7 concentrations in both normal and injured brain over the monitoring period, although this was not consistent in every patient. MMP-9 concentrations were elevated in pericontusional, compared to normal, brain, with the maximal difference at the earliest monitoring times (i.e., <24 h postinjury). Repeated-measures analysis of variance showed that MMP-9 concentrations were significantly higher in pericontusional brain (p=0.03) and within the first 72 h of injury, compared with later in the monitoring period (p=0.04). No significant differences were found for the other MMPs assayed. MMP-9 concentrations are increased in pericontusional brain early post-TBI and may represent a potential therapeutic target to reduce hemorrhagic progression and vasogenic edema.M.R.G. was supported by a National Institute for Health Research (NIHR) Academic Clinical Fellowship, a Royal College of Surgeons/Philip King Research Fellowship, and a Beverley and Raymond Sackler Fellowship. A.H. was supported by a joint Medical Research Council/ Royal College of Surgeons of England Clinical Research Training Fellowship. K.L.H.C. is supported by the NIHR Biomedical Research Center, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). J.D.P. is supported by the Traumatic Brain Injury NIHR Health Technology Cooperative. D.K.M. is supported by an NIHR Senior Investigator Award. P.J.A.H. is supported by the Cambridge NIHR BRC and an NIHR Research Professorship.This is the final published version. It was first made available by Mary Ann Liebert at http://dx.doi.org/10.1089/neu.2014.376

Macrosystems ecology: Understanding ecological patterns and processes at continental scales

Macrosystems ecology is the study of diverse ecological phenomena at the scale of regions to continents and their interactions with phenomena at other scales. This emerging subdiscipline addresses ecological questions and environmental problems at these broad scales. Here, we describe this new field, show how it relates to modern ecological study, and highlight opportunities that stem from taking a macrosystems perspective. We present a hierarchical framework for investigating macrosystems at any level of ecological organization and in relation to broader and finer scales. Building on well-established theory and concepts from other subdisciplines of ecology, we identify feedbacks, linkages among distant regions, and interactions that cross scales of space and time as the most likely sources of unexpected and novel behaviors in macrosystems. We present three examples that highlight the importance of this multiscaled systems perspective for understanding the ecology of regions to continents

Exercise therapy in adults with serious mental illness: a systematic review and meta-analysis

Background: Individuals with serious mental illness are at a higher risk of physical ill health. Mortality rates are at least twice those of the general population with higher levels of cardiovascular disease, metabolic disease, diabetes, and respiratory illness. Although genetics may have a role in the physical health problems of these patients, lifestyle and environmental factors such as levels of smoking, obesity, poor diet, and low levels of physical activity also play a prominent part.&lt;p&gt;&lt;/p&gt; Objective: To conduct a systematic review and meta-analysis of randomised controlled trials comparing the effect of exercise interventions on individuals with serious mental illness.&lt;p&gt;&lt;/p&gt; Methods: Searches were made in Ovid MEDLINE, Embase, CINAHL, PsycINFO, Biological Abstracts on Ovid, and The Cochrane Library (January 2009, repeated January 2013) through to February 2013.&lt;p&gt;&lt;/p&gt; Results: Eight RCTs were identified in the systematic search. Six compared exercise versus usual care. One study assessed the effect of a cycling programme versus muscle strengthening and toning exercises. The final study compared the effect of adding specific exercise advice and motivational skills to a simple walking programme. Exercise programmes were noted by their heterogeneity in terms of the type of exercise intervention, setting, and outcome measures. The review found that exercise improved levels of exercise activity (n=13, standard mean difference [SMD] 1.81, CI 0.44 to 3.18, p = 0.01). No beneficial effect was found on negative (n = 84, SMD = -0.54, CI -1.79 to 0.71, p = 0.40) or positive symptoms of schizophrenia (n = 84, SMD = -1.66, CI -3.78 to 0.45, p = 0.12). No change was found on body mass index compared with usual care (n= 151, SMD = -0.24, CI -0.56 to 0.08, p = 0.14), or body weight (n = 77, SMD = 0.13, CI -0.32 to 0.58, p = 0.57). No beneficial effect was found on anxiety and depressive symptoms (n = 94, SMD = -0.26, CI -0.91 to 0.39, p = 0.43), or quality of life in respect of physical and mental domains. One RCT measured the effect of exercise on exercise intensity, attendance, and persistence at a programme. No significant effect was found on these measures.&lt;p&gt;&lt;/p&gt; Conclusions: This systematic review showed that exercise therapies can lead to a modest increase in levels of exercise activity but overall there was no noticeable change for symptoms of mental health, body mass index, and body weight.&lt;p&gt;&lt;/p&gt

Characterising the dynamics of cerebral metabolic dysfunction following traumatic brain injury: A microdialysis study in 619 patients.

Funder: National Institute for Health Research (NIHR)Traumatic brain injury (TBI) is a major cause of death and disability, particularly amongst young people. Current intensive care management of TBI patients is targeted at maintaining normal brain physiology and preventing secondary injury. Microdialysis is an invasive monitor that permits real-time assessment of derangements in cerebral metabolism and responses to treatment. We examined the prognostic value of microdialysis parameters, and the inter-relationships with other neuromonitoring modalities to identify interventions that improve metabolism. This was an analysis of prospective data in 619 adult TBI patients requiring intensive care treatment and invasive neuromonitoring at a tertiary UK neurosciences unit. Patients had continuous measurement of intracranial pressure (ICP), arterial blood pressure (ABP), brain tissue oxygenation (PbtO2), and cerebral metabolism and were managed according to a standardized therapeutic protocol. Microdialysate was assayed hourly for metabolites including glucose, pyruvate, and lactate. Cerebral perfusion pressure (CPP) and cerebral autoregulation (PRx) were derived from the ICP and ABP. Outcome was assessed with the Glasgow Outcome Score (GOS) at 6 months. Relationships between monitoring variables was examined with generalized additive mixed models (GAMM). Lactate/Pyruvate Ratio (LPR) over the first 3 to 7 days following injury was elevated amongst patients with poor outcome and was an independent predictor of ordinal GOS (p70mmHg, PRx 18mmHg, and brain glucose >1mM. Deranged cerebral metabolism is an important determinant of patient outcome following TBI. Variations in cerebral perfusion, oxygenation and glucose supply are associated with changes in cerebral LPR and suggest therapeutic interventions to improve cerebral metabolism. Future prospective studies are required to determine the efficacy of these strategies

Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G

Background: The activating immunoreceptor NKG2D is expressed on Natural Killer (NK) cells and subsets of T cells. NKG2D contributes to anti-tumour and anti-viral immune responses in vitro and in vivo. The ligands for NKG2D in humans are diverse proteins of the MIC and ULBP/RAET families that are upregulated on the surface of virally infected cells and tumours. Two splicing variants of ULBP5/RAET1G have been cloned previously, but not extensively characterised. Methodology/Principal Findings: We pursue a number of approaches to characterise the expression, trafficking, and function of the two isoforms of ULBP5/RAET1G. We show that both transcripts are frequently expressed in cell lines derived from epithelial cancers, and in primary breast cancers. The full-length transcript, RAET1G1, is predicted to encode a molecule with transmembrane and cytoplasmic domains that are unique amongst NKG2D ligands. Using specific anti-RAET1G1 antiserum to stain tissue microarrays we show that RAET1G1 expression is highly restricted in normal tissues. RAET1G1 was expressed at a low level in normal gastrointestinal epithelial cells in a similar pattern to MICA. Both RAET1G1 and MICA showed increased expression in the gut of patients with celiac disease. In contrast to healthy tissues the RAET1G1 antiserum stained a wide variety or different primary tumour sections. Both endogenously expressed and transfected RAET1G1 was mainly found inside the cell, with a minority of the protein reaching the cell surface. Conversely the truncated splicing variant of RAET1G2 was shown to encode a soluble molecule that could be secreted from cells. Secreted RAET1G2 was shown to downregulate NKG2D receptor expression on NK cells and hence may represent a novel tumour immune evasion strategy. Conclusions/Significance: We demonstrate that the expression patterns of ULBP5RAET1G are very similar to the well-characterised NKG2D ligand, MICA. However the two isoforms of ULBP5/RAET1G have very different cellular localisations that are likely to reflect unique functionality

Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2-(13)C2 glucose.

Increased 'anaerobic' glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-(13)C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. (13)C enrichment for glycolytic 2,3-(13)C2 lactate was the median 5.4% (interquartile range (IQR) 4.6-7.5%) in TBI brain and 4.2% (2.4-4.4%) in 'normal' brain (P<0.01). The ratio of PPP-derived 3-(13)C lactate to glycolytic 2,3-(13)C2 lactate was median 4.9% (3.6-8.2%) in TBI brain and 6.7% (6.3-8.9%) in 'normal' brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 (r=-0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than 'normal' brain. Several TBI patients exhibited PPP-lactate elevation above the 'normal' range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain.We gratefully acknowledge financial support as follows. Study support: Medical Research Council (Grant Nos. G0600986 ID79068 and G1002277 ID98489) and National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors’ support: I.J. – Medical Research Council (Grant no. G1002277 ID 98489) and National Institute for Health Research Biomedical Research Centre, Cambridge; K.L.H.C. – National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); C.G. – the Canadian Institute of Health Research; A.H. – Medical Research Council/ Royal College of Surgeons of England Clinical Research Training Fellowship (Grant no. G0802251) and Raymond and Beverly Sackler Fellowship; D.K.M. and J.D.P. - National Institute for Health Research Senior Investigator Awards; P.J.H. – National Institute for Health Research Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship.This is the accepted manuscript version. The final version is available from the Nature Publishing Group http://www.nature.com/jcbfm/journal/v35/n1/full/jcbfm2014177a.html

Freeze-thaw treatment effects on the dynamic mechanical properties of articular cartilage

BACKGROUND: As a relatively non-regenerative tissue, articular cartilage has been targeted for cryopreservation as a method of mitigating a lack of donor tissue availability for transplant surgeries. In addition, subzero storage of articular cartilage has long been used in biomedical studies using various storage temperatures. The current investigation studies the potential for freeze-thaw to affect the mechanical properties of articular cartilage through direct comparison of various subzero storage temperatures. METHODS: Both subzero storage temperature as well as freezing rate were compared using control samples (4°C) and samples stored at either -20°C or -80°C as well as samples first snap frozen in liquid nitrogen (-196°C) prior to storage at -80°C. All samples were thawed at 37.5°C to testing temperature (22°C). Complex stiffness and hysteresis characterized load resistance and damping properties using a non-destructive, low force magnitude, dynamic indentation protocol spanning a broad loading rate range to identify the dynamic viscoelastic properties of cartilage. RESULTS: Stiffness levels remained unchanged with exposure to the various subzero temperatures. Hysteresis increased in samples snap frozen at -196°C and stored at -80°C, though remained unchanged with exposure to the other storage temperatures. CONCLUSIONS: Mechanical changes shown are likely due to ice lens creation, where frost heave effects may have caused collagen damage. That storage to -20°C and -80°C did not alter the mechanical properties of articular cartilage shows that when combined with a rapid thawing protocol to 37.5°C, the tissue may successfully be stored at subzero temperatures