[The value of synthetic MRI in differential diagnosis of benign and malignant breast lesions].

Objective: To explore the diagnostic value of synthetic magnetic resonance imaging (syMRI) quantitative parameters for benign and malignant breast lesions. Methods: From September 2018 to March 2019, a total of 43 cases of breast lesions which were confirmed by surgery and pathology in Cancer Hospital, Chinese Academy of Medical Sciences were enrolled in this study. All patients underwent syMRI sequence scans before and after enhancement except for conventional T2WI, DWI, and enhancement scans. GE AW4.7 workstation was used to generate syMRI parameter maps (T1, T2, proton density mappings), and ITK-SNAP software was used to delineate the volume of interest. The T1, T2, PD values before and after dynamic contrast enhanced (DCE) were obtained, and the change values of each parameter were calculated. Meanwhile, the apparent diffusion coefficient (ADC) and time intensity curve (TIC) of the lesions were measured. The differences of each parameter value were compared between benign and malignant breast lesions, and the receiver operating characteristic (ROC) curve was used to analyze the diagnostic performance of each parameter. Results: Among the 43 enrolled cases, 13 were benign and 30 were malignant. Among the syMRI parameters, the pre-enhancement parameters including T1pre (median 1 663.07 ms), T2pre (median 103.33 ms), post-enhancement parameters ΔT1 (median 1 022.68 ms) and ΔT2 (median 27.67 ms) of benign group, significantly higher than those of the malignant group (the medians were 1 141.74, 92.53, 664.95, and 16.19 ms, respectively, P<0.05). The ADC value of the benign group (median 1.66×10(-3)mm(2)/s) was significantly higher than that of the malignant group (median 1.00×10(-3)mm(2)/s, P<0.05). The benign group included 6 cases of TIC curve type Ⅰ, 5 cases of type Ⅱ, and 2 cases of type Ⅲ. The malignant group included 2 cases of TIC curve type Ⅰ, 17 cases of type Ⅱ, and 11 cases of type Ⅲ. The difference between the two groups was statistically significant (P<0.05). The area under the ROC curve (AUC) of T1pre before DCE was 0.869, higher than 0.806 of ADC and 0.697 of TIC. When the best cut-off value of 1 282.94 ms was chosen, the sensitivity and specificity of diagnosis were 76.9% and 93.3%, respectively. The combination of T1pre and T2pre can further improve the diagnostic performance (AUC=0.908). Conclusions: Among the syMRI quantitative parameters, T1pre, T2pre, ΔT1 and ΔT2 have good value for the differential diagnosis of benign and malignant breast lesions. T1pre has the best diagnostic performance, and the combination of T1pre and T2pre can further improve the diagnostic performance.

The thioredoxin redox potential and redox charge are surrogate measures for flux in the thioredoxin system.

The thioredoxin system plays a central role in intracellular redox regulation and its dysregulation is associated with a number of pathologies. However, the connectivity within this system poses a significant challenge for quantification and consequently several disparate measures have been used to characterize the system. For in vitro studies, the thioredoxin system flux has been measured by NADPH oxidation while the thioredoxin redox state has been used to estimate the activity of the system in vivo. The connection between these measures has been obscure although substrate saturation in the thioredoxin system results from the saturation of the thioredoxin redox cycle. We used computational modeling and in vitro kinetic assays to clarify the relationship between flux and the current in vivo measures of the thioredoxin system together with a novel measure, the thioredoxin redox charge (reduced thioredoxin/total thioredoxin). Our results revealed that the thioredoxin redox potential and redox charge closely tracked flux perturbations showing that these indices could be used as surrogate measures of the flux in vivo and, provide a mechanistic explanation for the previously observed correlations between thioredoxin oxidation and certain pathologies. While we found no significant difference in the linear correlations obtained for the thioredoxin redox potential and redox charge with the flux, the redox charge may be preferred because it is bounded between zero and one and can be determined over a wider range of conditions allowing for quantitative flux comparisons between cell types and conditions.

Saline conditions alter morpho-physiological intensification in purslane (Portulaca oleracea l.).

In this study, primary investigations of selected cultivar of purslane named as Tall Green under articular salinity stress were evaluated to understand the basic concept of different mechanisms of physiological attributes which will play an important role for molecular and proteomic level research. The evaluation of morphological and physiological attributes under 0 mM (without salt addition) 100 mM and 200 mM salt stress changed dramatically. The results showed high salt stress at 200 mM significantly decreasing the morphological attributes and performance of leaves, stems, and roots. At moderate salt stress levels, 100 mM, the ratio of Fv/Fm slightly increased compared to high stress. In addition, salt stress significantly decreased the total chlorophyll content (chl a+b) at 200 mM. The relative water content percentage was high at 0 mM. Moreover, the electrolyte leakage (EL) significantly increased with increasing salinity stress compared to control 0 mM.

Layer Polarizability and Easy-Axis Quantum Hall Ferromagnetism in Bilayer Graphene.

We report magnetotransport measurements of graphene bilayers at large perpendicular electric displacement fields, up to ∼1.5 V/nm, where we observe crossings between Landau levels with different orbital quantum numbers. The displacement fields at the studied crossings are primarily determined by energy shifts originating from the Landau level layer polarizability or polarization. Despite decreasing Landau level spacing with energy, successive crossings occur at larger displacement fields, resulting from decreasing polarizability with orbital quantum number. For particular crossings we observe resistivity hysteresis in displacement field, indicating the presence of a first-order transition between states exhibiting easy-axis quantum Hall ferromagnetism.

[Comparison of parameters for diffusion-weighted intravoxel incoherent motion imaging in lung cancer patients with different histopathological subtypes].

Objective: To explore the intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) model in lung cancer patients with different histopathological subtypes. Methods: A total of 105 patients were recruited, including 68 cases of adenocarcinoma, 22 cases of squamous carcinoma and 15 cases of small cell carcinoma. All patients underwent magnetic resonance examination consisting of axial IVIM-DWI sequence on a 3.0 T whole body scanner, then the standard ADC (sADC), diffusion coefficient (D), pseudo-diffusion coefficient(D(*)), perfusion fraction (f), distributed diffusion coefficient (DDC) and water diffusion heterogeneity index (α) were calculated for each lesion within the IVIM-DWI model. Results: Mean sADC values were (1.45±0.26) ×10(-3)mm(2)/s, (1.36±0.48) ×10(-3)mm(2)/s and (1.35±0.40) ×10(-3)mm(2)/s for adenocarcinoma, squamous carcinoma and small cell carcinoma, respectively. Mean f values were (59.75±16.37) %, (47.41±18.69) % and (48.96±19.88) % for adenocarcinoma, squamous carcinoma and small cell carcinoma, respectively. Mean α values were 0.72±0.13 for adenocarcinoma, 0.62±0.12 for squamous carcinoma, and 0.63±0.11 for small cell carcinoma, respectively. Statistical analyses indicated that the sADC, f and α values among different histopathological subtypes were significantly different (P<0.05), while there was no significant difference in D, D(*) and DDC values (P>0.05). Furthermore, the comparison showed that the sADC, f and α values of patients with adenocarcinoma were significantly higher than those with squamous carcinoma or small cell carcinoma (P<0.05), whereas there was no significant difference between squamous carcinoma group and small cell carcinoma group (P>0.05). Conclusions: The sADC, f and α values derived from the IVIM-DWI model can be used for comprehensive non-invasive evaluation of diffusion, perfusion and heterogeneity of microenvironment in lung cancer patients. And the IVIM-DWI model may be a promising tool for predicting histopathological subtypes of lung cancer.

The Development of Computational Biology in South Africa: Successes Achieved and Lessons Learnt.

Bioinformatics is now a critical skill in many research and commercial environments as biological data are increasing in both size and complexity. South African researchers recognized this need in the mid-1990s and responded by working with the government as well as international bodies to develop initiatives to build bioinformatics capacity in the country. Significant injections of support from these bodies provided a springboard for the establishment of computational biology units at multiple universities throughout the country, which took on teaching, basic research and support roles. Several challenges were encountered, for example with unreliability of funding, lack of skills, and lack of infrastructure. However, the bioinformatics community worked together to overcome these, and South Africa is now arguably the leading country in bioinformatics on the African continent. Here we discuss how the discipline developed in the country, highlighting the challenges, successes, and lessons learnt.

Dose and Duration of Opioid Use in Patients with Cancer and Noncancer Pain at an Outpatient Hospital Setting in Malaysia.

BACKGROUND: There are currently limited data available on the patterns of opioid prescribing in Malaysia. This study investigated the patterns of opioid prescribing and characterized the dosing and duration of opioid use in patients with noncancer and cancer pain. METHODS: This retrospective, cross-sectional study was conducted at an outpatient hospital setting in Malaysia. All prescriptions for opioids (dihydrocodeine, fentanyl, morphine, and oxycodone) issued between January 2013 and December 2014 were examined. The number of prescriptions and patients, the distribution of mean daily dose, annual total days covered with opioids, and annual total opioid dose at the individual level were calculated and stratified by noncancer and cancer groups. RESULTS: A total of 1015 opioid prescriptions were prescribed for 347 patients from 2013 to 2014. Approximately 41.5% of patients (N = 144/347) and 58.5% (N = 203/347) were associated with noncancer and cancer diagnosis, respectively. Oxycodone (38.0%) was the highest prescribed primarily for the noncancer group. The majority of patients in both noncancer (74.3%) and cancer (60.4%) groups were receiving mean daily doses of < 50 mg morphine equivalents. The chronic use of opioids (> 90 days per year) was associated with 21.8% of patients in the noncancer group and 17.5% in the cancer group. CONCLUSIONS: The finding from this study showed that 41.5% of opioid users at an outpatient hospital setting in Malaysia received opioids for noncancer pain and 21.8% of these users were using opioids for longer than 90 days. The average daily dose in the majority of patients in both groups of noncancer and cancer was modest.

miR-106a* inhibits the proliferation of esophageal carcinoma cells by targeting CDK2-associated Cullin 1 (CACUL1).

Previous studies suggest that aberrant microRNA expression is common in plenty of cancers. The expression of miR-106a* was decreased in follicular lymphoma, but the expression and functions of miR-106a* in esophageal carcinoma (EC) remain unclear. In this study, we explored the expression and anti-oncogenic roles of miR-106a* in human EC. The expression of miR-106a* is significantly decreased in EC tissues and EC cell lines. Overexpression of miR-106a* suppressed EC cell proliferation, clonogenicity, G1/S transition, and induced apoptosis in vitro, but inhibition of miR-106a* facilitated cell proliferation, clonogenicity, G1/S transition. Luciferase reporter assay results showed that CDK2-associated Cullin 1 (CACUL1) was a direct target of miR-106a* in EC cells. Moreover, silencing CACUL1 resulted in the same biologic effects of miR-106a* overexpression in EC cells, which included suppressed EC cell proliferation, clonogenicity, and blocked G1/S transition through CDK2 pathway by inhibiting cell cycle regulators (Cyclin A, Cyclin E). Our data indicate that miR-106a* might play an anti-oncogenic role in EC by regulating CACUL1 expression, which suggest miR-106a* as a new potential diagnostic and therapeutic target for EC.

Computational models as catalysts for investigating redoxin systems.

Thioredoxin, glutaredoxin and peroxiredoxin systems play central roles in redox regulation, signaling and metabolism in cells. In these systems, reducing equivalents from NAD(P)H are transferred by coupled thiol-disulfide exchange reactions to redoxins which then reduce a wide array of targets. However, the characterization of redoxin activity has been unclear, with redoxins regarded as enzymes in some studies and redox metabolites in others. Consequently, redoxin activities have been quantified by enzyme kinetic parameters in vitro, and redox potentials or redox ratios within cells. By analyzing all the reactions within these systems, computational models showed that many kinetic properties attributed to redoxins were due to system-level effects. Models of cellular redoxin networks have also been used to estimate intracellular hydrogen peroxide levels, analyze redox signaling and couple omic and kinetic data to understand the regulation of these networks in disease. Computational modeling has emerged as a powerful complementary tool to traditional redoxin enzyme kinetic and cellular assays that integrates data from a number of sources into a single quantitative framework to accelerate the analysis of redoxin systems.

Quantifying redox transcription factor dynamics as a tool to investigate redox signalling.

A critical feature of the cellular antioxidant response is the induction of gene expression by redox-sensitive transcription factors. In many cells, activating these transcription factors is a dynamic process involving multiple redox steps, but it is unclear how these dynamics should be measured. Here, we show how the dynamic profile of the Schizosaccharomyces pombe Pap1 transcription factor is quantifiable by three parameters: signal amplitude, signal time and signal duration. In response to increasing hydrogen peroxide concentrations, the Pap1 amplitude decreased while the signal time and duration showed saturable increases. In co-response plots, these parameters showed a complex, non-linear relationship to the mRNA levels of four Pap1-regulated genes. We also demonstrate that hydrogen peroxide and tert-butyl hydroperoxide trigger quantifiably distinct Pap1 activation profiles and transcriptional responses. Based on these findings, we propose that different oxidants and oxidant concentrations modulate the Pap1 dynamic profile, leading to specific transcriptional responses. We further show how the effect of combination and pre-exposure stresses on Pap1 activation dynamics can be quantified using this approach. This method is therefore a valuable addition to the redox signalling toolbox that may illuminate the role of dynamics in determining appropriate responses to oxidative stress.

Inhibition of microRNA-21 increases radiosensitivity of esophageal cancer cells through phosphatase and tensin homolog deleted on chromosome 10 activation.

The radioresistance of esophageal squamous cell carcinoma is a great obstacle to treatment. Although it has been demonstrated that microRNA-21 (miR-21) can act as an 'oncogene' in esophageal squamous cell carcinoma, its role in radioresistance remains unexplored. The aims of this study were to investigate the role of miR-21 in esophageal squamous carcinoma cells' radioresistance and to identify the possible mechanism. The relatively radioresistant esophageal squamous cancer TE-1 cells (TE-R60) was established by fractionated irradiation. By lentiviral transduction with miRZip-21, the miR-21 expression in TE-1 cells was stably downregulated, which was renamed as 'anti-miR-21 TE-1 cells.' The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was knocked down in anti-miR-21 TE-1 cells through short interfering RNA. The expression level of miR-21 and PTEN messenger RNA were measured by quantitative real-time reverse transcription polymerase chain reaction or reverse transcription polymerase chain reaction. The expression level of PTEN, phospho-Akt, and Akt protein were detected by Western blot. Clongenic assay was used to analyze the cells' radiosensitivity. miR-21 was overexpressed, and PTEN was suppressed in established radioresistant TE-R60 cells compared with the parent cells (1.3-fold and 70.83%). The inhibition of miR-21 significantly increased the cells' radiosensitivity (P < 0.05) and the PTEN protein expression (2.3-fold) in TE-1 cells. In addition, phospho-Akt protein, downstream target of PTEN, reduced significantly in anti-miR-21 TE-1 cells. Knockdown of PTEN in anti-miR-21 TE-1 cells could abrogate the miR-21 inhibition-induced radiosensitization (P < 0.05). Inhibition of miR-21 increased radiosensitivity of esophageal cancer TE-1 cells, and this effect was possibly through the activation of PTEN. Inhibition of miR-21 may form a novel therapeutic strategy to increase the radiosensitivity of esophageal cancer.

Family as a whole: elective surgery patients' perception of the meaning of family involvement in decision making.

AIMS AND OBJECTIVES: This study aimed to explore patient perception of the meaning of family involvement in elective surgery decision making in Taiwan. BACKGROUND: Informed consent is based on respecting patient autonomy. However in cultures where family plays a key role in medical decision making, a patient's perspective of family involvement has not been fully investigated. DESIGN AND METHODS: Based on a phenomenological approach, this study conducted semistructured interviews to elicit the experiences of 10 elective surgery patients in southern Taiwan who had family present during their surgery decision making. An adapted version of Colaizzi's (1978) method was used to analyse narratives. RESULTS: Three themes emerged from the elective surgery patients' perception of the meaning of family involvement in their surgery decision-making process: (1) Primacy of family well-being, (2) family as information broker, and (3) family as patient advocate. Patients articulated reciprocal relationships amongst family members, and they expressed overall family well-being as their ultimate concern when making their treatment decision. The essence of the elective surgery patients' perception of the meaning of family involvement in decision making was 'family as a whole'. CONCLUSIONS: Patients' concern for overall family well-being and their perspective that family plays a supportive role in transmitting information and acting as patient advocate during the decision-making process may both enhance and restrict individual patient autonomy. In cultures where family is central in decision making, appropriately involving the family in medical decisions should not be overlooked. RELEVANCE TO CLINICAL PRACTICE: Understanding and acknowledging the important roles of family in medical decision making from the patients' perspective can enable health professionals to more effectively communicate with patients and their family. Then, health professionals can empower the individual who is making the medical decision based on his or her own needs.

Modelling the Decamerisation Cycle of PRDX1 and the Inhibition-like Effect on Its Peroxidase Activity.

Peroxiredoxins play central roles in the detoxification of reactive oxygen species and have been modelled across multiple organisms using a variety of kinetic methods. However, the peroxiredoxin dimer-to-decamer transition has been underappreciated in these studies despite the 100-fold difference in activity between these forms. This is due to the lack of available kinetics and a theoretical framework for modelling this process. Using published isothermal titration calorimetry data, we obtained association and dissociation rate constants of 0.050 µM-4·s-1 and 0.055 s-1, respectively, for the dimer-decamer transition of human PRDX1. We developed an approach that greatly reduces the number of reactions and species needed to model the peroxiredoxin decamer oxidation cycle. Using these data, we simulated horse radish peroxidase competition and NADPH-oxidation linked assays and found that the dimer-decamer transition had an inhibition-like effect on peroxidase activity. Further, we incorporated this dimer-decamer topology and kinetics into a published and validated in vivo model of PRDX2 in the erythrocyte and found that it almost perfectly reconciled experimental and simulated responses of PRDX2 oxidation state to hydrogen peroxide insult. By accounting for the dimer-decamer transition of peroxiredoxins, we were able to resolve several discrepancies between experimental data and available kinetic models.

Atypical network topologies enhance the reductive capacity of pathogen thiol antioxidant defense networks.

Infectious diseases are a significant health burden for developing countries, particularly with the rise of multidrug resistance. There is an urgent need to elucidate the factors underlying the persistence of pathogens such as Mycobacterium tuberculosis, Plasmodium falciparum and Trypanosoma brucei. In contrast to host cells, these pathogens traverse multiple and varied redox environments during their infectious cycles, including exposure to high levels of host-derived reactive oxygen species. Pathogen antioxidant defenses such as the peroxiredoxin and thioredoxin systems play critical roles in the redox stress tolerance of these cells. However, many of the kinetic rate constants obtained for the pathogen peroxiredoxins are broadly similar to their mammalian homologs and therefore, their contributions to the redox tolerances within these cells are enigmatic. Using graph theoretical analysis, we show that compared to a canonical Escherichia coli redoxin network, pathogen redoxin networks contain unique network connections (motifs) between their thioredoxins and peroxiredoxins. Analysis of these motifs reveals that they increase the hydroperoxide reduction capacity of these networks and, in response to an oxidative insult, can distribute fluxes into specific thioredoxin-dependent pathways. Our results emphasize that the high oxidative stress tolerance of these pathogens depends on both the kinetic parameters for hydroperoxide reduction and the connectivity within their thioredoxin/peroxiredoxin systems.

Solvent effects on the conformation of DNA dodecamer segment: a simulation study.

Different solvent temperatures with five kinds of counterions are used to investigate solvent effects on the DNA microscopic structure. The dodecamer d (CGCGAATTCGCG) DNA segment is merged into the solvents and its conformation transition is studied with the molecular dynamics simulations in detail. For the simple point charge model of water molecule with Na(+) counterions, as temperature increases from 200 K to 343 K, the duplex DNA changes from stiff B form to a state between A form and B form, which we define as mixed (A-B) structure, with a double helix unwinding. To study the counterions effects, other four alkali cations, Li(+), K(+), Rb(+), or Cs(+) ions, are substituted for Na(+) ions at 298 K and 343 K, respectively. For the cases of Li(+), Rb(+), and Cs(+) ions, the duplex DNA becomes more flexible with sugar configuration changing form C2'-endo to C1'-endo type and the width and depth of minor groove at CpG and GpC steps moving towards A values, as the mass of the counterions decreasing. For the case of K(+) ions, DNA-K(+) interaction widens the width of minor and major grooves at ApA steps and TpT steps, respectively. It seems that the light ions (Li(+) or Na(+)) prefer to interact with the free phosphate oxygen atoms while the heavier ions (Rb(+) and Cs(+)) strongly interact with the base pairs.

The radiosensitization effect of NS398 on esophageal cancer stem cell-like radioresistant cells.

This study aimed to investigate the cancer stem cell (CSC) properties of radioresistant esophageal cancer cells and the radiosensitization effect of NS398, a cyclooxygenase (COX)-2 inhibitor, on them. Fractionated irradiation was applied to acquire radioresistant esophageal cancer cells. Clone formation assay was employed to detect cell radiosensitivity and cloning formation ability. Cell viability was determined by methyl tetrazolium colorimetry assay. Cell cycle distribution and apoptosis were detected by flow cytometry. Tumorigenicity was investigated by xenograft tumorigenicity assay. Expression levels of ß-catenin were detected by reverse transcription polymerase chain reaction or Western blot. As results, radioresistant Eca109R50Gy cells were obtained through fractional irradiation from Eca109 cells; Eca109R50Gy cells displayed higher ability of proliferation, colony-formation, and 40 times tumorigenic ability as high as that of the Eca109 cells in vivo. Meantime stem cell marker ß-catenin was elevated in Eca109R50Gy cells. All of the above implied that Eca109R50Gy cells have some properties of CSCs. NS398 enhanced the radiosensitivity of Eca109R50Gy cells accompanied by down-regulating the expression of ß-catenin. In conclusion, radioresistant Eca109R50Gy cells carried some CSC-like properties; NS398 enhanced the radiosensitivity of CSC-like Eca109R50Gy cells and this function may partly through down-regulating the expression of ß-catenin. These findings both stress the important role of CSCs in esophageal cancer radioresistance and provide new insight on possible application of COX-2 inhibitors on CSCs.

Can thiol-based redox systems be utilized as parts for synthetic biology applications?

OBJECTIVES: Synthetic biology has emerged from molecular biology and engineering approaches and aims to develop novel, biologically-inspired systems for industrial and basic research applications ranging from biocomputing to drug production. Surprisingly, redoxin (thioredoxin, glutaredoxin, peroxiredoxin) and other thiol-based redox systems have not been widely utilized in many of these synthetic biology applications. METHODS: We reviewed thiol-based redox systems and the development of synthetic biology applications that have used thiol-dependent parts. RESULTS: The development of circuits to facilitate cytoplasmic disulfide bonding, biocomputing and the treatment of intestinal bowel disease are amongst the applications that have used thiol-based parts. We propose that genetically encoded redox sensors, thiol-based biomaterials and intracellular hydrogen peroxide generators may also be valuable components for synthetic biology applications. DISCUSSION: Thiol-based systems play multiple roles in cellular redox metabolism, antioxidant defense and signaling and could therefore offer a vast and diverse portfolio of components, parts and devices for synthetic biology applications. However, factors limiting the adoption of redoxin systems for synthetic biology applications include the orthogonality of thiol-based components, limitations in the methods to characterize thiol-based systems and an incomplete understanding of the design principles of these systems.

Preliminary study of the plasma and cerebrospinal fluid concentrations of IL-6 and IL-10 in patients with chronic pain receiving intrathecal opioid infusions by chronically implanted pump for pain management.

OBJECTIVE: This preliminary study assessed possible relationships between plasma and/or cerebrospinal fluid (CSF) concentrations of the pleiotropic cytokine, interleukin (IL)-6, the anti-inflammatory cytokine, IL-10, and levels of pain reported by patients receiving intrathecal (i.t.) opioids. DESIGN: A prospective study quantifying IL-6 and IL-10 concentrations using enzyme-linked immunoassays in samples of plasma and CSF as well as assessment of pain scores in patients receiving intrathecal opioids for management of chronic noncancer pain. SETTING: Outpatient pain clinics. PATIENTS: Patients with chronic pain receiving intrathecal morphine or hydromorphone alone or in combination with local anesthetics. INTERVENTIONS: Two groups of patients were studied. The first group (n = 50) had been receiving long-term i.t. opioids by chronically implanted pump for approximately 5 years; paired samples of plasma and CSF were collected at the time of i.t. pump refill. For the second patient group (n = 10), possible temporal changes in the plasma and/or CSF concentrations of IL-6 and IL-10 were investigated for 3 months after initiation of i.t. opioid infusions. RESULTS: For patients receiving long-term i.t. opioid infusions, there were significant inverse correlations (P < or = 0.05) between pain intensity and the plasma (but not CSF) IL-10 and IL-6 concentrations. Despite the considerable inter-patient variability in the CSF concentrations of IL-6 in the long-term cohort, the mean CSF IL-6 concentration was approximately fivefold higher in patients receiving long-term i.t. opioids relative to those receiving i.t. opioids for only 3 months. CONCLUSIONS: The significant inverse correlations observed between pain intensity and the plasma IL-6 and IL-10 concentrations in patients receiving longterm i.t. opioids for chronic pain management, suggests that these cytokines are worthy of further investigation as possible biomarkers of persistent pain.

Enzymes or redox couples? The kinetics of thioredoxin and glutaredoxin reactions in a systems biology context.

Systems biology approaches, such as kinetic modelling, could provide valuable insights into how thioredoxins, glutaredoxins and peroxiredoxins (here collectively called redoxins), and the systems that reduce these molecules are regulated. However, it is not clear whether redoxins should be described as redox couples (with redox potentials) or as enzymes (with Michaelis-Menten parameters) in such approaches. We show that in complete redoxin systems, redoxin substrate saturation and other purported enzymatic behaviours result from limitations in the redoxin redox cycles in these systems. Michaelis-Menten parameters are therefore inappropriate descriptors of redoxin activity; data from redoxin kinetic experiments should rather be interpreted in terms of the complete system of reactions under study. These findings were confirmed by fitting kinetic models of the thioredoxin and glutaredoxin systems to in vitro datasets. This systems approach clarifies the inconsistencies with the descriptions of redoxins and emphasizes the roles of redoxin systems in redox regulation.